Review Multiple Sclerosis, Disease-Modifying Therapies and COVID-19: A Systematic Review on Immune Response and Vaccination Recommendations Verónica Cabreira 1,2,*, Pedro Abreu 1,2, Ricardo Soares-dos-Reis 1,2,3 , Joana Guimarães 1,2 and Maria José Sá 1,4 1 Serviço de Neurologia, Centro Hospitalar Universitário de São João, 4200-319 Porto, Portugal; [email protected] (P.A.); [email protected] (R.S.-d.-R.); [email protected] (J.G.); [email protected] (M.J.S.) 2 Departamento de Neurociências Clínicas e Saúde Mental, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal 3 i3S-Instituto de Investigação e Inovação da Universidade do Porto, 4200-135 Porto, Portugal 4 Faculdade de Ciências da Saúde, Universidade Fernando Pessoa, 4249-004 Porto, Portugal * Correspondence: [email protected] Abstract: Understanding the risks of COVID-19 in patients with Multiple Sclerosis (MS) receiving disease-modifying therapies (DMTs) and their immune reactions is vital to analyze vaccine response dynamics. A systematic review on COVID-19 course and outcomes in patients receiving different DMTs was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta- Analyses statement. Emerging data on SARS-CoV-2 vaccines was used to elaborate recommendations. Data from 4417 patients suggest that MS per se do not portend a higher risk of severe COVID-19. As Citation: Cabreira, V.; Abreu, P.; for the general population, advanced age, comorbidities, and higher disability significantly impact Soares-dos-Reis, R.; Guimarães, J.; Sá, COVID-19 outcomes. Most DMTs have a negligible influence on COVID-19 incidence and outcome, M.J. Multiple Sclerosis, while for those causing severe lymphopenia and hypogammaglobulinemia, such as anti-CD20 Disease-Modifying Therapies and therapies, there might be a tendency of increased hospitalization, worse outcomes and a higher risk COVID-19: A Systematic Review on Immune Response and Vaccination of re-infection. Blunted immune responses have been reported for many DMTs, with vaccination Recommendations. Vaccines 2021, 9, implications. Clinical evidence does not support an increased risk of MS relapse or vaccination 773. https://doi.org/10.3390/ failure, but vaccination timing needs to be individually tailored. For cladribine and alemtuzumab, it vaccines9070773 is recommended to wait 3–6 months after the last cycle until vaccination. For the general anti-CD20 therapies, vaccination must be deferred toward the end of the cycle and the next dose administered at Academic Editors: Ralph A. Tripp, least 4–6 weeks after completing vaccination. Serological status after vaccination is highly encouraged. Steven B. Bradfute and Scott Anthony Growing clinical evidence and continuous surveillance are extremely important to continue guiding future treatment strategies and vaccination protocols. Received: 28 May 2021 Accepted: 7 July 2021 Keywords: COVID-19; vaccines; multiple sclerosis; immunosuppression; multiple sclerosis/therapy Published: 11 July 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- iations. Coronavirus disease 2019 (COVID-19) is a severe acute respiratory syndrome caused by a variant of coronavirus (SARS-CoV-2). It emerged in December 2019, in the Wuhan province and rapidly spread worldwide [1]. After SARS-CoV-2 infection, the innate im- mune system (macrophages, dendritic cells, natural killer (NK) cells) triggers signalizing cascades leading to an increase of pro-inflammatory cytokines. Simultaneously, significant Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. T lymphocyte subside, limiting the establishment of adaptative immunity and the host abil- This article is an open access article ity to solve the infection [2]. Later, to establish a prolonged immunity and reduce the risk distributed under the terms and of re-infection, plasmacytes and memory B and T cells take place to produce neutralizing conditions of the Creative Commons antibodies. Since the outbreak of the pandemic, in addition to the well-known COVID-19 Attribution (CC BY) license (https:// symptoms, including neurological ones [1], there has been a concern with populations creativecommons.org/licenses/by/ facing a higher risk of infection [3]. Multiple sclerosis (MS) patients are usually under 4.0/). disease modifying therapies (DMTs) and have been identified as a high-risk population, Vaccines 2021, 9, 773. https://doi.org/10.3390/vaccines9070773 https://www.mdpi.com/journal/vaccines Vaccines 2021, 9, 773 2 of 18 both because inflammation is an integral part of MS pathogenesis, and infections are well known exacerbation triggers of MS-related disease activity [4]. While many immunotherapies, including DMTs used for MS, have been pointed as COVID-19 candidate therapies [5], the development of SARS-CoV-2 vaccines was early as- sumed to be the turning point for the still expanding pandemic, and a high priority research topic. Now that many vaccines have been developed and approved by the regulatory agencies, the vaccination campaigns are speeding up all over the world. Notwithstanding, besides the susceptibility and clearance of SARS-CoV-2 infection in patients under different DMTs, the question is now turning to understanding the vaccine response in MS patients. This will be the key to define the best vaccination strategy and a guarantee of effective immune response after vaccination. 2. Materials and Methods We conducted a systematic review on the incidence and outcomes of COVID-19 in MS patients on DMTs, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [6]. The following query was introduced to PubMed database: multiple sclerosis AND (SARS-CoV-2 OR COVID-19) AND (disease-modifying therap* OR DMT OR interferon OR glatiramer acetate OR teriflunomide OR dimethyl fumarate OR fumarate OR fingolimod OR natalizumab OR ocrelizumab OR rituximab OR cladribine OR alemtuzumab). A clinical trial database and conference abstracts were also analyzed. After selecting the articles related to the first part of this review, we looked for articles on ‘Multiple Sclerosis’; ‘COVID-19’; ‘SARS-CoV-2’; ‘vaccines’ and ‘vaccination’ to analyze the immune response dynamics to vaccines on MS patients. We focused on the approved SARS-CoV-2 vaccines and the data available on their safety and efficacy, including some recent data in patients with MS. Experience with previous vaccines in relation with DMTs was also deemed pertinent as a window for the new vaccines. Using this current evidence, the second part of the document was designed to elaborate expert recommendations that might guide vaccination protocols. Two qualified authors evaluated independently the titles and abstracts of each article and decided to include only original articles, case series (including safety data registries), case reports, letters, correspondence and short communications. Systematic reviews were not considered. Full text of included articles was reviewed for the extraction of patients’ clinical features. When we identified duplicated results, those articles were removed. 3. Results Study selection according to PRISMA criteria is represented in a flow-chart (Figure1). A total of 164 articles were retrieved from PubMed (last search on 27 April) as well as two conference abstracts. Of these, 80 articles were included in the review. Reports on vaccination and MS, as well as papers recovered from reference lists, were added, totalizing 110 studies meeting the final inclusion criteria. Several studies have already reported on SARS-CoV-2 infection and prognosis in MS patients under different DMTs. So far, 4417 MS patients were reported to have been infected with SARS-CoV-2, with 99 reported dead due to COVID-19 complications (Table1). Since lymphopenia is a rare event for patients under interferons-beta (IFN-beta), this treatment is unlikely to interfere with susceptibility and immune response to SARS-CoV-2. We identified a total of 218 MS patients on IFN treatment with a confirmed (n = 144) or suspected (n = 74) COVID-19 diagnosis [7–25]. Four (1.8%) of them were reported dead due to COVID-19 complications [21,25]. In the Italian real-world dataset, among the 73 patients on IFN, no ICU admissions or deaths were recorded. IFN-beta has been associated with the lowest risk of SARS-CoV-2 infection across all available series, comparing to other DMTs [18]. A mild protective effect of IFN-beta might possibly be related to the reversal of SARS-CoV-2 inhibition of type 1 IFN molecules production and intracellular antioxidant nuclear factor erythroid 2–related factor 2 pathway [9,26,27], which is further emphasized by reports of severe cases of COVID-19 among patients with genetic and non-genetic Vaccines 2021, 9, 773 3 of 18 Vaccines 2021, 9, x deficiencies in interferon system components, such as low expression of IFN receptor gene3 of 17 or anti-IFN neutralizing antibodies [28]. However, available clinical trial data suggest that IFNs (used alone or in combination with other antiviral agents) have yielded mixed results in patients with SARS-CoV-2. Identification of studies via databases and registers Records identified from: Records removed before MEDLINE database (n = 162) screening: Clinicaltrials.gov (n=1) Duplicate records removed Conference abstracts (n=2) (n = 1) Not eligible (n=1) Records screened Records excluded (n = 163) (n = 75) Reports sought for retrieval