Case 1

I have just had, unsurprisingly, a completely negative COVID-19 antibody test despite being double vaccinated with the AstraZenca-Oxford COVID-19 vaccine. My latest Ocrelizumab infusion was 3 weeks ago. When should I have the third and booster doses of the vaccine?

Case 2

Please could you tell me the optimum time to receive a third dose of the COVID-19 vaccine after having my third Ocrelizumab treatment? I had the treatment three weeks ago but I’ve been called up by the NHS for my third (not booster) jab. Should I also follow your advice for the seasonal flu jab?

Photo by Raghavendra V. Konkathi on Unsplash

Prof G’s opinion

Please note that in the UK the third dose of the COVID-19 vaccine in patients on immunosuppression is not considered a booster. This matters. The third dose is to try and increase the chances of someone on immunosuppression mounting a protective memory response to the spike protein. The third dose can be given as soon a 8 weeks after your second dose (please see JCVI guidance, 2 September 2021).

“At the current time, JCVI advises that a third primary dose be offered to individuals aged 12 years and over with severe immunosuppression in proximity of their first or second COVID-19 vaccine doses in the primary schedule. Severe immunosuppression at the time of vaccination is defined using the guidance [in Annex A] and timings stated below.”

In comparison, the booster vaccination has to be given at least 6 months after completing the initial course of vaccinations (primary vaccination), which in the case of patients on immunosuppression will be 6 months after their 3rd dose of the vaccine.

As these two people have just been recently dosed with ocrelizumab they will have zero B-cells in their peripheral blood and hence are very unlikely to mount an antibody response to a 3rd dose of the vaccine. Saying this there is data that people on ocrelizumab showing that they do make T-cell responses to the COVID-19 vaccine that is likely to offer some protection against the virus. This protection will be incomplete and is unlikely to prevent infection if exposed to the virus as sterilizing immunity is primarily due to antibodies. However, vaccine-induced T-cell immunity may provide protection from symptomatic infection, severe infection, hospitalisation, ITU admission and death. The phenomenon of immunity not preventing infection, but protecting you from symptomatic or severe infection is called non-sterilizing immunity.

(Apologies about all the immunology jargon, but I can’t avoid using it. COVID-19 has made the jargon spread into the lay lexicon.)

Please note that until we have data on the outcome of people on anti-CD20 therapies who have been vaccinated and we are able to compare the outcome between those who have and have not seroconverted, i.e. have antibodies, any advice will be an opinion. This is why what I say here may be very different to what your own HCP thinks and says.

So if these two people want to mount an antibody response to the third dose of the vaccine they will have to delay their next infusions to allow for partial B-cell recovery before having the next dose of the vaccine. The latter will take on average 9 months or more for those on ocrelizumab, 6 months or more for those on rituximab and 4 months or more for those on ofatumumab. By the time these people are in a position to mount an antibody response to the next dose of the vaccine, the pandemic will hopefully be over. I also don't know at this stage if delaying the third dose of the vaccine will make much difference to an individual’s outcome if they got COVID-19, i.e. before they have their third dose. In the past, I have said get vaccinated ASAP as some immunity is better than no immunity. Now that you have some immunity from the first two doses of the vaccine we have some immunological wiggle room with the third and booster doses. This wiggle room can be used depending on your risk of severe COVID-19 and when you were last dosed with ocrelizumab.

As these two people don't have any other risk factors for severe COVID-19 that I am aware of I would suggest having their 3rd dose when offered on the assumption it is going to boost their T-cell responses. I would then advise them to consider delaying or missing their next infusion and having the booster dose when they are or are likely to have B-cells in their peripheral blood. The latter can be checked for by ordering peripheral B-cell counts prior to being vaccinated. It looks like pwMS on anti-CD20 therapy need at least 10 B-cells per millilitre of blood to make an antibody response. I note from recent discussions with neurologists in the USA that this is widely practised.

Please note that both these patients have recently had ocrelizumab infusions. Would my advice be the same for pwMS who had their infusions many months ago? Probably not as these people have the option of delaying their infusions now and optimising their vaccine responses with the third dose of the vaccine and not having to wait 6 or more months for the booster. The latter is my current advice for older patients and those with comorbidities who are at high risk of getting severe COVID-19. These people need as much anti-SARS-CoV-2 immunity as possible to protect themselves from getting severe COVID-19 during the pandemic, i.e. in the next few months before the pandemic abates. In younger patients at very low risk of severe COVID-19 optimising their immunity now is not that important and they can probably wait for the booster.

Treating COVID-19

I am sure you are aware that REGEN-COV has just be licensed by the MHRA and is likely to become available on the NHS to treat acute COVID-19 in vulnerable patients. REGEN-COV is a combination of two monoclonal antibodies (Casirivimab and Iimdevimab) against SARS-CoV-2, which if started after developing COVID-19 reduces your chances of getting severe COVID-19 by 70%. I am sure the NHS will make REGEN-COV available to people with MS on anti-CD20 therapies in the event of them getting COVID-19 in the near future. In addition, a small molecule anti-viral agent, Molnupiravir (Merck), has just been shown to be effective against COVID-19 and is likely to be fast-tracked into clinical practice by regulators. In addition, to Molnupiravir there are several other promising antivirals in clinical development. The reason why I am emphasising this is that the need for optimising your immune response against SARS-CoV-2 will become less important as effective treatments for COVID-19 become available. As the risk of getting severe COVID-19 wanes, the need for optimal vaccine response will also wane.

What about delaying anti-CD20 therapy?

If you have been on an anti-CD20 therapy for 12 months or more I would not worry about delaying your next dose or missing one infusion as ocrelizumab's treatment effect on inflammatory disease activity extends beyond 12 months. The latter is based on data from the phase 2 ocrelizumab extension study, and other data, that shows the vast majority of subjects were still NEDA (no evident disease activity) up to 18 months after their last infusion. For those of you who have been on an anti-CD20 therapy for less than 12 months, we don’t have data on how long the MS treatment effect will last, which is why I would probably recommend treating your MS and not delaying or missing your next infusion for the vaccine.

What about the flu vaccine?

I would recommend having the flu vaccine approximately 3 months after your last infusion of ocrelizumab. The VELOCE ocrelizumab vaccine study showed anti-flu antibody titres rising in most patients on ocrelizumab albeit somewhat lower compared to patients on no treatment or interferon-beta. The reason why these results are different to the COVID-19 vaccine is that the flu vaccine is a recall antigen with some minor changes to the immunogen and the COVID-19 vaccine is a neoantigen, i.e. the immune system has not seen the antigen before. The difference between these two responses is based on the need for having a functional germinal centre in lymph nodes to make new antibody responses. Whereas recall antibody responses can occur without germinal centres, i.e. it is based on stimulating preexisting memory cells that live outside germinal centres.

Immunology 101

The germinal centres are the equivalent of a university for B-cells where the immune system takes naive B-cells, selects them, and educates them to make tightly binding antibodies before they graduate and leave the germinal centres to become memory B-cells or plasmablasts. In the germinal centres, innate immune cells and T-cells are the teachers that help the B-cells learn to make good quality antibodies. The B-cells who fail are sadly culled by a process of cell suicide called apoptosis. Anti-CD20 therapies generally ablate germinal centres, which is why they prevent or reduce antibody responses to new antigens.

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as generic advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.

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