COVID-19 Vaccines in Development: Scientific Approaches and Practical Considerations

Although a number of COVID-19 vaccines are currently in development, two messenger ribonucleic acid (mRNA) vaccines (one being co-developed by Pfizer and BioNTech and another from Moderna Inc.) are frontrunners and have been authorized for emergency use in the United States this month. While this emergency authorization allows deployment to high-risk groups, such as health care workers, by the end of the year, most Americans will likely need to wait until late spring or early summer for vaccination. This blog post will review the scientific strategy for development, the efficacy and safety data, the required storage conditions and other practical considerations for these two mRNA vaccines. This post also describes the scientific approaches for other COVID-19 vaccines that are further behind the mRNA vaccines in development; these include viral vector, inactivated, subunit and virus-like particle (VLP) vaccines.

The science behind mRNA vaccines

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of a large family of coronaviruses consisting of spherically-shaped viral particles covered with spike proteins protruding from their surface. These spikes bind onto human cells, allowing the virus to infect them.

Vaccines prepare the immune system to fight infections and prevent illnesses. Certain cells of the immune system produce antibodies that recognize viruses and other pathogens and make them harmless. Although some vaccines are made from a weakened or inactive virus, mRNA vaccines consist of mRNA, a genetic code that instructs cells how to make a harmless version of a target protein or piece of a protein.

With COVID-19 vaccination, mRNA gives instructions for our cells to make a harmless piece of the spike protein. Next, the cell displays the protein piece or immunogen on its surface. The immunogen activates the body’s immune system against the SARS-CoV-2 virus by generating protective antibodies. Ultimately, the immune systems learns how to recognize the SARS-CoV-2 virus upon exposure and prevent subsequent infection. Investigators are testing if the vaccines help the immune system produce effective antibodies against the SARS-CoV-2 virus so that, in case of exposure, the virus does not cause illness.

Efficacy and safety data of mRNA vaccines

BNT162b2. The mRNA-based COVID-19 vaccine candidate from Pfizer Inc. and BioNTech SE, met all of the primary efficacy endpoints in their ongoing Phase 3 study, per the final efficacy analysis. Analysis of the data determined a vaccine efficacy rate of 95% (p<0.0001) in participants without prior SARS-CoV-2 infection (first primary objective) and in participants with and without prior SARS-CoV-2 infection (second primary objective). Case capture started seven days after participants received the second dose and will continue beyond this analysis. The first primary objective analysis is based on 170 cases of COVID-19, of which 162 cases of COVID-19 occurred in the placebo group versus 8 cases in the BNT162b2 group. Efficacy was consistent across age, gender, race and ethnicity. The observed efficacy in adults age 65-plus was more than 94%.

Of the 10 severe cases of COVID-19 observed in the trial, nine occurred in the placebo group and one in the BNT162b2 vaccinated group.

The Phase 3 trial of BNT162b2 enrolled more than 40,000 participants. Approximately 42% of global participants and 30% of U.S. participants have racially and ethnically diverse backgrounds, and 41% of global and 45% of U.S. participants are age 55-plus. The trial will continue to collect efficacy and safety data in participants for an additional two years.

The Data Monitoring Committee for the study has not reported any serious safety concerns related to the vaccine. The vaccine was well tolerated, with most adverse events resolving shortly after vaccination. The only Grade 3 (severe) adverse events occurring at a frequency of 2% or greater after the first or second dose were fatigue at 3.8% and headache at 2.0% following dose 2. Older adults tended to report fewer and milder solicited adverse events following vaccination.

mRNA-1273. The Moderna vaccine being tested has also met the study’s primary endpoint, with a vaccine efficacy of 94.5% in the Phase 3 study, known as the COVE study, being conducted in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). The primary endpoint of the COVE study is based on the analysis of confirmed COVID-19 cases, starting two weeks following the second dose of vaccine. This first interim analysis was based on 95 cases, of which 90 cases of COVID-19 occurred in the placebo group versus five in the mRNA-1273 group, resulting in vaccine efficacy of 94.5% (p <0.0001).

For the secondary endpoint, severe cases of COVID-19 were analyzed and occurred in 11 patients in the first interim analysis. All 11 cases were in the placebo group; none occurred in the mRNA-1273 group.

The COVE study enrolled a total of more than 30,000 participants in the United States, with more than 7,000 age 65-plus. It also includes more than 5,000 participants younger than age 65 but have high-risk chronic diseases (such as diabetes, severe obesity and cardiac disease) that put them at increased risk of severe COVID-19. These high-risk groups represent 42% of the total participants in the study. The study also includes more than 11,000 participants from communities of color, representing 37% of the study population. More than 6,000 participants who identify as Hispanic or LatinX and more than 3,000 participants who identify as Black or African American were included.

A review of the available COVE study safety data by the NIH-appointed Data Safety Monitoring Board did not report any significant safety concerns. The vaccine was generally well tolerated, with the majority of adverse events being mild or moderate in severity. Grade 3 events occurring at a frequency of 2% or greater after the first dose included injection site pain (2.7%), and after the second dose, fatigue (9.7%), myalgia (8.9%), arthralgia (5.2%), headache (4.5%), pain (4.1%) and erythema/redness at the injection site (2.0%). These events were generally short-lived. These data are subject to change per ongoing and final analyses of Phase 3 COVE study data.

Emergency Use Authorization (EUA). Based on these Phase 3 study data, the manufacturers of both mRNA vaccines applied for EAUs from U.S. Food and Drug Administration (FDA). The data will also be included in submissions to other global regulatory agencies for authorized use. The Vaccines and Related Biological Products Advisory Committee of the FDA have met to review the EAU applications for both BNT162b2 and mRNA-1273 earlier this month. Both vaccines have been approved for emergency use in the United States, with the mRNA-1273 approval coming a week after the BNT162b2 EUA. In addition, the Medicines and Healthcare products Regulatory Agency (MHRA), which licenses drugs in the United Kingdom, approved the BNT162b2 vaccine for emergency use there.

Storage requirements and other practical considerations for mRNA vaccines

Storage requirements. The most important challenge for development and distribution of an mRNA vaccine remains its inherent instability because it is more likely to degrade above freezing temperatures. Thus, this class of vaccines requires unprecedented cold conditions for distribution and administration.

The BNT162b2 vaccine requires storage at minus 94 degrees Fahrenheit (minus 70 degrees Celsius) and will degrade in around five days at normal refrigeration temperatures of slightly above freezing.

In contrast, Moderna data show that the mRNA-1273 vaccine can be maintained at most home or medical freezer temperatures for up to six months for shipping and longer-term storage. The mRNA‑1273 vaccine is also expected to remain stable at standard refrigerated conditions, of 36 to 46 degrees Fahrenheit (2 to 8 degrees Celsius), for up to 30 days after thawing, as part of its six-month shelf life.

Vaccine distribution. The CDC has been working with manufacturers and state health departments to help plan distribution. Once vaccines have been approved for use by the FDA, the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) will vote on whether to recommend the vaccine and, if so, who should receive it. ACIP met on December 1 to recommend that COVID-19 vaccination be offered to the following groups in the initial phase (Phase 1a) of the U.S. COVID-19 vaccination program when vaccine supply is limited: 1) health care personnel and 2) long-term care facility residents.

Based on previous meetings of the ACIP, recommendations for early COVID-19 vaccination when supply is limited in the U.S. also include the following groups:

• Essential (non-healthcare) workers
• Individuals with high-risk medical conditions (e.g., chronic kidney disease, diabetes and immunocompromised state from solid organ transplant)
• Adults age 65-plus

In Phase 2, when a large number of vaccine doses are available, the focus will be on ensuring vaccine access for all critical populations not vaccinated in Phase 1, as well as for the general population. Finally, in Phase 3, when a surplus of doses exists, focus will be on ensuring equitable vaccination access across the entire population. However, it is up to individual states to decide whether or not to follow these recommendations.

Vaccine administration. Either of the mRNA vaccines needs to be administered as two intramuscular injections given 3 or 4 weeks apart. In fact, all of the COVID-19 vaccines in Phase 3 trials, except for one, require administration of two or more doses. The one COVID-19 vaccine that only requires one dose is a vector vaccine, which is described in the next section.

Other scientific approaches for COVID-19 vaccines

Ten COVID-19 vaccines of the following three main types that use platforms other than mRNA technology are currently in Phase 3 trials:

• Viral vector, non-replicating or replication incompetent, vaccines. Vector vaccines use another virus to carry the genetic instructions to make the protein immunogen. For SARS-CoV-2, they use adenoviruses (the common cold) to deliver a spike protein to stimulate an immune response. Non-replicating refers to the fact that the virus is self-limiting and does not undergo replication.
• Inactivated vaccines. Inactivated or “classic” vaccines are made from a virus germ that has been killed from heat or chemicals. They work when the body treats the deactivated pathogen as if it were active, producing antibodies without endangering the patient with full infection.
• Subunit vaccines. Subunit vaccines contain a fragment of the target virus to produce a similar immune response to inactivated vaccines. Some vaccines of this type use genetically engineered viruses to infect animals, whose cells then produce the pieces of the spike protein. Other subunit vaccines, called virus-like particles, are made in living plants acting as bioreactors to produce non-infectious versions of viruses.

Of these three types, the COVID-19 vector vaccines are furthest along in development, with one already approved for limited use in China and another for early or emergency use in Russia. Vector vaccines are close behind the mRNA vaccines in the United States; AstraZeneca will likely seek EAU approval from the FDA in January for the ChAdOx1-S vaccine that was co-developed with the University of Oxford, using a chimpanzee adenovirus.

This post, of course, is a snapshot in time of COVID-19 vaccines in development; however, other organizations, such as the World Health Organization (WHO) and the New York Times maintain living documents or vaccine trackers that are updated on a regular basis. Please refer to these resources for status updates of COVID-19 vaccines.