NeuroVoices: Ilya Kister, MD, on Understanding Long-Term Responses to Vaccines in MS

Ilya Kister, MD

With the introduction of mRNA vaccines to treat COVID-19 earlier this year, multiple sclerosis (MS) physicians have been keen on assuring the safety of their patients set to receive these vaccines who are on disease-modifying therapies (DMT). The VIOLA study (NCT04843774) is an open-label study that is currently looking at longitudinal antibody and cellular responses to these 2-dose vaccines in patients treated with ocrelizumab (Ocrevus; Genentech), an FDA-approved DMT for patients with MS since 2017.

Led by Ilya Kister, MD, interim results of the study, which included 4- and 12-week post-vaccination data on 16 patients, were presented at the 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), October 13-15. Early results suggested that approximately half of ocrelizumab-treated patients developed antibody responses that are comparable to healthy controls at 4 weeks after vaccination, and those with an even higher response had their responses maintained, though diminished, by 12 weeks.

Kister, professor of neurology, NYU Grossman School of Medicine, sat down with NeurologyLive as part of a new iteration of NeuroVoices to discuss the overall design of the study and the need to investigate longitudinal responses to vaccines. He also provided greater context on the early findings, as well as what he considers the most pressing need within the MS space.

What is the design of VIOLA and what was the reasoning behind it?

Ilya Kister, MD: VIOLA is a prospective study on patients with MS receiving ocrelizumab. The main objective of the study is to characterize the immune responses, both antibody and humoral, as well as cellular responses—mostly T-cell—to vaccines in patients who are essentially depleted of B-cells because that’s what ocrelizumab does. It doesn’t deplete all B-cells from the body, there are plenty of them in the bone marrow and lymphnodes, but it does deplete them from the peripheral circulation. If you measure B-cell levels and peripheral articulation of people who are treated with ocrelizumab, you usually don’t get any detectable levels of B-cells.

The question is, “How do those people who don’t have any peripheral B-cells develop responses to the vaccine?” There is a little bit of literature on that about pre-COVID-19 vaccines because it has been concerned before. There was a prospective study that looked at responses to the flu vaccine and other vaccines, and they did note that the antibody responses are diminished. That’s not entirely surprising, because you know the B-cell compartment is compromised in patients. That’s by design, that’s how the drug works. The trials that have been done with ocrelizumab didn’t look at T-cell responses. At the time they were done, COVID-19 was not around, thankfully.

Unfortunately, now it is, which raises new questions about how people on ocrelizumab, which makes up about one-third of patients with MS in this country, develop responses to the vaccine and whether they can be considered protected from the vaccine. That was the motivation for conducting the study. What makes it most interesting is that we didn’t want to check just one time point. Instead of a few weeks after vaccinations, observe it at a 1-year interval. That way we can see the kinetics of the responses, what happens to them with time, whether that’s 1, 3, 6, and 12 months after the vaccine.

COVID-19 is such a fast-paced landscape and it’s hard to keep track of everything going on, especially now with the potential of boosters, which have been used routinely in some countries. In this country, they have been approved for people with compromised immune systems, which certainly includes people on ocrelizumab. MS itself does not cause a compromised immune system, but treatment for MS can make patients compromised. That’s how those treatments work. We now have an additional agenda to look at those who choose to get the booster vaccination and how they will respond.

What was your overall reaction to the interim data set thus far, and is it in line with what you hoped to see?

We used a commercial assay to measure antibody responses, but the bulk of the assessment was done in a research setting, using our collaborators at NYU. So far, we had some antibody and T-cell data at prevaccine baseline, 1 month post vaccination, and 3 months post vaccination for 16 patients. We wanted the 3 time points because we wanted to look at the longitudinal responses. In the healthy controls, almost everybody generates an antibody response to spike protein 1-4 weeks after the vaccine. Those responses tend to go down a bit by 3 months. That’s a very consistent pattern for all healthy people. The healthy controls used were not recruited for this study but were from other studies. We just used their samples for reference.

When it comes to our patients on ocrelizumab, we saw that about half of them generated antibody responses that are comparable to the antibody responses in health people who are not on treatment. Additionally, half of them generated some degree of responses using sensitive assays, but they were much less than what was within range for the healthy population. Again, we saw a similar pattern where the antibody levels go up and at 4 weeks, they tended to go down. If they managed to go up quite a bit, they didn’t go down very much either—they stayed in a fairly high range. If they were elevated slightly after 4 weeks, their depression brought them down to a very low level by the end of 3 months.

Roughly half of our patients have antibody responses that are way out of range to what we saw in health controls. It’s not an entirely unexpected finding, as I mentioned similar things have been reported for flu vaccine. Now other groups are beginning to report similar things for COVID as well. It’s so interesting to quantitatively look at how patients do in terms of T-cell responses. Ocrelizumab is a drug that works on B-cell compartments and is not supposed to affect the T-cell compartment. We had hoped that the T-cell responses would be adequate in these depleted patients, and they were. They were comparable to healthy controls. Again, they went up a bit in the first 4 weeks, started to go down a little bit after that.

At this stage in the pandemic, what do we still need to learn regarding vaccines and DMT use?

I may be a bit biased, but the most pressing topic is how well these vaccines work. How long do they hold? Because we see it from real-life experience that the efficacy tends to wear off over time and the vaccines are not specifically designed for the delta variant. It’s a pressing question to see who is getting the maximum protection and how long they’re getting it for. What do we do for people who don’t generate a full response? It’s a critical question for these patients especially if we’re going to live with COVID-19 and it becomes a more endemic infection. At that point, what do we do for patients with MS? Unfortunately, we cannot cure them. You can suppress their MS with these effective B-cell depleting drugs, but if we cannot do that safely, we must rethink our paradigms. That’s what we’re trying to work out with this study and other studies in the area.

Transcript was edited for clarity. For more coverage of ECTRIMS 2021, click here.

REFERENCE

1. Kister I, Piquet A, Patskovsky Y, et al. Vaccine against SARS-CoV-2-generated immunity in ocrelizumab-treated patients: longitudinal assessments (VOILA): study design and early results. Presented at ECTRIMS 2021; October 13-15. Abstract P980