Age-specific mortality and immunity patterns of SARS-CoV-2.

Estimating the size of the coronavirus disease 2019 (COVID-19) pandemic and the infection severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is made challenging by inconsistencies in the available data. The number of deaths associated with COVID-19 is often used as a key indicator for the size of the epidemic, but the observed number of deaths represents only a minority of all infections1,2. In addition, the heterogeneous burdens in nursing homes and the variable reporting of deaths of older individuals can hinder direct comparisons of mortality rates and the underlying levels of transmission across countries3. Here we use age-specific COVID-19-associated death data from 45 countries and the results of 22 seroprevalence studies to investigate the consistency of infection and fatality patterns across multiple countries. We find that the age distribution of deaths in younger age groups (less than 65 years of age) is very consistent across different settings and demonstrate how these data can provide robust estimates of the share of the population that has been infected. We estimate that the infection fatality ratio is lowest among 5-9-year-old children, with a log-linear increase by age among individuals older than 30 years. Population age structures and heterogeneous burdens in nursing homes explain some but not all of the heterogeneity between countries in infection fatality ratios. Among the 45 countries included in our analysis, we estimate that approximately 5% of these populations had been infected by 1 September 2020, and that much higher transmission rates have probably occurred in a number of Latin American countries. This simple modelling framework can help countries to assess the progression of the pandemic and can be applied in any scenario for which reliable age-specific death data are available.

Reconstructing household transmission dynamics to estimate the infectiousness of asymptomatic influenza virus infections.

There has long been controversy over the potential for asymptomatic cases of the influenza virus to have the capacity for onward transmission, but recognition of asymptomatic transmission of COVID-19 stimulates further research into this topic. Here, we develop a Bayesian methodology to analyze detailed data from a large cohort of 727 households and 2515 individuals in the 2009 pandemic influenza A(H1N1) outbreak in Hong Kong to characterize household transmission dynamics and to estimate the relative infectiousness of asymptomatic versus symptomatic influenza cases. The posterior probability that asymptomatic cases [36% of cases; 95% credible interval (CrI): 32%, 40%] are less infectious than symptomatic cases is 0.82, with estimated relative infectiousness 0.57 (95% CrI: 0.11, 1.54). More data are required to strengthen our understanding of the contribution of asymptomatic cases to the spread of influenza.

Analytical framework to evaluate and optimize the use of imperfect diagnostics to inform outbreak response: Application to the 2017 plague epidemic in Madagascar.

During outbreaks, the lack of diagnostic "gold standard" can mask the true burden of infection in the population and hamper the allocation of resources required for control. Here, we present an analytical framework to evaluate and optimize the use of diagnostics when multiple yet imperfect diagnostic tests are available. We apply it to laboratory results of 2,136 samples, analyzed with 3 diagnostic tests (based on up to 7 diagnostic outcomes), collected during the 2017 pneumonic (PP) and bubonic plague (BP) outbreak in Madagascar, which was unprecedented both in the number of notified cases, clinical presentation, and spatial distribution. The extent of these outbreaks has however remained unclear due to nonoptimal assays. Using latent class methods, we estimate that 7% to 15% of notified cases were Yersinia pestis-infected. Overreporting was highest during the peak of the outbreak and lowest in the rural settings endemic to Y. pestis. Molecular biology methods offered the best compromise between sensitivity and specificity. The specificity of the rapid diagnostic test was relatively low (PP: 82%, BP: 85%), particularly for use in contexts with large quantities of misclassified cases. Comparison with data from a subsequent seasonal Y. pestis outbreak in 2018 reveal better test performance (BP: specificity 99%, sensitivity: 91%), indicating that factors related to the response to a large, explosive outbreak may well have affected test performance. We used our framework to optimize the case classification and derive consolidated epidemic trends. Our approach may help reduce uncertainties in other outbreaks where diagnostics are imperfect.

An ensemble model based on early predictors to forecast COVID-19 health care demand in France.

Short-term forecasting of the COVID-19 pandemic is required to facilitate the planning of COVID-19 health care demand in hospitals. Here, we evaluate the performance of 12 individual models and 19 predictors to anticipate French COVID-19-related health care needs from September 7, 2020, to March 6, 2021. We then build an ensemble model by combining the individual forecasts and retrospectively test this model from March 7, 2021, to July 6, 2021. We find that the inclusion of early predictors (epidemiological, mobility, and meteorological predictors) can halve the rms error for 14-d­ahead forecasts, with epidemiological and mobility predictors contributing the most to the improvement. On average, the ensemble model is the best or second-best model, depending on the evaluation metric. Our approach facilitates the comparison and benchmarking of competing models through their integration in a coherent analytical framework, ensuring that avenues for future improvements can be identified.

Comparing the Performance of Three Models Incorporating Weather Data to Forecast Dengue Epidemics in Reunion Island, 2018-2019.

We developed mathematical models to analyze a large dengue virus (DENV) epidemic in Reunion Island in 2018-2019. Our models captured major drivers of uncertainty including the complex relationship between climate and DENV transmission, temperature trends, and underreporting. Early assessment correctly concluded that persistence of DENV transmission during the austral winter 2018 was likely and that the second epidemic wave would be larger than the first one. From November 2018, the detection probability was estimated at 10%-20% and, for this range of values, our projections were found to be remarkably accurate. Overall, we estimated that 8% and 18% of the population were infected during the first and second wave, respectively. Out of the 3 models considered, the best-fitting one was calibrated to laboratory entomological data, and accounted for temperature but not precipitation. This study showcases the contribution of modeling to strengthen risk assessments and planning of national and local authorities.

Household Transmission Dynamics of Asymptomatic SARS-CoV-2-Infected Children: A Multinational, Controlled Case-Ascertained Prospective Study.

BACKGROUND: Asymptomatic SARS-CoV-2 infection in children is highly prevalent but its acute and chronic implications have been minimally described. METHODS: In this controlled case-ascertained household transmission study, we recruited asymptomatic children <18 years with SARS-CoV-2 nucleic acid testing performed at 12 tertiary care pediatric institutions in Canada and the United States. We attempted to recruit all test-positive children and 1 to 3 test-negative, site-matched controls. After 14 days' follow-up we assessed the clinical (ie, symptomatic) and combined (ie, test-positive, or symptomatic) secondary attack rates (SARs) among household contacts. Additionally, post-COVID-19 condition (PCC) was assessed in SARS-CoV-2-positive participating children after 90 days' follow-up. RESULTS: A total of 111 test-positive and 256 SARS-CoV-2 test-negative asymptomatic children were enrolled between January 2021 and April 2022. After 14 days, excluding households with co-primary cases, the clinical SAR among household contacts of SARS-CoV-2-positive and -negative index children was 10.6% (19/179; 95% CI: 6.5%-16.1%) and 2.0% (13/663; 95% CI: 1.0%-3.3%), respectively (relative risk = 5.4; 95% CI: 2.7-10.7). In households with a SARS-CoV-2-positive index child, age <5 years, being pre-symptomatic (ie, developed symptoms after test), and testing positive during Omicron and Delta circulation periods (vs earlier) were associated with increased clinical and combined SARs among household contacts. Among 77 asymptomatic SARS-CoV-2-infected children with 90-day follow-up, 6 (7.8%; 95% CI: 2.9%-16.2%) reported PCC. CONCLUSIONS: Asymptomatic SARS-CoV-2-infected children, especially those <5 years, are important contributors to household transmission, with 1 in 10 exposed household contacts developing symptomatic illness within 14 days. Asymptomatic SARS-CoV-2-infected children may develop PCC.

Addressing current limitations of household transmission studies by collecting contact data.

Modeling studies of household transmission data have helped characterize the role of children in influenza and COVID-19 epidemics. However, estimates from these studies may be biased since they do not account for the heterogeneous nature of household contacts. Here, we quantified the impact of contact heterogeneity between household members on the estimation of child relative susceptibility and infectivity. We simulated epidemics of SARS-CoV-2-like and influenza-like infections in a synthetic population of 1,000 households assuming heterogeneous contact levels. Relative contact frequencies were derived from a household contact study according to which contacts are more frequent in the father-mother pair, followed by the child-mother, child-child, and finally child-father pairs. Child susceptibility and infectivity were then estimated while accounting for heterogeneous contacts or not. When ignoring contact heterogeneity, child relative susceptibility was underestimated by approximately 20% in the two disease scenarios. Child relative infectivity was underestimated by 20% when children and adults had different infectivity levels. These results are sensitive to our assumptions of European-style household contact patterns; but they highlight that household studies collecting both disease and contact data are needed to assess the role of complex household contact behavior on disease transmission and improve estimation of key biological parameters.

Decreased risk of non-influenza respiratory infection after influenza B virus infection in children.

Previous studies suggest that influenza virus infection may provide temporary non-specific immunity and hence lower the risk of non-influenza respiratory virus infection. In a randomized controlled trial of influenza vaccination, 1 330 children were followed-up in 2009-2011. Respiratory swabs were collected when they reported acute respiratory illness and tested against influenza and other respiratory viruses. We used Poisson regression to compare the incidence of non-influenza respiratory virus infection before and after influenza virus infection. Based on 52 children with influenza B virus infection, the incidence rate ratio (IRR) of non-influenza respiratory virus infection after influenza virus infection was 0.47 (95% confidence interval: 0.27-0.82) compared with before infection. Simulation suggested that this IRR was 0.87 if the temporary protection did not exist. We identified a decreased risk of non-influenza respiratory virus infection after influenza B virus infection in children. Further investigation is needed to determine if this decreased risk could be attributed to temporary non-specific immunity acquired from influenza virus infection.

Reconstruction of antibody dynamics and infection histories to evaluate dengue risk.

As with many pathogens, most dengue infections are subclinical and therefore unobserved 1 . Coupled with limited understanding of the dynamic behaviour of potential serological markers of infection, this observational problem has wide-ranging implications, including hampering our understanding of individual- and population-level correlates of infection and disease risk and how these change over time, between assay interpretations and with cohort design. Here we develop a framework that simultaneously characterizes antibody dynamics and identifies subclinical infections via Bayesian augmentation from detailed cohort data (3,451 individuals with blood draws every 91 days, 143,548 haemagglutination inhibition assay titre measurements)2,3. We identify 1,149 infections (95% confidence interval, 1,135-1,163) that were not detected by active surveillance and estimate that 65% of infections are subclinical. After infection, individuals develop a stable set point antibody load after one year that places them within or outside a risk window. Individuals with pre-existing titres of ≤1:40 develop haemorrhagic fever 7.4 (95% confidence interval, 2.5-8.2) times more often than naive individuals compared to 0.0 times for individuals with titres >1:40 (95% confidence interval: 0.0-1.3). Plaque reduction neutralization test titres ≤1:100 were similarly associated with severe disease. Across the population, variability in the size of epidemics results in large-scale temporal changes in infection and disease risk that correlate poorly with age.

Impact of vaccination against severe COVID-19 in the French population aged 50 years and above: a retrospective population-based study.

BACKGROUND: Given the widespread implementation of COVID-19 vaccination to mitigate the pandemic from the end of 2020, it is important to retrospectively evaluate its impact, in particular by quantifying the number of severe outcomes prevented through vaccination. METHODS: We estimated the number of hospitalizations, intensive care unit (ICU) admissions and deaths directly averted by vaccination in France, in people aged ≥ 50 years, from December 2020 to March 2022, based on (1) the number of observed events, (2) vaccination coverage, and (3) vaccine effectiveness. We accounted for the effect of primary vaccination and the first booster dose, the circulating variants, the age groups, and the waning of vaccine-induced protection over time. RESULTS: An estimated 480,150 (95% CI: 260,072-582,516) hospitalizations, 132,156 (50,409-157,767) ICU admissions and 125,376 (53,792-152,037) deaths were directly averted by vaccination in people aged ≥ 50 years, which corresponds to a reduction of 63.2% (48.2-67.6), 68.7% (45.6-72.4) and 62.7% (41.9-67.1) respectively, compared to what would have been expected without vaccination over the study period. An estimated 5852 (2285-6853) deaths were directly averted among the 50-59 years old, 16,837 (6568-19,473) among the 60-69 years old, 32,136 (13,651-36,758) among the 70-79 years old and 70,551 (31,288-88,953) among the ≥ 80 years old. CONCLUSIONS: The vaccination campaign in France considerably reduced COVID-19 morbidity and mortality, as well as stress on the healthcare system.

Impact of palmiped farm density on the resilience of the poultry sector to highly pathogenic avian influenza H5N8 in France.

We analysed the interplay between palmiped farm density and the vulnerability of the poultry production system to highly pathogenic avian influenza (HPAI) H5N8. To do so, we used a spatially-explicit transmission model, which was calibrated to reproduce the observed spatio-temporal distribution of outbreaks in France during the 2016-2017 epidemic of HPAI. Six scenarios were investigated, in which the density of palmiped farms was decreased in the municipalities with the highest palmiped farm density. For each of the six scenarios, we first calculated the spatial distribution of the basic reproduction number (R0), i.e. the expected number of farms a particular farm would be likely to infect, should all other farms be susceptible. We also ran in silico simulations of the adjusted model for each scenario to estimate epidemic sizes and time-varying effective reproduction numbers. We showed that reducing palmiped farm density in the densest municipalities decreased substantially the size of the areas with high R0 values (> 1.5). In silico simulations suggested that reducing palmiped farm density, even slightly, in the densest municipalities was expected to decrease substantially the number of affected poultry farms and therefore provide benefits to the poultry sector as a whole. However, they also suggest that it would not have been sufficient, even in combination with the intervention measures implemented during the 2016-2017 epidemic, to completely prevent the virus from spreading. Therefore, the effectiveness of alternative structural preventive approaches now needs to be assessed, including flock size reduction and targeted vaccination.

Impact of non-pharmaceutical interventions, weather, vaccination, and variants on COVID-19 transmission across departments in France.

BACKGROUND: Multiple factors shape the temporal dynamics of the COVID-19 pandemic. Quantifying their relative contributions is key to guide future control strategies. Our objective was to disentangle the individual effects of non-pharmaceutical interventions (NPIs), weather, vaccination, and variants of concern (VOC) on local SARS-CoV-2 transmission. METHODS: We developed a log-linear model for the weekly reproduction number (R) of hospital admissions in 92 French metropolitan departments. We leveraged (i) the homogeneity in data collection and NPI definitions across departments, (ii) the spatial heterogeneity in the timing of NPIs, and (iii) an extensive observation period (14 months) covering different weather conditions, VOC proportions, and vaccine coverage levels. FINDINGS: Three lockdowns reduced R by 72.7% (95% CI 71.3-74.1), 70.4% (69.2-71.6) and 60.7% (56.4-64.5), respectively. Curfews implemented at 6/7 pm and 8/9 pm reduced R by 34.3% (27.9-40.2) and 18.9% (12.04-25.3), respectively. School closures reduced R by only 4.9% (2.0-7.8). We estimated that vaccination of the entire population would have reduced R by 71.7% (56.4-81.6), whereas the emergence of VOC (mainly Alpha during the study period) increased transmission by 44.6% (36.1-53.6) compared with the historical variant. Winter weather conditions (lower temperature and absolute humidity) increased R by 42.2% (37.3-47.3) compared to summer weather conditions. Additionally, we explored counterfactual scenarios (absence of VOC or vaccination) to assess their impact on hospital admissions. INTERPRETATION: Our study demonstrates the strong effectiveness of NPIs and vaccination and quantifies the role of weather while adjusting for other confounders. It highlights the importance of retrospective evaluation of interventions to inform future decision-making.

Estimated protection against COVID-19 based on predicted neutralisation titres from multiple antibody measurements in a longitudinal cohort, France, April 2020 to November 2021.

BackgroundThe risk of SARS-CoV-2 (re-)infection remains present given waning of vaccine-induced and infection-acquired immunity, and ongoing circulation of new variants.AimTo develop a method that predicts virus neutralisation and disease protection based on variant-specific antibody measurements to SARS-CoV-2 antigens.MethodsTo correlate antibody and neutralisation titres, we collected 304 serum samples from individuals with either vaccine-induced or infection-acquired SARS-CoV-2 immunity. Using the association between antibody and neutralisation titres, we developed a prediction model for SARS-CoV-2-specific neutralisation titres. From predicted neutralising titres, we inferred protection estimates to symptomatic and severe COVID-19 using previously described relationships between neutralisation titres and protection estimates. We estimated population immunity in a French longitudinal cohort of 905 individuals followed from April 2020 to November 2021.ResultsWe demonstrated a strong correlation between anti-SARS-CoV-2 antibodies measured using a low cost high-throughput assay and antibody response capacity to neutralise live virus. Participants with a single vaccination or immunity caused by infection were especially vulnerable to symptomatic or severe COVID-19. While the median reduced risk of COVID-19 from Delta variant infection in participants with three vaccinations was 96% (IQR: 94-98), median reduced risk among participants with infection-acquired immunity was only 42% (IQR: 22-66).ConclusionOur results are consistent with data from vaccine effectiveness studies, indicating the robustness of our approach. Our multiplex serological assay can be readily adapted to study new variants and provides a framework for development of an assay that would include protection estimates.

Transmission of Antimicrobial Resistant Yersinia pestis During a Pneumonic Plague Outbreak.

BACKGROUND: Pneumonic plague (PP), caused by Yersinia pestis, is the most feared clinical form of plague due to its rapid lethality and potential to cause outbreaks. PP outbreaks are now rare due to antimicrobial therapy. METHODS: A PP outbreak in Madagascar involving transmission of a Y. pestis strain resistant to streptomycin, the current recommended first-line treatment in Madagascar, was retrospectively characterized using epidemiology, clinical diagnostics, molecular characterization, and animal studies. RESULTS: The outbreak occurred in February 2013 in the Faratsiho district of Madagascar and involved 22 cases, including 3 untreated fatalities. The 19 other cases participated in funeral practices for the fatal cases and fully recovered after combination antimicrobial therapy: intramuscular streptomycin followed by oral co-trimoxazole. The Y. pestis strain that circulated during this outbreak is resistant to streptomycin resulting from a spontaneous point mutation in the 30S ribosomal protein S12 (rpsL) gene. This same mutation causes streptomycin resistance in 2 unrelated Y. pestis strains, one isolated from a fatal PP case in a different region of Madagascar in 1987 and another isolated from a fatal PP case in China in 1996, documenting this mutation has occurred independently at least 3 times in Y. pestis. Laboratory experiments revealed this mutation has no detectable impact on fitness or virulence, and revertants to wild-type are rare in other species containing it, suggesting Y. pestis strains containing it could persist in the environment. CONCLUSIONS: Unique antimicrobial resistant (AMR) strains of Y. pestis continue to arise in Madagascar and can be transmitted during PP outbreaks.

Measuring Basic Reproduction Number to Assess Effects of Nonpharmaceutical Interventions on Nosocomial SARS-CoV-2 Transmission.

Outbreaks of SARS-CoV-2 infection frequently occur in hospitals. Preventing nosocomial infection requires insight into hospital transmission. However, estimates of the basic reproduction number (R0) in care facilities are lacking. Analyzing a closely monitored SARS-CoV-2 outbreak in a hospital in early 2020, we estimated the patient-to-patient transmission rate and R0. We developed a model for SARS-CoV-2 nosocomial transmission that accounts for stochastic effects and undetected infections and fit it to patient test results. The model formalizes changes in testing capacity over time, and accounts for evolving PCR sensitivity at different stages of infection. R0 estimates varied considerably across wards, ranging from 3 to 15 in different wards. During the outbreak, the hospital introduced a contact precautions policy. Our results strongly support a reduction in the hospital-level R0 after this policy was implemented, from 8.7 to 1.3, corresponding to a policy efficacy of 85% and demonstrating the effectiveness of nonpharmaceutical interventions.

Impact of BNT162b2 Vaccination and Isolation on SARS-CoV-2 Transmission in Israeli Households: An Observational Study.

Several studies have characterized the effectiveness of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. However, estimates of their impact on transmissibility remain limited. Here, we evaluated the impact of isolation and vaccination (7 days after the second dose) on SARS-CoV-2 transmission within Israeli households. From December 2020 to April 2021, confirmed cases were identified among health-care workers of the Sheba Medical Centre and their family members. Recruited households were followed up with repeated PCR for at least 10 days after case confirmation. Data were analyzed using a data augmentation Bayesian framework. A total of 210 households with 215 index cases were enrolled; 269 out of 667 (40%) susceptible household contacts developed a SARS-CoV-2 infection. Of those, 170 (63%) developed symptoms. Compared with unvaccinated and unisolated adult/teenager (aged >12 years) contacts, vaccination reduced the risk of infection among unisolated adult/teenager contacts (relative risk (RR) = 0.21, 95% credible interval (CrI): 0.08, 0.44), and isolation reduced the risk of infection among unvaccinated adult/teenager (RR = 0.12, 95% CrI: 0.06, 0.21) and child contacts (RR = 0.17, 95% CrI: 0.08, 0.32). Infectivity was reduced in vaccinated cases (RR = 0.25, 95% CrI: 0.06, 0.77). Within households, vaccination reduces both the risk of infection and of transmission if infected. When contacts were unvaccinated, isolation also led to important reductions in the risk of transmission.

Transmission of Nipah Virus - 14 Years of Investigations in Bangladesh.

BACKGROUND: Nipah virus is a highly virulent zoonotic pathogen that can be transmitted between humans. Understanding the dynamics of person-to-person transmission is key to designing effective interventions. METHODS: We used data from all Nipah virus cases identified during outbreak investigations in Bangladesh from April 2001 through April 2014 to investigate case-patient characteristics associated with onward transmission and factors associated with the risk of infection among patient contacts. RESULTS: Of 248 Nipah virus cases identified, 82 were caused by person-to-person transmission, corresponding to a reproduction number (i.e., the average number of secondary cases per case patient) of 0.33 (95% confidence interval [CI], 0.19 to 0.59). The predicted reproduction number increased with the case patient's age and was highest among patients 45 years of age or older who had difficulty breathing (1.1; 95% CI, 0.4 to 3.2). Case patients who did not have difficulty breathing infected 0.05 times as many contacts (95% CI, 0.01 to 0.3) as other case patients did. Serologic testing of 1863 asymptomatic contacts revealed no infections. Spouses of case patients were more often infected (8 of 56 [14%]) than other close family members (7 of 547 [1.3%]) or other contacts (18 of 1996 [0.9%]). The risk of infection increased with increased duration of exposure of the contacts (adjusted odds ratio for exposure of >48 hours vs. ≤1 hour, 13; 95% CI, 2.6 to 62) and with exposure to body fluids (adjusted odds ratio, 4.3; 95% CI, 1.6 to 11). CONCLUSIONS: Increasing age and respiratory symptoms were indicators of infectivity of Nipah virus. Interventions to control person-to-person transmission should aim to reduce exposure to body fluids. (Funded by the National Institutes of Health and others.).

Epidemiology and control of SARS-CoV-2 epidemics in partially vaccinated populations: a modeling study applied to France.

BACKGROUND: Vaccination is expected to change the epidemiology and management of SARS-CoV-2 epidemics. METHODS: We used an age-stratified compartmental model calibrated to French data to anticipate these changes and determine implications for the control of an autumn epidemic. We assumed vaccines reduce the risk of hospitalization, infection, and transmission if infected by 95%, 60%, and 50%, respectively. RESULTS: In our baseline scenario characterized by basic reproduction number R0=5 and a vaccine coverage of 70-80-90% among 12-17, 18-59, and ≥ 60 years old, important stress on healthcare is expected in the absence of measures. Unvaccinated adults ≥60 years old represent 3% of the population but 43% of hospitalizations. Given limited vaccine coverage, children aged 0-17 years old represent a third of infections and are responsible for almost half of transmissions. Unvaccinated individuals have a disproportionate contribution to transmission so that measures targeting them may help maximize epidemic control while minimizing costs for society compared to non-targeted approaches. Of all the interventions considered including repeated testing and non-pharmaceutical measures, vaccination of the unvaccinated is the most effective. CONCLUSIONS: With the Delta variant, vaccinated individuals are well protected against hospitalization but remain at risk of infection and should therefore apply protective behaviors (e.g., mask-wearing). Targeting non-vaccinated individuals may maximize epidemic control while minimizing costs for society. Vaccinating children protects them from the deleterious effects of non-pharmaceutical measures. Control strategies should account for the changing SARS-CoV-2 epidemiology.

The transfer of maternal antibodies and dynamics of maternal and natural infection-induced antibodies against coxsackievirus A16 in Chinese children 0-13 years of age: a longitudinal cohort study.

BACKGROUND: A major hand-foot-and-mouth disease (HFMD) pathogen, coxsackievirus A16 (CVA16), has predominated in several of the last 10 years and caused the largest number of HFMD outbreaks between 2011 and 2018 in China. We evaluated the efficacy of maternal anti-CVA16 antibody transfer via the placenta and explored the dynamics of maternal and natural infection-induced neutralizing antibodies in children. METHODS: Two population-based longitudinal cohorts in southern China were studied during 2013-2018. Participants were enrolled in autumn 2013, including 2475 children aged 1-9 years old and 1066 mother-neonate pairs, and followed for 3 years. Blood/cord samples were collected for CVA16-neutralizing antibody detection. The maternal antibody transfer efficacy, age-specific seroprevalence, geometric mean titre (GMT) and immune response kinetics were estimated. RESULTS: The average maternal antibody transfer ratio was 0.88 (95% CI 0.80-0.96). Transferred maternal antibody levels declined rapidly (half-life: 2.0 months, 95% CI 1.9-2.2 months). The GMT decayed below the positive threshold (8) by 1.5 months of age. Due to natural infections, it increased above 8 after 1.4 years and reached 32 by 5 years of age, thereafter dropping slightly. Although the average duration of maternal antibody-mediated protection was < 3 months, the duration extended to 6 months on average for mothers with titres ≥ 64. CONCLUSIONS: Anti-CVA16 maternal antibodies are efficiently transferred to neonates, but their levels decline quickly. Children aged 0-5 years are the main susceptible population and should be protected by CVA16 vaccination, with the optimal vaccination time between 1.5 months and 1 year of age.

Minimal transmission in an influenza A (H3N2) human challenge-transmission model within a controlled exposure environment.

Uncertainty about the importance of influenza transmission by airborne droplet nuclei generates controversy for infection control. Human challenge-transmission studies have been supported as the most promising approach to fill this knowledge gap. Healthy, seronegative volunteer 'Donors' (n = 52) were randomly selected for intranasal challenge with influenza A/Wisconsin/67/2005 (H3N2). 'Recipients' randomized to Intervention (IR, n = 40) or Control (CR, n = 35) groups were exposed to Donors for four days. IRs wore face shields and hand sanitized frequently to limit large droplet and contact transmission. One transmitted infection was confirmed by serology in a CR, yielding a secondary attack rate of 2.9% among CR, 0% in IR (p = 0.47 for group difference), and 1.3% overall, significantly less than 16% (p<0.001) expected based on a proof-of-concept study secondary attack rate and considering that there were twice as many Donors and days of exposure. The main difference between these studies was mechanical building ventilation in the follow-on study, suggesting a possible role for aerosols.