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Population-based serological surveys are a key tool in epidemiology to characterize the level of population immunity and reconstruct the past circulation of pathogens. A variety of serocatalytic models have been developed to estimate the force of infection (FOI) (i.e., the rate at which susceptible individuals become infected) from age-stratified seroprevalence data. However, few tool currently exists to easily implement, combine, and compare these models. Here, we introduce an R package, Rsero, that implements a series of serocatalytic models and estimates the FOI from age-stratified seroprevalence data using Bayesian methods. The package also contains a series of features to perform model comparison and visualise model fit. We introduce new serocatalytic models of successive outbreaks and extend existing models of seroreversion to any transmission model. The different features of the package are illustrated with simulated and real-life data. We show we can identify the correct epidemiological scenario and recover model parameters in different epidemiological settings. We also show how the package can support serosurvey study design in a variety of epidemic situations. This package provides a standard framework to epidemiologists and modellers to study the dynamics of past pathogen circulation from cross-sectional serological survey data. Author summary: Antibodies are immune markers of past infections. Seroprevalence studies that characterize the seropositivity status in the population have been used for decades in epidemiological studies to assess epidemiological parameters such as population immunity and estimate the risk of future infections. In addition, when the age of participants is available, their seropositivity status can be used to reconstruct the history of circulation of the pathogen in the studied population. We developed Rsero, a R package that provides a pipeline of methods to store age-stratified serological datasets, analyze serological surveys, estimate the history of circulation of a pathogen and compare different transmission models. Statistical inference is done using Bayesian approaches. We introduce new models to detect past epidemics from serological surveys and we extend existing models of antibody decay to any transmission model. Rsero is easy to use and is designed for the broad community of epidemiologists and modellers that are working on serological studies. [ABSTRACT FROM AUTHOR]

Enterovirus A71 (EV-A71) and coxsackievirus A6 (CVA6) primarily cause hand, foot and mouth disease and have emerged to cause potential fatal neurological and systemic manifestations. However, limited surveillance data collected through passive surveillance systems hampers characterization of their epidemiological dynamics. We fit a series of catalytic models to age-stratified seroprevalence data for EV-A71 and CVA6 collected in England at three time points (2006, 2011 and 2017) to estimate the force of infection (FOI) over time and assess possible changes in transmission. For both serotypes, model comparison does not support the occurrence of important changes in transmission over the study period, and we find that a declining risk of infection with age and / or seroreversion are needed to explain the seroprevalence data. Furthermore, we provide evidence that the increased number of reports of CVA6 during 2006–2017 is unlikely to be explained by changes in surveillance. Therefore, we hypothesize that the increased number of CVA6 cases observed since 2011 must be explained by increased virus pathogenicity. Further studies of seroprevalence data from other countries would allow to confirm this. Our results underscore the value of seroprevalence data to unravel changes in the circulation dynamics of pathogens with weak surveillance systems and large number of asymptomatic infections. Author summary: Enteroviruses commonly cause infections in people of all ages with symptoms ranging from mild to severe. Enterovirus infections create a significant healthcare burden during outbreaks and large epidemics. However, the absence of consistent and systematic surveillance greatly impedes documentation of their true prevalence and collective impact on human health. In the UK, reporting from clinical settings is voluntary and passive, which limits accurate estimation of the overall infection incidence in the population. Here, we use data from seroprevalence surveys, which can detect past infections, to estimate the force of infection (rate at which susceptible individuals acquire infection) of enterovirus A71 and coxsackievirus A6 in England, UK, between 2006 and 2017. We found that transmission intensity for both enterovirus serotypes has remained relatively unchanged in this 12-year period. Furthermore, we analyze changes in serotype-specific enterovirus detections in England over the same period and found evidence that the increased number of reported CVA6 detections cannot only be related to changes in testing intensity. We therefore conclude that the increase in CVA6-related disease cases across England during this period could be attributed to the acquisition of increased pathogenicity (probability of disease after infection) of this serotype. Our approach may be useful to study the population-wide infection burden of other enterovirus serotypes for which clinical surveillance is limited. [ABSTRACT FROM AUTHOR]

India reported >10 million coronavirus disease (COVID-19) cases and 149,000 deaths in 2020. To reassess reported deaths and estimate incidence rates during the first 6 months of the epidemic, we used a severe acute respiratory syndrome coronavirus 2 transmission model fit to data from 3 serosurveys in Delhi and time-series documentation of reported deaths. We estimated 48.7% (95% credible interval 22.1%-76.8%) cumulative infection in the population through the end of September 2020. Using an age-adjusted overall infection fatality ratio based on age-specific estimates from mostly high-income countries, we estimated that just 15.0% (95% credible interval 9.3%-34.0%) of COVID-19 deaths had been reported, indicating either substantial underreporting or lower age-specific infection-fatality ratios in India than in high-income countries. Despite the estimated high attack rate, additional epidemic waves occurred in late 2020 and April-May 2021. Future dynamics will depend on the duration of natural and vaccine-induced immunity and their effectiveness against new variants. [ABSTRACT FROM AUTHOR]

When respiratory illness meets neurological symptoms: Enterovirus D68 (EV-D68) has been increasingly linked with the neurological condition acute flaccid myelitis (AFM) in the United States within the past decade, although the reason for their coincidence is not clear. Park et al. used recent surveillance data from a national repository of respiratory virus panels to predict the incidence of EV-D68. They then examined the dynamics of the spatiotemporal association between the predicted incidence of EV-D68 and reported AFM cases on regional and national scales. The authors also found evidence that the extent of EV-D68 and AFM transmission in the United States in 2020 was likely kept in check by current social distancing practices. Acute flaccid myelitis (AFM) recently emerged in the United States as a rare but serious neurological condition since 2012. Enterovirus D68 (EV-D68) is thought to be a main causative agent, but limited surveillance of EV-D68 in the United States has hampered the ability to assess their causal relationship. Using surveillance data from the BioFire Syndromic Trends epidemiology network in the United States from January 2014 to September 2019, we characterized the epidemiological dynamics of EV-D68 and found latitudinal gradient in the mean timing of EV-D68 cases, which are likely climate driven. We also demonstrated a strong spatiotemporal association of EV-D68 with AFM. Mathematical modeling suggested that the recent dominant biennial cycles of EV-D68 dynamics may not be stable. Nonetheless, we predicted that a major EV-D68 outbreak, and hence an AFM outbreak, would have still been possible in 2020 under normal epidemiological conditions. Nonpharmaceutical intervention efforts due to the ongoing COVID-19 pandemic are likely to have reduced the sizes of EV-D68 and AFM outbreaks in 2020, illustrating the broader epidemiological impact of the pandemic. [ABSTRACT FROM AUTHOR]

Genetic sequencing of polioviruses detected through clinical and environmental surveillance is used to confirm detection, identify their likely origin, track geographic patterns of spread, and determine the appropriate vaccination response. The critical importance of genetic sequencing and analysis to the Global Polio Eradication Initiative has grown with the increasing incidence of vaccine-derived poliovirus (VDPV) infections in Africa specifically (470 reported cases in 2019), and globally, alongside persistent transmission of serotype 1 wild-type poliovirus in Pakistan and Afghanistan (197 reported cases in 2019). Adapting what has been learned about the virus genetics and evolution to address these threats has been a major focus of recent work. Here, we review how phylogenetic and phylogeographic methods have been used to trace the spread of wild-type polioviruses and identify the likely origins of VDPVs. We highlight the analysis methods and sequencing technology currently used and the potential for new technologies to speed up poliovirus detection and the interpretation of genetic data. At a pivotal point in the eradication campaign with the threat of anti-vaccine sentiment and donor and public fatigue, innovation is critical to maintain drive and overcome the last remaining circulating virus. [ABSTRACT FROM AUTHOR]

Nonpolio enteroviruses are diverse and common viruses that can circulate year-round but tend to peak in summer. Although most infections are asymptomatic, they can result in a wide range of neurological and other diseases. Many serotypes circulate every year, and different serotypes predominate in different years, but the drivers of their geographical and temporal dynamics are not understood. We use national enterovirus surveillance data collected by the US Centers for Disease Control and Prevention during 1983-2013, as well as demographic and climatic data for the same period, to study the patterns and drivers of the seasonality of these infections. We find that the seasonal pattern of enterovirus cases is spatially structured in the United States and similar to that observed for historical prevaccination poliomyelitis (1931-1954). We identify latitudinal gradients for the amplitude and the timing of the peak of cases, meaning that those are more regularly distributed all year-round in the south and have a more pronounced peak that arrives later toward the north. The peak is estimated to occur between July and September across the United States, and 1 month earlier than that for historical poliomyelitis. Using mixed-effects models, we find that climate, but not demography, is likely to drive the seasonal pattern of enterovirus cases and that the dew point temperature alone explains ~30% of the variation in the intensity of transmission. Our study contributes to a better understanding of the epidemiology of enteroviruses, demonstrates important similarities in their circulation dynamics with polioviruses, and identifies potential drivers of their seasonality. [ABSTRACT FROM AUTHOR]

Background: Global withdrawal of serotype-2 oral poliovirus vaccine (OPV2) took place in April 2016. This marked a milestone in global polio eradication and was a public health intervention of unprecedented scale, affecting 155 countries. Achieving high levels of serotype-2 population immunity before OPV2 withdrawal was critical to avoid subsequent outbreaks of serotype-2 vaccine-derived polioviruses (VDPV2s).Methods and Findings: In August 2015, we estimated vaccine-induced population immunity against serotype-2 poliomyelitis for 1 January 2004-30 June 2015 and produced forecasts for April 2016 by district in Nigeria and Pakistan. Population immunity was estimated from the vaccination histories of children <36 mo old identified with non-polio acute flaccid paralysis (AFP) reported through polio surveillance, information on immunisation activities with different oral poliovirus vaccine (OPV) formulations, and serotype-specific estimates of the efficacy of these OPVs against poliomyelitis. District immunity estimates were spatio-temporally smoothed using a Bayesian hierarchical framework. Coverage estimates for immunisation activities were also obtained, allowing for heterogeneity within and among districts. Forward projections of immunity, based on these estimates and planned immunisation activities, were produced through to April 2016 using a cohort model. Estimated population immunity was negatively correlated with the probability of VDPV2 poliomyelitis being reported in a district. In Nigeria and Pakistan, declines in immunity during 2008-2009 and 2012-2013, respectively, were associated with outbreaks of VDPV2. Immunity has since improved in both countries as a result of increased use of trivalent OPV, and projections generally indicated sustained or improved immunity in April 2016, such that the majority of districts (99% [95% uncertainty interval 97%-100%] in Nigeria and 84% [95% uncertainty interval 77%-91%] in Pakistan) had >70% population immunity among children <36 mo old. Districts with lower immunity were clustered in northeastern Nigeria and northwestern Pakistan. The accuracy of immunity estimates was limited by the small numbers of non-polio AFP cases in some districts, which was reflected by large uncertainty intervals. Forecasted improvements in immunity for April 2016 were robust to the uncertainty in estimates of baseline immunity (January-June 2015), vaccine coverage, and vaccine efficacy.Conclusions: Immunity against serotype-2 poliomyelitis was forecasted to improve in April 2016 compared to the first half of 2015 in Nigeria and Pakistan. These analyses informed the endorsement of OPV2 withdrawal in April 2016 by the WHO Strategic Advisory Group of Experts on Immunization. [ABSTRACT FROM AUTHOR]

Reversion and spread of vaccine-derived poliovirus (VDPV) to cause outbreaks of poliomyelitis is a rare outcome resulting from immunisation with the live-attenuated oral poliovirus vaccines (OPVs). Global withdrawal of all three OPV serotypes is therefore a key objective of the polio endgame strategic plan, starting with serotype 2 (OPV2) in April 2016. Supplementary immunisation activities (SIAs) with trivalent OPV (tOPV) in advance of this date could mitigate the risks of OPV2 withdrawal by increasing serotype-2 immunity, but may also create new serotype-2 VDPV (VDPV2). Here, we examine the risk factors for VDPV2 emergence and implications for the strategy of tOPV SIAs prior to OPV2 withdrawal. We first developed mathematical models of VDPV2 emergence and spread. We found that in settings with low routine immunisation coverage, the implementation of a single SIA increases the risk of VDPV2 emergence. If routine coverage is 20%, at least 3 SIAs are needed to bring that risk close to zero, and if SIA coverage is low or there are persistently “missed” groups, the risk remains high despite the implementation of multiple SIAs. We then analysed data from Nigeria on the 29 VDPV2 emergences that occurred during 2004−2014. Districts reporting the first case of poliomyelitis associated with a VDPV2 emergence were compared to districts with no VDPV2 emergence in the same 6-month period using conditional logistic regression. In agreement with the model results, the odds of VDPV2 emergence decreased with higher routine immunisation coverage (odds ratio 0.67 for a 10% absolute increase in coverage [95% confidence interval 0.55−0.82]). We also found that the probability of a VDPV2 emergence resulting in poliomyelitis in >1 child was significantly higher in districts with low serotype-2 population immunity. Our results support a strategy of focused tOPV SIAs before OPV2 withdrawal in areas at risk of VDPV2 emergence and in sufficient number to raise population immunity above the threshold permitting VDPV2 circulation. A failure to implement this risk-based approach could mean these SIAs actually increase the risk of VDPV2 emergence and spread. [ABSTRACT FROM AUTHOR]

The polio eradication endgame aims to bring transmission of all polioviruses to a halt. To achieve this aim, it is essential to block viral replication in individuals via induction of a robust mucosal immune response. Although it has long been recognized that inactivated poliovirus vaccine (IPV) is incapable of inducing a strong mucosal response on its own, it has recently become clear that IPV may boost immunity in the intestinal mucosa among individuals previously immunized with oral poliovirus vaccine. Indeed, mucosal protection appears to be stronger following a booster dose of IPV than oral poliovirus vaccine, especially in older children. Here, we review the available evidence regarding the impact of IPV on mucosal immunity, and consider the implications of this evidence for the polio eradication endgame. We conclude that the implementation of IPV in both routine and supplementary immunization activities has the potential to play a key role in halting poliovirus transmission, and thereby hasten the eradication of polio. [ABSTRACT FROM AUTHOR]

Rabies is a worldwide zoonosis resulting from Lyssavirus infection. In Europe, Eptesicus serotinus is the most frequently reported bat species infected with Lyssavirus, and thus considered to be the reservoir of European bat Lyssavirus type 1 (EBLV-1). To date, the role of other bat species in EBLV-1 epidemiology and persistence remains unknown. Here, we built an EBLV-1−transmission model based on local observations of a three-cave and four-bat species (Myotis capaccinii, Myotis myotis, Miniopterus schreibersii, Rhinolophus ferrumequinum) system in the Balearic Islands, for which a 1995–2011 serological dataset indicated the continuous presence of EBLV-1. Eptesicus serotinus was never observed in the system during the 16-year follow-up and therefore was not included in the model. We used the model to explore virus persistence mechanisms and to assess the importance of each bat species in the transmission dynamics. We found that EBLV-1 could not be sustained if transmission between M. schreibersii and other bat species was eliminated, suggesting that this species serves as a regional reservoir. Global sensitivity analysis using Sobol's method revealed that following the rate of autumn−winter infectious contacts, M. schreibersii's incubation- and immune-period durations, but not the infectious period length, were the most relevant factors driving virus persistence. [ABSTRACT FROM AUTHOR]

Background: Mucosal human papillomavirus (HPV) infection is a necessary cause of cervical cancer. Vaccine and non-vaccine genotype prevalences may change after vaccine introduction. Therefore, it appears essential to rank HPV genotypes according to their oncogenic potential for invasive cervical cancer, independently of their respective prevalences.Methods: We performed meta-analyses of published observational studies and estimated pooled odds ratios with random-effects models for 32 HPV genotypes, using HPV-16 as the reference.Results: Twenty-seven studies yielded 9,252 HPV-infected women: 2,902 diagnosed with invasive cervical cancer and 6,350 with normal cytology. Expressed as (odds ratio [95% confidence interval]), HPV-18 (0.63 [0.51, 0.78]) ranked closest to HPV-16, while other genotypes showed continuously decreasing relative oncogenic potentials: HPV-45 (0.35 [0.22, 0.55]), HPV-69 (0.28 [0.09, 0.92]), HPV-58 (0.24 [0.15, 0.38]), HPV-31 (0.22 [0.14, 0.35]), HPV-33 (0.22 [0.12, 0.38]), HPV-34 (0.21 [0.06, 0.80]), HPV-67 (0.21 [0.06, 0.67]), HPV-39 (0.17 [0.09, 0.30]), HPV-59 (0.17 [0.09, 0.31]), HPV-73 (0.16 [0.06, 0.41]), and HPV-52 (0.16 [0.11, 0.23]).Conclusions: Our results support the markedly higher oncogenic potentials of HPV-16 and -18, followed by HPV-31, -33, -39, -45, -52, -58 and -59, and highlight the need for further investigation of HPV-34, -67, -69 and -73. Overall, these findings could have important implications for the prevention of cervical cancer. [ABSTRACT FROM AUTHOR]

Antibiotic-use policies may affect pneumococcal conjugate-vaccine effectiveness. The reported increase of pneumococcal meningitis from 2001 to 2009 in France, where a national campaign to reduce antibiotic use was implemented in parallel to the introduction of the 7-valent conjugate vaccine, provides unique data to assess these effects. We constructed a mechanistic pneumococcal transmission model and used likelihood to assess the ability of competing hypotheses to explain that increase. We find that a model integrating a fitness cost of penicillin resistance successfully explains the overall and age-stratified pattern of serotype replacement. By simulating counterfactual scenarios of public health interventions in France, we propose that this fitness cost caused a gradual and pernicious interaction between the two interventions by increasing the spread of nonvaccine, penicillin-susceptible strains. More generally, our results indicate that reductions of antibiotic use may counteract the benefits of conjugate vaccines introduced into countries with low vaccine-serotype coverages and high-resistance frequencies. Our findings highlight the key role of antibiotic use in vaccine-induced serotype replacement and suggest the need for more integrated approaches to control pneumococcal infections. [ABSTRACT FROM AUTHOR]