COVID-19 Vaccines 

Updated: Jun 18, 2022
Author: David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS; Chief Editor: John L Brusch, MD, FACP 

Overview

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.[1] As of June 13, 2022, The New York Times Coronavirus Vaccine Tracker lists 2 mRNA vaccines (Comirnaty by Pfizer and Spikevax by Moderna) that have gained full approval by the US Food and Drug Administration (FDA). One other, a viral vector vaccine (Janssen), has an emergency use approval (EUA) in the United States. An EUA was requested January 31, 2022 for a protein subunit vaccine by Novavax. Globally, 12 vaccines are approved for full use, 19 vaccines are authorized for early or limited use, and 40 vaccines are in phase 3 clinical trials.[2]  Numerous antiviral medications and immunotherapies are under investigation for coronavirus disease 2019 (COVID-19). 

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.[3]  Vaccine efficacy (VE) has shown to wane over time following an initial 2-dose primary series with the mRNA vaccines and the 1-dose regimen with the Janssen vaccine.[4]  Booster shots have improved VE.[5, 6]  Other variables also affect VE (eg, SARS-CoV-2 variant properties, immunosuppressive conditions). 

Table 1. CDC Interim COVID-19 Immunization Schedule (Open Table in a new window)

Product / Age Primary Series  Booster(s) Immunocomromised
Pfizer-BioNTech  6 month to < 5 years 3 doses: 3 mcg Give first 2 doses 3 weeks apart, then third dose at least 8 weeks after 2nd dose  Not applicable  Not applicable 

Moderna 

6 months through 5 years

2 doses: 25 mcg IM 4 weeks apart Not applicable  3-dose primary series: Give 3rd dose at least 4 weeks after dose 2

Pfizer-BioNTech 

5-11 years

2 doses: 10 mcg IM 3 weeks apart Booster 1: At least 5 months after primary dose 2

3-dose primary series: Give 3rd dose

at least 4 weeks after dose 2 

Booster 1: At least 5 months after primary dose 2

Moderna

 6-11 years 

2 doses: 50 mcg IM 4 weeks apart Not applicable 3-dose primary series: Give 3rd dose at least 4 weeks after dose 2

Pfizer-BioNTech 

12-17 years

2 doses: 30 mcg IM 3-8 weeks apart

Booster 1: At least 5 months after primary dose 2

3-dose primary series: Give 3rd dose at least 4 weeks after dose 2 

Booster 1: At least 3 months after primary dose 3 

Booster 2: At least 4 months after booster 1

Moderna 

12-17 years 

2 doses: 100 mcg 4-8 weeks apart Not applicable 3-dose primary series: give 3rd dose at least 4 weeks after dose 2

Pfizer-BioNTech 

18 years and older

2 doses: 30 mcg IM 3-8 weeks apart

First booster: At least 5 months after dose 2

 

Booster 2 for 50 years and older: At least 4 months after  booster 1

3-dose primary series: Give 3rd dose at least 4 weeks after dose 2 

Booster 1: At least 3 months after primary dose 3  

Booster 2: At least 4 months after booster 1

Moderna 

18 years and older

2 doses: 100 mcg IM 4-8 weeks apart

Booster 1: 50 mcg at least 5 months after primary dose 2 

 

Booster 2 for 50 years and older: At least 4 months after booster 1

3-dose primary series: Give 3rd 100-mcg dose at least 4 weeks after dose 2

Booster 1: 50 mcg at least 3 months after primary dose 3

Booster 2: At least 4 months after booster 1

Janssen 

18 years and older

 

Only recommended for who for whom other FDA-authorized or approved COVID-19 vaccines are not accessible or clinically appropriate, OR would not accept another vaccine 

1 dose

Booster 1: At least 8 weeks after completing primary series 

 

Booster 2 for 50 years and older (mRNA vaccine only): At least 4 months after booster 1

2-dose primary series: 2nd dose MUST be a mRNA vaccine given at least 28 days after dose 1 

Booster 1 (mRNA vaccine only): At least 8 weeks after primary dose 2 

Booster 2 (mRNA vaccine only): At least 4 months after booster 1

For more information, see the CDC Interim COVID-19 Immunization Schedule

 

mRNA Vaccines

Comirnaty (BNT-162b2; Pfizer)

Overview

  • June 17, 2022: EUA extended to include children aged 6 months through 4 years 
  • May 17, 2022: FDA authorized single booster dose for children aged 5-11 years 
  • March 29, 2022: FDA authorized second booster dose for adults aged 50 years and older or those 12 years and older who are immunosuppressed 
  • February 11, 2022: Pfizer extends rolling submission to FDA for EUA in children aged 6 months through 4 years to include data for a 3-dose primary series in this age group 
  • 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: EUA 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 12-15 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 

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.[7]  

Efficacy data was reported in April 2021 of 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.[8]

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.[9]  

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.[10]  

Vaccine efficacy was confirmed with real-world data from a data provided by a large health provider in Israel. The primary outcome was incidence rate of a SARS-CoV-2 infection confirmed with real-time polymerase chain reaction (rt-PCR), between 7 and 27 days after second dose (protection-period), and compared to days 1-7 after the first dose, where no protection by the vaccine is assumed (reference-period). Data of 1,178,597 individuals vaccinated with BNT162b2 were analyzed of whom 872,454 (74%) reached the protection period. Overall, 4,514 infections occurred during the reference period compared with 728 during the protection period, yielding a weighted mean daily incidence of 54.8 per 100 000 and 5.4 per 100 000, respectively. Vaccine effectiveness in preventing infection was 90% and 94% against COVID-19. Among immunosuppressed patients, vaccine effectiveness against infection was 71%.[11]

Spikevax (mRNA-1273; Moderna)

Overview

  • June 17, 2022: EUA extended to include children aged 6 months through 17 
  • March 29, 2022: FDA authorized 2nd booster dose for adults aged 50 years and older or those 18 years and older who are immunosuppressed
  • March 23, 2022: Requested EUA for children aged 6 months through 5 years 
  • January 31, 2022: FDA grants full approval for 2-dose primary series for adults 
  • 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
  • August 12, 2021: EUA granted for third dose for individuals aged 18 years and older who have undergone solid organ transplantation or who  have conditions with equivalent level of immunocompromise
  • December 2020: EUA in the United States for adults aged 18 years and older 

Spikevax encodes the S-2P antigen. It is administered as a two-dose primary 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.[12]  

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%).[12]  An updated analysis to determine effectiveness included 14,287 vaccine recipients and 14,164 placebo recipients 18 years of age and older who did not have evidence of SARS-CoV-2 infection beofre receiving the first dose. The data used for the analyses were accrued before the Omicron variant emerged. These data demonstrated that the vaccine was 93% effective in preventing COVID-19, with 55 cases of COVID-19 occurring in the vaccine group and 744 COVID-19 cases in the placebo group. The vaccine was also 98% effective in preventing severe disease.[13]  

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.[14]  

Booster Doses 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 (as of January 2022, this interval was reduced to 5 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. 

A second mRNA vaccine booster (ie, 4th dose) was authorized in March, 2022 for adults aged 50 years and older at least 4 months after the first booster of any authorized/approved COVID-19 vaccine. Individuals who are immmunosuppressed may also receive a second booster (ie, 5th dose) with the Pfizer vaccine (aged 12 years and older) or Moderna vaccine (aged 18 years and older). The decision to authorize a second booster was based on evidence that suggests vaccine protection wanes over time against serious COVID-19 infection in older adults and immunocompromised individuals.[5]

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

Studies in immunocompetent individuals 

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.[4]

Booster doses implemented in the United States in the autumn of 2021 provided protection from severe COVID-19 disease, hospitalization, and death. Data collected by the CDC during the omicron variant surge in January and February 2022 showed profoundly different outcomes on progression to hospitalization and/or death between vaccinated and unvaccinated individuals. Hospitalization was 2.2, 5, 7, and 9 times higher in unvaccinated people aged 12-17 years, 18-49 years, 50-64 years, and 65 years and older respectively. Additionally, those who had received a booster dose had a much lower rate of hospitalization, particularly with advancing age.[15]  In January 2022, unvaccinated people aged 12 years and older had a 3.5 times higher risk of testing positive for COVID-19 and a 21 times higher risk of dying from COVID-19 compared with people vaccinated with a primary series and a booster dose.[15]   

The CDC examined vaccine efficacy at 21 US medical centers during March 11, 2021 through January 24, 2022. Among recipients of 2 vaccine doses, vaccine efficacy was 92% at 14-150 days after receipt of the second dose versus 84% at more than 150 days postvaccination. Vaccine efficacy was 94% among recipients of 3 vaccine doses. Among immunocompetent adults with no chronic medical conditions, efficacy for 2 or 3 vaccine doses was 98%. Efficacy was lowest among adults with immunocompromising conditions (74%). However, among 123 vaccinated COVID-19 case-patients with immunocompromising conditions, only 17 (14%) had received 3 vaccine doses and were considered fully vaccinated. During the omicron period, efficacy against invasive mechanical ventilation or in-hospital death was 79% for recipients of 2 doses and 94% for recipients of 3 doses.[16]  

Emerging data from an open-label study in Israel supported the decision to authorize a second mRNA booster. Patients received either BNT162b2 (n = 154) or mRNA-1273 (n = 120) 4 months after their first booster dose. Both vaccines induced an increase in live neutralization of the B.1.1.529 (omicron) variant and other viral strains by approximately 10-fold. Using weekly PCR testing during a time of high omicron variant transmission, results showed 25% of participants in the control group were infected with the omicron variant, compared with 18.3% in the BNT162b2 group, and 20.7% of those in the mRNA-1273 group. One limitation of this study was it was in a younger healthcare workforce, and thus, may only have marginal benefits. Older and vulnerable populations were not assessed.[5]  

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.[6]  

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 5 age groups (range 9.0 to 17.2). Severe illness and mortality also were lower among those aged 60 years and older in the booster group by a factor of 17.9 and 14.7, respectively.[17]  

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.[18]

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.[19]  

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.[20, 21, 22]  

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).[23]

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.[24]  

A case series of 7 solid organ transplant recipients describes confirmed COVID-19 infection after receiving an mRNA vaccine. Two individuals had received 1 dose and the others had received 2 doses. Six patients were tested for antispike antibodies, of which 5 had undetectable levels; one patient had received their second mRNA-1273 vaccine 44 days prior and had low titer antispike antibody. None of these 6 patients had detectable nucleocapsid antibody.[20]  Others have confirmed low or nondetectable antispike antibody levels and nucleocapsid antibodies.[21, 22]  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 0, 1, or 2 doses of BNT162b2 vaccine. Overall, vaccination reduced disease severity, but 11% of infected patients who had received 2 doses died. Patients on MHD with humoral response similar to healthy volunteers after 2 doses did not generate more immune effectors after a third dose, but had more side effects. In contrast, 66% of patients on MHD with suboptimal response after2 doses reached an optimal titer of anti-RBD IgG and/or developed spike-specific CD8+ T cells after a third dose.[25]   

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.[26]   

Cases of myocarditis and pericarditis emerged in May 2021 with possible correlation of COVID-19 mRNA vaccine administration. A case series of 7 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.[27]   

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%).[28]  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. 

Among 192,405,448 persons receiving a total of 354,100,845 mRNA-based COVID-19 vaccines from December 2020 to August 2021, there were 1,991 reports of myocarditis to VAERS and 1,626 of these reports met the case definition of myocarditis. The median age was 21 years (range 16-31 years) and the median time to symptom onset was 2 days. Males comprised 82% of the myocarditis cases for whom sex was reported.[29]  The CDC’s has released an immunization schedule with an 8 week interval between mRNA primary series doses, as may be optimal for some people, including males 12-39 years of age because of the small risk of myocarditis associated with mRNA COVID-19 vaccines. 

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])

Overview

  • May 5, 2022: EUA indication revised to include limited use (ie, for individuals whom other authorized/approved COVID-19 vaccines are not accessible or clinically appropriate, or the individual elects the AD26.COV2.S vaccine and would otherwise not receive a vaccine) 
  • 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.[30]

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.[31]  

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.[31]  

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 Doses 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. 

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. 

A second booster with an mRNA vaccine may be administered at least 4 months after the first booster in those aged 50 years and older, or who are at least 12 years older and are immunosuppressed. 

Vaccine efficacy against COVID-19–associated emergency department/urgent care visits was 24% after 1 Janssen dose, 54% after 2 Janssen doses, and 79% after 1 Janssen/1 mRNA dose, compared with 83% after 3 mRNA doses. Efficacy for the same strategies against COVID-19–associated hospitalization was 31%, 67%, 78%, and 90%, respectively.[32]   

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.[33]   

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.[33]   

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 4 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)

Overview

  • January 31, 2022: Request for EUA submitted to the FDA for immunization of adults
  • 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 2-dose series given 21 days apart. 

The PREVENT-19 phase 3 clinical trial in the United States and Mexico demonstrated overall efficacy of 90.4% (p < 0.001). Results showed 77 cases of symptomatic COVID-19 disease that investigators observed among trial participants from January 25 through April 30, 2021. There were 63 cases among 9,868 participants who received placebo and 14 cases among 19,714 participants who received the investigational vaccine. Of the 63 COVID-19 cases in the placebo group, investigators classified 10 as moderate and 4 as severe. There were no cases of moderate or severe disease in the investigational vaccine group.[34]   

The phase 3 trial in the United Kingdom has completed enrollment and the phase 2b trial in South Africa has reported final results.[35]  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 [35]

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 [36]

Among over 6000 participants who underwent screening, 4387 patients received at least 1 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 3 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

Mutations

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.[37]   

In a December 8, 2021 press release, Pfizer-BioNTech announced that preliminary laboratory studies demonstrate that 3 doses of the BNT-162b2 COVID-19 vaccine neutralizes the omicron variant (B.1.1.529 lineage) whereas neutralization titers are significantly reduced with 2 doses.[38]   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 2 doses against the omicron variant; titers after the booster dose are comparable to titers observed after 2 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; 2 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 4 travelers from Brazil during routine screening at the Tokyo airport.[39]  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.[40]  

BNT162b2 vaccine

In a December 8, 2021 press release, Pfizer-BioNTech announced that preliminary laboratory studies demonstrate 3 doses of the BNT-162b2 COVID-19 vaccine neutralizes the Omicron variant (B.1.1.529 lineage) whereas 2 doses show significantly reduced neutralization titers.[38]  

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.[41]  

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)[40, 42]  and the B.1.351 variant (ie, South African variant).[40]  

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.[43]  

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.[44]  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.[45]   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.[46]  These data stress the importance of receiving 2 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.[47]   

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.[44]  

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.[35]  

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).[35]  

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 it 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.[31]  

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.[48]   

Minimal protection against mild-to-moderate COVID-19 infection from the B.1.351 variant in South Africa was observed after 2 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.[49]  

A study completed by Public Health England found 2-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 was the dominant variant in the United Kingdom as of Spring 2021.[45]

 

Vaccination in Adolescents and Children

BNT162b2 (Pfizer)

The BNT162b2 mRNA vaccine has full FDA approval for individuals aged 16 years and older. It also authorized for emergency use for children and adolescents aged 6 months and older. It is administered as a 2-dose primary series with a booster dose given 5 months after completing the primary series. 

A 3-dose primary series is recommended for severely immunosuppressed patients aged 5 years and older. 

For children aged 6 months through 4 years, it is administered as a 3-dose primary series.   

Adolescents

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.[28]  

Among adolescents aged 12-18 years (median interval since vaccination, 162 days) during the Omicron-predominant period, vaccine efficacy was 40% against hospitalization, 79% against critical Covid-19, and 20% against noncritical Covid-19.[50]  

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.

School-aged children 

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 2 doses administered 3 weeks apart. A 3-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. 

In May 2022, the EUA for the Pfizer mRNA vaccine was updated to recommend a single homologous booster dose at least 5 months after completing a primary series with the Pfizer-BioNTech COVID-19 vaccine to individuals aged 5-11 years. 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 3 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. 

During the omicron period, vaccine effectiveness against hospitalization among children aged 5 to 11 years was 68% (median interval since vaccination, 34 days).[50]  

Younger children 

On June 17, 2022, the FDA extended the EUA for the BNT162b2 vaccine to include children aged 6 months through 4 years. It is administered as a 3-dose primary series

Clinical trials for 2 doses (3 mcg/dose) of the BNT162b2 vaccine in younger children aged 6 months through 4 years have been completed. While 2 doses of the vaccine generated antibody responses comparable to older groups in children ages 6 months to 2 years, adequate antibody responses did not develop in children ages 2 to 5 years. A third 3-mcg dose was well tolerated among 1,678 children aged 6 months to 5 years with safety similar to placebo. Vaccine efficacy was 80.3% with 3 doses during a time when the omicron variant was predominant.[51]  

mRNA-1273 (Moderna)

On June 17, 2022, the FDA authorized the mRNA-1273 vaccine for children aged 6 months and older as a 2-dose primary series. A 3-dose primary series is recommended for patients aged 6 months through 17 years with certain kinds of immunocompromise. 

Adolescents

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.[52]  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. 

Children aged 6-11 years

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 administered 28 days apart, with a favorable safety profile. These responses were noninferior to those in young adults.[53]  

Canada, Australia, and the European Union have also authorized use for this age group. 

Children 6 months through 5 years 

The mRNA-1273 vaccine successfully met its primary endpoint in the KidCOVE study in children 6 months to under 6 years. Two 25-mcg doses showed robust neutralizing antibody titers similar to adults. Although not a primary endpoint, statistically significant vaccine efficacy was observed during the omicron wave that was consistent with the lower two-dose effectiveness against omicron seen in adults.[54]   

SARS-Cov-2-neutralizing antibody geometric mean ratio (GMR) comparing the response in children 6 months to under 2 years to the response in young adults (aged 18-25 years) from the Phase 3 COVE study was 1.3 (95% Cl: 1.1, 1.5) and was 1.0 (95% Cl: 0.9, 1.2) for the 2 to under 6 years age group. This also predicts protection from COVID-19 and severe COVID-19 disease down to 6 months of age. 

The Omicron variant predominated in the United States during the study in these younger age groups. The secondary endpoint of vaccine efficacy confirms statistically significant, but lower efficacy against COVID-19 infection as expected during the Omicron wave and consistent with adult observational data. Using the Phase 3 COVE study COVID-19 definition, vaccine efficacy in children 6 months to 2 years was 43.7% and vaccine efficacy was 37.5% in the 2 to under 6 years age group. Similar to adults, a booster trial is anticipated.[55]   

Infants 3-6 months 

The BabyCOVE clinical trial in children aged 3-6 months is planned to start recruiting in September 2022.

NVX-CoV2373

NVX-CoV2373 (Novavax) is a recombinant protein-based vaccine. The vaccine achieved its primary effectiveness endpoint in the pediatric expansion of its PREVENT-19 phase 3 trial and demonstrated 80% efficacy overall at a time when the Delta variant was the predominant circulating strain in the United States. The study enrolled 2,247 participants across 73 sites.[56]  

 

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.[57]  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.[58]  

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.[59]  

Immune transfer to neonates

A nationwide, register-based cohort study included all live-born infants born in Norway between September 1, 2021, and February 28, 2022. Of 21,643 live-born infants, 9,739 (45%) were born to women who received a second or third dose of a COVID-19 vaccine during pregnancy. The first 4 months of life incidence rate of a positive test for SARS-CoV-2 was 5.8 per 10 000 follow-up days. The study found infants of mothers vaccinated during pregnancy had a lower risk of a positive test compared with infants of unvaccinated mothers (0.5% vs 1.5% during delta phase; 4j% vs 4.2% during omicron phase). Evidence showed a lower risk during the delta variant-dominated period (incidence rate 1.2 vs 3 per 10,000 follow-up days) compared with the omicron period 7 vs 10.9 per 10,000 follow-up days).[60]  

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.[61]  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.[62]  

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 an infant antibody level about equal 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.[63]   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.[64]  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 human 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.[65]  

Anti-S IgG titers in the umbilical cord are correlated with maternal titers and are highest after late second and early third trimester vaccination.[63, 64]  Durability of anti-spike antibodies in infants after maternal COVID-19 vaccination or natural infection has been studied. Vaccination resulted in significantly greater antibody persistence in infants than infection. At 6 months, 57% (16 of 28) of infants born to vaccinated mothers had detectable antibodies compared with 8% (1 of 12) of infants born to infected mothers (P = .005).[66]    

 

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 9 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.[67]  

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.[68]  

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.[69, 70, 71]  

 

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

 

 

CVnCoV (CureVac, GSK)[72]

Second generation mRNA vaccine. Phase 1 dose-escalation study is being conducted at clinical sites in the United States and is expected to enroll up to 210 healthy adults to evaluate the safety, reactogenicity and immunogenicity of CV2CoV. 

Recombinant protein adjuvanted vaccine (SP0253; Sanofi and GSK) [73]  

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. 

In December 2021, preliminary results following a single booster dose showed neutralizing antibodies increased 9- to 43-fold regardless of the primary vaccine receive. 

SCB-2019 with CpG 1018 adjuvant (Clover and Dynavax) [74]   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. Data reported in September 2021 showed 100% efficacy against severe COVID-19 and hospitalizations and 84% efficacy against moderate-to-severe COVID-19 disease for all strains (79% against delta variant). 
VLA2001 with CpG 1018 adjuvant (Valneva and Dynavax) [75]   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. Results showed VLA2001 demonstrated superiority against AZD1222 (ChAdOx1-S), in terms of geometric mean titer for neutralization antibodies. It was noninferior in terms of seroconversion rates (SCR above 95% in both treatment groups) at two weeks after the second vaccination. Tolerability profile of VLA2001 was significantly more favorable compared with ChAdOx1-S. COV-BOOST trial showed VLA2001 increased antibody and neutralizing responses. 
UB-612 multitope peptide-based vaccine (Vaxxinity) [76]  

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. Phase 2 trial of 3 doses showed high titers including antibody activity against multiple variants, including omicron. Covaxx merged with its sister company (United Neuroscience) to form a new company call Vaxxinity to include both companies’ vaccine platforms. 

CoVLP (Medicago and GlaxoSmithKline) [77]  

Combines Medicago’s plant-based coronavirus virus-like particles (rCoVLP) with GSK’s adjuvant system. Phase 3 trial results showed overall efficacy rate against all variants of 69.5% for any symptomatic COVID-19. It was 78.8% effective against moderate-to-severe disease and 74% effective among participants who were seronegative at baseline. Administered as 2-dose regimen 21 days apart. Gained approval in Canada in February 2022.  

ZF2001 (Zifivax; Anhui Zhifei Longcom Biologic Pharmacy Co) [78]   Protein subunit vaccine. Developed by using a dimeric form of the receptor-binding domain of the SARS-CoV-2 spike protein as the antigen. Adult participants (N = 25,193) were randomly assigned in a 1:1 to receive three 25-mcg doses (30 days apart) of ZF2001 or placebo. COVID-19 cases were reported in 158 of 12,625 participants in the ZF2001 group and in 580 of 12,568 participants in the placebo group, for a vaccine efficacy of 75.7%. Severe-to-critical Covid-19 occurred in 6 participants in the ZF2001 group and in 43 in the placebo group, for a vaccine efficacy of 87.6%. Covid-19–related death occurred in 2 and 12 participants, respectively, for a vaccine efficacy of 86.5%. 
COH04S1 (City of Hope Biomedical Research Institute, California) [19]   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. Two coronavirus genes were added 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. Results from an open label phase 1 found the vaccine was well tolerated and induced spike-specific and neucleocapsid-specific antibody and T-cell responses. Phase 2 trial started August 2021 in patients who have received stem cell transplants.

Covaxin (BBV152; Bharat Biotech and Ocugen)[79]  

Whole-virion inactivated COVID-19 vaccine candidate. Contains Algel-IMDG (TLR 7/8) adjuvant. Administered as a 2-dose primary series. 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. Sera from Covaxin boosted individuals showed neutralizing activity against D614G (vaccine strain), delta, and omicron variants. As of March 2022, working with FDA to evaluate regulatory pathway.

Recombinant adenovirus type-5-vectored vaccine (Ad5-vectored vaccine; Sinopharm [China]) [80]   Approved in China and Saudi Arabia; preliminary data: 86% efficacy (original strain); 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 trial participants. World Health Organization approved vaccine for emergency use in May 2021 to improve distribution to poorer nations via Covax. 
CoronaVac (Sinovac [China]) [81]   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) [82] 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) [83]  

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. Phase 2 trials of the booster are ongoing. 

AKS-452 (Akston Biosciences) [84]  

Shelf-stable, protein subunit vaccine. Received regulatory approval in the Netherlands to conduct a phase 2, open-label study as a booster. Phase 2/3 study for 2-dose primary series underway in India. Positive results from the trial, released in late 2021, suggested the vaccine could produce a significant immune response without adverse reactions. The study was expanded into a Phase 2/3 trial with 1,600 volunteers in 2022. 

AG0302-COVID19 (AnGes and Brickell Biotech) [85]   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) [86]   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. 
MRT5500 (Sanofi and Translate Bio) [87]

Study terminated

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. 

INO-4800 (Inovio Pharmaceuticals) [88]

May 15, 2022: Phase 3 trial discontinued; focusing on booster testing.

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). 

 

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) [83]  

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) [89]  

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) [90]   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. Phase 2 trial initiated October 2021. 
Transdermal microneedle COVID-19 vaccines (U of Pittsburgh; U of Connecticut; Vaxess Technologies, Verndari) [91]   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. Anticipates launching phase 2/3 trial in second half of 2022. 
Oral vaccine (Esperovax)  Preclinical trial. Gained funding from BARDA for research on oral vaccine platform. 
Intranasal COVID-19 vaccine (Altimmune, Inc) [92]  

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). 

 

 

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