21 Sept Episode 175 Is immunity after vaccination waning?

Ep 175-1: A very nice “News Explainer” of 17 Sept concludes that there is evidence of waning immunity after 6 + months, but that, provisionally it is probably not worrying enough to hurry for a third dose for the general population. 

Below I will discuss some of their references, along with others.  

Data from UK

Ep 175-2 : Antonelli in one of these huge British population studies (Lancet Infect Dis) on 1.24 million vaccinated subjects in a community-based nested case-control setting between Dec 2020 and July 2021, using self-reported data by an app:

• Very few subjects got a documented SARS-CoV-2 infection: 0.5 % after the first and 0.2 % after the second dose.
• Risk factors:  frail, older adults and those living in more deprived areas,
• Fully vaccinated more likely asymptomatic, less likely to have > 5 symptoms, to be hospitalized or present “long COVID (> 28 days).

The authors  support maintaining personal protective measures especially in old, frail and deprived subjects, even if fully vaccinated. 

Clearly, follow-up for most individuals was less than 6 months.

Ep 175-3: Very nice longitudinal study (preprint) by Andrews in a test-negative case control design. (Test-negative studies recruit cases who attend a healthcare facility and test positive for a particular disease; controls are patients undergoing the same tests for the same reasons at the same healthcare facility and who test negative.  For more info on this design see https://pubmed.ncbi.nlm.nih.gov/31430265/  ).

As you can see in Fig 1 p. 7, there is indeed some waning, which is more pronounced for Astra-Zeneca than for Pfizer, especially after week 20.  As expected, waning was most pronounced for 65 + and 40-65 years old with underlying conditions, while in healthy subjects, including older ones, waning was very limited.

Data from Israel

Ep 175-4: Goldberg in medRxiv used all PCR(+) data from the Ministry and checked for disease severity and date of vaccination (only Pfizer was used).

• Fig 3 shows clear waning of protection against infection in all age groups
• Fig 4 shows clear waning of protection against severe disease but only in 60 + group

The waning in Israel at first view looks much more impressive than in UK.  The difference in set-up is that in the Israeli study only the vaccinated subjects are considered in function of time, so no direct comparison with unvaccinated as is done in UK.  This is important in view of the switch from alpha to delta variant during the observation period. The explanation given is that unvaccinated subjects are less well documented in Israel….

Nevertheless, the authors present a small sub-analysis in the Discussion:  The efficacy of the vaccine against severe disease for the 60+ age group decreases; from 91% to 86% between those vaccinated four months to those vaccinated six months before the study. The corresponding efficacies for the 40-59 age group are 98% and 94%. Thus, the vaccine seems to be highly effective even after six months compared to the unvaccinated population….

Clearly, this conclusion is more in line with the UK data.

Ep 175-5: Bar-On on the effect of a third dose (booster) in 60+, which administered from 30 July in a part of this population, provided that they received their second dose at least 5 months earlier. The analysis is based on 1 month observation (August 2021), comparing the persons who received a third dose versus those who did not.

Table 2 and Fig 2 show that at least 12 days after the booster and compared to non-booster:

• Confirmed infection rate drops by a factor 11
• Severe disease drops by a factor 19

The authors admit that confounding and detection bias may have contributed to the observed reduction in the infection rate.  Nevertheless, the booster seems beneficial in this age group.

Data from QATAR

Ep 175-6:  Chemaitelly in medRxiv of 27 August, a matched negative case-control approach comparing > 140,000 Pfizer vaccinated and non-vaccinated subjects.  The effectiveness of Pfizer against infection and any symptomatic infection also seems to wane strongly from 15 weeks after the second dose, while protection against severe disease and death only shows a non-significant decrease after 25 weeks (see Fig 2 p. 25).  In this study, only a small minority of participants was over 60 (Table 1 p. 23).

Data from US

Ep 175-7: Puranik in medRxiv of 7 Sept also reports on a test negative case control study on > 70,000 subjects vaccinated with Pfizer of all ages: clear-cut, but limited waning

• The adjusted odds of symptomatic infection were higher 120 days after full vaccination versus at the date of full vaccination (Odds Ratio [OR]: 3.21, 95% confidence interval [CI]: 1.33-7.74).
• However, the odds of infection were still lower 150 days after the first BNT162b2 dose as compared to 4 days after the first dose (OR: 0.3, 95% CI: 0.19-0.45), when immune protection approximates the unvaccinated status.
• Low rates of COVID-19 associated hospitalization or death in this cohort precluded analyses of these severe outcomes.

Ep 175-8: Pegu in Science 17 Sept reports on antibodies, elicited by Moderna (RNA 1273) vaccination: a clearly decreasing trend in all functional assays (including neutralization), with known differences between variants of concern (beta variant most resistant), but still detectable Ab after 6 months.  A small study, without clinical data.   

Data from Estonia

Ep 175-9: Naaber in Lancet Eur Reg Health reports on evolution of immune responses after full Pfizer:

• Spike-antibody responses similar evolution as described in Ep 175-7: clear waning after 6 months, but still at level of COVID 19-convalescent patients.  
• Antibody titers correlated positively with side effects of vaccine and negatively with age (most probably interdependent, as no multivariate done)
• .
• T cell responses evaluated at 3 months after vaccination:  
  • 87% of vaccinated individuals developed either CD4+ or CD8+ T cell responses.
  • CD4+ T cell response was decreased among vaccinated individuals with elevated levels of senescent CD8+ TEMRA cells

More fundamental work with regard to immunity

Ep 175-10: Lederer already in Dec 2020 Immunity on the importance of Germinal Center (GC) activation in lymphoid organs: GCs are microanatomical sites harboring the formation of high-quality, protective antibody responses by the interaction of follicular dendritic cells (who keep the viral antigen ready for presentation  to both T follicular helper (Tfh) and follicular B cells.  The latter then proliferate and  “mature” (gain affinity by somatic mutation) and switch class to IgG.

• Nucleoside-modified SARS-CoV-2 mRNA vaccines (such as Pfizer and Moderna) promote potent Germinal Center (GC) formation, whereas protein rRBD (recombinant receptor binding domain) vaccine formulated in AddaVax fails to trigger robust primary GC Responses.
• mRNA vaccines induce GC B and T follicular helper (Tfh) cell responses as well as long-lived plasma cells and memory B cells
• Importantly, GC responses strongly correlated with neutralizing antibody production

Ep 175-11: Duan in Current Medical Sciences presents a small series of 6 deceased COVID patients, compared with 4 “controls” ( focal organizing pneumonia).  They show:

• Absence of T follicukar helper cells and germinal centers in the lung hilus lymph nodes of deceased COVID.
• Reduced IgM and IgG levels compared to convalescent COVID-19 patients

Ep 175-12: Kaneko et al describe a specific block in germinal center type Bcl-6+ T follicular helper cell differentiation explains the loss of germinal centers and the accumulation of non-germinal center derived activated B cells. These data provide a mechanism for the lower quality and lack of durability of humoral immune responses observed during natural infection with SARS-CoV-2, since activation of B cells outside the context of GC results in low affinity antibodies and poor memory B cells.

Ep 175-13: Hoehn et al in J Immunol provide evidence that there is a clear distinction in B cell maturation and repertoire in  severe versus mild COVID:

• In severe COVID germinal centers are disrupted and therefore B cell response occurs outside of lymph follicles with resulting low quality antibodies (not “matured”, low affinity, no strong memory B cells).
• Mildly symptomatic COVID-19 have B cell repertoires enriched for clonally diverse, somatically hypermutated high quality memory B cells _30 d after the onset of symptoms. 

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Ep 175-14: Niedleman conducted a longitudinal study of T cells in infection-naive and COVID-19 convalescent donors before vaccination and after their first and second vaccine doses.

• Spike-specific T cells from convalescent vaccinees differed strikingly from those of infection-naive vaccinees: phenotypic features suggesting superior long-term persistence and ability to home to the respiratory tract including the nasopharynx.
• Vaccine-elicited spike-specific T cells responded similarly to stimulation by spike epitopes from the ancestral, B.1.1.7 and B.1.351 variant strains

Ep 175-15: Rella in Sci Rep modeling the importance of maintaining non-pharmacological interventions even after vaccination to avoid emergence of new resistant strains.  

… the highest risk of resistant strain establishment occurs when a large fraction of the population has already been vaccinated but the transmission is not controlled.

One simple specific recommendation is to keep transmission low even when a large fraction of the population has been vaccinated by implementing acute non-pharmaceutical interventions (i.e. strict adherence to social distancing) for a reasonable period of time, to allow emergent lineages of resistant strains to go extinct through stochastic genetic drift.

Without global coordination, vaccine resistant strains may be eliminated in some populations but could persist in others. Thus, a truly global vaccination effort may be necessary to reduce the chances of a global spread of a resistant strain.

General Conclusion:

• T and B cells of high quality are induced by vaccination (and after mild disease).  Germinal centers in lymph nodes are instrumental in this process.  GC deficiency or dysfunction may have an important role in the immunopathogenesis of severe COVID.
• The decrease of spike-specific and neutralizing antibodies in the blood, months after vaccination is a normal phenomenon.  The important question is how quickly the immune memory T and B cells can be activated by infection.
• Various studies in UK, Israel and US indicate that immune protection against infection and disease starts waning after 6 months, especially in older individuals (who are characterized by decreased capacity to mount high quality and persistent memory responses).
• A third dose of mRNA vaccine clearly boosts protection, even against delta variant.
• The discussion on whether, when and whom to provide a third dose is open, but it remains more important to provide a first and second dose to the Global South to control the pandemic and … to maintain a certain level of non-pharmacological interventions (NPI) in the North for a reasonable time.

The Global North has rushed to vaccinate those who are willing, but, unfortunately, vaccination levels are not high enough for herd immunity. In addition NPI are rapidly abandoned and the willingness to vaccinate the South is very limited. 

Hence, are we setting the scene for more transmissible/resistant/virulent variants?

Best wishes,

Guido