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Immunocompromised people suffer a higher burden of symptomatic SARS-CoV-2 infection and severe COVID-19 disease.
Here, we define immunocompromised populations as a heterogeneous group of people with inherited or acquired immune deficits, which affect multiple compartments of the immune system to varying degrees. Some specific immunocompromised populations include people with HIV and cancer as well as solid organ transplant recipients.
The mechanisms underlying immunocompromised people’s increased susceptibility to COVID-19 are complex and include:
- End-organ impairments related to the immunocompromising condition;
- Use of immunosuppressive medications that blunt the ability to control viral infections;
- Potential interference of exogenous and endogenous factors with COVID-19 vaccines’ immunogenicity and protective effects.
Notably, patient factors such as older age and common medical comorbidities (e.g., diabetes, obesity, kidney disease) continue to drive severe COVID-19 outcomes even among immunocompromised populations. Therefore, COVID-19 risk exists on a continuum for immunocompromised people, incorporating the net state of immunosuppression alongside other classical biological and sociodemographic factors.
Although immune responses to COVID-19 vaccines may be attenuated in immunocompromised populations, vaccination complemented by passive immunotherapies remain key cornerstones to reducing severe COVID-19.
At present, there are no longer FDA-authorized monoclonal antibodies for treatment or prevention of COVID-19 in immunocompromised people. This is due to mutations in the SARS-CoV-2 Omicron subvariants, which now predominate in the U.S. and demonstrate dramatic immune evasion of prior active monoclonal antibodies. Fortunately, oral and intravenous antiviral drugs are predicted to maintain activity against current variants and remain important tools to decrease severe COVID-19 in high-risk immunocompromised people. Additionally, high-titer convalescent plasma, particularly from donations during the Omicron era, may maintain activity against new subvariants and thus retains FDA authorization for treatment in immunocompromised individuals.
This figure outlines several considerations that impact risk for COVID-19, which exists on a continuum and is highly individualized. Listed comorbidities and immunosuppressive conditions are illustrative, not exhaustive; there is significant variability in the net state of immunocompromise even among people with the same condition.
For more information, visit Understanding Risk for Severe COVID-19.
What are examples of immunocompromising conditions in the context of COVID-19?
CDC and NIH have each provided broad definitions of “moderately or severely immunocompromising conditions” in the context of COVID-19. This includes people undergoing active cancer treatment, recipients of solid organ transplants, people with primary (“inborn”) immunodeficiencies, advanced or untreated HIV infection (i.e., CD4 T-cell count <200 cells/uL), or prolonged use of high-dose corticosteroids (e.g., >20 mg/day) and other drugs that suppress the immune system (e.g., calcineurin inhibitors, antimetabolites, biologics). “Severe immunocompromise” may be further defined as certain highest-risk transplant recipients such as lung recipients, people <1 year from receipt of lymphodepleting therapies and people with active graft-versus-host disease, as well as people with severe combined immunodeficiencies and those with advanced HIV/AIDS (CD4 <50 cells/uL).
Which immunocompromised people are at higher risk for severe COVID-19?
People at the intersection of severe immunocompromise and multiple medical comorbidities are likely at the greatest risk for severe COVID-19. This represents a group of people who are more easily infected by SARS-CoV-2, less able to mount antiviral immune responses after infection (at times despite vaccination) and therefore may suffer clinically significant disease (CDC, February 2022). Many studies throughout the COVID-19 pandemic have associated advanced age as well as a high number of comorbidities such as obesity, diabetes and chronic kidney disease with severe disease. This relationship endures in studies of immunocompromised populations with COVID-19, and, after controlling for medical conditions, incidence of severe disease and mortality may be similar between some immunocompromised and nonimmunocompromised people (Molnar, November 2020; Sharma, January 2021). The most severe immunocompromising conditions (detailed above) appear to connote additional risk for severe disease. For example, in people with HIV, lower CD4+ Tcell counts (<200-350 cells/uL) appear independently associated with worse COVID-19 outcomes. Among solid organ transplant recipients, people with recent organ rejection and lung transplant recipients (i.e., groups receiving high-dose immunosuppression) suffer higher burdens of severe COVID-19 (Heldman, August 2021).
What is the impact of immunosuppression on the immunogenicity and protection of COVID-19 vaccines?
As with other vaccinations, immunocompromising conditions and the medications used to treat them can decrease the immune response to the COVID-19 vaccines. This impact is not uniform and depends on many patient and medication factors. For example, multiple series indicate that people with active hematological malignancies (e.g., lymphomas, myeloma, leukemias) as well as recipients of organ transplants may have significantly reduced antibody and cellular responses to mRNA and adenoviral vaccination. Additionally, treatment with medications that impair lymphocyte function such as lymphodepleting agents (e.g., rituximab, ocrelizumab) and higher doses of antimetabolites (e.g., mycophenolate) appear to significantly blunt aspects of vaccine response; these effects are more pronounced when people have more recently received intense immunosuppression. Diminished vaccine immunogenicity has translated to higher rates of clinically significant COVID-19 after vaccination in many immunocompromised populations (Sun, December 2021; Wang, April 2022). This includes increased risk for hospitalization and severe disease, which has informed recommendations for intensified prevention and treatment measures (Kwon, April 2022; Embi, November 2021). As in the general population, the emergence of variants of concern that exhibit significant immune evasion does place immunocompromised people at higher risk for infection after vaccination.
What guidance exists regarding treatment and prevention of COVID-19 in immunocompromised populations?
As a result of more severe COVID-19 outcomes as well as poorer vaccine immunogenicity, CDC recommendations for prevention and treatment of COVID-19 differ for immunocompromised populations. This includes authorization of an additional vaccine dose (i.e., a third mRNA vaccine) to complete the primary vaccine series for moderate and severely immunocompromised people (CDC/Dooling, August 2021 [PDF]). This additional dose does appear to augment immune responses and vaccine effectiveness for many populations, including versus variants of concern (Hall, September 2021; Karaba, December 2021; Khan, April 2021).
What is the role for antibody testing in assessing risk for COVID-19 in immunocompromised populations?
Antibody and cellular responses to COVID-19 vaccines are attenuated in certain immunocompromised populations as compared to those of the general population, which likely contribute to decreased vaccine effectiveness. Increasing levels of anti-spike antibody appear to be associated with higher vaccine effectiveness against SARS-CoV-2 infection, though there is no specific antibody threshold that has been reliably associated with protection (Khoury, May 2021; Gilbert, November 2021; Feng, September 2021; Spitzer, January 2022). This is in part due to variability among antibody testing platforms, ongoing viral evolution and immune escape (evidenced by the Omicron variant) and expected waning of antibody levels over time. Additionally, in certain immunosuppressed populations, there is discordance between antibody levels and degree of anti-SARS-CoV-2 cellular responses; thus, antibody assessments may not represent the full nature of immunoprotection after COVID-19 vaccination (Hall, December 2021; Jyssum, March 2022; Apostolidis, September 2021).
Major governmental and society guidelines therefore do not currently recommend routine use of anti-spike antibody testing to determine immune response or COVID-19 risk after infection or vaccination (FDA, May 2021). Some societies do, however, consider people with negative anti-spike antibody levels after full vaccination to be at high risk for COVID-19, and thus testing may be used as a risk stratification factor for interventions such as administration of pre-exposure monoclonal antibody prophylaxis (American Society of Transplantation, March 2022 [PDF]).
Effectiveness of COVID-19 mRNA Vaccines Against COVID-19–Associated Hospitalizations Among Immunocompromised Adults During Omicron
Monovalent COVID-19 vaccine protection among immunocompromised adults during Omicron predominance was moderate after a 3-dose primary series or booster dose, according to this CDC MMWR.
Safety Monitoring of COVID-19 mRNA Vaccine First Booster Doses Among Persons Aged ≥12 Years with Presumed Immunocompromise Status
Among presumed immunocompromised persons aged 12 and up, only 17 serious adverse events were reported to VAERS after receiving an mRNA booster dose between January 2022 and March 2022, according to this CDC MMWR.
Factors Associated with Severe Outcomes Among Immunocompromised Adults Hospitalized for COVID-19
Immunocompromised patients accounted for 12.2% of adult COVID-19 hospitalizations among 10 states and had increased odds of ICU admission and in-hospital death, irrespective of vaccination status, according to this CDC MMWR.