COVID-19 Vaccines

Updated: Aug 26, 2022
  • Author: David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS; Chief Editor: John L Brusch, MD, FACP  more...
  • Print
Overview

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 August 12, 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). Two others, a viral vector vaccine (Janssen) and an adjuvanted protein subunit vaccine (Novavax), have emergency use approval (EUA) in the United States. Globally, 12 vaccines are approved for full use, 21 vaccines are authorized for early or limited use, and 42 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]  During this same time period, the Novavax vaccine showed 90.4% efficacy. [4] 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. [5]  Booster shots have improved VE. [6, 7]  Other variables also affect VE (eg, SARS-CoV-2 variant properties, immunosuppressive conditions). 

Table 1. CDC Interim COVID-19 Immunization Schedule for Children Aged 6 Months through 17 Years (Open Table in a new window)

Product Age

 Most People 

Doses and Intervals

Immunocompromised*

Doses and Intervals

Moderna 

(Blue vial cap/magenta

bordered label)

6 months through

5 years

Total doses: 2 

Dose 1 to 2: At least 4-8 weeks

Total doses: 3 

Dose 1 to 2: At least 4 weeks 

Dose 2 to 3: At least 4 weeks  

Moderna 

(Blue vial cap/purple

bordered label) 

6-11 years

Total doses: 2

Dose 1 to 2: At least 4-8 weeks 

Total doses: 3

Dose 1 to 2: At least 4 weeks 

Dose 2 to 3: At least 4 weeks 

Moderna 

(Red vial cap/blue

bordered label)

12-17 years

Total doses: 2

Dose 1 to 2: At least 4-8 weeks 

Total doses: 3

Dose 1 to 2: At least 4 weeks 

Dose 2 to 3: At least 4 weeks 

Pfizer

(Maroon vial cap/maroon

bordered label)

6 months through

4 years

Total doses: 3 

Dose 1-2: At least 3-8 weeks 

Dose 2-3: At least 8 weeks

Total doses: 3 

Dose 1-2: At least 3 weeks 

Dose 2-3: At least 8 weeks

Pfizer

(Orange vial cap/orange

bordered label)

5-11 years

Total doses: 3 

Dose 1-2: At least 3-8 weeks 

Dose 2-3: At least 5 months 

Total doses: 4

Dose 1-2: At least 3 weeks 

Dose 2-3: At least 4 weeks 

Dose 3 to 4: At least 3 months

Pfizer

(Purple or vial cap/purple

bordered label,

or gray cap/gray border)

12-17 years

Total doses: 3 

Dose 1-2: At least 3-8 weeks 

Dose 2-3: At least 5 months

Total doses: 5

Dose 1-2: At least 3 weeks 

Dose 2-3: At least 4 weeks 

Dose 3 to 4: At least 3 months 

Dose 4 to 5: At least 4 months 

Novavax 12-17 years

Total doses: 2 

Dose 1-2: At least 3-8 weeks

Total doses: 2 

Dose 1-2: At least 3-8 weeks

*Individuals who are moderately-to-severely immunocompromised

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

Table 2. CDC Interim COVID-19 Immunization Schedule for Adults Aged 18 Years and Older (Open Table in a new window)

Type Product

Most People 

Doses and intervals

Immunocompromised*

Doses and intervals

mRNA

Moderna 

(Red vial cap/blue

bordered label) 

Total doses: 3 or 4 

Dose 1 to 2: At least 4-8 weeks 

Dose 2 to 3: At least 5 months  

Dose 3 to 4: At least 4 months (aged 50 y and older) 

Total doses: 5 

Dose 1 to 2: At least 4 weeks  

Dose 2 to 3: At least 4 weeks   

Dose 3 to 4: At least 3 months  

Dose 4 to 5: At least 4 months 

mRNA

Pfizer

(Purple vial cap/purple

bordered label

or gray cap/gray border)

Total doses: 3 or 4 

Dose 1-2: At least 3-8 weeks  

Dose 2-3: At least 5 months 

Dose 3 to 4: At least 4 months (aged 50 y and older) 

Total doses: 5 

Dose 1-2: At least 3 weeks 

Dose 2-3: At least 4 weeks 

Dose 3 to 4: At least 3 months 

Dose 4 to 5: At least 4 months 

Viral

vector

Janssen

Total doses: 2 or 3 

Dose 1 to 2: At least 8 weeks 

Dose 2 to 3: At least 4 months (give mRNA vaccine

for 3rd dose in persons aged 50 y and older)** 

Total doses: 4*** 

Dose 1 to 2: At least 4 weeks (with mRNA vaccine) 

Dose 2 to 3: At least 8 weeks (with mRNA vaccine) 

Dose 3 to 4: At least 4 months (with mRNA vaccine)  

Adjuvanted

protein

subunit

Novavax 

Total doses: 2  

Dose 1 to 2: At least 3-8 weeks 

Total doses: 2 

Dose 1 to 2: At least 3 weeks  

*Individuals who are moderately-to-severely immunocompromised

**People aged 18-49 years: Those who received Janssen COVID-19 Vaccine as both their primary series dose and booster dose may receive a second booster dose using an mRNA COVID-19 vaccine at least 4 months after the Janssen booster dose.

***Age-appropriate mRNA COVID-19 vaccines are preferred over the Janssen COVID-19 Vaccine for all vaccine doses for all vaccine-eligible people 18 years of age and older. Janssen COVID-19 vaccine should only be used in limited situations

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

Next:

mRNA Vaccines

Comirnaty (BNT-162b2; Pfizer)

Overview

  • July 8, 2022: FDA give full approval for adolescents aged 12-17 years 
  • 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. [8]  

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. [9]

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. [10]  

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. [11]  

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%. [12]

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. [13]  

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%). [13]  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. [14]  

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. [15]  

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. [6]

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. [5]

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. [16]  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. [16]   

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. [17]  

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. [6]  

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. [7]  

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. [18]  

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. [19]

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. [20]   

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. [21]  

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. [22, 23, 24]  

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). [25]

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. [26]  

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. [22]  Others have confirmed low or nondetectable antispike antibody levels and nucleocapsid antibodies. [23, 24]  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. [27]   

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. [28]   

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. [29]   

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%). [30]  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. [31]  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.  

Previous
Next:

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. [32]

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. [33]  

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. [33]  

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. [34]   

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. [35]   

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. [35]   

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 
Previous
Next:

Protein Subunit Vaccines

NVX-CoV2373 (Novavax)

Overview

  • August 19, 2022: EUA expanded to include adolescents aged 12-17 years 
  • August 15, 2022: EUA request submitted for booster dose 
  • August 4, 2022: Phase 2b/3 Hummingbird trial initiated for children aged 6 months through 11 years 
  • July 13, 2022: FDA grants EUA for adults aged 18 years and older 
  • 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. [4]   

The phase 3 trial in the United Kingdom has completed enrollment and the phase 2b trial in South Africa has reported final results. [36]  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  [36]

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  [37]

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
Previous
Next:

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 VOCs

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. BA.1 sublineage (including BA.1.1) is causing the largest surge in COVID-19 cases to date. Omicron sublineages BA.2 and BA.2.12.1 emerged later and by late April 2022, accounted for most cases. The VISION Network examined 214,487 emergency department/urgent care visits and 58,782 hospitalizations with a COVID-19–like illness diagnosis among 10 states during December 18, 2021–June 10, 2022, to evaluate vaccine efficacy (VE) of 2, 3, and 4 doses of mRNA COVID-19 vaccines compared with no vaccination among immunocompetent adults. VE during the BA.2/BA.2.12.2 period was lower than that during the BA.1 period. A third vaccine dose provided additional protection against moderate and severe COVID-19–associated illness in all age groups, and a fourth dose provided additional protection in eligible adults aged 50 years and older. [38]     

Analysis of neutralizing antibody responses to the most recent omicron lineages circulating during summer 2022 (ie, BA.2.12.1, BA.4, BA.5) was published. The researchers found neutralizing antibody titers against the BA.4 or BA.5 subvariant and (to a lesser extent) against the BA.2.12.1 subvariant were lower than titers against the BA.1 and BA.2 subvariants, suggesting the SARS-CoV-2 omicron variant has continued to evolve with increasing neutralization escape. [39]  

The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted in favor to change the original COVID-19 vaccine strain composition to include an omicron BA.4/5 spike protein component to the current vaccine composition for fall-2022 booster doses.

For more information, see COVID-19 Variants

Previous
Next:

Vaccination in Adolescents and Children

BNT162b2 (Pfizer)

The BNT162b2 mRNA vaccine (Comirnaty) has full FDA approval for individuals aged 12 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

The phase 3 trial data lists the vaccine as 100% effective in preventing SARS-CoV-2 infection in the 12-15 year-old age group and it was determined to be noninferior to the 16-25 year-old participants. The study was conducted between October 15, 2020 and January 12, 2021. There were no cases of COVID-19 disease in adolescents aged 12 to 15 years who received the vaccine (n = 1131) compared with 18 cases in those who received placebo (n = 1129). [40]  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. [30]  

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. [41]  

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). [41]  

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. [42]  

Vaccine efficacy, a secondary endpoint in the trial, was 73.2% among children 6 months through 4 years without evidence of prior COVID-19 infection. This analysis was based on 13 cases in the active vaccine group (n = 794) and 21 cases in the placebo group (n = 351), diagnosed from March to June 2022. Consistent with the time period when the cases occurred, sequencing of viral RNA from illness visit nasal swabs indicated that observed cases were primarily caused by omicron BA.2, omicron BA.4, and BA.5 strains. [43]   

While the above results confirm a high level of protection at a time when BA.2 was highly prevalent, an EUA application for an omicron BA.4/BA.5-adapted bivalent vaccine for children aged 6 months through 11 years is in progress as of August 2022. 

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. [44]  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. [45]  

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. [46]   

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. [47]   

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 and is available via EUA for adults in the US. The vaccine achieved its primary effectiveness endpoint in the adolescent expansion of its PREVENT-19 phase 3 trial and demonstrated 78.29% efficacy overall at a time when the Delta variant was the predominant circulating strain in the United States. The efficacy analysis was also supported by assessment of antibody titers that were shown to be higher in adolescents than in young adults. The study enrolled 2,247 participants across 75 sites. [48]   

A phase 2b/3 global trial (Hummingbird) was initiated mid-summer 2022 in children aged 6 months through 11 years. [49]

Previous
Next:

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. [50]  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. [51]  

The Canadian National Vaccine Safety Network found no significant difference among miscarriage or stillbirth rates between vaccinated or unvaccinated pregnant women. [52]  

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. [53]  

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). [54]  

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. [55]  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. [56]  

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. [57]   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. [58]  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. [59]  

Anti-S IgG titers in the umbilical cord are correlated with maternal titers and are highest after late second and early third trimester vaccination. [57, 58]  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). [60]    

Previous
Next:

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. [61]  

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. [62]  

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. [63, 64, 65]  

Previous
Next:

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

Vaccine Comments

 

 

CV2CoV (CureVac, GSK) [66]

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) [67]  

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) [68]   Phase 2/3 trial (SPECTRA) of Clover’s protein-based S-Trimer COVID-19 subunit vaccine adjuvanted with Dynavax’s CpG 1018 plus alum. Regimen is 2 doses 3 weeks 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). Data from adolescent study elicited approximately 2-fold higher neutralizing antibody titers in adolescents compared with young adults. Clover plans to license as universal booster, particularly for low- and middle-income countries obtaining vaccines from COVAX. 
VLA2001 with CpG 1018 adjuvant (Valneva and Dynavax) [69]   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) [70]  

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) [71]  

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) [72]   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) [21]   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) [73, 74]   

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. Interim data from phase 2/3 trial (n = 526) in children aged 2-18 years showed the vaccine induced higher neutralizing antibody responses compared with adults. 

Recombinant adenovirus type-5-vectored vaccine (Ad5-vectored vaccine; Sinopharm [China]) [75]   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]) [76]   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) [77] 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) [78]  

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 (AmbiVax-C; Akston Biosciences) [79]  

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) [80]   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. 
SARS-CoV-2 spike ferritin nanoparticle (spFN) vaccine with ALFQ adjuvant (Walter Reed Army Institute of Research) [81]   Phase 1 study completed December, 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) [82]

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) [83]

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). 

Previous
Next:

Noninjectable Investigational Vaccines

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

Table 4. Noninjectable Investigational Vaccines (Open Table in a new window)

Noninjectable Vaccine Comments
hAd5 T-cell  (ImmunityBio and NantKwest) [78]  

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) [84]  

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. Initial data released October 2021 noted the vaccine produced high levels of antibodies in people’s noses. Plans to test the vaccine as a booster were announced April 2022. 

VXA-CoV2-1 oral vaccine (Vaxart) [85]   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. Results expected Q3 2022.
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 mRNA vaccine (Esperovax Preclinical trial. Gained funding from BARDA for research on oral vaccine platform. Goal to begin phase 1 trial in 2022.
Intranasal COVID-19 vaccine (Altimmune, Inc) [86]  

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). 

 

Previous
Next:

Booster Vaccine Candidates

Vaccines are in development to provide booster doses with improved efficacy against a broader range of viral variants. The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted in favor to change the original COVID-19 vaccine strain composition to include an omicron BA.4/5 spike protein component to the current vaccine composition for fall-2022 booster doses. As of August, the mRNA vaccines are those with data to include an omicron-containing component.  

Table 5. Booster Vaccine Candidates (Open Table in a new window)

Vaccine Comments
mRNA-1273.214 (Moderna) [87]   Approved in United Kingdom August 15, 2022. Bivalent booster candidate containing 25 mcg of currently authorized booster (mRNA-1273) and 25 mcg of an omicron subvariant. One month after administration in previously vaccinated and boosted participants, a 50-mcg booster dose of mRNA-1273.214 elicited significantly higher neutralizing antibody responses (5.4-fold higher) against omicron subvariants BA.4 and BA.5 compared with the currently authorized booster (mRNA-1273) regardless of prior infection status or age (all adults over 18 years, including younger or older 65 years). A second bivalent omicron booster candidate is also in process.
Omicron-adapted booster vaccines (Pfizer, BioNTech)  [88] Positive data evaluating safety, tolerability, and immunogenicity of 2 omicron-adapted COVID-19 vaccine candidates (a monovalent and bivalent) targeting the spike protein of omicron BA.1 variant of concern. One month after administration, a booster dose of the of the monovalent candidates (30 mcg or 60 mcg) increased neutralizing geometric mean titers (GMTs) against omicron BA.1 13.5 and 19.6-fold above prebooster dose levels. The omicron-adapted bivalent candidates conferred a 9.1 and 10.9-fold increase in neutralizing GMTs against Omicron BA.1. As of June 2022, additional data being collected regarding efficacy against omicron BA.4/5 variant. 

Bivalent vaccine (Sanofi, GSK) [89]

Adjuvanted bivalent D614 and Beta (B.1.351) vaccine candidate. Showed 72% efficacy in all adults and 93.2% in seropositives against omicron. 
Omicron BA.4/5 (Novavax) [90]   Preclinical data expected in fall 2022 on omicron BA.4/5-containing vaccine.
CV0501 (CureVac, GSK) [91] Phase 1 trial for mRNA booster vaccine targeting omicron variant initiated August 2022. Trial sites include U.S., Australia, and the Philippines. 

 

Previous
Next: