MS Minute: The COVID-19 Vaccine & Vaccine Readiness in MS

When the COVID-19 pandemic really kicked-off in March 2020, multiple sclerosis (MS) specialists had to respond to many questions proposed by the MS and wider neurology community and in particular from people with MS. The MS community should be congratulated for their efforts; they responded by setting-up national COVID-19 registers and international data sharing initiatives to answer some of these questions.¹ With the exception of antiCD20 therapies and possibly natalizumab treatment,² it has become clear that people with MS do not appear to have increased risk of contracting COVID-19 or having severe COVID-19 and dying from COVID-19.³ It is also clear that disease-modifying therapies (DMT) do not predict poor outcome, but the same factors that play out in the general population, (ie, advanced age, disability, male sex, obesity, comorbidities, and being from an historically minoritized background).³

Vaccine Readiness

Early in the pandemic the question arose of whether those with MS would be able to receive 1 of the many COVID-19 vaccines in development if and when they these were ready for use.⁴ Based on immunologic principles and scientific evidence from other vaccines, many commentators and we made predictions about the need to prepare people with MS who were using certain DMTs for future vaccines.⁴ At the time, we needed to balance “vaccine readiness” against the principle that because MS is a disabling disease we should continue to manage MS as we had before the COVID-19 pandemic.⁵ There were certain caveats to this argument, particularly in relation to treatment with alemtuzumab⁵ and hematopoietic stem cell treatment (HSCT),⁶ which affect both the innate (monocytes and/or neutrophils) and adaptive (particularly cytotoxic CD8⁺ T lymphocytes) immune systems required for the initial antiviral response to SARS-CoV-2.⁴ Our advice was that people treated with alemtuzumab or HSCT would need to self-isolate or quarantine and be more vigilant to prevent exposure to SARS-CoV-2. In comparison, for those using other DMTs, our advice was to simply to adhere to local guidelines in relation to social distancing and personal hygiene.

Our advice and position on vaccines and vaccine readiness has had to change since we began talking about it earlier in the COVID-19 pandemic.⁴ Now that several vaccines have arrived in parallel^7-9 with ambitious national vaccination programs, it is clear we do not have the luxury of time to “optimise” immune responses to these vaccines in our patients with MS using certain classes of DMTs known to blunt vaccine responses.

In our opinion, all COVID-19 vaccines that are approved can be given to people with MS. We base this on 2 key facts. First is that regulatory bodies have licensed or will license these vaccines for their safety and efficacy profile in the general population. Second is that the majority of the COVID-19 vaccines, including the mRNA and adenovirus vector vaccines, do not contain live infectious agents.

The COVID-19 Vaccines

There has been some confusion around the Oxford-AstraZeneca,⁹ Johnson & Johnson,¹⁰ and Russian Sputnik¹¹ vaccines, which use adenoviral vectors to deliver the message for the immunogen (eg, the Oxford-AstraZeneca vaccine uses a chimpanzee adenovirus vector to deliver the immunogen).⁹ Although the viral vector used is able to infect cells, resulting in translation and expression of the SARS-CoV-2 spike protein, the adenovirus genes required for viral replication are disabled. Thus, the adenovirus vector used in these vaccines is not able to cause adenoviral infection, making it highly likely to be safe for people with MS using immunosuppressive DMTs.

Although we say these COVID-19 vaccines are likely to be safe for those with MS using DMTs, to the best of our knowledge none of the vaccines has specifically been tested in people with MS. Safety for this population has to be extrapolated from safety data of the general population vaccine studies. This does not preclude, however, that there is something we don’t know about having MS that predisposes individuals to some rare complications. Based on other antiviral vaccines that have been used in MS, however, we think this is very unlikely.¹²

Use of some classes of immunosuppressive DMTs may reduce the chances of responding adequately to a vaccine and hence achieving full immunity to infection from wild-type SARS-CoV-2. Until detailed immunologic studies in people with MS using each specific DMT are performed this question cannot be answered with certainty. Evidence from people with MS vaccinated against other viruses while receiving DMTs and the known pharmacology of these drugs, however, enables us to draw some conclusions about risk and efficacy (Abbreviated Table; full version available at www.practicalneurology.com).¹²

Specific DMTs and COVID-19 Vaccination

Interferon-β, Glatiramer Acetate, Fumarates, Teriflunomide, and Natalizumab

No safety or efficacy concerns have been reported for interferon, fumarates and teriflunomide in relation to vaccinations in general,¹² although the influenza vaccine, may be less effective those with MS using glatiramer acetate.¹³ For natalizumab the available evidence on safety and efficacy of inactivated vaccines is inconclusive,¹² with some studies showing the influenza vaccine may be less effective in people takingn natalizumab.¹³ In general, use of interferon-β, glatiramer acetate, fumarates, teriflunomide, or natalizumab, none of which are associated with marked peripheral immunosuppression, is unlikely to interfere with COVID-19 vaccine responses. Therefore, we are recommending patients on these therapies do not interrupt or stop dosing prior to vaccination, and they should not delay getting a COVID-19 vaccine either.

Immune Reconstitution Therapies

Those who have been treated with an immune reconstitution therapies (eg, alemtuzumab, cladribine, mitoxantrone, or HSCT) in the past and have reconstituted their peripheral immune systems should be able respond to the COVID-19 vaccines. If an individual had an incomplete immune reconstitution, they may still consider having a COVID-19 vaccine with the potential for a blunted immune response. Vaccination within 6 months of treatment with either HSCT¹⁴ or alemtuzumab¹⁵ results in a smaller proportion of vaccine responders.

Postponing vaccination until after full immune reconstitution will clearly be a trade-off between wanting to protect patients with MS now or waiting several months when the peak of pandemic may be almost over and the benefits of the vaccine at an individual level are lower. We want to stress that COVID-19 vaccination is not only about the individual, but also about slowing and preventing transmission in the general population. The latter is a factor that needs to be considered and may be relevant, for example, if patients want to see unvaccinated vulnerable relatives or if they may want to travel to parts of the world with delayed COVID-19 vaccination programs.

Spinghospine-1-Phosphatase Modulators

For the so-called sphingosine-1-phosphate (S1P) modulators (ie, fingolimod, siponimod, ozanimod, and ponesimod) vaccine responses are likely to be blunted because these therapies affect both the afferent (ie, antigen processing and presentation) and efferent or effector limbs of adaptive immunity.¹⁶ Immune response to vaccines in people using fingolimod can be documented, however, although at a lower level compared with the general population.¹⁷ Whether blunted vaccine responses will be sufficient to prevent SARS-CoV-2 infection is, at present, a moot point. Vaccines are not recommended for up to 2 months after stopping treatment with S1P modulators. We would not recommend patients on S1P modulators stop their treatments to have one of the COVID-19 vaccines, however, because washout of these treatments, as well documented with fingolimod,¹⁸ is associated with MS rebound activity. Our advice for those using S1P modulators would be to go ahead with a COVID-19 vaccine when it is offered.

AntiCD20 Therapies

When we initially wrote about vaccine hesitancy, we suggested that people with MS using antiCD20 therapies (ie, rituximab, ocrelizumab, ofatumumab, ublituximab) may need to delay their next infusion or injection or even miss 1 or more treatments to allow B-cell reconstitution before receiving a COVID-19 vaccine .⁴ Since making this statement, however, more data has emerged to suggest this may not necessarily be the most appropriate course of action for people with MS using an antiCD20 therapy.

People on antiCD20 therapies are likely to have blunted antibody responses to wild-type SARS-CoV-2 infection,^19-21 and vaccines—including those containing neoantigens (eg, keyhole limpet hemocyanin [KLH]).²² A blunted antibody response, however, doesn’t mean these people don’t have long-lasting immunity to the infection. The vast majority of people with MS using antiCD20 therapy who have had COVID-19 make an uneventful recovery,^23-25 which is almost certainly due to cellular and not necessarily a humoral or antibody response.²⁶ Even individuals with agammaglobulinemia and no functional B-cells can recover from COVID-19.²⁷ This cellular immunity is likely to be long-lasting and protect against reinfection with wild-type SARS-CoV-2 infection. Even people without MS or immune conditions who have had COVID-19 and lost their antibody responses have detectable cellular immunity.²⁸ Our interpretation of these data is that people with MS using antiCD20 therapies should have the COVID-19 vaccine when it is offered and without concern for whether they mount an “adequate” antibody response.

We are aware that some using antiCD20 therapies plan to delay their next infusion regardless of what we or any health care professional recommends. The question we ask is for how long? Peripheral B-cell reconstitution can take months to years,²⁹ and even then, the question of how much B-cell reconstitution is considered good enough for an adequate vaccine response remains. Those with MS will need to weigh the current lack of evidence on delaying their next antiCD20 treatment or waiting for B-cell reconstitution against the time-sensitive nature of the potential benefits of COVID-19 vaccination to protect them during the current high-risk period of the pandemic. If people using antiCD20 therapies wait too long and the pandemic is over, both the personal and population benefits of the vaccine will be reduced.

The only evidence base we have at the moment is the recently published VELOCE study in which vaccination was delayed for 12 weeks after starting ocrelizumab treatment.²² This study demonstrated a blunted, but not absent, antibody response to recall and neoantigen (KLH) vaccines. Based on these data, if a person with MS has just had a recent course of antiCD20 therapy, they may want to delay COVID-19 vaccination until 12 weeks after their last treatment. If, on the other hand, a person with MS is due for their next course of ocrelizumab in the next couple of months, vaccination should be timed so that their second dose of the COVID-19 vaccine is given at least 4 weeks before ocrelizumab infusion to allow time for an adequate antibody response. COVID-19 vaccination shortly before starting or redosing with immunosuppressive therapies (<4 weeks) may decrease the odds of optimal immune response following vaccination.

In our opinion, it is more important for people using antiCD20 therapies to be vaccinated than not because at the height of the pandemic, having some immunity against SARS-CoV-2 is better than not. We anticipate that in the near future current planned studies will better define the optimal window of when to receive a vaccination in relation to the dosing of an antiCD20 therapy.

Vaccination and MS Relapses

A major concern about COVID-19 vaccines is the theoretical potential these may trigger MS relapses. This concern is based on extrapolating data from 2 cases of CNS demyelination in the Oxford-AstraZeneca trial, which have not undergone peer review,³⁰ and several cases of transverse myelitis (TM) in people who had COVID-19.^31-36 Of the cases in the Oxford-AstraZeneca trial, 1 person who was vaccinated had an initial attack or relapse and was subsequently diagnosed as having MS. We assume they likely had pre-existing lesions and were now shown to have a second attack or new lesions consistent with dissemination in time and the diagnosis of MS. The other individual had an episode of vaccine-related TM, which is also described with several other antiviral vaccines, although evidence for a causal association between vaccination and TM is inconclusive.³⁷ The only vaccine that has been reported to potentially trigger MS relapse is the live yellow-fever vaccine and this is based on 1 report,³⁸ which subsequently has not been replicated.³⁹ Therefore, there is no current evidence that COVID-19 vaccines trigger MS relapses or cause TM.³⁰ In our opinion, there is no reason to avoid the COVID-19 vaccine based on the hypothesis that these vaccines may trigger MS relapses or demyelinating disease. Clearly, our opinion may change if new data emerges to the contrary.

Summary

If your patients have not had COVID-19, having a vaccine will offer them the opportunity to prevent getting COVID-19 or at least lessen the risk of severe disease. All the currently licensed vaccines, which by definition have been shown to be safe in the general population, are likely to be safe for those with MS. Although some immunosuppressive therapies (ie, S1P modulators and anti-CD20 therapies) may be associated with blunted vaccine responses, even a blunt vaccine response is likely to protect them against infection or at least severe COVID-19. There is no evidence that stopping or delaying treatment possibly to boost vaccine responses will be effective; doing so may diminish protection when risk of infection is highest. Stopping some DMTs, in particular, natalizumab and S1P modulators, is associated with a rebound of MS disease activity and is not recommended. We are hopeful that the pharmaceutical industry and the wider MS community will collect data and do specific studies to answer the many questions that the wider MS community has around vaccination and vaccine responses in the context of specific DMTs.