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

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

ImportanceThe 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. ObjectiveQuantify 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). DesignAnalysis 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 participantsGeneral population of the United States, enrollees in the VA, and active users of VA healthcare. Exposure and main outcomeChanges in rates of death from any cause during the COVID-19 pandemic in 2020 compared to previous years. ResultsSharp 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 RelevanceDespite 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

BACKGROUNDIn young children, rates of lower respiratory infections (LRI) and invasive pneumococcal disease (IPD) have been associated with respiratory syncytial virus (RSV), human metapneumovirus (hMPV), influenza (flu), and parainfluenza (PIV) (collectively termed here as pneumonia and pneumococcal disease-associated viruses [PDA-viruses]). However, their contribution to the pathogenesis of these disease endpoints 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 previously collected in multiple ongoing prospective surveillance programs and include: hospital visits for community-acquired alveolar pneumonia (CAAP), non-CAAP LRI; nasopharyngeal pneumococcal carriage (<3 years of age); respiratory virus activity; and nationwide, all-ages COVID-19 episodes and IPD in children <5 years. A hierarchical statistical model was developed to estimate the proportion of the different clinical endpoints attributable to each virus from monthly time series data, stratified by age and ethnicity. A separate model was fit for each endpoint, 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 endpoints 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 endpoints 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 endpoints. 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 endpoints, 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 burden of disease typically attributed to bacteria. FUNDINGThere was no funding for this study. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSLower respiratory infections (LRI) 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 pneumonia and pneumococcal disease-associated viruses [PDA-viruses]). However, their causative role as co-pathogens has not yet been fully elucidated. There is already ample evidence that bacteria and viruses interact to cause severe disease. This could be seen after the introduction of pneumococcal conjugate vaccines (PCVs), when there was a significant reduction in hospitalisation for viral lower respiratory infections (LRIs). This suggests that viral-pneumococcal coinfections are common and play a role in the pathogenesis of pneumococcal respiratory infections. To demonstrate the contribution of viruses to the burden of pneumococcal disease specifically, and pneumonia in general, it would be necessary to eliminate one or more of the respiratory viruses. Shortly after the start of the COVID-19 pandemic, multiple reports demonstrated reduced IPD and LRI rates among young children, coincident with dramatically reduced rates of the PDA-viruses globally. Initially, the reduced rates of pneumococcal disease 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 2020 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 endpoints (in particular community-acquired alveolar pneumonia (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 other respiratory infections. Furthermore, the proportion attributable to each of the PDA-viruses for each of the four studied disease endpoints, and each of the age groups (<1, 1, and 2-4 years of age) could be estimated. Implication of all the available findingsOur findings add evidence about the absolute and relative contribution of common respiratory viruses to the burden of pneumonia and pneumococcal diseases and related conditions in young children. The strong contribution of RSV to disease burden compared to other viruses in all studied disease endpoints 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

BackgroundInfections 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. MethodsThe 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). ResultsAmong 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. ConclusionsPneumococcal 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. One Sentence SummaryPneumococcal lower respiratory tract infection, as detected by positive UAD, occurred in patients hospitalized with COVID-19 at rates similar to those reported prepandemic.

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

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

BackgroundThe 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. MethodsLeveraging 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. ResultsWe 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. ConclusionsLike 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

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

BackgroundInvasive 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. MethodsThe 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. FindingsCAAP and bacteremic pneumococcal pneumonia were strongly reduced (incidence rate ratios, [IRRs] 0{eta}07 and 0{eta}19, respectively); NA-LRI and non-pneumonia IPD were also reduced, with a lesser magnitude (IRRs, 0{eta}46 and 0{eta}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. InterpretationReductions 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. FundingPartially funded by Pfizer, Inc.

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

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

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. One-Sentence SummaryVaccination reduced both the rate of infection with SARS-CoV-2 and transmission to household contacts in Israel.

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

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

BackgroundState health departments have been responsible for prioritizing and allocating SARS-CoV-2 tests and vaccines. Testing and vaccination recommendations in the United States varied by state and over time, as did vaccine rollouts, COVID-19 cases, and estimates of excess mortality. MethodsWe compiled data about COVID-19 testing, cases, and deaths, and excess pneumonia + influenza + COVID-19 deaths to assess relationships between testing recommendations, per capita tests performed, epidemic intensity, and excess mortality during the early months of the COVID-19 pandemic in the United States. We compiled further data about state-level SARS-CoV-2 vaccination policies and doses administered during the early months of the vaccine rollout. ResultsAs of July 2020, 16 states recommended testing asymptomatic members of the general public. The rate of COVID-19 tests reported in each state correlated with more inclusive 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. Testing per capita during the first three months was associated with vaccination per capita in the first three months of rollout. Per capita vaccine doses in each state were not associated with adherence to national guidelines. ConclusionsReported deaths due to COVID-19 likely represent an undercount of the true burden of the pandemic. States that struggled with testing rollout have also frequently struggled with vaccine rollout. Coordinated, consistent guidelines for COVID-19 testing and vaccine administration should be a high priority for state and national health systems.

Pooling saliva to increase SARS-CoV-2 testing capacity

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

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

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.