Background Despite high vaccine coverage and effectiveness, the incidence of symptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been increasing in Israel. Whether the increasing incidence of infection is due to waning immunity after the receipt of two doses of the BNT162b2 vaccine is unclear. Methods We conducted a 6-month longitudinal prospective study involving vaccinated health care workers who were tested monthly for the presence of anti-spike IgG and neutralizing antibodies. Linear mixed models were used to assess the dynamics of antibody levels and to determine predictors of antibody levels at 6 months. Results The study included 4868 participants, with 3808 being included in the linear mixed-model analyses. The level of IgG antibodies decreased at a consistent rate, whereas the neutralizing antibody level decreased rapidly for the first 3 months with a relatively slow decrease thereafter. Although IgG antibody levels were highly correlated with neutralizing antibody titers (Spearman’s rank correlation between 0.68 and 0.75), the regression relationship between the IgG and neutralizing antibody levels depended on the time since receipt of the second vaccine dose. Six months after receipt of the second dose, neutralizing antibody titers were substantially lower among men than among women (ratio of means, 0.64; 95% confidence interval [CI], 0.55 to 0.75), lower among persons 65 years of age or older than among those 18 to less than 45 years of age (ratio of means, 0.58; 95% CI, 0.48 to 0.70), and lower among participants with immunosuppression than among those without immunosuppression (ratio of means, 0.30; 95% CI, 0.20 to 0.46). Conclusions Six months after receipt of the second dose of the BNT162b2 vaccine, humoral response was substantially decreased, especially among men, among persons 65 years of age or older, and among persons with immunosuppression.

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.

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Background Concurrent with the Pfizer–BioNTech BNT162b2 COVID-19 vaccine roll-out in Israel initiated on Dec 19, 2020, we assessed the early antibody responses and antibody kinetics after each vaccine dose in health-care workers of different ages and sexes, and with different comorbidities. Methods We did a prospective, single-centre, longitudinal cohort study at the Sheba Medical Centre (Tel-Hashomer, Israel). Eligible participants were health-care workers at the centre who had a negative anti-SARS-CoV-2 IgG assay before receiving the first dose of the intramuscular vaccine, and at least one serological antibody test after the first dose of the vaccine. Health-care workers with a positive SARS-CoV-2 PCR test before vaccination, a positive anti-SARS-CoV-2 IgG serology test before vaccination, or infection with COVID-19 after vaccination were excluded from the study. Participants were followed up weekly for 5 weeks after the first vaccine dose; a second dose was given at week 3. Serum samples were obtained at baseline and at each weekly follow-up, and antibodies were tested at 1–2 weeks after the first vaccine dose, at week 3 with the administration of the second vaccine dose, and at weeks 4–5 (ie, 1–2 weeks after the second vaccine dose). Participants with comorbidities were approached to participate in an enriched comorbidities subgroup, and at least two neutralising assays were done during the 5 weeks of follow-up in those individuals. IgG assays were done for the entire study population, whereas IgM, IgA, and neutralising antibody assays were done only in the enriched comorbidities subgroup. Concentrations of IgG greater than 0·62 sample-to-cutoff (s/co) ratio and of IgA greater than 1·1 s/co, and titres of neutralising antibodies greater than 10 were considered positive. Scatter plot and correlation analyses, logistic and linear regression analyses, and linear mixed models were used to investigate the longitudinal antibody responses. Findings Between Dec 19, 2020, and Jan 30, 2021, we obtained 4026 serum samples from 2607 eligible, vaccinated participants. 342 individuals were included in the enriched comorbidities subgroup. The first vaccine dose elicited positive IgG and neutralising antibody responses at week 3 in 707 (88·0%) of 803 individuals, and 264 (71·0%) of 372 individuals, respectively, which were rapidly increased at week 4 (ie, 1 week after the second vaccine dose) in 1011 (98·4%) of 1027 and 357 (96·5%) of 370 individuals, respectively. Over 4 weeks of follow-up after vaccination, a high correlation ( r =0·92) was detected between IgG against the receptor-binding domain and neutralising antibody titres. First-dose induced IgG response was significantly lower in individuals aged 66 years and older (ratio of means 0·25, 95% CI 0·19–0·31) and immunosuppressed individuals (0·21, 0·14–0·31) compared with individuals aged 18·00–45·99 years and individuals with no immunosuppression, respectively. Thi...

BACKGROUND The repeated waves of the COVID-19 pandemic have highlighted the necessity to optimize vaccine responses in immunocompromised populations. We investigated the safety and immunogenicity of a third, booster, dose of the Pfizer BNT162b2 vaccine in heart transplant (HT) patients. METHODS The cohort comprised 96 adult HT patients who received a third homologous dose of the BNT162b2 vaccine 168 days after the second dose. The vaccine-induced antibody responses of both receptor-binding domain (RBD) IgG and neutralizing antibodies were assessed in all patients, with a positive antibody response being defined as the presence of either IgG anti-RBD or neutralizing antibodies. For a subset of patients, T cell response was also studied. RESULTS The third dose was associated with a low rate of adverse events, mostly mild pain at the injection site. No serious adverse events were recorded, and there were no episodes of rejection. At 18 days following the third dose of the vaccine, the positive antibody response increased from 23% to 67%, with a corresponding increase in neutralizing capacity. The third dose elicited SARS-CoV-2 neutralization titers >9-fold and IgG anti-RBD antibodies >3-fold of the range achieved after the two primary doses. Mycophenolate use, lower eGFR and higher C-reactive protein were independently associated with a reduced likelihood of generating an immune response. Importantly, a specific T-cell response following the third dose was evident in the majority of transplant recipients. CONCLUSIONS An homologous third booster dose of the BNT162b2 vaccine gave overall consistent tolerability and a good safety profile, while eliciting humoral and cellular immune responses.

Background: An Israeli national taskforce performed a multi-center clinical and analytical validation of seven serology assays to determine their utility and limitations for SARS-CoV-2 diagnosis. Methods: Serology assays from Roche, Abbott, Diasorin, BioMerieux, Beckman-Coulter, Siemens, and Mt.-Sinai ELISA were included. Negative samples from 2391 individuals representative of the Israeli population, and 698 SARS-CoV-2 PCR positive patients, collected between March and May 2020, were analyzed Findings: Immunoassays sensitivities between 81.5%-89.4% and specificities between 97.7%-100% resulted in a profound impact on the expected Positive Predictive Value (PPV) in low (<15%) prevalence scenarios. No meaningful increase was detected in the false positive rate in children compared to adults. A positive correlation between disease severity and antibody titers, and no decrease in antibody titers in the first 8 weeks after PCR positivity was observed. We identified a subgroup of symptomatic SARS-CoV-2 positive patients (~5% of patients), who remained seronegative across a wide range of antigens, isotypes, and technologies. Interpretation: wThe commercially available automated immunoassays exhibit significant differences in performance and expected PPV in low prevalence scenarios. The low false-positivity rate in under 20 0 s suggests that cross-reactive immunity from previous CoV strains is unlikely to explain the milder disease course in children. Finding no decrease in antibody titers in the first 8 weeks is in contrast to some reports of short half-life for SARS-CoV-2 antibodies. The~5% who were seronegative non-responders, using multiple

Objectives The immunogenicity and safety of the Pfizer-BioNTech BNT162b2 mRNA vaccine in people living with HIV-1 (PLWH) are unknown. We thus aimed to assess the immunogenicity and safety of this vaccine in PLWH. Methods In this prospective open study, we enrolled 143 PLWH, aged ≥18 years, who attended our clinic and 261 immunocompetent health care workers (HCWs). SARS-CoV-2 receptor binding domain (RBD) IgG and neutralizing antibodies were measured. Adverse events, viral load and CD4 cell counts were monitored. Results At a median of 18 days (IQR 14-21) after the second dose, anti-RBD IgG was positive in 139/141 (98%) PLWH. Among HCWs, 258/261 (98.9%) developed anti-RBD IgG at a median of 26 (IQR 24-27) days after the second dose. Following the second dose, immune sera neutralized SARS-CoV-2 pseudo-virus in 97% and 98% of PLWH and HCW, respectively. Adverse events were reported in 60% of PLWH, mainly pain at the injection site, fatigue, and headache. AIDS-related adverse events were not reported. HIV viral load increased in 3/143 (2%) patients from < 40 copies/mL to ≤ 100 copies/mL. CD4+ T cell count decreased from a geometric mean of 700 (95% CI 648–757) cells per μL to 633.8 (95% CI 588–683) cells per μL (P<0.01). Conclusions BNT162b2 mRNA vaccine appears immunogenic and safe in PLWH who are on ART with unsuppressed CD4 count and suppressed viral load.

Data on the safety and efficacy of SARS-CoV-2 vaccines in immunocompromised populations are sparse. We conducted a prospective study of 77 heart transplant (HT) recipients vaccinated with two doses of BNT162b2 vaccine and monitored for adverse events following both doses, the receptor-binding domain (RBD) IgG response, and neutralizing antibodies. BNT162b2 vaccination was associated with a low rate of adverse events, characterized mostly by pain at the injection site. By a mean 41 days post second dose there were no clinical episodes of rejection, as suggested by a troponin leak or allograft dysfunction. At a mean 21 days following the second dose, IgG anti-RBD antibodies were detectable in 14 (18%) HT recipients. Immune sera neutralized SARS-CoV-2 pseudo-virus in 8 (57%) of those with IgG anti-RBD antibodies. Immunosuppressive regimen containing mycophenolic acid was associated with lower odds of an antibody response (OR=0.12, P=0.042). Whether a longer time-frame for observation of an antibody response is required after vaccination in immunosuppressed individuals remains unknown.