Author: David J Cennimo, MD, FAAP, FACP, AAHIVS
The genetic sequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was published on January 11, 2020, and the rapid emergence of research and collaboration among scientists and biopharmaceutical manufacturers followed. Various methods are used for vaccine discovery and manufacturing. As of December 17, 2020, The New York Times Coronavirus Vaccine Tracker listed 63 vaccines in human trials, and at least 85 preclinical vaccines were under investigation in animals.  A number of antiviral medications and immunotherapies are also under investigation for coronavirus disease 2019 (COVID-19).
On December 28, 2020, the National Institutes of Health announced the fifth phase 3 trial for COVID-19 vaccines in the United States has begun enrolling adult volunteers. Results from the phase 1 clinical trial for the NVX-CoV2373 vaccine were published online December 10, 2020 in The New England Journal of Medicine.
The Advisory Committee on Immunization Practices has published guidelines on the ethical principles for the initial allocation for this scarce resource. 
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). 
Young children are likely to be assigned lower priority for vaccines because it is young adults who are the main drivers of transmission in the United States. 
The next 2 priority groups will be front-line essential workers and adults 75 years and older (1c); and adults 65-74 years, individuals 16-64 years with high-risk medical conditions, and essential workers who did not qualify for inclusion in Phase 1b (1d).
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 (eg, frozen vs refrigerated) and whether more than a single injection is required for optimal immunity. Several technological methods (eg, DNA, RNA, inactivated, viral vector, protein subunit) are available for vaccine development. Vaccine attributes (eg, number of doses, speed of development, scalability) depend on the type of technological method employed. [5, 6, 7]
Some methods have been used in the development of previous vaccines, whereas others are newly developed. For example, mRNA vaccines for influenza, rabies, and Zika virus have been previously tested in animals. 
Examples of advantages and disadvantages of the various vaccine technologies are included in Table 1. [6, 7, 8]
Table 1. Vaccine Platform Characteristics (Open Table in a new window)
Vaccine Candidate (Manufacturer)
Fast development speed; low- to-medium manufacturing scale
BNT-162b2 (Pfizer, BioNTech);
Fast development speed; medium manufacturing scale
Medium development; high manufacturing scale
1 or 2
AZA-1222 Ad5-CoV (AstraZeneca; Oxford University);
Ad26.COV2.S (Johnson & Johnson)
Medium- to-fast development; high manufacturing scale
Vaccines in Late-Stage Development
The following vaccines are in, or have completed, phase 3 clinical trials in the United States.
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.
On December 11, 2020, the FDA granted [http://fda%20eua%20fact%20sheet%20for%20health%20care%20providers%20https/www.fda.gov/media/144413/download]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.
Table 2. Vaccines in Late-Stage Development (Open Table in a new window)
Phase 3 trial ongoing in individuals 16 y and older
In mid-October 2020, company allowed by FDA to expand phase 3 trial to adolescents 12 y and older.
Primary efficacy analysis:
· 95% effective against clinically evident COVID-19 infection 28 d after 1st dose across all subgroups 
· Well tolerated across all populations 
· 170 confirmed cases (placebo group, 162; vaccine group, 8) 10 severe cases after 1st dose (placebo group, 9; vaccine group, 1) 
· Efficacy consistent across age, sex, race, and ethnicity 
· Not evaluated for asymptomatic infection/carriage 
First approved in United Kingdom on December 2, 2020
Approved in early December 2020 by Bahrain and Canada
Emergency use authorized by FDA on December 11, 2020.
US phase 3 trial (COVE) ongoing
Phase 2/3 trial began in adolescents 12-17 y in December 2020
Primary efficacy analysis:
· Efficacy rate 94.1%
· 196 confirmed cases (placebo group, 185; vaccine group, 11)
· Only severe illness (30 cases) was in placebo group, including 1 death 
· 90 d after 2nd dose (30 participants): high levels of binding and neutralizing antibodies that fell but remained elevated
· Well tolerated 
Emergency use authorized
by FDA on December 18, 2020.
Phase 3 trials resumed on October 23, 2020 after being paused globally on September 6.
· Participant in United Kingdom diagnosed with transverse myelitis, triggering temporary hold on trial.
Interim analysis of phase 3 clinical trial in United Kingdom, Brazil, and South Africa:
· Efficacy 90%, depending on dosage; average efficacy of 70.4% in combined analysis of 2 dosing regimens.
· 131 COVID-19 cases: from 21 d after 1st dose, 10 hospitalizations, all in placebo group (2 classified as severe; 1 death)
Approved in United Kingdom December 29, 2020.
Phase 3 in United States.
Phase 3 trial (ENSEMBLE) ongoing
Second phase 3 trial (EMSEMBLE 2) announced November 15, 2020, to study effects of 2 doses
· Phase 1/2a study: antibodies to SARS-CoV-2 observed after a single injection
· 99% were positive for neutralizing antibodies against SARS-CoV-2 at day 29: strong T-cell responses and a T H1 response were also noted 
Rolling biologics license application submitted in Canada and Europe on December 1, 2020.
Phase 3 trial in United Kingdom concluded enrollment at end of November 2020.
US and Mexico phase 3 trial began December 2020.
· Phase 1 data showed the adjuvanted vaccine induced neutralization titers in healthy volunteers that exceeded responses in convalescent serum from mostly symptomatic patients with COVID-19. 
· 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
BNT-152b2 (Pfizer) is a nucleoside-modified messenger RNA (modRNA) vaccine that encodes an optimized SARS-CoV-2 receptor-binding domain (RBD) antigen.
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. 
· Genetic-code vaccine
· Dose: 2 injections 28days 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
The mRNA-1273 vaccine (Moderna) encodes the S-2P antigen. 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 (n = 30,420) included Americans 65 years and older (24.8%), younger individuals with high-risk chronic diseases (16.7%), individuals who identify as Hispanic or Latinx (20.5%), and individuals who identify as Black or African American (10.4%).
Immunogenicity data at 90 days after the second vaccination was evaluated in 34 participants in the phase 3 trial.  A phase 2/3 trial in adolescents 12-17 years begun in December 2020 is expected to enroll 3,000 participants.
· 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 there on October 23, 2020.
· Storage: Refrigeration
· Dose: 2 injections 28-days apart
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. Owing to the testing of a different coronavirus vaccine last year, development for AZD-1222 was faster than that of other viral vector vaccines.
Results of an interim analysis of the phase 3 clinical trial in the United Kingdom, Brazil, and South Africa are as follows:
One dosing regimen (n = 2741) showed vaccine efficacy of 90% when given as a half dose, followed by a full dose at least 1 month later. Another dosing regimen (n = 8895) showed 62% efficacy when given as 2 full doses at least 1 month apart. The combined analysis from both dosing regimens (N = 11,636) resulted in an average efficacy of 70.4%. All results were statistically significant (p< .0001).  The phase 3 efficacy trial in the United States is ongoing. Concerns about the clinical trial implementation and data analysis have emerged because the half-dose regimen was not in the approved study design. [16, 17] These concerns will be addressed by regulatory agencies and await publication of the trial data. Ad26.COV2.S Overview · Viral vector vaccine · Storage: Refrigeration · Dose: 1 injection · The phase 3 trial (ENSEMBLE) for adenovirus serotype 26 (Ad26) recombinant vector-based vaccine (JNJ-78436735; Johnson & Johnson) was launched in September 2020 with a goal of 60,000 participants in the United States, South Africa, and South America. In December 2020, the goal was revised to 40,000 participants. Because of the high prevalence of virus in the United States, researchers will be able to reach conclusions with a smaller trial. The vaccine uses Janssen’s AdVac technology, which enhances vaccine stability (ie, 2 years at -20ºC and at least 3 months at 2-8ºC). This makes the vaccine candidate compatible with standard vaccine distribution channels and new infrastructure would not be required for distribution to people who need it.  A second phase 3 trial (EMSEMBLE 2) to observe effects of 2 doses of the vaccine in up to 30,000 participants worldwide was announced on November 15, 2020. NVX-CoV2373 Overview · Subunit vaccine · Dose: 2 injections, 21 days apart · 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. This is combined with an adjuvant (Matrix-M). Results of preclinical studies showed that it binds efficiently with human receptors targeted by the virus. Phase 1/2 trials were initiated in May 2020. 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.  The 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. Other Investigational Vaccines Additional vaccine candidates are in various stages of development and clinical testing. Examples of these vaccines are provided in Table 3. Table 3. Other Investigational Vaccines (Open Table in a new window) Vaccine Comments INO-4800 (Inovio Pharmaceuticals)  DNA-based, 2-dose vaccine Stable at room temperature for more than 1 y; frozen shipment not needed; interim results from phase 1 human trial (n = 40): favorable safety and immunogenicity; expanded to include older participants.  Phase 2/3 trial (INNOVATE) ongoing; phase 2 to evaluate 2-dose regimen (1 mg or 2 mg) vs placebo in 400 participants. Grant from Bill and Melinda Gates Foundation to speed testing and scale up a smart device (Cellectra 3PSP) for large-scale intradermal vaccine delivery; company has also received funds from the US Department of Defense. CVnCoV (CureVac)  mRNA, 2-dose vaccine Preliminary data from phase 1 dose-escalating trial: 12-µg dose provided IgG antibody levels similar to convalescent plasma. phase 2b/3 trial enrollment (goal, 35,000 in Europe and Latin America) ongoing. Vaccine candidates V590 and V591 (Merck)  Vaccine V591 to be based on a modified measles virus that delivers portions of SARS-CoV-2 virus. phase 1 trial ongoing. Vaccine V590 uses Merck’s Ebola vaccine technology; human trials ongoing. COVID-19 S-Trimer (GlaxoSmithKline [GSK])  Partnering with multiple companies using GSK’s adjuvants (compounds that enhance vaccine efficacy). CpG 1018 adjuvant vaccine (Dynavax)  Under development with Sanofi’s S-protein COVID-19 antigen and GSK’s adjuvant technology that stimulates the immune system; phase 1/2 trial ongoing. UB-612 multitope peptide-based vaccine (COVAXX [division of United Biomedical, Inc])  Comprises SARS-CoV-2 amino acid sequences of the receptor binding domain; further formulated with designer Th and CTL epitope peptides derived from the S2 subunit, membrane, and nucleoprotein regions of SARS-CoV-2 structural proteins for induction of memory recall, T-cell activation, and effector functions against SARS-CoV-2. Company partnering with University of Nebraska Medical Center in the United States; phase 1, open-label, dose escalation study ongoing in Taiwan. HaloVax (Hoth Therapeutics; Voltron Therapeutics)  Collaboration with the Vaccine and Immunotherapy Center at Massachusetts General Hospital; use of VaxCelerate self-assembling vaccine platform offers 1 fixed immune adjuvant and 1 variable immune target to allow rapid development. Nanoparticle SARS-CoV-2 vaccine (Ufovax)  Vaccine prototype development utilizing self-assembling protein nanoparticle (1c-SapNP) vaccine platform technology. PDA0203 (PDS Biotechnology Corp)  Utilizes Versamune T-cell-activating platform for vaccine development. CoVLP recombinant coronavirus virus-like particles (Medicago and GlaxoSmithKline)  Combines Medicago’s recombinant coronavirus virus-like particles (rCoVLP) with GSK’s adjuvant system; phase 2/3 trial ongoing. AS03-adjuvanted SCB-2019 (Clover Pharmaceuticals)  Subunit vaccine containing SARS-CoV-2 spike (S) protein Phase 1 trial results reported in December 2020 showed high level of antibodies. Phase 2/3 trial launching by end of 2020 using GSK adjuvant with goal of 34,000 volunteers. Covaxin (Bharat Biotech and Ocugen)  Whole-virion inactivated vaccine Developed and manufactured in Bharat Biotech’s bio-safety level 3 biocontainment facility. Co-development with Ocugen announced for the US market. Elicited strong IgG responses against spike (S1) protein, receptor-binding domain (RBD) and the nucleocapsid (N) protein of SARS-CoV-2 along with strong cellular responses in Phase 1 and 2 clinical trials (n ~1000). Phase 3 trial is in progress in India that involves 26,000 volunteers. Recombinant adenovirus type-5-vectored vaccine (Ad5-vectored vaccine; Sinopharm [China])  Approved in China and Saudi Arabia; preliminary data: 86% efficacy; phase 2 trial: seroconversion of neutralizing antibodies seen in 59% and 47% of those in 2-dose groups; seroconversion of binding antibody seen in 96-97% of participants; Positive specific T-cell responses seen in 88-90% of participants. CoronaVac (Ad5-vectored vaccine; Sinovac [China])  Limited use in China. Interim phase 3 efficacy reports vary widely from several trials. A trial in Brazil reports efficacy of 50-90%. However, a Turkish trial reports 91.25% efficacy (n = 7,371; data analysis based on 1322 participants – 752 vaccine and 570 placebo). rAD26 (frozen) and rAd5 vector-based (lyophilized) formulations (Sputnik V; Moscow Gamaleya Institute)  Phase 1/2 trial complete; approved in Russi; both vaccines safe and well tolerated with mostly mild adverse events and no serious adverse events; all participants produced anti-spike protein and neutralizing antibodies after second dose, and generated CD4+ and CD8+ responses. hAd5 -COVID-19 (ImmunityBio)  Phase 1 trial ongoing; vaccine targets inner nucleocapsid (N) and outer spike (S) protein, which have been engineered to activate T cells and antibodies against SARS-CoV-2, respectively. These dual constructs offer the possibility for the vaccine candidate to provide durable, long-term cell-mediated immunity with potent antibody stimulation to patients against both the S and N proteins. MRT5500 (Sanofi and Translate Bio)  mRNA-based vaccine candidate; preclinical evaluation demonstrated favorable ability to elicit neutralizing antibodies using a 2-dose schedule administered 3 wk apart; phase 1/2 trial anticipated to start in Q4 2020. AG0302-COVID19 (AnGes and Brickell Biotech)  Adjuvanted DNA vaccine in phase 1/2 study in Japan; data readouts expected in Q1 2021; intent to follow with phase 3 trials in United States and South America.