Vaccines and Ocrelizumab (VELOCE): Old swords, new swords, and how to avoid stab wounds!

V

As approximately 70% of our newly diagnosed people with MS go onto ocrelizumab (a CD20 and thus B cell-depleting monoclonal antibody), a study that helps us understand how ocrelizumab affects the potential to mount (protective) antibody responses to vaccines and new antigens is more than welcome. Especially, as we are all hoping for the COVID-19 vaccine to be under the Christmas tree. 

B cells are the immune cells responsible to generate antibodies (= humoral immunity), and these antibodies are, at their turn, necessary to defend ourselves against new and old foes (= viral and bacterial pathogens). However, B cell depletion with ocrelizumab and other CD20-monoclonal antibodies (i.e. rituximab, ofatumumab, ublituximab) decimate valuable B cell subpopulations (i.e. naïve and memory B cells) and jolt the ‘germinal centres’ in the lymph nodes. 

This is detrimental to the production of qualitative antibodies because: 

  • Naïve B cells egress from the bone marrow and scout the peripheral blood for antigens. If they encounter a cognate antigen, they hurry to the lymph nodes and elicit a germinal center response.
  • Memory B cells hover in our blood and tissue for decades, and can generate an accelerated antibody-mediated immune respons in case of reinfection with an antigen you have encountered (potentially years) before. 
  • The germinal centres are the factories for the generation of affinity-matured B cells (= long-lived plasma cells) specialised in producing improved, very specific antibodies that effectively recognise infectious agents, and for the production of memory B cells. 

In the VELOCE study, researchers evaluate if people treated with ocrelizumab who are fully B cell depleted are able to raise an antibody response to vaccines and new antigens. The study population is being exposed to four different vaccine/antigenic triggers: tetanoid, pneumococcal and influenza vaccine as well as keyhole limpet hemocyanin (KLH). Importantly, the antigenic triggers require a different sort of immune equipment, which can be subdivided as follows: 

Old swords: 

For tetanoid, pneumococcal and influenza vaccine it is very likely that people starting with ocrelizumab will already have encountered some of the vaccine epitopes in the past. Tetanoid vaccine requires boosters every ten years, and pneumococcal and influenza strains are omnipresent pathogens. This means that long-lived plasma cells (which do not carry CD20 on their cell surface and are thus not depleted by ocrelizumab) can still exert their function and provide protection with well-targeted antibodies in the event of a recurring infection. 

The VELOCE study showed you are half as likely on ocrelizumab compared to controls to mount an antibody response against tetanoid vaccine and two thirds less likely to mount an antibody response to all the included pneumococcal serotypes. Based on these figures, it is fair to say that the antibody response to these vaccines is poor but not non-existent.

New swords: 

On the other hand, the VELOCE study evaluated the response to the keyhole limpet hemocyanin (KLH) which is an entirely new antigen. This means it will have to be recognised by the naïve B cells (or other antigen-presenting cells) and subsequently brought to the germinal centres in the lymph nodes.

The results of the VELOCE study are worrisome as 12 weeks after KLH administration there is a 5-fold difference in IgM antibody levels and an 11-fold difference in IgG antibody levels between ocrelizumab and controls. This means that the immune response against new pathogens (and thus potentially also COVID-19) cannot rely on an efficient antibody response and will have to be dependent on cellular immunity (e.g. cytotoxic T cells). 

How to prevent stab wounds? 

The VELOCE study has clearly pointed out that an antibody response to vaccines/new antigens while being B cell depleted is unreliable. Moreover, the people included in the VELOCE study only had received a single course of ocrelizumab. This implies that the picture might become more gloomy if you are continuously treated with six-monthly ocrelizumab infusions. We know that this causes hypogammaglobulinemia and prohibits replenishment off the long-lived plasma cell pool. Although this is definitely not good news, there are some ways to mitigate the risk. 

First, the results stress the importance of the biggest medical and human flaw: understanding the need for preventive action. The window of opportunity for a protective antibody response is clearly located before people start with ocrelizumab. Although pneumococcal and influenza vaccines are currently recommended rather than obligatory according to the product characteristics, the VELOCE results underscore the potential gain of this recommendation in terms of meaningful humoral immunity. In this context, we should also consider vaccinating our pwMS with the new Shingrix vaccine against the varicella zoster virus. In the phase III ocrelizumab trial, approximately 5 % of the people in the ocrelizumab group were affected with or oral or cutaneous zoster (compared to 3% in the interferon-beta group). Based on the reported efficacy of the Shingrix vaccine, the occurrence of zoster infections could be reduced with more than 90%. Imagine! 

Second, in the context of the current pandemic a low-dose high-frequency CD20-regimen with ofatumumab might be of interest. Ofatumumab is a new CD20-depleting antibody that will join the CD20 forces shortly, and is administered subcutaneously every month. If you have been treated with ocrelizumab (six-monthly high dose-infusions), it takes 72 weeks for your total B cell counts to reach the lower level of normal. If you have been treated with ofatumumab, it takes approximately 38 weeks which is twice as fast. Admittedly, this is still not very fast but definitely an advantage in terms of vaccine readiness. Obviously, vaccine readiness is not the full story when it comes to picking a CD20-depleting antibody as high-dose regimens have potential other advantages when it comes to preventing brain volume loss (cfr. DODO-study). 

Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis – The VELOCE study

Amit Bar-Or et al. Neurology 2020

Objective The phase IIIb A Study to Evaluate the Effects of Ocrelizumab on Immune Responses in Participants With Relapsing Forms of Multiple Sclerosis (VELOCE) study (NCT02545868) assessed responses to selected vaccines in ocrelizumab (OCR)-treated patients with relapsing multiple sclerosis.

Methods Patients were randomized 2:1 into the OCR group (n = 68; OCR 600 mg) or control group (n = 34; interferon beta or no disease-modifying therapy). All received tetanus toxoid (TT)-containing vaccine, Pneumovax (23-valent pneumococcal polysaccharide vaccine [23-PPV]), and keyhole limpet hemocyanin (KLH). The OCR group was subdivided into OCR1 (n = 33) and OCR2 (n = 35) at randomization. The OCR1 group received Prevnar (13-valent conjugate pneumococcal vaccine) 4 weeks after 23-PPV; the OCR2 and control groups received influenza vaccine. Vaccinations started 12 weeks after OCR initiation (OCR group) or on day 1 (control group).

Results Positive response rate to TT vaccine at 8 weeks was 23.9% in the OCR vs 54.5% in the control group. Positive response rate to ≥5 serotypes in 23-PPV at 4 weeks was 71.6% in the OCR and 100% in the control group. Prevnar did not enhance response to pneumococcal serotypes in common with Pneumovax. Humoral response to KLH was decreased in the OCR vs control group. Seroprotection rates at 4 weeks against 5 influenza strains ranged from 55.6% to 80.0% in the OCR2 group and 75.0% to 97.0% in the control group.

Conclusion Peripherally B-cell–depleted OCR recipients mounted attenuated humoral responses to clinically relevant vaccines and the neoantigen KLH, suggesting that use of standard nonlive vaccines while on OCR treatment remains a consideration. For seasonal influenza vaccines, it is recommended to vaccinate patients on OCR because a potentially protective humoral response, even if attenuated, can be expected.

Classification of evidence This study provides Class II evidence confirming that the humoral response to nonlive vaccines in patients with relapsing multiple sclerosis after OCR treatment is attenuated compared with untreated or interferon beta–treated patients, but they can still be expected to be protective.

Clinicaltrials.gov identifier NCT02545868.

About the author

Ide Smets

15 comments

  • Is there any point in us on anti CD20 even getting excited about the covid vaccine?

    I’m a health care worker so theoretically could be in the first roll out of vaccines (if they ever arrive) however,

    1) If it is a live vaccine can I even have it?

    2) Will it even work for me?

    Depressing times

    • Be prepared they are arriving..If you read the news they are preparing the roll out in december for Health care workers and 85+…I suspect it will be the oxford vaccine, which is the live adenovirus….There have been over 35,000 people who have taken this. The other vaccine that is most advanced is the Pfizer vacccine developed in Germany which is an RNA vaccine, used in over 40,000 people. These are based on the spike protein.

      1) At the moment live virues are contra indicated with ocrelizumab (based on fear). However, this is a replication defective virus and so the fact the there is an immune deficit should not matter. However the manufacturers will have to give this information. RNA vaccines should be no issue but they are an unknown entity.

      2) Will it even work for me/
      It depends on a few things. Are you going to make a productive immune response to the vaccine? at what level of immunity are you protected? This answer hopefully will come when the phase III data emerges. Now remember vaccines do not stop infections it just helps you deal with them when you are infected reducing your viral load to help you to survive.

      The vaccine will make you generate antibodies and some of them will be neutralizing antibodies. What is their level? What is the level of IgA (stops virus entering the body) and IgG. The assays that DrAngry has made can test this, so remember support ProfGs fund raising. However, the T cell response is key. I personally think the first vaccines are not optimised for T cell responses as it is evident that the major responses are to non spike targets. So an inactivate whole virus vaccine in adjuvant maybe what you want. How long will the antibodies last? I suspect that depends on whether we are shielding/distancing and even if it doesnt last long, we could get boostered with another vaccine.

      Now the other option would be monoclonal antibody treatment…A dose of a gramme would probably last 6 months to a year. Maybe I will post on this.

      Depressing times yes but hopeful times too that science has created a solution even a partial solution so quickly remeber they were saying 18 months in March it is Novemeber and they are now ready.

      In this study they gave the vaccine 4 weeks after ocrelizumab, the most sensible time to give this vaccine will be in month 4.5-5 at which time your B cells can respond the best as about 5% of people have B cells repopulating before 6 months. It is clear that people with ocrelizumab can make an anti-SARS-COV-2 response

      • Thanks for the comprehensive reply MD.

        I am actually perfectly timed to have my vaccine (if one of the ones produced is safe for us) because I delayed my ocrevus infusion in sept due to completely stable MRI and wanting to get over the winter in the NHS.

        So I’m on month 8 at the moment. If I can get a vaccine and then get my next dose in early 2021 that would be probably the best I can hope for!

        You’re right we all need to support Prof G’s fundraiser – I have donated and I am 100% behind it!

  • I see the England advice is for those clinically vulnerable to shield again….put out this afternoon, hours before a national lockdown…as useless as normal.

    If someone has had Ocrevus within the last 2 months would they be more at risk as someone who “just” has MS?

    • I will let ProfG answer this, I think we are offering differnt aadvice than ABN guideline we like to be sicence and reality driven

    • Hi Ali. Thank you for your question. There will probably be a slightly increased risk, especially if you have been treated with ocrelizumab for longer time periods, to develop moderate rather than mild or severe rather than moderate COVID-19 disease. However, it is clear now that other risk factors such as obesity, diabetes, hypertension, age >50, cancer etc. convey in a much higher risk of severe covid-19 than immune suppression on its own. Personally, I do not see the added benefit of shielding versus complying with lockdown rules.

  • And besides if it works or if it is necessary, you won’t get your universal basic income if you refuse to be vaccinated but don’t worry there won’t be any jobs as all the businesses will have shut down, so just take the vaccine like a good sheep and don’t think about the rushed, shoddy nature of what you’re being forced to have injected. Forget about what you’ve been told for years being immune suppressed you should only have non live vaccines, because this time its different.

  • I’ve just received a email from the government (Err Matt Hancok) for being defined as clinically Extrenely Vulnerable of getting seriously sick from COVID 19. Apart from the associated risk of taking DMT and the immune depletion that takes place. Is there something particular about the condition MS which cause more risk ? Like immune attacking one self to attack the virus?

    • Being disabled is a risk factor for worse outcome the higher the EDSS the higher the risk however a lowe risk to a low risk

  • On a CD20 therapy and Grasping at straws….Is there any possibility, however remote, that a prior exposure to a coronavirus may give some people cross-protective immunity to COvid? Could that explain why so many are asymptomatic? I remember scientists felt the The 2009 h1n1 swine flu age distribution suggested that people alive before 1976 may have been exposed to a similar virus, which gave some cross protective immunity against the 2009 virus.

    • Hi Sue! Indeed, there is emerging evidence that there is T cell reactivity against SARS-CoV-2 in 20% to 50% of people with no known exposure to the virus. However, the studies are small and we do not have precise estimates yet. The origin of this immunity might be ‘common cold’ coronaviruses, and it is possible that it contributes to a milder and potentially asymptomatic disease course (what has been shown for H1N1 as you mention). But still a lot of ifs and buts at this stage.

      • Thanks for your reply, Dr. Smets! A slight glimmer of a sparkle of hope about cross-protective immunity. Let’s figure out how to bottle it.

  • So would one of the new leading vaccine contenders like the Pfizer mRNA one fall under the category of “New Swords” using the KLH Administration?

By Ide Smets

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