How Should We Advise Our Immunocompromised Patients After COVID-19 Vaccination?

Because COVID-19 vaccines are highly effective and safe, the epidemic appears to be waning in the U.S.; thus, the CDC recently loosened the recommendation for masking among vaccinated individuals in most settings. However, because immunocompromised persons (who constitute up to 5% of U.S. adults) were generally not included in the vaccine trials, efficacy in this population remains unknown. Still, these patients need answers regarding the necessity of booster doses, utility of postvaccination antibody testing, and advisability of prolonged social distancing and mask wearing.

Much vaccine research to date consists of cohort studies assessing anti–SARS-CoV-2 spike-protein antibody responses after one or two doses of vaccine (mostly mRNA-based). Various serologic assays (whether commercial or “home grown”) are used, and responses are often compared to those in immunocompetent persons (who typically experience nearly 100% seroconversion). The peer-reviewed research to date is summarized in the table.

When interpreting these data, it is essential to realize that we do not yet know the clinical implications of spike-protein antibody responses. In fact, the FDA recently advised against checking postvaccination antibody levels, as positive titers may not reflect protection and negative titers may not indicate susceptibility.9 T-cell responses (which are not directly measured in serologic assays) may provide some degree of protection, especially against severe disease.

Nonetheless, some lessons may be emerging. Use of immunosuppressive agents that impair B-cell function (e.g., mycophenolate, rituximab) is associated with poor vaccine antibody responses, as is older age. Even low-dose corticosteroids may impair serologic response. Patients with cancer have increased likelihood of seroconversion if vaccination takes place when off treatment (although patients with B-cell chronic lymphocytic leukemia may be an exception).

Given that the efficacy of many vaccines is attenuated in immunosuppressed patients, the same may be true for COVID-19 vaccines — but could a third dose be beneficial? In a case series, researchers described outcomes in 30 recipients of solid-organ transplants who had low or no measurable antibody responses after two doses of mRNA vaccine. Half then received a booster with the Ad26.COV2.S (Johnson & Johnson) vaccine while the other half received a third dose of mRNA vaccine. Among the 6 patients with low initial antibody responses, 100% achieved high antibody titers after the third dose; among the 24 with no responses to the initial series, just 25% subsequently developed high titers.10

While we await further data and recommendations, how should we advise our immunocompromised patients?

Should Routine Spike-Protein Antibody Titers Be Checked After Vaccination?

• Since we do not yet know the clinical implications of these results, routine titers are not recommended as they may create false reassurance of protection or false concern of vulnerability.

• Some commercially available assays are not directed at spike protein and would only be expected to become positive after natural infection.

Should immunosuppressed patients receive additional doses of vaccine?

• Very limited safety or efficacy data are available to support this practice, which falls outside the current emergency use authorization; research to address this topic is ongoing.

Should Vaccinated Immunocompromised Patients Follow CDC Guidelines For Masking And Social Distancing?

• The new CDC guidelines linking vaccination and masking recommendations are particularly challenging for immunocompromised patients, who may be increasingly exposed to nonvaccinated individuals who choose not to mask (particularly as there is no practical way to enforce this recommendation).

• I inform all my immunocompromised patients that, while they should get vaccinated, they cannot rely on this intervention to keep them safe; therefore, they should continue to mask and practice social distancing. Encouraging vaccination of close contacts of immunocompromised patients should help reduce risk for transmission.

How Should Immunosuppression Alter The Timing Of Vaccination?

• Whenever possible, vaccination should occur at a time of reduced immunosuppression (e.g., between chemotherapy cycles, prior to solid-organ transplantation).

• Rituximab may be particularly problematic (likely due to its potent effect on B cells), and vaccination should be timed near the end of a cycle when possible.

• In most cases, reducing needed immunosuppression in an attempt to increase vaccine response is not recommended, particularly in transplant recipients. The American College of Rheumatology does, however, recommend holding some immunomodulatory therapy (e.g., mycophenolate or methotrexate) in those with stable disease for 1 to 2 weeks after vaccination.11

Several planned and ongoing studies should provide clearer answers to the questions faced by immunocompromised patients. In the meantime, we can offer reasonable guidance based on the limited data outlined above, as well as common sense.