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Mutation Sped Up by Lengthy COVID-19 Cases in Immunosuppressed Patients

Efforts to provide booster shots for immunosuppressed patients aren’t just to protect them but also might be better for the broader community. Recent research suggests that multimutational SARS-CoV-2 variants can arise during persistent cases of COVID-19 – a situation that is more common in immunocompromised patients than the general population. Adding to the risk is that those patients have unpredictable responses to the vaccines. Here are more details.

SEATTLE – New research underscores the importance of protecting immunosuppressed patients from contracting COVID-19 – for them and the community at large.

Researchers suggest that immunosuppression puts patients at greater risk for prolonged infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the same time, clinical studies have identified unpredictability in how those patients respond to vaccination against the novel coronavirus, with some developing few if any antibodies and others mounting responses equivalent to those without immunosuppression.

Concerns about COVID-19 in immunosuppressed patients don’t end there, however. A new study has suggested that multimutational SARS-CoV-2 variants can arise during persistent cases of coronavirus disease 2019. 

“These highly mutated variants are indicative of a form of rapid, multistage evolutionary jumps (which could preferentially occur in the milieu of partial immune control,)” wrote the authors of the Fred Hutchinson Cancer Research Center-led study. “The presence of a large number of mutations is also a hallmark of the variants of concern — including B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma), and B.1.617.2 (delta)⁵ — which suggests that viral evolution in immunocompromised patients may be an important factor in the emergence of such variants.”

“Since a large number of persons globally are living with innate or acquired immunosuppression, the association between immunosuppression and the generation of highly transmissible or more pathogenic SARS-CoV-2 variants requires further delineation and mitigation strategies,” the authors reported in the New England Journal of Medicine.

Shortly after the “Sounding Board” article appeared in NEJM, the Food and Drug Administration amended the emergency use authorizations (EUAs) for both the Pfizer-BioNTech COVID-19 vaccine and the Moderna COVID-19 vaccine to permit the use of an additional dose in certain immunocompromised individuals.

While the issue of generation of highly transmissible or more pathogenic SARS-CoV-2 variants was not mentioned in the FDA announcement, it remains a concern among researchers. They pointed to a case described in correspondence in the NEJM last December. The authors from Brigham and Women’s Hospital and colleagues described rapid viral evolution in an immunosuppressed patient with persistent SARS-CoV-2 infection. The immunosuppressed patient with antiphospholipid syndrome was hospitalized in August 2020 and treated with anticoagulants, glucocorticoids, cyclophosphamide, intermittent rituximab, and eculizumab. Over 152 days of persistent SARS-CoV-2 infection which ended in death, investigators said they identified 31 substitutions and three deletions in genome sequences.

In addition, they reported finding 12 spike mutations, including seven in a segment of the receptor-binding domain consisting of 24 amino acids, some at sites linked to immune evasion (478, 484, and 493).²

“These compilations of case reports indicate the need to identify whether certain forms of immunosuppression are associated with an increased risk of such multimutational escape patterns — for instance, specific cancers or specific therapies, such as the development of B-cell aplasia related to CAR T-cell or anti-CD20 therapy, prolonged use of glucocorticoids, long-term chemotherapy, or radiotherapy,” wrote the authors of the recent Sounding Board article. “Similarly, organ transplant recipients and those with untreated or poorly controlled human immunodeficiency virus infection may also have prolonged SARS-CoV-2 infection and could constitute a reservoir of divergent escape variants that can spread in the general community. Prolonged viral replication in the context of an inadequate immune response facilitates the emergence of immune-pressure escape mutations.”