Background

Anti-CD20 therapies rapidly induce a significant depletion of peripheral B cells in patients with multiple sclerosis (MS). As individuals with MS have previously demonstrated impaired responses to COVID-19 vaccines, a study was undertaken to determine whether patients who receive a vaccine prior to initiation of anti-CD20 therapy will demonstrate better responses to a third dose of the COVID-19 vaccines.

This Journal Club discussion will focus on a pilot study by Moser and colleagues that evaluated the antibody response to a third dose of a COVID-19 vaccine in patients with MS who were either receiving long-term anti-CD20 therapy at the time they received the first 2 doses of the COVID-19 vaccine (CD20-vaccine cohort) or received the first 2 doses of the COVID-19 vaccine series prior to initiating anti-CD20 therapy (vaccine-CD20-vaccine cohort).1 A panel of neurology experts from the University of Texas Southwestern Medical Center in Dallas led by Benjamin Greenberg, MD, MHS, reviewed the results of the study by Moser and colleagues and evaluated the implications on clinical practice.

Methods

A total of 15 participants with MS (women, 54%; mean age, 45.9 years) were enrolled into 2 cohorts. At baseline, the mean Expanded Disability Status Score of all participants was 4.5 years and the mean duration of MS was 9.7 years. The CD20-vaccine cohort included 4 participants while the vaccine-CD20-vaccine cohort included 11 participants. Both cohorts received a third dose, also referred to as a booster dose, of a COVID-19 vaccine prior to the initiation of the study while receiving anti-CD20 therapy. Antibody levels specific to the SARS-CoV-2 spike receptor-binding domain in peripheral blood samples were evaluated to compare the 2 cohorts.

Results

Among participants in the vaccine-CD20-vaccine cohort, 100% of participants experienced a measurable response to a third dose of a COVID-19 vaccine compared with 18% in the CD20-vaccine cohort. The mean antibody levels were significantly higher among the vaccine-CD20-vaccine cohort compared with the CD20-vaccine cohort (mean, 951.25±1137.96 binding antibody units (BAU)/mL vs 12.36±11.94 BAU/mL; mean difference, 938 BAU/ml [95% CI, 249-1629 BAU/mL]; P <.0001). Additionally, 75% of patients in the second cohort also demonstrated a 3.8- to 9.4-fold increase in SARS-CoV-2 spike antibody levels compared with the first 2 doses.

Discussion


Benjamin Greenberg, MD, MHS

Natalia Gonzalez Caldito, MD

Victor Salinas, MD, PhD

Benjamin Greenberg, MD, MHS, professor and the Cain Denius Scholar in Mobility Disorders; Natalia Gonzales Caldito, MD, fourth-year resident; and Victor Salinas, MD, PhD, fourth-year resident, Department of Neurology, University of Texas Southwestern Medical Center, Dallas participated in this journal club discussion.


Benjamin Greenberg, MD, MHS (BG): Natalia, will you provide us with an overview of the study design?

Natalia Gonzales Caldito, MD (NGC): In this study, the researchers investigated the humoral response to recall antigen by COVID-19 vaccines in patients with MS who had received anti-CD20 therapies.

They separated the patients into 2 groups. The first group of patients was on anti-CD20 therapies before they received the 3 doses of vaccine. The second group received 2 doses of vaccine before starting anti-CD20 therapy and then received the third dose.

The investigators looked at the antibody responses in these 2 groups to identify if having received the COVID-19 vaccine prior to anti-CD20 therapy would make any difference in outcomes.

BG: If you had to give a 10-second, single-sentence summary to somebody, what would you say is the study’s big clinical question and how it might impact our patient treatment?

NGC: I think that the study’s most important question is whether it is important to have received the vaccine before initiating anti-CD20 therapy. That was my takeaway from this paper.

BG: I agree, but I might say it slightly differently. We have heard about concerns from the literature about the impact of anti-CD20 on preventing COVID-19 vaccine efficacy. We hear less about what anti-CD20 therapy does to an existing immunity after vaccination. So, this is about the patients who are already on therapy when they are vaccinated and it is also about patients who are vaccinated and about to start therapy. The question is whether anti-CD20 therapy will negate the vaccine.

Victor, will you walk us through the 2 cohorts? The study gives us some data about them and admittedly, this was a pretty small study.

Victor Salinas, MD, PhD (VS): The skewed demographics may in part reflect this, but certainly the study has 2 cohorts, as Natalia noted. One is a cohort that received 2 doses of the COVID-19 vaccine before the initiation of anti-CD20 therapy and the other cohort received 2 doses of the vaccine while on anti-CD20 therapy for a period of time. You can see that the mean age for the former was significantly younger than the latter. That is also reflected in the disease duration. Patients who received the booster after initiating anti-CD20 therapy had a disease duration of almost 6 years compared to more than 12 years for patients on long-term anti-CD20 therapy.

Those receiving the booster after initiating anti-CD20 therapy were less disabled, likely related to their shorter disease duration. Curiously, on average, this cohort used more immunomodulating therapies compared with patients on long-term anti-CD20 therapy (2.25 vs 1). I thought this was interesting, again reflecting the biases in the skewed small sample. But it made me think about age because we know that immune responses decline to some degree with age. Could age have been a factor in some of the results? Maybe, but I certainly do not think it explains all of differences. I also would be interested to see the effects of different types of medications on the outcomes. It would be interesting to review a larger study that looked at other types of cell therapy and how they affect the immune response to COVID-19 vaccination.

BG: Yes, and you know the duration of being on anti-CD20 therapy is the definition of the 2 cohorts. By definition, patients in the CD20-vaccine cohort had been on therapy for quite a while compared with the individuals in the vaccine-CD20-vaccine cohort.

So, we have these 2 groups. We have the CD20-vaccine cohort who are the patients on anti-CD20 therapy prior to being vaccinated. Then we have vaccine-CD20-vaccine cohort who are the patients who received both doses of the COVID-19 vaccine, started anti-CD20 therapy, and then received the booster dose. Patients in vaccine-CD20-vaccine cohort was immunologically naive to CD20-depleting therapy when vaccinated and patients in the CD20-vaccine cohort were already B-cell depleted when their first vaccine exposure occurred. The researchers analyzed the data in a couple of different ways. Natalia, I will start with you. Months after the booster dose, the researchers looked to see what percentage of patients had a measurable anti-spike protein antibodies. Will you walk us through the differences between the 2 cohorts on that data point?

NGC: In the CD20-vaccine cohort, only 18% (2/11) had measurable antibody response after booster dose. In the vaccine-CD20-vaccine cohort, 100% (4/4) developed antibody response. That tells us that the group who received the vaccine prior to anti-CD20 therapy had a much more robust response to the vaccine compared with the group who were vaccinated after anti-CD20 therapy.  

BG: Out of those 11 individuals who had been on long-term anti-CD20 therapy followed by the vaccine and then the booster, 9 of the 11 did not mount an antibody response in the absence of B cells, even with all 3 doses. This means that our patients who are on anti-CD20 therapies prior to being vaccinated have a limited ability to elicit an antibody response. 

The researchers give the absolute numbers in the paper and the absolute numbers of antibodies generated is significantly higher in patients in the vaccine-CD20-vaccine cohort. The researchers note that there is a dramatic increase in spike antibody levels in this group. Can you recall what percentage of that population had this dramatic increase in their antibody levels?

VS: Natalia alluded to this earlier and it was 75% of these patients.  You can see it in Figure 1A, where in 3 of 4 patients, the increase in the antibody levels was significantly increased after the booster.

BG: The researchers talk about the reasons for this in their discussion and I want to get your thoughts, too. But let us start with their reasoning. Victor, despite being B-cell depleted — and they show in the data that individuals in the vaccine-CD20-vaccine cohort also had a depletion in B cells — there was a significant increase in antibody levels in 75% of the individuals. How is that possible? What is their explanation mechanistically for how patients had a robust antibody response in that cohort despite the lack of B cells?

VS: Anti-CD20 therapy was initiated after patients received their first 2 doses of the COVID-19 vaccine. What they suggest is that before the existing B-cell population was depleted, it was educated based on the effects of the immunization. Then those B cells matured into different B-cell subsets, including plasmablasts that likely went on to different compartments within the body, including the bone marrow. Those were effectively resistant to depletion by the antibody such that when these patients received the booster, it stimulated antibody production from those cells.

Additionally, it is interesting that they note that the 3.8- to 9.4-fold increase in antibody levels after the booster was probably an underestimate based on the timing of when they measured the antibody levels. I think it is a compelling argument that warrants further investigation.

BG: Natalia, when the study authors are going through their explanation, they cite other studies. They talked about the OPERA I (ClinicalTrials.gov Identifier: NCT01247324) and OPERA II (ClinicalTrials.gov Identifier: NCT01412333) studies, which assessed the effect of ocrelizumab, an anti-CD20 agent, on humoral immunity markers in patients with MS2 and was a much larger study than this one here. They referenced what happened to an individual’s preexisting immunity after being treated with an anti-CD20 therapy and found similar patterns to the study we are discussing.

NGC: The study authors did note that humoral immunity-based remains intact and does not wear off over time despite a patient receiving anti-CD20 therapy. I think that is a really important point to keep in mind when interpreting this study.

BG: Where I think we should end this discussion is in the clinical application of this. How should practitioners use this paper about antibody response for their patients with MS who are receiving anti-CD20 therapy and how should this study be applied to practice in the clinic? 

But first, it is worth mentioning that the authors acknowledge that there still can be T-cell responses even without an antibody response. This is an area with rich literature. In terms of antibody responses, how should this information affect the recommendations we provide our patients? I’ll give you an example and I am interested in your thoughts as well.

The authors of this paper talk about the notion of whether you should hold subsequent doses of anti-CD20 therapy to allow for B cells to replete somewhat before vaccinating patients against COVID-19 and then reinitiate anti-CD20 therapy after vaccination. Is there a role for this type of strategy or should clinicians try to administer all the appropriate vaccinations before initiating a patient on anti-CD20 therapy? Natalia, how are you going to incorporate this into your practice?

NGC: If I have a patient who comes to my practice and is in need of anti-CD20 therapy, I definitely would try to get them vaccinated before starting the anti-CD20 therapy. If I can get the patient even the first dose of the COVID-19 vaccine to develop some immunity, it would give the patient a better response to later doses of the vaccine. I am not sure whether studies have shown that patients with MS need extra doses to develop some type of significant immunity. Regardless, I would prefer to have patients vaccinated first and then begin anti-CD20 therapy if the patient is clinically stable.

BG: Victor, what are your thoughts in terms of the clinical application of the data?

VS: I agree with Natalia. It is pretty clear that when we encounter a patient who has not previously received anti-CD20 therapy, we should try to administer at least the first dose of a COVID-19 vaccine before initiating anti-CD20 treatment.

Concerning the other scenario that you described, it is worth looking at. In cases where you have an intuition about the patient’s individual clinical trajectory, you could potentially lengthen the duration between anti-CD20 therapy doses enough to where you get some degree of B-cell repopulation. The key is to know what the thresholds are. They are difficult to define, of course. Certainly, in other rheumatologic diseases in which the intervals are much longer, there may be some data that you can extrapolate. I don’t know, but I think it is worth looking at.

BG: Natalia, what would your next steps be in terms of researching these questions?

NGC: I think that that one of the future directions of this study is the need to look at timing, because even if we give a COVID-19 vaccine before anti-CD20 therapy, how long do we wait before initiating anti-CD20 therapy? Do we wait 4 weeks or 2 weeks? I think that needs to be clarified. One thing I noticed was that this study did not take into account the length of time between the administration of COVID-19 vaccines and anti-CD20 therapy. The study also did not specify how long a time had passed between anti-CD20 therapy and the booster, and I think that is also something that should be understood.

Interestingly, there is a study that showed no difference in antibody detectability according to vaccination timing since the last infusion of anti-CD20 therapy, specifically for ocrelizumab.3 However, I do not believe there is a great deal of data exploring the opposite situation (timing that has passed between vaccination and subsequent anti-CD20 therapy administration). Therefore, I think it is worth exploring this to understand if the timing makes any difference.

BG: Absolutely. In terms of time as a covariate, when you dose the COVID-19 vaccine, when you check for a titer relative to that dosing, and the timing of the anti-CD20 therapy are all variables that have to be taken into account. But I think we agree, and what I am hearing from both of you is that if you can get a patient vaccinated before you start an anti-CD20 therapy, it puts you in a great position clinically to respond to boosters and the challenges in the future. On the other hand, if you have been on anti-CD20 therapy when you get a COVID-19 vaccine for the first time, it is going to limit the efficacy of the vaccine even with subsequent doses and booster doses. It is something for our colleagues, practitioners, and patients to consider when choosing therapies and timing of therapies relative to vaccines.

VS: It is always interesting looking at data like this. We are looking at immunizations, which can be examined from the perspective of protecting people from infectious disease and public health and clearly there is a lot of benefit to vaccination. But we also can conceive of this as data on patients who are relatively immunocompromised. We are looking at the health of their immune system effectively by challenging them with some immunization and looking to see what kind of responses are able to mount. This is the kind of data that I think we are going to see more often as we try to transition away from relying on mouse models to looking at human data and allowing it to better inform our clinical decisions.

This article was edited for clarity and length.

References

1. Moser T, Otto F, O’Sullivan C, et al. Recall response to COVID-19 antigen is preserved in people with multiple sclerosis on anti-CD20 medications – a pilot study. Mult Scler Relat Disord. 2022;59:103560. doi:10.1016/j.msard.2022.103560 

2. Ziemssen T, Bar-Or A, Arnold D, et al. Effect of ocrelizumab on humoral immunity markers in the phase iii, double-blind, double-dummy, IFN β-1a–controlled OPERA I and OPERA II studies. 2016. Clin Neurophysiol. 128, e326–e327. CMSC Poster.

3. Novak S, Neilsen C, Holm DK, et al. Humoral response following SARS-CoV2 mRNA vaccination concomitant to ant-CD20 therapy in multiple sclerosis. Mult Scl Rel Dis. 2021;56:103521. doi:10.1016/j.msard.2021.103251

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Reviewed April 2022