ACIP Evidence to Recommendations for Use of an Additional COVID-19 Vaccine Dose in Immunocompromised People

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Question:

Should ACIP recommend vaccination with an additional dose of an mRNA COVID-19 vaccine (Pfizer-BioNTech, Moderna) following a primary series in immunocompromised people, under an Emergency Use Authorization?

Population:

People with medical conditions or people receiving treatments that are associated with moderate to severe immune compromise:

  • Active or recent treatment for solid tumor and hematologic malignancies
  • Receipt of solid-organ or recent hematopoietic stem cell transplants
  • Severe primary immunodeficiency
  • Advanced or untreated HIV infection
  • Active treatment with high-dose corticosteroids, alkylating agents, antimetabolites, tumor-necrosis (TNF) blockers, and other biologic agents that are immunosuppressive or immunomodulatory
  • Chronic medical conditions such as asplenia and chronic renal disease (degree of immune deficit varies)

Intervention:

An additional dose of Pfizer-BioNTech COVID-19 vaccine (≥12 years old) or Moderna COVID-19 vaccine (≥18 years old) at least 28 days after an initial 2-dose primary series of mRNA COVID-19 vaccine, in immunocompromised people.

Background: The emergence of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), has led to a global pandemic with substantial societal and economic impacts on individual persons and communities. In the United States, more than 45 million cases and more than 700,000 COVID-19-associated deaths have been reported as of October 20, 2021. Persons of all ages are at risk for infection and severe disease. However, the risk for severe illness from COVID-19 is higher in people who are immunocompromised.

Three COVID-19 vaccines are currently approved under a Biologics License Application 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): the two-dose mRNA-based Pfizer-BioNTech/Comirnaty and Moderna COVID-19 vaccines and the single-dose adenovirus vector-based Janssen (Johnson & Johnson) COVID-19 vaccine.

On August 12, 2021, the FDA amended the EUAs for Pfizer-BioNTech (persons aged ≥12 years) and Moderna (persons aged ≥18 years) COVID-19 vaccines to authorize an additional dose for certain immunocompromised persons. Due to insufficient data, the EUA amendment for an additional dose does not apply to Janssen COVID-19 vaccine or to individuals who received Janssen COVID-19 as a primary series.

Additional background information supporting the ACIP recommendation on the use of additional or booster doses of COVID-19 vaccine can be found in the relevant publication of the recommendation referenced on the ACIP website.

Problem

Problem
Criteria Work Group Judgements Evidence Additional Information
Is the problem of public health importance? Yes Immunocompromised people and SARS-CoV-2 infection
Immunocompromised people comprise approximately 2.7% of U.S. adults (~7 million adults).1 Immunocompromised people are more likely to get severely ill from COVID-191,2 and have a higher risk for prolonged SARS-CoV-2 infection and shedding3-7 as well as viral evolution during infection and treatment.3,6,8-13 In addition, antibody neutralization titers to SARS-CoV-2 variants are lower in immunocompromised people compared to non-immunocompromised people.14 Furthermore, immunocompromised people are more likely to transmit SARS-CoV-2 to household contacts.15 Immunocompromised people have lower vaccine effectiveness compared to non-immunocompromised people (59-72% vs. 90-94%, respectively).16-19 Immunocompromised people are also more likely to have serious breakthrough infections, with 40-44% of hospitalized breakthrough cases occurring among immunocompromised people.16,20		 Vaccination:
As of October 20, 2021, more than 189 million people in the United States are fully vaccinated against COVID-19, including over 104 million people who received Pfizer-BioNTech and 69 million who received Moderna.21
Variants of Concern:
As of October 20, 2021, the Delta variant is the dominant circulating variant in the United States and is more than twice as contagious as previous variants.22

Benefits and Harms

Benefits and Harms
Criteria Work Group Judgements Evidence Additional Information
How substantial are the desirable anticipated effects? Large In a series of small studies, 16–80% of solid organ transplant recipients and hemodialysis patients had no detectable antibody response following the 2nd dose of an mRNA COVID-19 vaccination series; among these, 33–55% developed antibodies after an additional dose.1,2,3,4 There are no efficacy or effectiveness studies of COVID-19 prevention following a 3rd dose in immunocompromised persons.
How substantial are the undesirable anticipated effects? Minimal Symptoms reported after an additional dose in certain immunocompromised persons were mostly mild to moderate and similar to those observed with previous doses2; no severe adverse events were reported.1 mRNA COVID-19 vaccines are associated with rare but serious adverse events, including anaphylaxis as well as myocarditis and pericarditis in young adults. The impact of immunocompromising conditions on these rare events is unknown. There are no safety studies of an additional mRNA dose in immunocompromised adolescents.
Do the desirable effects outweigh the undesirable effects? Favors the intervention The Work Group concluded that the desirable effects of an additional mRNA COVID-19 vaccine dose outweigh the undesirable effects.

Values

 

Values
Criteria Work Group Judgements Evidence Additional Information
Does the target population feel that the desirable effects are large relative to undesirable effects? Large Overall, intent to be vaccinated with a COVID-19 vaccine is high among immunocompromised populations. In a survey of individuals with cancer, autoimmune diseases, and other serious co-morbid conditions, 76% of respondents state they have either received, are trying to receive, or definitely will receive a COVID-19 vaccine.1
Is there important uncertainty about, or variability in, how much people value the main outcomes? Probably not important uncertainty or variability COVID-19 vaccine hesitancy in immunocompromised individuals appears to be associated with younger age, female gender, racial/ethnic minorities, and less formal education.1 Concerns about safety and possible side effects are major reasons for vaccine hesitancy.1,2

Acceptability

Acceptability
Criteria Work Group Judgements Evidence Additional Information
Is the intervention acceptable to key stakeholders? Yes Professional societies that advocate for access to high quality care for patients with immunocompromising conditions have voiced support for an additional dose of COVID-19 vaccine in immunocompromised persons.1 These include1:
  • Infectious Diseases Society of America
  • American College of Rheumatology
  • American Society of Transplantation
  • American Society of Transplant Surgeons
  • International Society for Heart and Lung Transplantation
  • Pediatric Infectious Diseases Society
  • Children’s Oncology Group
  • Leukemia and Lymphoma Society

Resource Use

Resource Use
Criteria Work Group Judgements Evidence Additional Information
Is the intervention a reasonable and efficient allocation of resources? Yes The U.S. government has purchased 600 million doses of mRNA vaccines.1 These doses are available at no cost to the recipient. Furthermore, immunocompromised patients experience high medical costs at baseline and are at higher risk for hospitalization. The cost of an additional dose of COVID-19 vaccine is small relative to these costs. The Work Group concluded that cost-effectiveness may not be a primary driver for decision-making during a pandemic and for vaccine use under an Emergency Use Authorization.

Equity

Equity
Criteria Work Group Judgements Evidence Additional Information
What would be the impact of the intervention on health equity? Probably no impact Several immunocompromised groups in the United States were identified by the Work Group as being potentially disadvantaged with respect to an additional mRNA COVID-19 vaccine dose: people living in rural/frontier areas, people in congregate settings, people experiencing homelessness, people belonging to certain racial and ethnic minority groups, people experiencing poverty, people with disabilities, people with substance use, and recipients of Janssen COVID-19 vaccine.

Feasibility

Feasibility
Criteria Work Group Judgements Evidence Additional Information
Is the intervention feasible to implement? Yes There are high levels of interaction between immunocompromised populations and the healthcare system, which will help to provide opportunities for an additional dose following the primary series. In addition, the mRNA COVID-19 vaccine supply in the United States is sufficient to allow for additional doses of vaccine in immunocompromised persons.

Balance of consequences

Desirable consequences clearly outweigh undesirable consequences in most settings.

Is there sufficient information to move forward with a recommendation? Yes.

Policy options for ACIP consideration

  • ACIP recommends the intervention

Draft recommendation: ACIP and CDC recommendations

Moderately-to-severely immunocompromised persons aged ≥12 years (Pfizer-BioNTech) or ≥18 years (Moderna) should receive an additional COVID-19 vaccine dose at least 28 days after completion of primary vaccination.

References

Problem:

  1. Harpaz, R., et al. (2016). “Prevalence of Immunosuppression Among US Adults, 2013.” JAMA 316(23): 2547-2548.
  2. Williamson, E. J., et al. (2020). “Factors associated with COVID-19-related death using OpenSAFELY.” Nature 584(7821): 430-436.
  3. Truong, T. T., et al. (2021). “Persistent SARS-CoV-2 infection and increasing viral variants in children and young adults with impaired humoral immunity.” medRxiv: 2021.2002.2027.21252099.
  4. Hensley, M. K., et al. (2021). “Intractable Coronavirus Disease 2019 (COVID-19) and Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Replication in a Chimeric Antigen Receptor-Modified T-Cell Therapy Recipient: A Case Study.” Clinical Infectious Diseases 73(3): e815-e821.
  5. Baang, J. H., et al. (2021). “Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 Replication in an Immunocompromised Patient.” The Journal of infectious diseases 223(1): 23-27.
  6. Choi, B., et al. (2020). “Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host.” New England Journal of Medicine 383(23): 2291-2293.
  7. Helleberg, M., et al. (2020). “Persistent COVID-19 in an Immunocompromised Patient Temporarily Responsive to Two Courses of Remdesivir Therapy.” The Journal of infectious diseases 222(7): 1103-1107.
  8. Clark, S. A., et al. (2021). “SARS-CoV-2 evolution in an immunocompromised host reveals shared neutralization escape mechanisms.” Cell 184(10): 2605-2617.e2618.
  9. Kemp, S. A., et al. (2021). “SARS-CoV-2 evolution during treatment of chronic infection.” Nature 592(7853): 277-282.
  10. Khatamzas, E., et al. (2021). “Emergence of multiple SARS-CoV-2 mutations in an immunocompromised host.” medRxiv: 2021.2001.2010.20248871.
  11. Avanzato, V. A., et al. (2020). “Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with Cancer.” Cell 183(7): 1901-1912.e1909.
  12. Nakajima, Y., et al. (2021). “Prolonged viral shedding of SARS-CoV-2 in an immunocompromised patient.” Journal of Infection and Chemotherapy 27(2): 387-389.
  13. Tarhini, H., et al. (2021). “Long-Term Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infectiousness Among Three Immunocompromised Patients: From Prolonged Viral Shedding to SARS-CoV-2 Superinfection.” The Journal of infectious diseases 223(9): 1522-1527.
  14. Strengert, M., et al. (2021). “Cellular and humoral immunogenicity of a SARS-CoV-2 mRNA vaccine in patients on hemodialysis.” medRxiv: 2021.2005.2026.21257860.
  15. Lewis, N. M., et al. (2020). “Household Transmission of Severe Acute Respiratory Syndrome Coronavirus-2 in the United States.” Clinical Infectious Diseases 73(7): e1805-e1813.
  16. Tenforde, M. W., et al. (2021). “Effectiveness of SARS-CoV-2 mRNA Vaccines for Preventing Covid-19 Hospitalizations in the United States.” medRxiv: 2021.2007.2008.21259776.
  17. Chodick, G., et al. (2021). “The Effectiveness of the Two-Dose BNT162b2 Vaccine: Analysis of Real-World Data.” Clinical Infectious Diseases.
  18. Khan, N. and N. Mahmud (2021). “Effectiveness of SARS-CoV-2 Vaccination in a Veterans Affairs Cohort of Patients With Inflammatory Bowel Disease With Diverse Exposure to Immunosuppressive Medications.” Gastroenterology 161(3): 827-836.
  19. Chemaitelly, H., et al. (2021). “SARS-CoV-2 vaccine effectiveness in immunosuppressed kidney transplant recipients.” medRxiv: 2021.2008.2007.21261578.
  20. Brosh-Nissimov, T., et al. (2021). “BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel.” Clinical Microbiology and Infection.
  21. CDC COVID Data Tracker. https://covid.cdc.gov/covid-data-tracker/#vaccinations_vacc-total-admin-rate-total. Accessed: October 20, 2021
  22. Delta Variant: What We Know About the Science. www.cdc.gov/coronavirus/2019-ncov/variants/delta-variant.html. Accessed: October 20, 2021

Benefits and harms:

  1. Kamar, N., et al. (2021). “Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients.” New England Journal of Medicine 385(7): 661-662.
  2. Espi, M., et al. (2021). “Justification, safety, and efficacy of a third dose of mRNA vaccine in maintenance hemodialysis patients: a prospective observational study.” medRxiv: 2021.2007.2002.21259913.
  3. Hall, V. G., et al. (2021). “Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients.” New England Journal of Medicine 385(13): 1244-1246.
  4. Ducloux, D., et al. (2021). “Humoral response after 3 doses of the BNT162b2 mRNA COVID-19 vaccine in patients on hemodialysis.” Kidney Int 100(3): 702-704.

Values:

  1. Tsai, R., et al. (2021). “COVID-19 vaccine hesitancy among individuals with cancer, autoimmune diseases, and other serious comorbid conditions.” medRxiv: 2021.2004.2006.21254014.
  2. Garcia, P., et al. (2021). “SARS-CoV-2 Vaccine Acceptability in Patients on Hemodialysis: A Nationwide Survey.” Journal of the American Society of Nephrology 32(7): 1575-1581.

Acceptability:

  1. Dooling, K. Evidence to Recommendation Framework: An Additional Dose of COVID-19 Vaccine Following a Primary Series in Immunocompromised People. Presentation to ACIP. August 13, 2021

Resource Use

  1. HHS.gov. Biden administration purchases additional doses of COVID-19 vaccines from Pfizer and Moderna. https://www.hhs.gov/about/news/2021/02/11/biden-administration-purchases-additional-doses-covid-19-vaccines-from-pfizer-and-moderna.html. February 11, 2021
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