Durability of the immune response to a third BNT162b2 dose; five months follow-up (preprint)

BackgroundTwo doses of the BNT162b2 vaccine yielded high effectiveness that wanes within several months. The third dose was effective in mounting a significant humoral and cellular immune response.. MethodsWe followed BNT162b2-vaccinated health-care workers monthly for IgG and neutralizing antibody (NeutAb) titers. Avidity, T-cell activation and microneutralization of sera against different variants of concern (VOC) were assessed for a sub-cohort. Linear mixed models were used to compare the durability of the second and third doses, and to assess if Omicron breakthrough infections were associated with waning dynamics. ResultsOverall 3972 participants with a third dose were followed, the rate of waning of IgG and NeutAb was slower after the third (1.32%/day and 1.32%/day, respectively) compared to the second (2.26%/per day and 3.34%/day) dose. Live-neutralization of Omicron VOC was lower compared to previous strains and demonstrated similar waning from 111 (95%CI:75-166) to 26 (95%CI:16-42) within 4 months. Mean T cell activity decreased from 98{+/-}5.4 T cells/106 PBMC to 59{+/-}9.3, within 3-5 months. Omicron breakthrough infections were associated with lower IgG peak (ratio of means 0.86 95%CI 0.80-0.91), and among participants over 65y with faster waning of both IgG and NeutAb (ratio of mean rates 1.40 95% CI 1.13-1.68 and 3.58 95% CI 1.92-6.67). No waining in IgG avidity was obsereved during 112 days after the 3rd dose. ConclusionThe third dose is more durable than the second dose, yet Omicron is relatively resistant to direct neutralization. The level of humoral response may predict breakthrough infections.

Fourth Dose COVID mRNA Vaccines' Immunogenicity & Efficacy Against Omicron VOC (preprint)

BACKGROUND Following the emergence of the Omicron variant of concern, we investigated immunogenicity, efficacy and safety of BNT162b2 or mRNA1273 fourth dose in an open-label, clinical intervention trial. METHODS Primary end-points were safety and immunogenicity and secondary end-points were vaccine efficacy in preventing SARS-CoV-2 infections and COVID-19 symptomatic disease. The two intervention arms were compared to a matched control group. Eligible participants were healthcare-workers (HCW) vaccinated with three BNT162b2 doses, and whose IgG antibody levels were [≤]700 BAU (40-percentile). IgG and neutralizing titers, direct neutralization of live VOCs, and T-cell activation were assessed. All participants were actively screened for SARS-CoV-2 infections on a weekly basis. RESULTS Of 1050 eligible HCW, 154 and 120 were enrolled to receive BNT162b2 and mRNA1273, respectively, and compared to 426 age-matched controls. Recipients of both vaccine types had a ~9-10-fold increase in IgG and neutralizing titers within 2 weeks of vaccination and an 8-fold increase in live Omicron VOC neutralization, restoring titers to those measured after the third vaccine dose. Breakthrough infections were common, mostly very mild, yet, with high viral loads. Vaccine efficacy against infection was 30% (95%CI:-9% to 55%) and 11% (95%CI:-43% to +43%) for BNT162b2 and mRNA1273, respectively. Local and systemic adverse reactions were reported in 80% and 40%, respectively. CONCLUSIONS The fourth COVID-19 mRNA dose restores antibody titers to peak post-third dose titers. Low efficacy in preventing mild or asymptomatic Omicron infections and the infectious potential of breakthrough cases raise the urgency of next generation vaccine development.

Superior immunogenicity and effectiveness of the 3rd BNT162b2 vaccine dose (preprint)

In a prospective cohort study involving 12,413 Health Care Workers (HCW), we assessed immunogenicity, vaccine-effectiveness (VE) and safety of the third BNT162b2 vaccine dose. One month after third dose, anti-RBD-IgG were induced 1.7-folds compared to one month after the second. A significant increase in avidity from 61.1% (95%CI:56.1-66.7) to 96.3% (95%CI:94.2-98.5) resulted in a 6.1-folds neutralizing antibodies induction. Linear mixed model demonstrated that the third dose elicited a greater response among HCW[≥]60 or those with [≥]two comorbidities who had a lower response following the second dose. VE of the third dose relative to two doses was 85.6% (95% CI, 79.2-90.1%). No serious adverse effects were reported. These results suggest that the third dose is superior to the second dose in both quantity and quality of IgG-antibodies and safely boosts protection from SARS-CoV-2 infection by generating high avidity antibodies to levels that are not significantly different between healthy and vulnerable populations.

BNT162b2 Vaccination efficacy is marginally affected by the SARS-CoV-2 B.1.351 variant in fully vaccinated individuals (preprint)

ABSTRACT Background Israeli has vaccinated over 80% of its adult population, with two doses of the Pfizer BNT162b2 vaccine. This intervention has been highly successful in curtailing the coronavirus 2 outbreak. One major concern is the ability of the virus to mutate which potentially can cause SARS-CoV-2 to partially escape from the immune system. Here we evaluate the efficacy of the Pfizer vaccine against the B.1.351 variant. Methods The Ministry of Health, initiated sequencing of selected positive swab samples identified as being of interest. We used logistic regression, with variant type as the dependent variable, vaccination status as the main explanatory variable, controlling for age, sex, subpopulation, place of residence and time of sample, to estimate the odds ratio for a vaccinated case to have the B. 1.351 versus the B.1.1.7 variant, within vaccinated and unvaccinated persons who tested positive. Findings There were 19 cases of B.1.351 variant (3.2%) among those vaccinated more than 14 days before the positive sample and 88 (3.5%) among the unvaccinated. The estimated odds ratio was 1.29 [95% CI: 0.66-2.50]. From this result, assuming the efficacy against the B.1.1.7 variant to be 95%, the estimated efficacy against the B.1.351 variant was 94% [95% CI: 87-97%]. Interpretation Despite the concerns caused by the B.1.351 variant, the BNT162b2 vaccine seems to provide substantial immunity against both that variant and the B.1.1.7. Our results suggest that from 14 days following the second vaccine dose the efficacy of BNT162b2 vaccine is at most marginally affected by the B.1.351 variant. Funding No funding

BNT162b2 Vaccination Efficacy is Marginally Affected by the SARS-CoV-2 B.1.351 Variant in Fully Vaccinated Individuals (preprint)

Background: Israeli has vaccinated over 80% of its adult population, with two doses of the Pfizer BNT162b2 vaccine. This intervention has been highly successful in curtailing the coronavirus 2 outbreak. One major concern is the ability of the virus to mutate which potentially can cause SARS-CoV-2 to partially escape from the immune system. Here we evaluate the efficacy of the Pfizer vaccine against the B.1.351 variant.Methods: The Ministry of Health, initiated sequencing of selected positive swab samples identified as being of interest. We used logistic regression, with variant type as the dependent variable, vaccination status as the main explanatory variable, controlling for age, sex, subpopulation, place of residence and time of sample, to estimate the odds ratio for a vaccinated case to have the B. 1.351 versus the B.1.1.7 variant, within vaccinated and unvaccinated persons who tested positive.Findings: There were 19 cases of B.1.351 variant (3.2%) among those vaccinated more than 14 days before the positive sample and 88 (3.5%) among the unvaccinated. The estimated odds ratio was 1.29 [95% CI: 0.66-2.50]. From this result, assuming the efficacy against the B.1.1.7 variant to be 95%, the estimated efficacy against the B.1.351 variant was 94% [95% CI: 87-97%].Interpretation: Despite the concerns caused by the B.1.351 variant, the BNT162b2 vaccine seems to provide substantial immunity against both that variant and the B.1.1.7. Our results suggest that from 14 days following the second vaccine dose the efficacy of BNT162b2 vaccine is at most marginally affected by the B.1.351 variant.Funding Information: No funding.Declaration of Interests: I confirm that none of the authors has related work submitted to another journal and that none have any conflict of interest regarding the content of the manuscript.

Protection of previous SARS-CoV-2 infection is similar to that of BNT162b2 vaccine protection: A three-month nationwide experience from Israel (preprint)

Worldwide shortage of vaccination against SARS-CoV-2 infection while the pandemic is still uncontrolled leads many states to the dilemma whether or not to vaccinate previously infected persons. Understanding the level of protection of previous infection compared to that of vaccination is critical for policy making. We analyze an updated individual-level database of the entire population of Israel to assess the protection efficacy of both prior infection and vaccination in preventing subsequent SARS-CoV-2 infection, hospitalization with COVID-19, severe disease, and death due to COVID-19. Vaccination was highly effective with overall estimated efficacy for documented infection of 92·8% (CI:[92·6, 93·0]); hospitalization 94·2% (CI:[93·6, 94·7]); severe illness 94·4% (CI:[93·6, 95·0]); and death 93·7% (CI:[92·5, 94·7]). Similarly, the overall estimated level of protection from prior SARS-CoV-2 infection for documented infection is 94·8% (CI:[94·4, 95·1]); hospitalization 94·1% (CI:[91·9, 95·7]); and severe illness 96·4% (CI:[92·5, 98·3]). Our results question the need to vaccinate previously-infected individuals.