#COVID19MS: antibodies matter

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Barts-MS rose-tinted-odometer: ★★★  (An ECTRIMS red Wednesday #e52330)

I am getting endless questions about when is it the best time to have the 3rd and/or booster dose of the COVID-19 vaccine in relation to ocrelizumab infusions, which is why I did an MS-Selfie Case Study on this topic on the weekend. 

Unfortunately, until we have good evidence that shows people on ocrelizumab who seroconvert do better than those who don’t seroconvert after the COVID-19 vaccine there is no right or wrong answer. I think we just need to tell pwMS that they are likely not to seroconvert if they are on an anti-CD20 therapy (ocrelizumab, rituximab & ofatumumab) and still have peripheral B-cell depletion. However, if pwMS on anti-CD20  therapy want to optimise their immunity by seroconverting they will need to delay or miss infusions or injections until they B-cell reconstitute. The latter is more important for older patients and those with comorbidities, who are at higher risk of severe COVID-19 and dying from the infection. 

The following vaccine study from Israel in this week’s NEJM tells us why antibodies are important post-vaccination. Breakthrough vaccine infections in healthcare workers who had been double vaccinated with the Pfizer-BionTech mRNA vaccine were much more likely in those with lower antibody titres. In summary breakthrough infections with SARS-CoV-2 is correlated with low neutralizing antibody titers during the peri-infection period. The good news is that most breakthrough infections were mild or asymptomatic, although persistent long-COVID-like symptoms did occur.

Can we extrapolate this to pwMS? Yes, definitely. Why would the biology of neutralizing anti-SARS-CoV-2 antibody protection be different in pwMS compared to people in the general population or in this case healthcare workers? This is why pwMS on anti-CD20 therapy who have not seroconverted after being fully vaccinated with a COVID-19 vaccine must consider themselves at-risk of breakthrough infections, which may be severe, particularly in older age groups and those with comorbidities and not to mention long-COVID.  

Bergwerk et al. Covid-19 Breakthrough Infections in Vaccinated Health Care Workers. N Engl J Med. 2021 Jul 28; NEJMoa2109072. 

Background: Despite the high efficacy of the BNT162b2 messenger RNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rare breakthrough infections have been reported, including infections among health care workers. Data are needed to characterize these infections and define correlates of breakthrough and infectivity.

Methods: At the largest medical center in Israel, we identified breakthrough infections by performing extensive evaluations of health care workers who were symptomatic (including mild symptoms) or had known infection exposure. These evaluations included epidemiologic investigations, repeat reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays, antigen-detecting rapid diagnostic testing (Ag-RDT), serologic assays, and genomic sequencing. Correlates of breakthrough infection were assessed in a case-control analysis. We matched patients with breakthrough infection who had antibody titers obtained within a week before SARS-CoV-2 detection (peri-infection period) with four to five uninfected controls and used generalized estimating equations to predict the geometric mean titers among cases and controls and the ratio between the titers in the two groups. We also assessed the correlation between neutralizing antibody titers and N gene cycle threshold (Ct) values with respect to infectivity.

Results: Among 1497 fully vaccinated health care workers for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented. Neutralizing antibody titers in case patients during the peri-infection period were lower than those in matched uninfected controls (case-to-control ratio, 0.361; 95% confidence interval, 0.165 to 0.787). Higher peri-infection neutralizing antibody titers were associated with lower infectivity (higher Ct values). Most breakthrough cases were mild or asymptomatic, although 19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha) variant was found in 85% of samples tested. A total of 74% of case patients had a high viral load (Ct value, <30) at some point during their infection; however, of these patients, only 17 (59%) had a positive result on concurrent Ag-RDT. No secondary infections were documented.

Conclusions: Among fully vaccinated health care workers, the occurrence of breakthrough infections with SARS-CoV-2 was correlated with neutralizing antibody titers during the peri-infection period. Most breakthrough infections were mild or asymptomatic, although persistent symptoms did occur.

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

Preventive Neurology

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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 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. 

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

8 comments

  • tx for posting – but then on the other side as most breakthroughs seem mild or asympto its prove that t-cells work well (and should protect a bit longer than 4month protection of b-cell antibodies). would then t-cell through vaccine + drugs like molnupivarir not be “enough” to be safe? (even for persons with risks?)

  • Very useful post, thanks ProfG! Should we consider the reported titers of anti-S as just a preliminary indication to evaluate how protected we are?

    • Yes! If you have anti-Spike antibodies it is a good sign and they are likely to be neutralizing and associated with T-cell responses as well.

        • Yes and no. Yes, if this is going to change the management of the patient and no if there is nothing that can be done about it. This is a blog post in its own right and I will write something about this in the next few days.

          At the moment the T-cell assays are not validated and approved for clinical use. To the best of my knowledge, they remain a research tool.

          • If antibody levels are adequate we could be spared the SEs of a third primary or booster. I’ve felt unwell after all 3. I didn’t get out of bed the w/e following my second. The highlights of the 3rd were increased clonus, malaise, cough, rigors, diarrhoea, arm weakness and headache. Spike protein mRNA isn’t benign and I found it difficult navigating the MHRA web yellow card reporting. I wasn’t impressed that a standard email followed indicating that they hadn’t read my report, because there was replication of questions that I had already answered. If you don’t want to know about vaccine drawbacks then mess up the reporting system so that ADRs don’t get reported/recorded. Antibody levels would enable my informed decision about when/if to accept a 4th.

  • Numbers (data)

    Among 1497 fully vaccinated health care workers

    39 SARS-CoV-2 breakthrough infections were documented = 2,60%

    Of 39 SARS-CoV-2 breakthrough infections 7,41 Health care workers had persistent symptoms (>6 weeks)=19% off the breakthrough infections

    Only 7,41 persons

    And they recover

    Why? if not for the Nab them what else?

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