mRNA-1273

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mRNA-1273
Moderna COVID-19 vaccine (2020).jpg
Vaccine description
Target diseaseCOVID-19
TypemRNA
Clinical data
Other namesModerna COVID-19 Vaccine, CX-024414
License data
Routes of
administration		Intramuscular
ATC code
  • None
Legal status
Legal status
Identifiers
DrugBank
UNII
Part of a series on the
COVID-19 pandemic
SARS-CoV-2 without background.png
SARS-CoV-2 (Wikimedia colors).svg COVID-19 Portal

mRNA-1273, more commonly known as the Moderna COVID-19 vaccine, is a COVID-19 vaccine developed by the National Institute of Allergy and Infectious Diseases (NIAID), the Biomedical Advanced Research and Development Authority (BARDA), and Moderna. It is administered by intramuscular injection. On 18 December 2020, mRNA-1273 was issued an emergency use authorization by the United States Food and Drug Administration (FDA).[3][6][7][8] It was authorized for use in Canada on 23 December 2020.[1][2]

Design[edit]

In January 2020, Moderna announced development of an RNA vaccine, named mRNA-1273, to induce immunity to SARS-CoV-2.[9][10][11] Moderna's technology is a nucleoside-modified messenger RNA (modRNA) compound named mRNA-1273, which induces immunity to SARS-CoV-2 by encoding a prefusion stabilized spike (S) protein naturally present on the surface of SARS-CoV-2 particles. From the announcement, Moderna's shares rose dramatically, and the CEO and other corporate executives began large program sales of their shareholdings.[12]

The drug delivery system of mRNA-1273 uses a PEGylated lipid nanoparticle drug delivery (LNP) system.[13]

Composition[edit]

The vaccine contains the following ingredients [14]

Clinical trials[edit]

Phase I / II[edit]

In March 2020, the Phase I human trial of mRNA-1273 began in partnership with the US National Institute of Allergy and Infectious Diseases.[15] In April, the U.S. Biomedical Advanced Research and Development Authority (BARDA) allocated up to $483 million for Moderna's vaccine development.[16] Plans for a Phase II dosing and efficacy trial to begin in May were approved by the FDA.[17] Moderna signed a partnership with Swiss vaccine manufacturer Lonza Group,[18] to supply 300 million doses per annum.[19]

On 25 May 2020, Moderna began a Phase IIa clinical trial recruiting 600 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.[20] 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.[21]

On 9 July, Moderna announced an in-fill manufacturing deal with Laboratorios Farmacéuticos Rovi, in the event that its vaccine is approved.[22]

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.[23][24] 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.[23]

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.[23][25] "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."[26] The troublesome higher doses were discarded in July from future studies.[26]

Phase III[edit]

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 30,000 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.[27] As of 7 August, over 4,500 volunteers had enrolled.

In September 2020, Moderna published the detailed study plan for the clinical trial.[28] 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.[29] As of October 2020, Moderna had completed the enrollment of 30,000 participants needed for its Phase III trial.[30] The US National Institutes of Health announced on 15 November 2020 that overall trial results were positive.[31]

On 30 December 2020, Moderna published results from the Phase III clinical trial, indicating 94% efficacy in preventing COVID-19 infection.[32][33][34] Side effects included flu-like symptoms, such as pain at the injection site, fatigue, muscle pain, and headache.[33] The clinical trial is ongoing and is set to conclude in late-2022[35]

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".[36]

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.[37]

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.[6]

It remains unknown whether the Moderna vaccine candidate is safe or effective in people under age 18, how long it provides immunity, whether it requires a booster shot,[33] or whether it is effective in people of color.[38] 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).[39][33]

Efficacy[edit]

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 2 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.[40] The data is presented below

Interim analysis a for primary efficacy endpoint, COVID-19 starting 14 days after the 2nd dose, per-protocol set[40]
Primary endpoint: COVID-19 Vaccine group (N=13,934)

cases n (%)

incidence per 1000 person-years

Placebo group (N=13,883)

cases n (%)

incidence per 1000 person-years

Vaccine efficacy %

(confidence interval of 95%)

All participants 5 cases in 13,934 (<0.1%)

1.840

90 cases (0.6%)

33.365

94.5% (86.5-97.8%)
Participants 18-64 years of age 5 cases in 10,407 (<0.1%)

2.504

75 cases in 10,384 (0.7%)

37.788

93.4% (83.7-97.3%)
65 and older 0 cases in 3,527 15 cases in 3,499 (0.4%) 100%
Chronic lung disease 0/661 6/673 100%
Significant cardiac disease 0/686 3/678 100%
Severe obesity (BMI>40) 1/901 11/884 91.2% (32-98.9%)
Diabetes 0/1338 7/1309 100%
Liver disease 0/93 0/90
Obesity (BMI>30) 2/5269 46/5207 95.8% (82.6-99%)

Manufacturing[edit]

Moderna COVID-19 vaccine stored in a refrigerator.

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, and Visp, Switzerland, and is purchasing the necessary lipid excipients from CordenPharma.[41] 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.[41]

Purchase commitments[edit]

On 11 August 2020, the US government signed an agreement to buy 100 million doses of Moderna's anticipated vaccine,[42] which the Financial Times said Moderna planned to price its vaccine between $50–60 per course.[43] On November 2020, Moderna has stated that it will charge governments who purchase its vaccine between $25 and $37 per dose while the EU is seeking a price of under $25 per dose for the 160 million doses it plans to purchase from Moderna.[44][45]

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.[46][47] On 17 December, a tweet by the Belgium Budget State Secretary revealed the EU would pay US$18 per dose, while The New York Times reported that the US would pay US$15 per dose.[48]

Emergency use authorization[edit]

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.[49][50][51][52]

On 18 December 2020, mRNA-1273 was authorized by the United States Food and Drug Administration (FDA) under an EUA.[3][5][6] This is the first product from Moderna that has been authorized by the FDA.[53][7]

On 23 December 2020, mRNA-1273 was authorized by Health Canada.[1][2] Prime Minister Justin Trudeau previously stated that deliveries would begin within 48 hours of approval and that 168,000 doses would be delivered by the end of December.[54]

Society and culture[edit]

Controversies[edit]

Criticisms[edit]

In May 2020, after releasing partial and non-peer reviewed results for only 8 of 45 candidates in a preliminary pre-Phase I stage human trial direct to stock markets, the CEO announced on CNBC an immediate $1.25 billion rights issue to raise funds for the company, at a $30 billion valuation.[55] while Stat said, "Vaccine experts say Moderna didn't produce data critical to assessing COVID-19 vaccine".[56]

On 7 July, disputes between Moderna and government scientists over the company's unwillingness to share data from the clinical trials were revealed.[57]

Pregnant and breastfeeding women were excluded from the initial trials used to obtain Emergency Use Authorization,[58] though trials in those populations are expected to be performed in 2021.[59]

Patent litigation[edit]

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.[13][60] On 4 September 2020, Nature Biotechnology reported that Moderna had lost a key challenge in the ongoing case.[61]

See also[edit]

References[edit]

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External links[edit]

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