Case study: ocrelizumab and COVID-19 vaccine boosters
Are you on an anti-CD20? To estimate your chances of mounting an antibody response to the COVID-19 vaccine you need to know the difference between primary and secondary or booster responses.
Case study
I am a 49-year-old man diagnosed in 2003. Double AZ vaccination in March this year. I started Ocrelizumab in April (having been moved after 12 years on Natalizumab). I was due my first full dose on October 11th. Originally being told by my MS team to delay booster jab by up to 3 months after infusion. Then at the 11th hour, I was told they have come up with their guidelines and to go ahead and have a booster at least two weeks before infusion (therefore to put back first full dose). Do you think this is right? Please could you give any advice regarding Ocrelizumab? I am hoping to have an antibody test when I go for infusion as although I started it after the COVID-19 jab it was only a matter of four weeks spacing, is this enough to have built any antibody?
Prof G’s Opinion
The good news is that you had your COVID-19 vaccine prior to starting ocrelizumab. So based on probabilities you are likely to have made an adequate immune response to the vaccine, including both antibodies and T-cell responses. Despite saying this there is a small number of people (approximately 5%), in the population, who don’t respond to the vaccines.
I think your team wanted to delay your next infusion, i.e. your second course of ocrelizumab, to maximise your chances of boosting your COVID-19 immunity. This makes sense and delaying your next course of ocrelizumab by such a short period of time is unlikely to make a large difference to your MS management.
Please note that primary and secondary or booster vaccine responses are different immunologically. A primary immune response to a new protein or antigen, such as the SARS-CoV-2 spike protein in the current COVID-19 vaccines, need functioning germinal centres.
Germinal centres (GCs) are the immune system’s equivalent of a University. In the GCs B-cells are educated by a combination of antigen-presenting cells (dendritic cells) and T-follicular helper cells (CD4+ T-helper cells). During the B-cell’s education, B-cells class switch their antibody production from IgM to IgG, IgA or IgE and then undergo a process of affinity maturation. Affinity maturation is a process whereby the B-cells mutate the variable portion of their immunoglobulin’s antigen-binding domain to increase their ability to bind to the antigen. This part of the antibody is called the CDR or complementary determining region (see image below).
Only the B-cells who make high-affinity good quality antibodies are able to graduate from or leave the GCs to become memory B-cells or plasmablasts. B-cells who don’t affinity mature are denied growth signals and die by a process called programmed cell death or apoptosis.
In comparison, the booster or secondary response occurs outside of GCs and involves memory B-cells. If memory B-cells recognise their antigen via their B-cell or immunoglobulin receptors they start to proliferate and produce a new generation of plasmablasts and plasma cells. The booster antibody response occurs within days of receiving a booster and rapidly peaks within 7-14 days. In comparison, a primary immune response takes 8-10 days to be detected and takes 3-4 weeks to reach a peak.
Why is all this immunological knowledge important? As ocrelizumab and other anti-CD20 therapies ablate germinal centres they prevent or severely impair a primary vaccine response. In comparison, secondary or booster responses are better preserved. These differences were clearly shown in the so-called VELOCE study in which ocrelizumab-treated patients made blunted IgM and very poor IgG response to a new antigen called KHA (keyhole limpet haemocyanin) (figure 5 below), but had detectable, although blunted, booster response to tetanus toxoid, pneumococcal and influenza vaccines (figures 2-4 below).
This is why you are in a good place having had your primary COVID-19 vaccine prior to starting ocrelizumab. As you are now having your booster after starting ocrelizumab you should be able to boost your antibody and T-cell responses.
Please note the COVID-19 vaccines are not 100% effective and appear to be non-sterilizing, i.e. they may not prevent you from getting infected, but they should prevent you from severe infection.
The good news is that REGEN-COV (Ronapreve) is now being used on the NHS in people who are vulnerable, for example, people who are immunosuppressed to treat COVID-19. REGEN-COV is a cocktail of two monoclonal antibodies (casirivimab and imdevimab) that bind to the critical receptor binding domain of SARS-CoV-2’s spike protein. NICE recommends offering REGEN-COV, made by Regeneron Pharmaceuticals, to COVID-19 patients aged 12 and over who are in hospital. Eligible patients will need to be seronegative, meaning they do not have existing levels of SARS-CoV-2 antibodies in their system. If patients do already have SARS-CoV-2 antibodies (seropositive) or their antibody status cannot be determined, then they should not be offered monoclonal antibody therapy, as they will receive no benefit from the treatment. In comparison, evidence shows that patients who are seronegative see a significant reduction in mortality when compared to normal care.
REGEN-COV is the first of many targeted treatments for COVID-19 to come. As other specific treatments get licensed, in particular the small molecule antiviral agents, the issue about COVID-19 vaccine responses on anti-CD20 therapy will become less important.
I hope the above addresses your concerns.
I would recommend reading my Newsletter on COVID-19 vaccinations from the 1st July 2021, which explains the science behind vaccinations.
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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.
I had my COVID vaccines at 11months post AHSCT (12 weeks apart), I checked for antibodies 6 months later and thankfully I had some, though tither was not specified. I still went ahead and had my third shot last week, so I hope I have a good level of immunity against COVID at this time. I am due to start Ocrevus as I relapsed.
My VZV level is low and the other titters have just been checked, I assume they will be low to non existent too, redoing all my child hood vaccinations will be time consuming, and delay starting a dmt, I feel more concerned about my active MS right now, could I propose a middle ground, would the same principle apply? could I start the DMT and revaccinate as far away from the Infusion/ before the next as possible, say at 4.5/ 5 months for these other illnesses which thankfully are not so widespread in circulation?
I know you don’t give direct advice but I value your opinion
With ocrelizumab after B cell depletion, should the new lymphocytes function properly? Is the mechanism of action for this part of lymphocytes the same as for alemtuzumab?
Or do the new lymphocytes still have the MS habit? So once the therapy with ocrelizumab is interrupted after years (2-3 years) and the maintenance one is chosen, the problems continue to exist?