Lorna Galleguillos (LG)
Neurology and Psychiatry Department, Clínica alemana Neurology and Neurosurgery Department, Clínica Dávila Santiago, Chile
lgalleguillos@alemana.cl

Ricardo Alonso (RA)
Neurology Department, Hospital Ramos Mejías Buenos Aires, Argentina ricardoalonsohrm@gmail.com

Corresponding author
Lorna Galleguillos(LG)
Neurology and Psychiatry Department, Clínica alemana
Neurology and Neurosurgery Department, Clínica Dávila
Santiago, Chile
lgalleguillos@alemana.cl
phone +56952097044
mailing address Avenida Vitacura 5951, 10th floor, Vitacura, Santiago, Chile

Introduction

It has been a little over a year since we heard of the first case of COVID-19 in China. It spread quickly and was declared a pandemic in March 2020.1,2 Since then, significant research effort has been mobilized to develop a vaccine to halt the disease. Prior to this era, vaccines were not pursued against coronavirus because the four common strains (2 alpha coronavirus NL63 and 229E and 2 betacoronaviruses HKU1 and 229E) that affect people cause a mild flu, and the impact of the vaccine would be minimal against the wide range of viruses that cause the common cold.1 Today, we are running against the clock, and there are currently more than 30 vaccines in clinical trials with over 200 in various stages of development. It is important to note that only very few vaccines are currently approved and, in many countries, only for emergency use.3 There has been great interest in the new Covid-19 vaccines and how they might affect people with multiple sclerosis. In this brief review we consider three key points to keep in mind related to COVID-19 vaccines in people with MS.

 

Key Point 1: Immune response to SARS COV 2 and vaccine

 

 

The immune system plays a crucial role in the pathogenesis of COVID-19. To develop an understanding of the immune response and the underlying mechanism is relevant to developing an effective vaccine. A study published by Grifoni A et al., showed that infected

 

individuals have a strong T cell response to the virus: helper T cells recognize the spike protein on SARSCoV-2, stimulate B cells to further release antibodies and stimulate cytotoxic T cells.4 These helper T cells may be triggered from a previous coronavirus infection since there is some similarity in S proteins between the different coronaviruses3. Furthermore, patients who have recovered from COVID-19 have CD4+ and CD8+ T cells against nucleocapsid protein (NP) of SARS-CoV-25, supporting the theory that the T cell immune response can be stimulated following exposure to other beta coronaviruses.5 On other hand, levels of SARSCoV-2-specific neutralizing antibodies (NAbs) have shown to be varied between different groups of populations (elderly patients develop high levels of SARS-CoV-2 specific NAbs compared to younger patients).6 Therefore, T cell response plays an important role and may suggest a strong cellular immune response. However, whether high levels of Nabs protect such patients from contracting a severe disease requires further evaluation.5 Regarding B cells, plasma cells and memory B cells that emerge in response to the primary infection are involved in long-term protection against a reinfection7, and the IgG antibody titers increase in the first 3 weeks following symptom onset to then start declining by the second month while always maintaining levels above the detectable threshold in the serum, indicating the possibility of protection against a reinfection.8

 

Protection achieved by vaccines depends on three factors: period of incubation, quality of the immune response, and levels of antibodies produced by memory B cells. Memory response may be sufficient to protect against disease if there is an extensive incubation period between pathogen exposure and the onset of symptoms to allow for the 3 to 4 days required for memory B cells to generate antibody titers above the protective threshold.9 An important concept arises here, one that may improve vaccination strategies, known as ‘original antigenic sin.’ This phenomenon occurs when the immune system fails to generate an immune response against a strain of a pathogen if the host had previously been exposed to a closely related strain (as demonstrated in a number of infections, including dengue and influenza).10 This could have important implications for vaccine development if only a single pathogen strain or pathogen antigen is included in a vaccine, as vaccine recipients might demonstrate impaired immune responses if later exposed to different strains of the same pathogen, potentially putting them at increased risk of infection or more severe disease.9,10 Strategies to overcome this include the use of adjuvants that stimulate innate immune responses, which can induce sufficiently cross-

 

reactive B cells and T cells that recognize different strains of the same pathogen, or the inclusion of as many strains in a vaccine as possible (now that new strains of COVID-19 are appearing).11

 

Biologically speaking it is important to understand the disease process and to keep in mind the immune dysregulation in MS in order to make a recommendation regarding vaccination against COVID-19.12 Furthermore, vaccination immune response rates are low in patients under immunosuppressive treatments (see Key Point 2). Accordingly, information concerning COVID-19 vaccines is needed to make responsible recommendations to our patients in an era of fast track approval and the lack of real world evidence regarding effectiveness in our patients. Nevertheless, the current information we have concerning other vaccine responses coming from different MS therapy trials may be helpful.

 

Key Point 2: Well-known vaccine responses from therapies used in MS

 

 

Several studies have evaluated the impact of MS disease-modifying therapies (DMT) on immune response to vaccines. Responses to any vaccination depend on the vaccine type, the type of response (humoral and/ or cellular response), and the impact of the DMT on immunity in response to that vaccine type. Regarding teriflunomide, 97% of patients achieved post-vaccination antibody for H1N1 vaccine and B strain, and 77% for H3N2.13 In this study, patients treated with interferon B1 achieved post-vaccination antibody titers of more than 90% for H1N1, H3N2 and B strain.13 Dimethyl fumarate and interferon beta response to specific pneumococcal strain, tetanus-diphtheria toxoid and meningococcal vaccines were analyzed. No meaningful differences were observed between drugs in proportion to responders.14

 

For fingolimod, a trial showed that 54% of MS patients at 3 weeks after the vaccine mounted a protective antibody response, while 85% of patients on placebo and 6 weeks post-vaccination had only a 43% response15 showing that they had a response, but blunted. Flu and pneumococcal vaccine response in patients treated with siponimod was studied prior to and during treatment and after drug interruption. For Influenza “A/California strain”, protective antibody levels occurred in 86.7% of subjects on placebo in 92.9% of those vaccinated preceding, 74.1% during, and 71.4% with interrupted treatment. For Influenza “B/Massachusetts strain”, response rates were 50% preceding, 25.9% during

 

and 28.6% on interrupted treatment. It is noteworthy that 100% of subjects immunized with pneumococcal vaccination prior or during siponimod treatment mounted protective antibody levels.16

 

A small trial with alemtuzumab showed that immunologic memory to common viruses (in the form of IgG titers) and responses to T-cell–dependent recall antigens (tetanus, diphtheria, and polio), a T-cell–dependent novel antigen (meningococcus C), and T-cell– independent antigens (pneumococcal) vaccinations appear normal. 17 In this trial, the only patient vaccinated within 2 months of alemtuzumab treatment had a poor response to several vaccines, suggesting that immunization very early after alemtuzumab may not be effective17 suggesting that we should vaccinate before alemtuzumab or after 2 months of receining the infusion.

 

Anti-CD20 antibodies can decrease optimal immune responses to certain vaccines.18-20 There is evidence concerning the effect of rituximab on the decrease in the humoral response to the influenza and pneumococcal vaccine.19 The VELOCE trial20 showed that in MS patients, flu-virus antibody responses were 56%-80% on ocrelizumab compared to 75- 90% on placebo or interferon. In addition, antibody response rates for pneumococcal vaccination was reduced. We must remember that antibody responses to vaccines rely on B cells and plasma cells; therefore, 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 ocrelizumab21, proposing a dose interruption to maintain inflammatory  disease control while allowing effective vaccination against SARSCoV-2.

 

Key Point 3: COVID-19 vaccine mechanism of action and main candidates

 

 

Vaccines that induce large quantities of high affinity virus-neutralizing antibodies may optimally prevent infection and avoid unfavorable effects. Vaccination trials require precise clinical management complemented with detailed evaluation of safety and immune responses.1-3 Different platforms are currently being used around the world for the development of vaccine candidates: a) inactivated vaccines, where the entire virus is presented to the immune system; therefore, the immune responses are likely to target not only the spike protein of SARS-CoV-2 but also the matrix, envelope and nucleoprotein22;

 

1. b) recombinant protein vaccines can be divided into recombinant spike-protein-based vaccines, recombinant receptor-binding domain (RBD)-based vaccines, and virus-like particle (VLP)-based vaccines. These recombinant proteins can be expressed in different expression systems. One advantage of this is that they can be produced without handling live viruses. However, spike protein is relatively difficult to express, and this is likely to have an effect on production yields and on how many doses can be produced. The RBD is easier to express, but it is a relatively small protein when expressed alone and, although potent neutralizing antibodies bind to the RBD, it lacks other neutralizing epitopes that are present on the full-length spike23; c) replication-incompetent vectors are typically based on another virus that has been engineered to express the spike protein and has been disabled from replication in vivo by the deletion of parts of its genome. The majority of these approaches are based on adenovirus (AdV) vectors, the majority of which are delivered intramuscularly, enter the cells of the vaccinated individual and then express the spike protein, to which the host immune system responds. Advantages of this platform are that it is not necessary to handle live SARS-CoV-2 during production and that the vectors show good stimulation of both B cell and T cell responses. The disadvantage is that some of these vectors are affected and are partially neutralized by pre-existing vector immunity. In addition, vector immunity can be problematic when prime–boost regimens are used, although this can be circumvented by priming with one vector and boosting with a different vector24, 25 d) with RNA vaccines, the genetic information for the antigen is delivered instead of the antigen itself, and the antigen is then expressed in the cells of the vaccinated individual. Either mRNA (with modifications) or a self-replicating RNA can be used. Higher doses are required for mRNA than for self-replicating RNA, which amplifies itself, and the RNA is usually delivered via lipid nanoparticles (LNPs). The advantage here is that the vaccine can be produced completely in vitro. However, there is a disadvantage in that the technology is new and, as frozen storage is required, it is unclear what issues will be encountered in terms of large-scale production and long-term storage stability. In addition, these vaccines are administered by injection and are therefore unlikely to induce strong mucosal 26

 

No more than 20 vaccines have reached the final stages of testing in clinical trials on humans, and very few have been approved in different countries around the world. Sputinik vaccine, a recombinant adenovirus type 26 (rAd26) vector and a recombinant adenovirus type 5 (rAd5) vector, both carrying the gene for severe acute respiratory

 

syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (rAd26-S and rAd5-S)27, enrolled healthy adult volunteers aged 18-60 years. All participants produced antibodies to SARS-CoV-2 glycoprotein. At day 42 the seroconversion rate was 100% (receptor binding domain-specific IgG and neutralizing antibodies), and cell-mediated responses were detected in all participants at day 28 with a good safety profile. The controversy arises from the percentage of the results outcome, which may have been influenced by other factors not discussed.28 Recently, Astrazenenca / Oxford University published the interim analysis of the trial where they used a deficient chimpanzee adenoviral vector ChAdOx1 containing the SARS-CoV-2 structural surface glycoprotein antigen (spike protein; nCoV-

• In this trial, healthy volunteers aged 18–70 years were enrolled, but in some sites people with pre-existing conditions such as cardiovascular, respiratory and diabetes mellitus were included.29

 

Vaccine efficacy was 62.1% in the ChAdOx1 nCoV-19 group vs 71% in the control group. In participants who received a low dose followed by a standard dose, efficacy was 90% vs 30%. From 21 days after the first dose, there were ten cases hospitalized for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74,341 person-months of safety follow-up, 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group.29 Regarding the mRNA vaccines, the BNT162b2 mRNA Covid-19 vaccine (Pfizer/Biontech)

30 enrolled volunteers of 16 years of age or older who were healthy or had stable chronic

medical conditions, including but not limited to human immunodeficiency virus, hepatitis B virus, or hepatitis C virus infection. Results show that the vaccine is 95% effective in preventing Covid-19. The safety profile was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. The mRNA-1273 SARS-CoV- 2 vaccine (Moderna)31 included eligible participants of 18 years of age or older with no known history of SARS-CoV-2 infection and with locations or circumstances that put them at an appreciable risk of SARS-CoV-2 infection, a high risk of severe Covid-19 or both. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV- 2 vaccine. Efficacy was 94.1%.

Conclusion

Although we have no evidence of how these vaccines will protect MS patients against COVID-19, biology of the infective disease and of the demyelinating disorders has raised a red alert: are these vaccines safe and/or effective for these patients? Can patients under immunosuppressive treatment generate an immune response? Will they trigger a relapse or another autoimmune phenomenon? Which vaccine should we recommend?

 

The vaccines analyzed use a technology that appears to be safe in our patients.1-3 The only vaccine type red-flagged for immunosuppressed patients is the live attenuated virus. Moreover, a report related to the yellow fever vaccine (not replicated) has  demonstrated an increased risk of relapse in MS.32 Currently, there are 3 COVID-19 vaccine candidates in the preclinical evaluation stage that have been developed using this platform.3 To date, none of the vaccines approved fulfill this criterion. It is worth recalling that he Astrazeneca/ Oxford University or the Sputnik use an incompetent vector. Immunologically speaking, these two vaccines will generate a more robust immune response and probably stimulate immunological memory (T cell driven), although the best option for these would be inactivated whole viruses. On the other hand, mRNA vaccines will elicit only humoral responses and target the spike protein. We do not know if there will be a similar response for all COVID-19 strains that are appearing nor how long the humoral (B cell-dependent) immunity will last. Data are not currently available to establish vaccine safety and efficacy nor the potential for reduced immune responses in persons under immunosuppressive therapies.33 Persons with stable HIV infection have been included in mRNA COVID-19 vaccine clinical trials, though data remain limited.33 No data are currently available on the safety and efficacy of COVID-19 vaccines in persons with autoimmune conditions (such as MS). Nevertheless, no imbalances were observed in the occurrence of symptoms consistent with autoimmune conditions or inflammatory disorders in clinical trial participants who received a COVID-19 vaccine compared to placebo.22-30

 

The vaccines seem to be effective in preventing severe COVID-19, and the previous data from the trials and published data for the different treatments for MS can be extrapolated  to affirm our recommendation that our patients should get vaccinated against COVID-19 and with any vaccine except live attenuated viruses. Most likely, if patients are being treated with fingolimod or siponimod we would prefer mRNA vaccines for the humoral

 

immunity (preferring humoral memory in the acute phase, thereby they have a blunted cellular response)15, 16, while for anti-CD20 therapy, alemtuzumab and cladribine17-20 there is a preference for inactivated vectors over mRNA because they already have a blunted humoral immunity and we would like to boost the cellular response. Regarding cladribine,  it remains unclear whether patients can mount an effective immune response during lymphocyte depletion; therefore, treatment should not be initiated within four weeks after vaccination with an attenuated live vaccine. Additionally, MS patients treated with cladribine should not receive live vaccines until their white blood cell and total lymphocyte counts have returned to within their normal reference ranges.34 There is no special recommendation to platform treatments. All of this information is dynamic and changes every day. In the near future perhaps we will recommend a boost using different vaccines in order to induce perdurable immunological memory.

Conflict of interest

Lorna Galleguillos has nothing g to declare Ricardo Alonso has nothing to declare

 

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