mRNA COVID vaccines found ‘worthwhile’ in patients on anti-CD20 treatment

BY KATE JOHNSON


Patients who are on anti-CD20 treatment for multiple sclerosis (MS) still benefit from receiving a COVID-19 mRNA vaccine, despite having an impaired antibody response to the injection, according to a new study.

The findings, published in Nature Medicine, show that vaccination is “worthwhile” for this group, noted one of the senior authors, E. John Wherry, PhD, chair of Systems Pharmacology and Translational Therapeutics and director of the Penn Institute for Immunology at the University of Pennsylvania, Philadelphia.

“There have been questions I have gotten from patients wondering why they should get vaccinated if they can’t make antibodies,” he said in an interview with MS Journey. “Getting vaccinated is not only about making antibodies. Our study shows that the immune system has other capacity to respond to vaccination. So, we urge patients with MS receiving anti-CD20 treatment to get a COVID-19 vaccine if they haven’t already.”


Dr. E. John Wherry



Dr. Amit Bar-Or
“Even though people on this type of treatment are likely to exhibit very attenuated or even absent antibody responses to the vaccine, it is not a waste of time to get vaccinated,” agreed another senior author, Amit Bar-Or, MD, FRCPC, director of the Center for Neuroinflammation and Experimental Therapeutics and chief of the Division of MS and Related Disorders at the university. “The immune system will still mount very good immune responses on the T-cell side.”

The study included 20 patients with MS who were being treated with anti-CD20 monotherapy and 10 controls without MS, all of whom were vaccinated with either of the two mRNA COVID-19 vaccines: BNT162b2 (Pfizer-BioNTech) and mRNA1273 (Moderna). To assess the participants’ antibody and T-cell response to the vaccine, researchers analyzed plasma and peripheral blood mononuclear cell samples five times over the study period: prior to, and then 10-12 days after the first vaccine dose; prior to, and then 10-12 days after the second dose; and finally, 25-30 days after the second dose.

When you give a treatment with anti-CD20 you deplete many B cells. To mount the most complete vaccine response you’d like to have your B cells around for two reasons: because B cells are responsible for turning into the cells that make the antibodies, and also because the B cells are involved – to some extent at least – in shaping the T-cell responses. It’s kind of a collaboration between B cells and T cells that contributes to the most complete vaccine response.

While all subjects who did not have MS produced increasing levels of antibodies after the first and then second vaccine doses, this response was impaired in patients who did have MS, among whom only 85% had developed anti-spike antibodies, and 50% had developed anti-receptor-binding domain (RBD) antibodies at 30 days post second dose. In contrast, subpopulations of T cells responded similarly in MS patients, compared with controls. Specifically, CD4 and CD8 responses were robust in MS patients – particularly in those with the weakest antibody response.

The findings add some nuance to juggling the timing of vaccination with anti-CD20 treatment, said Dr. Bar-Or, who also serves on the National MS Society’s taskforce on COVID-19. “The imperative is to get vaccinated as opposed to not,” he emphasized, but if possible, timing the vaccine for when anti-CD20 therapy is waning would illicit the best response.

“When you give a treatment with anti-CD20 you deplete many B cells. To mount the most complete vaccine response you’d like to have your B cells around for two reasons: because B cells are responsible for turning into the cells that make the antibodies, and also because the B cells are involved – to some extent at least – in shaping the T-cell responses. It’s kind of a collaboration between B cells and T cells that contributes to the most complete vaccine response.”

Dr. Bar-Or said timing vaccination as long as possible from the last anti-CD20 infusion will allow B cells to return and improve vaccine response. But should that involve delaying the vaccine, or delaying the anti-CD20? And what are the risks?


Encapsulated mRNA vaccine
Image credit: Trinset / iStock / Getty Images Plus

“This is very much a context-dependent question – and the conversation may be very different depending on the patient population and also if you’re waiting for an initial course of vaccination versus a booster,” said Dr. Bar-Or. For patients with primary progressive MS (PPMS), delaying anti-CD20 would likely be the safer option. “People with primary progressive MS are on average older, more disabled and with more comorbidities [than those with relaxing-remitting MS] all of which are associated with higher risk of severe outcomes from COVID.

In that context, you have more risk if you’re not protected for COVID-19 – very real risk – and very little risk of your MS being impacted in an important way if you extend the anti-CD20 dose interval by a couple of months. On the other hand, people who are younger and less likely to have comorbidities – who are therefore not in the higher-risk category of severe outcomes from COVID – and whose MS may be more active, should still try, if possible, to maximize the interval from treatment to vaccination but they may not be as comfortable extending the interdose interval.”

According to the National MS Society guidance on this, on which Dr. Bar-Or collaborated, patients should consider getting fully vaccinated 2-4 weeks or more prior to initiating anti-CD20 infusions, or if they are already taking this treatment, should consider getting vaccinated 12 weeks or more after an infusion. However, “This suggested scheduling is not always possible, and getting the vaccine may be more important than timing the vaccine with your MS medicine,” notes the National MS Society guidance.

As long as vaccination occurs, there is no right or wrong when it comes to timing, added Dr. Wherry. “I think the landscape has shifted a bit even since we wrote this paper. Yes, patients made better antibody responses if they were vaccinated late in the anti-CD20 cycle which might suggest trying to optimize that timing. But, depending on local infection rates, patient risks, behavior, masking, and many other factors, the decision of when to vaccinate is complex and really something that should be decided individually – with physician input – taking all of these factors into consideration.”

The researchers also noted that their findings have wider implications, beyond the field of MS. “These results are evidence of effective immune priming by mRNA vaccines in the absence of circulating B cells, findings that may also be relevant for the application of mRNA vaccines in other settings, such as neoantigen cancer vaccines in patients with B-cell deficiencies. … Overall, these data provide key insights about the ability to generate immune responses in immunocompromised populations that will be relevant for clinical guidance in these patients and possible public health recommendations for vulnerable populations.

Top image credit: franckreporter / E+ / Getty Images
Image credit: DrAfter123 / DigitalVision Vectors / Getty Images


Study funding

The study was supported by grants from the National Institutes of Health, with funding also provided by the Allen Institute for Immunology; Chen Family Research Fund; the National Multiple Sclerosis Society-American Brain Foundation Clinician Scientist Award; the Parker Institute for Cancer Immunotherapy; the Penn Center for Research on Coronavirus and Other Emerging Pathogens; the University of Pennsylvania Perelman School of Medicine COVID Fund; the University of Pennsylvania Institute for Immunology Glick COVID-19 research award; the University of Pennsylvania Perelman School of Medicine 21st Century Scholar Fund; a philanthropic gift from Jeffrey Lurie, Joel Embiid, Josh Harris, and David Blitzer; the Penn Center for Neuroinflammation and Experimental Therapeutics; and the Melissa and Paul Anderson Fund.


Disclosures

Dr. Bar-Or has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from Accure Therapeutics, Atara Biotherapeutics, Biogen, Bristol Myers Squibb/Celgene/Receptos, GlaxoSmithKline, Gossamer Bio, Janssen/Actelion, MedImmune, Merck/EMD Serono, Novartis, Roche/Genentech, and Sanofi-Genzyme.

Dr. Wherry is consulting or is an advisor for Merck, Marengo, Janssen, Related Sciences, Synthekine, and Surface Oncology; is a founder of Danger Bio, Surface Oncology, and Arsenal Biosciences; and is an inventor on a patent (US patent no. US10370446B2) submitted by Emory University that covers the use of PD-1 blockade to treat infections and cancer.

Suggested Reading

Apostolidis SA, et al. Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy. Nat Med. 2021 Sept. 14. https://www.nature.com/articles/s41591-021-01507-2.