BIOLOGICAL RHYTHMS IN COVID-19 VACCINE EFFECTIVENESS (preprint)

Importance Circadian rhythms affect fundamental immune processes, but how this translates to clinical outcomes like real-world vaccine effectiveness is unclear. Objective To examine associations between Coronavirus Infectious Disease 2019 (COVID-19) vaccination timing and effectiveness. Design, Setting, and Participants Retrospective cohort study of database records from Maccabi Healthcare Services (MHS), a major Israeli Health Maintenance Organization (HMO). We included all individuals over 12 with at least one timestamped vaccine dose and no documented COVID-19 infection prior to completing the initial 2-dose immunization series (n=1,515,754, 99.2% receiving BNT162b2). Database records spanned December 19, 2020, to April 25, 2022, encompassing two spikes in COVID infection dominated by the delta (B.1.617.2) and omicron (B.1.1.529) SARS-CoV-2 variants. Main Outcomes and Measures Outcomes included COVID-19 breakthrough infection and COVID-19 associated emergency department (ED) visits. Our main comparison was between patients vaccinated exclusively during morning hours (8:00-11:59), afternoon (12:00-15:59), or evening hours (16:00-19:59). We employed Cox multivariate regression to adjust for differences in age, sex, and co-morbidities. Results. Breakthrough infections differed based on vaccination time, with lowest rates associated with late morning to early afternoon, and highest rates with evening vaccination. Vaccination timing remained significant after adjustment for patient age, sex, and co-morbidities (HR=0.88 afternoon vs. evening, [95% CI 0.87-0.90]). Results were consistent in patients who received the basic two-dose vaccine series and who received booster doses. The association between COVID immunization time and infection risk followed a sinusoidal pattern, consistent with a biological rhythm in vaccine effectiveness that modifies clinical effectiveness by 8.6-25% depending on the vaccine dose (initial vaccine series, first booster, or second booster). The benefits of daytime vaccination were concentrated in younger and elderly patients. In contrast to breakthrough infections, COVID-19 related ED visits correlated with age and medical comorbidities but not with time of vaccination. Conclusions and Relevance We report a significant association between the time of COVID-19 vaccination and its clinical effectiveness in terms of breakthrough infection. These data have implications for mass vaccination programs.

Describing COVID-19 Patients During The First Two Months of Paxlovid (Nirmatrelvir/Ritonavir) Initiation in a Large HMO in Israel (preprint)

Objective The objective of this feasibility study was to assess the number of patients that could be included in a future Real World Evidence study, which would be designed to explore the impact of Paxlovid (nirmatrelvir/ritonavir) on patient outcomes and healthcare resource utilization (HCRU). We also intend to assess the comparability of the patients who were treated with Paxlovid versus patients who did not receive the treatment, either because they declined any COVID-19 treatment or were diagnosed with COVID-19 prior to Paxlovid availability. Methods This retrospective observational secondary data study used data from the Maccabi Healthcare Services database during the identification period of June 1, 2021, to February 28, 2022. The study population included patients with at least one positive SARS-CoV-2 RT-PCR test, or a formal rapid antigen test for SARS-CoV-2, during the identification period, the date of which also served as the COVID-19 diagnosis date. We then divided the study population into the following cohorts: Pre-Paxlovid Time Period and Paxlovid Time Period, which was further split into Paxlovid Treated and Paxlovid Untreated. Results Application of inclusion and exclusion criteria to the study population rendered 20,284 patients in the Pre-Paxlovid Time Period cohort and 5,542 in the Paxlovid Time Period cohort that were eligible to receive Paxlovid. This resulted in 3,714 in the Paxlovid Treated and 1,810 in the Paxlovid Untreated cohorts. Conclusions This RWE feasibility study of patients with a positive test for COVID-19 between June 1, 2021 to February 28, 2022 illustrates potential comparability between cohorts, as described by their demographics and characteristics.

Dynamics in COVID-19 Symptoms During Different Waves of the Pandemic Among Children Infected with SARS-CoV-2 (preprint)

The aim of this real-life, big data population-based study was to evaluate differences in symptomatic presentation of children infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) between the third and fourth waves of the pandemic in Israel, dominated by the Alpha and Delta variants, respectively. Our cohort included all children and adolescents, members of the second-largest Health Maintenance Organisation in Israel that had positive real-time polymerase chain reaction (RT-PCR) test during the third and fourth waves of the pandemic (December 1, 2020 - April 30, 2021, and June 1, 2021 - October 10, 2021, respectively). A total of 32,485 and 44,130 children and adolescents in the third and fourth waves were included in the final analysis. The rate of children with symptomatic disease among patients with documented SARS-CoV-2 infection was higher in the fourth wave compared to the third wave (49.9% vs. 37.5%). The most commonly reported symptom and the only symptom that substantially differed between waves was fever, with 33% of SARS-CoV-2 infected children in the fourth wave vs. 13.6% in the third wave. Preschool children had the lowest prevalence of febrile illness compared to other age groups.Conclusion: Children and adolescents infected during the fourth wave of the pandemic in Israel, a Delta-dominant period, had a significantly higher rate of symptomatic febrile illness than the Alpha-dominant period. This phenomenon occurred across all age groups.

Waning of SARS-CoV-2 booster viral-load reduction effectiveness (preprint)

The BNT162b2 COVID-19 vaccine has been shown to reduce viral load of breakthrough infections (BTIs), an important factor affecting infectiousness. This viral-load protective effect has been waning with time post the second vaccine and later restored with a booster shot. It is currently unclear though for how long this regained effectiveness lasts. Analyzing Ct values of SARS-CoV-2 qRT-PCR tests of over 22,000 infections during a Delta-variant-dominant period in Israel, we found that this viral-load reduction effectiveness significantly declines within months post the booster dose. Adjusting for age, sex and calendric date, Ct values of RdRp gene initially increased by 2.7 [CI: 2.3-3.0] relative to unvaccinated in the first month post the booster dose, yet then decayed to a difference of 1.3 [CI: 0.7-1.9] in the second month and became small and insignificant in the third to fourth months. The rate and magnitude of this post-booster decline in viral-load reduction effectiveness mirror those observed post the second vaccine. These results suggest rapid waning of the booster’s effectiveness in reducing infectiousness, possibly affecting community-level spread of the virus.

Viral loads of Delta-variant SARS-CoV2 breakthrough infections following vaccination and booster with the BNT162b2 vaccine (preprint)

The BNT162b2 vaccine showed high real-life effectiveness both at preventing disease and in reducing viral loads of breakthrough infections, but coincidental with the rise of the Delta-variant SARS-CoV2, these protective effects have been decreasing, prompting a third, booster, vaccine inoculation. Here, analyzing viral loads of over 11,000 infections during the current wave in Israel, we find that even though this wave is dominated by the Delta-variant, breakthrough infections in recently vaccinated patients, still within 2 months post their second vaccine inoculation, do have lower viral loads compared to unvaccinated patients, with the extent of viral load reduction similar to pre-Delta breakthrough observations. Yet, this infectiousness protection starts diminishing for patients two months post vaccination and ultimately vanishes for patients 6 months or longer post vaccination. Encouragingly, we find that this diminishing vaccine effectiveness on breakthrough infection viral loads is restored following the booster vaccine. These results suggest that the vaccine is initially effective in reducing infectiousness of breakthrough infections even with the Delta variant, and that while this protectiveness effect declines with time it can be restored, at least temporarily, with a booster vaccine.

Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity: reinfections versus breakthrough infections (preprint)

BackgroundReports of waning vaccine-induced immunity against COVID-19 have begun to surface. With that, the comparable long-term protection conferred by previous infection with SARS-CoV-2 remains unclear. MethodsWe conducted a retrospective observational study comparing three groups: (1)SARS-CoV-2-naive individuals who received a two-dose regimen of the BioNTech/Pfizer mRNA BNT162b2 vaccine, (2)previously infected individuals who have not been vaccinated, and (3)previously infected and single dose vaccinated individuals. Three multivariate logistic regression models were applied. In all models we evaluated four outcomes: SARS-CoV-2 infection, symptomatic disease, COVID-19-related hospitalization and death. The follow-up period of June 1 to August 14, 2021, when the Delta variant was dominant in Israel. ResultsSARS-CoV-2-naive vaccinees had a 13.06-fold (95% CI, 8.08 to 21.11) increased risk for breakthrough infection with the Delta variant compared to those previously infected, when the first event (infection or vaccination) occurred during January and February of 2021. The increased risk was significant (P<0.001) for symptomatic disease as well. When allowing the infection to occur at any time before vaccination (from March 2020 to February 2021), evidence of waning natural immunity was demonstrated, though SARS-CoV-2 naive vaccinees had a 5.96-fold (95% CI, 4.85 to 7.33) increased risk for breakthrough infection and a 7.13-fold (95% CI, 5.51 to 9.21) increased risk for symptomatic disease. SARS-CoV-2-naive vaccinees were also at a greater risk for COVID-19-related-hospitalizations compared to those that were previously infected. ConclusionsThis study demonstrated that natural immunity confers longer lasting and stronger protection against infection, symptomatic disease and hospitalization caused by the Delta variant of SARS-CoV-2, compared to the BNT162b2 two-dose vaccine-induced immunity. Individuals who were both previously infected with SARS-CoV-2 and given a single dose of the vaccine gained additional protection against the Delta variant.

SARS-CoV-2 infection risk among unvaccinated is negatively associated with community-level vaccination rates (preprint)

Mass vaccination has the potential to curb the current COVID-19 pandemic by protecting vaccinees from the disease and possibly lowering the chance of transmission to unvaccinated individuals. The high effectiveness of the widely-administered BNT162b vaccine in preventing not only the disease but also infection suggests a potential for a population-level effect, critical for disease eradication. However, this putative effect is difficult to observe, especially in light of highly fluctuating spatio-temporal epidemic dynamics. Here, analyzing vaccination records and test results collected during a rapid vaccine rollout for a large population from 223 geographically defined communities, we find that the rates of vaccination in each community are highly correlated with a later decline in infections among a cohort of under 16 years old which are unvaccinated. These results provide observational evidence that vaccination not only protects individual vaccinees but also provides cross-protection to unvaccinated individuals in the community.

Associations of the BNT162b2 COVID-19 vaccine effectiveness with patient age and comorbidities (preprint)

Vaccinations are considered the major tool to curb the current SARS-CoV-2 pandemic. A randomized placebo-controlled trial of the BNT162b2 vaccine has demonstrated a 95% efficacy in preventing COVID-19 disease. These results are now corroborated with statistical analyses of real-world vaccination rollouts, but resolving vaccine effectiveness across demographic groups is challenging. Here, applying a multivariable logistic regression analysis approach to a large patient-level dataset, including SARS-CoV-2 tests, vaccine inoculations and personalized demographics, we model vaccine effectiveness at daily resolution and its interaction with sex, age and comorbidities. Vaccine effectiveness gradually increased post day 12 of inoculation, then plateaued, around 35 days, reaching 91.2% [CI 88.8%-93.1%] for all infections and 99.3% [CI 95.3%-99.9%] for symptomatic infections. Effectiveness was uniform for men and women yet declined mildly but significantly with age and for patients with specific chronic comorbidities, most notably type 2 diabetes. Quantifying real-world vaccine effectiveness, including both biological and behavioral effects, our analysis provides initial measurement of vaccine effectiveness across demographic groups.

Predictive and Causal Analysis of No-Shows for Medical Exams During COVID-19: A Case Study of Breast Imaging in a Nationwide Israeli Health Organization (preprint)

"No-shows", defined as missed appointments or late cancellations, is a central problem in healthcare systems. It has appeared to intensify during the COVID-19 pandemic and the nonpharmaceutical interventions, such as closures, taken to slow its spread. No-shows interfere with patients' continuous care, lead to inefficient utilization of medical resources, and increase healthcare costs. We present a comprehensive analysis of no-shows for breast imaging appointments made during 2020 in a large medical network in Israel. We applied advanced machine learning methods to provide insights into novel and known predictors. Additionally, we employed causal inference methodology to infer the effect of closures on no-shows, after accounting for confounding biases, and demonstrate the superiority of adversarial balancing over inverse probability weighting in correcting these biases. Our results imply that a patient's perceived risk of cancer and the COVID-19 time-based factors are major predictors. Further, we reveal that closures impact patients over 60, but not patients undergoing advanced diagnostic examinations.

A 1 to 1000 SARS-CoV-2 reinfection proportion in members of a large healthcare provider in Israel: a preliminary report (preprint)

With more than 100 million confirmed COVID-19 cases as of March 2021, reinfection is still considered to be rare. In light of increasing reports of reinfected COVID-19 patients, the need to better understand the real risk for reinfection is critical, with potential effects on public health policies aimed at containing the spread of SARS-CoV-2. In this descriptive preliminary report, we conducted a large-scale assessment on the country level of the possible occurrence of COVID-19 reinfection within the members of a large healthcare provider in Israel. Out of 149,735 individuals with a documented positive PCR test between March 2020 and January 2021, 154 had two positive PCR tests at least 100 days apart, reflecting a reinfection proportion of 1 per 1000. Given our strict inclusion criteria, we believe these numbers represent true reinfection incidence in MHS and should be clinically regarded as such.

Kinetics of SARS-CoV-2 anti-s IgG after BNT162b2 vaccination (preprint)

Deployment of the BNT162b2 mRNA Covid-19 Vaccine in Israel began in December 2020. This is a retrospective analysis of serological data, describing SARS-CoV-2 anti-S IgG kinetics in 116 Israeli healthcare workers administrated the BNT162b2 vaccine. Seroconversion occurred by day 14 in all individuals, with IgG levels peaking approximately 30 days post inoculation. This study demonstrated the kinetics of the antibody response post vaccination with BNT162b2. The robustness of seroconversion was observed, alongside a statistically significant difference in IgG levels between employees over and younger 50 years of afge. Further research is required in order to examine the antibody kinetics overtime, as well as whether the age-dependent difference persists.

Decreased SARS-CoV-2 viral load following vaccination (preprint)

Beyond their substantial protection of individual vaccinees, it is hoped that the COVID-19 vaccines would reduce viral load in breakthrough infections thereby further suppress onward transmission. Here, analyzing positive SARS-CoV-2 test results following inoculation with the BNT162b2 mRNA vaccine, we find that the viral load is reduced 4-fold for infections occurring 12-28 days after the first dose of vaccine. These reduced viral loads hint to lower infectiousness, further contributing to vaccine impact on virus spread.

The Effectiveness of the First Dose of BNT162b2 Vaccine in Reducing SARS-CoV-2 Infection: Real-World Evidence (preprint)

Background: BNT162b2 vaccines showed high efficacy against COVID-19 in a randomised controlled phase-III trial. A vaccine effectiveness evaluation in real life settings is urgently needed, especially given the global disease surge. Hence, we assessed the short-term effectiveness of the first dose of BNT162b2-vaccine against SARS-CoV-2 infection. Given the BNT162b2 Phase-III results, we hypothesized that the cumulative incidence of SARS-CoV-2 infection among vaccinees will decline after 12 days following immunization compared to the incidence during the preceding days.Methods: We conducted a retrospective cohort study using data from 2·6 million-member state-mandated health provider in Israel. Study population consisted of all members aged 16 or above years who were vaccinated with BNT162b2-vaccine between December/19/2020 and January/15/2021. We collected information regarding medical history and positive SARS-CoV-2 polymerase chain reaction test from days after first dose to January/17/2021. Daily and cumulative infection rates in days 13-24 were compared to days 1-12 after first dose using Kaplan-Meier survival analysis and generalized linear models.Findings: Data of 503,875 individuals (mean age 59·7 years SD=14·7, 47·8% males) were analysed, of whom 351,897 had 13-24 days of follow-up. The cumulative incidence of SARS-CoV-2 infection was 0·57% (n=2484) during days 1-12 and 0·27% (n=614) in days 13-24. A 51·4% relative risk reduction (RRR) was calculated in weighted-average daily incidence of SARS-CoV-2 infection from 43·41-per-100,000(SE=12·07) in days 1-12 to 21·08-per-100,000(SE=6·16) in days 13-24 following immunization. The decrement in incidence was evident from day 18 after first dose. Similar RRRs were calculated in individuals aged 60 or above (44.5%), younger individuals (50.2%), females (50.0%) and males (52.1%). Findings were similar in sub-populations and patients with various comorbidities.Interpretation: We demonstrated an effectiveness of 51% of BNT162b2 vaccine against SARS-CoV-2 infection 13-24 days after immunization with the first dose. Immunization with the second dose should be continued to attain the anticipated protection.Funding: No external funding was available for this study.Declaration of Interests: We declare no competing interests.Ethics Approval Statement: We obtained ethical approval from Maccabi Healthcare Services Ethics Committee.

Association of COVID-19 RT-qPCR test false-negative rate with patient age, sex and time since diagnosis (preprint)

Background Routine testing for SARS-CoV-2 in the community is essential for guiding key epidemiological decisions from the quarantine of individual patients to enrolling regional and national preventive measures. Yet, the primary testing tool, the RT-qPCR based testing, is notoriously known for its low sensitivity, i.e. high risk of missed detection of carriers. Quantifying the false-negative rate (FNR) of the RT-qPCR test at the community settings and its dependence on patient demographic and disease progression is therefore key in designing and refining strategies for disease spread prevention. Methods Analyzing 843,917 test results of 521,696 patients, we identified false-negative (FN) and true-positive (TP) results as negative and positive results preceded by a COVID-19 diagnosis and followed by a later positive test. Regression analyses were used to determine associations of false-negative results with time of sampling after diagnosis, patient demographics and viral loads based on RT-qPCR Ct values of the next positive tests. Findings The overall FNR was 22.8%, which is consistent with previous studies. Yet, this rate was much lower at the first 5 days following diagnosis (10.7%) and only increased in later dates. Furthermore, the FNR was strongly associated with demographics, with odds ratio of 1.74 (95% CI: 1.58-1.9) for women over men and 2.54 (95% CI: 2.39-2.69) for a 20 versus a 50 year old patient. Finally, FNR was associated with viral loads (p-value 0.002), with a difference of 1.1 (95% CI: 0.60-1.57) between the average Ct of the N gene in a positive test following a false-negative compared to a positive test following a true-positive. Interpretation Our results show that in the first few days following diagnosis, when results are critical for quarantine decisions, RT-qPCR testing is more reliable than previously reported. Yet the reliability of the test result is reduced in later days as well as for women and younger patients, where the viral loads are typically lower. Funding This research was supported by the ISRAEL SCIENCE FOUNDATION (grant No. 3633/19) within the KillCorona-Curbing Coronavirus Research Program.

Longitudinal symptom dynamics of COVID-19 infection in primary care (preprint)

Objective : Data regarding the clinical characteristics of COVID-19 infection is rapidly accumulating. However, most studies thus far are based on hospitalized patients and lack longitudinal follow up. As the majority of COVID-19 cases are not hospitalized, prospective studies of symptoms in the population presenting to primary care are needed. Here, we assess the longitudinal dynamic of clinical symptoms in non-hospitalized individuals prior to and throughout the diagnosis of SARS-CoV-2 infection. Design Data on symptoms were extracted from electronic health records (EHR) consisting of both results of PCR tests and symptoms recorded by primary care physicians, and linked longitudinal self reported symptoms. Setting The second largest Health Maintenance Organization in Israel , Maccabi Health Services Participants From 1/3/2020 to 07/06/2020, information on symptoms from either surveys or primary care visits was available for 206,377 individuals, including 2,471 who tested positive for COVID-19. Main Outcomes Longitudinal prevalence of clinical symptoms in COVID-19 infection diagnosed by PCR testing for SARS-CoV-2 from nasopharyngeal swabs. Results: In adults, the most prevalent symptoms recorded in EHR were cough (11.6%), fever (10.3%), and myalgia (7.7%) and the most prevalent self-reported symptoms were cough (21%), fatigue (19%) and rhinorrhea and/or nasal congestion (17%). In children, the most prevalent symptoms recorded in the EHR were fever (7%), cough (5.5%) and abdominal pain (2.4%) . Emotional disturbances were documented in 15.9% of the positive adults and 4.2% of the children. Loss of taste and smell, either self-reported or documented by a physician, 3 weeks prior to testing, were the most discriminative symptoms in adults (OR =11.18 and OR=5.47 respectively). Additional symptoms included self reported headache (OR = 2.03) and fatigue (OR = 1.73) and a documentation of syncope, rhinorrhea (OR = 2.09 for both ) and fever (OR= 1.62 ) by a physician. Mean time to recovery was 23.5 +- 9.9 days. Children had a significantly shorter disease duration (21.7 +- 8.8 days, p-value=0.01). Several symptoms, including fatigue, myalgia, runny nose and shortness of breath were reported weeks after recovery. Conclusions As the COVID-19 pandemic progresses rapidly worldwide, obtaining accurate information on symptoms and their progression is of essence. Our study shed light on the full clinical spectrum of symptoms experienced by infected individuals in primary care, and may alert physicians for the possibility of COVID-19 infection.

Characteristics of SARS-CoV-2 positive and complicated COVID-19 patient cohorts in Israel: A comparative analysis (preprint)

Reliably identifying patients at increased risk for COVID-19 complications could guide clinical decisions, public health policies, and preparedness efforts. To date, the most globally accepted definitions of at-risk patients rely, primarily, on epidemiological characterization of hospitalized COVID-19 patients. However, such characterization overlooks, and fails to correct for, the prevalence of existing conditions in the wider SARS-CoV-2 positive population. Here, we analyze the complete medical records of all SARS-CoV-2 infected individuals (N=4,353) in a large Israeli health organization (representing a population of 2.3 million people), of whom 173 experienced moderate or severe symptoms of COVID-19, to identify the conditions that increase the risk of disease complications, in various age and sex strata. Our analysis suggests that cardiovascular and kidney diseases, obesity, and hypertension are significant risk factors for COVID-19 complications, as previously reported. Interestingly, it also indicates that depression (e.g., odds ratio, OR, for males 65 years or older: 2.94, 95% confidence intervals [1.55, 5.58]; P-value = 0.014) as well cognitive and neurological disorder (e.g., OR for individuals [≥] 65 year old: 2.65 [1.69, 4.17]; P-value < 0.001) are significant risk factors; and that smoking and background of respiratory diseases do not significantly increase the risk of complications. Adjusting existing risk definitions following these observations may improve their accuracy and impact the global pandemic containment efforts.