Development of the Covid-19 vaccines has been unprecedented in human history. The genetic sequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was published on January 11, 2020. The rapid emergence of research and collaboration among scientists and biopharmaceutical manufacturers followed. Various methods are being used for vaccine discovery and manufacturing. As of December 27, 2020, The New York Times Coronavirus Vaccine Tracker listed 64 vaccines in human trials, and at least 85 preclinical vaccines were under investigation in animals. Some methods have been used in the development of previous vaccines, whereas others are newly developed. For example, mRNA vaccines (like the Pfizer and Moderna vaccines currently available) for influenza, rabies, and Zika virus have been previously tested in animals.
On December 28, 2020, the National Institutes of Health announced the fifth phase 3 trial for COVID-19 vaccines (NVX-CoV2373) in the United States has begun enrolling adult volunteers.
According to recommendations of the Centers for Disease Control and Prevention's (CDC's) Advisory Committee on Immunization Practices, the first 2 groups to get the vaccines will be healthcare workers (1a) and residents of long-term care facilities (1b). Phase 1c would include adults with high-risk medical conditions and those aged 65 years or older.
In addition to the complexity of finding the most effective vaccine candidates, the production process is also important for manufacturing the vaccine to the scale needed globally. Other variables that increase complexity of distribution include storage requirements (frozen vs refrigerated) and whether more than a single injection is required for optimal immunity. Several technological methods described below (DNA, RNA, inactivated, viral vector, protein subunit) are available for vaccine development and the type of technological method used to develop the vaccine determines the vaccine attributes (number of doses, speed of development, scalability).
Information on the five vaccines in late-stage development which are currently approved or nearing approval is below.
BNT-162b2 (Pfizer - currently in use) is a nucleoside-modified messenger RNA (mRNA) vaccine that encodes an optimized SARS-CoV-2 receptor-binding domain (RBD) antigen. On December 11, 2020, the FDA granted EUA for the BNT-162b2 SARS-CoV-2 vaccine in patients 16 years and older on December 11, 2020, after its VRBPAC voted to recommend (17 yes, 4 no, 1 abstention) the EUA on December 10.
- Genetic-code vaccine
- Storage and shipping requirements: Frozen; ultra-cold storage of -70ºC
- Requires reconstitution
- Once thawed, stable while refrigerated for up to 5 days
- Room temperature stability: 2 hours
- Dose: 2 intramuscular injections in deltoid muscle 21 days apart
- 95% effective, well-tolerated across all populations
- Not evaluated for asymptomatic infection/carriage
The ongoing multinational phase 3 trial included 43,548 participants 16 years and older who were randomly assigned to receive vaccine or placebo by injection; 43,448 participants received vaccine or placebo (vaccine group, 21,720; placebo group, 21,728). Approximately 42% of global participants and 30% of US participants were of racially and ethnically diverse backgrounds, and 41% of global and 45% of US participants were 56-85 years of age.
Vaccine efficacy was 95%, and no serious safety concerns were observed. The only grade 3 adverse event with a frequency of greater than 2% was fatigue at 3.8%; headache occurred in 2% of participants. Short-term mild-to-moderate pain at the injection site was the most commonly reported reaction, and severe pain occurred in less than 1% of participants across all age groups.
mRNA-1273 (Moderna - currently in use) is an mRNA vaccine which encodes the S-2P antigen. On December 18, 2020, the US Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) for the mRNA-1273 SARS-CoV-2 vaccine in individuals 18 years and older, after its Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted to recommend (20 yes, 0 no, 1 abstention) the EUA on December 17.
- Genetic-code vaccine
- Dose: 2 injections 28 days apart
- No dilution required
- Shipping and long-term storage: Frozen (-20°C) for 6 months
- After thawing: Standard refrigerator temperatures (2-8°C) for 30 days
- Room temperature: Up to 12 hours
- 94.1% effective, well-tolerated
The US phase 3 trial (COVE) launched on July 27, 2020. The trial was conducted in cooperation with the National Institute of Allergy and Infectious Diseases and included more than 30,000 participants who received 2 100-µg doses or matched placebo on days 1 and 29. The primary efficacy analysis was released November 30, 2020. The COVE study included Americans 65 years and older, younger individuals with high-risk chronic diseases, individuals who identify as Hispanic or Latinx, and individuals who identify as Black or African American.
AZD-1222 (ChAdOx1 nCoV-19; AstraZeneca) is a replication-deficient chimpanzee adenoviral vector vaccine containing the surface glycoprotein antigen (spike protein) gene. This vaccine primes the immune system by eliciting antibodies to attack the SARS-CoV-2 virus if it later infects the body.
- Viral vector vaccine
- Phase 3 trial was temporarily put on hold globally on September 6, 2020 after a study participant in the United Kingdom was diagnosed with transverse myelitis. After FDA review in the United States, phase 3 trials resumed here on October 23, 2020.
- Storage: Refrigeration
- Dose: 2 injections 28-days apart (half dose then full dose most effective)
- Efficacy 90%
- United Kingdom approval expected soon. Phase 3 trial in US is ongoing.
- Owing to the testing of a different coronavirus vaccine last year, development for AZD-1222 was faster than that of other viral vector vaccines.
Ad26.COV2.S (Johnson & Johnson)
- Viral vector vaccine
- Storage: Refrigeration
- Dose: 1 injection (antibodies observed after single injection)
- 99% positive for antibodies at day 29 and strong T-cell and T helper cell responses noted.
- Application pending in Canada and Europe
NVX-CoV2373 (Novavax) is engineered using recombinant nanoparticle technology from SARS-CoV-2 genetic sequence to generate an antigen derived from the coronavirus spike protein.
- Subunit vaccine
- Dose: 2 injections, 21 days apart
- Results of preclinical studies showed that it binds efficiently with human receptors targeted by the virus.
- Phase 1 data in healthy adults showed that the adjuvanted vaccine induced neutralization titers that exceeded responses in convalescent serum from mostly symptomatic patients with COVID-19.
- Phase 3 trial in the United Kingdom has completed enrollment of 15,000 participants, including more than 25% who were older than 65 years.
- Researchers conducting the US and Mexico phase 3 trial, which started in December 2020, plan to enroll up to 30,000 participants.
In addition to these 5 vaccines which are in use or in stage 3 trials, there are 19 other vaccines in later phases of development using various technologies. These include a DNA based 2-dose vaccine which will be stable at room temperature for over 1 year, additional mRNA vaccines, a vaccine using Ebola vaccine technology based on modified measles virus, antigen vaccines, self-assembling nanoparticles, T-cell activating platform, inactivated whole viron, and recombinant adenovirus (among others). Additionally, there are a number of noninjectable vaccines in development including intranasal, inhaled, oral, and transdermal.
Moving forward, I expect that there will be multiple vaccines available over the next few months. I would expect that if this is an annual or somewhat frequent immunization (3-5 years) that one of the single dose, easily stored vaccines will be the most commonly used.