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COVID-19 in Immunocompromised Patients: Vaccine Responsiveness and the Potential for SARS-CoV-2 Variants in Patients With Prolonged Infection

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Christopher J. Lehmann, MD

Fellow Physician
Section of Infectious Diseases and Global Health
Department of Medicine
University of Chicago Medicine
Chicago, Illinois

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Gregory Olson, MD

Clinical Instructor

Department of Infectious Diseases
University of Chicago Medical Center
Chicago, Illinois

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Renslow Sherer, MD

Director, International HIV Training Center
Professor of Medicine
Section of Infectious Diseases and Global Health
Department of Medicine
University of Chicago
Chicago, Illinois

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Released: June 28, 2021

For all the tragedies of the COVID-19 pandemic, the development of safe and effective vaccines for SARS-CoV-2 has been a victory, providing a pathway to reduce infections, save lives, and return to normalcy. However, for the 3 million immunocompromised patients in the United States, vaccine efficacy remains in question.

Immunocompromised Patients Rare in COVID-19 Vaccine Trials
Few immunocompromised patients were included in the randomized clinical trials for COVID-19 vaccines, so efficacy in these patients was less clear at the start of the vaccination rollout. Data are emerging to better understand efficacy in these patients. For example, one study found that a lower proportion of solid organ transplant recipients mount an antibody response to SARS-CoV-2 messenger RNA vaccines compared with the general population. Of 658 transplant recipients who received 2 doses of the vaccine, only 15% had a measurable antibody response after the first dose, 39% had a measurable antibody response only after the second dose, and 46% had no antibody response after either dose. Antibody response to vaccination is also impaired in patients with chronic lymphocytic leukemia especially those patients exposed to anti-CD20 antibodies and those currently receiving treatment for chronic lymphocytic leukemia.

Similar impairments have been demonstrated in a case series of patients with rheumatic and musculoskeletal disease who were treated with, most commonly, rituximab and mycophenolate. In a prospective observational study of 151 patients with cancer, antibody response was poor to the first dose (38% of patients with solid cancer and 18% of patients with hematologic cancer vs 94% of healthy controls) but improved significantly after the second dose to 88% (21/24 patients with solid or hematologic cancers) supporting the 2-dose series in this population. In summary, there is growing evidence of significantly weaker antibody responses in solid organ transplant recipients, patients with cancer, and patients with rheumatic diseases on certain high-risk medications, particularly following the first dose of the vaccine series.

Cell-Mediated Immunity Against SARS-CoV-2
It should be noted that antibody testing may be limited and incomplete as a surrogate marker for vaccine efficacy. Cell-mediated immunity, specifically CD4+ and CD8+ T-cells, likely plays an important role in defense against COVID-19. Circulating SARS-CoV-2–specific T-cells have been identified in patients who recovered from COVID-19, even mild COVID-19 disease, and specific T-cell responses have been noted following vaccination, including the mobilization of monocytes and cytokines such as IL-2, TNF, and IFN-γ. Although anti–SARS-Cov-2 antibody titers decay following infection, bone marrow aspirates have found long-living plasma cells with activity against the spike protein of SARS-CoV-2 7-8 months after infection in recovered patients, suggesting an ongoing reservoir for immunity. Although the implications of these findings in immunocompromised individuals are not yet well defined, antibody titers alone may not be a complete measure of vaccine responsiveness.

COVID-19 Vaccines in Immunocompromised Patients
Vaccination in immunocompromised patients is critical for more than just preventing morbidity and mortality. Immunocompromised patients shed infectious virus much longer than the general population. Some reports detected SARS-CoV-2 RNA beyond 120 days of illness and infectious virus up to 95 days. Alarmingly, prolonged shedding of infectious virus occurs asymptomatically long after symptom resolution. Prolonged infection also appears to support rapid acquisition of SARs-CoV-2 mutations in this population. Kemp and colleagues found de novo acquisition of 2 mutations present in the B.1.1.7 variant in a single patient. The mutations arrived after administration of convalescent plasma, possibly selected by subneutralizing antibody levels. In all of these studies, a disproportionate number of mutations appears to occur in the spike protein.

The combination of prolonged shedding and accelerated spike protein mutation raises concern that infection in immunocompromised patients could drive vaccine escape variants, and threaten vaccine efficacy generally. Antibody therapy in this population, via convalescent plasma or monoclonal antibodies, appears to improve symptoms. In one series, viral clearance followed convalescent plasma administration in 20 of 23 patients. It should be noted that the current Emergency Use Authorization for monoclonal antibodies does not recommend their use in hospitalized patients, given the lack of evidence of overall clinical efficacy. Vaccination may serve as a way to avoid prolonged shedding and variant emergence by preventing infection in the immunocompromised population altogether.

Final Thoughts
At this time, national societies recommend vaccination of immunocompromised hosts, with counseling regarding the potential for reduced efficacy. Even if the vaccine response is less robust than the general population, any immunity is better than no immunity at all. From a population perspective, preventing infection in immunocompromised patients is even more important than preventing infection in the general population, because immunocompromised hosts shed infectious virus longer and serve as potential reservoirs for spike protein mutations. Consequently, the vaccination of immunocompetent close contacts and community members is critical to decrease the chance that immunocompromised individuals encounter the virus in the first place.

Your Thoughts?
What concerns do the immunocompromised patients in your practice express about vaccination against COVID-19? Answer the polling question and join the conversation by posting in the discussion section.

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