Vaccine and Hybrid Immunogenicity after Three or Four Doses of BNT162b2 - Results from 22 Months Follow-Up of a Healthcare Workers Cohort, Israel, 2020-2022 (preprint)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global health concern three years after its emergence. Safe and effective vaccines mitigate the pandemic impact but the optimal schedule remains unclear especially in a context where a high proportion of the population was infected.Methods: We periodically measured anti-spike SARS-CoV-2 IgG titres using a quantitative assay in an Israeli healthcare worker cohort who all received at least two BNT162b2 doses and either received further doses and/or were subsequently infected, up to 22 months post-dose two, and compared geometric mean concentrations according to number of doses received and infection status using Kruskall-Wallis tests.Findings: Among the 993 included participants, infection post-dose two led to higher GMC IgG titres than a third dose (4285 vs 2845 AU/ml one-two months post-infection/vaccination, p=0·03). IgG increase 1-2 months post-dose 4 was similar to infection post-dose 3 (2804 vs 3131 AU/ml, p=0.76) but more transient. 16-18 months post-dose two, those infected and those who received three or four vaccine doses all had IgG GMC levels above 1000 AU/ml with no significant differences among groups (p=0·36). IgG levels plateaued 16-22 months post-dose two.Interpretation: Three BNT162b2 doses provide long-term immunogenicity comparable to breakthrough infection post-dose two. Dose four transiently increases IgG levels and may be especially important for providing additional protection to vulnerable individuals during periods of increased transmission risk.Funding: This study was partially funded by the Russell Berrie Foundation through a non-committed research grant to Ziv Medical Centre.Declaration of Interest: All authors declare that there are no any actual or potential conflict of interest including financial, personal or any other relationships with other people or organizations.Ethical Approval: The study was approved by ZMC’s ethics committee (0133-20-ZIV). Written consent was obtained from all participants.

Associations Between Reported Post-COVID-19 Symptoms and Subjective Well-Being, Israel, July 2021 -April 2022 (preprint)

The impact of individual symptoms reported post-COVID-19 on subjective well-being (SWB) is unknown. We described associations between SWB and selected reported symptoms following SARS-CoV-2 infection. We analysed reported symptoms and subjective well being from 2295 participants (of which 576 reporting previous infection) in an ongoing longitudinal cohort study taking place in Israel. We estimated changes in SWB associated with reported selected symptoms at three follow-up time points (3-6, 6-12, and 12-18 months post infection) among participants reporting previous SARS-CoV-2 infection, adjusted for key demographic variables, using linear regression. Our results suggest that the biggest and most sustained changes in SWB stems from non-specific symptoms (fatigue -7.7 percentage points (pp), confusion/ lack of concentration -10.7 pp, and sleep disorders -11.5pp, p<0.005), whereas the effect of system-specific symptoms, such as musculoskeletal symptoms (weakness in muscles and muscle pain) on SWB, are less profound and more transient. Taking a similar approach for other symptoms and following individuals over time to describe trends in SWB changes attributable to specific symptoms will help understand the post-acute phase of COVID-19 and how it should be defined and better managed.

Association between vaccination status and reported incidence of post-acute COVID-19 symptoms in Israel: a cross-sectional study of patients tested between March 2020 and November 2021 (preprint)

Background Long COVID is a post-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection syndrome characterised by not recovering for several weeks or months following the acute episode. The effectiveness of COVID-19 vaccines against long-term symptoms of COVID-19 is not well understood. We determined whether vaccination was associated with the incidence of reporting long-term symptoms post-SARS-CoV-2 infection Methods We invited individuals who were PCR tested for SARS-CoV-2 infection at participating hospitals between March 2020-November 2021 to fill an online questionnaire that included baseline demographics, details of their acute episode and information about symptoms they were currently experiencing. Using binomial regression, we compared vaccinated individuals with those unvaccinated and those uninfected in terms of self-reported symptoms post-acute infection. Results We included 951 infected and 2437 uninfected individuals. Of the infected, 637(67%) were vaccinated. The most commonly reported symptoms were; fatigue (22%), headache (20%), weakness (13%), and persistent muscle pain (10%). After adjusting for follow-up time and baseline symptoms, those who received two doses less likely than unvaccinated individuals to report any of these symptoms by 64%, 54%, 57%, and 68% respectively, (Risk ratios 0.36, 0.46, 0.43, 0.32, p<0.04 in the listed sequence). Those who received two doses were no more likely to report any of these symptoms than individuals reporting no previous SARS-CoV-2 infection. Conclusions Vaccination with at least two doses of COVID-19 vaccine was associated with a substantial decrease in reporting the most common post-acute COVID-19 symptoms, bringing it back to baseline. Our results suggest that, in addition to reducing the risk of acute illness, COVID-19 vaccination may have a protective effect against long COVID.

Protective effect of BNT162b2 vaccination on aerobic capacity following mild to moderate SARS-CoV-2 infection: a cross sectional study, Israel, March-December 2021 (preprint)

We compared 23 unvaccinated to 15 vaccinated patients previously infected with SARS-CoV-2 in terms of their aerobic capacity measured by a cardio pulmonary exercise test (CPET). Compared with unvaccinated individuals, those vaccinated had a higher heart rate, higher VO2. Our results suggest objective limitations to exercise capacity in the months following acute COVID19 illness, mitigated by vaccination

Antibody-mediated Immunogenicity against SARS-CoV-2 following priming, boosting and hybrid immunity: insights from 11 months of follow-up of a healthcare worker cohort in Israel, December 2020-October 2021 (preprint)

Background We determined circulating anti-S SARS-CoV-2 IgG antibody titres in a vaccinated healthcare workers (HCWs) cohort from Northern Israel in the 11 months following primary vaccination according to age, ethnicity, boosting timing and previous infection status. Methods All consenting HCWs were invited to have their circulating IgG levels measured before vaccination and at 6 subsequent timepoints. All HCWs with suspected COVID-19 were PCR tested. We described trends in circulating IgG geometric mean concentration by age, ethnicity, timing of boosting and previous infection status and compared strata using Kruskall-Wallis tests. Results Among 985 vaccinated HCWs. IgG titres gradually decreased in all groups over the study duration. Younger or previously infected individuals had higher initial IgG levels (p<0.001 in both cases); differences substantially decreased or disappeared at 7-9 months, before boosting. Pre-infection IgG levels in infected participants were similar to levels measured at the same timepoint in HCWs who remained uninfected (p>0.3). IgG GMC in those boosted 6-7 months after dose 2 was lower compared with those boosted 8-9 months after (1999-vs 2736, p=0.02). Conclusions Immunity waned 6 months post-priming in all age groups and in previously infected individuals, reversed by boosting. IgG titres decrease among previously infected individuals and the proportion of reinfected individuals in this group, comparable to the proportion of breakthrough infection in previously uninfected individuals suggests individuals with hybrid immunity (infection+vaccination) may also require further doses. Our study also highlights the difficulty in determining protective IgG levels and the need to clarify the optimal timing in 3 dose regimens

SARS-CoV-2 Immunogenicity in individuals infected before and after COVID-19 vaccination: Israel, January-March 2021: Implications for vaccination policy (preprint)

Between December 2020-March 2021 we measured anti-SARS-CoV-2 IgG titers post-vaccination with the BNT162b2 vaccine among 725 Israeli hospital workers. Previously infected individuals who received one dose had higher IgG titres than fully vaccinated, never-infected workers. Post-vaccination infection did not increase IgG titres. Individuals infected post-dose one should receive the second.

Impact of age, gender, ethnicity and prior disease status on immunogenicity following administration of a single dose of the BNT162b2 mRNA Covid-19 Vaccine: real-world evidence from Israeli healthcare workers, December-January 2020 (preprint)

The Pfizer Covid-19 vaccine showed high efficacy in clinical trials but observational data from populations not included in trials are needed. We described immunogenicity 21 days post-dose 1 among 514 Israeli healthcare workers by age, gender, ethnicity and prior COVID19 infection. Immunogenicity was similar by gender and ethnicity but decreased with age. Those with prior infection had antibody titres one magnitude order higher than naive individuals regardless of the presence of detectable IgG antibodies pre-vaccination.