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• W3130201612 abstract "COVID-19 has reminded us that vaccines are lifesaving in high, middle and low-income countries. People with multiple sclerosis (pwMS), who are prone to inflammation-triggered disease exacerbation and treatment-induced opportunistic infections, might even be more at risk (Reyes et al., 2020Reyes S. et al.Protecting people with multiple sclerosis through vaccination.Pract. Neurol. 2020; (practneurol-2020-002527)https://doi.org/10.1136/practneurol-2020-002527Crossref PubMed Scopus (35) Google Scholar). As the current treatment landscape directs a significant proportion of our patients towards ocrelizumab and other emerging anti-CD20 therapies, a study that helps us understand how this drug, as an example of CD20-monoclonal antibodies (mAb), affects the potential to mount antibody responses to vaccines and new antigens is much acclaimed. From a mechanistic point of view, we know that CD20-mAb deplete all B cells apart from the long-lived plasma cells, most plasmablasts and lymphoid stem cells (Hauser et al., 2017Hauser S.L. et al.Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis.N. Engl. J. Med. 2017; 376: 221-234https://doi.org/10.1056/NEJMoa1601277Crossref PubMed Scopus (1081) Google Scholar) and that they ablate germinal centres (Ramwadhdoebe et al., 2019Ramwadhdoebe T.H. et al.Effect of rituximab treatment on T and B cell subsets in lymph node biopsies of patients with rheumatoid arthritis.Rheumatology. 2019; 58: 1075-1085https://doi.org/10.1093/rheumatology/key428Crossref PubMed Scopus (62) Google Scholar). This implies that crucial B cell functions such as antigen presentation (naïve and memory B cells), antibody formation, including class-switching, affinity maturation and production (naïve, memory and germinal centres B cells) are impaired. However, the extent of this dysfunction in the context of vaccine responses has remained poorly studied. Up until now, we had only indirect evidence available coming from mainly rituximab-treated subjects. Most informative were the results of a controlled trial including 103 people with rheumatoid arthritis comparing antibody responses in a methotrexate and methotrexate-rituximab arm (Bingham et al., 2010Bingham C.O. et al.Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a controlled clinical trial.Arthritis Rheum. 2010; 62: 64-74https://doi.org/10.1002/art.25034Crossref PubMed Scopus (357) Google Scholar). Vaccine responses against tetanus vaccine were preserved among both immunosuppressed groups 24 weeks after treatment while responses to a neoantigen and pneumococcal vaccine were decreased. These findings were in line with the reduced seroprotection rate at 3–5 weeks following vaccination against influenza (H1N1) virus in rituximab (18.8%) vs. azathioprine (83.3%), IFN-β (87.5%) and healthy controls (100%) in 26 people with neuromyelitis spectrum disorder (Kim et al., 2013Kim W. et al.Reduced antibody formation after influenza vaccination in patients with neuromyelitis optica spectrum disorder treated with rituximab.Eur. J. Neurol. 2013; 20: 975-980https://doi.org/10.1111/ene.12132Crossref PubMed Scopus (48) Google Scholar). Other studies also showed blunted post-rituximab responses following vaccination with haemophilus influenzae (Nazi et al., 2013Nazi I. et al.The effect of rituximab on vaccine responses in patients with immune thrombocytopenia.Blood. 2013; 122: 1946-1953https://doi.org/10.1182/blood-2013-04-494096Crossref PubMed Scopus (152) Google Scholar) and hepatitis B (Richi et al., 2020Richi P. et al.Evaluation of the immune response to hepatitis B vaccine in patients on biological therapy: results of the RIER cohort study.Clin. Rheumatol. 2020; 39: 2751-2756https://doi.org/10.1007/s10067-020-05042-2Crossref PubMed Scopus (18) Google Scholar) component vaccines. However, these studies are largely retrospective and heterogeneous in terms of the included age groups, autoimmune pathology and the extent of rituximab-induced B cell depletion. In the VELOCE study, researchers evaluated if people on ocrelizumab who were fully B cell depleted were able to raise an antibody response to common vaccines and a neoantigen (Bar-Or et al., 2020Bar-Or A. et al.Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis.Neurology. 2020; 95 (e1999–e2008)https://doi.org/10.1212/WNL.0000000000010380Crossref Scopus (229) Google Scholar). The study population (68 ocrelizumab, 34 controls) was exposed to four different vaccines/antigenic triggers: tetanus toxoid, pneumococcal and influenza vaccines as well as keyhole limpet haemocyanin (KLH). Response rates were evaluated at 4- and 8-weeks post-vaccination which corresponds to 16 and 20 weeks post-ocrelizumab dosing, respectively. Importantly, the antigenic triggers can be subdivided in two groups based on the likelihood of a previous exposure. First, it is very probable to have encountered some of the vaccine epitopes of the tetanus, pneumococcal and influenza vaccines. Tetanus vaccine requires boosters every ten years, and pneumococcal and influenza strains are ubiquitous pathogens. This implies that long-lived plasma cells can still exert their memory function and provide protection with well-targeted antibodies in the event of a recurrent infection. The VELOCE study showed that ocrelizumab-treated individuals are half as likely to mount an antibody response against tetanus toxoid vaccine (23.9% ocrelizumab vs. 54.5% controls) and two thirds less likely to mount an antibody response to 12 or more pneumococcal serotypes (37.3% ocrelizumab vs. 97.1% controls). On the other hand, the VELOCE study evaluated the response to the neoantigen KLH that requires recognition by naïve B cells (or other antigen-presenting cells) and subsequent transport to the germinal centres. The resulting antibody responses are worrisome as 12 weeks after KLH administration there was a 5-fold difference in IgM antibody levels and an 11-fold difference in IgG antibody levels between ocrelizumab-treated subjects and control subjects. Overall, immune responses against pathogens encountered before ocrelizumab administration are significantly reduced but not absent. However, responses to entirely new pathogens (and thus realistically speaking also SARS-CoV-2 or COVID-19-related virus) (Doshi, 2020Doshi P. Covid-19: do many people have pre-existing immunity?.BMJ. 2020; 370 (m3563)https://doi.org/10.1136/bmj.m3563Crossref Scopus (57) Google Scholar) cannot rely on an efficient antibody response and will be largely dependent on possible cellular immunity. Of note, patients included in the VELOCE study had only received a single course of ocrelizumab. As repeated 6-monthly infusions with ocrelizumab induce hypogammaglobulinemia and prohibit replenishment off the long-lived plasma cell pool, a reduction or greater blunting in the vaccine responses over time is to be expected, unless shown otherwise. Although the VELOCE study focuses on ocrelizumab, diminished responses after vaccination have also been reported for several other MS disease-modifying treatments rendering the topic of general relevance to derisk treatments (Reyes et al., 2020Reyes S. et al.Protecting people with multiple sclerosis through vaccination.Pract. Neurol. 2020; (practneurol-2020-002527)https://doi.org/10.1136/practneurol-2020-002527Crossref PubMed Scopus (35) Google Scholar). First and foremost, this study highlights the importance of immunizations prior to the initiation of ocrelizumab treatment. Although pneumococcal and influenza vaccines prior to ocrelizumab treatment are currently recommended and not obligatory (EMA 2020EMA, 2020. Summary of product characteristics ocrelizumab [WWW Document]. URL https://www.ema.europa.eu/en/documents/product-information/ocrevus-epar-product-information_en.pdf (accessed 11.16.20).Google Scholar), the potential gain in terms of meaningful humoral immunity is apparent. In this context, we recommend to vaccinate against varicella zoster virus with the component vaccine (Shingrex™) to boost immunity to lower the risk of herpes zoster reactivation (Reyes et al., 2020Reyes S. et al.Protecting people with multiple sclerosis through vaccination.Pract. Neurol. 2020; (practneurol-2020-002527)https://doi.org/10.1136/practneurol-2020-002527Crossref PubMed Scopus (35) Google Scholar). In people older than 50 years old, vaccine efficacy was 91.3% against herpes zoster infection and 88.8% against the development of postherpetic neuralgia compared to placebo (Cunningham et al., 2016Cunningham A.L. et al.Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of Age or Older.N. Engl. J. Med. 2016; 375: 1019-1032https://doi.org/10.1056/NEJMoa1603800Crossref PubMed Scopus (632) Google Scholar). Moreover, an efficacy of 63.6% was shown in adults with solid tumor malignancies receiving chemotherapy compared to placebo (Mullane et al., 2019Mullane K.M. et al.Safety and efficacy of inactivated varicella zoster virus vaccine in immunocompromised patients with malignancies: a two-arm, randomised, double-blind, phase 3 trial.Lancet Infect. Dis. 2019; 19: 1001-1012https://doi.org/10.1016/S1473-3099(19)30310-XAbstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). Based on these recent data, the component vaccine has now officially been licensed by the European Medicine Agency for use in immunocompromised people. As approximately 2.1% of people treated with ocrelizumab are affected with zoster in the first year and a half of their treatment compared to 1.0% of individuals on interferon-beta (Hauser et al., 2017Hauser S.L. et al.Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis.N. Engl. J. Med. 2017; 376: 221-234https://doi.org/10.1056/NEJMoa1601277Crossref PubMed Scopus (1081) Google Scholar), the component zoster vaccine offers an opportunity to reduce the opportunistic burden associated with this treatment. Moreover, the repopulation kinetics of a low-dose/high-frequency CD20-mAb regimen with ofatumumab vs. a high-dose/low-frequency ocrelizumab regimen might reflect on vaccine readiness. Also, the differences between both mAb when it comes to complement- vs. antibody-dependent lysis might be of relevance in this context (Hauser et al., 2020Hauser S.L. et al.Ofatumumab versus Teriflunomide in Multiple Sclerosis.N. Engl. J. Med. 2020; 383: 546-557https://doi.org/10.1056/NEJMoa1917246Crossref PubMed Scopus (277) Google Scholar). After four intravenous infusions with 600 mg ocrelizumab, it takes a median time of 72 weeks for the total B cell counts to reach the lower level of normal (Baker et al., 2020Baker D. et al.The ocrelizumab phase II extension trial suggests the potential to improve the risk: benefit balance in multiple sclerosis.Mult. Scler. Relat. Disord. 2020; 44102279https://doi.org/10.1016/j.msard.2020.102279Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). Based on the repopulation kinetics of other similar doses of ofatumumab, it is expected to take approximately 40 weeks for B cells to recover after 20 mg subcutaneous injections (Bar-Or et al., 2018Bar-Or A. et al.Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis.Neurology. 2018; 90 (e1805–e1814)https://doi.org/10.1212/WNL.0000000000005516Crossref PubMed Scopus (132) Google Scholar). Although still far from ideal, the shorter time to repopulate B cells expedites vaccine readiness after treatment with ofatumumab. Nonetheless, the exposure-response profile of high- vs. low-dose CD20-mAb regimens also needs to be addressed in future studies. Higher doses of ocrelizumab have namely been associated with a greater risk reduction in terms of confirmed disability progression (Kletzl et al., 2019Kletzl H. et al.Pharmacokinetics, Pharmacodynamics and Exposure-Response Analyses of Ocrelizumab in Patients With Multiple Sclerosis (N4.001).Neurology. 2019; 92 (N4.001)Google Scholar). Studies are needed to determine T cell responses to vaccine epitopes and titres of neutralizing antibodies to confer protection and whether dosing within the treatment cycle can achieve these. I.S. and S.R. report no conflict of interests. In the last 5 years, G.G. has received compensation for serving as a consultant or speaker for or has received research support from AbbVie, Actelion, Atara Bio, Biogen, Canbex, Celgene, EMD Serono, Japanese Tobacco, Sanofi-Genzyme, Genentech, GlaxoSmithKline, GW Pharma, Merck, Novartis, Roche, Synthon BV and Teva. D.B. has received compensation for consultancy activities related to: Canbex therapeutics, InMune Bio, Lundbeck, Merck, Novartis and Roche. I.S. (2020) and S.R. (2019) have been generously funded by an ECTRIMS clinical fellowship grant." @default.
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• W3130201612 title "Blunted vaccines responses after ocrelizumab highlight need for immunizations prior to treatment" @default.
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