B-cell depleting therapies ‘biggest threat’ for reduced SARS-CoV-2 mRNA vaccine response
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B-cell depleting agents, glucocorticoids and mycophenolate mofetil have all been associated with reduced antibody responses to SARS-CoV-2 vaccination, noted a presenter at the 2022 Association of Women in Rheumatology Annual Conference.
“We don’t know what antibody levels are actually sufficient in order to protect someone,”
Alfred H. J. Kim, MD, PhD, assistant professor in the division of medicine at the School of Medicine at Washington University in St. Louis, said in his presentation. “I don’t think we are going to be able to define that at all with these type of vaccines, unfortunately.”
In his talk, Kim aimed primarily to describe the classes of immunosuppressive drugs that are most likely to attenuate COVID-19 vaccine antibody production. Specifically, he highlighted B-cell depleting therapies and high-dose mycophenolate mofetil as the two biggest culprits, but added that patients being treated with methotrexate, glucocorticoids, azathioprine and Janus kinase inhibitors all have been studied for a reduced vaccine response. “There have been 40-plus efforts globally examining the impact of immunosuppression on vaccine responses,” he said.
The good news is that the consensus is that most patients across rheumatologic conditions and regardless of the drug can mount a sufficient response immediately after completing a full series of vaccination with an mRNA product. “Probably closer to 80% to 90%” of rheumatology patients from what Kim called this “mishmash” of cohorts across disease states and types of immunosuppression were able to show some response.
The downside to this is obvious, however. “We still have that vulnerable pocket,” Kim said.
While it has been difficult to draw solid conclusions on vaccine response in rheumatology patients, there is one obvious take-home message. “B-cell depleting agents obviously are the biggest threat.”
Early data from small cohorts have shown a nearly 60-fold reduction in antibody response in patients receiving B-cell depleting therapies such as rituximab (Rituxan, Genentech) compared to immunocompetent individuals. “This has been shown globally,” he said.
Turning to glucocorticoids, Kim said that the data show around a 10-fold reduction in antibody response to SARS-CoV-2 vaccination among patients being treated with these drugs, regardless of the dose, in comparison with the immunocompetent. “This is in people on any dose of glucocorticoids,” he said. “That was a surprise.”
However, there is a key confounding factor in the steroid data that is worth noting, according to Kim. “We are reporting all of this on one drug and one target, but, obviously, everyone is on multiple drugs, so this ends up muddying some of the interpretation,” he said. “It may be one of the other drugs on top of prednisone that may be the problem.”
Kim then addressed data for patients being treated with mycophenolate showing that there may be as much as a 21-fold reduction in antibody response to COVID-19 vaccination compared to immunocompetent individuals. “There is a substantial reduction in [antibody] levels, with a whole bunch of people not responding,” he said.
By comparison, early data from other cohorts have shown a 4.4-fold reduction in antibody response in patients being treated with MTX and a 3.5-fold reduction associated with azathioprine. Again, both of these numbers are in comparison with the immunocompetent.
“JAK inhibition was associated with a nearly 10-fold reduction in response,” Kim said, but qualified this number from his own experience. “We never had a patient with a JAK inhibitor who did not mount some response. There are reductions, but, again, are those reductions going to be clinically meaningful?”
After describing the problem, Kim then offered some solutions. In short, he stressed that it is possible to mitigate the poor COVID-19 vaccine responses in patients on immunosuppression.
The key factor for B-cell depleting therapies is timing. Administering the vaccine 6 to 9 months after the last dose of rituximab can increase response, according to Kim. “If they are able to get beyond 9 months, almost all of them are able to generate good response,” he said.
For patients taking other drugs, booster vaccines can be useful. “You can give additional dosing if they can tolerate that,” Kim said.
Perhaps the most important consideration is to treat patients on immunosuppression with pre-exposure prophylaxis using tixagevimab co-packaged with cilgavimab (Evusheld, AstraZeneca). “The new data that is coming out is just so compelling in terms of its ability to reduce harmful outcomes due to SARS-CoV-2,” Kim said.
“Keep vaccinating,” he concluded. “Get Evusheld into your patients regardless of what mechanism of immunosuppression they are on.”
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