How important are COVID-19 vaccine responses in patients with MS on disease-modifying therapies?

Abstract

people with multiple sclerosis The paper by Garjani and colleagues (García-Lledó et al., 2021García-Lledó A. Gómez-Pavón J. González Del Castillo J. Hernández-Sampelayo T. Martín-Delgado M.C. Martín Sánchez F.J. Martínez-Sellés M. Molero García J.M. Moreno Guillén S. Rodríguez-Artalejo F.J. Ruiz-Galiana J. Cantón R. De Lucas Ramos P. García-Botella A. Bouza E. Pharmacological treatment of COVID-19: an opinion paper.Rev. Esp. Quimioter. 2021; https://doi.org/10.37201/req/158.2021Crossref Scopus (6) Google Scholar) provides initial evidence that the risk of SARS-CoV-2 infection in patients with MS on ocrelizumab (anti-CD20) or fingolimod (S1P-modulator) is increased compared to the general population despite the mass COVID-19 vaccination in England. This pattern was not seen with other MS disease-modifying therapies. In an Italian study of 1705 patients with MS who had been double vaccinated with one of the mRNA COVID-19 vaccines, there were 23 breakthrough COVID-19 infections, which were detected on average 108 days after the second dose (range, 18–230) (Sormani et al., 2021aSormani M.P. Inglese M. Schiavetti I. Carmisciano L. Laroni A. Lapucci C. Da Rin G. Serrati C. Gandoglia I. Tassinari T. Perego G. Brichetto G. Gazzola P. Mannironi A. Stromillo M.L. Cordioli C. Landi D. Clerico M. Signoriello E. Frau J. Ferrò M.T. Di Sapio A. Pasquali L. Ulivelli M. Marinelli F. Callari G. Iodice R. Liberatore G. Caleri F. Repice A.M. Cordera S. Battaglia M.A. Salvetti M. Franciotta D. Uccelli A. CovaXiMS study group on behalf of the Italian Covid-19 Alliance in MSEffect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.EBioMedicine. 2021; 72103581Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). Nine were on ocrelizumab, one on rituximab, four on fingolimod, six on dimethyl-fumarate, one on teriflunomide, and two were untreated. Importantly only two patients, one on ocrelizumab and one on teriflunomide, required hospitalisation (Sormani et al., 2021aSormani M.P. Inglese M. Schiavetti I. Carmisciano L. Laroni A. Lapucci C. Da Rin G. Serrati C. Gandoglia I. Tassinari T. Perego G. Brichetto G. Gazzola P. Mannironi A. Stromillo M.L. Cordioli C. Landi D. Clerico M. Signoriello E. Frau J. Ferrò M.T. Di Sapio A. Pasquali L. Ulivelli M. Marinelli F. Callari G. Iodice R. Liberatore G. Caleri F. Repice A.M. Cordera S. Battaglia M.A. Salvetti M. Franciotta D. Uccelli A. CovaXiMS study group on behalf of the Italian Covid-19 Alliance in MSEffect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.EBioMedicine. 2021; 72103581Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). In this study the probability of being infected was associated with SARS-CoV-2 anti-spike antibody levels measured after 4 weeks from the second vaccine dose; an antibody level of less than 660 U/mL was associated with a higher risk of infection (Sormani et al., 2021aSormani M.P. Inglese M. Schiavetti I. Carmisciano L. Laroni A. Lapucci C. Da Rin G. Serrati C. Gandoglia I. Tassinari T. Perego G. Brichetto G. Gazzola P. Mannironi A. Stromillo M.L. Cordioli C. Landi D. Clerico M. Signoriello E. Frau J. Ferrò M.T. Di Sapio A. Pasquali L. Ulivelli M. Marinelli F. Callari G. Iodice R. Liberatore G. Caleri F. Repice A.M. Cordera S. Battaglia M.A. Salvetti M. Franciotta D. Uccelli A. CovaXiMS study group on behalf of the Italian Covid-19 Alliance in MSEffect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.EBioMedicine. 2021; 72103581Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). These data are not surprising given that it has been confirmed that patients on ocrelizumab and fingolimod have blunted antibody responses to COVID-19 vaccines (Achiron et al., 2021aAchiron A. Mandel M. Dreyer-Alster S. Harari G. Dolev M. Menascu S. Magalashvili D. Flechter S. Givon U. Guber D. Sonis P. Zilkha-Falb R. Gurevich M. Humoral immune response in multiple sclerosis patients following PfizerBNT162b2 COVID19 vaccination: up to 6 months cross-sectional study.J. Neuroimmunol. 2021; 361577746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, Achiron et al., 2021bAchiron A. Mandel M. Dreyer-Alster S. Harari G. Magalashvili D. Sonis P. Dolev M. Menascu S. Flechter S. Falb R. Gurevich M. Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies.Ther. Adv. Neurol. Disord. 2021; 1417562864211012835Google Scholar; Apostolidis et al., 2021Apostolidis S.A. Kakara M. Painter M.M. Goel R.R. Mathew D. Lenzi K. Rezk A. Patterson K.R. Espinoza D.A. Kadri J.C. Markowitz D.M. E Markowitz C. Mexhitaj I. Jacobs D. Babb A. Betts M.R. Prak E.T.L. Weiskopf D. Grifoni A. Lundgreen K.A. Gouma S. Sette A. Bates P. Hensley S.E. Greenplate A.R. Wherry E.J. Li R. Bar-Or A. Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy.Nat. Med. 2021; 27: 1990-2001Crossref PubMed Scopus (164) Google Scholar; Gadani et al., 2021Gadani S.P. Reyes-Mantilla M. Jank L. Harris S. Douglas M. Smith M.D. Calabresi P.A. Mowry E.M. Fitzgerald K.C. Bhargava P. Discordant humoral and T cell immune responses to SARS-CoV-2 vaccination in people with multiple sclerosis on anti-CD20 therapy.EBioMedicine. 2021; 73103636Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar; Sormani et al., 2021aSormani M.P. Inglese M. Schiavetti I. Carmisciano L. Laroni A. Lapucci C. Da Rin G. Serrati C. Gandoglia I. Tassinari T. Perego G. Brichetto G. Gazzola P. Mannironi A. Stromillo M.L. Cordioli C. Landi D. Clerico M. Signoriello E. Frau J. Ferrò M.T. Di Sapio A. Pasquali L. Ulivelli M. Marinelli F. Callari G. Iodice R. Liberatore G. Caleri F. Repice A.M. Cordera S. Battaglia M.A. Salvetti M. Franciotta D. Uccelli A. CovaXiMS study group on behalf of the Italian Covid-19 Alliance in MSEffect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.EBioMedicine. 2021; 72103581Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar; Tallantyre et al., 2022Tallantyre E.C. Vickaryous N. Anderson V. Asardag A.N. Baker D. Bestwick J. Bramhall K. Chance R. Evangelou N. George K. Giovannoni G. Godkin A. Grant L. Harding K.E. Hibbert A. Ingram G. Jones M. Kang A.S. Loveless S. Moat S.J. Robertson N.P. Schmierer K. Scurr M.J. Shah S.N. Simmons J. Upcott M. Willis M. Jolles S. Dobson R. COVID-19 vaccine response in people with multiple sclerosis.Ann. Neurol. 2022; 91: 89-100Crossref PubMed Scopus (43) Google Scholar). What cannot be ascertained from these figures is whether cross-protective ancestral T-cell immunity to the Wuhan strain of SARS-CoV-2 (Gao et al., 2022Gao Y. Cai C. Grifoni A. Müller T.R. Niessl J. Olofsson A. Humbert M. Hansson L. Österborg A. Bergman P. Chen P. Olsson A. Sandberg J.K. Weiskopf D. Price D.A. Ljunggren H.-G. Karlsson A.C. Sette A. Aleman S. Buggert M. Ancestral SARS-CoV-2-specific T cells cross-recognize the Omicron variant.Nat. Med. 2022; https://doi.org/10.1038/s41591-022-01700-xCrossref Scopus (112) Google Scholar), in the absence of humoral or antibody immunity, is sufficient to protect these patients from severe COVID-19, in particular serious infection with emerging immune escape variants such as Omicron (Sievers et al., 2022Sievers B.L. Chakraborty S. Xue Y. Gelbart T. Gonzalez J.C. Cassidy A.G. Golan Y. Prahl M. Gaw S.L. Arunachalam P.S. Blish C.A. Boyd S.D. Davis M.M. Jagannathan P. Nadeau K.C. Pulendran B. Singh U. Scheuermann R.H. Frieman M.B. Vashee S. Wang T.T. Tan G.S. Antibodies elicited by SARS-CoV-2 infection or mRNA vaccines have reduced neutralizing activity against Beta and Omicron pseudoviruses.Sci. Transl. Med. 2022; : eabn7842Crossref PubMed Scopus (34) Google Scholar). The Omicron strain and the likelihood of future immune escape variants challenge the widespread and rapidly adopted dogma to delay the introduction and/or further dosing of ocrelizumab (Baker et al., 2021Baker D. MacDougall A. Kang A.S. Schmierer K. Giovannoni G. Dobson R. Seroconversion following COVID-19 vaccination: can we optimize protective response in CD20-treated individuals?.Clin. Exp. Immunol. 2021; https://doi.org/10.1093/cei/uxab015Crossref PubMed Scopus (7) Google Scholar) and fingolimod (personal communication Prof. Anat Achiron, Tel-Aviv University, Israel). The object of the latter is to permit sufficient peripheral B-cell reconstitution to facilitate an antibody response to the vaccine(s). Unless B-cell reconstitution is fully optimised, i.e. near normal, the level of neutralizing anti-spike SARS-CoV-2 antibody produced may not provide protective immunity against the Omicron variant (Achiron et al., 2021aAchiron A. Mandel M. Dreyer-Alster S. Harari G. Dolev M. Menascu S. Magalashvili D. Flechter S. Givon U. Guber D. Sonis P. Zilkha-Falb R. Gurevich M. Humoral immune response in multiple sclerosis patients following PfizerBNT162b2 COVID19 vaccination: up to 6 months cross-sectional study.J. Neuroimmunol. 2021; 361577746Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). The potential downside to delayed dosing of ocrelizumab and fingolimod is whether their therapeutic efficacy is compromised. This is particularly relevant for fingolimod and other S1P modulators that are frequently associated with rebound inflammatory disease activity (Barry et al., 2019Barry B. Erwin A.A. Stevens J. Tornatore C. Fingolimod rebound: a review of the clinical experience and management considerations.Neurol. Ther. 2019; 8: 241-250Crossref PubMed Scopus (51) Google Scholar). This latter complication is less likely with ocrelizumab and other anti-CD20 therapies, which are associated with a treatment effect that extends beyond the period of B-cell reconstitution (Baker et al., 2020bBaker D. Pryce G. James L.K. Marta M. Schmierer K. The ocrelizumab phase II extension trial suggests the potential to improve the risk: benefit balance in multiple sclerosis.Mult. Scler. Relat. Disord. 2020; 44102279Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar; Rolfes et al., 2021Rolfes L. Pawlitzki M. Pfeuffer S. Nelke C. Lux A. Pul R. Kleinschnitz C. Kleinschnitz K. Rogall R. Pape K. Bittner S. Zipp F. Warnke C. Goereci Y. Schroeter M. Ingwersen J. Aktas O. Klotz L. Ruck T. Wiendl H. Meuth S.G. Ocrelizumab extended interval dosing in multiple sclerosis in times of COVID-19.Neurol. Neuroimmunol. Neuroinflamm. 2021; 8https://doi.org/10.1212/NXI.0000000000001035Crossref Scopus (27) Google Scholar; Sahi et al., 2021Sahi N.K. Abidi S.M.A. Salim O. Abraham R. Kalra S. Al-Araji A. Clinical impact of Ocrelizumab extended interval dosing during the COVID-19 pandemic and associations with CD19B-cell repopulation.Mult. Scler. Relat. Disord. 2021; 56103287Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar; Salzer et al., 2016Salzer J. Svenningsson R. Alping P. Novakova L. Björck A. Fink K. Islam-Jakobsson P. Malmeström C. Axelsson M. Vågberg M. Sundström P. Lycke J. Piehl F. Svenningsson A. Rituximab in multiple sclerosis: a retrospective observational study on safety and efficacy.Neurology. 2016; 87: 2074-2081Crossref PubMed Scopus (193) Google Scholar). Effective antiviral therapies for treating COVID-19 (García-Lledó et al., 2021García-Lledó A. Gómez-Pavón J. González Del Castillo J. Hernández-Sampelayo T. Martín-Delgado M.C. Martín Sánchez F.J. Martínez-Sellés M. Molero García J.M. Moreno Guillén S. Rodríguez-Artalejo F.J. Ruiz-Galiana J. Cantón R. De Lucas Ramos P. García-Botella A. Bouza E. Pharmacological treatment of COVID-19: an opinion paper.Rev. Esp. Quimioter. 2021; https://doi.org/10.37201/req/158.2021Crossref Scopus (6) Google Scholar) and the better management of severe COVID-19 (“Update to living WHO guideline on drugs for covid-19, 2021Update to living WHO guideline on drugs for covid-19, 2021. BMJ 374, n2219.Google Scholar) have now emerged. They permit vulnerable people with MS (pwMS) whose vaccine responses are blunted, the opportunity to receive these treatments to prevent and/or manage severe COVID-19. Based on these observations and the fact that the now dominant Omicron variant is less severe than the other strains (Abdullah et al., 2021Abdullah F. Myers J. Basu D. Tintinger G. Ueckermann V. Mathebula M. Ramlall R. Spoor S. de Villiers T. Van der Walt Z. Cloete J. Soma-Pillay P. Rheeder P. Paruk F. Engelbrecht A. Lalloo V. Myburg M. Kistan J. van Hougenhouck-Tulleken W. Boswell M.T. Gray G. Welch R. Blumberg L. Jassat W. Decreased severity of disease during the first global omicron variant covid-19 outbreak in a large hospital in Tshwane, South Africa.Int. J. Infect. Dis. 2021; 116: 38-42Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar) it is hard to justify a pause in DMT administration or delaying COVID-19 vaccination, be it the primary or booster vaccine doses. The maxim that some immunity is better than no immunity still holds and the general advice to pwMS would be to get vaccinated or boosted as soon as possible. It is clear that the COVID-19 pandemic, and the emergence of effective COVID-19 vaccines, has taught us much about MS disease-modifying therapies and their impact on immune function (Baker et al., 2020aBaker D. Amor S. Kang A.S. Schmierer K. Giovannoni G. The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic.Mult. Scler. Relat. Disord. 2020; 43102174Abstract Full Text Full Text PDF Scopus (51) Google Scholar; Giovannoni et al., 2021Giovannoni G. Hawkes C.H. Lechner-Scott J. Levy M. Yeh E.A. Baker D. COVID-19 vaccines and multiple sclerosis disease-modifying therapies.Mult. Scler. Relat. Disord. 2021; 53103155Abstract Full Text Full Text PDF Scopus (7) Google Scholar). At some point, healthcare professionals and pwMS must accept that chronic continuous immunosuppression, which has transformed the prognosis of MS, comes at a cost, albeit relatively small, from infections, absent or suboptimal vaccine responses and secondary malignancies. There will always be a trade-off between efficacy and the short- and long-term safety of DMTs. As an MS community, we must generate robust evidence to allow patients and their healthcare professionals to make informed decisions about their care. National studies such as the ones highlighted here (Garjani et al., 2021Garjani A. Patel S. Bharkhada D. Rashid W. Coles A. Law G.R. Evangelou N. Impact of mass vaccination on SARS-CoV-2 infections among multiple sclerosis patients taking immunomodulatory disease-modifying therapies in England.Mult. Scler. Relat. Disord. 2021; 57103458PubMed Google Scholar; Sormani et al., 2021bSormani M.P. Schiavetti I. Inglese M. Carmisciano L. Laroni A. Lapucci C. Visconti V. Serrati C. Gandoglia I. Tassinari T. Perego G. Brichetto G. Gazzola P. Mannironi A. Stromillo M.L. Cordioli C. Landi D. Clerico M. Signoriello E. Frau J. Ferrò M.T. Sapio A.D. Pasquali L. Ulivelli M. Marinelli F. Manzino M. Callari G. Iodice R. Liberatore G. Caleri F. Repice A.M. Cordera S. Battaglia M.A. Salvetti M. Franciotta D. Uccelli A. the CovaXiMS study groupBreakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies.bioRxiv. 2021; https://doi.org/10.1101/2021.12.23.21268177Crossref Scopus (0) Google Scholar) are helpful, but they need further revision to enable clinical decision making for individual patients.