What evidence is available regarding the efficacy of COVID-19 vaccine booster shots in adults?
Introduction
On August 18th, 2021, the U.S Department of Health and Human Services (HHS) released a public statement outlining the administration’s plan for COVID-19 vaccine booster roll-out.1 Based on evidence of reduced protection following the initial doses of vaccine and the dominance of the Delta variant, the HHS concluded that a booster shot would be necessary to maximize vaccine-induced protection and durability. On September 22, 2021, Pfizer-BioNTech received the first U.S Food and Drug Administration (FDA) emergency use authorization (EUA) for a COVID-19 vaccine booster.2 The Moderna and Janssen (Johnson & Johnson) COVID-19 vaccine boosters were both approved on October 20, 2021.3 The Janssen vaccine booster was approved for adults ≥ 18 years old, following primary vaccination with the single-shot Janssen vaccine or a different authorized COVID-19 vaccine.4 The Pfizer-BioNTech and Moderna vaccine boosters were initially approved for patients ≥ 65 years old and patients 18 to 64 years old at a high risk for severe COVID-19 infection or who were at risk for institutional or occupational exposure. However, as of November 19, 2021, the FDA amended the EUAs for the Pfizer-BioNTech and Moderna booster vaccines to authorize use for all individuals ≥ 18 years old after primary vaccination with an FDA-approved COVID-19 vaccine.5
Terminology for COVID-19 Vaccine Dosing
The Centers for Disease Control and Prevention (CDC) has issued interim clinical considerations for different types of COVID-19 vaccines including dosing schedule, recommendations for specific populations, and product interchangeability.6 The following terminology as defined by the CDC will be used throughout this article, shown below in Table 1.
| Table 1. Vaccine terminology.6 | |
|---|---|
| Term | Definition |
| Primary series | 2-dose series of a COVID-19 vaccine (Pfizer-BioNTech and Moderna) or a single dose of Janssen vaccine |
| Additional primary dose | Subsequent dose of vaccine administered to people after initial vaccination who may not have mounted a protective immune response after initial vaccination. Is recommended for moderate/severely immunocompromised patients who already received a 2-dose vaccine primary series |
| Booster dose | Subsequent dose of vaccine administered to enhance or restore protection by the primary series |
| Homologous booster dose | Subsequent dose of vaccine that is the same product as the primary series |
| Heterologous booster dose (mix-and-match booster) | Subsequent dose of vaccine that is a different product than the primary series |
Booster Dose Scheduling
The following Table 2 illustrates the dosing series for COVID-19 vaccine boosters of the 3 EUA approved vaccines.
| Table 2. Vaccine booster dosing.6 | |||||
|---|---|---|---|---|---|
| Manufacturer | Age of Recipient | Dose | Dose Volume | Number of Doses | Interval Between Last Primary (Including Additional) to Booster Dose |
| Pfizer-BioNTech | ≥18 years | 30 µg | 0.3 mL | 1 | ≥6 months |
| Moderna | ≥18 years | 50 µg a | 0.25 mL | 1 | ≥6 months |
| Janssen | ≥18 years | 5×1010 viral particles b | 0.5 mL | 1 | ≥2 months |
| a This is a different dose than what is used for the primary series dose and the additional primary dose b 5×1010 viral particles in a volume of 0.5 mL (same dose as the primary series dose) |
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For heterologous vaccine products, intervals between the primary vaccine series and booster dose should follow the interval recommended by the primary series.6 For example, patients who receive a Janssen primary series vaccine (single-dose) may receive a booster dose of an mRNA vaccine (Pfizer-BioNTech or Moderna) at least 2 months after getting the Janssen primary vaccine. If a patient received a COVID-19 vaccine outside of the United States that is not FDA-authorized, there is currently no recommendation regarding the utilization of a booster vaccine in these patients.
Are COVID-19 Vaccine Boosters Needed?
According to recently published data by the CDC in Morbidity and Mortality Weekly (MMWR) reports, there is a growing concern for decreased vaccine effectiveness against COVID-19 infection over time. A study conducted utilizing New York State Department of Health data during May 3 to July 25, 2021, evaluated vaccine effectiveness for fully vaccinated individuals across the state.7 The overall age-adjusted vaccine effectiveness for all 3 authorized vaccines declined from 91.7% to 79.8% during the study period. This illustrates reduced effectiveness against new COVID-19 cases, which seems to coincide with the increase in the Delta variant of SARS-CoV-2 in the United States.
A vulnerable population that is susceptible to COVID-19 infection are patients residing in skilled nursing facilities or nursing homes. Data reported by skilled nursing facilities or nursing homes were analyzed to assess the effectiveness of the mRNA COVID-19 vaccines (Pfizer-BioNTech or Moderna) prior to Delta variant circulation (March 1 to May 9, 2021) compared to when there was a predominance of the Delta variant (June 21 to August 1, 2021).8 The study found that in facilities (N=3,862) during the pre-Delta period, there was a 74.7% adjusted effectiveness rate against COVID-19 infection. In the intermediate period (May 10 to June 20, 2021) there was a 67.5% adjusted effectiveness rate in 11,581 facilities. During the predominant period of the Delta variant, there was a 53.1% adjusted effectiveness rate in 14,917 facilities. The trend in decreasing vaccine effectiveness indicates that mRNA COVID-19 vaccines had reduced protection in nursing home and long-term care facility residents during the period when the Delta variant was the predominant circulating strain.
Vaccine effectiveness among frontline workers is also a growing concern. To evaluate whether there was reduced vaccine protection in this population, a prospective cohort study was conducted during December 14, 2020 to August 14, 2021.9 Healthcare personnel, first responders and other essential workers in 6 states were tested weekly for SARS-CoV-2 infection. During the study period, COVID-19 vaccines were overall 80% effective in preventing infection in the 2,976 frontline workers who were fully vaccinated. Vaccine effectiveness declined from 91% (pre-Delta variant) to 66% (post-Delta variant predominance). These findings suggest a moderate reduction in the effectiveness of COVID-19 vaccines after Delta variant predominance.
Vaccine Booster Efficacy Studies
Pfizer-BioNTech
The clinical trial data included in the Pfizer-BioNTech COVID-19 booster vaccine section in the EUA was a subset of the Phase 2/3 clinical multicenter, randomized, controlled Pfizer-BioNTech COVID-19 vaccine clinical trial.10 The subset trial assessed immunogenicity of the booster vaccine by assessing correlates of vaccine protection (eg, humoral response parameters) and included 306 adult participants (18 to 55 years old) who received a booster dose approximately 6 months after completion of the primary vaccine series. Analysis of the vaccine booster 1 month after administration demonstrated noninferiority compared to 1 month after primary series vaccination for both geometric mean ratio (GMR) and difference in seroresponse rates. Seroresponse for a patient was defined as achieving a >4-fold rise in 50% neutralizing antibody titers (NT50) from baseline (before primary series). Table 3 summarizes the study characteristics and outcomes associated for assessing the immunogenicity of a Pfizer-BioNTech booster dose following a Pfizer-BioNTech vaccine primary series.
| Table 3. Summary of study included in Pfizer-BioNTech EUA reporting on vaccine booster.10 | ||||||
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| Study Population | Assay Used | Outcome | Number of Patients Vaccinated with Booster b | Immunogenicity Measure | Result | Met Noninferiority Objective |
| Adults aged 18-55 years without evidence of infection up to 1 month after booster dose | SARS-CoV-2 neutralization assay of 50% neutralizing antibody titers (NT50) aagainst SARS-CoV-2 | Effectiveness of a booster dose (30 µg) based on assessment of GMT of NT50 | 212 | Ratio: (1 month after booster dose /1 month after primary series) GMR c (97.5% CI) | 3.29 (2.77, 3.90) | Yes e |
| Effectiveness of a booster dose (30 µg) based on assessment of seroresponse rate | 200 | Difference: (1 month after booster dose -1 month after primary series) % d (97.5% CI) | 1.5 (-0.7, 3.7) | Yes f | ||
| Abbreviations: CI=confidence interval; GMT=geometric mean titer; GMR=geometric mean ratio. a The sample NT50 is defined as the reciprocal serum dilution at which 50% of the virus is neutralized b Number of participants with valid and determinate assay results at both sampling time points within the specified window c GMRs and 2-sided 97.5% CIs were calculated by exponentiating the mean differences in the logarithms of the assay (GMTs) and the corresponding CIs d Difference in proportions, expressed as a percentage (1 month after booster dose – 1 month after Dose 2 from primary series) e Non inferiority was declared if the lower bound of the 2-sided 97.5% Cl for the GMR was >0.67 and the point estimate of the GMR was ~0.80 f Noninferiority was declared if the lower bound of the 2-sided 97.5% CI for the percentage difference was > -10%. |
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Moderna
The Moderna COVID-19 booster vaccine clinical trial data centered around an ongoing, randomized, controlled Phase 2 clinical trial that assessed booster dose vaccine immunogenicity in 149 patients ≥ 18 years old.11 Patients received the booster dose at least 6 months after completion of the primary vaccine series. Immunogenicity analysis included an assessment of geometric mean titer (GMT) ratio of neutralizing antibody titers (ID50) to pseudotyped virus neutralizing antibodies and difference in seroresponse rates. Seroresponse for a patient was defined as achieving a >4-fold rise in 50% ID50 from baseline (before booster dose in the study population and before primary series in the comparator group). Analysis of the vaccine booster 1 month after administration demonstrated noninferiority compared to 1 month after primary series vaccination for both GMR and difference in seroresponse rates. Table 4 summarizes the study characteristics and outcomes associated for the study for assessing immunogenicity of a Moderna booster dose following a Moderna vaccine primary series.
| Table 4. Summary of study included in Moderna EUA reporting on vaccine booster.11 | |||||||
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| Study Population | Assay Used | Outcome | Number of Patients Vaccinated with Booster | Number of Patients in Comparator Group b | Immunogenicity Measure | Result | Met Noninferiority Objective |
| Adults aged ≥18 years without evidence of infection prior to the first primary series dose and prior to the booster dose | Neutralizing antibody titers (ID50) against a pseudovirus expressing the SARS-CoV-2 spike protein | Effectiveness of a booster dose (50 µg) based on assessment of GMT ratio of ID50 | 149 | 1053 | Ratio: (1 month after booster dose/1 month after primary series) GMR (95% CI) | 1.8 (1.5, 2.1) | Yes c |
| Effectiveness of a booster dose (50 µg) based on assessment of seroresponse rate | 149 | 1050 | Difference: (1 month after booster dose - 1 month after primary series) % d (95% CI) | -10.5 (-16.7, -6.1) | Yes d | ||
| Abbreviations: CI=confidence interval; GMT=geometric mean titer; GMR=geometric mean ratio. a The sample ID50 is defined as the reciprocal serum dilution at which 50% of the pseudovirus is neutralized b A random subset of participants who received just the Moderna primary series vaccines (two doses [0.5 mL each] 1 month apart) in an ongoing phase 3 clinical study (Study 1) of primary series dosing c Non inferiority was declared based on prespecified criteria: point estimate of GMR ≥1 and lower bound of 95% CI ≥0.67 d Noninferiority was declared if the lower limit of the 2-sided 95% CI for the percentage difference is > -10%. |
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Janssen
A randomized, double-blind, controlled Phase 2 trial evaluated the immunogenicity of a Janssen vaccine booster dose following Janssen primary series vaccination.4 Thirty-nine patients who were 18 to 55 years old (n=24) and ≥65 years old (n=15) received a Janssen booster dose 2 months after primary vaccination. A wild-type virus neutralization assay (wtVNA) was used to assess immunogenicity by measuring neutralizing antibodies to SARS-CoV-2. A rise in neutralizing antibody titers from pre-booster to 14- and 28-days post-booster was observed in study population. Table 5 summarizes the study characteristics and outcomes associated for the study for assessing immunogenicity of a Janssen booster dose following a Janssen vaccine primary series.
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| Table 5. Summary of study included in Janssen EUA reporting on vaccine booster.4 | ||||||
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| Study Population | Assay Used | Outcome | Immunogenicity Measure | Na | Result | GMT Fold Increase (95% CI) from Pre-Booster |
| Healthy adults aged 18-55 years and ≥65 years old who received the primary series Janssen COVID-19 vaccine | Wild-type virus neutralization assay (wtVNA) | Effectiveness of a booster dose (5×1010 viral particles) based on assessment of GMT | Baseline (day 1) GMT (95% CI) | 38 | <LLOQ | N/A |
| Pre-booster dose (day 57) GMT (95% CI) | 39 | 212 (142, 314) | N/A | |||
| 14 days post-booster dose (day 71) GMT (95% CI) | 39 | 518 (354, 758) | 2.3 (1.7, 3.1) | |||
| 28 days post-booster dose (day 85) GMT (95% CI) | 38 | 424 (301, 597) | 1.8 (1.4, 2.4) |
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| Abbreviations: N/A=not applicable; CI=confidence interval; GMT=geometric mean titer; LLOQ=lower limit of quantification. a Population includes all randomized and vaccinated patients for whom immunogenicity data are available excluding patients with major protocol deviations expected to impact the immunogenicity outcomes |
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Interchanging COVID-19 Vaccine Products
As shown by the trial data from homologous COVID-19 booster doses, there has been an increase in immune response against SARS-CoV-2 when homologous booster doses are utilized. For patients who are to receive a vaccine booster, the CDC does not recommend one booster vaccine over another, and patients can receive any of the authorized vaccine boosters.6 The CDC advises that patients consider the benefits and risks of each product and discuss them with their healthcare provider.
Currently, there is 1 ongoing non-randomized, open-label study by the National Institute of Allergy and Infectious Diseases (NIAID) which is evaluating heterologous COVID-19 vaccine booster regimens.12 Patients (N=458) who had gotten an EUA authorized COVID-19 vaccine 12 weeks prior to study enrollment and had no reported history of SARS-CoV-2 infection received a booster injection of either Moderna (n=154), Pfizer-BioNTech (n=154) or Janssen (n=150). Preliminary results (through study day 29) indicate that heterologous booster vaccines increased the neutralizing activity against a SARS-CoV-2 pseudovirus (ranging from 4.2 to 76 mean fold increase) and increased binding antibody titers (ranging from 4.6 to 56 mean fold increase) for all heterologous combinations. These results indicate that heterologous booster vaccine combinations provide immunogenicity to patients who completed a primary vaccine series.
Conclusion
There are proven immunogenicity benefits of COVID-19 booster vaccines as shown by both homologous and heterologous vaccine studies. Immunogenicity benefits may include reduced risk of SARS-CoV-2 infection and a reduced risk for severe infection. Vaccine boosters extend the durability of COVID-19 vaccines, and this may prevent morbidity and may reduce transmission of the virus.6 More data are needed to assess the long-term impact of vaccine boosters, but for the time being clinical data is promising on the benefits that vaccine booster doses offer for adult patients.
References
- Joint statement from HHS public health and medical experts on COVID-19 booster shots. U.S. Department of Health & Human Services. Published August 18, 2021. Accessed November 9, 2021. https://www.hhs.gov/about/news/2021/08/18/joint-statement-hhs-public-health-and-medical-experts-covid-19-booster-shots.html
- Pfizer And BioNTech receive first U.S. FDA emergency use authorization of a COVID-19 vaccine booster. Pfizer. Published September 22, 2021. Accessed November 9, 2021. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-receive-first-us-fda-emergency-use
- Coronavirus (COVID-19) update: FDA takes additional actions on the use of a booster dose for COVID-19 vaccines. U.S Food & Drug Administration. Published October 20, 2021. Accessed November 9, 2021. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-takes-additional-actions-use-booster-dose-covid-19-vaccines
- Janssen COVID-19 vaccine [package insert]. Horsham, PA: Janssen Biotech Inc; 2021.
- Coronavirus (COVID-19) update: FDA expands eligibility for COVID-19 vaccine boosters. U.S Food & Drug Administration Published November 19, 2021. Accessed November 22, 2021. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-expands-eligibility-covid-19-vaccine-boosters
- Interim clinical considerations for use of COVID-19 vaccines currently approved or authorized in the United States. Centers for Disease Control and Prevention (CDC). Updated November 3, 2021. Accessed November 9, 2021. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html#underlying-conditions
- Rosenberg ES, Holtgrave DR, Dorabawila V, et al. New COVID-19 cases and hospitalizations among adults, by vaccination status – New York, May 3-July 25, 2021. MMWR Morb Mortal Wkly Rep. 2021;70(37):1306-1311. doi:10.15585/mmwr.mm7037a7
- Nanduri S, Pilishvili T, Derado G, et al. Effectiveness of Pfizer-BioNTech and Moderna vaccines in preventing SARS-CoV-2 infection among nursing home residents before and during widespread circulation of the SARS-CoV-2 B.1.617.2 (Delta) variant – National Healthcare Safety Network, March 1-August 1, 2021. MMWR Morb Mortal Wkly Rep. 2021;70(34):1163-1166. doi:10.15585/mmwr.mm7034e3
- Fowlkes A, Gaglani M, Groover K, et al. Effectiveness of COVID-19 vaccines in preventing SARS-CoV-2 infection among frontline workers before and during B.1.617.2 (Delta) variant predominance – eight U.S. locations, December 2020-August 2021. MMWR Morb Mortal Wkly Rep. 2021;70(34):1167-1169. doi:10.15585/mmwr.mm7034e4
- Pfizer-BioNTech COVID-19 vaccine [package insert]. New York, NY: Pfizer Inc; 2021.
- Moderna COVID-19 vaccine [packag insert]. Cambridge, MA: Moderna US, Inc; 2021.
- Atmar RL, Lyke KE, Deming ME, et al. Heterologous SARS-CoV-2 booster vaccinations – preliminary report. medRxiv. 2021. doi:10.1101/2021.10.10.21264827
Prepared by:
Faria Munir, PharmD, MS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
December 2021
The information presented is current as November 22, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.