Assessing COVID-19 vaccination strategies in varied demographics using an individual-based model (preprint)

Background: New variants of SARS-CoV-2 are constantly discovered. Administration of COVID-19 vaccines and booster doses, combined with applications of non-pharmaceutical interventions (NPIs), is often used to prevent outbreaks of emerging variants. Such outbreak dynamics are further complicated by the population's behavior and demographic composition. Hence, realistic simulations are needed to estimate the efficiency of proposed vaccination strategies in conjunction with NPIs. Methods: We developed an individual-based model of COVID-19 dynamics that considers age-dependent parameters such as contact matrices, probabilities of symptomatic and severe disease, and households' age distribution. As a case study, we simulate outbreak dynamics under the demographic compositions of two Israeli cities with different household sizes and age distributions. We compare two vaccination strategies: vaccinate individuals in a currently prioritized age group, or dynamically prioritize neighborhoods with a high estimated reproductive number. Total infections and hospitalizations are used to compare the efficiency of the vaccination strategies under the two demographic structures, in conjunction with different NPIs. Results: We demonstrate the effectiveness of vaccination strategies targeting highly infected localities and of NPIs actively detecting asymptomatic infections. We further show that there are different optimal vaccination strategies for each demographic composition of sub-populations, and that their application is superior to a uniformly applied strategy. Conclusion: Our study emphasizes the importance of tailoring vaccination strategies to subpopulations' infection rates and to the unique characteristics of their demographics (e.g., household size and age distributions). The presented simulation framework and our findings can help better design future responses against the following emerging variants.

Initial protection against Omicron in children and adolescents by BNT162b2 (preprint)

BACKGROUND The BNT162b2 (Pfizer-BioNTech) 2-dose vaccine for children and the BNT162b2 3rd dose for adolescents were approved shortly before the Omicron outbreak in Israel. The effects of these vaccines on the rates of Omicron confirmed infection are not yet clear. METHODS We extracted data for the Omicron-dominated (sub-lineage BA.1) period December 26, 2021 through January 8, 2022. We compared rates of confirmed Covid-19 infection between children 5-10 years old 14-35 days after receiving the 2nd dose to an internal control group of children 3-7 days after receiving the 1st dose (when the vaccine is not yet effective). Similarly, we compared confirmed infection rates in adolescents 12-15 years old 14-60 days after receiving a booster dose to an internal control group of adolescents 3-7 days after receiving the booster dose. We used Poisson regression, adjusting for age, sex, socioeconomic status, calendar week, and exposure. RESULTS In the 5-10 age group, the estimated rate of confirmed infection was 2.3 fold (95% CI, 2.0 to 2.5) lower in the 2nd dose group than in the internal control group. In adolescents, the third dose decreased confirmed infection rates by 3.3-fold (95% CI, 2.8 to 4.0). CONCLUSIONS A recent 2-dose BNT162b2 vaccination in children and a recent booster dose in adolescents reduced the rate of confirmed infection compared to the respective internal control groups. Future studies are needed to assess the duration of this protection and protection against other outcomes such as PIMS and long-COVID.

Protection against omicron severe disease 0-7 months after BNT162b2 booster (preprint)

Following a rise in cases due to the delta variant and evidence of waning immunity after 2 doses of the BNT162b2 vaccine, Israel began administering a third BNT162b2 dose (booster) in July 2021. Recent studies showed that the 3rd dose provides a much lower protection against infection with the omicron variant compared to the delta variant and that this protection wanes quickly. In this study, we used data from Israel to estimate the protection of the 3rd dose against severe disease up to 7 months from receiving the booster dose. The analysis shows that protection conferred by the 3rd dose against omicron did not wane over a 7-month period and that a 4th dose further increased protection, with a severe disease rate approximately 3-fold lower than in the 3-dose cohorts.

Viral load dynamics of SARS-CoV-2 Delta and Omicron variants following multiple vaccine doses and previous infection (preprint)

An important , and often neglected, aspect of vaccine effectiveness is its impact on pathogen transmissibility, harboring major implications for public health policies. As viral load is a prominent factor affecting infectivity, its laboratory surrogate, qRT-PCR cycle threshold (Ct), can be used to investigate the infectivity-related component of vaccine effectiveness. While vaccine waning has previously been observed for viral load, during the Delta wave, it is yet unknown how Omicron viral load is affected by vaccination status, and whether vaccine-derived and natural infection protection are sustainable. By analyzing results of more than 460,000 individuals we show that while recent vaccination reduces Omicron viral load, its effect wanes rapidly. In contrast, a significantly slower waning rate is demonstrated for recovered COVID-19 individuals. Thus, while the vaccine is effective in decreasing morbidity and mortality, their relative minute effect on transmissibility and rapid waning call for reassessment of the scientific justification for "vaccine certificate", as it may promote false reassurance and promiscuous behavior.

Protection by 4th dose of BNT162b2 against Omicron in Israel (preprint)

BACKGROUND On January 2, 2022, Israel began administering a fourth dose of BNT162b2 vaccine (Pfizer-BioNTech) to people aged over 60 years and at-risk populations, who had received a third dose of vaccine at least 4 months earlier. The effect of the fourth dose on confirmed coronavirus 2019 disease (Covid-19) and severe illness are still unclear. METHODS We extracted data for the Omicron-dominated period January 15 through January 27, 2022, from the Israeli Ministry of Health database regarding 1,138,681 persons aged over 60 years and eligible for the fourth dose. We compared the rate of confirmed Covid-19 and severe illness between those who had received a fourth dose at least 12 days earlier, those who had received only three doses, and those 3 to 7 days after receiving the fourth dose. We used Poisson regression after adjusting for possible confounding factors. RESULTS The rate of confirmed infection was lower in people 12 or more days after their fourth dose than among those who received only three doses and those 3 to 7 days after vaccination by factors of 2.0 (95% confidence interval [CI], 2.0 to 2.1) and 1.9 (95% CI, 1.8 to 2.0), respectively. The rate of severe illness was lower by factors of 4.3 (95% CI, 2.4 to 7.6) and 4.0 (95% CI, 2.2 to 7.5). CONCLUSIONS Rates of confirmed Covid-19 and severe illness were lower following a fourth dose compared to only three doses.

Protection following BNT162b2 booster substantially exceeds that of a fresh 2-dose vaccine: a quasi-experimental study (preprint)

Israel began administering a BNT162b2 booster dose to restore protection following the waning of the 2-dose vaccine. Biological studies have shown that a fresh booster leads to increased antibody levels compared to a fresh 2-dose vaccine, which may suggest increased effectiveness. To compare the real-world effectiveness of a fresh booster dose with that of a fresh 2-dose vaccine, we conduct a quasi-experimental study that compares populations that were eligible to receive the vaccine at different times due to age cutoff policies. Our analysis shows that a fresh booster increases protection against confirmed infection by 3.7 (95% CI: 2.7 to 5.2) fold compared to a fresh 2-dose vaccine.

Protection and waning of natural and hybrid COVID-19 immunity (preprint)

BACKGROUND Infection with SARS-CoV-2 provides substantial natural immunity against reinfection. Recent studies have shown strong waning of the immunity provided by the BNT162b2 vaccine. The time course of natural and hybrid immunity is unknown. METHODS Data on confirmed SARS-CoV-2 infections were extracted from the Israeli Ministry of Health database for the period August to September 2021 regarding all persons previously infected or vaccinated. We compared infection rates as a function of time since the last immunity-conferring event using Poisson regression, adjusting for possible confounding factors. RESULTS Confirmed infection rates increased according to time elapsed since the last immunity-conferring event in all cohorts. For unvaccinated previously infected individuals they increased from 10.5 per 100,000 risk-days for those previously infected 4-6 months ago to 30.2 for those previously infected over a year ago. For individuals receiving a single dose following prior infection they increased from 3.7 per 100,000 person days among those vaccinated in the past two months to 11.6 for those vaccinated over 6 months ago. For vaccinated previously uninfected individuals the rate per 100,000 person days increased from 21.1 for persons vaccinated within the first two months to 88.9 for those vaccinated more than 6 months ago. CONCLUSIONS Protection from reinfection decreases with time since previous infection, but is, nevertheless, higher than that conferred by vaccination with two doses at a similar time since the last immunity-conferring event. A single vaccine dose after infection helps to restore protection.

Duration of Effectiveness of Vaccines Against SARS-CoV-2 Infection and COVID-19 Disease: Results of a Systematic Review and Meta-Regression (preprint)

Background: Knowing whether and to what extent COVID-19 vaccine effectiveness wanes is critical to informing vaccine policy, such as the need for and timing of booster doses. Methods: We performed a systematic review from June 17 to October 27, 2021, using a structured search strategy of multiple databases. Studies with vaccine efficacy or effectiveness (VE) estimates for any WHO Emergency-Use-Listed COVID-19 vaccine at discrete time intervals after full vaccination and meeting pre-defined screening criteria underwent full-text review and risk of bias assessment. Random effects meta-regression was used to estimate the average change in VE from one to six months after full vaccination. Findings: Of 9,261 studies screened, 217 underwent full text review, and 14 were included in analyses. Vaccines evaluated were Pfizer/BioNTech-Comirnaty (n=11), Moderna-mRNA-1273 (n=8), Janssen-Ad26.COV2.S (n=3), and AstraZeneca-Vaxzevria (n=2). On average, VE against SARS-CoV-2 infection decreased between 1 and 6 months after full vaccination by 18·5 percentage points (95% CI 8·4-33·4, p=0·0006) among persons of all ages and 19·9 percentage points (95% CI 9·2-36·7, p=0·0007) among older persons; for symptomatic COVID-19 disease, VE decreased by 25·4 (95% CI 13·7-42·5) and 32·0 percentage points (95% CI 11·0-69·0), respectively; and for severe COVID-19 disease, VE decreased by 8·0 (95% CI 3·6-15·2) and 9·7 percentage points (95% CI 5·9-14·7), respectively. The majority of VE estimates against severe disease remained over 70% for all time points. Interpretation: COVID-19 vaccine efficacy or effectiveness against COVID-19 severe disease remained high (>70%) in most studies in the six months after full vaccination, although it did decrease some (on average, 8-10 percentage points) between one and six months after full vaccination. In contrast, VE against SARS-CoV-2 infection and symptomatic COVID-19 disease decreased approximately 20-30 percentage points during the six months after vaccination. The decrease in VE is likely due, at least in part, to waning immunity, although we cannot rule out the effect of bias. Continued follow-up of VE beyond six months is critical for updating COVID-19 vaccine policy. . Funding Information: Coalition for Epidemic Preparedness Innovations (CEPI)Declaration of Interests: MMH reports research grants from World Health Organization (WHO, Coalition for Epidemic Preparedness Innovations (CEPI), Asian Development Bank (ADB), Bill & Melinda Gates Foundation (BMGF), and Pfizer (all paid to the institution). RA reports a contract from the United States Centers for Disease Control and Prevention, a grant from the Chile Ministry of Science, and consulting fees from Mayo Clinic and Chile Ministry of Health. YG reports research grants from the United States-Israel Binational Science Foundation (BSF) and Israel Science Foundation. MJG reports research grants from South African Medical Research Council and BMGF (all paid to the institution) and participation on a data safety monitoring board for a study on the effectiveness of COVID-19 vaccination against SARS-CoV-2-associated hospitalization and death. AH reports research grants from United States-Israel BSF. KLO serves as the Secretariat for the WHO Strategic Advisory Group of Experts on Immunization. MDK reports research grants from WHO, CEPI, ADB, and Pfizer (all paid to the institution) and consultancy fees from Merck. All other authors have nothing to declare.

Protection Across Age Groups of BNT162b2 Vaccine Booster against Covid-19 (preprint)

BACKGROUND Following administration to persons 60+ years of age, the booster vaccination campaign in Israel was gradually expanded to younger age groups who received a second dose >5 months earlier. We study the booster effect on COVID-19 outcomes. METHODS We extracted data for the period July 30, 2021 to October 5, 2021 from the Israeli Ministry of Health database regarding 4,616,994 persons. We compared confirmed Covid-19 infections, severe illness, and death of those who received a booster [≥]12 days earlier (booster group) with a nonbooster group. In a secondary analysis, we compared the rates 3-7 days with [≥]12 days after receiving the booster dose. We used Poisson regressions to estimate rate ratios after adjusting for possible confounding factors. RESULTS Confirmed infection rates were {approx}10-fold lower in the booster versus nonbooster group (ranging 8.8-17.8 across five age groups) and 4.7-11.4 fold lower in the secondary analysis. Severe illness rates in the primary and secondary analysis were 19.1-fold (95% CI, 15.9-23) and 6.5-fold (95% CI, 5.1-8.4) lower for ages 60+, and 20.7-fold (95% CI, 9.7-44.2) and 2.9-fold (95% CI, 1-8.8) lower for ages 40-60. For ages 60+, COVID-19 associated death rates were 13.9-fold (95% CI, 8.8-22) lower in the primary analysis and 4.6-fold (95% CI, 2.7-7.9) lower in the secondary analysis. CONCLUSIONS Across all age groups, rates of confirmed infection and severe illness were substantially lower among those who received a booster dose of the BNT162b2 vaccine.

BNT162b2 vaccine booster dose protection: A nationwide study from Israel (preprint)

BackgroundOn July 30, 2021, a third (booster) dose of the Pfizer BNT162b2 vaccine was approved in Israel for individuals 60 years or older who had been fully vaccinated (i.e., received two doses) at least five months previously. Here, we estimate the reduction in relative risk for confirmed infection and severe COVID-19 provided by the booster dose. Methods1,144,690 individuals aged 60y and older who were eligible for a booster dose were followed between July 30 and August 22, 2021. We defined dynamic cohorts where individuals initially belong to the non-booster cohort, leave it when receiving the booster dose and join the booster cohort 12 days later. Rates of infection and severe COVID-19 outcomes per person-days at risk were compared between the cohorts using Poisson regression, adjusting for possible confounding factors. ResultsTwelve days or more after the booster dose we found an 11.4-fold (95% CI: [10.0, 12.9]) decrease in the relative risk of confirmed infection, and a >10-fold decrease in the relative risk of severe illness. Under a conservative sensitivity analysis, we find {approx}5-fold protection against confirmed infection. ConclusionsIn conjunction with safety reports, this study demonstrates the effectiveness of a third vaccine dose in both reducing transmission and severe disease and indicates the great potential of curtailing the Delta variant resurgence by administering booster shots.

Waning immunity of the BNT162b2 vaccine: A nationwide study from Israel (preprint)

BackgroundStarting December 2020, Israel began a mass vaccination campaign against coronavirus administering the Pfizer BNT162b2 vaccine, which led to a sharp curtailing of the outbreak. After a period with almost no SARS-CoV-2 infections, a resurgent COVID-19 outbreak initiated mid June 2021. Possible reasons for the breakthrough were reduced vaccine effectiveness against the Delta variant, and waning immunity. The aim of this study was to quantify the extent of waning immunity using Israels national-database. MethodsData on all PCR positive test results between July 11-31, 2021 of Israeli residents who became fully vaccinated before June 2021 were used in this analysis. Infection rates and severe COVID-19 outcomes were compared between individuals who were vaccinated in different time periods using a Poisson regression, stratifying by age group and adjusting for possible confounding factors. ResultsThe rates of both documented SARS-CoV-2 infections and severe COVID-19 exhibit a statistically significant increase as time from second vaccine dose elapsed. Elderly individuals (60+) who received their second dose in March 2021 were 1.6 (CI: [1.3, 2]) times more protected against infection and 1.7 (CI: [1.0, 2.7]) times more protected against severe COVID-19 compared to those who received their second dose in January 2021. Similar results were found for different age groups. ConclusionsThese results indicate a strong effect of waning immunity in all age groups after six months. Quantifying the effect of waning immunity on vaccine effectiveness is critical for policy makers worldwide facing the dilemma of administering booster vaccinations.

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.

Immunogenicity and Safety of the BNT162b2 mRNA COVID-19 Vaccine in People Living with HIV-1 (preprint)

Background: 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 ³18 years, who attended our clinic. Patients who had recovered from COVID-19 were excluded. SARS-CoV-2 receptor binding domain (RBD) IgG and neutralizing antibodies were measured and compared to those in a cohort of vaccinated health care workers (HCWs). Adverse events, viral load and CD4 cell counts were monitored.Findings: At a median of 15 (IQR 14-19) days following the first dose of the BNT162b2 vaccine and 18 (IQR 14-21) days after the second dose, anti-RBD IgG was positive in 66/128 (51%) and 139/141 (98%) PLWH, respectively. Among the HCWs, 235/399 (59%) and 269/272 (99%) developed anti-RBD IgG at a median of 14 (IQR 14-14) and 26 (IQR 24-27) days after first and second doses, respectively. Following the second dose, immune sera neutralized SARS-CoV-2 pseudo-virus (psSARS-2) in 97% and 98% of PLWH and HCW, respectively. Vaccination was associated with adverse events 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/mm3 to 633.8 (95% CI 588–683) cells/mm 3 (P<0.01). Interpretation: This study on BNT162b2 vaccination in PLWH revealed a high antibody response without detrimental effect on viral load. A small decline in CD4 cell count was noted, but it was not accompanied by clinical deterioration. This study thus provides support for the immunization of PLWH against COVID-19 with the BNT162b2 mRNA Covid-19 vaccine.Funding Statement: None.Declaration of Interests: None.Ethics Approval Statement: Written informed consent was obtained from all participants and the study protocol and informed consent were approved by the Institutional review board of Sheba Medical Center.

Evidence for increased breakthrough rates of SARS-CoV-2 variants of concern in BNT162b2 mRNA vaccinated individuals (preprint)

The SARS-CoV-2 pandemic has been raging for over a year, creating global detrimental impact. The BNT162b2 mRNA vaccine has demonstrated high protection levels, yet apprehension exists that several variants of concerns (VOCs) can surmount the immune defenses generated by the vaccines. Neutralization assays have revealed some reduction in neutralization of VOCs B.1.1.7 and B.1.351, but the relevance of these assays in real life remains unclear. Here, we performed a case-control study that examined whether BNT162b2 vaccinees with documented SARS-CoV-2 infection were more likely to become infected with B.1.1.7 or B.1.351 compared with unvaccinated individuals. Vaccinees infected at least a week after the second dose were disproportionally infected with B.1.351 (odds ratio of 8:1). Those infected between two weeks after the first dose and one week after the second dose, were disproportionally infected by B.1.1.7 (odds ratio of 26:10), suggesting reduced vaccine effectiveness against both VOCs under different dosage/timing conditions. Nevertheless, the B.1.351 incidence in Israel to-date remains low and vaccine effectiveness remains high against B.1.1.7, among those fully vaccinated. These results overall suggest that vaccine breakthrough infection is more frequent with both VOCs, yet a combination of mass-vaccination with two doses coupled with non-pharmaceutical interventions control and contain their spread.

Decreased Infectivity Following BNT162b2 Vaccination (preprint)

Background: BNT162b2 was shown to be 92% effective in preventing COVID-19. Prioritizing vaccine rollout, and achievement of herd immunity depend on SARS-CoV-2 transmission reduction. The vaccine’s effect on infectivity is thus a critical priority.Methods: In a cohort of all 9650 HCW of a large single tertiary medical center, we calculated the prevalence of positive SAR-CoV-2 qRT-PCR cases with an asymptomatic presentation, tested following known or presumed exposure and the infectious subset (N-gene-Ct-value<30) of these and the prevalence of never-symptomatic infections. Additionally, infection incidence rates were calculated for symptomatic cases and infectious (Ct<30) cases. Vaccine effectiveness within three months of vaccine rollout was measured as one minus the relative risk or rate ratio, respectively. To further assess infectiousness, we compared the mean Ct-value and the proportion of infections with a positive SARS-CoV-2 antigen test of vaccinated vs. unvaccinated. The correlation between IgG levels within the week before detection and Ct level was assessed.Findings: Reduced prevalence among fully vaccinated HCW was observed for (i) infections detected due to exposure, with asymptomatic presentation (VE(i)=65.1%, 95%CI 45-79%), (ii) the presumed infectious (Ct<30) subset of these (VE(ii)=69.6%, 95%CI 43-84%) (iii) never-symptomatic infections (VE(iii)=72.3%, 95%CI 48-86%), and (iv) the presumed infectious (Ct<30) subset (VE(iv)=83.0%, 95%CI 51-94%).Incidence of (v) symptomatic and (vi) symptomatic-infectious cases was significantly lower among fully vaccinated vs. unvaccinated individuals (VE(v)= 89.7%, 95%CI 84-94%, VE(vi)=88.1%, 95%CI 80-95%).The mean Ct-value was significantly higher in vaccinated vs. unvaccinated (27.3±1.2 vs. 22.2±1.0, p<0.001) and the proportion of positive SARS-CoV-2 antigen tests was also significantly lower among vaccinated vs. unvaccinated PCR-positive HCW (80% vs. 31%, p<0.001). Lower infectivity was correlated with higher IgG concentrations (R=0.36, p=0.01).Interpretation: These results suggest that BNT162b2 is moderately to highly effective in reducing infectivity, via preventing infection and through reducing viral shedding. Funding: Sheba Medical Center, IsraelDeclaration of Interest: All authors declare they have no competing interestsEthical Approval: The Sheba Ethical committee, reviewed the protocol and approved thestudy.

DOPE: D-Optimal Pooling Experimental design with application for SARS-CoV-2 screening (preprint)

Testing individuals for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen causing the coronavirus disease 2019 (COVID-19), is crucial for curtailing transmission chains. Moreover, rapidly testing many potentially infected individuals is often a limiting factor in controlling COVID-19 outbreaks. Hence, pooling strategies, wherein individuals are grouped and tested simultaneously, are employed. We present a novel pooling strategy that implements D-Optimal Pooling Experimental design (DOPE). DOPE defines optimal pooled tests as those maximizing the mutual information between data and infection states. We estimate said mutual information via Monte-Carlo sampling and employ a discrete optimization heuristic for maximizing it. DOPE outperforms common pooling strategies both in terms of lower error rates and fewer tests utilized. DOPE holds several additional advantages: it provides posterior distributions of the probability of infection, rather than only binary classification outcomes; it naturally incorporates prior information of infection probabilities and test error rates; and finally, it can be easily extended to include other, newly discovered information regarding COVID-19. Hence, we believe that implementation of Bayesian D-optimal experimental design holds a great promise for the efforts of combating COVID-19 and other future pandemics.

An Accurate Model for SARS-CoV-2 Pooled RT-PCR Test Errors (preprint)

PCR testing is an important tool to mitigate outbreaks of infectious diseases. One way of increasing testing throughput is by simultaneously testing multiple samples for the presence of a pathogen, a technique known as pooling . During the current COVID-19 pandemic, rapidly testing individuals for the presence of SARS-CoV-2 is conducted in large amounts. Since testing is often a bottleneck in mitigating the spread of SARS-CoV-2, pooling is increasing in popularity. Most analyses of the error rates of pooling schemes assume that including more than a single infected sample in a pooled test does not increase the probability of a positive outcome. We challenge this assumption with experimental data and suggest a novel probabilistic model for the outcomes of pooled tests. As an application, we analyze the false-negative rates of one common pooling scheme known as Dorfman pooling. We show that the false-negative rates of Dorfman pooling increase when the prevalence of infection decreases. However, low infection prevalence is exactly the condition under which Dorfman pooling achieves highest throughput. We therefore implore the cautious use of pooling and development of pooling schemes that consider correctly accounting for tests’ error rates.

The role of children in the spread of COVID-19: Using household data from Bnei Brak, Israel, to estimate the relative susceptibility and infectivity of children (preprint)

BackgroundOne of the significant unanswered questions about COVID-19 epidemiology relates to the role of children in transmission. In this study we estimate susceptibility and infectivity of children compared to those of adults. Understanding the age-structured transmission dynamics of the outbreak provides precious and timely information to guide epidemic modelling and public health policy. MethodsData were collected from households in the city of Bnei Brak, Israel, in which all household members were tested for COVID-19 using PCR. To estimate relative transmission parameters in the absence of data on who infected whom, we developed an estimation method based on a discrete stochastic dynamic model of the spread of the epidemic within a household. The model describes the propagation of the disease between household members allowing for susceptibility and infectivity parameters to vary among two age groups. The parameter estimates are obtained by a maximum likelihood method, where the likelihood function is computed based on the stochastic model via simulations. FindingsInspection of the data reveals that children are less likely to become infected compared to adults (25% of children infected over all households, 44% of adults infected over all households, excluding index cases), and the chances of becoming infected increases with age. An interesting exception is that infants up to age one year are more likely to be infected than children between one and four. Using our modelling approach, we estimate that the susceptibility of children (under 20 years old) is 45% [40%, 55%] of the susceptibility of adults. The infectivity of children was estimated to be 85% [65%, 110%] relative to that of adults. InterpretationIt is widely observed that the percentage of children within confirmed cases is low. A common explanation is that children who are infected are less likely to develop symptoms than adults, and thus are less likely to be tested. We estimate that children are less susceptible to infection, which is an additional factor explaining their relatively low rate of occurrence within confirmed cases. Moreover, our results indicate that children, when infected, are somewhat less prone to infect others compared to adults; however, this result is not statistically significant. The resulting estimates of susceptibility and infectivity of children compared to adults are crucial for deciding on appropriate interventions, and for controlling the epidemic outbreak and its progress. These estimates can guide age-dependent public health policy such as school closure and opening. However, while our estimates of childrens susceptibility and infectivity are lower than those of adults within a household, it is important to bear in mind that their role in the spread of COVID-19 outside the household, is also affected by different contact patterns and hygiene habits.