The recognition of B.1.1.529 a new SARS-CoV-2 variant in Botswana and South Africa is worrying and unfortunately not unexpected. This is how evolution works; it is an arms race between the virus and the immune system. The worrying thing about this B.1.1.529 variant is that it has evolved from the beta or South African variant, the sheer number of mutations in its spike protein (>30), the rapid rise of COVID-19 cases in South Africa and the identification of the strain in a person in Hong Kong.
As you know the beta-variant was already a partial immune escape variant in that vaccines based on the original Wuhan strain are much less effective against the beta strain and its descendants.
The B.1.1.529 contains more than 30 changes to the spike protein, which is the SARS-CoV-2 protein that recognises human cells and is the main target of the body’s immune response against the virus and the protein that our current 1st-generation of vaccines are based on. In addition, many of the changes in the spike protein are also found in other variants such as Delta and Alpha variants, which are linked to greater infectivity and the ability to evade infection-blocking antibodies. Another worry is this new strain may also evade T-cell immunity (see Ewen Callaway, Nature 25-Nov-2021). In short, it is highly likely that this strain will be an immune escape variant with heightened infectivity. The observation that the number of COVID-19 cases has doubled in South Africa in the last 24 hours supports this. Also, the finding of a case in Hong Kong suggests this strain may have already spread to other countries.
Please note this new variant is likely to be called the Nu variant by the WHO, but I suspect it will be referred to at the Botswana variant by the press and general public.
For people with MS the B.1.1.529 strain has implications:
The pandemic is clearly far from over so we are going to have to learn to live with it and adapt our MS treatment strategy to deal with the virus and the emerging strains.
Current vaccine immunity is likely to be insufficient to protect against this and other emerging variants.
The new monoclonal treatments for COVID-19, such as casirivimab & imdevimab (Ronapreve, REGEN-COV or REGEN-COV2), regdanvimab (Regkirona) and tixagevimab & cilgavimab (AZD7442), which are based on older SARS-CoV-2 spike protein may have less or no effect against this new and other emerging strains.
Oral small molecule anti-virals such as molnupiravir (Lagevrio, MSD), PF-07321332 (Paxlovid, Pfizer) and others will become more important in fighting the pandemic as these agents are not targeting the spike protein. However, don’t be surprised when these agents become widely used that strains of the virus will emerge that are resistant to these agents as well. We are fighting an evolutionary war.
Booster doses with new vaccines will almost certainly be necessary to cover the new strains. This clearly has implications for pwMS on S1P-modulators and anti-CD20 therapies as these classes of therapies blunt vaccine responses.
If this strain behaves like the delta strain there will be a new wave of infections globally and Governments will have to reinstate some public health measures to prevent the spread of the virus. I hope I am wrong, but based on the modelling data presented on this new strain I think we need to brace ourselves for another rollercoaster ride. This is why I referred to this strain yesterday as Grinch-2 and the alpha strain as Grinch-1; i.e the virus strains that steal Christmas. I hope I am wrong.
What to do?
Please follow your Government’s advice. Despite the politicisation of the COVID-19 pandemic Governments now know how to respond to the threat of this new strain. My advice to you is to get vaccinated as soon as possible if you are not vaccinated already. Get your third or booster doses of the vaccine if you are eligible for them. And remember if you are (1) immunocompromised, (2) anti-SARS-CoV-2 spike antibody-negative despite being vaccinated, (3) have confirmed COVID-19 (PCR or antigen test positive) and need hospital then you are eligible for Ronapreve treatment.
What is the third dose of the vaccine?
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 as 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.”
I am therefore advising all my patients to get their 3rd dose ASAP as it is part of the primary vaccine.
What is a booster dose of the vaccine?
In comparison, the booster vaccination has to be given at least 5 months after completing the initial course of vaccinations (primary vaccination), which in the case of patients on immunosuppression will be 5 months after your 3rd dose of the vaccine. The UK government reduced the time from 6 months to 5 months a few weeks ago.
If you have recently been dosed with an anti-CD20 therapy (ocrelizumab, ofatumumab, rituximab) you are likely to have zero B-cells in your peripheral circulation and hence are unlikely to mount an antibody response to a 3rd dose of the vaccine. Saying this there are data from people on ocrelizumab and rituximab 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. All this, however, may change with the new B.1.1.529 strain.
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, my advice is just an opinion. This is why what I say here may be very different to what your own HCP thinks and says.
So if you want to mount an antibody response to the third or booster dose of the vaccine you may 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 from the last infusion of ocrelizumab, 6 months or more for those on rituximab and 4 months or more for those on ofatumumab.
Saying this I don't know if delaying the booster dose of the vaccine will make much difference to an individual’s outcome if they got COVID-19, i.e. before they have their next dose of the vaccine. 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 or three doses of the vaccine we have some immunological wriggle room with the booster dose. This wriggle room can be used depending on your risk of severe COVID-19 and when you were last dosed with an anti-CD20 and the fact that effective treatments for COVID-19 are emerging, which clearly change the risk-benefit ratio. Whether or not this new viral strain will throw a spanner in the works will emerge in the next few weeks.
What about delaying anti-CD20 therapy?
If you have been on an anti-CD20 therapy for 12 months or more I would not necessarily worry about delaying your next dose or missing one infusion as ocrelizumab’s and rituximab’s treatment effect on inflammatory disease activity extends beyond 12 months. 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, in this situation, I recommend treating your MS and not delaying or missing your next infusion for the vaccine.
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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 general 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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