Are MS patients who had SARS-CoV-2 infection while on disease-modifying therapies (DMTs) able to mount appropriate immune responses to SARS-CoV-2?

A

Guest Post Ilya Kister

This question is important on a theoretical level – to better understand the impact of disease modifying drugs (DMTs) on immunity, and on a practical level – to understand whether previously infected MS patients on DMTs are likely to derive a similar degree of immune protection against reinfection as those who were not on DMT.

To answer this question, we enrolled 389 people with MS from NYU MS Care Center in New York City, one of the epicenters of 2020-2021 COVID-19 pandemic, and comprehensively assessed their antibody responses with three independent antibody tests and T-cell responses with two independent cellular response tests. To be included in the study, patients had to be 18-60 years old and to receive an approved MS therapy or be on no therapy. Patients who were very disabled (bed-bound), or had other major medical problems, such as cancer or HIV, were excluded.

The patients enrolled into our study were relatively young (mean age: 40 years), racially diverse (38% White, 29% Black, 27% Hispanic, 6% Other), mostly non-disabled (68% fully ambulatory), and otherwise healthy (68% without any conditions that are known to increase risk of COVID-19 complications). The most common DMTs in this group were ocrelizumab (OCR) – 40%; natalizumab – 17%, Sphingosine 1-phosphate receptor (S1P) modulators (fingolimod, siponimod) -12%; and no DMT – 15%. The study was conducted mostly before vaccines became available, and none of the patients had received the COVID-19 vaccine at time of enrollment.

The main findings of our study were as follows:

  • 177 / 389 patients (46%) of MS patients in our MS Center had evidence of prior SARS CoV-2 infection (2 or more antibodies highly specific for SARS CoV-2).
    • All infections predate the spread of Delta and Omicron variants in our area.
  • Among 177 patients with prior infection:  
    • 130 / 177 (73%) had clinical symptoms consistent with COVID-19 (symptomatic infection)
    • 47 / 177 (27%) had no clinical symptoms (asymptomatic infection)
  • Clinical severity of infection was mild-to-moderate in the great majority of our relatively young and otherwise healthy patients
    • 54 / 130 (42%) symptomatic patients reported respiratory symptoms
    • 9 / 130 (7%) symptomatic patients were hospitalized; 2 were admitted to Intensive Care Units
    • Clinical severity of infection was similar across of DMTs, and across race/ethnic groups
  • Binding antibodies specific to SARS CoV-2 were measured in all patients with NYU proprietary custom Multi-epitope bead-based immunoassay (MBI) and commercially available Elecsys Anti-SARS-CoV-2 immunoassay. MBI was more sensitive than Elecsys for diagnosing prior infection, especially in patients who were on Ocrelizumab at the time of infection and asymptomatic infections
    • Elecsys detected only 36% of infections in OCR-treated group, while MBI detected 86% pror infections in ocrelizumab-treated groups
  • Levels of anti-Spike antibodies by Elecsys and MBI were approximately 10-fold lower in patients who were on ocrelizumab patients at the time of infection compared to patients who were on no DMT at the time of infection
  • Neutralizing antibodies (Nabs) were measured with live virus neutralization assays in a subset of 77 patients with binding antibodies against SARS CoV-2. Nab levels correlated strongly with binding antibodies measured with MBI and Elecsys, but 21% of patients with high levels of binding antibodies did not have detectable functional Nabs.
  • Compared to untreated patients, Nab titers were marginally lower in OCR- treated (p=0.055), and higher in natalizumab-treated patients (p=0.01)
    • Most (85%) patients who had infection within 6 months of OCR infusion had low or undetectable Nab level.
  • We performed in-vitro T-cell stimulation studies on 159 patients with prior SARS-CoV-2 infection and detected positive cellular immune responses in 39% of these patients.
  • We also detected positive T-cell response in 11% patients who did not have antibodies to SARS CoV-2. It is unknown whether cases were false positives, or represent true infection without antibody response
  • OCR group had similar responses on T-cell stimulation studies compared to the untreated reference group, while S1P showed depressed responses and Natalizumab – elevated responses  

Full preprint is available: https://www.medrxiv.org/content/10.1101/2022.01.10.22268752v1

Ilya Kister, Yury Patskovsky, Ryan Curtin, Jinglan Pei, Katherine Perdomo, Zoe Rimler, Iryna Voloshyna, Marie I. Samanovic, Amber R. Cornelius, Yogambigai Velmurugu, Samantha Nyovanie, Joseph Kim, Ethan Tardio, Tamar E. Bacon, Lana Zhovtis Ryerson, Pranil Raut, Rosetta Pedotti, Kathleen Hawker, Catarina Raposo, Jessica Priest, Mark Cabatingan, Ryan C. Winger, Mark J. Mulligan, Michelle Krogsgaard, Gregg J. Silverman Cellular and humoral immunity to SARS-CoV-2 infection in multiple sclerosis patients on ocrelizumab and other disease-modifying therapies: a multi-ethnic observational studymedRxiv 2022.01.10.22268752; doi: https://doi.org/10.1101/2022.01.10.22268752

Objective To determine the impact of MS disease-modifying therapies (DMTs) on the development of cellular and humoral immunity to SARS-CoV-2 infection.

Methods MS patients aged 18-60 were evaluated for anti-nucleocapsid and anti-Spike RBD antibody with electro-chemiluminescence immunoassay; antibody responses to Spike protein, RBD, N-terminal domain with multiepitope bead-based immunoassays (MBI); live virus immunofluorescence-based microneutralization assay; T-cell responses to SARS-CoV-2 Spike using TruCulture ELISA; and IL-2 and IFNγ ELISpot assays. Assay results were compared by DMT class. Spearman correlation and multivariate analyses were performed to examine associations between immunologic responses and infection severity.

Results Between 1/6/2021 and 7/21/2021, 389 MS patients were recruited (mean age 40.3 years; 74% female; 62% non-White). Most common DMTs were ocrelizumab (OCR) – 40%; natalizumab – 17%, Sphingosine 1-phosphate receptor (S1P) modulators −12%; and 15% untreated. 177 patients (46%) had laboratory evidence of SARS-CoV-2 infection; 130 had symptomatic infection, 47 – asymptomatic. Antibody responses were markedly attenuated in OCR compared to other groups (p≤ 0001). T-cell responses (IFNγ were decreased in S1P (p=0.03), increased in natalizumab (p<0.001), and similar in other DMTs, including OCR. Cellular and humoral responses were moderately correlated in both OCR (r=0.45, p=0.0002) and non-OCR (r=0.64, p<0.0001). Immune responses did not differ by race/ethnicity. COVID-19 clinical course was mostly non-severe and similar across DMTs; 7% (9/130) were hospitalized.

Interpretation DMTs had differential effects on humoral and cellular immune responses to SARS-CoV-2 infection. Immune responses did not correlate with COVID-19 clinical severity in this relatively young and non-disabled group of MS patients.

Disclosures: Scientific advisory board for Biogen Idec, Genentech, Alexion, EMDSerono; Consulting fees from Roche; Research support from Guthy-Jackson Charitable Foundation, National Multiple Sclerosis Society, Biogen Idec, Serono, Genzyme,Genentech/Roche; Royalties from Wolters Kluwer for ‘Top 100 Diagnosis in Neurology‘

Disclaimer: The opinions expressed here are those of the author and do not necessarily reflect the position of any Institution.

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The MS Bloggger

10 comments

  • Can you summarise this pls for those of us at the back of the class!
    Those young patients with MS on DMDs that are known to affect vaccine response- did they make their own immune response after Covid infection? My impression is that it was variable but very muted compared to the non DMD population. So eg being on Ocrevus, getting Covid itself provides no better ongoing immunity than vaccination does as no B cell response? T cell response hard to interpret.
    Is that right?

    • Dear A,

      We did not compare in this paper how immunity to infection differs from immunity to vaccination, so I cannot answer your question about how the two responses would compare. Several groups, including ours, have shown that T cell responses to COVID-19 vaccine are intact in patients on Ocrevus.

      It is reassuring that patients on B-cell depleting drugs still have T-cell responses because T-cell responses are critical for preventing COVID progression (i.e. hospitalization, ICU). This makes it imperative – in my view – that MS patients on these therapies get vaccinated and boosted without delay.

      • Hi Ilya. Thanks for sharing your study.

        How important are the T-cell responses in the absence of B-cell responses? Is there any knowledge on this? Do the CD4+ and CD8+ T-cells function properly without B-cell stimulation? (both generally and in the specific case of T-cell responses to covid-19 vaccines).

        • Hi Markus,

          As an oversimplification, we may help to think of COVID-19 as a two-stage disease: 1. virus gets into the upper respiratory tract (nose, throat) and starts to replicate causing ‘cold symptoms’ such as congestion, sore throat, loss of smell; 2. virus descends into lower respiratory tracts – lungs – causing pneumonia and, in the really severe cases, respiratory and multi-organ failure.

          One needs lots of high-quality (neutralizing) antibodies against SARS CoV-2 virus on hand to prevent symptomatic infection (stage 1), but one needs  SARS CoV-2-specific T-cells to prevent severe infection (stage 2). Thus, without the specific antiSARS CoV-2 antibodies – or without too many of them – people are susceptible to infection (stage 1), but with T-cells on stand-by, we can expect a less severe disease (i.e. less likely to go to stage 2).

          Here’s what we had to say on this subject in our manuscript:
          “Taken together, our data suggests that previously infected or vaccinated patients on aCD20 are less likely to be protected against ‘breakthrough’ infection than others, a prediction born out by a recent population-based study from UK,43 but are probably still protected against COVID progression due to intact T cell immunity.15, 18, 44, 45 Memory T cells that contribute to protection against severe disease by eliminating infected cells and limiting viral replication may explain, at least in part, why vaccines prevent hospitalizations and death even against variants that exhibit limited neutralization by vaccine-induced humoral immunity.46, 47 Indeed, T cells responses to Beta and Omicron variants have been documented following the third dose of mRNA vaccines even in aCD20-treated patients.48”

          Hope this helps.

          Best wishes
          ,
          IK

    • Has anyone else noticed the remarkable resemblance between an Anonymous photo posted on this site around a month ago and a particularly relaxed moggie answering to the name of Reece?
      (nb subs: do I have any reason do believe I need to be told?)
      PMR

  • Fabulous study!

    What was the difference on binding antibodies, spike antibodies, and neutralizing antibodies particularly for Ocrevus patients? It sounded like some tests were on subsets of subsets, and I don’t understand the clinical implications of these different antibodies.

    • Hi,

      Neutralizing antibodies are the high-quality antibodies that prevent the virus from getting inside cells. Binding antibodies – even though they are highly specific to viral Spike protein – are not necessarily effective in blocking the virus from getting into cells (e.g. they may bind to the ‘wrong part’ of Spike protein, which may not stop Spike from binding to receptor on human cells). Neutralizing antibodies are therefore the most important indicator of whether someone is protected from getting a symptomatic infection, but the antibody test you can get in the commercial lab is a measure of binding not neutralizing antibodies. (Neutralizing antibodies are much more difficult to measure – as far as I know this can only be done in research lab as of now).
      T cells also play a critical role, as I tried to explain in response to Markus in a previous post.

      Best wishes,

      IK

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