COVID-19 Vaccines 

Updated: Jan 07, 2022
Author: David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS; Chief Editor: John L Brusch, MD, FACP 


After publication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genetic sequence on January 11, 2020, research and collaboration among scientists and biopharmaceutical manufacturers quickly followed. 

Various methods are used for vaccine discovery and manufacturing. As of January 3, 2022, The New York Times Coronavirus Vaccine Tracker lists one vaccine (Comirnaty; Pfizer) that has gained full approval by the US Food and Drug Administration (FDA) for those aged 16 years and older and emergency use authroization (EUA) for children aged 6 years and older. Two other vaccines have EUAs in the United States. Globally, nine vaccines are approved for full use, 19 vaccine authorized for early or limited use, and 34 vaccine are in phase 3 clinical trials.[1]  Numerous antiviral medications and immunotherapies are under investigation for coronavirus disease 2019 (COVID-19). 

The US Food and Drug Administration (FDA) has granted emergency use authorizations (EUAs) for three SARS-CoV-2 vaccines since December 2020. Two are mRNA vaccines – BNT-162b2 (Pfizer) and mRNA-1273 (Moderna), whereas the third is a viral vector vaccine – Ad26.COV2.S (Johnson & Johnson). Other vaccines are in or nearing phase 3 trials. 

Effectiveness of full vaccination in older adults to prevent hospitalization was estimated for the period between February through April 2021. Efficacy among adults aged 65 to 74 years is approximately 96% for the mRNA vaccines and 84% for Janssen vaccine. Among adults aged 75 years and older, effectiveness of full vaccination is estimated at 91% for Pfizer-BioNTech, 96% for Moderna, and 85% for Janssen vaccine products.[2]  

Vaccination in previously infected individuals

The CDC recommends COVID-19 vaccination for all eligible persons as soon as possible, including unvaccinated individuals previously infected with SARS-CoV-2. Vaccinations provide a safer and more reliable way to build antibodies compared with infection. Patients may receive the vaccine once they have recovered from the acute illness (if symptomatic) and meet the criteria to discontinue isolation. Patients who received monoclonal antibodies or convalescent plasma should wait 90 days before receiving the vaccine. 

Supporting evidence for CDC’s recommendation is based on results from the VISION Network trial. The trial compared the early protection against COVID-19 conferred by SARS-CoV-2 infection and by receipt of mRNA COVID-19 vaccines (ie, 90-179 days after infection or vaccination) in adults with confirmed COVID-19 infection from 187 hospitals across nine states during January to September 2021. The adjusted odds of laboratory-confirmed COVID-19 among unvaccinated adults with previous SARS-CoV-2 infection were 5.49-fold higher than the odds among fully vaccinated recipients of an mRNA COVID-19 vaccine who had no previous documented infection.[3]  

Evidence shows vaccines provide substantially higher protection against COVID-19 infection compared with immunity from a previous COVID-19 infection. mRNA vaccinees have higher antibody titers (up to 10 times higher) than convalescent plasmas from donors who recovered from natural infection.[4]  

Early studies found vaccination of patients with prior SARS-CoV-2 infection enhances T cell immunity and antibody-secreting memory B cell response, and neutralizing antibodies effective against emerging variants. These data emphasize the importance of vaccinating both uninfected and previously infected persons to elicit cross-variant neutralizing antibodies.[5, 6, 7]  

Vaccination in adolescents and children

BNT162b2 (Pfizer)

In the United States, vaccination was opened to all aged 16 years and older in early April 2021. On May 10, 2021, the FDA extended the EUA for the BNT162b2 vaccine (Pfizer) to include younger adolescents aged 12 to 15 years. The phase 3 trial data included in the EUA lists the vaccine as 100% effective in preventing SARS-CoV-2 infection in this age group. There were no cases of COVID-19 disease in adolescents aged 12 to 15 years who received the vaccine (n = 1119) compared with 18 cases in those who received placebo (n = 1110). Adverse events after receipt of BNT162b2 vaccine reported to the Vaccine Adverse Event Reporting System (VAERS) and adverse events and health impact assessments reported in v-safe (a smartphone-based safety surveillance system) were reviewed for US adolescents aged 12 to 17 years during December 14, 2020 to July 16, 2021.[8]  

On October 29, 2021, the FDA authorized the BNT162b2 vaccine for children aged 5 to 11 years. The CDC Advisory Committee on Immunization Practices unanimously endorsed use for this population on November 2, 2021. The dose for this age group is smaller than the dose for adults and adolescents (ie, 10 mcg vs 30 mcg). As with adults and adolescents, the primary vaccine series consists of two doses administered 3 weeks apart. A three-dose primary series is recommended for severely immunosuppressed individuals aged 5 years and older. The vaccine is packaged in a smaller vial size and strength specific for younger children. 

The EUA for the Pfizer mRNA vaccine also recommends a single homologous booster dose at least 5 months after completing a primary series with the Pfizer-BioNTech COVID-19 vaccine to individuals aged 12 years and older. Heterologous boosters are not part of the EUA for patients younger than 18 years. 

The phase 2/3 trial in the United States included approximately 4500 children aged 5 to 11 years (2268 from the initial enrollment group [1518 vaccine; 750 placebo] and 2379 from the supplemental safety group who entered the study later than the initial enrollment group). Participants were randomly assigned in a 2:1 ratio to receive active vaccine or a placebo. The vaccine efficacy rate was 90.7% in the initial enrollment participants without prior SARS-CoV-2 infection (n = 1968), measured from 7 days after the second dose. Among these participants, the number testing positive for SARS-CoV-2 was three of 1273 in the vaccine group and 16 of 637 in the placebo group. The cutoff date for the data in the initial group was October 8, 2021, during a period when the Delta variant was prevalent and pediatric cases accounted for approximately 25% of cases in the United States. 

Clinical trials for younger children aged 6 months through 4 years are also nearing completion.

mRNA-1273 (Moderna)

The Teen COVE trial showed mRNA-1273 vaccine (Moderna) to be 93.3% effective 14 days after receiving two doses in adolescents aged 12 to 17 years. Vaccine efficacy of 92.7% in seronegative participants was observed starting 14 days after the first dose, using the secondary CDC case definition of COVID-19, which tested for milder disease. The phase 2/3 trial included 3732 participants randomly assigned in a 2:1 ratio to receive mRNA-1273 or placebo between December 9, 2020 and February 28, 2021.[9]  An EUA was submitted June 10, 2021 to expand the current EUA to include this population. However, the decision to expand the EUA to include adolescents has been delayed to determine whether there is heightened risk for myocarditis among younger males. 

Interim analysis of the KidCOVE phase 2/3 trial (n = 4753) for the mRNA-1273 vaccine in children aged 6 through 11 years neutralizing antibody response after two 50-mcg doses, with a favorable safety profile. 


A trial for NVX-CoV2373 (Novavax) in adolescents aged 12 to 17 years has enrolled 2248 participants as of mid-June 2021. 

Vaccine Characteristics

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.[10, 11, 12]  

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 previously have been tested in animals.[13]  

Examples of advantages and disadvantages of the various vaccine technologies are included in Table 1.[11, 12, 13]

Table 1. Vaccine Platform Characteristics (Open Table in a new window)

Platform Attributes  Doses Vaccine Candidate (Manufacturer)
mRNA Fast development speed; low- to-medium manufacturing scale 2

BNT-162b2 (Pfizer, BioNTech);

mRNA-1273 (Moderna)

DNA Fast development speed; medium manufacturing scale 2 INO-4800 (Inovio)
Viral vector Medium development; high manufacturing scale 1 or 2

AZD-1222 Ad5-CoV (AstraZeneca; Oxford University);

Ad26.COV2.S (Johnson & Johnson)

Protein subunit Medium- to-fast development; high manufacturing scale  2 NVX-CoV2373 (Novavax)
Whole virion inactivated 

Ability to quickly produce large amounts of vaccine


Covaxin; BBV152 (Ocugen and Bharat Biotech)



mRNA Vaccines

Comirnaty (BNT-162b2; Pfizer)


  • January 3, 2022: EUA expanded to allow a homologous booster dose for individuals aged 12 years and older at least 5 months after completing the primary series with BNT-162b2 and as a heterologous booster at the interval authorized for the vaccine use for primary vaccination
  • January 3, 2022: EUA expanded to allow a homologous booster dose for individuals aged 12 years and older at least 5 months after completing the primary series with BNT-162b2 
  • January 3, 2022: EUA expanded to a third primary dose for individuals aged 5 years and older who have undergone solid organ transplantation or who  have conditions with equivalent level of immunocompromise 
  • December 9, 2021: The EUA was expanded to allow a single booster dose (0.3 mL) that may be administered at least 6 months after completing a primary series of the Pfizer-BioNTech COVID-19 vaccine to individuals aged 16 years and older. 
  • November 19, 2021: EUA revised to include a single booster dose at least 6 months after completing the primary series for all adults aged 18 years and older
  • October 29, 2021: EUA amended to include a two-dose primary series in children aged 5 to 11 years
  • October 20, 2021: EUA revised to allow heterologous boosters for each available COVID-19 vaccine in United States
  • August 23, 2021: FDA granted full approval for a two-dose regimen in individuals aged 16 years and older
  • EUA granted in the United States for individuals aged 12 to 15 years 
  • August 12, 2021: EUA granted for third primary dose for individuals aged 12 years and older who have undergone solid organ transplantation or who  have conditions with equivalent level of immunocompromise 
  • NIH  phase 2 trial of allergic reactions to vaccine in participants with severe allergies underway
  • Phase 2/3 trial in pregnant persons started in February 2021 
  • Phase 1/2/3 trials starting spring 2021 in infants and younger children aged 6 months and older 
  • Phase 3 trial in older adults of BNT-162b2 booster dose followed by 20-valent pneumococcal conjugate vaccine (20vPnC) 

Comirnaty is the first vaccine to gain full approval in the United States to prevent COVID-19 disease. It is a nucleoside-modified messenger RNA (modRNA) vaccine that encodes an optimized SARS-CoV-2 receptor-binding domain (RBD) antigen. It is administered as a two-dose series 21 days apart.

A multinational phase 3 trial randomly assigned 43,448 participants to receive vaccine or placebo (vaccine group, 21,720; placebo group, 21,728) by injection. 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 aged 56 to 85 years. 

Vaccine efficacy was 95% against the original SARS-CoV-2 strain at 7 days after dose 2, and no serious safety concerns were observed. There were 170 confirmed cases (placebo group, 162; vaccine group, 8); 10 severe cases occurred after the first dose (placebo group, 9; vaccine group, 1) as of November 14, 2020. Updated data through 6 months (March 13, 2021) showed vaccine efficacy against COVID-19 was 91.3%. Vaccine efficacy of 86 to 100% was seen across countries and in diverse populations and risk factors for Covid-19 among participants without evidence of previous infection with SARS-CoV-2. Vaccine efficacy against severe disease was 96.7% and in South Africa, where the B.1.351 (beta) variant was predominant during the study, a vaccine efficacy of 100% was observed.[14]  

Efficacy data in an ongoing, real-world, phase 3 assessment of 46,307 participants showed 91.3% efficacy against COVID-19, when gauged as cases 7 days to 6 months after the second vaccine dose. Among 927 confirmed symptomatic COVID-19 cases, 850 were in the placebo group compared with 77 in the vaccine group. It was 100% effective in preventing severe disease (CDC definition). All 32 severe disease cases occurred in the placebo group.[15]

Results from an observational study of real-world data from healthcare workers (HCWs) employed in a large medical center in Israel after their first vaccine dose have been published. Among 9109 eligible staff, 7214 (79%) received a first dose and 6037 (66%) received the second dose in December 2020 and January 2021. Compared with a symptomatic COVID-19 rate of 5 per 10,000 person-days in unvaccinated HCWs, disease rates were 2.8 per 10,000 person-days on days 1 to 14, and 1.2 per 10,000 per 10,000 person-days on days 15 to 28 after the first vaccine dose. Adjusted rate reductions of COVID-19 disease were 47% for days 1 to 14 and 85% for days 15 to 28 after the first dose.[16]  

In another observational study, researchers used integrated data repositories in Israel’s largest health care organization to evaluate mass immunization effectiveness. All newly vaccinated persons during the period from December 20, 2020, to February 1, 2021 were matched to unvaccinated controls in a 1:1 ratio according to demographic and clinical characteristics. Each study group included 596,618 persons. Study outcomes included documented infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), symptomatic Covid-19, Covid-19–related hospitalization, severe illness, and death. Results at 7 or more days after the second dose showed 92% efficacy against documented infection, 94% efficacy against symptomatic COVID-19, 87% effective for preventing hospitalization, and 92% effective for preventing severe disease.[17]

Moderna COVID-19 Vaccine (mRNA-1273; Moderna TX)


  • January 7, 2022: EUA amended to allow a homologous booster dose for individuals aged 18 years and older at least 5 months after completing the primary series with mRNA-1273 and as a heterologous booster at the interval authorized for the vaccine used for primary vaccination
  • November 19, 2021: EUA revised to include a single booster dose at least 6 months after completing the primary series for all adults aged 18 years and older
  • October 20, 2021: EUA revised to allow heterologous boosters for each available COVID-19 vaccine in the United States
  • EUA in the United States for adults aged 18 years and older 
  • August 12, 2021: EUA granted for third dose for individuals aged 12 years and older who have undergone solid organ transplantation or who  have conditions with equivalent level of immunocompromise
  • EUA submitted June 10, 2021 for adolescents based on phase 2/3 TeenCOVE trial (n = 3732) completed in adolescents aged 12 to 17 years showing 100% efficacy after 2 doses
  • June 1, 2021: Rolling BLA initiated for US licensure in adults 
  • September 1, 2021: BLA submitted for third dose administration to individuals aged 18 years and older 
  • NIH  phase 2 trial of allergic reactions to vaccine in participants with severe allergies underway
  • US phase 3 trial (COVE) in adults complete  
  • Phase 2/3 KidCOVE trial children aged 6 months and older began in March 2021 (target enrollment 6750) 
  • Phase 2 study started for booster vaccine candidates 
  • Phase 3 trial in university students planned to assess nasal viral load and shedding 

The Moderna COVID-19 Vaccine (ModernaTX) encodes the S-2P antigen. It is administered as a two-dose series given 28 days apart. The US phase 3 trial (COVE) launched in July 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 two 100-mcg doses or matched placebo on days 1 and 29. Overall efficacy was 94.1% for the original viral strain. There were 196 confirmed cases (placebo group, 185; vaccine group, 11). Among the 185 cases in the placebo group, 30 cases were severe, including one death.[18]  

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%).[18]  At 6 months after the second dose, efficacy was greater than 90% against COVID-19 infection and greater than 95% against severe COVID-19 in identified cases (data adjudicated from over 900 cases, of which over 100 were severe).[19]  

In an ongoing phase 1 trial, 33 adult participants in all age groups showed high antibody activity elicited at 6 months after the second dose.[20]  

Booster Dose After Completing Primary Vaccination Series

The FDA amended the EUAs for the Pfizer and Moderna mRNA vaccines during September and October, 2021 to allow use of a single booster dose to be administered at least 6 months after completing the primary series for all individuals aged 18 years and older who had received an mRNA vaccine. Heterologous boosters are also allowed  for either mRNA vaccine to be given 2 months after those who received the single-dose Ad26.COV2.S vaccine. 

The EUA for the Pfizer mRNA vaccine recommends a single homologous booster dose at least 5 months after completing a primary series with the Pfizer-BioNTech COVID-19 Vaccine to individuals aged 12 years and older. Heterologous boosters are not part of EUA for patients younger than 18 years. The Moderna mRNA vaccine booster is also 5 months after completion of the primary series in patients aged 18 years and older.

The booster for BNT-162b2 (Pfizer) is the same dose as that used for the primary vaccine series. The mRNA-1273 vaccine (Moderna) uses a half dose for the booster. 

Studies in immunocompetent individuals 

Broad use of a booster dose in the general population has been debated. Boosting may benefit some individuals in whom primary vaccination may not provoke a robust response (eg, highly immunocompromised individuals, older adults). Widespread administration of a booster dose may ultimately be required owing to waning immunity to the primary vaccine or emergence of new variants.[21]  Following an aggressive mass immunization program starting in December 2020 resulting in a sharp decline of COVID-19 cases, waning immunity was observed in Israel across all age groups by mid-June 2021.[22]

Continued study of when and to whom to provide a booster dose is needed to better define maturation and heterogeneity of antibodies and how they affect viral variants. Neutralizing antibody levels do not necessarily indicate protection or correlate with protection. Immunity in the blood stream may not reflect immunity where the body is exposed to the virus (eg, nasopharynx). Additionally, continued measurement of the risk-benefit ratio of a booster dose needs to be considered.[23]  

BNT-162b2 vaccine

On July 30, 2021, the administration of a third dose of the BNT162b2 mRNA vaccine (Comirnaty, Pfizer–BioNTech) was approved in Israel for persons aged 60 years and older who had received a second dose of vaccine at least 5 months earlier. Increased severe cases and hospitalizations in vaccinated individuals in June 2021 prompted an analysis of Israeli data. The analysis concluded the outbreak of the delta variant indicated a high degree of waning immunity. At least 12 days after the booster dose, the rate of confirmed infection was lower in the booster group than in the nonbooster group by a factor of 11.3; the rate of severe illness was lower by a factor of 19.5). In a secondary analysis, the rate of confirmed infection at least 12 days after vaccination was lower than the rate after 4 to 6 days by a factor of 5.4.[24]  

The booster dose was expanded to younger age groups in Israel after positive initial results in those aged 60 years and older. The rate of confirmed infection was lower in the booster group compared with the nonbooster group by approximately 10-fold across five age groups (range 9.0 to 17.2). Severe illness and mortality were also was lower among those aged 60 years and older in the booster group by a factor of 17.9 and 14.7, respectively.[25]  

mRNA-1273 vaccine booster

A booster dose of mRNA-1273 (Moderna COVID-19 Vaccine; ModernaTX) or mRNA-1273.351 (a strain-matched vaccine candidate) increased neutralizing titers against SARS-CoV-2 and two variants of concern (B.1.351, P.1) in previously vaccinated clinical trial participants. The booster dose of mRNA-1273.351 achieved higher titers against B.1.351 compared with mRNA-1273.[26]

Evaluation of a multivalent vaccine booster, mRNA-1273.211, that combines mRNA-1273 ancestral strains and mRNA-1273.351 in a single vaccine is ongoing. 

Heterologous boosters

As of October 20, 2021, the EUAs for COVID-19 vaccines in the United States also allow use as a heterologous (or “mix and match”) booster dose in adults aged 18 years and older following completion of primary vaccination with a different available COVID-19 vaccine. 

Eligible population(s) and dosing interval are the same as those authorized for a booster dose of the vaccine used for primary vaccination – at least 5 months after mRNA-Moderna or Pfizer vaccines, or 2 months after a single-dose Janssen (Johnson & Johnson) vaccine.

Third Primary Dose for Immunocompromised Individuals

On August 12, 2021, the FDA reauthorized the EUAs for the mRNA SARS-CoV-2 vaccines to allow a third primary dose administered at least 28 days after the two-dose regimen in individuals who have undergone solid organ transplantation or who are diagnosed with conditions that are considered to have an equivalent level of immunocompromise. The Pfizer EUA allows for severely immunocompromised individuals aged 5 years and older, whereas the Moderna EUA allows a third dose for adults aged 18 years and older. 

Studies in immunocompromised individuals

The mRNA vaccines are highly effective in the general population. As with other vaccines, it is important to determine if immunosuppressed populations (eg, patients who have cancer, are solid organ transplant recipients, on hemodialysis, and/or taking immunosuppressive therapies) are able to mount a sufficient immunologic response following two doses of mRNA vaccine. One example of continued study of this population is a multiantigenic SARS-COV-2 vaccine using a synthetic poxvirus platform (COH04S1 [City of Hope Biomedical Research Institute, California]). A phase 2 trial for this vaccine was initiated in August 2021 in stem cell transplant recipients.[27]  

Solid organ transplant recipients 

Low or nondetectable antispike antibody levels and nucleocapsid antibodies following full vaccination with mRNA vaccines have been described in solid organ transplant recipients.[28, 29, 30]  

A randomized, placebo-controlled trial at the University Health Network in Canada enrolled 120 transplant recipients between May 25 and June 3, 2021. None had COVID-19 previously and all of them had received two doses of mRNA-1273 vaccine. Participants were randomly assigned in a 1:1 ratio to receive a third vaccine dose or placebo 2 months after their second vaccine dose. The primary outcome was a serologic response characterized by an anti-receptor-binding domain (RBD) antibody level of at least 100 U/mL at month 4. This outcome was prespecified and was based on the protective anti-RBD titer in a challenge study involving nonhuman primates and further corroborated in a large clinical cohort as the upper boundary of the estimated level required to confer 50% protective neutralization. At month 4, an anti-RBD antibody level of at least 100 U/mL was observed in 33 of 60 patients (55%) in the mRNA-1273 group and in 10 of 57 patients (18%) in the placebo group (P< 0.001).[31]

Kamar et al reported results of the humoral response of 101 consecutive solid-organ transplant recipients given a third dose of mRNA vaccine (BNT-152b2; Pfizer) 61 days after the second dose. Prevalence of anti–SARS-CoV-2 antibodies was 0% before the first dose, 4% before the second dose, 40% before the third dose, and 68% 4 weeks after the third dose. Among the 59 patients who had been seronegative before the third dose, 26 (44%) were seropositive at 4 weeks after the third dose. All 40 patients who had been seropositive before the third dose were still seropositive 4 weeks later, and their antibody titers increased from 36 ± 12 before the third dose to 2676 ± 350 at 1 month after the third dose (P< 0.001). Patients who did not have an antibody response were older, had a higher degree of immunosuppression, and had a lower estimated glomerular filtration rate compared with patients who had an antibody response.[32]  

A case series of seven solid organ transplant recipients describes confirmed COVID-19 infection after receiving an mRNA vaccine. Two individuals had received one dose and the others had received two doses. Six patients were tested for antispike antibodies, of which five had undetectable levels; one patient had received their second mRNA-1273 vaccine 44 days prior and had low titer antispike antibody. None of these six patients had detectable nucleocapsid antibody.[28]  Others have confirmed low or nondetectable antispike antibody levels and nucleocapsid antibodies.[29, 30]  These reports prompted the French National Authority for Health to recommend the use of a third dose in immunosuppressed patients. 

Patients on maintenance hemodialysis 

A national registry in France was used to compare severity of 1474 COVID-19 cases in patients on maintenance hemodialysis (MHD) after zero, one, or two doses of BNT162b2 vaccine. Overall, vaccination reduced disease severity, but 11% of infected patients who had received two doses died. Patient on MHD with humoral response similar to healthy volunteers after two doses did not generate more immune effectors after a third dose, but and had more side effects. In contrast, 66% of patients on MHD with suboptimal response after two doses reached an optimal titer of anti-RBD IgG and/or developed spike-specific CD8+ T cells after a third dose.[33]   

Myocarditis and Pericarditis with mRNA Vaccines 

Myocarditis is an inflammatory disease of the myocardium with a wide range of clinical presentations, from subtle to devastating myocyte damage. Historically, common etiologies include viral, parasitic, bacterial, fungal, and protozoal infectious agents. Noninfectious etiologies include toxins (eg, cocaine), drug hypersensitivity, and immunologic syndromes. The annual incidence of pediatric myocarditis in adolescents is 0.8 per 100,000, and 66% are males. This incidence gradually decreases with age over the ensuing decades.[34]   

Cases of myocarditis and pericarditis emerged in May 2021 with possible correlation of COVID-19 mRNA vaccine administration. A case series of seven adolescent males presenting with symptomatic acute myocarditis describes similar symptom onset of within a few days (ie, 2-4) after vaccine administration, particularly after the second dose. Diagnostic test results were similar among the group and included elevated troponin, ST elevation, and diffuse myocardial edema. None were critically ill, and all responded quickly to treatment with NSAIDs; several also received glucocorticoids.[35]   

Preliminary myocarditis/pericarditis reported to VAERS after approximately 300 million mRNA doses administered through June 11, 2021 total 1226. Most are after the second dose and nearly 80% are in males. Data from December 14, 2020 to July 16, 2021 indicate approximately 8.9 million US adolescents aged 12 to 17 years had received Pfizer-BioNTech vaccine. VAERS received 9246 reports after Pfizer-BioNTech vaccination in this age group; 90.7% of these were for nonserious adverse events and 9.3% were for serious adverse events, including myocarditis (4.3%).[8]  The CDC and American Academy of Pediatrics stress the benefit of the vaccine at preventing severe COVID-19 disease, hospitalization, and death, and they recommend vaccination. 

The CDC has published clinical considerations relevant to myocarditis and pericarditis with mRNA COVID-19 vaccines. Instruct patients to seek immediate medical attention if they experience chest pain, dyspnea, or palpitations after receiving the vaccine. Treatment consists of anti-inflammatory agents including NSAIDs, IVIG, and glucocorticoids. Additionally, athletic activity restrictions may be needed depending on when serum markers of myocardial injury and inflammation, ventricular systolic function, and clinically relevant arrhythmias return to normal.  


Viral Vector Vaccines

Ad26.COV2.S (Janssen [Johnson & Johnson])


  • October 20, 2021: EUA revised to recommend a booster (second dose) 2 months after the single-dose primary series of Ad26.COV2.S for individuals aged 18 years and older 
  • October 20, 2021: EUA revised to allow heterologous boosters for other available COVID-19 vaccines in the United States after completion of the primary series at 6 months (mRNA vaccines) or at 2 months (Ad26.COV2.S vaccine)
  • EUA in the United States for adults aged 18 years and older
  • Phase 3 trial (ENSEMBLE) in adults completed  
  • Phase 2 trial in pregnant individuals launched February 2021 
  • Phase 2a trial (ENSEMBLE 2) to assess efficacy of one or two doses began late 2020 
  • ENSEMBLE 2 trial expanded to include adolescents April 2021 

Ad26.COV2.S is an adenovirus serotype 26 (Ad26) recombinant vector-based vaccine (JNJ-78436735, VAC31518; Johnson & Johnson) administered as a single injection. 

The phase 3 trial (ENSEMBLE) began in September 2020 in the United States, South Africa, and South America. In December 2020, it was fully enrolled. Interim results for the phase 1/2a trial describing neutralizing antibody titers of more than 90% at day 29 and 100% at day 57 were published in January 2021.[36]

The EMSEMBLE trial randomly assigned more than 40,000 participants worldwide to receive one injection of either Ad26.COV2.S (n = 19,630) or placebo (n = 19,691). Ad26.COV2.S protected against moderate to severe–critical Covid-19 with onset at least 14 days after administration (vaccine group,116 cases; placebo group, 348; efficacy, 66.9%) and at least 28 days after administration (66 vs 193 cases; efficacy, 66.1%). The vaccine showed higher efficacy against severe–critical Covid-19 (76.7% for onset at 14 days and 85.4% for onset at 28 days). The vaccine was 100% effective against COVID-19–related hospitalization and death at Day 28; 16 hospitalizations occurred in the placebo group.[37]  

Ad26.COV2.S showed consistent protection across race; age groups, including older adults (participants aged 60 years and older were 34.6% of the vaccine arm); and across all variants and regions studied, including South Africa, where nearly all cases of COVID-19 (95%) were due to infection with a SARS-CoV-2 variant from the B.1.351 lineage.[37]  

The EUA Fact Sheet for Health Care Professionals states the vaccine's safety and efficacy in older study participants showed no overall differences compared with younger participants. At least 28 days post vaccination, efficacy against moderate to severe/critical disease at all study sites (ie, United States, Latin America, South Africa) was 66.2% for those aged 60 years and older compared with 66.1% for those 18 to 59 years. In the United States, estimated efficacy was 85.9% at least 28 days after vaccination.  

Booster Dose After Completing Primary Vaccination Series

The FDA amended the EUA for the Ad26.COV2.S vaccine (Janssen [Johnson & Johnson]) October 20, 2021 recommends a single booster dose to be administered at least 2 months after completing the primary vaccination.

Heterologous boosters

As of October 20, 2021, the EUAs for COVID-19 vaccines in the United States also allow use as a heterologous (or “mix and match”) booster dose in eligible individuals following completion of primary vaccination with a different available COVID-19 vaccine. 

Eligible population(s) and dosing interval are the same as those authorized for a booster dose of the vaccine used for primary vaccination – at least 6 months after mRNA-Moderna or Pfizer vaccines, or 2 months after a single-dose Janssen (Johnson & Johnson) vaccine. 

AZD-1222 (ChAdOx1 nCoV-19; AstraZeneca)


  • Pending EUA submission in United States; approved for use in United Kingdom and other countries 
  • Phase 3 trials in United States completed March 2021 
  • Phase 3 trial in United Kingdom planned to assess safety and immune response in children and young adults aged 6 to 17 years 

AZD-1222 (ChAdOx1 nCoV-19; AstraZeneca) is a replication-deficient chimpanzee adenoviral vector vaccine containing the surface glycoprotein antigen (spike protein) gene. It is administered as a two-dose series 28 days apart. 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 in 2019, 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 62.1% efficacy when given as two 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% (P < .0001 for all). From 21 days after the first dose, 10 patients in the control group were hospitalized for COVID-19 (2 severe, 1 death).[38]  Concerns about the clinical trial implementation and data analysis have emerged because the half-dose regimen was not in the approved study design.[39]  These concerns will be addressed by regulatory agencies and await publication of the trial data. 

In another trial, researchers studied the second vaccine dose administered at 3 months after the first dose instead of at 1 month. After the initial 21-day exclusion period, there were no hospitalizations in the vaccine group compared with 15 in the control group. Vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 was 76%. Modelled analysis indicated that protection did not wane during the initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90. In the group that received two doses of the standard dose, vaccine efficacy was higher with a longer prime-boost interval (3 months) compared with an interval less than 6 weeks (82.4% vs 54.9%, respectively).[40]

Nasal swabs were obtained from trial participants every week in the UK study, regardless of symptoms. This allowed assessment of the overall impact of the vaccine on risk for infection, and thus was a surrogate for potential onward transmission. A single standard dose of AZD-1222 reduced PCR positivity by 67%, and after the second dose, reduced PCR positivity by 49.5% overall. These data indicate that ChAdOx1 nCoV-19, used in the authorized schedules, may have a substantial impact on transmission by reducing the number of infected individuals in the population.[40]  

Thrombosis with thrombocytopenia syndrome (TTS) 

Cases of thrombosis with thrombocytopenia with the Ad26.COV2.S (Janssen [Johnson & Johnson]) and AZD-1222 (ChAdOx1 nCoV-19; AstraZeneca) vaccines have been reported. The FDA temporarily paused use of Ad26.COV2.S in mid-April 2021 to allow the CDC's Advisory Committee on Immunization Practices (ACIP) to evaluate rare cases of cerebral venous sinus thrombosis. After discussing the benefits and risks of resuming vaccination, ACIP reaffirmed its interim recommendation for use of the Janssen COVID-19 vaccine in all persons aged 18 years and older under the FDA’s EUA. The EUA now includes a warning that rare clotting events may occur after vaccination, primarily among women aged 18 to 49 years. The risks for death and serious outcomes of COVID-19, including thrombosis, far outweigh the risk for TTS possibly associated with highly efficacious vaccines.[41]   

Thrombocytopenia syndrome is a rare syndrome that involves acute venous or arterial thrombosis and new-onset thrombocytopenia in patients with no known recent exposure to heparin. Although the mechanism that causes TTS is not fully understood, it appears similar to heparin-induced thrombocytopenia, a rare reaction to heparin treatment. In the United States, 12 of 15 persons with TTS that occurred after Janssen COVID-19 vaccination had CVST with thrombocytopenia.[41]   

The American Society of Hematology and the American Heart Association/American Stroke Association have published documents for clinicians to be aware of symptoms, diagnosis, and urgent treatment if TTS is suspected.  

Diagnosis includes the following four criteria:

  • COVID vaccine (Johnson & Johnson/AstraZeneca only to date) 4 to 30 days previously  
  • Venous or arterial thrombosis (often cerebral or abdominal) 
  • Thrombocytopenia 
  • Positive PF4 ‘HIT’ (heparin-induced thrombocytopenia) ELISA 

The following symptoms associated with TTS may emerge 4 to 30 days after vaccination with Ad26.COV2.S or AZD-1222:

  • Severe headache 
  • Visual changes 
  • Abdominal pain 
  • Nausea and vomiting 
  • Back pain 
  • Shortness of breath 
  • Leg pain or swelling 
  • Petechiae, easy bruising, or bleeding 

Protein Subunit Vaccines

NVX-CoV2373 (Novavax)


  • Phase 3 trial (PREVENT-19) demonstrated 90.4% overall efficacy and 100% protection against moderate-to-severe disease 
  • Crossover studies initiated in ongoing trials in South Africa, the United Kingdom, and the United States in March/April 2021 to ensure all participants receive vaccine
  • Trial in adolescents aged 12 to 17 years has enrolled 2248 participants as of mid-June 2021 with enrollment goal of 3000 across 75 US sites 
  • Refrigerate (2-8ºC) for shipping and storage; solution for IM injection 

NVX-CoV2373 (Novavax) is engineered using recombinant nanoparticle technology from SARS-CoV-2 genetic sequence to generate full-length, prefusion spike (S) 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. It is administered as a two-dose series given 21 days apart. 

The PREVENT-19 phase 3 clinical trial demonstrated overall efficacy of 90.4%. Results are based on 77 cases of symptomatic COVID-19 that investigators observed among trial participants from January 25 through April 30, 2021. There were 63 cases among the approximately 10,000 participants who received placebo and 14 cases among the approximately 20,000 participants who received the investigational vaccine. Of the 63 COVID-19 cases in the placebo group, investigators classified 10 as moderate and four as severe. There were no cases of moderate or severe disease in the investigational vaccine group.[42]   

The phase 3 trial in the United Kingdom has completed enrollment and the phase 2b trial in South Africa has reported final results.[43]  Results of these trials are timely, as new circulating viral variants in the United Kingdom and South Africa have emerged during the trials. 

UK phase 3 results [43]

The study randomized 15,187 adults aged 18 to 84 years, including 27.9% older than 65 years. There were 14,039 participants who were included in the per-protocol efficacy population. 

  • Final analysis based on 106 cases (96 placebo, 10 who received NVX-CoV2373) 
  • 101 cases were mild or moderate; five were severe (placebo group); four of the five attributed to B.1.1.7 variant (UK strain) 
  • Overall efficacy: 89.7%
  • Calculated efficacy alpha (B.1.1.7) variant: 86.3%
  • Calculated efficacy original virus: 96.4%

South Africa phase 2b results [44]

Among over 6000 participants who underwent screening, 4387 patients received at least one injection of vaccine or placebo beginning in August 2020, with COVID-19 cases counted from September through mid-January. During this time, the triple mutant variant, containing three critical mutations in the RBD and multiple mutations outside the RBD, was widely circulating in South Africa.

  • 60.1% efficacy for the prevention of mild, moderate, and severe COVID-19 disease was observed in the study population that was baseline seronegative and HIV-negative
  • 49.4% overall efficacy with results from both patient populations (ie, HIV positive and negative) 
  • 100% protection against severe disease observed, including all hospitalization and death

Viral Variants and Vaccines


Viral mutations may naturally occur anywhere in the SARS-CoV-2 genome. Unlike the human DNA genome, which is slow to mutate, RNA viruses are able to readily, and quickly, mutate. A mutation may alter the viral function (eg, enhance receptor binding), or may have no discernable function. A new virus variant emerges when the virus develops one or more mutations that differentiate it from the predominant virus variants circulating in a population. The CDC surveillance of SARS-CoV-2 variants includes US COVID-19 cases caused by variants. The site also includes which mutations are associated with particular variants. The CDC has launched a genomic surveillance dashboard and a website tracking US COVID-19 case trends caused by variants. Researchers are studying how variants may or may not alter the extent of protection by available vaccines. 

Variants of concern

Variants of concern (VOCs) may reduce vaccine effectiveness, which may be evident by a high number of vaccine breakthrough cases or a very low vaccine-induced protection against severe disease. The CDC tracks variant proportions in the United States. 

Omicron VOC

The omicron variant (B.1.1.529), initially identified in South Africa, was declared a variant of concern in the United States by the CDC November 30, 2021. This VOC contains several dozen mutations, including a large number in the spike gene, more than previous VOCs. These mutations include several associated with increased transmission. Facts regarding if this variant is more transmissible are not yet available; however, extrapolation from other variants and the mutations they include suggest omicron may be more easily transmitted. As of early December, it is unclear how this variant will affect vaccine or monoclonal antibody treatment efficacy, although the available vaccines are expected to be effective at preventing severe illness, hospitalizations, and deaths.[45]   

In a December 8, 2021 press release, Pfizer-BioNTech announced that preliminary laboratory studies demonstrate that three doses of the BNT-162b2 COVID-19 vaccine neutralizes the omicron variant (B.1.1.529 lineage) whereas neutralization titers are significantly reduced with two doses.[46]   Additional observations from the preliminary evaluation are as follows: 

  • Data indicate that a booster dose of BNT162b2 increases the neutralizing antibody titers by 25-fold compared with two doses against the omicron variant; titers after the booster dose are comparable to titers observed after two doses against the wild-type virus that are associated with high levels of protection. 
  • As 80% of epitopes in the spike protein recognized by CD8+ T cells are not affected by the mutations in the omicron variant; two doses may still induce protection against severe disease.

Delta VOC 

On June 15, 2021, the CDC named the delta variant (B.1.617.2) that originated in India a variant of concern in the United States. As of mid-June 2021, the CDC estimates the delta variant accounts for 10% of new cases in the United States. By mid-July 2021 it accounted for approximately 80% of cases. As of December 2021, it still accounted for nearly 100% of cases. 

Previous VOCs

Enhanced genomic surveillance in some countries detected other VOCs earlier in 202 and 2021. Examples include B.1.351 (501Y.V2) first detected in South Africa and the B.1.1.28 (renamed P.1) (501Y.V3), which was detected in four travelers from Brazil during routine screening at the Tokyo airport.[47]  A change of the B.1.1.7 variant that includes the E484K mutation (B.1.1.7 + E484K) was discovered in early 2021 that furthers these concerns. The CDC is also tracking VOCs B.1.427 and B.1.429, which emerged in California. 

The immune response provoked by vaccines includes protection from the antigen by eliciting antibodies, T cells, and interferons. Variants that have emerged in the United Kingdom and South Africa in late 2020 have multiple mutations in their S glycoproteins (ie, the spike protein), which are key targets of currently available vaccines.[48]  

BNT162b2 vaccine

In a December 8, 2021 press release, Pfizer-BioNTech announced that preliminary laboratory studies demonstrate three doses of the BNT-162b2 COVID-19 vaccine neutralizes the omicron variant (B.1.1.529 lineage) whereas two doses show significantly reduced neutralization titers.[46]  

A two-thirds reduced neutralization of BNT162b2 vaccines against the B.1.351 variant was shown in vitro when compared with the reference viral strain.[49]  

Other in vitro studies comparing sera of neutralizing antibody titers from participants in vaccine studies described use of sera from BNT162b2 SARS-CoV-2 vaccine showed no reduction in neutralization of pseudoviruses bearing the B.1.1.7 variant (ie, UK variant)[48, 50]  and the B.1.351 variant (ie, South African variant).[48]  

However, another study suggests that antibodies elicited by primary infection and by the BNT162b2 mRNA vaccine are likely to maintain protective efficacy against B.1.1.7 and most other variants, but that the partial resistance of virus with the B.1.351 spike protein could render some individuals less well protected, supporting a rationale for the development of modified vaccines containing the E484K mutation.[51]  

The delta variant (B.1.617.2) that was first identified in India became the dominant variant in the United States mid-July 2021. Edra et al found this variant 6.8-fold more resistant to neutralization by sera from COVID-19 convalescent and mRNA vaccinated individuals.[52]  However, a study completed by Public Health England found the BNT162b2 vaccine was slightly reduced from 93.7% with the B.1.1.7 variant to 88% for the delta variant 2 weeks after the second dose.[53]   Another UK analysis found neutralizing antibodies among single-dose recipients are significantly lower against B.1.617.2 and B.1.351 VOCs relative to B.1.1.7, implying that although a single dose might still afford considerably more protection than no vaccination, single-dose recipients are likely to be less protected against these SARS-CoV-2 variants.[54]  These data stress the importance of receiving two doses and adhering to the typical regimen of injections approximately 3 weeks apart. 

mRNA-1273 vaccine

Similarly, the mRNA-1273 vaccine neutralizing capabilities were assessed against the UK and South African variants. No significant impact on neutralization against the B.1.1.7 variant was detected in the first phase of testing and reported in February 2021. In contrast, just a month later, decreased titers of neutralizing antibodies were observed against the P.1 variant, the B.1.427/B.1.429 variant (versions 1 and 2), the B.1.1.7+E484K variant, and the B.1.351 variant as well as a subset of its mutations in the RBD. The researchers detected reductions by a factor of between 2.3 and 6.4 in titers of neutralizing antibodies against the tested panel of variants. The largest effect on neutralization, reduction by a factor of 6.4, was measured against the B.1.351 variant.[55]   

Edra et al estimated the delta variant (B.1.617.2), first identified in India, to be 6.8-fold more resistant to neutralization by sera from COVID-19 convalescent and mRNA vaccinated individuals.[52]  

A slight decrease in neutralization is not considered to be clinically significant regarding vaccine efficacy, owing to the very high efficacy of each mRNA vaccine (ie, approximately 95%) to the Wuhan reference viral strain. Continued variant surveillance in both nonhuman primates and humans will allow foresight for any needed changes to vaccine development or future booster doses that may be warranted. In February, 2021, Moderna announced it is advancing its variant-specific vaccine candidate, mRNA-1273.351, against the B.1.351 variant first identified in South Africa into preclinical studies and a Phase 1 study in the United States. A multivalent booster candidate, mRNA-1273.211, which combines mRNA-1273 and mRNA-1273.351 in a single vaccine and a third lower-dose of mRNA-1273 vaccine have also been forwarded to the National Institutes of Health for phase 1 clinical testing. 

NVX-CoV2373 vaccine

Novavax confirmed preliminary efficacy results for NVX-CoV2373 vaccine from the phase 3 trial in the United Kingdom (n > 15,000). The final analysis showed vaccine efficacy of 96.4% against the original strain of SARS-CoV-2.[43]  

Final analysis from the Phase 2b trial (n > 4,400) conducted in South Africa for NVX-CoV2373 reported 55.4% efficacy among HIV-negative participants. The South African escape variant was the predominant variant (more than 90% of cases analyzed).[43]  

Ad26.COV2.S vaccine

Johnson & Johnson reported phase 3 trial results (EMSEMBLE; n= 43,783) for their single-dose Ad26.COV2.S viral vector vaccine in late January 2021. The trial was conducted in geographic regions and during the time when several variants emerged. FDA analysis of the data at Day 28 determined the vaccine was 72% effective in the United States, 61% in Latin America, and 64% in South Africa at preventing moderate-to-severe COVID-19 infection. Importantly, the vaccine was 85% effective in preventing severe disease and provided complete protection against COVID-related hospitalization and death in all geographic regions. Additionally, it showed consistent protection across all variants and regions studied, including South Africa where nearly all cases of COVID-19 (95%) were due to infection with a SARS-CoV-2 variant from the B.1.351 lineage.[37]  

AZD-1222 (ChAdOx1 nCoV-19) vaccine

A study in the United Kingdom between October 1, 2020 and January 14, 2021 determine efficacy of AZD-1222 against the B.1.1.7 variant is similar to the efficacy of the vaccine against other lineages.[56]   

Minimal protection against mild-to-moderate COVID-19 infection from the B.1.351 variant in South Africa was observed following two doses in non-HIV infected young adults (n ~2000). Mild-to-moderate COVID-19 developed in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9%. Among the 42 participants with COVID-19, 39 cases (92.9%) were caused by the B.1.351 variant. The incidence of serious adverse events was balanced between the vaccine and placebo groups. These results prompted South Africa to halt rollout of the vaccine in early February.[57]  

A study completed by Public Health England found two-dose effectiveness reduced from 66.1% for the B.1.1.7 variant to 59.8% for the B.1.617.2 variant (delta) first identified in India, which is the dominant variant in the United Kingdom as of Spring 2021.[53]


COVID-19 Vaccination During Pregnancy or Lactation

On August 11, 2021, the CDC endorsed vaccination for persons who are pregnant, breastfeeding, trying to get pregnant, or who might become pregnant in the future. The American College of Obstetricians and Gynecologists (ACOG) guidelines regarding vaccination concur with the CDC guidelines.

Data from the CDC concluded pregnant individuals are at an increased risk for severe illness from coronavirus disease 2019 (COVID-19) and death, compared with nonpregnant individuals. In addition, pregnant persons may be at increased risk for other adverse outcomes (eg, preterm delivery). Owing to these risks, preventing severe COVID-19 infection is essential for both mother and fetus. 

Preliminary findings regarding safety of mRNA COVID-19 vaccines during pregnancy from the CDC v-safe registry did not show obvious safety signals.[58]  Additional data were analyzed from the CDC v-safe registry among 2456 individuals who received an mRNA COVID-19 vaccine preconception or prior to 20 weeks’ gestation. No increased risk for spontaneous abortion was shown.[59]  

A cohort study (n = 131) by Gray et al found mRNA SARS-CoV-2 vaccines generated humoral immunity in pregnant and lactating persons, similarly to that observed in nonpregnant individuals. All serum titers from vaccination were significantly higher compared with titers induced by SARS-CoV-2 infection during pregnancy (P< 0.0001). Importantly, vaccine-generated antibodies were present in all umbilical cord blood and breastmilk samples, showing immune transfer to neonates vial placenta and breastmilk.[60]  In another study, maternal and cord blood sera were collected from 20 parturients who received two doses of the mRNA BNT162b2 vaccine. All mothers and infants were positive for anti S- and Anti-RBD-specific IgG.[61]  

Additional studies support the above findings in cord blood and provide further information regarding potential timing of maternal vaccination. In one study (n = 27), mean placental IgG transfer ratio following vaccination (mRNA vaccines) provides about an equal in infant antibody level to maternal level. It also appears to increase with latency from vaccination, suggesting that earlier vaccination in the third trimester may produce greater infant immunity.[62]   A similar study (n = 122) observed women vaccinated with mRNA vaccines lead to maternal antibody production as soon as 5 days after the first dose and passive immunity to the neonate as soon as 16 days. The placental IgG transfer ratio increased over time.[63]  Collier et al observed binding, neutralizing, and functional nonneutralizing antibody responses, as well as CD4 and CD8 T-cell responses were present in pregnant, lactating, and nonpregnant women following vaccination. Binding and neutralizing antibodies were also observed in infant cord blood and breast milk. Binding and neutralizing antibody titers against the SARS-CoV-2 B.1.1.7 and B.1.351 variants of concern were reduced, but T-cell responses were preserved against viral variants.[64]

Researchers studied placentas of pregnant individuals vaccinated with mRNA vaccines after delivery. mRNA vaccines induce an immune response through activation of TLR3, which has been linked to decidual arteriopathy, growth restriction, preterm delivery, and fetal loss in mouse models. Placental examination in women with vaccination showed no increased incidence of decidual arteriopathy, fetal vascular malperfusion, low-grade chronic villitis, or chronic histiocytic intervillositis compared with women in the control group. Incidence of high-grade chronic villitis was higher in the control group than in the vaccinated group.[65]  


Other Investigational Vaccines

Additional vaccine candidates are in various stages of development and clinical testing. Examples of these vaccines are provided in Table 2.

Table 2. Other Investigational Vaccines (Open Table in a new window)

Vaccine Comments

INO-4800 (Inovio Pharmaceuticals)[66]

DNA-based, 2-dose vaccine. Stable at room temperature for more than 1 y; frozen shipment not needed. Phase 3 trial (INNOVATE) in Latin America, Asia, and Africa starting Fall 2021 using 2 mg-dose (showed high T-cell response in phase 2 trial). Another study evaluating heterologous boost dose using INO-4800 and CoronaVac (in China). 

CVnCoV (CureVac)[67]

mRNA, 2-dose vaccine. Phase 3 study conducted in 10 countries in Europe and Latin America. 15 variant strains were present for efficacy analysis and the original strain was almost completely absent. Vaccine efficacy was 48% for any severity across all age groups and 15 variants. Efficacy among participants aged 18-60 years showed 53% against any severity, 77% against moderate and severe disease, and full protection against hospitalization or death.  
Recombinant protein adjuvanted vaccine (SP0253; Sanofi and GSK) [68]

Interim phase 2 results (n = 722) showed 95-100% seroconversion after 2 doses with strong neutralizing antibody levels comparable to natural infection. After a single injection, high neutralizing antibody levels were generated in participants with evidence of prior SARS-CoV-2 infection, suggesting strong potential for development as a booster vaccine. Phase 3 trial in the United States, Asia, Africa, and Latin America started in late May 2021 with target enrollment of 35,000.

S-Trimer with CpG 1018 adjuvanted vaccine (Clover and Dynavax) [69]   Phase 2/3 trial (SPECTRA) of Clover’s protein-based S-Trimer COVID-19 subunit vaccine adjuvanted with Dynavax’s CpG 1018 plus alum. Trial began in March 2021 in Latin America, Asia, Europe, and Africa. Administered as 2 doses, 21 days apart. 
VLA2001 with CpG 1018 adjuvant (Valneva and Dynavax) [70]   Inactivated whole virus vaccine. Phase 3 trial (Cov-Compare) in the United Kingdom will compare immunogenicity of VLA2001 with AZD-1222 in ~4,000 adults. 
UB-612 multitope peptide-based vaccine (COVAXX [United Biomedical, Inc]) [71]  

Comprised of 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. Starting phase 2 trial in Taiwan and phase 2/3 trial in Brazil in Q1 2021. Covaxx is merging with its sister company (United Neuroscience) to form a new company call Vaxinity to include both companies’ vaccine platforms. 

CoVLP (Medicago and GlaxoSmithKline) [72]   Combines Medicago’s plant-based coronavirus virus-like particles (rCoVLP) with GSK’s adjuvant system. Phase 3 trial results announce December 2021 states overall efficacy rate against all variants of 71% and 75.3% against the delta variant. Regulatory submission in Canada has been initiated. A VLP COVID-19 booster trial slated for January 2022. 
COH04S1 (City of Hope Biomedical Research Institute, California) [27]   Viral vector vaccine based on weakened form of virus (modified vaccinia Ankara [MVA]). It is a multiantigenic SARS-COV-2 vaccine using a synthetic poxvirus platform. They added 2 coronavirus genes to the virus — 1 for the spike protein, and 1 for the nucleocapsid protein. The intent is to enable the vaccine to produce immunity that is both fast and long-lasting. Phase 2 trial started August 2021 in patients who have received stem cell transplants.

Covaxin (BBV152; Bharat Biotech and Ocugen)[73]  

Whole-virion inactivated COVID-19 vaccine candidate. Developed and manufactured in Bharat Biotech’s bio-safety level 3 biocontainment facility. Co-development with Ocugen announced for the US market. Received EUA in India in January 2021 after a fully enrolled phase 3 trial (n ~25,800). Interim phase 3 results reported March 2021 in India reported 81% efficacy. Second interim analysis of phase 3 results in late April 2021 found 78% efficacy against mild-to-moderate infection and 100% efficacy against severe COVID-19. Plans to pursue full US approval (biologics license application [BLA]) instead of an EUA upon recommendation from the FDA. 

Recombinant adenovirus type-5-vectored vaccine (Ad5-vectored vaccine; Sinopharm [China]) [74]   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. Approved in UAE for children aged 3-17 years in August 2021 based on 900 tiral participants. World Health Organization approved vaccine for emergency use in May 2021 to improve distribution to poorer nations via Covax. 
CoronaVac (Sinovac [China]) [75]   Inactivated vaccine. 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). A prospective national cohort study (N ~10.2 million) in Chile (February 2 through May 1, 2021) showed efficacy of 65.9% for prevention of COVID-19, 87.5% for prevention of hospitalization, 90.3% for prevention of ICU admission, and 86.3% for prevention of COVID-19 – related death. 
rAd26 (frozen) and rAd5 vector-based (lyophilized) formulations (Sputnik V; Moscow Gamaleya Institute) [76] Approved in Russia. Each vaccine vector carries gene for full-length SARS-CoV-2 glycoprotein S. The phase 3 trial administered 2 doses, 21 days apart (rAd26 then rAd5) assigned in a 3:1 ratio of vaccine (n = 16,501) or placebo (n = 5,476). Interim analysis of results 21 days after first dose (ie, day of dose 2) confirm COVID-19 infection in 0.1% of the vaccine group compared with 1.3% of the placebo group. Vaccine effectiveness, 91.3%. 
hAd5 T-cell (ImmunityBio and NantKwest) [77]  

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. Starting trials of booster in South Africa late 2021. 

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.

Phase 1 trial expanded to include the initial SC prime vaccine with a room-temperature oral or sublingual booster to induce comprehensive immune protection and generate both systemic and mucosal antibodies. 

MRT5500 (Sanofi and Translate Bio) [78] mRNA-based vaccine candidate; preclinical evaluation demonstrated favorable ability to elicit neutralizing antibodies using a 2-dose schedule administered 3 wk apart in Fall 2020. Despite this, Sanofi announced the vaccine will not be ready to start clinical trials until second half of 2021 and it could be of use at a later stage against variants. 
AG0302-COVID19 (AnGes and Brickell Biotech) [79]   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. Results expected in Q3 2021. 
SARS-CoV-2 spike ferritin nanoparticle (spFN) vaccine with ALFQ adjuvant (Walter Reed Army Institute of Research) [80]   Phase 1 study launched April 1, 2021. Preclinical trial in monkeys showed 2-dose vaccine delivered high antibody levels. Development plans include new vaccine version with proteins from other coronaviruses. 

Noninjectable Investigational Vaccines

Routes of vaccine administration other than injection are also undergoing development.

Table 3. Noninjectable Investigational Vaccines (Open Table in a new window)

Noninjectable Vaccine Comments
hAd5 T-cell  (ImmunityBio and NantKwest) [77]  

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. 

Phase 1/2 trial studying the safety, reactogenicity, and immunogenicity of a SC and orally administered supplement vaccine to enhance T cell based immunogenicity in patients who already received vaccine authorized for emergency use. 

MV-014-212 (Meissa Vaccines) [81]  

Intranasal live attenuated vaccine. Generates both mucosal IgA antibodies in nasal cavity and systemically circulating antibodies. The company created the SARS-CoV-2 intranasal vaccine using their existing RSV vaccine platform. Phase 1 dose-escalating study announced in March 2021. 

VXA-CoV2-1 oral vaccine (Vaxart) [82]   Recombinant adenovirus vector type 5 (Ad5) expressing coronavirus antigen and a toll-like receptor 3 (TLR3) agonist as an adjuvant. Preliminary phase 1 trial (n = 495) showed induced CD8 T-cell responses to the viral spike protein. Neutralizing antibodies not detected in most subjects. Company is evaluating optimal dosing schedule in order to assess efficacy in phase 2 trials. 
Transdermal microneedle COVID-19 vaccines (U of Pittsburgh; U of Connecticut; Vaxess Technologies, Verndari) [83]   Preclinical trial. Various universities and companies are working with transdermal microneedle delivery for COVID-19 vaccines. Testing in mice produced antibodies over a 2-wk period; microneedles are made of sugar, making it easy to mass-produce and store without refrigeration.
Triple antigen oral vaccine (Oravax)  Preclinical trial. Oravax is a collaboration between Premas Biotech and Oramed Pharmaceuticals. Clinical trial planned for mid-2021. 
Oral vaccine (Esperovax)  Preclinical trial. Gained funding from BARDA for research on oral vaccine platform. 
Intranasal COVID-19 vaccine (Altimmune, Inc) [84]  

Study terminated.

Phase 1 dose-ranging study (AdCOVID) of 1 or 2 intranasal doses in participants aged 18-55 years showed an inferior immune response compared with intranasal vaccines given to individuals with prior immunity (eg, influenza). 



Questions & Answers