Killian Meara

prevention of coronavirus 2019 (COVID-19)

 in the United States began rolling out to distribution sites around the country over the weekend thanks to the granting of an emergency use authorization (EUA) for Moderna’s mRNA-1273 vaccine. The US Food and Drug Administration granted the EUA last Friday night. It follows close on the heels of the FDA’s 

 of the BNT162b2 vaccine by Pfizer/BioNTech for persons aged 16 years and older last week.

The FDA granted the authorization to Moderna, a biotechnology company based in Massachusetts that specializes in messenger RNA (mRNA) therapeutics and vaccines, based on 

 prior to the Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting last Thursday.

Accompanying the Pfizer product, the novel vaccine is of the first of its kind to gain license for use in the US, making this a groundbreaking achievement in the field of vaccination research and implementation.

The mRNA-1273 is encoded for a prefusion stabilized form of the SARS-CoV-2 Spike S protein, a protein complex that is critical for membrane fusion and host cell infection. The vaccine was created in collaboration between Moderna and investigators from the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases (NIAID).

Moderna’s mRNA-1273 is a new approach to vaccines to protect against infectious diseases. Although the technology of nucleoside-modified messenger RNA platform-hosted vaccines have been studied for decades, none have ever been employed for use in the US prior to COVID-19. The interest in this type of vaccine grew at the very beginning of the pandemic, due to the fact they can be created using readily-available materials and can be easily standardized and scaled, allowing for a faster development process.

Unlike traditional forms, mRNA vaccines do not put weakened or inactivated germs inside the body. Rather, they teach cells to make proteins that will trigger an immune response by injecting ribonucleic acid into cells which gives them instructions. The cells then display the protein on their surface, activating the creation of antibodies as in a natural infection. This in turn stimulates a more potent response by the immune system.

“Think of mRNA as a messenger, it transfers genetic instructions [and] it gets information from DNA,” said William Schaffner, MD, Professor of Preventive Medicine at the Vanderbilt University Medical Center. “[Then] it goes into the cell and goes to the factory that’s in the cells that makes protein. This messenger carries the message for the cells to manufacture a specific protein, which we call the spike protein. That’s the part of the virus which is very important against which the vaccine is working. You can’t get COVID from the vaccine and after it gets that instruction into the cell, it disappears.”

The ongoing randomized, stratified, observer-blind, placebo-controlled study assessing the vaccine has included 30,351 participants who were randomized 1:1 to receive intramuscular injections of either 100 μg mRNA-1273 or placebo. The vaccine was administered in 2 doses given 28 days apart in adults who were 18 years of age or older.

Included in the study were 24,907 (82.1%) participants who were considered to be at occupational risk for acquiring the SARS-CoV-2 infection, of whom 7,613 (25.1%) were healthcare workers.

At the interim analysis provided to FDA in the EUA application, mRNA-1273 was found to have an efficacy of 94.5% (95% CI, 86.5%-97.8%) against confirmed COVID-19 14 days after the second dose in participants without evidence of a prior SARS-CoV-2 infection. In total, 11 cases of severe COVID-19 were observed, but all of them occurred in the placebo group.

Data was submitted as an amendment after the initial EUA request from a final efficacy analysis. However, the FDA has not yet independently verified the data from this dataset. The final scheduled efficacy analysis on the primary endpoint, demonstrated an efficacy of 94.1% (95% CI, 89.3%, 96.8%). A lower efficacy was observed in participants ≥65 years of age compared to that in younger adults 18 to <65 years of age.

Moderna has announced that its short-term goal is to produce approximately 500 million doses of mRNA-1273 per year, with the hopes of scaling up global manufacturing to produce a potential 1 billion doses of the vaccine per year in the future.

The company has reached an agreement with the United States government to continue using its U.S.-based manufacturing infrastructure to supply 200 million doses. The US also retains the option to purchase a further 300 million doses as part of the agreement under Operation Warp Speed.

Although the mRNA vaccines pose some meaningful challenges as it pertains to distribution, unlike Pfizer’sBNT162b2, which needs to be kept at a temperature of -70°C, Moderna has recently announced that mRNA1273 can remain stable at temperatures ranging from 2° to 8°C for up to 30 days. This will allow for easier transportation and a wider availability of storage options, permitting the vaccine to be held in places that would not be able to properly preserve Pfizer’s.

Though the authorization, as was granted to Pfizer, allows for the emergency-based and ongoing review-dependent distribution of the vaccine, Moderna would still seek Biologic License Application (BLA) approval for mRNA-1273, making it a marketed vaccine for preventing COVID-19. Additional manufacturing, efficacy, and safety data that provides a greater assurance of the product would warrant a BLA application.

There are still vital questions that need to be answered when it comes to vaccines for COVID-19, such as their safety when given to a larger number of people and the potential for waning immunity over time. How the vaccines influence viral loads and community transmission risks still need to be investigated, however this can only occur when the therapy has been introduced to more people.

The coming weeks and months may bring more potential vaccines forward, most notably AstraZeneca, who has been on the heels of Pfizer and Moderna but ran into issues with their data 

For now, the rollout of Pfizer’s and Moderna’s vaccines show great hope that in the not-too-far future, society can resume some sense of normalcy.

“We appreciate the confidence that the US government continues to have in mRNA-1273, our COVID-19 vaccine candidate,” Stéphane Bancel, Chief Executive Officer of Moderna said. “We continue to scale up our manufacturing capability in the U.S. and outside of the U.S…we will continue to work with regulatory agencies around the globe to continue the rolling review process. We remain committed to helping address this global pandemic with our vaccine.”

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Unlike traditional forms, Moderna’s mRNA-1273 vaccine does not put weakened or inactivated germs inside the body. Rather, it teaches cells to make proteins that will trigger an immune response by injecting ribonucleic acid into cells which gives them instructions.

Moderna’s COVID-19 Vaccine Approved by FDA

Now it’s Moderna’s turn. All eyes last week were on the US Food and Drug Administration (FDA) as it went through the process of examining the data on the Pfizer-BioNTech vaccine for coronavirus disease 2019 (COVID-19) which led to the vaccine being granted emergency use authorization (EUA). Now, while that vaccine is being divvied out among more than 500 distribution sites around the country, Moderna tomorrow will get its chance to present data about its messenger RNA (mRNA) vaccine vaccine to the FDA’s advisory panel of experts, the Vaccines and Related Biologic Products Advisory Committee (VRBPAC). If the panel likes what it hears, it could grant the EUA quickly.

The messenger RNA (mRNA) vaccine was created in collaboration between Moderna and investigators from the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases (NIAID). The phase 3 trial data will be evaluated in a full-day meeting by a panel of experts, along with input from the public. A vote will then be taken on the therapy’s benefit-risk ratio for its prospective use as a preventive vaccine for confirmed COVID-19.

The meeting comes a week after Pfizer and BioNTech were granted an EUA by the FDA for their BNT162b2 vaccine, which was the first vaccine approved for the coronavirus disease 2019 (COVID-19) in the United States. All signs point to a similar outcome for Moderna.

The phase 3 data submitted to the FDA as part of the EUA application can be found 

The ongoing randomized, stratified, observer-blind, placebo-controlled study has included 30,351 participants who were randomized 1:1 to receive intramuscular injections of either 100 μg of mRNA-1273 or a placebo. The vaccine was administered in 2 doses given 28 days apart in adults who were 18 years of age or older.

The participants were stratified by age and health risk into 3 groups:

18 to <65 years of age and not at risk for progression to severe COVID-19

18 to <65 years of age and at risk for progression to severe COVID-19

The latter 2 groups constituted 41.4% of the study population. The risk for progression to severe was based on underlying comorbidities, including diabetes, chronic lung disease, severe obesity, significant cardiovascular disease, liver disease, or infection with HIV.

Included in the study were 24,907 (82.1%) participants who were considered to be at occupational risk for acquiring the SARS-CoV-2 infection, of whom 7613 (25.1%) were healthcare workers.

Investigators sought a primary endpoint of vaccine efficacy for mRNA-1273 against COVID-19 occurring at least 14 days after the second dose in participants negative for SARS-CoV-2 at baseline.

The second primary efficacy endpoint included preventing severe COVID-19 and death due to the disease. Also included was disease occurring at least 14 days after the first or second dose of the vaccine, regardless of a prior SARS-CoV-2 infection.

At the interim analysis, the mRNA-1273 vaccine was found to have an efficacy of 94.5% (95% CI 86.5-97.8% against confirmed COVID-19 14 days after the second dose in participants without evidence of a prior SARS-CoV-2 infection. In total, 11 cases of severe COVID-19 were observed, but all of them occurred in the placebo group.

Efficacy after just 1 dose of the vaccine was found to be 80.2% (95% CI, 55.2-92.5) in a median follow up time of 28 days. This cannot support a conclusion on single dose efficacy though, due to the fact that the numbers of participants and time of observation are limited.

Data was submitted as an amendment after the initial EUA request from a final efficacy analysis. However, the FDA has not yet independently verified the data from this dataset. The final scheduled efficacy analysis on the primary endpoint, demonstrated an efficacy of 94.1% (95% CI, 89.3-96.8). A lower efficacy was observed in participants ≥65 years of age compared to that in younger adults 18 to <65 years of age.

The primary safety goal in the trial was to describe how safe the vaccine was after both 1 and 2 doses. Participants reported local reactions, systemic events, and antipyretic/pain medication usage from day 1 through day 7 after each dose. Participants who received the vaccine had a higher proportion of adverse events in comparison to the placebo group in the 7 days following its receival. The overall rate of adverse events were lower in the participants who had a positive SARS-CoV-2 baseline.

The rate of solicited local and systemic adverse reactions within 7 days of each dose were assessed through all groups. Across both of the age cohorts, the most frequently recorded local adverse reaction was pain, reported by 83.7% of vaccine recipients after the first dose (2.8%) and 88.4% after the second dose (4.1%). The median durations of pain were reported to be 2 days after dose 1 and 3 days after dose 2.

Participants in the age cohort of 18 to <64 years reported the highest rates of pain after the second dose, with 90.1% reporting any pain and 4.6% reporting Grade 3 pain. In the subgroup analyses of adults ≥65 years of age, the rates of solicited reactions were comparable to those observed in all of the participants.

Regarding unsolicited adverse events, a higher frequency was reported in the vaccine group (21.9%) compared to the placebo group (19.4%) within 28 days. These were primarily attributed to local and systemic reactogenicity. Participants who reported severe unsolicited events after any vaccine dose was 1.4%. These included headache, myalgia, arthralgia, injection site erythema, and injection site pain. Thirteen total deaths were reported in the trial, with 2 in the age cohort of >75 years who both had pre-existing cardiac disease.

The meeting takes place tomorrow morning through the early evening, with a panel of FDA experts hosting an open session to discuss whether the evidence available shows that the benefits of the Moderna COVID-19 Vaccine outweigh its risks for use in individuals 18 years of age and older.

The planned sessions, as per the FDA’s 

Presentation on Emergency Use Authorization

Considerations for placebo-controlled trial design if an unlicensed vaccine becomes available

The FDA’s advisory committee’s votes have historically aligned with eventual marketing decisions. Considering the current rise of the COVID-19 pandemic and fears of a continuing second wave, coupled with the approval of Pfizer’s vaccine last week, an EUA approval is anticipated for mRNA-1273 by the VRBPAC.

Moderna’s phase 3 trial data about its messenger RNA (mRNA) vaccine will be presented tomorrow to the FDA’s advisory panel of experts who could then grant an emergency use authorization.

Killian Meara

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Moderna’s COVID-19 Vaccine Approved by FDA

FDA Experts to Review Moderna’s COVID Vaccine Tomorrow