CME INDIA Presentation by Dr. Rajeev Jayadevan, MD, DNB, MRCP, ABIM (Med) ABIM (Gastro), NY. Vice Chairman, Kerala state IMA Research Cell. Member, National IMA Task Force on Corona Epidemic, Cochin.
Hybrid immunity is what we are looking for
The recent studies suggest that hybrid immunity is, at least partly, due to immune players called memory B cells.
It is a well-known fact that the bulk of antibodies made after infection or vaccination come from short-lived cells called plasmablasts, and antibody levels fall when these cells inevitably die off. Once plasmablasts are gone, the main source of antibodies becomes much rarer memory B cells that are triggered by either infection or vaccination.
We have noticed the unique properties of the vaccine responses of people who had previously caught and recovered from COVID-19.
“We saw that the antibodies come up to these astro… You get a sniff of antigen, in this case of mRNA vaccine, and those cells just explode,” – Rishi Goel, an immunologist at the University of Pennsylvania in Philadelphia.
A first vaccine dose in someone who has previously been infected is doing the same job as a second dose in someone who has never had COVID-19 – Rishi Goel, an immunologist at the University of Pennsylvania in Philadelphia
Booster benefits now the most talked science
“A third vaccine dose might allow people who haven’t been infected to achieve the benefits of hybrid immunity.” -Matthieu Mahévas, an immunologist at the Necker Institute for Sick Children in Paris.
Extending the interval between vaccine doses could also mimic aspects of hybrid immunity.
The tale of two walls
- The most talked science today is hybrid immunity.
- It is, at least partly, due to immune players called memory B cells.
- The bulk of antibodies made after infection or vaccination come from short-lived cells called plasmablasts.
- Antibody levels fall when plasmablasts inevitably die off.
- Once plasmablasts are gone, the main source of antibodies becomes much rarer memory B cells.
- B cells are triggered by either infection or vaccination.
What a new randomized trial points?
- No hospitalisations occurred in the “regular” 2-dose vaccine group (N = 5044) in the 1st randomised trial of booster. In spite of the fact that 44% people in the study were over age 55.
- This means 2nd dose was enough to protect against severe disease.
- Overall “infection rate” (number of people testing positive for virus in their nose or throat) was predictably lower soon after the 3rd dose (this is expected after bump in antibodies). Naturally, more infections means more severe disease, but the point is that the proportion (%) does not change. Non-pharma interventions are effective at reducing total number of infections too.
- See my diagrams.
- The “second wall” of immunity (T cell immunity) prevents organ damage, ‘maxes out’ at 2nd dose. In other words, this part of immunity does not decline and cannot be “topped up.” (As far as current evidence and understanding goes).
- Note that a randomised trial is the most powerful evidence one can get on this topic, unlike observational studies that are prone to error from multiple (known and unknown) confounding factors.
Study Design C4591031
- Recruited approximately 10,000 participants ≥16 years of age who completed a 2 dose primary series of BNT162b2 30 µg in Study C4591001
- Randomized at a 1:1 ratio into Study C4591031 to receive either a booster dose of BNT162b2 30 µg or a placebo dose at least 6 months after the second dose.
- Randomization was stratified by age, such that approximately 60% of participants enrolled would be ≥16 to 55 years of age and approximately 40% of participants >55 years of age.
- Assessments include safety evaluations of adverse events and COVID-19 case surveillance for booster efficacy estimation after the booster dose.
- Reactogenicity data were not collected in this study but booster reactogenicity was reported from study 1001 S.
What was safety profile?
See the Curve diverge rapidly, starting even before 7 days of booster
Conclusions worth Pondering
CME INDIA Learning Points
(by Dr. Rajeev Jayadevan)
- Point No 1: Unvaccinated people were 10 times more likely to test positive compared to fully vaccinated: analysis of Kerala data from 13 November If we take 100,000 Kerala adults, only 4500 are unvaccinated. 60,000 are fully vaccinated. Out of 5429 adult cases, 35% were unvaccinated; 45% were fully vaccinated. Note the denominators are different for both of these i.e. 35% cases arose out of only the 4.5% unvaccinated population, while the 45% arose among the fully vaccinated 60%. The difference was 10-fold.
- Point No 2: Waning of immunity is a serious issue.
- Point No 3: Booster appear to be the need of the hour.
- Point No 4: New RCT result confirms that adding a 3rd dose is only effective in strengthening the “first wall” of immunity (reduces no. of infections).
CME INDIA Tail Piece
- Vaccines never promised to interrupt transmission. They prevent severe disease and death.
- Clear messaging from WHO Regional Director for Europe, Dr. Hans Kluge
- Vaccination increases all components of the humoral response.
- The mechanism underlying broad-based responses involves ongoing antibody somatic mutation, memory B cell clonal turnover, and development of monoclonal antibodies that are exceptionally resistant to SARS-CoV-2 RBD mutations, including those found in variants of concern.
- B cell clones expressing broad and potent antibodies are selectively retained in the repertoire over time and expand dramatically after vaccination. The data suggest that immunity in convalescent individuals will be very long lasting and that convalescent individuals who receive available mRNA vaccines will produce antibodies and memory B cells that should be protective against circulating SARS-CoV-2 variants. (4)
- “Whatever the potential benefits — the risks of a SARS-CoV-2 infection mean that it should be avoided. “We are not inviting anybody to get infected and then vaccinated to have a good response. Because some of them will not make it through.”– Finzi.
- Efficacy & Safety of BNT162b2 booster – C4591031 2 month interim analysis John L. Perez, MD, MBA, MA Pfizer, Vice President Vaccine Clinical Research & Development 19 November 2021
- Nordström, Peter and Ballin, Marcel and Nordström, Anna, Effectiveness of Covid-19 Vaccination Against Risk of Symptomatic Infection, Hospitalization, and Death Up to 9 Months: A Swedish Total-Population Cohort Study. Available at SSRN: https://ssrn.com/abstract=3949410 or http://dx.doi.org/10.2139/ssrn.3949410
- Wang, Z., Muecksch, F., Schaefer-Babajew, D. et al. Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection. Nature 595,426–431 (2021). https://doi.org/10.1038/s41586-021-03696-9
- COVID super-immunity: one of the pandemic’s great puzzles.Nature 598, 393-394 (2021)doi: https://doi.org/10.1038/d41586-021-02795-x
- Nature 597, 606-607 (2021)doi: https://doi.org/10.1038/d41586-021-02532-4
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