COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases

Abstract

Although most autoimmune diseases are considered to be CD4 T cell- or antibody-mediated, many respond to CD20-depleting antibodies that have limited influence on CD4 and plasma cells. This includes rituximab, oblinutuzumab and ofatumumab that are used in cancer, rheumatoid arthritis and off-label in a large number of other autoimmunities and ocrelizumab in multiple sclerosis. Recently, the COVID-19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments. However, based on the known and emerging biology of autoimmunity and COVID-19, it was hypothesised that while B cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit protective immunity following infection and vaccination. As such, drug-induced B cell subset inhibition, that controls at least some autoimmunities, would not influence innate and CD8 T cell responses, which are central to SARS-CoV-2 elimination, nor the hypercoagulation and innate inflammation causing severe morbidity. This is supported clinically, as the majority of SARS-CoV-2-infected, CD20-depleted people with autoimmunity have recovered. However, protective neutralizing antibody and vaccination responses are predicted to be blunted until naive B cells repopulate, based on B cell repopulation kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here. This suggests that it may be possible to undertake dose interruption to maintain inflammatory disease control, while allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available.

Keywords: B cell; CD20; COVID-19; autoimmunity; immunotherapy; multiple sclerosis; ocrelizumab; rheumatoid arthritis; rituximab.

Conflict of interest statement

D. B., M. M., K. S. and G. G. have received compensation for either consultancies and presentations and advisory board activities from Genentech/Roche. However, Roche/Genentech were not involved in the decision to write and submit this manuscript. S. A. has received consultancy from Novartis and Roche. C. A. K. K., G. P., A. S. K. and S. R. have nothing to disclose. D. B. has received compensation for activities related to Canbex therapeutics, InMune Biol, Lundbeck, Japan tobacco, Merck and Novartis. M. M. has received speaking honoraria from Sanofi‐Genzyme. K. S. has received compensation for activities related to Biogen, Eisai, Elan, Fiveprime, Lipomed, Merck KGAa, Novartis, Sanofi‐Genzyme and Teva. G. G. has received compensation for activities from AbbVie, Actelion, Atara Bio, Bayer‐Schering Healthcare, Biogen, Celgene, GW Pharma, GSK, Ironwood, Japanese Tobacco, Merck, Merck‐Serono, Mertz, Novartis, Pfizer, Sanofi‐Genzyme, Synthon, Takeda, Teva, UCB Pharma and Vertex Pharmaceuticals.

© 2020 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.

Figures

Fig. 1

Pathobiology of COVID‐19. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infects cells in the lung and the gut via the angiotensin‐converting enzyme 2 (ACE2). This blocks ACE2‐induced formation of anti‐oxidant angiotensin, facilitating oxygen free‐radical formation and vascular damage. The innate immune response provides the initial line of defence against the virus, while a CD8 anti‐viral T cell response and neutralizing and complement‐fixing antibody response serve to remove the virus in the majority of people. However, the virus triggers suppression of interferon responses and other viral escape mechanisms that in a minority of people stimulate the innate immune response leading to lymphocyte apoptosis that blocks their regulatory signals and, in some cases, releases a cytokine storm that drives hyper‐innate inflammation. This, in part, causes acute respiratory distress. Importantly, this augments vascular damage that accentuates the respiratory distress and leads to von Willebrand factor release into the blood. This contributes to the formation of microthrombi, contributing to respiratory distress and vascular embolism that may be fatal. Adapted from Henry et al. 2020 [22].

Fig. 2

Ocrelizumab inhibits vaccination responses. People with multiple sclerosis who did not receive ocrelizumab (control) or were infused with 300 mg ocrelizumab on days 0 and 15 and were vaccinated from weeks 12–24 after ocrelizumab. The experimental details and results were from www.clinicaltrials.gov NCT02545868 [91]. The results show: (a) The frequency of seroconversion in people treated with ocrelizumab following injection pneumococcal 23‐polyvalent pneumococcal vaccine (PPV) vaccine, 4 weeks after vaccination (n = 66–68). A 23‐PPV vaccine response against a serotype was defined by a twofold increase in anti‐pneumococcal antibody or > 1 µg/ml compared with prevaccination levels, following Food and Drug Administration guidance. (b) The titre of response to the initial challenge with 23‐PPV 4 weeks after vaccination. (c) The frequency of seroconversion in people treated with ocrelizumab following injection of a booster pneumococcal 13‐PPV vaccine 4 weeks after 23‐PPV (n = 33–34). The frequency of responders is shown 8 weeks after 23‐PPV vaccination. (d) The geometric mean and 95% confidence interval (CI) anti‐tetanus toxoid antibody levels measured by enzyme‐linked immunosorbent assay (ELISA) before and following vaccination (n = 34–68). (e,f) The geometric mean and 95% confidence interval titre of (e) immunoglobulin (Ig)M or (f) IgG keyhole limpet haemocyanin (KLH)‐specific antibody after vaccination with keyhole limpet haemocyanin at baseline, weeks 4 and 8 started 12 weeks after ocrelizumab infusion (n = 34–68). (g–i) The response to: A/California/7/2009 (H1N1, n = 33–35); B/Phuket/3073/2013 (BPH, n = 31–33), A/Switzerland/9715293/2013 (H3N2, n = 27–30), B/Brisbane/60/2008 (BBR, n = 16–18), A/Hong Kong/4801/2014 (AHK, n = 5–6) influenza strain vaccination 12 weeks after ocrelizumab infusion was assessed. The results represent (g) the percentage of people with seroconversion, defined either a prevaccination haemagglutination inhibition (HI) titre < 10 and ≥ 40 at 4 weeks or a prevaccination ≥ 10 and at least a fourfold increase in HI titre, and seroprotection defined by titres > 40 at 4 weeks after vaccination. (h) The change in the geometric mean HI titres before and after vaccination (I) The percentage of people with a fourfold increase in strain‐specific > 40) at 4 weeks after vaccination.

Fig. 3

Long‐term depletion of memory B cells induced by ocrelizumab. These data were extracted from the ocrelizumab Phase II clinical study report [105], supplied by the trial sponsor via the www.clinicaltrialdatarequest.com portal. (a) The data represents the mean percentage change from baseline, defined as the last observation up to the first day of ocrelizumab treatment. The subjects received placebo and three cycles of 600 mg ocrelizumab every 24 weeks. This was followed by a treatment‐free period to monitor B cell repletion in the Phase II extension study. The time represents the period from the last ocrelizumab infusion (n = 22–43). Naive [CD19+, CD21+, immunoglobulin (IgD)+, IgM+] and memory B cells (CD19+, CD27+, CD38low) and other immune subsets were assessed (n = 22–43/group). (b) Depletion of memory B cells was maintained during treatment. These data were obtained from people (n = 88) entering the open‐label extension (OLE) study after the treatment‐free period that had received three or four 6‐monthly cycles of at least 600 mg ocrelizumab to week 72, followed by a treatment‐free period to week 144, before entering the OLE phase where 600‐mg cycles of ocrelizumab were maintained at 24‐week intervals. The results represent the mean ± standard deviation of cells/μl (n = 22–69/group weeks 22–72). Although CD19 B cell numbers were consistent with the original levels, the baseline memory B cell levels failed to return to original levels at the start of the OLE. PMN = polymorphonuclear neutrophil.