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Immune response was attenuated after a third COVID-19 vaccine dose for multiple sclerosis (MS) patients taking certain disease-modifying treatments, interim data from a longitudinal study showed.

Two weeks after a third shot, many MS patients on anti-CD20 drugs and sphingosine-1-phosphate (S1P) receptor modulators still had significantly reduced total spike and receptor-binding domain (RBD) antibody responses, reported Joseph Sabatino, Jr., MD, PhD, of the University of California San Francisco, at ACTRIMS Forum 2022, the annual meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis.

"It is difficult to achieve clinically protective antibody responses following a third SARS-CoV-2 vaccination in patients on anti-CD20 and S1P therapies, especially in patients who have been on these types of therapies for at least several years," Sabatino told 番茄社区app.

"This raises the concern that patients on these types of disease-modifying therapies will remain vulnerable to breakthrough COVID-19 infections despite repeated vaccinations," Sabatino said. "In my opinion, implementation of Evusheld -- a cocktail of two monoclonal antibodies against the SARS-CoV-2 spike protein -- is vital for pre-exposure prophylaxis against breakthrough infection in these vulnerable patient populations."

Earlier research by Sabatino and colleagues showed that antibody responses 2 weeks after the second mRNA shot were reduced in patients either on S1P receptor modulators or anti-CD20 therapies like ocrelizumab (Ocrevus) and rituximab (Rituxan). Detectable CD19 B cells and shorter duration of treatment were associated with improved antibody responses.

Research by others also showed that significantly reduced spike-specific and RBD-specific antibody and memory B-cell responses after two doses of either Pfizer-BioNTech (Comirnaty) or Moderna (Spikevax) mRNA vaccines, an effect that was ameliorated with longer duration from the last anti-CD20 treatment.

The current study looked at the effects of a third shot in MS patients treated with the anti-CD20 antibodies ocrelizumab and ofatumumab (Kesimpta) or the S1P receptor modulators fingolimod (Gilenya) and siponimod (Mayzent).

The interim sample included 25 MS patients on ocrelizumab, 11 on ofatumumab, and 13 on S1P receptor modulators (11 on fingolimod and two on siponimod). In addition, the researchers evaluated 11 healthy controls. Controls tended to be younger and had a longer time between their second and third vaccine doses than MS patients.

The total length of treatment with ocrelizumab and S1P drugs was more than 4 years. For ofatumumab, treatment length was less than 1 year (ofatumumab was approved in August 2020). All patients received mRNA vaccines, except two patients on fingolimod who received the Johnson & Johnson vaccine for their first shot. Not all participants had blood samples available at all time points.

At 2 weeks after the third shot, seropositivity for total spike IgG, which included activity against any epitope on spike protein that may not correlate to neutralizing antibodies, was 62.5% for ofatumumab, 75.5% for ocrelizumab, 100% for S1P receptor modulators, and 100% for controls.

Spike RBD IgG seropositivity 2 weeks after the third dose was 62.5% for ofatumumab, 50.0% for ocrelizumab, 71.4% for S1P drugs, and 100% for controls.

"IgG reactivity against the spike receptor binding domain indicates reactivity against only the RBD portion of the spike protein, which is a surrogate for antibody-mediated neutralization of SARS-CoV-2," Sabatino said. "RBD is a subset of total spike and is a more specific and a better correlate for neutralizing antibodies against SARS-CoV-2 vaccination."

All participants who were seropositive 2 weeks after their second shot remained seropositive after a third dose. A subset of people who were seronegative after their second shot seroconverted after the third dose: one of four patients on ofatumumab, none of seven on ocrelizumab, and one of three on S1P drugs seroconverted for spike RBD IgG.

Patients who started ofatumumab after they received their first and second vaccines had high antibody titers after their third shot. "Length of treatment may impact immune response," Sabatino said. Vaccination prior to starting disease-modifying treatment may improve antibody responses, he added.

At 2 weeks after the third shot, all participants appeared to have both a CD4 and CD8 T-cell response.

The interim data had several limitations, Sabatino pointed out, most notably its small sample size. "Due to limited sample size, it is not possible to account for differences between groups," he said. The study assessed immune data only and did not explore clinical outcomes, he added.

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