Moderna COVID-19 vaccine, mRNA 1273

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]

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