Barts-MS rose-tinted-odometer: ★ (It’s a Black-and-White Friday #000000 & #FFFFFF)
At the beginning of the COVID-19 pandemic, we made the case that B-cells and antibodies against SARS-CoV-2 were not necessary to clear the coronavirus and protecting you from severe disease. However, almost all emerging data challenges this position, therefore I have changed my position.
It is now clear that cross-reactive immunity from common coronavirus infections provides some protection from COVID-19. IVIG (intravenous immunoglobulin) formulations collected prior to COVID-19 contain neutralizing anti-SARS-CoV-2 antibodies and may have contributed to the survival of agammaglobulinaemic patients who had COVID-19.
Neutralizing monoclonal anti-SARS-CoV2 antibodies have been shown to be effective against COVID-19 and severe COVID-19 and are now part of our therapeutic armamentarium for treating COVID-19.
People on anti-CD20 therapy are more likely to get COVID-19, severe COVID-19, are more likely to need ITU and hence more likely to die from COVID-19.
The study below shows that antibody neutralization levels against SARS-CoV-2 and the observed protection from SARS-CoV-2 infection are clearly related. In other words, anti-SARS-CoV-2 antibodies are important.
They estimate the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20% of the mean antibody level in convalescent serum from people who have recovered from COVID-19. The estimated neutralization level required for 50% protection from severe infection was significantly lower at 3% of the mean convalescent level. This means you need fewer antibodies to protect you against severe disease. Another interpretation, which I think is more likely, is that antibodies are a marker of protective T-cell immunity.
Worryingly the modelled decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained as you need less antibody. Again the latter may be due to T-cell immunity that must be present in the background. Despite this, it is quite clear that antibody neutralization level is highly predictive of immune protection be it via the antibodies themselves or the associated T-cell immunity.
This study implies that if you don’t have antibodies you won’t be protected. The question that needs to be urgently answered is ‘ is T-cell immunity in the absence of antibody immunity sufficient to protect you against SARS-CoV-2 infection and severe disease?’. Unfortunately, we don’t have real-life data on this at the moment.
My interpretation of this – based on the observation that people who are on anti-CD20 therapy have a higher risk of severe COVID-19 and hence have on average less cross-reactive anti-SARS-CoV-2 neutralizing antibodies – is that if possible it would be better to have anti-SARS-CoV-2 antibodies than not to have them. The is really important for pwMS on anti-CD20 therapies or S1P modulators who have blunted antibody responses to the COVID-19 vaccines. This is why I have moved my position from getting vaccinated ASAP to let’s time your vaccine to give you the best chance of seroconverting. This means waiting for B-cell reconstitution post-anti-CD20 before vaccinating.
An adaptive vaccination/vaccine-booster strategy is logistically challenging for the simple reason that B-cell reconstitution post anti-CD20 therapy is quite variable. This means that after a certain period of time, say 9 months after your last dose of ocrelizumab, 6 months after your last dose of rituximab and 4 months after your last dose of ofatumumab you will have to have monthly B-cell counts to make sure your peripheral B-cell count is above 10 B-cells/mm3 before you can get vaccinated. I also suspect we will then have to check if you seroconvert and if not re-vaccinate you before redosing with the relevant anti-CD20.
What this strategy won’t answer is even if these patients make an antibody response will the antibody and associated T-cell responses are good enough to protect you from infection or reinfection with the emerging variants?
So until we have more evidence I am sitting on the fence. It is only fair to tell pwMS about the problem and the uncertainty around this issue and give them the choice to delay or miss their next dose of anti-CD20 therapy. So far some patients are delaying their next course of treatment and others are not on the grounds that they are not prepared to take a chance of undertreating their MS. A lot of the former group of patients are older with more comorbidities and hence are at higher risk of dying from COVID-19. In contrast, the latter group tend to be younger and hence are more willing to take their chances if they get COVID-19. As with all decisions around managing MS during the COVID-19 pandemic, there are no easy black-and-white answers.
What is clear from this study below is that there is a clear hierarchy when it comes to vaccine potency with the mRNA vaccine, Moderna in particular, being superior to the other vaccines in inducing protective immunity. So if you have a choice I would go with one of the mRNA vaccines when it comes to maximising your antibody levels.
Khoury et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med. 2021 Jul;27(7):1205-1211.
Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4-28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level; 95% CI = 0.7-13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.