Safety Monitoring of an Additional Dose of COVID-19 Vaccine — United States, August 12–September 19, 2021

On August 12, 2021, the Food and Drug Administration (FDA) amended Emergency Use Authorizations (EUAs) for the Pfizer-BioNTech and Moderna COVID-19 vaccines to authorize administration of an additional dose after completion of a primary vaccination series to eligible persons with moderate to severe immunocompromising conditions (1,2). On September 22, 2021, FDA authorized an additional dose of Pfizer-BioNTech vaccine ≥6 months after completion of the primary series among persons aged ≥65 years, at high risk for severe COVID-19, or whose occupational or institutional exposure puts them at high risk for COVID-19 (1). Results from a phase 3 clinical trial conducted by Pfizer-BioNTech that included 306 persons aged 18–55 years showed that adverse reactions after receipt of a third dose administered 5–8 months after completion of a 2-dose primary mRNA vaccination series were similar to those reported after receipt of dose 2; these adverse reactions included mild to moderate injection site and systemic reactions (3). CDC developed v-safe, a voluntary, smartphone-based safety surveillance system, to provide information on adverse reactions after COVID-19 vaccination. Coincident with authorization of an additional dose for persons with immunocompromising conditions, the v-safe platform was updated to allow registrants to enter information about additional doses of COVID-19 vaccine received. During August 12–September 19, 2021, a total of 22,191 v-safe registrants reported receipt of an additional dose of COVID-19 vaccine. Most (97.6%) reported a primary 2-dose mRNA vaccination series followed by a third dose of the same vaccine. Among those who completed a health check-in survey for all 3 doses (12,591; 58.1%), 79.4% and 74.1% reported local or systemic reactions, respectively, after dose 3, compared with 77.6% and 76.5% who reported local or systemic reactions, respectively, after dose 2. These initial findings indicate no unexpected patterns of adverse reactions after an additional dose of COVID-19 vaccine; most of these adverse reactions were mild or moderate. CDC will continue to monitor vaccine safety, including the safety of additional doses of COVID-19 vaccine, and provide data to guide vaccine recommendations and protect public health.

V-safe is a voluntary, smartphone-based U.S. safety surveillance system; vaccinated persons eligible to receive authorized or licensed vaccine product may register in v-safe. The v-safe platform allows existing registrants to report receiving an additional dose of COVID-19 vaccine and new registrants to enter information about all doses of COVID-19 vaccine received. V-safe health surveys are sent during days 0–7 after each dose of vaccine and include questions about local injection site and systemic reactions and health impacts.* Surveys are sent for the most recent dose entered.^† Staff members from the Vaccine Adverse Event Reporting System (VAERS) contact registrants who indicate that medical attention was sought after vaccination and encourage or facilitate completion of a VAERS report, if indicated.^§

Among v-safe registrants who reported receipt of an additional COVID-19 vaccine dose during August 12–September 19, 2021, demographic data, local and systemic reactions, and health impacts reported during days 0–7 were described by pattern of vaccination (i.e., manufacturer of vaccine received for each dose). Persons who reported receiving a primary series from different manufacturers or a manufacturer that was unknown or unavailable in the United States, or 2 doses of vaccine after receipt of a Janssen (Johnson & Johnson) single-dose vaccine (150) were excluded from the analysis of adverse reactions after receipt of the additional dose. Time elapsed from completion of the primary vaccination series to receipt of an additional dose was described by pattern of vaccination. Adverse event profiles after doses 2 and 3 were compared for registrants who received mRNA vaccine from the same manufacturer for all 3 doses.^¶ SAS software (version 9.4; SAS Institute) was used to conduct all analyses. These surveillance activities were reviewed by CDC and conducted consistent with applicable federal law and CDC policy.**

During August 12–September 19, 2021, a total of 22,191 v-safe registrants reported receipt of an additional dose of COVID-19 vaccine after completing the primary series (Table 1). Among these, 14,048 (63.3%) were female, and approximately 30% each were aged 18–49, 50–64, and 65–74 years. Most registrants (21,662; 97.6%) reported that they received a third dose from the same manufacturer as their primary mRNA vaccine series, including 98.6% of Moderna recipients and 98.2% of Pfizer-BioNTech recipients. Few registrants (341; 1.5%) reported a primary mRNA vaccine series followed by an additional dose of mRNA vaccine from a different manufacturer, a dose of Janssen vaccine after receipt of a primary mRNA vaccination series (10; 0.05%), or an additional dose of COVID-19 vaccine from any manufacturer after Janssen vaccine (178; 0.8%).

Among the 22,191 v-safe registrants, the median interval from completion of the primary COVID-19 vaccination series to receipt of an additional dose was 182 days (interquartile range [IQR] = 160–202 days) (Table 2). Among those who received 2 doses of Janssen vaccine, the median interval between doses was shorter (84 days; IQR = 16–136 days).

Local (16,615; 74.9%) and systemic (15,503; 69.9%) reactions were frequently reported during the week after an additional dose of COVID-19 vaccine, most commonly on the day after vaccination. Frequently reported reactions were injection site pain (15,761; 71.0%), fatigue (12,429; 56.0%), and headache (9,636; 43.4%).

Among 22,191 additional dose recipients, a total of 7,067 (31.8%) reported health impacts, and approximately 28.3% (6,287) reported they were unable to perform normal daily activities, most commonly on the day after vaccination. Medical care was sought by 401 (1.8%) registrants, and thirteen (0.1%) were hospitalized. Reasons for receiving medical care or hospitalization were not identified in the v-safe survey; however, registrants who indicate that medical attention was sought after vaccination are contacted by VAERS staff and encouraged to complete a VAERS report.

Among 21,658 v-safe registrants who received the same mRNA vaccine for all 3 doses, 12,591 (58.1%) completed at least one health check-in survey on days 0–7 after all 3 doses; 79.4% and 74.1% reported local or systemic reactions, respectively, after dose 3, compared with 77.6% and 76.5% who reported local or systemic reactions, respectively, after dose 2. Among registrants who received 3 doses of Moderna (6,283), local reactions were reported more frequently after dose 3 than dose 2 (5,323; 84.7% and 5,249; 83.5%; p-value = 0.03) (Figure). Systemic reactions were reported less frequently after dose 3 than dose 2 (4,963; 79.0% and 5,105; 81.3%; p-value <0.001). Among registrants who received 3 doses of Pfizer-BioNTech (6,308), local reactions were reported more frequently after dose 3 than dose 2 (4,674; 74.1% and 4,523; 71.7%; p-value < 0.001). Systemic reactions were reported less frequently after dose 3 than dose 2 (4,363; 69.2% and 4,524; 71.7%; p-value <0.001). Among those who reported pain after dose 3 of an mRNA vaccine, most reactions were mild (4,909; 51.4%) or moderate (4,000; 41.9%); severe pain (defined as pain that makes daily activities difficult or impossible) was reported by 637 (6.7%).

Corresponding author: Anne M. Hause, eocevent416@cdc.gov.

¹CDC COVID-19 Response Team.

References

1. Food and Drug Administration. Pfizer-BioNTech COVID-19 vaccine letter of authorization. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2021. https://www.fda.gov/media/150386/download
2. Food and Drug Administration. Moderna COVID-19 vaccine letter of authorization. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2021. https://www.fda.gov/media/144636/download
3. Pfizer Inc. Pfizer and BioNTech initiate rolling submission of supplemental biologics license applications to U.S. FDA for booster dose of Comirnaty in individuals 16 and older. New York City, NY: Pfizer Inc.; 2021. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-initiate-rolling-submission
4. Chapin-Bardales J, Gee J, Myers T. Reactogenicity following receipt of mRNA-based COVID-19 vaccines. JAMA 2021;325:2201–2. https://doi.org/10.1001/jama.2021.5374 PMID:33818592
5. CDC. Interim clinical considerations for use of COVID-19 vaccines currently approved or authorized in the United States. Atlanta, GA: US Department of Health and Human Services, CDC; 2021. Accessed September 25, 2021. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html
6. Brown CM, Vostok J, Johnson H, et al. Outbreak of SARS-CoV-2 infections, including COVID-19 vaccine breakthrough infections, associated with large public gatherings—Barnstable County, Massachusetts, July 2021. MMWR Morb Mortal Wkly Rep 2021;70:1059–62. https://doi.org/10.15585/mmwr.mm7031e2 PMID:34351882
7. Fowlkes A, Gaglani M, Groover K, Thiese MS, Tyner H, Ellingson K; HEROES-RECOVER Cohorts. 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;70:1167–9. https://doi.org/10.15585/mmwr.mm7034e4 PMID:34437521
8. CDC. Booster shot. Atlanta, GA: US Department of Health and Human Services, CDC; 2021. Accessed September 25, 2021. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/booster-shot.html

Abbreviations: AI/AN = American Indian/Alaska Native; NHPI = Native Hawaiian or other Pacific Islander.
* Percentage of registrants who completed at least one v-safe health check-in survey on days 0–7 after vaccination.
^† Primary vaccination series.
^§ Includes persons who received a primary Janssen single-dose and 1 additional dose of vaccine from the listed manufacturers.

Abbreviation: IQR = interquartile range.
* Percentage of registrants who completed at least one v-safe health check-in survey on days 0–7 after vaccination.
^† Primary vaccination series.
^§ Includes persons who received a primary Janssen single-dose and one additional dose of vaccine from the listed manufacturers.

FIGURE. Adverse reactions and health impacts reported by persons who received 3 doses* of Moderna (N = 6,283) or Pfizer-BioNTech (N = 6,308) COVID-19 vaccine and completed at least one v-safe health check-in survey on days 0–7 after each dose, by dose number — United States, August 12–September 19, 2021

* The odds of reporting an event after dose 2 and 3 were compared using a multivariable generalized estimating equations model that accounted for the correlation between registrants and adjusted for demographic variables (receipt of care was not adjusted because of small numbers); p-values <0.05 were considered statistically significant. For Moderna recipients, all differences except any health impact and inability to perform daily activities were statistically significant. For Pfizer-BioNTech, all differences except the need for medical care were statistically significant.