Genome-wide association study between SARS-CoV-2 single nucleotide polymorphisms and virus copies during infections (preprint)

Variations in viral loads generated during SARS-CoV-2 infections can influence COVID-19 disease progression and the likelihood of onward transmission. However, the host and virus factors that may impact viral loads and infection dynamics are not fully understood. Here, we conducted virus whole genome sequencing and measured viral copies using RT-qPCR from 9,902 SARS-CoV-2 infections over a 2-year period to examine the relative impact of host factors and virus genetic variation on changes in viral copies. We first used statistical regression models to show that host age and SARS-CoV-2 variant significantly impact viral copies, but vaccination status does not. Then, using a genome-wide association study (GWAS) approach, we identified multiple nucleotide substitutions corresponding to amino acid changes in the SARS-CoV-2 genome associated with variations in viral copies. In particular, we analyzed the temporal patterns and found that SNPs associated with higher viral copies were predominantly observed in Omicron BA.2/BA.4/BA.5/XBB infections, whereas those associated with decreased viral copies were mostly observed in infections with Delta and Omicron BA.1 variants. Our work showcases how GWAS can be a useful tool for probing phenotypes related to SNPs in viral genomes, which can be used to characterize emerging variants and monitor therapeutic interventions.

Global patterns of rebound to normal RSV dynamics following COVID-19 suppression (preprint)

Introduction Annual epidemics of respiratory synctial virus (RSV) had consistent timing and intensity between seasons prior to the SARS-CoV-2 pandemic (COVID-19). However, starting in April 2020, RSV seasonal activity declined due to COVID-19 non-pharmaceutical interventions (NPIs) before re-emerging after relaxation of NPIs. We described the unusual patterns of RSV epidemics that occurred in multiple subsequent waves following COVID-19 in different countries and explored factors associated with these patterns. Methods Weekly cases of RSV from twenty-eight countries were obtained from the World Health Organisation and combined with data on country-level characteristics and the stringency of the COVID-19 response. Dynamic time warping and regression were used to describe epidemic characteristics, cluster time series patterns, and identify related factors. Results While the first wave of RSV epidemics following pandemic suppression exhibited unusual patterns, the second and third waves more closely resembled typical RSV patterns in many countries. Post-pandemic RSV patterns differed in their intensity and/or timing, with several broad patterns across the countries. The onset and peak timings of the first and second waves of RSV epidemics following COVID-19 suppression were earlier in the Southern Hemisphere. The second wave of RSV epidemics was also earlier with higher population density, and delayed if the intensity of the first wave was higher. More stringent NPIs were associated with lower RSV growth rate and intensity and a shorter gap between the first and second waves. Conclusion Patterns of RSV activity have largely returned to normal following successive waves in the post-pandemic era. Onset and peak timings of future epidemics following disruption of normal RSV dynamics need close monitoring to inform the delivery of preventive and control measures. Keywords: Respiratory synctial virus, epidemic onset, epidemic peak, epidemic rebound, dynamic time warping

Escalating combinations of enhanced infectivity and immune escape define SARS-CoV-2 Omicron lineage replacement (preprint)

In 2022, consecutive sweeps of the highly transmissible SARS-CoV-2 Omicron-family maintained high viral transmission levels despite extensive antigen exposure on the population level resulting from both vaccinations and infections. To better understand variant fitness in the context of the highly dynamic immunity landscape of 2022, we aimed to dissect the interplay between immunity and fitness advantages of emerging SARS-CoV-2 Omicron lineages on the population-level. We evaluated the relative contribution of higher intrinsic transmissibility or immune escape on the fitness of emerging lineages by analyzing data collected through our local genomic surveillance program from Connecticut, USA. We compared growth rates, estimated infections, effective reproductive rates, average viral copy numbers, and likelihood for causing vaccine break-through infections. Using these population-level data, we find that newly emerging Omicron lineages reach dominance through a specific combination of enhanced intrinsic transmissibility and immune escape that varies over time depending on the state of the host-population. Using similar frameworks that integrate whole genome sequencing together with clinical, laboratory, and epidemiological data can advance our knowledge on host-pathogen dynamics in the post-emergence phase that can be applied to other communicable diseases beyond SARS-CoV-2.

Evaluating the Association between Routine Pneumococcal Vaccination and COVID-19 Severity among Older Adults in the United States (preprint)

BackgroundThe relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Streptococcus pneumoniae remains uncertain. This study investigates the association between routine pneumococcal vaccination and the progression to severe COVID-19 outcomes in a cohort of older adults in the United States. MethodsOur cohort study includes adults aged 65 and older from a subset of adults covered by Medicare in the United States with a documented COVID-19 diagnosis. Logistic regression models were employed to assess the association between pneumococcal vaccination (13-valent conjugate vaccine [PCV13] and 23-valent pneumococcal polysaccharide vaccine [PPSV23]) and COVID-19 severity. ResultsAmong 90,070 Medicare enrollees with a COVID-19 diagnosis, 28,124 individuals exhibited severe respiratory symptoms or were admitted to the intensive care unit (ICU). The odds ratio (OR) for progression from non-severe symptoms to respiratory symptoms with or without ICU admission with prior PCV13 receipt was 0.91 (95% confidence interval [CI], 0.88, 0.93), the OR for progression from severe respiratory symptoms to ICU critical care with prior PCV13 receipt was 0.92 (95% CI, 0.88, 0.97), and the OR for progression from non-severe symptoms to ICU critical care with prior PCV13 receipt was 0.85 (95% CI, 0.81, 0.90). There was no association between PPSV23 received more than five years before the COVID-19 diagnosis and the COVID-19 outcomes. ConclusionsOverall, our findings indicate moderate to no association between PCV vaccination and COVID-19 severity.

Absolute and relative excess mortality across demographic and clinical subgroups during the COVID-19 pandemic: an individual-level cohort study from a nationwide healthcare system of US Veterans (preprint)

Background. Most analyses of excess mortality during the COVID-19 pandemic have employed aggregate data. Individual-level data from the largest integrated healthcare system in the US may enhance understanding of excess mortality. Methods. We performed an observational cohort study following patients receiving care from the Department of Veterans Affairs (VA) between 1 March 2018 and 28 February 2022. We estimated excess mortality on an absolute scale (i.e., excess mortality rates, number of excess deaths), and a relative scale by measuring the hazard ratio (HR) for mortality comparing pandemic and pre-pandemic periods, overall, and within demographic and clinical subgroups. Comorbidity burden and frailty were measured using the Charlson Comorbidity Index and Veterans Aging Cohort Study Index, respectively. Results. Of 5,905,747 patients, median age was 65.8 years and 91% were men. Overall, the excess mortality rate was 10.0 deaths/1000 person-years (PY), with a total of 103,164 excess deaths and pandemic HR of 1.25 (95% CI 1.25-1.26). Excess mortality rates were highest among the most frail patients (52.0/1000 PY) and those with the highest comorbidity burden (16.3/1000 PY). However, the largest relative mortality increases were observed among the least frail (HR 1.31, 95% CI 1.30-1.32) and those with the lowest comorbidity burden (HR 1.44, 95% CI 1.43-1.46). Conclusions. Individual-level data offered crucial clinical and operational insights into US excess mortality patterns during the COVID-19 pandemic. Notable differences emerged among clinical risk groups, emphasising the need for reporting excess mortality in both absolute and relative terms to inform resource allocation in future outbreaks.

Year-round RSV Transmission in the Netherlands Following the COVID-19 Pandemic - A Prospective Nationwide Observational and Modeling Study (preprint)

A nationwide prospective study showed year-round RSV transmission in the Netherlands after an initial 2021 summer outbreak. The pattern was unprecedented and distinct from neighboring countries. Our dynamic simulation model suggests that this transmission pattern could be associated with waning immunity because of low RSV circulation during the COVID-19 pandemic.

Excess mortality in the general population versus Veterans Healthcare System during the first year of the COVID-19 pandemic in the United States (preprint)

Importance The COVID-19 pandemic had a substantial impact on the overall rate of death in the United States during the first year. It is unclear whether access to comprehensive medical care, such as through the VA healthcare system, altered death rates compared to the US population. Objective: Quantify the increase in death rates during the first year of the COVID-19 pandemic in the general US population and among individuals who receive comprehensive medical care through the Department of Veterans Affairs (VA). Design: Analysis of changes in all-cause death rates by quarter, stratified by age, sex race/ethnicity, and region, based on individual-level data. Hierarchical regression models were fit in a Bayesian setting. Standardized rates were used for comparison between populations. Setting and participants: General population of the United States, enrollees in the VA, and active users of VA healthcare. Exposure and main outcome: Changes in rates of death from any cause during the COVID-19 pandemic in 2020 compared to previous years. Results Sharp increases were apparent across all of the adult age groups (25 years and older) in both the general US population and the VA populations. Across all of 2020, the relative increase in death rates was similar in the general US population (RR: 1.20 (95% CI: 1.17, 1.22)), VA enrollees (RR: 1.20 (95% CI: 1.14, 1.29)), and VA active users (RR: 1.19 (95% CI: 1.14, 1.26)). Because the pre-pandemic standardized mortality rates were higher in the VA populations prior to the pandemic, the absolute rates of excess mortality were higher in the VA populations. Conclusions and Relevance: Despite access to comprehensive medical care, active users of the VA had similar relative mortality increases from all causes compared with the general US population. Factors that influenced baseline rates of death and that mitigated viral transmission in the community are more likely to have influenced the impact of the pandemic.

The COVID-19 Pandemic as an Opportunity for Unravelling the Causative Association between Respiratory Viruses and Pneumococcus-Associated Disease in Young Children: A Prospective Cohort Study (preprint)

BACKGROUNDIn young children, rates of community-acquired alveolar pneumonia (CAAP) or invasive pneumococcal disease (IPD) have been associated with respiratory syncytial virus (RSV), human metapneumovirus (hMPV), influenza (flu), and parainfluenza (PIV) (collectively termed here as pneumococcal disease-associated viruses [PDA-viruses]). However, their contribution to the pathogenesis of pneumococcal-associated disease has not yet been elucidated. The COVID-19 pandemic provided a unique opportunity to examine the question. METHODSThis prospective study comprised all children <5 years, living in southern Israel, during 2016 through 2021. The data were derived from multiple ongoing prospective cohort surveillance programs and include: hospital visits for CAAP, non-CAAP lower respiratory infections (LRI); nasopharyngeal pneumococcal carriage (<3 years of age); respiratory virus activity; all-ages COVID-19 episodes; and IPD in children <5 years (nationwide) A hierarchical negative binominal regression model was developed to estimate the proportion of the disease outcomes attributable to each of the viruses from monthly time series data, stratified by age and ethnicity. A separate model was fit for each outcome, with covariates that included a linear time trend, 12-month harmonic variables to capture unexplained seasonal variations, and the proportion of tests positive for each virus in that month. FINDINGSDuring 2016 through 2021, 3,204, 26,695, 257, and 619 episodes of CAAP, non-CAAP LRI, pneumococcal bacteremic pneumonia and non-pneumonia IPD, respectively, were reported. Compared to 2016-2019, broad declines in the disease outcomes were observed shortly after the pandemic surge, coincident with a complete disappearance of all PDA-viruses and continued circulation of rhinovirus (RhV) and adenovirus (AdV). From April 2021, off-season and abrupt surges of all disease outcomes occurred, associated with similar dynamics among the PDA-viruses, which re-emerged sequentially. Using our model fit to the entire 2016-2021 period, 82% (95% CI, 75-88%) of CAAP episodes in 2021 were attributable to the common respiratory viruses, as were 22%-31% of the other disease outcomes. Virus-specific contributions to CAAP were: RSV, 49% (95% CI, 43-55%); hMPV, 13% (10-17%); PIV, 11% (7-15%); flu, 7% (1-13%). RhV and AdV did not contribute. RSV was the main contributor in all outcomes, especially in infants. Pneumococcal carriage prevalence remained largely stable throughout the study. INTERPRETATIONRSV and hMPV play a critical role in the burden of CAAP and pneumococcal disease in children. Interventions targeting these viruses could have a secondary effect on the disease burden typically attributed to bacteria. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSCommunity-acquired alveolar pneumonia (CAAP) and invasive pneumococcal disease (IPD) in young children have often been associated with specific respiratory viruses, namely respiratory syncytial virus (RSV) human metapneumovirus (hMPV) influenza viruses (flu), and parainfluenza viruses (PIV) (termed in the current article pneumococcal disease-associated viruses [PDA-viruses]). However, their causative role as co-pathogens has not yet been fully elucidated. Pneumococcal conjugate vaccines (PCVs) significantly reduce hospitalization for viral lower respiratory infections (LRIs), suggesting that viral-pneumococcal coinfections are common and play a role in the pathogenesis of pneumococcal respiratory infections. However, in theory, the strongest demonstration of the causative role of respiratory viruses on pneumococcus-associated diseases would derive from measuring the impact of elimination of one or more of the respiratory viruses during the expected respiratory season. Shortly after the start of the COVID-19 pandemic, multiple reports have demonstrated reduced IPD and LRI rates among young children, coincident with dramatically reduced rates of the PDA-viruses globally. Initially, the reduced pneumococcal disease rates were attributed to non-pharmaceutical interventions that might reduce pneumococcal transmission in the community. However, continuous, virtually unchanged pneumococcal carriage rates were reported in multiple studies, strongly suggesting the reduced circulation of S. pneumoniae was not significantly contributing to disease reduction. Surprisingly, pneumococcus-associated diseases and PDA-viruses simultaneously re-emerged in 2021 during the off-season. In contrast to PDA-viruses, other viruses, such as adenovirus and rhinovirus did not show any of the patterns discussed above. We searched PubMed on June 1st, 2022, for studies since 2012 using the following terms: ("COVID-19" or "SARS-Cov-2") and ("S. pneumoniae" or "pneumococcus" or "IPD" or "respiratory virus" or respiratory syncytial virus" or "hMPV" or "influenza" or "parainfluenza" or "adenovirus" or "rhinovirus" or "lower respiratory infection"). The search was for English literature and unrestricted by date. Added value of this studyThree unique characteristics of the COVID-19 pandemic-induced abnormal dynamics, coupled with multiple ongoing cohort studies in young children, contributed to the historic opportunity to model and quantify the attributable role of the various common respiratory viruses to four pneumococcus-associated disease outcomes (CAAP, non-CAAP LRIs, pneumococcal bacteremic pneumonia and non-pneumonia IPD): First, the full seasonal disappearance of all PDA-viruses shortly after the start of the pandemic, in the presence of continuous, uninterrupted pneumococcal carriage and continuous unchanged rhinovirus and adenovirus activity. Second, the off-season resurgence of the PDA-viruses in 2021. Third, the sequential, rather than simultaneous, re-emergence of the PDA-viruses. The analysis in this study suggests that several of the respiratory viruses, particularly RSV and hMPV, play an important causative role in the pathogenesis of pneumococcal diseases and related conditions. Furthermore, the proportion attributable to each of the PDA-viruses for each of the four studied disease outcomes, and each of the age groups (<1, 1, and 2-4 years of age) could be demonstrated. Implication of all the available findingsOur findings add evidence about the absolute and relative contribution of common respiratory viruses to the burden of pneumococcal diseases and related conditions in young children, likely to be caused, at least in part, by virus-pneumococcus interaction or coinfections. The strong predominance of RSV contribution compared to other viruses in all studied disease outcomes suggests that interventions that target viruses could have secondary effects on the burden of diseases typically attributed to bacteria.

Detection of pneumococcus during hospitalization for SARS-CoV-2 (preprint)

Background. Infections with respiratory viruses (e.g., influenza, RSV) can increase the risk of severe pneumococcal infections. Likewise, pneumococcal co-infection is associated with poorer outcomes in viral respiratory infection. However, there are limited data describing the frequency of pneumococcus and SARS-CoV-2 co-infection and the role of co-infection in influencing COVID-19 severity. Methods. The study included patients admitted to Yale-New Haven Hospital who were symptomatic for respiratory infection and tested positive for SARS-CoV-2 during March-August 2020. Patients were tested for pneumococcus through culture-enrichment of saliva followed by RT-qPCR (to identify carriage) and serotype-specific urine antigen detection (UAD) assays (to identify presumed lower respiratory tract pneumococcal disease). Results. Among 148 subjects, the median age was 65 years; 54.7% were male; 50.7% had an ICU stay; 64.9% received antibiotics; 14.9% died while admitted. Pneumococcal carriage was detected in 3/96 (3.1%) individuals tested by saliva RT-qPCR. Additionally, pneumococcus was detected in 14/127 (11.0%) individuals tested by UAD, and more commonly in severe than moderate COVID-19 (OR: 2.20; 95% CI: [0.72, 7.48]); however, the numbers were small with a high degree of uncertainty. None of the UAD-positive individuals died. Conclusions. Pneumococcal LRTI, as detected by positive UAD, occurred in patients hospitalized with COVID-19. Moreover, pneumococcal LRTI was more common in those with more serious COVID-19 outcomes. Future studies should assess how pneumococcus and SARS-CoV-2 interact to influence COVID-19 severity in hospitalized patients.

Rapid emergence of SARS-CoV-2 Omicron variant is associated with an infection advantage over Delta in vaccinated persons (preprint)

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continues to shape the coronavirus disease 2019 (Covid-19) pandemic. The detection and rapid spread of the SARS-CoV-2 Omicron variant (lineage B.1.1.529) in Botswana and South Africa became a global concern because it contained 15 mutations in the spike protein immunogenic receptor binding domain and was less neutralized by sera derived from vaccinees compared to the previously dominant Delta variant. To investigate if Omicron is more likely than Delta to cause infections in vaccinated persons, we analyzed 37,877 nasal swab PCR tests conducted from 12-26 December 2021 and calculated the test positivity rates for each variant by vaccination status. We found that the positivity rate among unvaccinated persons was higher for Delta (5.2%) than Omicron (4.5%). We found similar results in persons who received a single vaccine dose. Conversely, our results show that Omicron had higher positivity rates than Delta among those who received two doses within five months (Omicron = 4.7% vs. Delta = 2.6%), two doses more than five months ago (4.2% vs. 2.9%), and three vaccine doses (2.2% vs. 0.9%). Our estimates of Omicron positivity rates in persons receiving one or two vaccine doses were not significantly lower than unvaccinated persons but were 49.7% lower after three doses. In comparison, the reduction in Delta positivity rates from unvaccinated to 2 vaccine doses was 45.6-49.6% and to 3 vaccine doses was 83.2%. Despite the higher positivity rates for Omicron in vaccinated persons, we still found that 91.2% of the Omicron infections in our study occurred in persons who were eligible for 1 or more vaccine doses at the time of PCR testing. In conclusion, escape from vaccine-induced immunity likely contributed to the rapid rise in Omicron infections.

Waning Effectiveness of the BNT162b2 Vaccine Against Infection in Adolescents (preprint)

Background: The short-term effectiveness of a two-dose regimen of the BioNTech/Pfizer mRNA BNT162b2 vaccine for adolescents has been demonstrated. However, little is known about the long-term effectiveness in this age group. It is known, though, that waning of vaccine-induced immunity against infection in adult populations is evident within a few months. Methods: Leveraging the centralized computerized database of Maccabi Healthcare Services (MHS), we conducted a matched case-control design for evaluating the association between time since vaccination and the incidence of infections, where two outcomes were evaluated separately: a documented SARS-CoV-2 infection (regardless of symptoms) and a symptomatic infection (COVID-19). Cases were defined as individuals aged 12 to 16 with a positive PCR test occurring between June 15 and December 8, 2021, when the Delta variant was dominant in Israel. Controls were adolescents who had not tested positive previously. Results: We estimated a peak vaccine effectiveness between 2 weeks and 3 months following receipt of the second dose, with 85% and 90% effectiveness against SARS-CoV-2 infection and COVID-19, respectively. However, in line with previous findings for adults, waning of vaccine effectiveness was evident in adolescents as well. Long-term protection conferred by the vaccine was reduced to 75-78% against infection and symptomatic infection, respectively, 3 to 5 months after the second dose, and waned to 58% against infection and 65% against COVID-19 after 5 months. Conclusions: Like adults, vaccine-induced protection against both SARS-CoV-2 infection and COVID-19 wanes with time, starting three months after inoculation and continuing for more than five months.

Short Term Reduction in the Odds of Testing Positive for SARS-CoV-2; a Comparison Between Two Doses and Three doses of the BNT162b2 Vaccine (preprint)

With the evidence of waning immunity of the BNT162b2 vaccine, a national third dose vaccination campaign was initiated in Israel during August 2021; other countries have announced their intention to administer a booster shot as well. Leveraging data from Maccabi Healthcare Services, we conducted a preliminary retrospective study aimed at evaluating initial short-term effectiveness of a three dose versus a two dose regimen against infection due to the Delta variant of SARS-CoV-2, using two complementary approaches; a test-negative design and a matched case-control design. We found that 7-13 days after the booster shot there is a 48-68% reduction in the odds of testing positive for SARS-CoV-2 infection and that 14-20 days after the booster the marginal effectiveness increases to 70-84%. Further studies are needed to determine the duration of protection conferred by the third dose and its effect on severe disease.

Decline in pneumococcal disease in young children during the COVID-19 pandemic associated with suppression of seasonal respiratory viruses, despite persistent pneumococcal carriage: A prospective cohort study (preprint)

Background: Invasive pneumococcal disease (IPD) declined during the COVID-19 pandemic. Previous studies hypothesized that this was due to reduced pneumococcal transmission resulting from non-pharmacological interventions. We used multiple ongoing cohort surveillance projects in children <5 years to test this hypothesis. Methods: The first SARS-CoV-2 cases were detected in February-2020, resulting in a full lockdown, followed by several partial restrictions. Data from ongoing surveillance projects captured the incidence dynamics of community-acquired alveolar pneumonia (CAAP), non-alveolar lower respiratory infections necessitating chest X-rays (NA-LRI), nasopharyngeal pneumococcal carriage in non-respiratory visits, nasopharyngeal respiratory virus detection (by PCR), and nationwide invasive pneumococcal disease (IPD). Monthly rates (January-2020 through February-2021 vs. mean monthly rates 2016-2019 [expected rates]) adjusted for age and ethnicity, were compared. Findings: CAAP and bacteremic pneumococcal pneumonia were strongly reduced (incidence rate ratios, [IRRs] 0.07 and 0.19, respectively); NA-LRI and non-pneumonia IPD were also reduced, with a lesser magnitude (IRRs, 0.46 and 0.42, respectively). In contrast, pneumococcal carriage prevalence was only slightly reduced and density of colonization and pneumococcal serotype distributions were similar to previous years. The pneumococcus-associated disease decline was temporally associated with a full suppression of RSV, influenza viruses, and hMPV, often implicated as co-pathogens with pneumococcus. In contrast, adenovirus, rhinovirus, and parainfluenza activities were within or above expected levels. Interpretation: Reductions in pneumococcal and pneumococcus-associated diseases occurring during the COVID-19 pandemic were not predominantly related to reduced pneumococcal transmission and carriage but were strongly associated with the complete disappearance of specific respiratory viruses. Funding: Partially funded by Pfizer, Inc.

Re-emergence of respiratory syncytial virus following the COVID-19 pandemic in the United States: a modeling study (preprint)

ImportanceRespiratory syncytial virus (RSV) is a leading cause of hospitalizations in young children. RSV largely disappeared in 2020 due to precautions taken because of the COVID-19 pandemic. Projecting the timing and intensity of the re-emergence of RSV and the age groups affected is crucial for planning for the administration of prophylactic antibodies and anticipating hospital capacity. ObjectiveTo project the potential timing and intensity of re-emergent RSV epidemics in different age groups. Design, Setting, ParticipantsMathematical models were used to reproduce the annual RSV epidemics before the COVID-19 pandemic in New York and California. These models were modified to project the trajectory of RSV epidemics in 2020-2025 under different scenarios with varying stringency of mitigation measures for SARS-CoV-2: 1) constant low RSV transmission rate from March 2020 to March 2021; 2) an immediate decrease in RSV transmission in March 2020 followed by a gradual increase in transmission until April 2021; 3) a decrease in non-household contacts from April to July 2020. Simulations also evaluated factors likely to impact the re-emergence of RSV epidemics, including introduction of virus from out-of-state sources and decreased transplacentally-acquired immunity in infants. Main Outcomes and MeasuresThe primary outcome of this study was defined as the predicted number of RSV hospitalizations each month in the entire population. Secondary outcomes included the age distribution of hospitalizations among children <5 years of age, incidence of any RSV infection, and incidence of RSV lower respiratory tract infection (LRI). ResultsIn the 2021-2022 RSV season, we expect that the lifting of mitigation measures and build-up of susceptibility will lead to a larger-than-normal RSV outbreak. We predict an earlier-than-usual onset in the upcoming RSV season if there is substantial external introduction of RSV. Among children 1-4 years of age, the incidence of RSV infections could be twice that of a typical RSV season, with infants <6 months of age having the greatest seasonal increase in the incidence of both severe RSV LRIs and hospitalizations. Conclusions and RelevancePediatric departments, including pediatric intensive care units, should be alert to large RSV outbreaks. Enhanced surveillance is required for both prophylaxis administration and hospital capacity management.

Vaccination with BNT162b2 reduces transmission of SARS-CoV-2 to household contacts in Israel (preprint)

The individual - level effectiveness of vaccines against clinical disease caused by SARS-CoV-2 is well-established. However, few studies have directly examined the effect of COVID-19 vaccines on transmission. We quantified the effectiveness of vaccination with BNT162b2 (Pfizer-BioNTech mRNA-based vaccine) against household transmission of SARS-CoV-2 in Israel. We fit two time-to-event models - a mechanistic transmission model and a regression model - to estimate vaccine effectiveness against susceptibility to infection and infectiousness given infection in household settings. Vaccine effectiveness against susceptibility to infection was 80-88%. For breakthrough infections among vaccinated individuals, the vaccine effectiveness against infectiousness was 41-79%. The overall vaccine effectiveness against transmission was 88.5%. Vaccination provides substantial protection against susceptibility to infection and slightly lower protection against infectiousness given infection, thereby reducing transmission of SARS-CoV-2 to household contacts.

Bayesian Model Averaging to Account for Model Uncertainty in Estimates of a Vaccine's Effectiveness (preprint)

Vaccine effectiveness (VE) studies are often conducted after the introduction of new vaccines to ensure they provide protection in real-world settings. Although susceptible to confounding, the test-negative case-control study design is the most efficient method to assess VE post-licensure. Control of confounding is often needed during the analyses, which is most efficiently done through multivariable modeling. When a large number of potential confounders are being considered, it can be challenging to know which variables need to be included in the final model. This paper highlights the importance of considering model uncertainty by re-analyzing a Lyme VE study using several confounder selection methods. We propose an intuitive Bayesian Model Averaging (BMA) framework for this task and compare the performance of BMA to that of traditional single-best-model-selection methods. We demonstrate how BMA can be advantageous in situations when there is uncertainty about model selection by systematically considering alternative models and increasing transparency.

Variations in state-level SARS-COV-2 testing recommendations in the United States, March-July 2020 (preprint)

Testing recommendations for COVID-19 in the United States have varied by state and over time in the spring and summer of 2020. As of July 2020, 16 states recommended testing asymptomatic members of the general public. The rate of COVID-19 tests reported in each state correlates with more permissive testing recommendations and with higher epidemic intensity. Higher per capita testing was associated with more complete reporting of COVID-19 deaths, which is a fundamental requirement for analyzing the pandemic. Coordinated, consistent guidelines for COVID-19 testing should be a high priority for state and national health systems.

Pooling saliva to increase SARS-CoV-2 testing capacity (preprint)

Expanding testing capabilities is integral to managing the further spread of SARS-CoV-2 and developing reopening strategies, particularly in regards to identifying and isolating asymptomatic and pre-symptomatic individuals. Central to meeting testing demands are specimens that can be easily and reliably collected and laboratory capacity to rapidly ramp up to scale. We and others have demonstrated that high and consistent levels of SARS-CoV-2 RNA can be detected in saliva from COVID-19 inpatients, outpatients, and asymptomatic individuals. As saliva collection is non-invasive, extending this strategy to test pooled saliva samples from multiple individuals could thus provide a simple method to expand testing capacity. However, hesitation towards pooled sample testing arises due to the dilution of positive samples, potentially shifting weakly positive samples below the detection limit for SARS-CoV-2 and thereby decreasing the sensitivity. Here, we investigated the potential of pooling saliva samples by 5, 10, and 20 samples prior to RNA extraction and RT-qPCR detection of SARS-CoV-2. Based on samples tested, we conservatively estimated a reduction of 7.41%, 11.11%, and 14.81% sensitivity, for each of the pool sizes, respectively. Using these estimates we modeled anticipated changes in RT-qPCR cycle threshold to show the practical impact of pooling on results of SARS-CoV-2 testing. In tested populations with greater than 3% prevalence, testing samples in pools of 5 requires the least overall number of tests. Below 1% however, pools of 10 or 20 are more beneficial and likely more supportive of ongoing surveillance strategies.

SARS-CoV-2 RNA concentrations in primary municipal sewage sludge as a leading indicator of COVID-19 outbreak dynamics (preprint)

We report a time course of SARS-CoV-2 RNA concentrations in primary sewage sludge during the Spring COVID-19 outbreak in a northeastern U.S. metropolitan area. SARS-CoV-2 RNA was detected in all environmental samples, and when adjusted for the time lag, the virus RNA concentrations tracked the COVID-19 epidemiological curve. SARS-CoV-2 RNA concentrations were a leading indicator of community infection ahead of compiled COVID-19 testing data and local hospital admissions. Decisions to implement or relax public health measures and restrictions require timely information on outbreak dynamics in a community.

The impact of changes in diagnostic testing practices on estimates of COVID-19 transmission in the United States (preprint)

Estimates of the reproductive number for novel pathogens such as SARS-CoV-2 are essential for understanding the potential trajectory of the epidemic and the level of intervention that is needed to bring the epidemic under control. However, most methods for estimating the basic reproductive number (R0) and time-varying effective reproductive number (Rt) assume that the fraction of cases detected and reported is constant through time. We explore the impact of secular changes in diagnostic testing and reporting on estimates of R0 and Rt using simulated data. We then compare these patterns to data on reported cases of COVID-19 and testing practices from different United States (US) states. We find that changes in testing practices and delays in reporting can result in biased estimates of R0 and Rt. Examination of changes in the daily number of tests conducted and the percent of patients testing positive may be helpful for identifying the potential direction of bias. Changes in diagnostic testing and reporting processes should be monitored and taken into consideration when interpreting estimates of the reproductive number of COVID-19.