Monday 28 December 2020

Coronavirus (33) mRNA vaccine candidate for COVID-19: mRNA-1273 (part a)

Coronavirus (33) mRNA vaccine candidate for COVID-19: mRNA 1273 (part a)
2. mRNA-1273 vaccine by Moderna
The mRNA vaccine, mRNA-1273, is also called COVID-19 Vaccine Moderna. The vaccine was issued an emergency use authorization by the US Food and Drug Administration for the prevention of COVID-19 on 18th December, 2020. It was the second vaccine approved to be used against COVID-19 in the US.1 It was also the second mRNA vaccine ever approved to be used in the world. Under the emergency use authorization, individuals 18 years of age or older are allowed to be vaccinated with this mRNA vaccine.

According to the press release from Moderna, approximately 20 million doses will be delivered to the government by the end of December, 2020. The company expects to have between 100 million and 125 million doses available globally in the first quarter of 2021, with 85-100 million of those available in the US.1 Moderna’s European production capacity is achieved with its strategic manufacturing partner Lonza of Switzerland, and ROVI of Spain for fill-finish services.

The mRNA-1273 is a lipid-nanoparticle (LNP) encapsulated mRNA vaccine expressing the SARS-CoV-2 spike glycoprotein with a transmembrane anchor. The mRNA sequence is modified so that the conformation of the expressed glycoprotein remains stable once it is produced.2 The increase in the conformation stability of the expressed glycoprotein triggers production of antibodies with a higher level of specificity. The lipid-nanoparticle capsule of the vaccine composed of four lipids was formulated in a fixed ratio of mRNA and lipid, but the exact ratio is not mentioned.2

The development of the mRNA-1273
It took only 11 months for Moderna, a 10-year biotech startup, to develop the vaccine and finally get the authorization for its use. A major reason for this is the collaboration of the company with various public organizations. The company obtained scientific leadership and clinical trial support from the National Institute of Health (NIH) and the National Institute of Allergy and Infectious Disease (NIAID), and financial support from the Coalition for Epidemic Preparedness Innovations (CEPI) and from the Biomedical Advanced Research and Development Authority (BARDA).1 The collective effort of private-public partnerships in dealing with the global health crisis is nicely illustrated in this case.

As soon as the SARS-CoV-2 genetic sequence was determined in January 2020, the mRNA-1273 with modified mRNA sequence was then designed and developed by Moderna and the Vaccine Research Center at the NIAID, a part of the NIH.3 In February, NIAID helped to conduct Investigational New Drug (IND)-enabling studies to evaluate potential toxicity risks of the mRNA vaccine prior to human studies.3 Results from a non-human primate preclinical viral challenge study evaluating the vaccine were published in late July.4

A Phase 1 study led by NIAID began in mid-March.5 Results from the first and the second interim analysis of the Phase 1 study were separately published in mid-July and September respectively.2,6 Then, on 3rd December, a letter to the editor in The New England Journal of Medicine reported that participants in the Phase 1 study of the Moderna COVID-19 Vaccine still have high levels of neutralizing antibodies 119 days after first vaccination, i.e. 90 days after second vaccination.7

The Phase 2 study of the vaccine in the US started on 29th May, and enrolment completed on 8th July.8,9 This was a placebo-controlled, dose-confirmation study evaluating the safety, reactogenicity* and immunogenicity** of two doses of mRNA-1273 given 28 days apart. Each participant received either a placebo, a 50μg or a 100μg dose at both shots.

The Phase 3 trial of the vaccine, the Coronavirus Efficacy (COVE), was launched in late July 2020. It was a randomized 1:1 placebo-controlled study testing the vaccine at the 100µg dose level in 30,000 participants ages 18 and older in the US. Forty-two percent of total participants in the Phase 3 COVE study were in medically high-risk groups: people aged over 65 and people with chronic diseases such as diabetes, severe obesity and cardiac disease. And although the trial was conducted in America, the study included more than 11,000 participants from diverse communities such as Hispanic or Latin, and Black or African American. The enrolment of Phase 3 COVE Study was completed on 22nd October, 2020.10 According to the primary efficacy analysis report of the Phase 3 study of 196 cases on the 30th November, the vaccine efficacy against COVID-19 was 94.1%; vaccine efficacy against severe COVID-19 was 100%. The results also suggests a broadly consistent safety and efficacy profile across all evaluated subgroups.

All participants in the COVE study will be continued to be monitored for two years (the duration of the study) to assess long-term protection and safety. Safety data continue to accrue, and the study continues to be monitored by an independent Data Safety Monitoring Board (DSMB) appointed by the NIH.1



* Reactogenicity refers to reactions (side effects) that occur soon after vaccination, These include both local reactions (such as injection site pain, tenderness, erythema), and systemic reactions (such as fever, headache, myalgia).
* Immunogenecity refers to the ability of human body to provoke an immune response after vaccination.



References
1. Moderna announces FDA authorization of Moderna COVID-19 Vaccine in US. Moderna press release, Dec. 18, 2020. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-fda-authorization-moderna-covid-19-vaccine-us/
2. L.A. Jackson, E.J. Anderson, N.G. Rouphael, et al. An mRNA vaccine against SARS-CoV-2 — preliminary report. N. Engl. J. Med., 2020; 383:1920-1931. DOI: 10.1056/NEJMoa2022483.
3. Moderna announces funding award from CEPI to accelerate development of messenger RNA (mRNA) vaccine against novel coronavirus. Moderna press release, Jan. 23, 2020. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-funding-award-cepi-accelerate-development
4. K.S. Corbett, B. Flynn, K.E. Foulds, et al. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. N. Engl. J. Med., 2020; 383:1544-1555.
5. Moderna announces first participant dosed in NIH-led phase 1 study of mRNA vaccine (mRNA-1273) against novel coronavirus. Moderna press release, March 16, 2020. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-first-participant-dosed-nih-led-phase-1-study
6. E.J. Anderson, N.G. Rouphael, A.T. Widge, et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N. Engl. J. Med., 2020; 383:2427-2438. DOI: 10.1056/NEJMoa2028436
7. A.T. Widge, N.G. Rouphael, L.A. Jackson, et al. Durability of responses after SARS-CoV-2 mRNA-1273 vaccination. N Engl J Med 2021; 384:80-82. DOI: 10.1056/NEJMc2032195
8. Moderna announces first participants in each age cohort dosed in phase 2 study of mRNA Vaccine (mRNA-1273) against novel coronavirus. Moderna press release, May 29, 2020. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-first-participants-each-age-cohort-dosed-phase
9. Moderna completes enrolment of phase 2 study of its mRNA vaccine against COVID-19 (mRNA-1273). Moderna press release, July 8, 2020. https://investors.modernatx.com/news-releases/news-release-details/moderna-completes-enrollment-phase-2-study-its-mrna-vaccine
10. Moderna completes enrollment of phase 3 COVE study of mRNA vaccine against COVID-19 (mRNA-1273). Moderna press release, October 22, 2020. https://investors.modernatx.com/news-releases/news-release-details/moderna-completes-enrollment-phase-3-cove-study-mrna-vaccine

No comments:

Post a Comment