Q: How will my DMT affect my response to a SARS-CoV-2 vaccine?

So if you are someone with MS who is shielding or being very careful about social distancing and want to avoid getting COVID-19 you may be considering what your own exit strategy is.

How do you de-risk yourself and prevent yourself from becoming infected with SARS-CoV-2?

At present, it looks as if the UK government’s strategy is to ring-fence you with people who are immune to SARS-CoV-2, the so-called herd immunity paradigm, and hope an effective vaccine emerges in the next 12-18 months to secure the safety of the high-risk or vulnerable population. This strategy is high-risk because there is no guarantee that sufficient numbers of healthy people in the general population will get COVID-19 to ring-fence the vulnerable. To be honest there are too many vulnerable people. In addition, there will always be holes in the science behind the herd-immunity paradigm; who says immunity to SARS-CoV-2 will be long-term and why wouldn’t new strains of virus emerge to fool the immune system. This means that vulnerable people will have to live in fear that they may acquire COVID-19 unless they get an asymptomatic/mild infection and/or vaccinated and have proof they have neutralising anti-viral protective immunity against SARS-CoV-2.

When an effective SARS-CoV-2 vaccine emerges (1) how good will the vaccine be and (2) if I am on a disease-modifying therapy will I respond to the vaccine?

In general, vaccines can be hit and miss. Politicians, particularly Donald Trump, and the general public seem to think that an effective vaccine is imminent. Yes, it may be but it is more likely, based on industry timelines, that an effective vaccine for SARS-CoV-2 is years away. Developing a vaccine for respiratory viruses is not easy, particularly for viruses that mutate rapidly and have mechanisms built into their nucleic acid which results in antigenic drift, i.e. the proteins they express on their surface rapidly mutate to escape immune detection. The latter is a particular problem with for example the influenza virus; antigenic drift happens annually. We also know this is a problem with coronaviruses because immunity is not life long and wanes within years. This is why we get recurrent common colds.

The other problem with viruses and vaccines is the so-called original antigenic sin. This is when you make an immune response to a virus or vaccine antigen. The virus then mutates and when you get infected with the new strain the antibodies you make to the original strain or vaccine don’t neutralise the new strain and may even enhance infection with the new strain. In addition, your immune system doesn’t treat the new strain as a new infection and thinks it is the original strain and hence doesn’t make new antibodies against the new strain. This why it is referred to as antigenic sin. Vaccine development has a long history of failing because of these sorts of issues and is why we haven’t got highly effective vaccines against major viruses such as dengue fever.

Another issue with SARS-CoV-2 is that it looks like some of the important binding sites on the spike protein of the virus are heavily modified with sugar molecules. This means that neutralising antibodies against SARS-CoV-2 may need to be against so-called glycoprotein segments of the spike protein. Glycoprotein vaccines are much more difficult to make and in themselves are less effective in inducing antibodies than pure protein vaccines. The reason for this is that the immune system processes sugar (glyco) antigens differently to protein antigens.

I am telling you all this to make you aware that vaccine development is difficult, very difficult, and there are a lot of issues that will need to be considered to make sure a vaccine against SARS-CoV-2 is effective and safe.

The other issue is having an immune system that is capable of mounting an immune response to a vaccine. I think in general a live-attenuated SARS-CoV-2 vaccine is unlikely to be developed. Live vaccines tend to be legacy vaccines from an era before we had the tools to make recombinant proteins. Therefore it is highly likely that all the vaccines that will be developed will either be nucleic acid, protein or glycoprotein component vaccines. In general immune responses to vaccines are blunted by immunosuppressive therapies. This has relevance to pwMS because the DMT you are on may block the required immune response to the vaccine. So your careful and patient waiting for an effective vaccine may be futile.

In general, interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate and natalizumab are unlikely to block or attenuate immune responses to a component SARS-CoV-2 vaccine. Similarly, once immune system reconstitution has occurred post alemtuzumab, cladribine, mitoxantrone or HSCT vaccine responses should be restored to normal or near normal. In the depletion phase of IRTs (immune reconstitution therapies) it is likely that vaccine responses will be blunted. In the case of S1P modulators, such as fingolimod and siponimod, and the anti-CD20 therapies (ocrelizumab and rituximab), which are continuous immunosuppressive therapies, vaccine responses are likely to be blunted. I use the term blunted rather than inhibited responses because pwMS on these therapies may still make antibodies to the vaccine components but not to the required level to create protective immunity.

The story with anti-CD20 therapies is potentially more complex. Surprisingly, antibody response to common vaccines occur on anti-CD20 therapies, but antibody response to glycoprotein vaccines, for example, the pneumococcal vaccine are blunted or inhibited the most. This may be particularly relevant to a SARS-CoV-2 vaccine that is likely to require antibodies to glycoprotein antigens to generate neutralising antibodies, i.e. antibodies that neutralise the virus and prevent infection.

Is this information important for pwMS? Yes, I think it is and may affect whether or not pwMS start or continue treatment with S1P modulators or anti-CD20 therapies. In other words, if you want to make yourself ‘vaccine ready’ you need to consider your DMT choice.

As a research group, we are very interested in the antibody responses to SARS-CoV-2 in pwMS who have had COVID-19. We are in the process of trying to rapidly develop an antibody assay for IgG and IgM antibodies that can differentiate between binding and neutralizing anti-SARS-CoV-2 antibodies. This will allow us to study whether or not the immune response to SARS-CoV-2 is different in patients on S1P-modulators and anti-CD20 therapies and to compare these responses to patients on other DMTs and to patients who are not on DMTs. This will potentially allow us to give patients detailed information in the future about their risk of getting delayed COVID-19 and whether or not they respond to emerging vaccines once they arrive.

Date & Disclaimer: 20-April-2020; please note this information will be time limited and will change as new data emerges.