Moderna COVID-19 vaccine, mRNA 1273

CAS 2457298-05-2

An mRNA vaccine against SARS-CoV-2 expressing the prefusion-stabilized SARS-CoV-2 spike trimer

• MRNA-1273 SARS-COV-2
• CX 024414
• CX-024414
• CX024414
• mRNA-1273

NAME	DOSAGE	STRENGTH	ROUTE	LABELLER	MARKETING START	MARKETING END
Covid-19 Vaccine Moderna	Injection		Intramuscular	Moderna Therapeutics Inc	2020-12-23	Not applicable
Moderna COVID-19 Vaccine	Injection, suspension	0.2 mg/1mL	Intramuscular	Moderna US, Inc.	2020-12-18	Not applicable

REFNature (London, United Kingdom) (2020), 586(7830), 516-527.bioRxiv (2020), 1-39Nature (London, United Kingdom) (2020), 586(7830), 567-571.  Nature Biotechnology (2020), Ahead of PrintJournal of Pure and Applied Microbiology (2020), 14(Suppl.1), 831-840.Chemical & Engineering News (2020), 98(46), 12.New England Journal of Medicine (2020), 383(16), 1544-1555.  Science of the Total Environment (2020), 725, 138277.JAMA, the Journal of the American Medical Association (2020), 324(12), 1125-1127.Advanced Drug Delivery Reviews (2021), 169, 137-151. bioRxiv (2021), 1-62.  bioRxiv (2021), 1-51.

The Moderna COVID-19 Vaccine (mRNA-1273) is a novel mRNA-based vaccine encapsulated in a lipid nanoparticle that encodes for a full-length pre-fusion stabilized spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronavirus disease 2019 (COVID-19) is a highly contagious infectious disease caused by the novel coronavirus, SARS-CoV-2, leading to a respiratory illness alongside other complications. COVID-19 has high interpatient variability in symptoms, ranging from mild symptoms to severe illness.⁵ A phase I, open-label, dose-ranging clinical trial (NCT04283461) was initiated in March 2020 in which 45 subjects received two intramuscular doses (on days 1 and 29).⁴ This trial was later followed by phase II and III trials, where the Moderna COVID-19 Vaccine demonstrated vaccine efficacy of 94.1%.⁵

On December 18, 2020, the FDA issued an emergency use authorization (EUA) for the Moderna COVID-19 Vaccine as the second vaccine for the prevention of COVID-19 caused by SARS-CoV-2 in patients aged 18 years and older, after the EUA issued for the Pfizer-BioNTech Covid-19 Vaccine on December 11, 2020. The Moderna COVID-19 Vaccine is administered as a series of two intramuscular injections, one month (28 days) apart. In clinical trials, there were no differences in the safety profiles between younger and older (65 years of age and older) study participants; however, the safety and effectiveness of the Moderna COVID-19 Vaccine have not been assessed in persons less than 18 years of age.⁵ On December 23, 2020, Health Canada issued an expedited authorization for the Moderna COVID-19 Vaccine.⁷

It is an RNA vaccine composed of nucleoside-modified mRNA (modRNA) encoding a spike protein of SARS-CoV-2, which is encapsulated in lipid nanoparticles. It is one of the two RNA vaccines developed and deployed in 2020 against COVID‑19, the other being the Pfizer–BioNTech vaccine.The Moderna COVID‑19 vaccine, codenamed mRNA-1273, is a COVID‑19 vaccine developed by the United States National Institute of Allergy and Infectious Diseases (NIAID), the Biomedical Advanced Research and Development Authority (BARDA), and Moderna. It is administered by two 0.5 mL doses given by intramuscular injection given four weeks apart.^[12]

On 18 December 2020, mRNA-1273 was issued an Emergency Use Authorization by the United States Food and Drug Administration (FDA).^{[6][13][14][15]} It was authorized for use in Canada on 23 December 2020,^[2][3] in the European Union on 6 January 2021,^[10][16][11] and in the United Kingdom on 8 January 2021.^[17]

Design

Upon the announcement Moderna’s shares rose dramatically, and the chief executive officer (CEO) and other corporate executives began large program sales of their shareholdings.^[26]In January 2020, Moderna announced development of an RNA vaccine, named mRNA-1273, to induce immunity to SARS-CoV-2.^[18][19][20] Moderna’s technology uses a nucleoside-modified messenger RNA (modRNA) compound named mRNA-1273. Once the compound is inside a human cell, the mRNA links up with the cell’s endoplasmic reticulum. The mRNA-1273 is encoded to trigger the cell into making a specific protein using the cell’s normal manufacturing process. The vaccine encodes a version of the spike protein called 2P, which includes two stabilizing mutations in which the regular amino acids are replaced with prolines, developed by researchers at the University of Texas at Austin and the National Institute of Allergy and Infectious Diseases‘ Vaccine Research Center.^{[21][22][23][24]} Once the protein is expelled from the cell, it is eventually detected by the immune system, which begins generating efficacious antibodies. The mRNA-1273 drug delivery system uses a PEGylated lipid nanoparticle drug delivery (LNP) system.^[25]

Composition

The vaccine contains the following ingredients:^[7][27]

• nucleoside-modified messenger RNA encoding the SARS-CoV-2 spike glycoprotein (S) stabilized in its prefusion configuration;^[28]
• lipids:
  • SM-102,
  • polyethylene glycol [PEG] 2000-dimyristoyl glycerol [DMG],
  • cholesterol,
  • and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC];
• tromethamine;
• tromethamine hydrochloride;
• acetic acid;
• sodium acetate;
• and sucrose.

Clinical trials

Phase I / II

In March 2020, the Phase I human trial of mRNA-1273 began in partnership with the U.S. National Institute of Allergy and Infectious Diseases.^[29] In April, the U.S. Biomedical Advanced Research and Development Authority (BARDA) allocated up to $483 million for Moderna’s vaccine development.^[30] Plans for a Phase II dosing and efficacy trial to begin in May were approved by the U.S. Food and Drug Administration (FDA).^[31] Moderna signed a partnership with Swiss vaccine manufacturer Lonza Group,^[32] to supply 300 million doses per annum.^[33]

On 25 May 2020, Moderna began a Phase IIa clinical trial recruiting six hundred adult participants to assess safety and differences in antibody response to two doses of its candidate vaccine, mRNA-1273, a study expected to complete in 2021.^[34] In June 2020, Moderna entered a partnership with Catalent in which Catalent will fill and package the vaccine candidate. Catalent will also provide storage and distribution.^[35]

On 9 July, Moderna announced an in-fill manufacturing deal with Laboratorios Farmacéuticos Rovi, in the event that its vaccine is approved.^[36]

On 14 July 2020, Moderna scientists published preliminary results of the Phase I dose escalation clinical trial of mRNA-1273, showing dose-dependent induction of neutralizing antibodies against S1/S2 as early as 15 days post-injection. Mild to moderate adverse reactions, such as fever, fatigue, headache, muscle ache, and pain at the injection site were observed in all dose groups, but were common with increased dosage.^[37][38] The vaccine in low doses was deemed safe and effective in order to advance a Phase III clinical trial using two 100-μg doses administered 29 days apart.^[37]

In July 2020, Moderna announced in a preliminary report that its Operation Warp Speed candidate had led to production of neutralizing antibodies in healthy adults in Phase I clinical testing.^[37][39] “At the 100-microgram dose, the one Moderna is advancing into larger trials, all 15 patients experienced side effects, including fatigue, chills, headache, muscle pain, and pain at the site of injection.”^[40] The troublesome higher doses were discarded in July from future studies.^[40]

Phase III

Moderna and the National Institute of Allergy and Infectious Diseases began a Phase III trial in the United States on 27 July, with a plan to enroll and assign thirty thousand volunteers to two groups – one group receiving two 100-μg doses of mRNA-1273 vaccine and the other receiving a placebo of 0.9% sodium chloride.^[41] As of 7 August, more than 4,500 volunteers had enrolled.

In September 2020, Moderna published the detailed study plan for the clinical trial.^[42] On 30 September, CEO Stéphane Bancel said that, if the trial is successful, the vaccine might be available to the public as early as late March or early April 2021.^[43] As of October 2020, Moderna had completed the enrollment of 30,000 participants needed for its Phase III trial.^[44] The U.S. National Institutes of Health announced on 15 November 2020 that overall trial results were positive.^[45]

On 30 December 2020, Moderna published results from the Phase III clinical trial, indicating 94% efficacy in preventing COVID‑19 infection.^[46][47][48] Side effects included flu-like symptoms, such as pain at the injection site, fatigue, muscle pain, and headache.^[47] The clinical trial is ongoing and is set to conclude in late-2022^[49]

In November 2020, Nature reported that “While it’s possible that differences in LNP formulations or mRNA secondary structures could account for the thermostability differences [between Moderna and BioNtech], many experts suspect both vaccine products will ultimately prove to have similar storage requirements and shelf lives under various temperature conditions.”^[50]

Since September 2020, Moderna has used Roche Diagnostics‘ Elecsys Anti-SARS-CoV-2 S test, authorized by the US Food and Drug Administration (FDA) under an Emergency Use Authorization (EUA) on 25 November 2020. According to an independent supplier of clinical assays in microbiology, “this will facilitate the quantitative measurement of SARS-CoV-2 antibodies and help to establish a correlation between vaccine-induced protection and levels of anti-receptor binding domain (RBD) antibodies.” The partnership was announced by Roche on 9 December 2020.^[51]

A review by the FDA in December 2020, of interim results of the Phase III clinical trial on mRNA-1273 showed it to be safe and effective against COVID‑19 infection resulting in the issuance of an EUA by the FDA.^[13]

It remains unknown whether the Moderna vaccine candidate is safe and effective in people under age 18 and how long it provides immunity.^[47] Pregnant and breastfeeding women were also excluded from the initial trials used to obtain Emergency Use Authorization,^[52] though trials in those populations are expected to be performed in 2021.^[53]

In January 2021, Moderna announced that it would be offering a third dose of its vaccine to people who were vaccinated twice in its Phase I trial. The booster would be made available to participants six to twelve months after they got their second doses. The company said it may also study a third shot in participants from its Phase III trial, if antibody persistence data warranted it.^[54][55][56]

In January 2021, Moderna started development of a new form of its vaccine, called mRNA-1273.351, that could be used as a booster shot against the 501.V2 variant of SARS-CoV-2 first detected in South Africa.^[57][58] It also started testing to see if a third shot of the existing vaccine could be used to fend off the virus variants.^[58] On 24 February, Moderna announced that it had manufactured and shipped sufficient amounts of mRNA-1273.351 to the National Institutes of Health to run Phase{ I clinical trials.^[59] To increase the span of vaccination beyond adults, Moderna started the clinical trials of vaccines on childern age six to eleven in the U.S. and in Canada.^[60]

Storage requirements

 Moderna vaccine being stored in a conventional medical freezer

The Moderna news followed preliminary results from the Pfizer–BioNTech vaccine candidate, BNT162b2, with Moderna demonstrating similar efficacy, but requiring storage at the temperature of a standard medical refrigerator of 2–8 °C (36–46 °F) for up to 30 days or −20 °C (−4 °F) for up to four months, whereas the Pfizer-BioNTech candidate requires ultracold freezer storage between −80 and −60 °C (−112 and −76 °F).^[61][47] Low-income countries usually have cold chain capacity for refrigerator storage.^[62][63] In February 2021, the restrictions on the Pfizer vaccine were relaxed when the U.S. Food and Drug Administration (FDA) updated the emergency use authorization (EUA) to permit undiluted frozen vials of the vaccine to be transported and stored at between −25 and −15 °C (−13 and 5 °F) for up to two weeks before use.^[27][64][65]

Efficacy

The interim primary efficacy analysis was based on the per-protocol set, which consisted of all participants with negative baseline SARS-CoV-2 status and who received two doses of investigational product per schedule with no major protocol deviations. The primary efficacy endpoint was vaccine efficacy (VE) in preventing protocol defined COVID-19 occurring at least 14 days after dose 2. Cases were adjudicated by a blinded committee. The primary efficacy success criterion would be met if the null hypothesis of VE ≤30% was rejected at either the interim or primary analysis. The efficacy analysis presented is based on the data at the first pre-specified interim analysis timepoint consisting of 95 adjudicated cases.^[66] The data are presented below.

Manufacturing

 An insulated shipping container with Moderna vaccine boxes ensconced by cold packs

Moderna is relying extensively on contract manufacturing organizations to scale up its vaccine manufacturing process. Moderna has contracted with Lonza Group to manufacture the vaccine at facilities in Portsmouth, New Hampshire in the United States, and in Visp in Switzerland, and is purchasing the necessary lipid excipients from CordenPharma.^[67] For the tasks of filling and packaging vials, Moderna has entered into contracts with Catalent in the United States and Laboratorios Farmacéuticos Rovi in Spain.^[67]

Purchase commitments

In June 2020, Singapore signed a pre-purchase agreement for Moderna, reportedly paying a price premium in order to secure early stock of vaccines, although the government declined to provide the actual price and quantity, citing commercial sensitivities and confidentiality clauses.^[68][69]

On 11 August 2020, the U.S. government signed an agreement to buy one hundred million doses of Moderna’s anticipated vaccine,^[70] which the Financial Times said Moderna planned to price at US$50–60 per course.^[71] On November 2020, Moderna said it will charge governments who purchase its vaccine between US$25 and US$37 per dose while the E.U. is seeking a price of under US$25 per dose for the 160 million doses it plans to purchase from Moderna.^[72][73]

In 2020, Moderna also obtained purchase agreements for mRNA-1273 with the European Union for 160 million doses and with Canada for up to 56 million doses.^[74][75] On 17 December, a tweet by the Belgium Budget State Secretary revealed the E.U. would pay US$18 per dose, while The New York Times reported that the U.S. would pay US$15 per dose.^[76]

In February 2021, Moderna said it was expecting US$18.4 billion in sales of its COVID-19 vaccine.^[77]

Authorizations

Expedited

 U.S. military personnel being administered the Moderna vaccineKamala Harris, Vice President of the United States, receiving her second dose of the Moderna vaccination in January 2021.

As of December 2020, mRNA-1273 was under evaluation for emergency use authorization (EUA) by multiple countries which would enable rapid rollout of the vaccine in the United Kingdom, the European Union, Canada, and the United States.^{[97][98][99][100]}

On 18 December 2020, mRNA-1273 was authorized by the United States Food and Drug Administration (FDA) under an EUA.^[6][8][13] This is the first product from Moderna that has been authorized by the FDA.^[101][14]

On 23 December 2020, mRNA-1273 was authorized by Health Canada.^[2][3] Prime Minister Justin Trudeau had previously said deliveries would begin within 48 hours of approval and that 168,000 doses would be delivered by the end of December.^[102]

On 5 January 2021, mRNA-1273 was authorized for use in Israel by its Ministry of Health.^[103]

On 3 February 2021, mRNA-1273 was authorized for use in Singapore by its Health Sciences Authority;^[104] the first shipment arrived on 17 February.^[105]

Standard

On 6 January 2021, the European Medicines Agency (EMA) recommended granting conditional marketing authorization^[10][106] and the recommendation was accepted by the European Commission the same day.^[11][16]

On 12 January 2021, Swissmedic granted temporary authorization for the Moderna COVID-19 mRNA Vaccine in Switzerland.^[107][108]

Society and culture

Controversies

In May 2020, after releasing partial and non-peer reviewed results for only eight of 45 candidates in a preliminary pre-Phase I stage human trial directly to financial markets, the CEO announced on CNBC an immediate $1.25 billion rights issue to raise funds for the company, at a $30 billion valuation,^[109] while Stat said, “Vaccine experts say Moderna didn’t produce data critical to assessing COVID-19 vaccine.”^[110]

On 7 July, disputes between Moderna and government scientists over the company’s unwillingness to share data from the clinical trials were revealed.^[111]

Moderna also faced criticism for failing to recruit people of color in clinical trials.^[112]

Patent litigation

The PEGylated lipid nanoparticle (LNP) drug delivery system of mRNA-1273 has been the subject of ongoing patent litigation with Arbutus Biopharma, from whom Moderna had previously licensed LNP technology.^[25][113] On 4 September 2020, Nature Biotechnology reported that Moderna had lost a key challenge in the ongoing case.^[114]

Notes

1. ^ US authorization also includes the three sovereign nations in the Compact of Free Association: Palau, the Marshall Islands, and Micronesia.^[93][94]

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Further reading

• World Health Organization (2021). Background document on the mRNA-1273 vaccine (Moderna) against COVID-19: background document to the WHO Interim recommendations for use of the mRNA-1273 vaccine (Moderna), 3 February 2021 (Report). World Health Organization (WHO). hdl:10665/339218. WHO/2019-nCoV/vaccines/SAGE_recommendation/mRNA-1273/background/2021.1.

External links

Scholia has a profile for mRNA-1273 (Q87775025).

Wikimedia Commons has media related to Category:MRNA-1273.

• “VRBPAC mRNA-1273 Sponsor Briefing Document” (PDF). Moderna. 17 December 2020.
• “Clinical Study Protocol mRNA-1273-P301” (PDF). Moderna.
• COVID-19 Vaccine Moderna assessment report European Medicines Agency
• “How Moderna’s Covid-19 Vaccine Works”. The New York Times.
• “Moderna COVID-19 Vaccine”. Centers for Disease Control and Prevention (CDC).

1. Kaur SP, Gupta V: COVID-19 Vaccine: A comprehensive status report. Virus Res. 2020 Oct 15;288:198114. doi: 10.1016/j.virusres.2020.198114. Epub 2020 Aug 13. [PubMed:32800805]
2. Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN, McCullough MP, Chappell JD, Denison MR, Stevens LJ, Pruijssers AJ, McDermott A, Flach B, Doria-Rose NA, Corbett KS, Morabito KM, O’Dell S, Schmidt SD, Swanson PA 2nd, Padilla M, Mascola JR, Neuzil KM, Bennett H, Sun W, Peters E, Makowski M, Albert J, Cross K, Buchanan W, Pikaart-Tautges R, Ledgerwood JE, Graham BS, Beigel JH: An mRNA Vaccine against SARS-CoV-2 – Preliminary Report. N Engl J Med. 2020 Jul 14. doi: 10.1056/NEJMoa2022483. [PubMed:32663912]
3. Pharmaceutical Business Review: Moderna’s mRNA-1273 vaccine [Link]
4. Clinical Trials: Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis SARS CoV-2 Infection [Link]
5. FDA EUA Drug Products: Moderna COVID-19 Vaccine [Link]
6. FDA Press Announcements: FDA Takes Additional Action in Fight Against COVID-19 By Issuing Emergency Use Authorization for Second COVID-19 Vaccine [Link]
7. Health Canada: Regulatory Decision Summary – Moderna COVID-19 Vaccine [Link]

////////CX 024414, CX-024414, CX024414, mRNA 1273, Moderna COVID-19 vaccine, COVID 19, CORONA VIRUS

CX 024414, CX-024414, CX024414, mRNA 1273, Moderna COVID-19 vaccine, COVID 19, CORONA VIRUS

#CX 024414,#CX-024414, #CX024414, #mRNA 1273, #Moderna COVID-19 vaccine, #COVID 19, #CORONA VIRUS

Sitravatinib

1-N‘-[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

1-N’-[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

MG-91516

1,1-Cyclopropanedicarboxamide, N-[3-fluoro-4-[[2-[5-[[(2-methoxyethyl)amino]methyl]-2-pyridinyl]thieno[3,2-b]pyridin-7-yl]oxy]phenyl]-N’-(4- fluorophenyl)-

N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

MG-516

Sitravatinib (MGCD516)

UNII-CWG62Q1VTB

CWG62Q1VTB

MGCD-516

MGCD516

Antineoplastic, Receptor tyrosine kinase inhibitor

Sitravatinib (MGCD516) is an experimental drug for the treatment of cancer. It is a small molecule inhibitor of multiple tyrosine kinases.

Sitravatinib is being developed by Mirati Therapeutics.^[1]

Ongoing phase II trials include a trial for liposcarcoma,^[2] a combination trial for non-small cell lung cancer,^[3] and a combination trial with nivolumab for renal cell carcinoma.^[4]

Mirati Therapeutics and licensee BeiGene are developing sitravatinib, an oral multitargeted kinase inhibitor which inhibits Eph, Ret, c-Met and VEGF-1, -2 and -3, DDR, Trk, Axl kinases, CHR4q12, TYRO3 and Casitas B-lineage, in combination with immune checkpoint inhibitors, for treating advanced solid tumors.

In March 2021, sitravatinib was reported to be in phase 3 clinical development.

PDT PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009026717

WO2009026717 , in which sitravatinib was first disclosed, claiming heterocyclic compounds as multi kinase inhibitors.

Scheme 10

Example 52
N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7- yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide

Step 1 : tert-Butyl (6-(7-(2-Fluoro-4-(1-(4-fluorophenylcarbamoyl)-cyclopropanecarboxamido)phenoxy)thieno [3 ,2-b]pyridin-2-yl)pyridin-3 -y l)methyl(2-methoxyethyl)carbamate (146)
To aniline 126 (0.58 g, 1.1 mmol) and DIPEA (0.58 mL, 0.43 g, 3.3 mmol) in dry DMF

(20 mL) was added 1-(4-fluorophenylcarbamoyl)cyclopropanecarbpxylic acid (0.35 g, 1.5 mmol) and HATU (0.72 g, 1.9 mmol) and the mixture was stirred at r.t. for 18 h. It was then partitioned between ethyl acetate and water, the organic phase was washed with water, IM NaOH, brine, dried (MgSO₄), filtered, and concentrated. Silica gel chromatography (ethyl acetate) afforded title compound Ϊ46 (0.60 g, 74 % yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.40 (s, 1H), 10.01 (s, 1H), 8.52-8.49 (m, 2H), 8.33 (s, 1H), 8.27-8.24 (m, 1H), 7.92-7.88 (m, 1H), 7.78 (dd, J = 8.2, 2.1 Hz, 1H) 7.65-7.60 (m, 2H), 7.52-7.42 (m, 2H), 7.14 (t, J = 8.8 Hz, 2H), 6.65 (d, J = 5.1 Hz 1H), 4.47 (s, 2H), 3.42-3.30 (m, 4H), 3.22 (s, 3H), 1.46-1.30 (m, 13H). MS (m/z): 730.1 (M+H).
Step 2. N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-blpyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (147)
To the compound 146 (0.59 g, 0.81 mmol) in dichloromethane (50 mL) was added TFA (3 mL). The solution was stirred for 18 h then concentrated. The residue was partitioned between dichloromethane and 1 M NaOH, and filtered to remove insolubles. The organic phase was collected, washed with IM NaOH, brine, dried (MgSO₄), filtered, and concentrated to afford title compound 147 (0.35 g, 69 % yield).

1H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.40 (s, 1H), 10.01 (s, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.51 (d, J = 5.3 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.92-7.87 (m, 2H), 7.65-7.61 (m, 2H), 7.52-7.43 (m, 2H), 7.17-7.12 (m, 2H), 6.64 (d, J = 5.5 Hz, 1H), 3.77 (s, 2H), 3.40 (t, J = 5.7 Hz, 2H), 3.23 (s, 3H), 2.64 (t, J = 5.7 Hz, 2H), 1.46 (br s, 4H). MS (m/z): 630.1 (M+H).

PATENT

WO 2009026720 

https://patents.google.com/patent/WO2009026720A1

PATENT

WO-2021050580

Novel, stable crystalline polymorphic forms (form D) of sitravatinib , useful for treating a multi tyrosine kinase-associated cancer eg sarcoma, glioma, non-small cell lung, bladder, kidney, ovarian, gastric, breast or liver cancer. 

 International publication No. W02009/026717A disclosed compounds with the inhibition activities of multiple protein tyrosine kinases, for example, the inhibition activities of VEGF receptor kinase and HGF receptor kinase. In particular, disclosed N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane- 1,1 -di carboxamide (Compound 1) is a multi-tyrosine kinase inhibitor with demonstrated potent inhibition of a closely related spectrum of tyrosine kinases, including RET, CBL, CHR4ql2, DDR and Trk, which are key regulators of signaling pathways that lead to cell growth, survival and tumor progression.

[003]

Compound 1

[004] Compound 1 shows tumor regression in multiple human xenograft tumor models in mice, and is presently in human clinical trials as a monotherapy as well as in combination for

treating a wide range of solid tumors. Compound 1 is presently in Phase 1 clinical trial for patients with advanced cancer, in Phase 2 studies for patients with advanced liposarcoma and non-small cell lung cancer (NSCLC).

[005] The small scale chemical synthesis of the amorphous Compound 1 had been disclosed in the Example 52 (compound 147) of W02009/026717A, however, in order to prepare the API of Compound 1 with high quality and in large quantity, crystalline forms of Compound 1 would be normally needed so the process impurities could be purged out by recrystallization.

Practically, it is difficult to predict with confidence which crystalline form of a particular compound will be stable, reproducible, and suitable for phamaceutical processing. It is even more difficult to predict whether or not a particular crystalline solid state form will be produced with the desired physical properties for pharmaceutical formulations.

[006] For all the foregoing reasons, there is a great need to produce crystalline forms of Compound 1 that provide manufacturing improvements of the pharmaceutical composition.

The present invention advantageously addresses one or more of these needs.

EXAMPLE 1

Preparation of N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2- yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-l,l- dicarboxamide (Compound 1)

[0085] This Example illustrates the preparation ofN-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane- 1,1 -di carboxamide (Compound 1).

[0086] Step 1: N-(Y6-bromopyridin-3-vDmethvD-2-methoxyethan-l-amine (Compound 1A)

Compound 1A

[0087] To a stirred solution of 2-Methoxyethylamine (3.0 eq) in dichloromethane (DCM) (12 vol) was added Molecular sieves (0.3 w/w) and stirred for 2 hours at 25±5°C under nitrogen atmosphere. The reaction mass water content was monitored by Karl Fischer analysis until the water content limit reached 0.5 % w/w. Once the water content limit was reached, the reaction mass cooled to 5±5°C and 6-bromonicotinaldehyde (1.0 eq) was added lot wise over period of 30 minutes to the above reaction mass at 5±5°C. The reaction mass was stirred for 30±5 minutes at 5±5°C and acetic acid (1.05 eq) was added drop wise at 5±5°C. After completion of the addition, the mass was slowly warmed to 25±5°C and stirred for 8 h to afford Compound 1 A. The imine formation was monitored by HPLC.

[0088] Step 2: tert-butyl (Y6-brom opyri din-3 -vQmethvO(2-m ethoxy ethvDcarbamate (Compound

IB)

Compound 1B

[0089] Charged Compoud 1A (1.0 eq) in THF (5.0 vol) was added and the reaction mass was stirred for 30 minutes at 25±5°C under nitrogen atmosphere. The reaction mass was cooled to temperature of about 10±5°C. Di-tert- butyl dicarbonate (1.2 eq) was added to the reaction mass at 10±5°C under nitrogen atmosphere and the reaction mass temperature was raised to 25±5°C and the reaction mass for about 2 hours. The progress of the reaction was monitored by HPLC. After IPC completion, a prepared solution of Taurine (1.5 eq) in 2M aq NaOH (3.1 vol) was charged and stirred at 10±5°C for 16 h to 18 h. The reaction mass was further diluted with 1M aq.NaOH solution (3.7 vol) and the layers were separated. The aqueous layer was extracted with DCM (2 x 4.7vol) and the extract combined with the organic layer. The combined organic layers were washed with 1M aq.NaOH solution (3.94 vol), followed by water (2×4.4 vol), and dried over sodium sulfate (2.0 w/w) . The filtrate was concentrated under reduced pressure below 40° C until no distillate was observed. Tetrahydrofuran (THF) was sequentially added (1×4 vol and lx 6vol) and concentrated under reduced pressure below 40°C until no distillate was observed to obtained Compound IB as light yellow colored syrup liquid.

[0090] Step 3: tert-butyl 7-chlorothieno[3.2-b1pyridin-2-yl)pyridin-3-yl )methyl)(2- 

methoxyethvDcarbamate (Compound 1C)

Compound 1C

[0091] To a stirred solution of 7-chlorothieno[3,2-b]pyridine (1.05 eq) in tetrahydrofuran (7 vol) was added n-butyl lithium (2.5 M in hexane) drop wise at -15±10°C and stirred for 90 minutes at same temperature under nitrogen atmosphere. Zinc chloride (1.05 eq) was added to the reaction mass at -15±10°C. The reaction mass was slowly warmed to 25±5°C and stirred for 45 minutes under nitrogen atmosphere to afford Compound 1C. The progress of the reaction was monitored by HPLC.

[0092] Step 4: tert-butyl (Y6-(7-(4-amino-2-fluorophenoxy)thieno[3.2-b1pyridin-2-v0pyridin-3-vDmethvD(2-methoxyethvDcarbamate (Compound ID)

Compound 1D

[0093] 3-fluoro-4-hydroxybenzenaminium chloride (1.2 eq) in DMSO (3.9 vol) at 25±5°C was charged under nitrogen atmosphere and the reaction mass was stirred until observance of a clear solution at 25±5°C. t-BuOK was added lot wise under nitrogen atmosphere at 25±10°C. The reaction mass temperature was raised to 45±5°C and maintained for 30 minutes under nitrogen atmosphere. Compound 1C was charged lot-wise under nitrogen atmosphere at 45±5°C and stirred for 10 minutes at 45± 5°C.The reaction mixture was heated to 100± 5°C and stirred for 2 hrs. The reaction mass is monitored by HPLC.

[0094] After reaction completion, the reaction mass was cooled to 10± 5°C and quenched with chilled water (20 vol) at 10±5°C. The mass temperature was raised to 25± 5°C and stirred for 7-8 h. The resulting Compound ID crude was collected by filtration and washed with 2 vol of water. Crude Compound ID material taken in water (10 vol) and stirred for up to 20 minutes at 25±5°C. The reaction mass was heated to 45±5°C and stirred for 2-3 h at 45±5°C, filtered and vacuum-dried.

[0095] Crude Compound ID was taken in MTBE (5 vol) at 25±5°C and stirred for about 20 minutes at 25±5°C. The reaction mass temperature was raised to 45±5°C, stirred for 3-4 h at 45±5°C and then cooled to 20±5°C. The reaction mass was stirred for about 20 minutes at 20±5°C, filtered, followed by bed wash with water (0. 5 vol) and vacuum-dried.

[0096] The crude material was dissolved in acetone (10 vol) at 25±5°C and stirred for about 2h at 25±5°C. The reaction mass was filtered through a celite bed and washed with acetone (2.5 vol). The filtrate was slowly diluted with water (15 vol) at 25±5°C. The reaction mass was stirred for 2-3 h at 25±5°C, filtered and bed washed with water (2 vol) & vacuum-dried to afford Compound ID as brown solid.

[0097] Step 5 : 1 -((4-((2-(5-(((tert-butoxycarbonv0(2-methoxy ethvOaminolmethvOpyri din-2 -yl )thieno[3.2-b]pyridin-7-yl )oxy)-3 -fluorophenyl icarbamoyl level opropane-1 -carboxylic acid (Compound IE)

Compound 1E

[0098] To a solution of Compound ID (1.0 eq.) in tetrahydrofuran (7 vol.), aqueous potassium carbonate (1.0 eq.) in water (8 vol.) was added. The solution was cooled to 5±5°C, and stirred for about 60 min. While stirring, separately triethylamine (2.0 eq.) was added to a solution of 1,1-cyclopropanedicarboxylic acid (2.0 eq.) in tetrahydrofuran (8 vol.), at 5±5°C, followed by thionyl chloride (2.0 eq.) and stirred for about 60 min. The acid chloride mass was slowly added to the Compound ID solution at 5±5°C. The temperature was raised to 25±5°C and stirred for 3.0 h. The reaction was monitored by HPLC analysis.

[0099] After reaction completion, the mass was diluted with ethyl acetate (5.8 vol.), water (5.1 vol.), 10% (w/w) aqueous hydrochloric acid solution (0.8 vol.) and 25% (w/w) aqueous sodium chloride solution (2 vol.). The aqueous layer was separated and extracted with ethyl acetate (2 x 5 vol.). The combined organic layers were washed with a 0.5M aqueous sodium bicarbonate solution (7.5 vol.). The organic layer was treated with Darco activated charcoal (0.5 w/w) and sodium sulfate (0.3 w/w) at 25±5°C for 1.0 h. The organic layer was filtered through celite and washed with tetrahydofuran (5.0 vol.). The filtrate was concentrated under vacuum below 50°C to about 3 vol and co-distilled with ethyl acetate (2 x 5 vol.) under vacuum below 50°C up to ~ 3.0 vol. The organic layer was cooled to 15±5°C, stirred for about 60 min., filtered, and the solid was washed with ethyl acetate (2.0 vol.). The material was dried under vacuum at 40±5°C until water content was less than 1% to afford Compound IE as brown solid.

[00100] Step 6: tert-butyl (Y6-(7-(2-fluoro-4-(T-(Y4-fluorophenvDcarbamovDcvclopropane-l-carboxamido)phenoxy)thieno[3.2-b]pyridin-2-v0pyri din-3 – (2- 
methoxyethvDcarbamate (Compound IF)

[00101] Pyridine (1.1 eq.) was added to a suspension of Compound IE (1.0 eq.) in tetrahydrofuran (10 vol.) and cooled to 5±5°C. Thionyl chloride (2.0 eq.) was added and stirred for about 60 min. The resulting acid chloride formation was confirmed by HPLC analysis after quenching the sample in methanol. Separately, aqueous potassium carbonate (2.5 eq.) solution (7.0 vol. of water) was added to a solution of 4-fluoroaniline (3.5 eq.) in tetrahydrofuran (10 vol.), cooled to 5±5°C, and stirred for about 60 min. The temperature of the acid chloride mass at 5±5°C was raised to a temperature of about 25±5°C and stirred for 3 h. The reaction monitored by HPLC analysis.

[00102] After completion of the reaction, the solution was diluted with ethyl acetate (25 vol.), the organic layer was separated and washed with a 1M aqueous sodium hydroxide solution (7.5 vol.), a 1M aqueous hydrochloric acid solution (7.5 vol.), and a 25% (w/w) aqueous sodium chloride solution (7.5 vol.). The organic layer was dried and and filtered with sodium sulfate (1.0 w/w). The filtrate was concentrated ~ 3 vol under vacuum below 50°C and co-distilled with ethyl acetate (3 x 5 vol.) under vacuum below 50°C to ~ 3.0 vol. Ethyl acetate (5 vol.) and MTBE (10 vol.) were charged, heated up to 50±5°C and stirred for 30-60 min. The mixture was cooled to 15±5°C, stirred for about 30 min., filtered, and the solid was washed with ethyl acetate (2.0 vol.). MGB3 content was analyzed by HPLC analysis. The material was dried under vacuum at 40±5°C until the water content reached about 3.0% to afford Compound IF as brown solid.

[00103] Step 7 : N-(3-fluoro-4-((2-(5-(((2-methoxyethv0amino)methv0pyridin-2-yl )thieno[3.2-b]pyridin-7-yl )oxy)phenyl)-N-(4-fluorophenyl level opropane-1. 1 -dicarboxamide (Compound 1)

Compound 1

[0100] To a mixture of Compound IF in glacial acetic acid (3.5 vol.) concentrated hydrochloric acid (0.5 vol.) was added and stirred at 25±5°C for 1.0 h. The reaction was monitored by HPLC analysis.

[0101] After reaction completion, the mass was added to water (11 vol.) and stirred for 20±5°C for 30 min. The pH was adjusted to 3.0 ± 0.5 using 10% (w/w) aqueous sodium bicarbonate solution and stirred for 20±5°C for approximately 3.0 h.. The mass was filtered, washed with water (4 x 5.0 vol.) and the pH of filtrate was checked after every wash. The material was dried under vacuum at 50±5°C until water content was about 10%.

[0102] Crude Compound 1 was taken in ethyl acetate (30 vol.), heated to 70±10°C, stirred for 1.0 h., cooled to 25±5°C, filtered, and washed with ethyl acetate (2 vol.). The material was dries under vacuum at 45±5°C for 6.0 h.

[0103] Crude Compound 1 was taken in polish filtered tetrahydrofuran (30 vol.) and pre washed Amberlyst A-21 Ion exchange resin and stirred at 25±5°C until the solution became clear. After getting the clear solution, the resin was filtered and washed with polish filtered tetrahydrofuran (15 vol.). The filtrate was concentrated by -50% under vacuum below 50°C and co-distilled with polish filtered IPA (3 x 15.0 vol.) and concentrated up to -50% under vacuum below 50°C. Charged polish filtered IPA (15 vol.) was added and the solution concentrated under vacuum below 50°C to – 20 vol. The reaction mass was heated to 80±5°C, stirred for 60 min. and cooled to 25±5°C. The resultant reaction mass was stirred for about 20 hours at 25±5°C. The reaction mass was cooled to 0±5°C, stirred for 4-5 hours, filtered, and washed with polish filtered IPA (2 vol.). The material was dried under vacuum at 45±5°C, until the water content was about 2%, to obtain the desired product Compound 1. ¾-NMR (400 MHz, DMSO- d): 510.40 (s, 1H), 10.01 (s, 1H), 8.59 – 8.55 (m, 1H), 8.53 (d, J= 5.6 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J= 8.0 Hz, 1H), 7.96 – 7.86 (m, 2H), 7.70 – 7.60 (m, 2H), 7.56 – 7.43 (m, 2H), 7.20 – 7.11 (m, 2H), 6.66 (d, J= 5.6 Hz, 1H), 3.78 (s, 2H), 3.41 (t, J= 5.6 Hz, 2H), 3.25 (s, 3H), 2.66 (t, J= 5.6 Hz, 2H), 1.48 (s, 4H)ppm. MS: M/e 630 (M+l)⁺.

EXAMPLE 2

Preparation of Crystalline Form D of N-(3-fluoro-4-((2-(5-(((2- methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4- fluorophenyl)cyclopropane-l, 1-dicarboxamide

EXAMPLE 2A: Preparation of Compound 1 Crystalline Form D

[0104] To a 50 L reactor, 7.15 Kg of Compound 1, 40 g of Form D as crystal seed and 21 L acetone (>99%) were added. The mixture was heated to reflux ( ~56 °C) for 1~2 h. The mixture was agitated with an internal temperature of 20±5 °C for at least 24 h. Then, the suspension was filtered and washed the filter cake with 7 L acetone. The wet cake was dried under vacuum at <45 °C, to obtain 5.33 kg of Compound 1 of desired Form D

[0105] X-Ray Powder Diffraction (XRPD)

The XRPD patterns were collected with a PAN alytical X’ Pert PRO MPD diffractometer using auincident beam of Cu radiation produced using au Optix long, fine-focus source. An elliptically graded multilayer mirror was used to focus Cu Ka X -rays through the specimens and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify the observed position of the Si Ill peak is consistent with the NIST-certified position. A specimen of each sample was sandwiched between 3 -pm -thick films and analyzed in transmission geometly. A beam-stop, short autiscatter extension, and an autiscatter knife edge were used to minimize the background generated by air. Sober slits for the incident aud diffracted beauls were used to minimize broadening from axial divergence. The diffraction patterns were collected using a scanning position-sensitive detector (X’Celerator) located 240 mm from the specimens and Data Collector software v. 2.2b. Pattern Match v2.3.6 was used to create XRPD patterns.

[0106] The X-ray powder diffraction (XRPD) pattern was used to characterize the Compound 1 obtained, which showed that the Compound 1 was in Crystalline Form D of Compound 1 (Compound 1 Form D), see Figure 1A. The XRPD pattern yielded is substantially the same as that shown in Figure 3C.

[0107] Differential Scanning Calorimetry (DSC)

[0108] DSC was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Temperature calibration was performed using octane, phenyl salicylate, indium, tin, and zinc. The TAWN sensitivity was 11.9. The samples were placed into aluminum DSC pans, covered with lids, and the weights were accurately recorded. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The pan lids were pierced prior to sample analyses. The method name on the thermograms is an abbreviation for the start and end temperature as well as the heating rate; e.g., -30-250-10 means “from ambient to 250°C, at 10°C/min.” The nitrogen flow rate was 50.0 mL/min. This instrument does not provide gas pressure value as required by USP because it is the same as atmospheric pressure.

[0109] A broad small endotherm with a peak maximum at approximately 57°C to 62°C (onset ~20°C to 22°C) followed by a sharp endotherm with a peak maximum at approximately 180°C (onset ~178°C) were observed. These events could be due to the loss of volatiles and a melt, respectively (see Figure IB).

[0110] In an alternative embodiment Form D was prepared as follows. Designated Material O was suspended in 600 pL of acetone. Initial dissolution was observed followed by re precipitation. The amount of suspended solids was not measured because the target of the experiment was to get a suspension with enough solids to slurry isolate and collect XRPD data. Based on the solubility of Form D in acetone a very rough estimate for the scale of the experiment is about 80-100mg. The suspension was stirred at ambient temperature for approximately 2 5 weeks after which the solids were isolated by centrifugation with filtration. XRPD data appeared to be consistent with Form D The sample was then dried in vacuum oven at ~40 °C for ~2 5 hours. The XRPD pattern of the final solids was consistent with Form D EXAMPLE 2B: Preparation of Compound 1 Form D

[0111] 427.0 mg of Compound 1 was dissolved in 5 mL of THF to obtain a clear brown solution. The resulting solution was filtered, and the filtrate evaporated under flow of nitrogen. A sticky solid was obtained, which was dried under vacuum in room temperature for ~5 min, still a sticky brown solid obtained. It was dissolved in 0.2 mL of EtOAc and sonicated to dissolve. The solution obtained was stirred at room temperature for 15 min and a solid precipitated. The resulting solid was added 0.4 mL of EtOAc and stirred in room temperature for 21 h 40 min to ontian a suspension. The solid was spparated from mother liquor by centrifugation, then the resulting solid was resuspended the in 0.6 mL of EtOAc and stirred in room temperature for 2 days. The solid was isolated by centrifugation, to obtain Compound 1 of desired Form D.

[0112] The X-ray powder diffraction (XRPD) pattern was used to characterize the Compound 1 obtained, which showed that the Compound 1 was in Crystalline Form D of Compound 1 (Compound 1 Form D).

EXAMPLE 2C: Preparation of Compound 1 Form D

[0113] Single crystal X-ray diffraction data of Compound 1 was collected at 180 K on a Rigaku XtaLAB PRO 007HF(Mo) diffractometer, with Mo Ka radiation (l = 0.71073 A). Data reduction and empirical absorption correction were performed using the CrysAlisPro program. The structure was solved by a dual-space algorithm using SHELXT program. All non-hydrogen atoms could be located directly from the difference Fourier maps. Framework hydrogen atoms were placed geometrically and constrained using the riding model to the parent atoms. Final structure refinement was done using the SHELXL program by minimizing the sum of squared deviations of F2 using a full-matrix technique.

Preparation of Compound 1 Form D ( a Single Crystal )

[0114] Compound 1 Form D was dissolved in a mixture of acetone/ ACN (1/2) with the concentration of Compound 1 at ~7 mg/mL. A block single crystal was obtained, which was a single crystal.

[0115] The XRPD pattern was used to characterize the single crystal of Compound 1 Form D obtained, see Figure 2A. The crystal structural data are summarized in Table IB. The refined single crystal structure were shown in Figure 2B. The single crystal structure of Compound 1 Form D is in the P-1 space group and the triclinic crystal system. The terminal long alkyl chain is found to have large ellipsoids, indicating high mobility with disordered atoms.

[0116] The theoretical XRPD calculated from the single crystal structure and experimental XRPD are essentially similar (Figure 2A). A few small peaks are absent or shift because of orientation preference, disorder and tested temperature (180 K for single crystal data and 293 K for experimental one).

[0117] Table IB. Crystal Data and Structure Refinement for Compound 1 Form D (a Single Crystal)

References

1. ^ http://www.mirati.com/go/mgcd516/
2. ^ “MGCD516 in Advanced Liposarcoma and Other Soft Tissue Sarcomas – Full Text View – ClinicalTrials.gov”.
3. ^ “Phase 2 Study of Glesatinib, Sitravatinib or Mocetinostat in Combination With Nivolumab in Non-Small Cell Lung Cancer – Full Text View – ClinicalTrials.gov”.
4. ^ “MGCD516 Combined With Nivolumab in Renal Cell Cancer (RCC) – Full Text View – ClinicalTrials.gov”.

///////////// sitravatinib, phase 3, シトラバチニブ , MGCD516, MG-516, Sitravatinib (MGCD516), UNII-CWG62Q1VTB, CWG62Q1VTB, MGCD-516, ситраватиниб , سيترافاتينيب , 司曲替尼 , Antineoplastic, MGCD 516

#sitravatinib, #phase 3, #シトラバチニブ , #MGCD516, #MG-516#Sitravatinib (MGCD516), #UNII-#CWG62Q1VTB, #CWG62Q1VTB, #MGCD-516, ситраватиниб , سيترافاتينيب , 司曲替尼 , #Antineoplastic, #MGCD516

COCCNCC1=CN=C(C=C1)C2=CC3=NC=CC(=C3S2)OC4=C(C=C(C=C4)NC(=O)C5(CC5)C(=O)NC6=CC=C(C=C6)F)F

BBIBP-CorV, Sinopharm COVID-19 vaccine

• Inactivated novel coronavirus (2019-CoV) vaccine (Vero cells)
• Purified inactivated SARS-CoV-2 Vaccine

ref Lancet Infectious Diseases (2021), 21(1), 39-51.

BBIBP-CorV, also known as the Sinopharm COVID-19 vaccine,^[1] is one of two inactivated virus COVID-19 vaccines developed by Sinopharm. In late December 2020, it was in Phase III trials in Argentina, Bahrain, Egypt, Morocco, Pakistan, Peru, and the United Arab Emirates (UAE) with over 60,000 participants.^[2]

On December 9, the UAE announced interim results from Phase III trials showing BBIBP-CorV had a 86% efficacy against COVID-19 infection.^[3] In late December, Sinopharm announced that its internal analysis indicated a 79% efficacy.^[4] While mRNA vaccines like the Pfizer–BioNTech COVID-19 vaccine and mRNA-1273 showed higher efficacy of +90%, those present distribution challenges for some nations as they require deep-freeze facilities and trucks. BIBP-CorV could be transported and stored at normal refrigerated temperatures.^[5]

BBIBP-CorV shares similar technology with CoronaVac and BBV152, other inactivated virus vaccines for COVID-19 being developed in Phase III trials.^[6][7]

BBIBP-CorV is being used in vaccination campaigns by certain countries in Asia,^[8][9][10] Africa,^[11][12][13] South America,^[14][15] and Europe.^[16][17][18] Sinopharm expects to produce one billion doses of BBIBP-CorV in 2021.^[19] By February 21, Sinopharm said more than 43 million doses of the vaccine had been administered in total.^[20]

BBIBP-CorV vaccine contains a SARS-CoV-2 strain inactivated inside Vero Cells. Investigation shows this vaccine induces neutralizing antibodies in several mammalian species while also showing protective efficacy with SARS-CoV-2 challenge in rhesus macaques². As of August 2020, this vaccine is being tested for prophylaxis against COVID-19 in human clinical trials.

A vaccination certificate of BBIBP-CorV (Beijing Institute of Biological Products, Sinopharm).

Clinical research

Main article: COVID-19 vaccine

Phases I and II

In April 2020, China approved clinical trials for a candidate COVID-19 vaccine developed by Sinopharm‘s Beijing Institute of Biological Products^[21] and the Wuhan Institute of Biological Products.^[22] Both vaccines are chemically-inactivated whole virus vaccines for COVID-19.

On October 15, the Beijing Institute of Biological Products published results of its Phase I (192 adults) and Phase II (448 adults) clinical studies for the BBIBP-CorV vaccine, showing BBIBP-CorV to be safe and well-tolerated at all tested doses in two age groups. Antibodies were elicited against SARS-CoV-2 in all vaccine recipients on day 42. These trials included individuals older than 60.^[21]

On August 13, the Wuhan Institute of Biological Products published interim results of its Phase I (96 adults) and Phase II (224 adults) clinical studies. The report noted the inactivated COVID-19 vaccine had a low rate of adverse reactions and demonstrated immunogenicity, but longer-term assessment of safety and efficacy would require Phase III trials.^[22]

BIBP-CorV may have characteristics favorable for vaccinating people in the developing world. While mRNA vaccines, such as the Pfizer–BioNTech COVID-19 vaccine and Moderna COVID-19 vaccine showed higher efficacy of +90%, mRNA vaccines present distribution challenges for some nations, as some may require deep-freeze facilities and trucks. By contrast, BIBP-CorV can be transported and stored at normal refrigeration temperatures.^[23] While Pfizer and Moderna are among developers relying on novel mRNA technology, manufacturers have decades of experience with the inactivated virus technology Sinopharm is using.^[23]

Phase III

Africa and Asia

On July 16, Sinopharm began conducting a Phase III vaccine trial of 31,000 volunteers in the UAE in collaboration with G42 Healthcare, an Abu Dhabi-based company.^[24] By August, all volunteers had received their first dose and were to receive the second dose within the next few weeks.^[25] On December 9, UAE’s Ministry of Health and Prevention announced the official registration of BBICP-CorV, after an interim analysis of the Phase III trial showed BBIBP-CorV to have a 86% efficacy against COVID-19 infection.^[26] The vaccine had a 99% sero-conversion rate of neutralizing antibodies and 100% effectiveness in preventing moderate and severe cases of the disease.^[27]

On September 2, Sinopharm began a Phase III trial in Casablanca and Rabat on 600 people.^[28][29] In September, Egypt opened registration for a Phase III trial to last one year and enroll 6,000 people.^[30]

In August 2020, Sinopharm began a Phase III clinical trial in Bahrain on 6,000 citizens and resident volunteers.^[31][32] In a November update, 7,700 people had volunteered in the trials.^[33] Also in late August, Sinopharm began a Phase III clinical trial in Jordan on 500 volunteers at Prince Hamzah Hospital.^[34][35]

In Pakistan, Sinopharm began working with the University of Karachi on a trial with 3,000 volunteers.^[36]

South America

On September 10, Sinopharm began a Phase III trial in Peru with the long-term goal of vaccinating a total of 6,000 people between the ages of 18 and 75.^[37] In October, the trials were expanded to include an additional 6,000 volunteers.^[38] On January 26, a volunteer in the placebo group of the vaccine trials had died.^[39]

On September 16, Argentina began a Phase III trial with 3,000 volunteers.^[40]

Manufacturing

Sinopharm’s Chariman Yang Xioyun has said the company could produce one billion doses in 2021.^[19]

In October, Dubai’s G42 Healthcare reached manufacturing agreements to provide UAE and other regional states with BBIBP-CorV, with the UAE producing 75 to 100 million doses in 2021.^[41]

In December, Egypt announced an agreement between Sinopharm and Egyptian Holding Company for Biological Products & Vaccines (VACSERA) for the vaccine to be manufactured locally,^[42] which would also be exported to other African countries.^[43]

In December, AP reported Morocco plans to produce BBIBP-CorV locally.^[44]

In March, Serbia announced plans to produce 24 million doses of BBIBP-CorV annually starting in October. The production volume would be sufficient to meet the needs of Serbia and all of its neighbors, deputy prime minister Branislav Nedimović noted.^[45]

In March, Belarus was looking to produce BBIBP-CorV locally.^[18]

Marketing and Distribution

On February 21, 2021 Sinopharm said more than 43 million doses of BBIBP-CorV had been administered so far, including more than 34 million administered in China and the rest internationally.^[20]

Asia

In February, Afghanistan was pledged 400,000 doses of BBIBP-CorV by China.^[82]

In November 3, 2020 Bahrain granted emergency use authorization of BBIBP-CorV for frontline workers.^[33] In December, Bahrain approved Sinopharm’s vaccine, citing data from Phase III clinical trials that showed an 86% efficacy rate.^[87]

In February, Brunei received the first batch of Sinopharm vaccines donated by China.^[84]

In January, Cambodia said China would provide a million doses.^[88] Cambodia granted emergency use authorization on February 4^[89] and started the vaccination campaign on February 10 with the first 600,000 doses.^[90]

In China, Sinopharm obtained an EUA in July.^[91] In October, it began offering the vaccine for free to students going abroad for higher studies.^[92] On December 30, China‘s National Medical Products Administration approved BBIBP-CorV for general use.^[93][8] In February, Macau received the first 100,000 doses of 400,000 doses.^[94]

In October, Indonesia reached an agreement with Sinopharm to deliver 15 million dual-dose vaccines in 2020.^[95]

In February, Iran approved emergency use of BBIBP-CorV,^[96] and received the first batch of 250,000 doses on February 28.^[97]

In January, Iraq approved BBIBP-CorV for emergency use^[98] and has signed agreements for 2 million doses. The first doses arrived on March 2.^[99]

In January, Jordan approved BBIBP-CorV for emergency use^[100] and started its vaccination campaign on January 13.^[101]

In March, Kyrgyzstan received a donation of 150,000 doses of the vaccine.^[102]

In January, Laos began vaccinating medical workers at hospitals in Vientiane ^[103] and received another 300,000 doses in early February.^[104]

In March, Lebanon received a donation of 50,000 doses at its request,^[105] for which it granted emergency use authorization on March 2.^[106]

In March, Maldives granted emergency approval for use. At the time of approval, the country had received 18,000 doses and was awaiting 200,000 additional doses.^[107]

In February, Mongolia received a donation of 300,000 doses.^[108] On March 10, Governor of Ulaanbaatar D. Sumiyabazar and Deputy Prime Minister S. Amarsaikhan received the first doses of BBIBP-CorV.^[109]

In February, Nepal approved the vaccine for emergency use, allowing a donation of 500,000 doses to enter the country.^[110]

In December, Pakistan‘s purchased 1.2 million doses,^[111] which was approved for emergency use on January 18,^[112] and began a vaccination campaign on February 2.^[10]

In March, Palestine said it would receive 100,000 doses donated by China.^[113]

In March 19, Sri Lanka approved the vaccine for emergency use, allowing a donation of 600,000 doses by China to enter the country.^[114]

On 14 September 2020, the United Arab Emirates approved the vaccine for front-line workers following successful interim Phase III trials.^[24] In December, the country registered BBIBP-CorV after it reviewed the results of the interim analysis.^[26] In March, a small number of people who have reduced immunity against diseases, have chronic illnesses, or belong to high-risk groups have been given a 3rd booster shot.^[115]

Africa

In February, Algeria received a donation of 200,000 doses.^[83]

Egypt plans to buy 40 million doses of Sinpharm’s vaccine^[116] which was approved for regulatory use on January 3.^[116] President Abdel Fattah el-Sisi announced a vaccination campaign starting 24 January.^[11]

In February, Equatorial Guinea received a donation of 100,000 doses which arrived on February 10. The country began vaccinations on February 15.^[56]

In March, Gabon received a donation of 100,000 doses which was the second vaccine approved for use in the country.^[117]

Morocco placed orders for 41 million vaccine doses from Sinopharm and 25 million from AstraZeneca, for a total of 66 million doses.^[118] Morocco granted emergency use approval on January 23,^[119] and the first 500,000 doses arrived on January 27.^[12]

In February, Mozambique received a donation of 200,000 doses^[120] and planned to start vaccinations on March 8.^[121]

In March, Namibia received a donation of 100,000 doses and announced the start of vaccinations in the Khomas and Erongo regions.^[122]

In March, Niger received a donation of 400,000 doses with vaccinations to begin on March 27.^[123]

In February, Senegal received 200,000 doses in Dakar^[124] and began vaccinating health workers on February 22.^[125]

In February, Sierra Leone received a donation of 200,000 doses.^[126] It was approved for emergency use and vaccinations began on March 15.^[127]

In January, Seychelles said it would begin administering vaccinations on January 10 with 50,000 doses it had received as a gift from the UAE.^[128]

In March, Republic of the Congo received 100,000 doses with vaccinations prioritizing the medically vulnerable and those over 50.^[129]

In February, Zimbabwe purchased 600,000 doses on top of 200,000 doses donated by China,^[130] and started vaccinations on February 18.^[13] Zimbabwe later purchased an additional 1.2 million doses.^[131]

North America

In February, the Dominican Republic ordered 768,000 doses of BBIBP-CorV.^[132]

In March, Dominica received 20,000 doses of BBIBP-CorV which it began using in its vaccination campaign on March 4.^[133]

In March, Mexico announced it would order 12 million doses of BBIBP-CorV pending approval by its health regulator.^[134]

South America

In February, Argentina authorized emergency use of BBIBP-CorV^[135] ahead of the arrival of 904,000 doses on February 26.^[136]

In February, Bolivia purchased 400,000 doses on top of 100,000 doses donated by China,^[137] and started its vaccination campaign on February 26.^[15]

In March, Guyana received a donation of 20,000 doses of BBIBP-CorV.^[138] Vaccinations were to start on March 7.^[139]

In January, Peru purchased 38 million doses of BBIBP-CorV.^[140] Peru granted emergency approval for BBIBP-CorV on January 27^[141] and started vaccinations on February 9 with the first 300,000 doses.^[14]

In March, Venezuela granted approval for BBIBP-CorV to be used in the country.^[142] The first 500,000 doses arrived on March 2.^[143]

Europe

In February, Belarus received a donation of 100,000 doses^[144] and began using the vaccine on March 15.^[18]

In January, Hungary became first EU member to approve BBIBP-CorV, signing a deal for 5 million doses.^[145] The first 550,000 doses arrived in Budapest on February 16^[146] and vaccinations started on February 24.^[17] Prime Minister Viktor Orbán was vaccinated with BBIBP-CorV on February 28.^[147]

In March, Moldova received 2,000 doses donated by the UAE^[148] which will be used to vaccinate doctors at the State University of Mediecne and Pharmacy starting on March 22.^[149]

In March 3, Montenegro received a donation of 30,000 doses of BBIBP-CorV.^[85]

In February, North Macedonia signed an agreement for 200,000 doses of BBIBP-CorV, with which they hoped to launch their vaccination program later that month.^[150]

In January, Serbia received one million doses, making it the first country in Europe to receive BBIBP-CorV.^[151] On January 19, Serbia approved the vaccine and Health Minister Zlatibor Lončar became the first person to receive a shot.^[16]

Controversies

Lack of public data

Unlike Moderna‘s MRNA-1273, Oxford–AstraZeneca‘s AZD1222, and Johnson & Johnson‘s Ad26.COV2.S, there is little public information about the Chinese vaccine’s safety or efficacy.^[152] The UAE said it had reviewed Sinopharm’s interim data analysis which showed the vaccine was 100% effective to prevent moderate and severe instances of COVID-19, but did not say whether it had independently analyzed the case data in its review. It was unclear how Sinopharm drew conclusions, since the UAE announcement of the approval for BBIBP-CorV noticeably lacked details such as the number of COVID-19 cases in the placebo or active group or the volunteers ages.^[153]

As of December 30, 2020, no detailed efficacy data of the vaccine has been released to the public. A Sinopharm executive said detailed data would be released later and published in scientific journals in China and internationally.^[8]

Sinopharm president Wu Yonglin said the trial results exceeded the WHO’s requirements, but a director at a large pharmaceutical company in Shanghai expressed skepticism over the trials and the expectation that drug regulators in Bahrain and the UAE would not hold the same standard as the U.S. Food and Drug Administration.^[154]

Unauthorized use in Asia

On December 30, Philippine Defense Secretary Delfin Lorenzana said in an interview that at least one minister and president Rodrigo Duterte‘s bodyguards were provided BBIBP-CorV which were “smuggled” but that he felt what happened was “justified”. Brigadier General Jesus Durante, head of the Presidential Security Guard (PSG), said he felt compelled and “took the risk” to have some of his men vaccinated because they provide close-in security to Duterte, who at 75 is highly vulnerable to COVID-19.^[155] Ingming Aberia, an author at The Manila Times commented that FDA director-general Enrique Domingo had reason to believe Sinopharm may cause harm to the consuming public given that no COVID-19 vaccine license was issued, but out of “self-preservation”, he would not initiate charges against PSG.^[156]

On January 1, Mainichi Shimbun reported that 18 wealthy people, including several owners of leading Japanese companies, have been vaccinated with Sinopharm vaccines since November 2020. The vaccines were brought in by a Chinese consultant close to a senior member of the Chinese Communist Party.^[157] The Chinese embassy in Japan later expressed its dissatisfaction at the unverified claims by Japanese news media.^[158]

References

1. ^ https://www.nytimes.com/interactive/2020/health/sinopharm-covid-19-vaccine.html
2. ^ Reuters Staff (2020-11-19). “China Sinopharm’s coronavirus vaccine taken by about a million people in emergency use”. Reuters. Retrieved 2020-12-09.
3. ^ “UAE: Ministry of Health announces 86 per cent vaccine efficacy”. gulfnews.com. Retrieved 2020-12-13.
4. ^ Wee, Sui-Lee; Qin, Amy (2020-12-30). “China Approves Covid-19 Vaccine as It Moves to Inoculate Millions”. The New York Times. ISSN 0362-4331. Retrieved 2021-02-12.
5. ^ “China State-Backed Covid Vaccine Has 86% Efficacy, UAE Says”. Bloomberg.com. 2020-12-09. Retrieved 2020-12-09.
6. ^ Cohen J (December 2020). “China’s vaccine gambit”. Science. 370 (6522): 1263–1267. Bibcode:2020Sci…370.1263C. doi:10.1126/science.370.6522.1263. PMID 33303601.
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External links

• “How the Sinopharm Covid-19 Vaccine Works”. The New York Times.

How the Sinopharm Vaccine Works

By Jonathan Corum and Carl ZimmerUpdated March 22, 2021Leer en español

In early 2020, the Beijing Institute of Biological Products created an inactivated coronavirus vaccine called BBIBP-CorV. Clinical trials run by the state-owned company Sinopharm showed that it had an efficacy rate of 79 percent. China approved the vaccine and soon began exporting it to other countries.

A Vaccine Made From Coronaviruses

BBIBP-CorV works by teaching the immune system to make antibodies against the SARS-CoV-2 coronavirus. The antibodies attach to viral proteins, such as the so-called spike proteins that stud its surface.

Spikes

Spike

protein

gene

CORONAVIRUS

To create BBIBP-CorV, the Beijing Institute researchers obtained three variants of the coronavirus from patients in Chinese hospitals. They picked one of the variants because it was able to multiply quickly in monkey kidney cells grown in bioreactor tanks.

Killing the Virus

Once the researchers produced large stocks of the coronaviruses, they doused them with a chemical called beta-propiolactone. The compound disabled the coronaviruses by bonding to their genes. The inactivated coronaviruses could no longer replicate. But their proteins, including spike, remained intact.

Beta-

propiolactone

INACTIVATED

CORONAVIRUS

Inactivated

genes

The researchers then drew off the inactivated viruses and mixed them with a tiny amount of an aluminum-based compound called an adjuvant. Adjuvants stimulate the immune system to boost its response to a vaccine.

Inactivated viruses have been used for over a century. Jonas Salk used them to create his polio vaccine in the 1950s, and they’re the bases for vaccines against other diseases including rabies and hepatitis A.

Prompting an Immune Response

Because the coronaviruses in BBIBP-CorV are dead, they can be injected into the arm without causing Covid-19. Once inside the body, some of the inactivated viruses are swallowed up by a type of immune cell called an antigen-presenting cell.

INACTIVATED

CORONAVIRUS

Engulfing

the virus

ANTIGEN-

PRESENTING

CELL

Digesting

virus proteins

Presenting

virus protein

fragments

HELPER

T CELL

The antigen-presenting cell tears the coronavirus apart and displays some of its fragments on its surface. A so-called helper T cell may detect the fragment. If the fragment fits into one of its surface proteins, the T cell becomes activated and can help recruit other immune cells to respond to the vaccine.

Making Antibodies

Another type of immune cell, called a B cell, may also encounter the inactivated coronavirus. B cells have surface proteins in a huge variety of shapes, and a few might have the right shape to latch onto the coronavirus. When a B cell locks on, it can pull part or all of the virus inside and present coronavirus fragments on its surface.

A helper T cell activated against the coronavirus can latch onto the same fragment. When that happens, the B cell gets activated, too. It proliferates and pours out antibodies that have the same shape as their surface proteins.

ACTIVATED

HELPER

T CELL

INACTIVATED

CORONAVIRUS

Activating

the B cell

Matching

surface proteins

B CELL

SECRETED

ANTIBODIES

Stopping the Virus

Once vaccinated with BBIBP-CorV, the immune system can respond to an infection of live coronaviruses. B cells produce antibodies that stick to the invaders. Antibodies that target the spike protein can prevent the virus from entering cells. Other kinds of antibodies may block the virus by other means.

ANTIBODIES

LIVE

VIRUS

Remembering the Virus

Sinopharm’s clinical trials have demonstrated that BBIBP-CorV can protect people against Covid-19. But no one can yet say how long that protection lasts. It’s possible that the level of antibodies drops over the course of months. But the immune system also contains special cells called memory B cells that might retain information about the coronavirus for years or even decades.

Vaccine Timeline

January, 2020 Sinopharm begins developing an inactivated vaccine against the coronavirus.

June Researchers report the vaccine produces promising results in monkeys. A Phase 1/2 trial shows that the vaccine doesn’t cause any serious side effects and enables people to make antibodies against the coronavirus.

A Sinopharm production plant in Beijing.Zhang Yuwei/Xinhua, via Associated Press

July A Phase 3 trial begins in the United Arab Emirates.

August Phase 3 trials begin in Morocco and Peru.

Preparing a Sinopharm dose in Lima, Peru.Ernesto Benavides/Agence France-Presse

Sept. 14 The U.A.E. gives emergency approval for Sinopharm’s vaccine to use on health care workers. Government officials and others begin to receive it.

November The chairman of Sinopharm says almost a million people in China have received Sinopharm vaccines.

Nov. 3 The ruler of Dubai, Sheikh Mohammed bin Rashid al-Maktoum, announces he received the vaccine.

Sheikh Mohammed before receiving the vaccine.Agence France-Presse

Dec. 9 The U.A.E. gives full approval to BBIBP-CorV, announcing it has an efficacy rate of 86 percent. But the government did not release any details with their announcement, leaving it unclear how they had come to their conclusions.

Dec. 13 Bahrain also approves the vaccine.

Vials of the Sinopharm vaccine at a packaging plant.Zhang Yuwei/Xinhua, via Associated Press

Dec. 30 Sinopharm announces that the vaccine has an efficacy of 79.34 percent, leading the Chinese government to approve it. The company has yet to publish detailed results of their Phase 3 trial.

Jan. 3, 2021 Egypt authorizes the vaccine for emergency use.

Sources: National Center for Biotechnology Information; Science; The Lancet; Lynda Coughlan, University of Maryland School of Medicine; Jenna Guthmiller, University of Chicago.

Data

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NOVAWAX

NVX-CoV2373

SARS-CoV-2 rS Nanoparticle Vaccine

MCDC OTA agreement number W15QKN-16-9-1002

Novavax COVID-19 vaccine, Coronavirus disease 19 infection

SARS-CoV-2 rS,  TAK 019

Novavax, Inc. is an American vaccine development company headquartered in Gaithersburg, Maryland, with additional facilities in Rockville, Maryland and Uppsala, Sweden. As of 2020, it had an ongoing Phase III clinical trial in older adults for its candidate vaccine for seasonal influenza, NanoFlu and a candidate vaccine (NVX-CoV2373) for prevention of COVID-19.

NVX-CoV2373 is a SARS-CoV-2 rS vaccine candidate and was shown to have high immunogenicity in studies. The vaccine is created from the genetic sequence of COVID-19 and the antigen derived from the virus spike protein is generated using recombinant nanoparticle technology. The vaccine was developed and tested by Novavax. As of May 2020, the company is pursuing a Phase 1 clinical trial (NCT04368988) to test the vaccine.

History

Novavax was founded in 1987. It focused principally on experimental vaccine development, but did not achieve a successful launch up to 2021.^[4]

In June 2013, Novavax acquired the Matrix-M adjuvant platform with the purchase of Swedish company Isconova AB and renamed its new subsidiary Novavax AB.^[5]

In 2015, the company received an $89 million grant from the Bill & Melinda Gates Foundation to support the development of a vaccine against human respiratory syncytial virus for infants via maternal immunization.^[6][7][8][9]

In March 2015 the company completed a Phase I trial for its Ebola vaccine candidate,^[10] as well as a phase II study in adults for its RSV vaccine, which would become ResVax.^[11] The ResVax trial was encouraging as it showed significant efficacy against RSV infection.^[11]

2016 saw the company’s first phase III trial, the 12,000 adult Resolve trial,^[11] for its respiratory syncytial virus vaccine, which would come to be known as ResVax, fail in September.^[3] This triggered an eighty-five percent dive in the company’s stock price.^[3] Phase II adult trial results also released in 2016 showed a stimulation of antigencity, but failure in efficacy.^[11] Evaluation of these results suggested that an alternative dosing strategy might lead to success, leading to plans to run new phase II trials.^[3] The company’s difficulties in 2016 led to a three part strategy for 2017: cost reduction through restructuring and the termination of 30% of their workforce; pouring more effort into getting ResVax to market; and beginning clinical trials on a Zika virus vaccine.^[3]

Alongside the adult studies of ResVax, the vaccine was also in 2016 being tested against infant RSV infection through the route of maternal immunization.^[11]

In 2019, late-stage clinical testing of ResVax, failed for a second time, which resulted in a major downturn in investor confidence and a seventy percent reduction in capital value for the firm.^[12][13] As a secondary result, the company was forced to conduct a reverse stock split in order to maintain Nasdaq minimum qualification, meaning it was in risk of being delisted.^[13]

The company positions NanoFlu for the unmet need for a more effective vaccine against influenza, particularly in the elderly who often experience serious and sometimes life-threatening complications. In January 2020, it was granted fast track status by the U.S. Food and Drug Administration (FDA) for NanoFlu.

External sponsorships

In 2018, Novavax received a US$89 million research grant from the Bill and Melinda Gates Foundation for development of vaccines for maternal immunization.^[14]

In May 2020, Novavax received US$384 million from the Coalition for Epidemic Preparedness Innovations to fund early-stage evaluation in healthy adults of the company’s COVID-19 vaccine candidate NVX-CoV2373 and to develop resources in preparation for large-scale manufacturing, if the vaccine proves successful.^[15] CEPI had already invested $4 million in March.^[15]

Drugs in development

ResVax is a nanoparticle-based treatment using a recombinant F lipoprotein or saponin, “extracted from the Quillaja saponaria [or?] Molina bark together with cholesterol and phospholipid.”^[16] It is aimed at stimulating resistance to respiratory syncytial virus infection, targeting both adult and infant populations.^[11]

In January 2020, Novavax was given Fast Track status by the FDA to expedite the review process for NanoFlu, a candidate influenze vaccine undergoing a Phase III clinical trial scheduled for completion by mid-2020.^[17]

COVID-19 vaccine candidate

See also: NVX-CoV2373 and COVID-19 vaccine

In January 2020, Novavax announced development of a vaccine candidate, named NVX-CoV2373, to establish immunity to SARS-CoV-2.^[18] NVX-CoV2373 is a protein subunit vaccine that contains the spike protein of the SARS-CoV-2 virus.^[19] Novavax’s work is in competition for vaccine development among dozens of other companies.

In January 2021, the company released phase 3 trials showing that it has 89% efficacy against Covid-19, and also provides strong immunity against new variants.^[20] It has applied for emergency use in the US and UK but will be distributed in the UK first.Novavax COVID-19 Vaccine Demonstrates 89.3% Efficacy in UK Phase 3 TrialJan 28, 2021 at 4:05 PM ESTDownload PDF

First to Demonstrate Clinical Efficacy Against COVID-19 and Both UK and South Africa Variants

• Strong efficacy in Phase 3 UK trial with over 50% of cases attributable to the now-predominant UK variant and the remainder attributable to COVID-19 virus
• Clinical efficacy demonstrated in Phase 2b South Africa trial with over 90% of sequenced cases attributable to prevalent South Africa escape variant
• Company to host investor conference call today at 4:30pm ET

GAITHERSBURG, Md., Jan. 28, 2021 (GLOBE NEWSWIRE) — Novavax, Inc. (Nasdaq: NVAX), a biotechnology company developing next-generation vaccines for serious infectious diseases, today announced that NVX-CoV2373, its protein-based COVID-19 vaccine candidate, met the primary endpoint, with a vaccine efficacy of 89.3%, in its Phase 3 clinical trial conducted in the United Kingdom (UK). The study assessed efficacy during a period with high transmission and with a new UK variant strain of the virus emerging and circulating widely. It was conducted in partnership with the UK Government’s Vaccines Taskforce. Novavax also announced successful results of its Phase 2b study conducted in South Africa.

“With today’s results from our UK Phase 3 and South Africa Phase 2b clinical trials, we have now reported data on our COVID-19 vaccine from Phase 1, 2 and 3 trials involving over 20,000 participants. In addition, our PREVENT-19 US and Mexico clinical trial has randomized over 16,000 participants toward our enrollment goal of 30,000. NVX-CoV2373 is the first vaccine to demonstrate not only high clinical efficacy against COVID-19 but also significant clinical efficacy against both the rapidly emerging UK and South Africa variants,” said Stanley C. Erck, President and Chief Executive Officer, Novavax. “NVX-CoV2373 has the potential to play an important role in solving this global public health crisis. We look forward to continuing to work with our partners, collaborators, investigators and regulators around the world to make the vaccine available as quickly as possible.”

NVX-CoV2373 contains a full-length, prefusion spike protein made using Novavax’ recombinant nanoparticle technology and the company’s proprietary saponin-based Matrix-M adjuvant. The purified protein is encoded by the genetic sequence of the SARS-CoV-2 spike (S) protein and is produced in insect cells. It can neither cause COVID-19 nor can it replicate, is stable at 2°C to 8°C (refrigerated) and is shipped in a ready-to-use liquid formulation that permits distribution using existing vaccine supply chain channels.

UK Phase 3 Results: 89.3% Efficacy

The study enrolled more than 15,000 participants between 18-84 years of age, including 27% over the age of 65. The primary endpoint of the UK Phase 3 clinical trial is based on the first occurrence of PCR-confirmed symptomatic (mild, moderate or severe) COVID-19 with onset at least 7 days after the second study vaccination in serologically negative (to SARS-CoV-2) adult participants at baseline.

The first interim analysis is based on 62 cases, of which 56 cases of COVID-19 were observed in the placebo group versus 6 cases observed in the NVX-CoV2373 group, resulting in a point estimate of vaccine efficacy of 89.3% (95% CI: 75.2 – 95.4). Of the 62 cases, 61 were mild or moderate, and 1 was severe (in placebo group).

Preliminary analysis indicates that the UK variant strain that was increasingly prevalent was detected in over 50% of the PCR-confirmed symptomatic cases (32 UK variant, 24 non-variant, 6 unknown). Based on PCR performed on strains from 56 of the 62 cases, efficacy by strain was calculated to be 95.6% against the original COVID-19 strain and 85.6% against the UK variant strain [post hoc].

The interim analysis included a preliminary review of the safety database, which showed that severe, serious, and medically attended adverse events occurred at low levels and were balanced between vaccine and placebo groups.

“These are spectacular results, and we are very pleased to have helped Novavax with the development of this vaccine. The efficacy shown against the emerging variants is also extremely encouraging. This is an incredible achievement that will ensure we can protect individuals in the UK and the rest of the world from this virus,” said Clive Dix, Chair, UK Vaccine Taskforce.

Novavax expects to share further details of the UK trial results as additional data become available. Additional analysis on both trials is ongoing and will be shared via prepublication servers as well as submitted to a peer-reviewed journal for publication. The company initiated a rolling submission to the United Kingdom’s regulatory agency, the MHRA, in mid-January.

South Africa Results:   Approximately 90% of COVID-19 cases attributed to South Africa escape variant

In the South Africa Phase 2b clinical trial, 60% efficacy (95% CI: 19.9 – 80.1) for the prevention of mild, moderate and severe COVID-19 disease was observed in the 94% of the study population that was HIV-negative. Twenty-nine cases were observed in the placebo group and 15 in the vaccine group. One severe case occurred in the placebo group and all other cases were mild or moderate. The clinical trial also achieved its primary efficacy endpoint in the overall trial population, including HIV-positive and HIV-negative subjects (efficacy of 49.4%; 95% CI: 6.1 – 72.8).

This study enrolled over 4,400 patients beginning in August 2020, with COVID-19 cases counted from September through mid-January. During this time, the triple mutant variant, which contains three critical mutations in the receptor binding domain (RBD) and multiple mutations outside the RBD, was widely circulating in South Africa. Preliminary sequencing data is available for 27 of 44 COVID-19 events; of these, 92.6% (25 out of 27 cases) were the South Africa escape variant.

Importantly in this trial, approximately 1/3 of the patients enrolled (but not included in the primary analyses described above) were seropositive, demonstrating prior COVID-19 infection at baseline. Based on temporal epidemiology data in the region, the pre-trial infections are thought to have been caused by the original COVID-19 strain (i.e., non-variant), while the subsequent infections during the study were largely variant virus. These data suggest that prior infection with COVID-19 may not completely protect against subsequent infection by the South Africa escape variant, however, vaccination with NVX-CoV2373 provided significant protection.

“The 60% reduced risk against COVID-19 illness in vaccinated individuals in South Africans underscores the value of this vaccine to prevent illness from the highly worrisome variant currently circulating in South Africa, and which is spreading globally. This is the first COVID-19 vaccine for which we now have objective evidence that it protects against the variant dominating in South Africa,” says Professor Shabir Maddi, Executive Director of the Vaccines and Infectious Diseases Analytics Research Unit (VIDA) at Wits, and principal investigator in the Novavax COVID-19 vaccine trial in South Africa. “I am encouraged to see that Novavax plans to immediately begin clinical development on a vaccine specifically targeted to the variant, which together with the current vaccine is likely to form the cornerstone of the fight against COVID-19.”

Novavax initiated development of new constructs against the emerging strains in early January and expects to select ideal candidates for a booster and/or combination bivalent vaccine for the new strains in the coming days. The company plans to initiate clinical testing of these new vaccines in the second quarter of this year.

“A primary benefit of our adjuvanted platform is that it uses a very small amount of antigen, enabling the rapid creation and large-scale production of combination vaccine candidates that could potentially address multiple circulating strains of COVID-19,” said Gregory M. Glenn, M.D., President of Research and Development, Novavax. “Combined with the safety profile that has been observed in our studies to-date with our COVID-19 vaccine, as well as prior studies in influenza, we are optimistic about our ability to rapidly adapt to evolving conditions.”

The Coalition for Epidemic Preparedness Innovations (CEPI) funded the manufacturing of doses of NVX-CoV2373 for this Phase 2b clinical trial, which was supported in part by a $15 million grant from the Bill & Melinda Gates Foundation.

Significant progress on PREVENT-19 Clinical Trial in US and Mexico

To date, PREVENT-19 has randomized over 16,000 participants and expects to complete our targeted enrollment of 30,000 patients in the first half of February.  PREVENT-19 is being conducted with support from the U.S. government partnership formerly known as Operation Warp Speed, which includes the Department of Defense, the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services (HHS) Office of the Assistant Secretary for Preparedness and Response, and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH) at HHS. BARDA is also providing up to $1.75 billion under a Department of Defense agreement.

PREVENT-19 (the PRE-fusion protein subunit Vaccine Efficacy Novavax Trial | COVID-19) is a Phase 3, randomized, placebo-controlled, observer-blinded study in the US and Mexico to evaluate the efficacy, safety and immunogenicity of NVX-CoV2373 with Matrix-M in up to 30,000 subjects 18 years of age and older compared with placebo. The trial design has been harmonized to align with other Phase 3 trials conducted under the auspices of Operation Warp Speed, including the use of a single external independent Data and Safety Monitoring Board to evaluate safety and conduct an unblinded review when predetermined interim analysis events are reached.

The trial’s primary endpoint is the prevention of PCR-confirmed, symptomatic COVID-19. The key secondary endpoint is the prevention of PCR-confirmed, symptomatic moderate or severe COVID-19. Both endpoints will be assessed at least seven days after the second study vaccination in volunteers who have not been previously infected with SARS-CoV-2.

Conference Call

Novavax will host a conference call today at 4:30pm ET. The dial-in numbers for the conference call are (877) 212-6076 (Domestic) or (707) 287-9331 (International), passcode 7470222. A replay of the conference call will be available starting at 7:30 p.m. ET on January 28, 2021 until 7:30 p.m. ET on February 4, 2021. To access the replay by telephone, dial (855) 859-2056 (Domestic) or (404) 537-3406 (International) and use passcode 7470222.

A webcast of the conference call can also be accessed on the Novavax website at novavax.com/events. A replay of the webcast will be available on the Novavax website until April 28, 2021.

About NVX-CoV2373

NVX-CoV2373 is a protein-based vaccine candidate engineered from the genetic sequence of SARS-CoV-2, the virus that causes COVID-19 disease. NVX-CoV2373 was created using Novavax’ recombinant nanoparticle technology to generate antigen derived from the coronavirus spike (S) protein and is adjuvanted with Novavax’ patented saponin-based Matrix-M to enhance the immune response and stimulate high levels of neutralizing antibodies. NVX-CoV2373 contains purified protein antigen and can neither replicate, nor can it cause COVID-19. Over 37,000 participants have participated to date across four different clinical studies in five countries. NVX-CoV2373 is currently being evaluated in two pivotal Phase 3 trials: a trial in the U.K that completed enrollment in November and the PREVENT-19 trial in the U.S. and Mexico that began in December.

About Matrix-M

Novavax’ patented saponin-based Matrix-M adjuvant has demonstrated a potent and well-tolerated effect by stimulating the entry of antigen presenting cells into the injection site and enhancing antigen presentation in local lymph nodes, boosting immune response.

About Novavax

Novavax, Inc. (Nasdaq: NVAX) is a biotechnology company that promotes improved health globally through the discovery, development and commercialization of innovative vaccines to prevent serious infectious diseases. The company’s proprietary recombinant technology platform combines the power and speed of genetic engineering to efficiently produce highly immunogenic nanoparticles designed to address urgent global health needs. Novavax is conducting late-stage clinical trials for NVX-CoV2373, its vaccine candidate against SARS-CoV-2, the virus that causes COVID-19. NanoFlu, its quadrivalent influenza nanoparticle vaccine, met all primary objectives in its pivotal Phase 3 clinical trial in older adults and will be advanced for regulatory submission. Both vaccine candidates incorporate Novavax’ proprietary saponin-based Matrix-M adjuvant to enhance the immune response and stimulate high levels of neutralizing antibodies.

For more information, visit www.novavax.com and connect with us on Twitter and LinkedIn.

Candidate: NVX-CoV2373

Category: VAX

Type: Stable, prefusion protein made using Novavax’ proprietary nanoparticle technology, and incorporating its proprietary saponin-based Matrix-M adjuvant.

2021 Status: Novavax on March 11 announced final efficacy of 96.4% against mild, moderate and severe disease caused by the original COVID-19 strain in a pivotal Phase III trial in the U.K. of NVX–CoV2373. The study enrolled more than 15,000 participants between 18-84 years of age, including 27% over the age of 65.

The company also announced the complete analysis of its Phase IIb trial in South Africa, showing the vaccine had an efficacy of 55.4% among a cohort of HIV-negative trial participants, and an overall efficacy of 48.6% against predominantly variant strains of SARS-CoV-2 among 147 PCR-positive cases (51 cases in the vaccine group and 96 in the placebo group). Across both trials, NVX-CoV2373 demonstrated 100% protection against severe disease, including all hospitalization and death.

Philippines officials said March 10 that they secured 30 million doses of NVX-CoV2373 through an agreement with the Serum Institute of India, the second vaccine deal signed by the national government, according to Agence France-Presse. The first was with AstraZeneca for 2.6 million doses of its vaccine, developed with Oxford University.

The Novavax vaccine will be available from the third quarter, at a price that has yet to be finalized. The government hopes to secure 148 million doses this year from seven companies—enough for around 70% of its population.

In announcing fourth quarter and full-year 2020 results on March 1, Novavax said it could file for an emergency use authorization with the FDA in the second quarter of 2021. Novavax hopes it can use data from its Phase III U.K. clinical trial in its FDA submission, and expects the FDA to examine data in May, a month after they are reviewed by regulators in the U.K., President and CEO Stanley C. Erck said on CNBC. Should the FDA insist on waiting for U.S. data, the agency may push the review timeline by one or two months, he added.

The company also said that NVX-CoV2373 showed 95.6% efficacy against the original strain of COVID-19 and 85.6% against the UK variant strain, and re-stated an earlier finding that its vaccine met the Phase III trial’s primary endpoint met with an efficacy rate of 89.3%.

Novavax said February 26 that it signed an exclusive license agreement with Takeda Pharmaceutical for Takeda to develop, manufacture, and commercialize NVX-CoV2373 in Japan.

Novavax agreed to transfer the technology for manufacturing of the vaccine antigen and will supply its Matrix-M adjuvant to Takeda. Takeda anticipated the capacity to manufacture over 250 million doses of the COVID-19 vaccine per year. Takeda agreed in return to pay Novavax undisclosed payments tied to achieving development and commercial milestones, plus a portion of proceeds from the vaccine.

Takeda also disclosed that it dosed the first participants in a Phase II clinical trial to test the immunogenicity and safety of Novavax’ vaccine candidate in Japanese participants.

Novavax on February 18 announced a memorandum of understanding with Gavi, the Vaccine Alliance (Gavi), to provide 1.1 billion cumulative doses of NVX-CoV2373 for the COVAX Facility. Gavi leads the design and implementation of the COVAX Facility, created to supply vaccines globally, and has committed to working with Novavax to finalize an advance purchase agreement for vaccine supply and global distribution allocation via the COVAX Facility and its partners.

The doses will be manufactured and distributed globally by Novavax and Serum Institute of India (SII), the latter under an existing agreement between Gavi and SII.

Novavax and SK Bioscience said February 15 that they expanded their collaboration and license agreement, with SK finalizing an agreement to supply 40 million doses of NVX-CoV2373 to the government of South Korea beginning in 2021, for an undisclosed price. SK also obtained a license to manufacture and commercialize NVX-CoV2373 for sale to South Korea, as a result of which SK said it will add significant production capacity.

The agreement also calls on Novavax to facilitate technology transfer related to the manufacturing of its protein antigen, its Matrix M adjuvant, and support to SK Bioscience as needed to secure regulatory approval.

Rolling review begins—On February 4, Novavax announced it had begun a rolling review process for authorization of NVX-CoV2373 with several regulatory agencies worldwide, including the FDA, the European Medicines Agency, the U.K. Medicines and Healthcare products Regulatory Agency (MHRA), and Health Canada. The reviews will continue while the company completes its pivotal Phase III trials in the U.S. and U.K., and through initial authorization for emergency use granted under country-specific regulations, and through initial authorization for emergency use.

A day earlier, Novavax executed a binding Heads of Terms agreement with the government of Switzerland to supply 6 million doses of NVX-CoV2373, to the country. Novavax and Switzerland plan to negotiate a final agreement, with initial delivery of vaccine doses slated to ship following successful clinical development and regulatory review.

On January 28, Novavax electrified investors by announcing that its COVID-19 vaccine NVX-CoV2373 showed efficacy of 89.3% in the company’s first analysis of data from a Phase III trial in the U.K., where a variant strain (B.1.1.7) accounted for about half of all positive cases.

However, NVX-CoV2373 achieved only 60% efficacy in a Phase IIb trial in South Africa, where that country’s escape variant of the virus (B.1.351, also known as 20H/501Y.V2) was seen in 90% of cases, Novavax said.

Novavax said January 7 it executed an Advance Purchase Agreement with the Commonwealth of Australia for 51 million doses of NVX-CoV2373 for an undisclosed price, with an option to purchase an additional 10 million doses—finalizing an agreement in principle announced in November 2020. Novavax said it will work with Australia’s Therapeutics Goods Administration (TGA), to obtain approvals upon showing efficacy in clinical studies. The company aims to deliver initial doses by mid-2021.

2020 Status: Phase III trial launched—Novavax said December 28 that it launched the pivotal Phase III PREVENT-19 trial (NCT04611802) in the U.S. and Mexico to evaluate the efficacy, safety and immunogenicity of NVX-CoV2373. The randomized, placebo-controlled, observer-blinded study will assess the efficacy, safety and immunogenicity of NVX-CoV2373 in up to 30,000 participants 18 years of age and older compared with placebo. The trial’s primary endpoint is the prevention of PCR-confirmed, symptomatic COVID-19. The key secondary endpoint is the prevention of PCR-confirmed, symptomatic moderate or severe COVID-19. Both endpoints will be assessed at least seven days after the second study vaccination in volunteers who have not been previously infected with SARS-CoV-2.

Two thirds of the participants will be assigned to randomly receive two intramuscular injections of the vaccine, administered 21 days apart, while one third of the trial participants will receive placebo. Trial sites were selected in locations where transmission rates are currently high, to accelerate the accumulation of positive cases that could show efficacy. Participants will be followed for 24 months following the second injection

PREVENT-19 is being conducted with support from federal agencies involved in Operation Warp Speed, the Trump administration’s effort to promote development and distribution of COVID-19 vaccines and drugs. Those agencies include the Department of Defense (DoD), the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), and the Biomedical Advanced Research and Development Authority (BARDA)—which has committed up to $1.6 billion to Novavax under a DoD agreement (identifier MCDC OTA agreement number W15QKN-16-9-1002).

Novavax is also conducting a pivotal Phase III study in the United Kingdom, a Phase IIb safety and efficacy study in South Africa, and an ongoing Phase I/II trial in the U.S. and Australia. Data from these trials are expected as soon as early first quarter 2021, though timing will depend on transmission rates in the regions, the company said.

Novavax said November 9 that the FDA granted its Fast Track designation for NVX-CoV2373. By the end of November, the company expected to finish enrollment in its Phase III U.K. trial, with interim data in that study expected as soon as early first quarter 2021.

Five days earlier, Novavax signed a non-binding Heads of Terms document with the Australian government to supply 40 million doses of NVX-CoV2373 to Australia starting as early as the first half of 2021, subject to the successful completion of Phase III clinical development and approval of the vaccine by Australia’s Therapeutic Goods Administration (TGA). The vaccine regimen is expected to require two doses per individual, administered 21 days apart.

Australia joins the U.S., the U.K., and Canada in signing direct supply agreements with Novavax. The company is supplying doses in Japan, South Korea, and India through partnerships. Australian clinical researchers led the global Phase I clinical trial in August, which involved 131 Australians across two trial sites (Melbourne and Brisbane). Also, approximately 690 Australians have participated in the Phase II arm of the clinical trial, which has been conducted across up to 40 sites in Australia and the U.S.

Novavax joined officials in its headquarters city of Gaithersburg, MD, on November 2 to announce expansion plans. The company plans to take 122,000 square feet of space at 700 Quince Orchard Road, and has committed to adding at least 400 local jobs, nearly doubling its current workforce of 450 worldwide. Most of the new jobs are expected to be added b March 2021.

Maryland’s Department of Commerce—which has prioritized assistance to life sciences companies—approved a $2 million conditional loan tied to job creation and capital investment. The state has also approved a $200,000 Partnership for Workforce Quality training grant, and the company is eligible for several tax credits, including the Job Creation Tax Credit and More Jobs for Marylanders.

Additionally, Montgomery County has approved a $500,000 grant tied to job creation and capital investment, while the City of Gaithersburg said it will approve a grant of up to $50,000 from its Economic Development Opportunity Fund. The city accelerated its planning approval process to accommodate Novavax’ timeline, given the company’s role in fighting COVID-19 and resulting assistance from Operation Warp Speed, the Trump administration’s effort to accelerate development of COVID-19 vaccines.

On October 27, Novavax said that it had enrolled 5,500 volunteers in the Phase III U.K. trial, which has been expanded from 10,000 to 15,000 volunteers. The increased enrollment “is likely to facilitate assessment of safety and efficacy in a shorter time period,” according to the company.

The trial, which is being conducted with the U.K. Government’s Vaccines Taskforce, was launched in September and is expected to be fully enrolled by the end of November, with interim data expected by early first quarter 2021, depending on the overall COVID-19 attack rate. Novavax has posted the protocol for the Phase III U.K. trial online. The protocol calls for unblinding of data once 152 participants have achieved mild, moderate or severe endpoints. Two interim analyses are planned upon occurrence of 66 and 110 endpoints.

Novavax also said it expects to launch a second Phase III trial designed to enroll up to 30,000 participants in the U.S. and Mexico by the end of November—a study funded through the U.S. government’s Operation Warp Speed program. The patient population will reflect proportional representation of diverse populations most vulnerable to COVID-19, across race/ethnicity, age, and co-morbidities.

The company cited progress toward large-scale manufacturing while acknowledging delays from original timeframe estimates. Novavax said it will use its contract manufacturing site at FUJIFILM Diosynth Biotechnologies’ Morrisville, NC facility to produce material for the U.S. trial.

On September 25, Novavax entered into a non-exclusive agreement with Endo International subsidiary Par Sterile Products to provide fill-finish manufacturing services at its plant in Rochester, MI, for NVX-CoV2373. Under the agreement, whose value was not disclosed, the Rochester facility has begun production of NVX-CoV2373 final drug product, with initial batches to be used in Novavax’ Phase III clinical trial in the U.S. Par Sterile will also fill-finish NVX-CoV2373 vaccine intended for commercial distribution in the U.S.

A day earlier, Novavax launched the U.K. trial. The randomized, placebo-controlled, observer-blinded study to evaluate the efficacy, safety and immunogenicity of NVX-CoV2373 with Matrix-M in up to 10,000 subjects 18-84 years of age, with and without “relevant” comorbidities, over the following four to six weeks, Novavax said. Half the participants will receive two intramuscular injections of vaccine comprising 5 µg of protein antigen with 50 µg Matrix‑M adjuvant, 21 days apart, while half of the trial participants will receive placebo. At least 25% of the study population will be over age 65.

The trial’s first primary endpoint is first occurrence of PCR-confirmed symptomatic COVID-19 with onset at least seven days after the second study vaccination in volunteers who have not been previously infected with SARS-CoV-2. The second primary endpoint is first occurrence of PCR-confirmed symptomatic moderate or severe COVID-19 with onset at least seven days after the second study vaccination in volunteers who have not been previously infected with SARS-CoV-2

“The data from this trial is expected to support regulatory submissions for licensure in the UK, EU and other countries,” stated Gregory M. Glenn, M.D., President, Research and Development at Novavax.

Maryland Gov. Larry Hogan joined state Secretary of Commerce Kelly M. Schulz and local officials in marking the launch of Phase III studies with a tour of the company’s facilities in Gaithersburg: “The coronavirus vaccine candidate that’s been developed by Novavax is one of the most promising in the country, if not the world.”

On August 31, Novavax reached an agreement in principle with the government of Canada to supply up to 76 million doses of NVX-CoV2373. The value was not disclosed. Novavax and Canada did say that they expect to finalize an advance purchase agreement under which Novavax will agree to supply doses of NVX-CoV2373 to Canada beginning as early as the second quarter of 2021.

The purchase arrangement will be subject to licensure of the NVX-CoV2373 by Health Canada, Novavax said. The vaccine is in multiple Phase II clinical trials: On August 24, Novavax said the first volunteers had been enrolled in the Phase II portion of its ongoing Phase I/II clinical trial (NCT04368988), designed to evaluate the immunogenicity and safety of two doses of of NVX-CoV2373 (5 and 25 µg) with and without 50 µg of Matrix‑M adjuvant in up to 1,500 volunteers ages 18-84.

The randomized, placebo-controlled, observer-blinded study is designed to assess two dose sizes (5 and 25 µg) of NVX-CoV2373, each with 50 µg of Matrix‑M. Unlike the Phase I portion, the Phase II portion will include older adults 60-84 years of age as approximately half of the trial’s population. Secondary objectives include preliminary evaluation of efficacy. The trial will be conducted at up to 40 sites in the U.S. and Australia, Novovax said.

NVX-CoV2373 is in a pair of Phase II trials launched in August—including a Phase IIb study in South Africa to assess efficacy, and a Phase II safety and immunogenicity study in the U.S. and Australia.

On August 14, the U.K. government agreed to purchase 60 million doses of NVX-CoV2373 from the company, and support its planned Phase III clinical trial in the U.K., through an agreement whose value was not disclosed. The doses are set to be manufactured as early as the first quarter of 2021.

The trial will be designed to evaluate the ability of NVX-CoV2373 to protect against symptomatic COVID-19 disease as well as evaluate antibody and T-cell responses. The randomized, double-blind, placebo-controlled efficacy study will enroll approximately 9,000 adults 18-85 years of age in the U.K., and is expected to start in the third quarter.

Novavax also said it will expand its collaboration with FUJIFILM Diosynth Biotechnologies (FDB), which will manufacture the antigen component of NVX-CoV2373 from its Billingham, Stockton-on-Tees site in the U.K., as well as at U.S. sites in Morrisville, NC, and College Station, TX. FDB’s U.K. sitevis expected to produce up to 180 million doses annually.

On August 13, Novavax said it signed a development and supply agreement for the antigen component of NVX-CoV2373 with Seoul-based SK bioscience, a vaccine business subsidiary of SK Group. The agreement calls for supply to global markets that include the COVAX Facility, co-led by Gavi, the Coalition for Epidemic Preparedness Innovations (CEPI) and the World Health Organization.

Novavax and SK signed a letter of intent with South Korea’s Ministry of Health and Welfare to work toward broad and equitable access to NVX-CoV2373 worldwide, as well as to make the vaccine available in South Korea. SK bioscience agreed to manufacture the vaccine antigen component for use in the final drug product globally during the pandemic, at its vaccine facility in Andong L-house, South Korea, beginning in August. The value of the agreement was not disclosed.

On August 7, Novavax licensed its COVID-19 vaccine technology to Takeda Pharmaceutical through a partnership by which Takeda will develop, manufacture, and commercialize NVX‑CoV2373 in Japan, using Matrix-M adjuvant to be supplied by Novavax. Takeda will also be responsible for regulatory submission to Japan’s Ministry of Health, Labour and Welfare (MHLW).

MHLW agreed to provide funding to Takeda—the amount was not disclosed in the companies’ announcement—for technology transfer, establishment of infrastructure, and scale-up of manufacturing. Takeda said it anticipated the capacity to manufacture over 250 million doses of NVX‑CoV2373 per year.

Five days earlier, Serum Institute of India agreed to license rights from Novavax to NVX‑CoV2373 for development and commercialization in India as well as low- and middle-income countries (LMIC), through an agreement whose value was not disclosed. Novavax retains rights to NVX-CoV2373 elsewhere in the world.

Novavax and Serum Institute of India agreed to partner on clinical development, co-formulation, filling and finishing and commercialization of NVX-CoV2373. Serum Institute will oversee regulatory submissions and marketing authorizations in regions covered by the collaboration. Novavax agreed to provide both vaccine antigen and Matrix‑M adjuvant, while the partners said they were in talks to have the Serum Institute manufacture vaccine antigen in India. Novavax and Seerum Institute plan to split the revenue from the sale of product, net of agreed costs.

A day earlier, Novavax announced positive results from the Phase I portion of its Phase I/II clinical trial (NCT04368988), designed to evaluate two doses of NVX-CoV2373 (5 and 25 µg) with and without Matrix‑M adjuvant in 131 healthy adults ages 18-59. NVX-CoV2373, adjuvanted with Matrix-M, elicited robust antibody responses numerically superior to human convalescent sera, according to data submitted for peer-review to a scientific journal.

All participants developed anti-spike IgG antibodies after a single dose of vaccine, Novavax said, many also developing wild-type virus neutralizing antibody responses. After the second dose, all participants developed wild-type virus neutralizing antibody responses. Both anti-spike IgG and viral neutralization responses compared favorably to responses from patients with clinically significant COVID‑19 disease, the company said—adding that IgG antibody response was highly correlated with neutralization titers, showing that a significant proportion of antibodies were functional.

For both dosages of NVX‑CoV2373 with adjuvant, the 5 µg dose performed “comparably” with the 25 µg dose, Novavax said. NVX‑CoV2373 also induced antigen-specific polyfunctional CD4⁺ T cell responses with a strong bias toward the Th1 phenotype (IFN-g, IL-2, and TNF-a).

Based on an interim analysis of Phase I safety and immunogenicity data, the trial was expanded to Phase II clinical trials in multiple countries, including the U.S. The trial—which began in Australia in May—is being funded by up-to $388 million in funding from the Coalition for Epidemic Preparedness Innovations (CEPI). If the Phase I/II trial is successful, CEPI said, it anticipates supporting further clinical development that would advance NVX-CoV2373 through to licensure.

On July 23, Novavax joined FDB to announce that FDB will manufacture bulk drug substance for NVX-CoV2373, under an agreement whose value was not disclosed. FDB’s site in Morrisville, NC has begun production of the first batch of NVX-CoV2373. Batches produced at FDB’s Morrisville site will be used in Novavax’s planned pivotal Phase III clinical trial, designed to assess NVX-CoV2373 in up to 30,000 participants, and set to start this fall.

The Phase III trial is among R&D efforts to be funded through the $1.6 billion awarded in July to Novavax through President Donald Trump’s “Operation Warp Speed” program toward late-stage clinical trials and large-scale manufacturing to produce 100 million doses of its COVID-19 vaccine by year’s end. Novavax said the funding will enable it to complete late-stage clinical studies aimed at evaluating the safety and efficacy of NVX-CoV2373.

In June, Novavax said biotech investor and executive David Mott was joining its board as an independent director, after recently acquiring nearly 65,000 shares of the company’s common stock. Also, Novavax was awarded a $60 million contract by the U.S. Department of Defense (DoD) for the manufacturing of NVX‑CoV2373. Through the Defense Health Program, the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense Enabling Biotechnologies (JPEO-CBRND-EB) agreed to support production of several vaccine components to be manufactured in the U.S.  Novavax plans to deliver this year for DoD 10 million doses of NVX‑CoV2373 that could be used in Phase II/III trials, or under an Emergency Use Authorization (EUA) if approved by the FDA.

Also in June, AGC Biologics said it will partner with Novavax on large-scale GMP production of Matrix-M– significantly increasing Novavax’ capacity to deliver doses in 2020 and 2021—through an agreement whose value was not disclosed. And Novavax joined The PolyPeptide Group to announce large-scale GMP production by the global CDMO of two unspecified key intermediate components used in the production of Matrix-M.

In May, Novavax acquired Praha Vaccines from the India-based Cyrus Poonawalla Group for $167 million cash, in a deal designed to ramp up Novavax’s manufacturing capacity for NVX-CoV2373. Praha Vaccines’ assets include a 150,000-square foot vaccine and biologics manufacturing facility and other support buildings in Bohumil, Czech Republic. Novavax said the Bohumil facility is expected to deliver an annual capacity of over 1 billion doses of antigen starting in 2021 for the COVID-19 vaccine.

The Bohumil facility is completing renovations that include the addition of Biosafety Level-3 (BSL-3) capabilities. The site’s approximately 150 employees with “significant experience” in vaccine manufacturing and support have joined Novavax, the company said.

On May 11, Novavax joined CEPI in announcing up to $384 million in additional funding for the company toward clinical development and large-scale manufacturing of NVX-CoV2373. CEPI agreed to fund preclinical as well as Phase I and Phase II studies of NVX-CoV2373. The funding multiplied CEPI’s initial $4 million investment in the vaccine candidate, made two months earlier. Novavax’s total $388 million in CEPI funding accounted for 87% of the total $446 million awarded by the Coalition toward COVID-19 vaccine R&D as of that date.

Novavax identified its COVID-19 vaccine candidate in April. The company said NVX-CoV2373 was shown to be highly immunogenic in animal models measuring spike protein-specific antibodies, antibodies that block the binding of the spike protein to the receptor, and wild-type virus neutralizing antibodies. High levels of spike protein-specific antibodies with ACE-2 human receptor binding domain blocking activity and SARS-CoV-2 wild-type virus neutralizing antibodies were also seen after a single immunization.

In March, Emergent Biosolutions disclosed it retained an option to allocate manufacturing capacity for an expanded COVID-19 program under an agreement with Novavax to provide “molecule-to-market” contract development and manufacturing (CDMO) services to produce Novavax’s NanoFlu, its recombinant quadrivalent seasonal influenza vaccine candidate.

Earlier in March, Emergent announced similar services to support clinical development of Novavax’s COVID-19 vaccine candidate, saying March 10 it agreed to produce the vaccine candidate and had initiated work, anticipating the vaccine candidate will be used in a Phase I study within the next four months. In February, Novavax said it had produced and was assessing multiple nanoparticle vaccine candidates in animal models prior to identifying an optimal candidate for human testing.

References

1. ^ “Company Overview of Novavax, Inc”. Bloomberg.com. Archived from the original on 24 February 2017. Retrieved 2 June2019.
2. ^ https://www.globenewswire.com/news-release/2021/03/01/2184674/0/en/Novavax-Reports-Fourth-Quarter-and-Full-Year-2020-Financial-Results-and-Operational-Highlights.html
3. ^ Jump up to:^{a b c d e} Bell, Jacob (November 14, 2016). “Novavax aims to rebound with restructuring, more trials”. BioPharma Dive. Washington, D.C.: Industry Dive. Archived from the original on 2017-03-29. Retrieved 2017-03-28.
4. ^ Thomas, Katie; Twohey, Megan (2020-07-16). “How a Struggling Company Won $1.6 Billion to Make a Coronavirus Vaccine”. The New York Times. ISSN 0362-4331. Retrieved 2021-01-29.
5. ^ Taylor, Nick Paul (3 June 2013). “Novavax makes $30M bid for adjuvant business”. FiercePharma. Archived from the original on 14 September 2016. Retrieved 9 September 2016.
6. ^ “Gaithersburg Biotech Receives Grant Worth up to $89 million”. Bizjournals.com. Archived from the original on 2017-04-01. Retrieved 2017-03-28.
7. ^ “With promising RSV data in hand, Novavax wins $89M Gates grant for PhIII | FierceBiotech”. Fiercebiotech.com. Archivedfrom the original on 2017-04-14. Retrieved 2017-03-28.
8. ^ “Novavax RSV vaccine found safe for pregnant women, fetus”. Reuters. 2016-09-29. Archived from the original on 2016-10-07. Retrieved 2017-03-28.
9. ^ Herper, Matthew. “Gates Foundation Backs New Shot To Prevent Babies From Dying Of Pneumonia”. Forbes. Archived from the original on 2016-09-21. Retrieved 2017-03-28.
10. ^ “Novavax’s Ebola vaccine shows promise in early-stage trial”. Reuters. 2017-07-21. Archived from the original on 2016-10-02. Retrieved 2017-03-28.
11. ^ Jump up to:^{a b c d e f} Adams, Ben (September 16, 2016). “Novavax craters after Phase III RSV F vaccine failure; seeks path forward”. FierceBiotech. Questex. Archived from the original on 18 August 2020. Retrieved 25 Jan 2020.
12. ^ Shtrubel, Marty (December 12, 2019). “3 Biotech Stocks That Offer the Highest Upside on Wall Street”. Biotech. Nasdaq. Archived from the original on 2020-01-26. Retrieved 25 Jan 2020.
13. ^ Jump up to:^a b Budwell, George (January 20, 2020). “3 Top Biotech Picks for 2020”. Markets. Nasdaq. Novavax: A catalyst awaits. Archivedfrom the original on 2020-01-25. Retrieved 25 Jan 2020.
14. ^ Mark Terry (February 16, 2018). “Why Novavax Could be a Millionaire-Maker Stock”. BioSpace. Archived from the original on 22 November 2020. Retrieved 6 March 2020.
15. ^ Jump up to:^a b Eric Sagonowsky (2020-05-11). “Novavax scores $384M deal, CEPI’s largest ever, to fund coronavirus vaccine work”. FiercePharma. Archived from the original on 2020-05-16. Retrieved 2020-05-12.
16. ^ “Novavax addresses urgent global public health needs with innovative technology”. novavax.com. Archived from the original on 10 September 2020. Retrieved 30 August 2020.
17. ^ Sara Gilgore (January 15, 2020). “Novavax earns key FDA status for its flu vaccine. Wall Street took it well”. Washington Business Journal. Archived from the original on 10 November 2020. Retrieved 6 March 2020.
18. ^ Sara Gilgore (February 26, 2020). “Novavax is working to advance a potential coronavirus vaccine. So are competitors”. Washington Business Journal. Archived from the original on March 16, 2020. Retrieved March 6, 2020.
19. ^ Nidhi Parekh (July 24, 2020). “Novavax: A SARS-CoV-2 Protein Factory to Beat COVID-19”. Archived from the original on November 22, 2020. Retrieved July 24, 2020.
20. ^ “Covid-19: Novavax vaccine shows 89% efficacy in UK trials”. BBC news. Retrieved 1 February 2021.

Further reading

• “Novavax, Inc. Common Stock (NVAX) News Headlines”. Market Activity. Nasdaq. Retrieved 25 Jan 2020. Continuously updated listing of Nasdaq publications related to Novavax, newest items first.

External links

• Official website
• Business data for Novavax, Inc.:
  • SEC filings
  
   

General References

1. Novavax Pipeline Page [Link]
2. Novavex News Release [Link]

Type	Public
Traded as	Nasdaq: NVAX Russell 2000 Component
Industry	Biotechnology
Founded	1987; 34 years ago [1]
Headquarters	Gaithersburg, Maryland,United States
Area served	Worldwide
Key people	Stanley Erck (CEO)
Products	Vaccines
Revenue	$475.2 Million (2020)[2]
Number of employees	500+[3]
Website	www.novavax.com

The Novavax COVID-19 vaccine, codenamed NVX-CoV2373, and also called SARS-CoV-2 rS (recombinant spike) protein nanoparticle with Matrix-M1 adjuvant, is a COVID-19 vaccine candidate developed by Novavax and Coalition for Epidemic Preparedness Innovations (CEPI). It requires two doses^[1] and is stable at 2 to 8 °C (36 to 46 °F) (refrigerated).^[2]

Description

NVX-CoV2373 has been described as both a protein subunit vaccine^[3][4][5] and a virus-like particle vaccine,^[6][7] though the producers call it a “recombinant nanoparticle vaccine”.^[8]

The vaccine is produced by creating an engineered baculovirus containing a gene for a modified SARS-CoV-2 spike protein. The baculovirus then infects a culture of Sf9 moth cells, which create the spike protein and display it on their cell membranes. The spike proteins are then harvested and assembled onto a synthetic lipid nanoparticle about 50 nanometers across, each displaying up to 14 spike proteins.^[3][4][8]

The formulation includes a saponin-based adjuvant.^[3][4][8]

Development

In January 2020, Novavax announced development of a vaccine candidate, codenamed NVX-CoV2373, to establish immunity to SARS-CoV-2.^[9] Novavax’s work is in competition for vaccine development among dozens of other companies.^[10]

In March 2020, Novavax announced a collaboration with Emergent BioSolutions for preclinical and early-stage human research on the vaccine candidate.^[11] Under the partnership, Emergent BioSolutions will manufacture the vaccine at large scale at their Baltimore facility.^[12] Trials have also taken place in the United Kingdom, and subject to regulatory approval, at least 60 million doses will be manufactured by Fujifilm Diosynth Biotechnologies in Billingham for purchase by the UK government.^[13][14] They also signed an agreement with Serum Institute of India for mass scale production for developing and low-income countries.^[15] It has also been reported, that the vaccine will be manufactured in Spain.^[16] The first human safety studies of the candidate, codenamed NVX-CoV2373, started in May 2020 in Australia.^[17][18]

In July, the company announced it might receive $1.6 billion from Operation Warp Speed to expedite development of its coronavirus vaccine candidate by 2021—if clinical trials show the vaccine to be effective.^[19][20] A spokesperson for Novavax stated that the $1.6 billion was coming from a “collaboration” between the Department of Health and Human Services and Department of Defense,^[19][20] where Gen. Gustave F. Perna has been selected as COO for Warp Speed. In late September, Novavax entered the final stages of testing its coronavirus vaccine in the UK. Another large trial was announced to start by October in the US.^[21]

In December 2020, Novavax started the PREVENT-19 (NCT04611802) Phase III trial in the US and Mexico.^{[22][full citation needed][23]}

On 28 January 2021, Novavax reported that preliminary results from the United Kingdom trial showed that its vaccine candidate was more than 89% effective.^[24][2] However, interim results from a trial in South Africa showed a lower effectiveness rate against the 501.V2 variant of the virus, at around 50-60%.^[1][25]

On 12 March 2021, they announced their vaccine candidate was 96.4% effective in preventing the original strain of COVID-19 and 86% effective against the U.K variant. It proved 55% effective against the South African variant in people without HIV/AIDS. It was also 100% effective at preventing severe illness.^{[citation needed]}

Deployment

On 2 February 2021, the Canadian Prime Minister Justin Trudeau announced that Canada has signed a tentative agreement for Novavax to produce millions of doses of its COVID-19 vaccine in Montreal, Canada, once it’s approved for use by Health Canada, making it the first COVID-19 vaccine to be produced domestically.^[26]

References

1. ^ Jump up to:^a b Wadman M, Jon C (28 January 2021). “Novavax vaccine delivers 89% efficacy against COVID-19 in UK—but is less potent in South Africa”. Science. doi:10.1126/science.abg8101.
2. ^ Jump up to:^a b “New Covid vaccine shows 89% efficacy in UK trials”. BBC News. 28 January 2021. Retrieved 28 January 2021.
3. ^ Jump up to:^a b c Wadman M (November 2020). “The long shot”. Science. 370 (6517): 649–653. Bibcode:2020Sci…370..649W. doi:10.1126/science.370.6517.649. PMID 33154120.
4. ^ Jump up to:^a b c Wadman M (28 December 2020). “Novavax launches pivotal U.S. trial of dark horse COVID-19 vaccine after manufacturing delays”. Science. doi:10.1126/science.abg3441.
5. ^ Parekh N (24 July 2020). “Novavax: A SARS-CoV-2 Protein Factory to Beat COVID-19”. Archived from the original on 22 November 2020. Retrieved 24 July 2020.
6. ^ Chung YH, Beiss V, Fiering SN, Steinmetz NF (October 2020). “COVID-19 Vaccine Frontrunners and Their Nanotechnology Design”. ACS Nano. 14 (10): 12522–12537. doi:10.1021/acsnano.0c07197. PMC 7553041. PMID 33034449.
7. ^ Medhi R, Srinoi P, Ngo N, Tran HV, Lee TR (25 September 2020). “Nanoparticle-Based Strategies to Combat COVID-19”. ACS Applied Nano Materials. 3 (9): 8557–8580. doi:10.1021/acsanm.0c01978. PMC 7482545.
8. ^ Jump up to:^a b c “Urgent global health needs addressed by Novavax”. Novavax. Retrieved 30 January 2021.
9. ^ Gilgore S (26 February 2020). “Novavax is working to advance a potential coronavirus vaccine. So are competitors”. Washington Business Journal. Archived from the original on 16 March 2020. Retrieved 6 March 2020.
10. ^ “COVID-19 vaccine tracker (click on ‘Vaccines’ tab)”. Milken Institute. 11 May 2020. Archived from the original on 6 June 2020. Retrieved 12 May 2020. Lay summary.
11. ^ Gilgore S (10 March 2020). “Novavax’s coronavirus vaccine program is getting some help from Emergent BioSolutions”. Washington Business Journal. Archived from the original on 9 April 2020. Retrieved 10 March 2020.
12. ^ McCartney R. “Maryland plays an outsized role in worldwide hunt for a coronavirus vaccine”. Washington Post. Archived from the original on 7 May 2020. Retrieved 8 May 2020.
13. ^ Boseley S, Davis N (28 January 2021). “Novavax Covid vaccine shown to be nearly 90% effective in UK trial”. The Guardian. Retrieved 29 January 2021.
14. ^ Brown M (14 August 2020). “60m doses of new covid-19 vaccine could be made in Billingham – and be ready for mid-2021”. TeesideLive. Reach. Retrieved 29 January 2021.
15. ^ “Novavax signs COVID-19 vaccine supply deal with India’s Serum Institute”. Reuters. 5 August 2020.
16. ^ “Spain, again chosen to produce the vaccine to combat COVID-19”. This is the Real Spain. 18 September 2020.
17. ^ Sagonowsky E (11 May 2020). “Novavax scores $384M deal, CEPI’s largest ever, to fund coronavirus vaccine work”. FiercePharma. Archived from the original on 16 May 2020. Retrieved 12 May 2020.
18. ^ “Novavax starts clinical trial of its coronavirus vaccine candidate”. CNBC. 25 May 2020. Archived from the original on 26 May 2020. Retrieved 26 May 2020.
19. ^ Jump up to:^a b Thomas K (7 July 2020). “U.S. Will Pay $1.6 Billion to Novavax for Coronavirus Vaccine”. The New York Times. Archived from the original on 7 July 2020. Retrieved 7 July 2020.
20. ^ Jump up to:^a b Steenhuysen J (7 July 2020). “U.S. government awards Novavax $1.6 billion for coronavirus vaccine”. Reuters. Archived from the original on 14 September 2020. Retrieved 15 September 2020.
21. ^ Thomas K, Zimmer C (24 September 2020). “Novavax Enters Final Stage of Coronavirus Vaccine Trials”. The New York Times. ISSN 0362-4331. Archived from the original on 28 September 2020. Retrieved 28 September 2020.
22. ^ Clinical trial number NCT04611802 for “A Study Looking at the Efficacy, Immune Response, and Safety of a COVID-19 Vaccine in Adults at Risk for SARS-CoV-2” at ClinicalTrials.gov
23. ^ “Phase 3 trial of Novavax investigational COVID-19 vaccine opens”. National Institutes of Health (NIH). 28 December 2020. Retrieved 28 December 2020.
24. ^ Lovelace B (28 January 2020). “Novavax says Covid vaccine is more than 89% effective”. CNBC.
25. ^ Facher L, Joseph A (28 January 2021). “Novavax says its Covid-19 vaccine is 90% effective in late-stage trial”. Stat. Retrieved 29 January 2021.
26. ^ “Canada signs deal to produce Novavax COVID-19 vaccine at Montreal plant”. CP24. 2 February 2021. Retrieved 2 February2021.

////////////// Novavax,  COVID-19,  vaccine, CORONA VIRUS, NVX-CoV2373, SARS-CoV-2 rS,  TAK 019

#Novavax,  #COVID-19,  #vaccine, #CORONA VIRUS, #NVX-CoV2373, #SARS-CoV-2 rS,  #TAK 019

Johnson & Johnson COVID-19 vaccine, JNJ 78436735

• Ad26.COV2.S
• JNJ-78436735
• Ad26COVS1
• VAC31518
•  UNII: JT2NS6183B

NAME	DOSAGE	STRENGTH	ROUTE	LABELLER	MARKETING START	MARKETING END
Covid-19 Vaccine Janssen	Injection, suspension	0.95 Inf. U	Intramuscular	Janssen Cilag International Nv	2021-03-17	Not applicable
Janssen COVID-19 Vaccine	Injection, suspension	50000000000 {VP}/0.5mL	Intramuscular	Janssen Products, LP	2021-01-04	Not applicable

NAME	INGREDIENTS	DOSAGE	ROUTE	LABELLER	MARKETING START	MARKETING END
Janssen COVID-19 Vaccine	Ad26.COV2.S (50000000000 {VP}/0.5mL)	Injection, suspension	Intramuscular	Janssen Products, LP	2021-01-04	Not applicable

The Johnson & Johnson COVID-19 vaccine is a human adenovirus viral vector COVID-19 vaccine^[12] developed by Janssen Vaccines in Leiden in The Netherlands,^[13] and its Belgian parent company Janssen Pharmaceuticals,^[14] subsidiary of American company Johnson & Johnson (J&J).^[15][16]

The vaccine is based on a human adenovirus that has been modified to contain the gene for making the spike protein of the SARS-CoV-2 virus that causes COVID-19.^[3] The vaccine requires only one dose and does not need to be stored frozen.^[17]

The vaccine started clinical trials in June 2020, with Phase III trials involving around 43,000 people.^[18] On 29 January 2021, Janssen announced that the vaccine was 66% effective in a one-dose regimen in preventing symptomatic COVID-19, with an 85% efficacy in preventing severe COVID-19.^[19][20][21] The most common side effects were pain at the injection site, headache, fatigue, muscle aches and nausea.^[22] Most of these side effects were mild to moderate in severity and lasted one or two days.

The vaccine has been granted an Emergency Use Authorization by the US Food and Drug Administration^[23] and a conditional marketing authorisation by the European Medicines Agency.^[11][24][25]

Ad26.COV2.S is a lead recombinant vaccine candidate that contains an adenovirus serotype 26 (Ad26) vector expressing a stabilized SARS-CoV-2 spike protein. The vaccine was created in collaboration with Johnson and Johnson (J&J), Janssen Pharmaceutical, and the Beth Israel Deaconess Medical Center. This vaccine lead candidate uses Janssen’s AdVac® and PER.C6® technologies. A preclinical study in hamsters infected with SARS-COV-2 infection¹ showed a single immunization with the vaccine elicited neutralizing responses and protected against SARS-CoV-2 induced pneumonia and mortality, providing protection against the disease progression. Follow up preclinical studies in rhesus monkeys² showed that the Ad26 vaccine produced a robust response and provided near perfect protection in nasal swabs and bronchoalveolar lavage following SARS-COV-2 challenge. As of June 2020, a Phase 1/2 clinical trial in adult humans was announced to evaluate the safety, immunogenicity, and efficacy of the ad26.COV.S vaccine in 1045 healthy adults between the ages of 18-55 (NCT04436276).

Description

The Johnson & Johnson COVID-19 vaccine consists of a replication-incompetent recombinant adenovirus type 26 (Ad26) vector expressing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein in a stabilized conformation.^[26][4] The stabilized version of the spike protein – that includes two mutations in which the regular amino acids are replaced with prolines – was developed by researchers at the National Institute of Allergy and Infectious Diseases‘ Vaccine Research Center and the University of Texas at Austin.^[27][28][29] The vaccine also contains the following inactive ingredients: citric acid monohydrate, trisodium citrate dihydrate, ethanol (alcohol), 2-hydroxypropyl-β-cyclodextrin (HBCD) (hydroxypropyl betadex), polysorbate 80, sodium chloride, sodium hydroxide, and hydrochloric acid.^[26][1]

Characteristics

The Johnson & Johnson COVID-19 vaccine can remain viable for months in a standard refrigerator.^[30][31][32] Unlike the Pfizer–BioNTech COVID-19 vaccine and the Moderna COVID-19 vaccine, the Johnson & Johnson COVID-19 vaccine is administered as a single dose instead of two separate doses and it is not shipped frozen.^[33][17]

The storage and handling information in the Fact Sheet supersedes the storage and handling information on the carton and vial labels.^[17] The vaccine should not be stored frozen.^[17] Unpunctured vials may be stored between 9 to 25 °C (48 to 77 °F) for up to twelve hours.^[26][17]

Development

During the COVID-19 pandemic, Johnson & Johnson committed over US$1 billion toward the development of a not-for-profit COVID-19 vaccine in partnership with the Biomedical Advanced Research and Development Authority (BARDA) Office of the Assistant Secretary for Preparedness and Response (ASPR) at the U.S. Department of Health and Human Services (HHS).^[34][35] Johnson & Johnson stated that its vaccine project would be “at a not-for-profit level” as the company viewed it as “the fastest and the best way to find all the collaborations in the world to make this happen”.^[36]

Inside of an Emergent BioSolutions facility where, in collaboration with Johnson & Johnson, vaccines are produced.

Janssen Vaccines, in partnership with Beth Israel Deaconess Medical Center (BIDMC), is responsible for developing the vaccine candidate, based on the same technology used to make its Ebola vaccine.^[16][37][38]

Clinical trials

Phase I-II

In June 2020, Johnson & Johnson and the National Institute of Allergy and Infectious Diseases (NIAID) confirmed its intention to start a clinical trials of the Ad26.COV2.S vaccine in September 2020, with the possibility of Phase I/IIa human clinical trials starting at an accelerated pace in the second half of July.^[39][40][41]

A Phase I/IIa clinical trial started with the recruitment of the first subject on 15 July 2020, and enrolled study participants in Belgium and the US.^[42] Interim results from the Phase I/IIa trial established the safety, reactogenicity, and immunogenicity of Ad26.COV2.S.^[43][44]

Phase III

A Phase III clinical trial called ENSEMBLE started enrollment in September 2020, and completed enrollment on 17 December 2020. It was designed as a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the safety and efficacy of a single-dose vaccine versus placebo in adults aged 18 years and older. Study participants received a single intramuscular injection of Ad26.COV2.S at a dose level of 5×10¹⁰ virus particles on day one.^[45] The trial was paused on 12 October 2020, because a volunteer became ill,^[46] but the company said it found no evidence that the vaccine had caused the illness and announced on 23 October 2020, that it would resume the trial.^[47][48] On 29 January 2021, Janssen announced safety and efficacy data from an interim analysis of ENSEMBLE trial data, which demonstrated the vaccine was 66% effective at preventing the combined endpoints of moderate and severe COVID-19 at 28 days post-vaccination among all volunteers. The interim analysis was based on 468 cases of symptomatic COVID-19 among 43,783 adult volunteers in Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, and the United States. No deaths related to COVID-19 were reported in the vaccine group, while five deaths in the placebo group were related to COVID-19.^[49] During the trial, no anaphylaxis was observed in participants.^[49]

A second Phase III clinical trial called ENSEMBLE 2 started enrollment on 12 November 2020. ENSEMBLE 2 differs from ENSEMBLE in that its study participants will receive two intramuscular (IM) injections of Ad26.COV2.S, one on day 1 and the next on day 57.^[50]

Manufacturing

In April 2020, Johnson & Johnson entered a partnership with Catalent who will provide large-scale manufacturing of the Johnson & Johnson vaccine at Catalent’s Bloomington, Indiana facility.^[51] In July 2020, the partnership was expanded to include Catalent’s Anagni, Italy facility.^[52]

In July 2020, Johnson & Johnson pledged to deliver up to 300 million doses of its vaccine to the U.S., with 100 million upfront and an option for 200 million more. The deal, worth more than $1 billion, will be funded by the Biomedical Advanced Research and Development Authority (BARDA) and the U.S. Defense Department.^[53][54] The deal was confirmed on 5 August.^[55]

In September 2020, Grand River Aseptic Manufacturing agreed with Johnson & Johnson to support the manufacture of the vaccine, including technology transfer and fill and finish manufacture, at its Grand Rapids, Michigan facility.^[56]

In December 2020, Johnson & Johnson and Reig Jofre, a Spanish pharmaceutical company, entered into an agreement to manufacture the vaccine at Reig Jofre’s Barcelona facility.^[57] If the European Medicines Agency (EMA) grants approval to the vaccine by March 2021, a European Union regulator said that Johnson & Johnson could start supplying vaccines to EU states starting on April 2021.^[58][59]

In August 2020, Johnson & Johnson signed a contract with the U.S. federal government for US$1 billion, agreeing to deliver 100 million doses of the vaccine to the U.S. following the U.S. Food and Drug Administration (FDA) grant of approval or emergency use authorization (EUA) for the vaccine.^[54] Under its agreement with the U.S. government, Johnson & Johnson was targeted to produce 12 million doses by the end of February 2021, more than 60 million doses by the end of April 2021, and more than 100 million doses by the end of June 2021. However, in January 2021, Johnson & Johnson acknowledged manufacturing delays would likely prevent it from meeting its contract of 12 million doses delivered to the U.S. by the end of February.^[60] In late February 2021 congressional testimony by a company executive, however, Johnson & Johnson indicated that the company could deliver 20 million doses to the U.S. government by the end of March, and 100 million doses in the first half of 2021.^[61]

In February 2021, Sanofi and Johnson & Johnson struck a deal for Sanofi to provide support and infrastructure at Sanofi’s Marcy-l’Étoile, France facility to manufacture approximately 12 million doses of the Johnson & Johnson vaccine per month once authorized.^[62]

In March 2021, Merck & Co and Johnson & Johnson struck a deal for Merck to manufacture the Johnson & Johnson vaccine at two facilities in the United States to help expand the manufacturing capacity of the vaccine using provisions of the Defense Production Act.^[63]

Regulatory approval process

Europe

Beginning on 1 December 2020, clinical trial of the vaccine candidate has been undergoing a “rolling review” process by the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA), a step to expedite EMA consideration of an expected conditional Marketing Authorisation Application.^[58][78] On 16 February 2021, Janssen applied to the EMA for conditional marketing authorization of the vaccine.^[3][79] The Committee for Medicinal Products for Human Use (CHMP) approved the COVID-19 Vaccine Janssen on 11 March.^[11][25] Shipments of the vaccine are scheduled to start in the second half of April, with a commitment to deliver at least 200 million doses to the EU in 2021.^[80]

United States

On 4 February 2021, Janssen Biotech applied to the U.S. Food and Drug Administration (FDA) for an EUA, and the FDA announced that its Vaccines and Related Biological Products Advisory Committee (VRBPAC) would meet on 26 February to consider the application.^{[30][33][81][82]} Johnson & Johnson announced that it planned to ship the vaccine immediately following authorization.^[49] On 24 February, ahead of the VRBPAC meeting, briefing documents from Janssen and the FDA were issued; the FDA document recommends granting the EUA, concluding that the results of the clinical trials and safety data are consistent with FDA EUA guidance for COVID-19 vaccines.^{[83][84][26][85]} At the 26 February meeting, VRBPAC voted unanimously (22–0) to recommend that a EUA for the vaccine be issued.^[86] The FDA granted the EUA for the vaccine the following day.^[9][10][87] On 28 February, the CDC Advisory Committee on Immunization Practices (ACIP) recommended the use of the vaccine for those aged 18 and older.^[88][23]

Elsewhere

On 11 February 2021, Saint Vincent and the Grenadines issued an EUA for the Johnson & Johnson vaccine, as well as the Moderna vaccine, the Pfizer–BioNTech vaccine, the Sputnik V vaccine, and the Oxford–AstraZeneca vaccine.^[89]

In December 2020, Johnson & Johnson entered into an agreement in principle with Gavi, the Vaccine Alliance to support the COVAX Facility. On 19 February 2021, Johnson & Johnson submitted its formal request and data package to the World Health Organization for an Emergency Use Listing (EUL); an EUL is a requirement for participation in COVAX. Johnson & Johnson anticipates providing up to 500 million doses through 2022 for COVAX.^[90][31][91]

On 25 February 2021, Bahrain authorized the vaccine for emergency use.^[92][93]

On 26 February 2021, the South Korean Ministry of Food and Drug Safety began a review of Johnson & Johnson’s application for approval of its vaccine.^[94]

In late November 2020, Johnson & Johnson submitted a rolling review application to Health Canada for approval of its vaccine.^[95] The Canadian government has placed an order with Johnson & Johnson for 10 million doses, with an option to purchase up to 28 million additional doses; on 5 March, the vaccine became the fourth to receive Health Canada approval.^[96]

In February 2021, the vaccine received emergency authorization in South Africa.^[97][98][99]

Deployment and impact

Given the Johnson & Johnson vaccine is a single dose and has a lower cost, it is expected that it will play an important role in low and middle-income countries.^[100] With lower costs and lower requirements of storage and distribution in comparison to the COVID-19 vaccines by Pfizer and Moderna, the Johnson & Johnson vaccine will be more easily transported, stored, and administered.^[101] South African health minister Zweli Mkhize announced on 9 February 2021 that the country would sell or swap its one million doses of AstraZeneca vaccine.^[102] Once it did so, South Africa began vaccination using the Johnson & Johnson vaccine on 17 February 2021,^[99] marking the vaccine’s first use outside of a clinical trial.^[103]

Ethical concerns

The United States Conference of Catholic Bishops has expressed ethical concerns about the vaccine due to the use of tissue from aborted fetuses in the 1980s.^[104]

See also

• Adenoviruses as vaccine vectors

Notes

1. ^ US authorization also includes the three sovereign nations in the Compact of Free Association: Palau, the Marshall Islands, and Micronesia.^[75][76]

References

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External links

Scholia has a profile for Ad26.COV2.S (Q98655215).

• “How the Johnson & Johnson Covid-19 Vaccine Works”. The New York Times.
• “Janssen COVID-19 Vaccine (Johnson & Johnson)”. Centers for Disease Control and Prevention (CDC).

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SARS-CoV-2

• Gam-COVID-Vac Lyo

Gam-COVID-Vac was created by Gamaleya Research Institute of Epidemiology and MIcrobiology in Russia. The vaccine candidate is a heterologous COVID-19 vaccine containing two components, recombinant adenovirus type 26 (rAd26) vector and recombinant adenovirus type 5 (rAd5) vector which both carry the SARS-CoV-2 spike glycoprotein. The vaccine is offered in both a frozen (Gam-COVID-Vac) and freeze-dried formulation (lyophilizate; Gam-COVID-Vac Lyo). Phase 1/2 human trials with 76 participants evaluated the safety, tolerability, and immunogenicity of both frozen (Gam-COVID-Vac;NCT04436471) and freeze-dried (Gam-COVID-Vac Lyo;NCT04437875) vaccine candidates in June 2020, and were completed in early August 2020. Preliminary results suggested that all participants developed antibodies to the SARS-CoV-2 glycoproteins with a good safety profile in both trials.

Sputnik V (Russian: Спутник V, literally Traveler V) is a COVID-19 vaccine developed by the Gamaleya Research Institute of Epidemiology and Microbiology. Registered on 11 August 2020 by the Russian Ministry of Health as Gam-COVID-Vac (Russian: Гам-КОВИД-Вак, romanized: Gam-KOVID-Vak),^[2][3] Sputnik V is an adenovirus viral vector vaccine. The “V” in the name is the letter V, not the Roman numeral for five.^[4]

Gam-COVID-Vac was initially approved for distribution in Russia on the preliminary results of Phase I–II studies eventually published on 4 September 2020.^[5] The quick approval in early August of Gam-COVID-Vac was met with criticism in mass media and precipitated discussions in the scientific community whether this decision was justified in the absence of robust scientific research confirming the safety and efficacy of the vaccine.^{[2][3][6][7][8]} On 2 February 2021, an interim analysis from the trial was published in The Lancet, indicating 91.6% efficacy without unusual side effects.^[9]

Emergency mass-distribution of the vaccine began in December 2020 in multiple countries including Russia, Argentina, Belarus, Hungary, Serbia and the United Arab Emirates. As of February 2021, over a billion doses of the vaccine were ordered for immediate distribution globally.^[10]

Technology

 President Putin‘s meeting with government members, on 11 August 2020 via videoconference, at which he announced a conditionally registered vaccine against COVID-19.^[2][3] Medical worker in Moscow with the vaccineSee also: COVID-19 vaccine

Gam-COVID-Vac is a viral two-vector vaccine based on two human adenoviruses – a common cold virus – containing the gene that encodes the full-length spike protein (S) of SARS-CoV-2 to stimulate an immune response.^[5][11][12] The Gam-COVID-Vac vaccine was developed by a cellular microbiologists team of the government-backed Gamaleya Research Institute of Epidemiology and Microbiology. The group was led by MD and RAS associate member Denis Logunov, who also worked on vaccines for the Ebolavirus and the MERS-coronavirus.^[13]

The recombinant adenovirus types 26 and 5 are both used as vectors in the vaccine. They were biotechnology-derived and contain the SARS-CoV-2 S protein cDNA. Both of them are administered into the deltoid muscle: the Ad26-based vaccine is used on the first day and the Ad5 vaccine is used on the 21st day to boost immune response.^[11][14][15]

The vaccine can be formulated as frozen (storage temperature must be −18 °C or 0 °F or lower) and freeze-dried (“Gam-COVID-Vac-Lyo”, storage temperature is 2–8 °C or 36–46 °F) dosage forms.^[16] The first formulation was developed for large-scale use, it is cheaper and easier to manufacture. The production of a lyophilized formulation takes much more time and resources, although it is more convenient for storage and transportation. Gam-COVID-Vac-Lyo was developed especially for vaccine delivery to hard-to-reach regions of Russia.^[17] The head of the Gamaleya Research Institute Alexander Ginzburg estimates that it will take 9–12 months to vaccinate the vast majority of the Russian population, assuming in-country resources are adequate.^[18][19] A single-dose version is also being developed to speed up vaccination outside Russia. It will offer less protection than the two-dose versions, but it is still expected to reach an efficacy of 85%.^[20][21]

Clinical research

Phase I–II

A phase I safety trial began on 18 June.^[2] On 4 September, data on 76 participants in a phase I–II trial were published, indicating preliminary evidence of safety and an immune response.^[5] The results were challenged by international vaccine scientists as being incomplete, suspicious, and unreliable when identical data were reported for many of the trial participants,^[22] but the authors responded that there was a small sample size of nine, and the measured results of titration could only take discrete values (800, 1600, 3200, 6400). Coupled with the observation that values tended to reach a plateau after three to four weeks, they contend that it is not unlikely that several participants would show identical results for days 21 to 28.^[23]

Phase III

 Sputnik V, efficacy for different conditions. The error bars indicate the confidence interval containing the efficacy with 95% probability

In early November 2020, Israel Hadassah Medical Center director-general Prof. Zeev Rotstein stated that Hadassah’s branch in Moscow’s Skolkovo Innovation Center was collaborating on a phase III clinical trial.^[24]

The ongoing phase III study is a randomised, double-blind, placebo-controlled, multi-centre clinical trial involving 40,000 volunteers in Moscow, and is scheduled to run until May 2021.^[25] In 2020–2021, phase III clinical studies were also being conducted in Belarus,^[26] UAE,^[27] India^[28] and Venezuela.^[29]

On 2 February 2021, an interim analysis from the Moscow trial was published in The Lancet, indicating 91.6% efficacy (95% CI 85.6–95.2) after the second vaccination, without unusual side effects.^[30] The trial started on 7 September 2020 using the frozen liquid form of the vaccine, and data was analysed up to the second database lock on 24 November 2020. The over-60-years-old group in the trial (oldest participant was 87) had essentially the same efficacy (91.8%) as for all ages. The lowest age participants were 18 years old.^[9][31]

Sputnik–AstraZeneca COVID-19 vaccine trials

On 21 December 2020 the Russian Direct Investment Fund (RDIF), the Gamaleya National Center, AstraZeneca and R-Pharm have signed an agreement aimed at the development and implementation of a clinical research program to assess the immunogenicity and safety of the combined use of one of the components of the Sputnik V vaccine developed by the Gamaleya Center, and one of the components of the AZD1222 vaccine, developed by AstraZeneca and the University of Oxford.^[32] The study program will last 6 months in several countries, and it is planned to involve 100 volunteers in each study program. On 9 February 2021, the Ministry of Health of the Republic of Azerbaijan allowed clinical studies in the country for the combined use of the Sputnik V vaccine and the vaccine developed by AstraZeneca, stating that the trials would begin before the end of February 2021.^[33][34]

Composition

The Gam-COVID-Vac is a two-vector vaccine.^[1] The active component for both vectors is a modified (recombinant) replication-defective adenovirus of a different serotype (Serotype 26 for the first vaccination and serotype 5 for the second vaccination), which has been modified to include the protein S-expressing gene of SARS-CoV-2.^[1]

The other ingredients (excipients) are the same, both quantitatively and qualitatively, in the two components.^[35]

• Tris(hydroxymethyl)aminomethane
• Sodium chloride
• Sucrose
• Magnesium chloride hexahydrate
• Disodium EDTA dihydrate (buffer)
• Polysorbate 80
• Ethanol 95%
• Water

As per the official datasheet, no further components or ingredients, including other adjuvants, should be included in the vaccine.^[1]

History

In May 2020, the Gamaleya Research Institute of Epidemiology and Microbiology announced that it had developed the vaccine without serious side effects. By August 2020, phases I and II of two clinical trials (involving 38 patients each) were completed. Only one of them used the formulation which later obtained marketing authorization under limited conditions.^[36][37] This vaccine was given the trade name “Sputnik V”, after the world’s first artificial satellite.^[3][7][38]

During preclinical and clinical trials, 38 participants who received one or two doses of the Gam-COVID-Vac vaccine had produced antibodies against SARS-CoV-2’s spike protein, including potent neutralizing antibodies that inactivate viral particles.^[2] On 11 August 2020, the Russian minister of Health Mikhail Murashko announced at a government briefing with the participation of President Vladimir Putin regulatory approval of the vaccine for widespread use. The state registration of the vaccine was carried out “conditionally” with post-marketing measures according to the decree of the Government of the Russian Federation. The registration certificate for the vaccine stated that it could not be used widely in Russia until 1 January 2021, and before that, it may be provided to “a small number of citizens from vulnerable groups”, such as medical staff and the elderly, according to a Ministry of Health spokesperson.^[3] The license under register number No. ЛП-006395 (LP-006395) was issued on 11 August by the Russian Ministry of Health. Although the announcement was made even before the vaccine candidate had been entered into Phase III trials, the practice of marketing authorization “on conditions” also exists in other countries.^[39][40] On 26 August, certificate No. ЛП-006423 (LP-006423) was issued for the lyophilized formulation “Gam-COVID-Vac-Lyo”.^{[2][3][7][41][5]}

The commercial release of the Gam-COVID-Vac was first scheduled for September 2020. In October, Mikhail Murashko said that the Gam-COVID-Vac will be free for all Russian citizens after the launching of mass production.^[42][43] Later on, Russian Ministry of Health registered maximum ex-factory price equal to 1,942 rubles for two components and included them into The National List of Essential medicines.^[44] There were also suggestions to include the vaccine in the National Immunisation Calendar of Russia.^[44]

According to Russian media, the mass production of the Gam-COVID-Vac was launched by 15 August. By that moment, the Russian Federation has already received applications from 20 countries for the supply of 1 billion doses of vaccine. Three facilities were able to produce about a million doses per month at each with a potential doubling of capacity by winter. By the end of 2020, Gamaleya Research Institute’s production, according to an interview with the organization’s spokesperson, was planned to produce 3–5 million doses.^[45][46]

On 9 March 2021, an agreement was signed by the RDIF sovereign wealth fund and Swiss-based pharmaceutical company Adienne to produce the vaccine in Italy. Kirill Dmitriev, RDIF’s head, told Russian state TV his fund had also struck deals with production facilities in Spain, France and Germany for local manufacturing of the vaccine.^[47]

Scientific assessment

Balram Bhargava, director of the Indian Council of Medical Research, said that Russia had managed to fast-track a COVID-19 vaccine candidate through its early phases.^[48]

On 11 August 2020, a World Health Organization (WHO) spokesperson said, “… prequalification of any vaccine includes the rigorous review and assessment of all required safety and efficacy data”.^[8]

• A WHO assistant director said, “You cannot use a vaccine or drugs or medicines without following through all of these stages, having complied with all of these stages”.^[49]
• Francois Balloux, a geneticist at University College London, called the Russian government’s approval of Gam-COVID-Vac a “reckless and foolish decision”.^[2] Professor Paul Offit, the director of the Vaccine Education Center at Children’s Hospital of Philadelphia, characterized the announcement was a “political stunt”, and stated that the untested vaccine could be very harmful.^[8]

Stephen Griffin, Associate Professor in the School of Medicine, University of Leeds, said “that we can be cautiously optimistic that SARS-CoV2 vaccines targeting the spike protein are effective.” Moreover, as the Sputnik antigen is delivered via a different modality, namely using a disabled Adenovirus rather than formulated RNA, this provides flexibility in terms of perhaps one or other method providing better responses in certain age-groups, ethnicities, etc., plus the storage of this vaccine ought to be more straightforward.^{[50][failed verification][51]}

Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene and Tropical Medicine, said “the data [is] compatible with the vaccine being reasonably effective … These results are consistent with what we see with other vaccines, because the really big message for global health scientists is that this disease [COVID-19] is able to be addressed by vaccines.”^[50]

Julian Tang, clinical virologist at the University of Leicester, said: “Despite the earlier misgivings about the way this Russian Sputnik V vaccine was rolled out more widely – ahead of sufficient Phase 3 trial data – this approach has been justified to some extent now.”^[52]

Ian Jones, a professor of virology at the University of Reading, and Polly Roy, professor and Chair of Virology at The London School of Hygiene and Tropical Medicine, commenting on phase III results published in the Lancet in February 2021, said “The development of the Sputnik V vaccine has been criticised for unseemly haste, corner cutting, and an absence of transparency. But the outcome reported here is clear and the scientific principle of vaccination is demonstrated, which means another vaccine can now join the fight to reduce the incidence of COVID-19.”^[53]

Hildegund C. J. Ertl, a vaccine scientist at the Wistar Institute, called the phase-III results published on 2 February 2021 “great”: “Good safety profile, more than 90% efficacy across all age groups, 100% efficacy against severe disease or death, can be stored in the fridge and low cost. What more would we want?”^[54]

According to preliminary review by experts,^[who?] the lyophilized formulation of Gam-COVID-Vac is similar to the smallpox vaccine, circumventing the need for continuous “colder chain” or cold-chain storage – as required for the Pfizer–BioNTech and Moderna vaccines respectively – and allowing transportation to remote locations with reduced risk of vaccine spoilage.^[55][56]

On 6 March 2021, Director of the U.S. National Institute of Allergy and Infectious Diseases (NIAID), Anthony Fauci, said that the data from Sputnik V “looked pretty good” to him.^[57]

Distribution, vaccination and public perception

Early perception

An opinion poll of Canadians conducted by Léger in August 2020 found that a majority (68%) would not take the Russian vaccine if offered a free dose, compared to 14% who said they would take it. When Americans were asked the same question, 59% would not take the Russian vaccine if offered a free dose, compared to 24% who said they would take it.^[58][59]

• At that time, British and American officials stated that the Gam-COVID-Vac vaccine would likely be rejected due to concerns that the normally rigorous process of vaccine clinical testing was not followed.^[60] One public health expert said the quick approval of Gam-COVID-Vac by the Russian government was “cutting corners”, and may harm public confidence if the vaccine proves to be unsafe or ineffective.^[7] “There is a huge risk that confidence in vaccines would be damaged by a vaccine that received approval and was then shown to be harmful”, said immunologist Peter Openshaw.^[7]

As for early September 2020, according to public opinion polls, only half of the Russian population would take the vaccine voluntarily.^[61]

In Russia

 Vaccination of military personnel and civilian specialists of the Northern Fleet with the second component of the drug “Gam-COVID-Vac” (“Sputnik V”).

In the beginning of December 2020, Russian authorities announced the start of a large-scale free of charge vaccination with Gam-COVID-Vac for Russian citizens: the “immunization” program was launched on 5 December 2020 (with 70 Moscow-based medical centers providing vaccinations).^[62]

Doctors and other medical workers, teachers, and social workers were given priority due to their highest risk of exposure to the disease.^[63] The age for those receiving shots was initially capped at 60, later this restriction was lifted.^[64]

Potential recipients were notified via text messaging, which says “You are working at an educational institution and have top-priority for the COVID-19 vaccine, free of charge”. Patients are asked a few general health questions before getting the vaccine. Program’s leaflet is handed to the patient, which warns of possible side effects, suggesting those are most likely to be mild and last a couple of days at most.^[65][66][67] People with certain underlying health conditions, pregnant women, and those who have had a respiratory illness for the past two weeks are barred from vaccination.^[63] Vaccine vial is removed from medical centre’s freezer about 15 minutes before use.

In early December 2020, the Minister of Health, Mikhail Murashko, said that Russia had already vaccinated more than 100,000 high-risk people.^[68] Forty thousand of those are volunteers in Sputnik V’s Phase 3 trials, another 60,000 medics and doctors have also taken the vaccine.^[69] The head of the Russian Direct Investment Fund, Kirill Dmitriev, said in an interview with the BBC that Russian medics expect to give about 2 million people coronavirus vaccinations in December.^[70]

Up to the beginning of December 2020, Generium (which is supervised by Pharmstandard) and Binnopharm (which is supervised by AFK Sistema) companies produced Gam-COVID-Vac on a large scale.

On 10 December, Deputy Prime Minister Tatyana Golikova announced that approximately 6.9 million doses of the Sputnik V vaccine will enter civilian circulation in Russia before the end of February 2021.^[71] Moscow Mayor Sergei Sobyanin announced that the newly-opened Moscow-based “R-Pharm” will become a leading manufacturer of Russia’s Sputnik V coronavirus vaccine. Working at full capacity, the factory will produce up to 10 million doses a month.^[72]

Outside of Russia

 In dark green are the countries that ordered (Russian or licensed domestic production; China also plans to produce Sputnik V on its territory.) or approved Sputnik V vaccine against COVID-19 (w/disputed Crimea). In light green are the countries that have shown interest in obtaining the vaccine.

According to the Russian Direct Investment Fund, they had received orders for more than 1.2 billion doses of the vaccine as of December 2020. Over 50 countries had made requests for doses, with supplies for the global market being produced by partners in India, Brazil, China, South Korea, Hungary, and other countries.^[73][74] In August 2020, according to the Russian authorities, there were at least 20 countries that wanted to obtain the vaccine.^[75]

While free in Russia, the cost per dose would be less than US$10 (or less than US$20 for the two doses needed to vaccinate one person) on international markets, which makes it much more affordable compared to mRNA vaccines from other manufacturers. Kirill Dmitriev, head of the fund, told reporters that over 1 billion doses of the vaccine are expected to be produced in 2021 outside of Russia.^[76][77]

The Israeli Hadassah Medical Center has signed a commercial memorandum of understanding to obtain 1.5–3 million doses.^[78]

• According to The New York Times’ sources,^[79] to secure the release of an Israeli civilian held in Syria, Israel agreed to finance a supply of Russian-made Covid-19 vaccines for Damascus.

Argentina had agreed to buy 25 million doses of Russia’s Covid-19 vaccine.^[80] The vaccine was registered and approved in Argentina in late December 2020.^[81] The Brazilian state of Bahia has also signed an agreement to conduct Phase III clinical trials of the Sputnik V vaccine and plans to buy 50 million doses to market in northeastern Brazil.^[82]

On 21 January 2021, the Argentine president Alberto Fernández became the first Latin American leader to be inoculated against the disease via the then recently approved Sputnik V.^[83][84]

Due to the delay in shipping of doses from Italy and the European Union, San Marino imported doses of the Sputnik V vaccine (not approved by the E.M.A.) and started a mass vaccination on 28 February of its healthcare workers.^[85]

EMA’s human medicines committee (CHMP) has started a rolling review of Sputnik V (Gam-COVID-Vac), a COVID-19 vaccine developed by Russia’s Gamaleya National Centre of Epidemiology and Microbiology. ^[86] Asked about the prospect of Austria taking the same step (as some other European countries chose to do), EMA management board chair Christa Wirthumer-Hoche told Austria’s ORF broadcaster: “It’s somewhat comparable to Russian roulette. I would strongly advise against a national emergency authorisation,” she said, pointing to the fact that there was not yet sufficient safety data about those who had already been given the vaccine. “We could have Sputnik V on the market in future, when we’ve examined the necessary data,” she said, adding that the vaccine needed to match up to European criteria on quality control and efficacy.^[87]

Although vaccination rates in Russia are below those of other developed nations (as of March 2021),^[88] Russia is pursuing deals to supply its vaccine abroad.^[89]

Emergency use authorization

As of December 2020, Belarus and Argentina granted emergency use authorization for the vector-based vaccine.^[145] On 21 January 2021, Hungary became the first European Union country to register the shot for emergency use, as well as the United Arab Emirates in the Gulf region.^{[146][147][148][149][150]}

On 19 January 2021, the Russian authorities applied for the registration of Sputnik V in the European Union, according to the RDIF.^[151] On 10 February, the European Medicines Agency (EMA) said that they had “not received an application for a rolling review or a marketing authorisation for the vaccine”. The developers have only expressed their interest that the vaccine be considered for a rolling review, but EMA’s Human Medicines Committee (CHMP) and the COVID-19 EMA pandemic Task Force (COVID-ETF) need to give their agreement first before developers can submit their application for initiation of the rolling review process.^[152] On 4 March 2021, the Committee for Medicinal Products for Human Use (CHMP) of the EMA started a rolling review of Sputnik V.^[153] The EU applicant is R-Pharm Germany GmbH.^[153]

Emergency use has also been authorized in Algeria, Bolivia, Serbia, the Palestinian territories,^[154] and Mexico.^[155]

On 25 January 2021, Iran approved the vaccine, with Foreign Minister Mohammad Javad Zarif saying the country hopes to begin purchases and start joint production of the shot “in the near future”, after Supreme Leader Ayatollah Ali Khamenei banned the government from importing vaccines from the United States and United Kingdom.^[156][157]

On 1 March 2021, Slovakia bought two million Sputnik V vaccines. Slovakia received the first batch of 200,000 vaccines, and expects to receive another 800,000 doses in March and April. Another 1 million vaccines are set to arrive in May and June.^[158] The Czech Republic is also considering buying Sputnik V.^[159]

On 18 March 2021, German regional leaders including State Premiers and the major of Berlin called for the swift approval of the Russian vaccine by the European Medicines Agency to counteract the acute shortages of effective vaccines in Europe. German medical experts have recommended its approval also, and consider the Sputnik Vaccine “clever” and “highly safe”.^[160]

On 19 March 2021, the Philippine Food and Drug Administration granted emergency use authorization for Sputnik V, the fourth COVID-19 vaccine to be given authorization. The Philippine government is planning to buy 20 million doses of the vaccine.^[161][162]

As of March 23, 2021, 56 countries have granted Sputnik V emergency use authorization.^[163]

Production

As of March 2021, RDIF has licensed production in India, China, South Korea and Brazil. In the EU, RDIF has signed production agreements, subject to European Medicines Agency approval, with companies in Germany, Spain and France, and is in negotiations with a Swiss/Italian company. By the end of March 2021 RDIF anticipates 33 million doses will have been manufactured in Russia, less than 5% of which will have been exported.^[164]

An agreement for the production of over 100 million doses of vaccine in India has been made with Dr. Reddy’s Laboratories, who on 11 January 2021 submitted mid-stage trial data to the Indian regulator and recommended moving onto late-stage trials.^[154] The RDIF announced plans to sell 100 million doses to India, 35 million to Uzbekistan, and 32 million to Mexico, as well as 25 million each to Nepal and Egypt.^[165]

In March 2021, the Italian-Russian Chamber of Commerce announced that Italy would be the first EU country to manufacture the two-dose COVID-19 vaccine under license. From July to the end of 2021, the Italian-Swiss pharmaceutical company Adienne in Caponago will manufacture 10 million doses. The announcement came in a time of acute vaccine shortages in Europe while the Sputnik V vaccine was still under review by the European Medicines Agency. Russian authorities said they would be able to provide a total of 50 million doses to European countries beginning in June 2021.^[166]

The Sputnik V doses to be manufactured in South Korea are not for domestic use. The vaccine is to be exported to Russia, Algeria, Argentina, Hungary, Iran and the United Arab Emirates.^[167]

References

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