The Advisory Committee on Immunization Practices’ Interim Recommendations for Additional Primary and Booster Doses of COVID-19 Vaccines — United States, 2021

Three COVID-19 vaccines are currently approved under a Biologics License Application (BLA) or authorized under an Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) and recommended for primary vaccination by the Advisory Committee on Immunization Practices (ACIP) in the United States: the 2-dose mRNA-based Pfizer-BioNTech/Comirnaty and Moderna COVID-19 vaccines and the single-dose adenovirus vector-based Janssen (Johnson & Johnson) COVID-19 vaccine (1,2) (Box 1). In August 2021, FDA amended the EUAs for the two mRNA COVID-19 vaccines to allow for an additional primary dose in certain immunocompromised recipients of an initial mRNA COVID-19 vaccination series (1). During September–October 2021, FDA amended the EUAs to allow for a COVID-19 vaccine booster dose following a primary mRNA COVID-19 vaccination series in certain recipients aged ≥18 years who are at increased risk for serious complications of COVID-19 or exposure to SARS-CoV-2 (the virus that causes COVID-19), as well as in recipients aged ≥18 years of Janssen COVID-19 vaccine (1) (Table). For the purposes of these recommendations, an additional primary (hereafter additional) dose refers to a dose of vaccine administered to persons who likely did not mount a protective immune response after initial vaccination. A booster dose refers to a dose of vaccine administered to enhance or restore protection by the primary vaccination, which might have waned over time. Health care professionals play a critical role in COVID-19 vaccination efforts, including for primary, additional, and booster vaccination, particularly to protect patients who are at increased risk for severe illness and death.

After the EUA amendments, ACIP and CDC issued interim recommendations for vaccine use*^,†,§ (2). Moderately to severely immunocompromised persons aged ≥12 years (Pfizer-BioNTech recipients) or ≥18 years (Moderna recipients) should receive an additional homologous dose of mRNA COVID-19 vaccine (i.e., the same vaccine product that was administered for the primary series) ≥28 days after receipt of the second dose. Regarding booster dose recommendations, recipients of a primary mRNA COVID-19 vaccination series who are 1) aged ≥65 years, 2) aged ≥18 years and reside in long-term care settings, or 3) aged 50–64 years with certain underlying medical conditions^¶ should receive a COVID-19 vaccine booster dose ≥6 months after completion of the primary vaccination series. In addition, persons aged 18–49 years with certain underlying medical conditions and those aged 18–64 years who are at increased risk for occupational or institutional exposure to SARS-CoV-2 may receive a booster dose based on their individual benefits and risks. Recipients of Janssen COVID-19 vaccine aged ≥18 years should receive a COVID-19 vaccine booster dose ≥2 months after primary vaccination. Any approved or authorized COVID-19 vaccine may be used for the booster dose, regardless of vaccine received for primary vaccination (Box 2). For Pfizer-BioNTech and Janssen, the dose and volume are the same for primary and booster vaccination; for Moderna, the dose and volume of the booster dose (50 μg; 0.25 ml) are one half that used for the primary series (100 μg; 0.5 ml) (Table). As of October 28, 2021, more than 191 million persons in the United States have been fully vaccinated against COVID-19, and more than 15 million have received an additional or booster dose.**

Since June 2020, ACIP has convened 20 public meetings to review data relevant to the potential use of COVID-19 vaccines.^†† To assess the certainty of evidence for benefits and harms of a booster dose, ACIP used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.^§§ To further guide its deliberations around the use of an additional or booster dose, ACIP used the Evidence to Recommendations (EtR) Framework to evaluate other factors, including the importance of COVID-19 as a public health problem as well as matters of resource use, benefits and harms, patients’ values and preferences, acceptability, feasibility, and equity for use of the vaccines.^¶¶

ACIP recommendations for an additional dose of mRNA COVID-19 vaccine in certain immunocompromised persons were guided by data on reduced immunogenicity and effectiveness of the initial primary COVID-19 vaccination series in this population, as well as evidence of an immune response and an acceptable safety profile after an additional mRNA COVID-19 vaccine dose. During the period preceding the emergence of the highly transmissible SARS-CoV-2 B.1.617.2 (Delta) variant, vaccine effectiveness (VE) of a primary mRNA COVID-19 vaccination series against SARS-CoV-2 infection in persons aged ≥16 years was estimated to be 71% (95% confidence interval [CI] = 37%–87%) in immunocompromised persons versus 90% (95% CI = 83%–96%) in the general population and 59% (95% CI = 12%–81%) against COVID-19–associated hospitalization in immunocompromised persons aged ≥18 years versus 91% (95% CI = 86%–95%) in persons who were not immunocompromised (3). In a series of small studies, 16% to 80% of solid organ transplant recipients and hemodialysis patients had no detectable antibody response after the second dose of an mRNA COVID-19 vaccine; among these persons, 33% to 55% developed antibodies after receiving an additional dose (3). Local and systemic reactions reported after an additional dose of mRNA COVID-19 vaccine in certain immunocompromised persons were mostly mild to moderate and similar to those observed after previous doses; no severe adverse events were reported (3). Data were not available to assess immunogenicity or safety of an additional dose in immunocompromised recipients of Janssen COVID-19 vaccine.

To help determine the need for a booster dose in certain populations, ACIP reviewed data on the effectiveness of COVID-19 vaccines after a primary series. In the context of waning vaccine-induced immunity and emergence of the Delta variant in the United States, declines in VE of a primary mRNA COVID-19 vaccination series against SARS-CoV-2 infection have been observed, including among groups recommended to receive early vaccine doses: VE was 75% (95% CI = 60%–85%) to 84% (95% CI = 83%–86%) among adults aged ≥65 years, 53% (95% CI = 49%–57%) among residents of long-term care facilities, and 66% (95% CI = 26%–84%) among health care personnel and other frontline workers during periods of Delta variant predominance (4,5). VE of a primary mRNA COVID-19 vaccination series against COVID-19–associated hospitalization overall remains high (78% [95% CI = 62%–87%] to 100% [95% CI = 96%–100%]), although some studies show a slightly lower VE against hospitalization in older adults. Although data are limited, some studies suggest stable VE of Janssen vaccine over time; however, VE of the Janssen vaccine is 58% (95% CI = 12%–80%) to 83% (95% CI = 61%–93%) against SARS-CoV-2 infection and 60% (95% CI = 31%–77%) to 83% (95% CI = 61%–93%) against COVID-19–associated hospitalization among persons aged ≥18 years, which is lower than the estimates reported for mRNA vaccines in most studies (5).

ACIP recommendations for a COVID-19 vaccine booster dose in certain persons who had completed primary vaccination were guided by data on immunogenicity, efficacy, and effectiveness of COVID-19 vaccines after booster vaccination, and a review of safety data after COVID-19 vaccine booster doses. Compared with 1 month after the last dose in the primary series, geometric mean ratios of neutralization titers were 1.8 to 3.3-fold higher 1 month after a homologous mRNA COVID-19 vaccine booster dose administered 6 months after completing the primary series, and spike binding antibody titers were 4.6 to 12-fold higher after a homologous Janssen COVID-19 booster dose administered 2–6 months after completing primary vaccination (6,7). In a small phase I/II clinical trial, both homologous and heterologous (mix-and-match) booster dose administration, in which participants received either a Pfizer-BioNTech, Moderna, or Janssen COVID-19 vaccine primary series followed by a booster dose of the same or different vaccine, resulted in anamnestic immune responses; neutralizing antibody titers after a heterologous booster dose were similar to or higher than those observed after homologous booster vaccination (6). Observational studies from Israel demonstrated that the short-term incremental VE of a Pfizer-BioNTech COVID-19 primary series plus booster dose (administered ≥5 months after the second dose) compared with 2 doses, ranged from 70% (95% CI = 62%–76%) in persons aged ≥40 years to 91% (95% CI = 90%–92%) in persons aged ≥60 years (8). In placebo-controlled clinical trials, overall efficacy of the Janssen vaccine against moderate to severe COVID-19 ≥14 days after vaccination was 75% (95% CI = 55%–87%) for 2 doses administered 2 months apart versus 53% (95% CI = 47%–58%) for a single dose; in the U.S. study population, efficacy was 94% (95% CI = 59%–100%) after 2 doses and 70% (61%–77%) after 1 dose (6).

In clinical trials for mRNA and Janssen COVID-19 vaccine booster doses, rates of local or systemic adverse events were similar or lower after a booster dose (whether homologous or heterologous) than after the last primary series dose. No serious adverse events related to the vaccine were reported for mRNA COVID-19 vaccine booster doses; for Janssen, three serious adverse events (facial paresis, pulmonary embolism, and cerebrovascular accident) were attributed by the site investigators to booster vaccination within 6 months of administration, among 5,070 booster recipients in the evaluable population (6,7). Outside of clinical trials, more than 13 million persons in the United States had received an additional or booster dose of a COVID-19 vaccine as of October 25, 2021 (predominantly with Pfizer-BioNTech), and no unexpected patterns of adverse events have been observed in national safety surveillance systems (6).

From the GRADE evidence assessment, the level of certainty for all benefits and harms of a Pfizer-BioNTech, Moderna, or Janssen COVID-19 vaccine booster dose was type 4 (very low certainty) for the prevention of symptomatic COVID-19, prevention of hospitalization attributable to COVID-19 (Pfizer-BioNTech and Janssen), prevention of death attributable to COVID-19 (Janssen), serious adverse events, and reactogenicity (6,7). No data were available to assess the GRADE benefit of prevention of SARS-CoV-2 transmission. The main reasons for the low level of certainty in the evidence assessment include small study sizes, lack of a randomized primary series comparison group, short duration of follow-up, and use of immunobridging to infer vaccine efficacy (mRNA vaccines). The GRADE evidence profiles, which provide details on methods for identifying and assessing the supporting evidence, are available at https://www.cdc.gov/vaccines/acip/recs/grade/covid-19-booster-doses.html.

ACIP concluded that the evidence reviewed, including data and considerations from the EtR Frameworks, supported the use of an additional primary dose of an mRNA COVID-19 vaccine for certain immunocompromised recipients of an initial mRNA series, a COVID-19 vaccine booster dose for certain recipients of an mRNA primary series who are at increased risk for exposure to or serious complications of COVID-19, and a COVID-19 vaccine booster dose for all recipients of a Janssen COVID-19 vaccine dose. Additional supporting evidence for the EtR is available at https://www.cdc.gov/vaccines/acip/recs/grade/covid-19-immunocompromised-etr.html and https://www.cdc.gov/vaccines/acip/recs/grade/covid-19-booster-doses-etr.html.

In its deliberations, ACIP discussed the rationale for two different categories of booster dose recommendations among recipients of an mRNA primary series. Persons belonging to groups that ACIP recommends should be vaccinated with a booster dose (Box 2) are groups that are at highest risk for severe COVID-19; several studies suggest waning of VE against hospitalization in older adults. In groups that ACIP recommends may be vaccinated with a booster dose based on individual benefits and risks, evidence suggests that although VE against hospitalization remains high, waning of VE against SARS-CoV-2 infection has been observed. At the September 22–23, 2021, meeting, when booster dose deliberations were limited to Pfizer-BioNTech COVID-19 vaccine, ACIP initially recommended against booster vaccination for persons with frequent occupational or institutional exposure to SARS-CoV-2, given that protection against severe disease in the overall population remains high. However, CDC recommended that persons in this group may receive a booster dose based on their individual benefits and risks, given the implications of waning immunity against infection on health care personnel and other frontline workers, or in settings where the ability to maintain physical distancing or isolation of persons with COVID-19 is more challenging, such as correctional or detention facilities.***^,††† During the October meeting when booster dose deliberations expanded to Moderna and Janssen vaccines, ACIP voted to recommend a COVID-19 vaccine booster dose to recipients of an mRNA primary series (including those who had received Pfizer-BioNTech) who were currently in the risk groups recommended by CDC to receive booster vaccination, including those at occupational or institutional risk for exposure based on individual benefits and risks. This recommendation supersedes the previous recommendations issued by ACIP and CDC in September. Additional information on individual benefit-risk assessments for mRNA booster vaccination is available at https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html. Regarding Janssen COVID-19 vaccine, ACIP discussed the importance of optimizing vaccine-induced protection against SARS-CoV-2 in all recipients of primary vaccination because although VE against infection and hospitalization appears stable over time, VE estimates for Janssen vaccine are overall lower than those observed for mRNA vaccines.

ACIP also emphasized that achieving high and equitable coverage with a COVID-19 primary vaccination series remains the highest priority and is fundamental to reducing COVID-19–related morbidity and mortality. ACIP also stressed the importance of ensuring global equity in access to COVID-19 vaccines for the prevention of disease in vulnerable persons and mitigation of the emergence of SARS-CoV-2 variants.

Before vaccination, providers should provide the EUA Fact Sheet for the vaccine being administered and counsel vaccine recipients about expected systemic and local reactogenicity. Additional clinical education materials are available at https://www.cdc.gov/vaccines/covid-19/index.html, including additional clinical considerations at https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html. The interim recommendations and clinical considerations are based on use of an additional or booster dose of COVID-19 vaccine under an EUA and might change as more evidence becomes available.

Acknowledgments

Karen Broder, Amanda Cohn, Rachel Gorwitz, Anne Hause, Ruth Link-Gelles, Lauri Markowitz, Tom Shimabukuro, Rachel Slayton, John Su, Naomi Tepper, Erin Tromble, Melinda Wharton, CDC COVID-19 Response Team. Voting members of the Advisory Committee on Immunization Practices: Kevin A. Ault, University of Kansas Medical Center; Lynn Bahta, Minnesota Department of Health; Wilbur Chen, University of Maryland School of Medicine; Sybil Cineas, Warren Alpert Medical School of Brown University; James Loehr, Cayuga Family Medicine; Sarah Long, Drexel University College of Medicine; Veronica V. McNally, Franny Strong Foundation; Katherine A. Poehling, Wake Forest School of Medicine; Pablo J. Sánchez, The Research Institute at Nationwide Children’s Hospital. Members of the Advisory Committee on Immunization Practices COVID-19 Vaccines Work Group: Edward Belongia, Center for Clinical Epidemiology & Population Health, Marshfield Clinic Research Institute; Henry Bernstein, Zucker School of Medicine at Hofstra/Northwell Cohen Children’s Medical Center; Dayna Bowen Matthew, George Washington University Law School; Uzo Chukwuma, Indian Health Service; Marci Drees, Society for Healthcare Epidemiology of America; Jeffrey Duchin, Infectious Diseases Society of America; Kathy Kinlaw, Center for Ethics, Emory University; Doran Fink, Food and Drug Administration; Sandra Fryhofer, American Medical Association; Jason M. Goldman, American College of Physicians; Michael Hogue, American Pharmacists Association; Denise Jamieson, American College of Obstetricians and Gynecologists; Jeffery Kelman, Centers for Medicare & Medicaid; David Kim, U.S. Department of Health and Human Services; Susan Lett, Council of State and Territorial Epidemiologists; Kendra McMillan, American Nurses Association; Kathleen Neuzil, Center for Vaccine Development and Global Health, University of Maryland School of Medicine; Sean O’Leary, American Academy of Pediatrics; Christine Oshansky, Biomedical Advanced Research and Development Authority; Stanley Perlman, Department of Microbiology and Immunology, University of Iowa; Marcus Plescia, Association of State and Territorial Health Officials; Chris Roberts, National Institutes of Health; José R. Romero, Arkansas Department of Health; William Schaffner, National Foundation for Infectious Diseases; Rob Schechter, Association of Immunization Managers; Kenneth Schmader, American Geriatrics Society; Bryan Schumacher, Department of Defense; Peter Szilagyi, University of California, Los Angeles; Jonathan Temte, American Academy of Family Physicians; Matthew Tunis, National Advisory Committee on Immunization Secretariat, Public Health Agency of Canada; Matt Zahn, National Association of County and City Health Officials; Rachel Zhang, Food and Drug Administration.

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