Antigenic distance between primary and secondary dengue infections correlates with disease risk.

Many pathogens continuously change their protein structure in response to immune-driven selection, resulting in weakened protection even in previously exposed individuals. In addition, for some pathogens, such as dengue virus, poorly targeted immunity is associated with increased risk of severe disease through a mechanism known as antibody-dependent enhancement. However, it remains unclear whether the antigenic distances between an individual's first infection and subsequent exposures dictate disease risk, explaining the observed large-scale differences in dengue hospitalizations across years. Here, we develop a framework that combines detailed antigenic and genetic characterization of viruses with details on hospitalized cases from 21 years of dengue surveillance in Bangkok, Thailand, to identify the role of the antigenic profile of circulating viruses in determining disease risk. We found that the risk of hospitalization depended on both the specific order of infecting serotypes and the antigenic distance between an individual's primary and secondary infections, with risk maximized at intermediate antigenic distances. These findings suggest that immune imprinting helps determine dengue disease risk and provide a pathway to monitor the changing risk profile of populations and to quantifying risk profiles of candidate vaccines.

Protective Role of NS1-Specific Antibodies in the Immune Response to Dengue Virus through Antibody-Dependent Cellular Cytotoxicity.

BACKGROUND: Dengue virus (DENV) non-structural protein 1 (NS1) has multiple functions within infected cells, on the cell surface, and in secreted form, and is highly immunogenic. Immunity from previous DENV infections is known to exert both positive and negative effects on subsequent DENV infections, but the contribution of NS1-specific antibodies to these effects is incompletely understood. METHODS: We investigated the functions of NS1-specific antibodies and their significance in DENV infection. We analyzed plasma samples collected in a prospective cohort study prior to symptomatic or subclinical secondary DENV infection. We measured binding to purified recombinant NS1 protein and to NS1-expressing CEM cells, antibody-mediated NK cell activation by plate-bound NS1 protein, and antibody-dependent cellular cytotoxicity (ADCC) of NS1-expressing target cells. RESULTS: We found that antibody responses to NS1 were highly serotype-cross-reactive and that subjects who experienced subclinical DENV infection had significantly higher antibody responses to NS1 in pre-infection plasma than subjects who experienced symptomatic infection. We observed strong positive correlations between antibody binding and NK activation. CONCLUSIONS: These findings demonstrate the involvement of NS1-specific antibodies in ADCC and provide evidence for a protective effect of NS1-specific antibodies in secondary DENV infection.

Chikungunya seroprevalence, force of infection, and prevalence of chronic disability after infection in endemic and epidemic settings: a systematic review, meta-analysis, and modelling study.

BACKGROUND: Chikungunya is an arboviral disease transmitted by Aedes aegypti and Aedes albopictus mosquitoes with a growing global burden linked to climate change and globalisation. We aimed to estimate chikungunya seroprevalence, force of infection (FOI), and prevalence of related chronic disability and hospital admissions in endemic and epidemic settings. METHODS: In this systematic review, meta-analysis, and modelling study, we searched PubMed, Ovid, and Web of Science for articles published from database inception until Sept 26, 2022, for prospective and retrospective cross-sectional studies that addressed serological chikungunya virus infection in any geographical region, age group, and population subgroup and for longitudinal prospective and retrospective cohort studies with data on chronic chikungunya or hospital admissions in people with chikungunya. We did a systematic review of studies on chikungunya seroprevalence and fitted catalytic models to each survey to estimate location-specific FOI (ie, the rate at which susceptible individuals acquire chikungunya infection). We performed a meta-analysis to estimate the proportion of symptomatic patients with laboratory-confirmed chikungunya who had chronic chikungunya or were admitted to hospital following infection. We used a random-effects model to assess the relationship between chronic sequelae and follow-up length using linear regression. The systematic review protocol is registered online on PROSPERO, CRD42022363102. FINDINGS: We identified 60 studies with data on seroprevalence and chronic chikungunya symptoms done across 76 locations in 38 countries, and classified 17 (22%) of 76 locations as endemic settings and 59 (78%) as epidemic settings. The global long-term median annual FOI was 0·007 (95% uncertainty interval [UI] 0·003-0·010) and varied from 0·0001 (0·00004-0·0002) to 0·113 (0·07-0·20). The highest estimated median seroprevalence at age 10 years was in south Asia (8·0% [95% UI 6·5-9·6]), followed by Latin America and the Caribbean (7·8% [4·9-14·6]), whereas median seroprevalence was lowest in the Middle East (1·0% [0·5-1·9]). We estimated that 51% (95% CI 45-58) of people with laboratory-confirmed symptomatic chikungunya had chronic disability after infection and 4% (3-5) were admitted to hospital following infection. INTERPRETATION: We inferred subnational heterogeneity in long-term average annual FOI and transmission dynamics and identified both endemic and epidemic settings across different countries. Brazil, Ethiopia, Malaysia, and India included both endemic and epidemic settings. Long-term average annual FOI was higher in epidemic settings than endemic settings. However, long-term cumulative incidence of chikungunya can be similar between large outbreaks in epidemic settings with a high FOI and endemic settings with a relatively low FOI. FUNDING: International Vaccine Institute.

Integration of population-level data sources into an individual-level clinical prediction model for dengue virus test positivity.

The differentiation of dengue virus (DENV) infection, a major cause of acute febrile illness in tropical regions, from other etiologies, may help prioritize laboratory testing and limit the inappropriate use of antibiotics. While traditional clinical prediction models focus on individual patient-level parameters, we hypothesize that for infectious diseases, population-level data sources may improve predictive ability. To create a clinical prediction model that integrates patient-extrinsic data for identifying DENV among febrile patients presenting to a hospital in Thailand, we fit random forest classifiers combining clinical data with climate and population-level epidemiologic data. In cross-validation, compared to a parsimonious model with the top clinical predictors, a model with the addition of climate data, reconstructed susceptibility estimates, force of infection estimates, and a recent case clustering metric significantly improved model performance.

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 immunity and individual risk of infection with dengue virus in a prospective, longitudinal cohort study.

Although it is known that household infections drive the transmission of dengue virus (DENV), it is unclear how household composition and the immune status of inhabitants affect the individual risk of infection. Most population-based studies to date have focused on paediatric cohorts because more severe forms of dengue mainly occur in children, and the role of adults in dengue transmission is understudied. Here we analysed data from a multigenerational cohort study of 470 households, comprising 2,860 individuals, in Kamphaeng Phet, Thailand, to evaluate risk factors for DENV infection. Using a gradient-boosted regression model trained on annual haemagglutination inhibition antibody titre inputs, we identified 1,049 infections, 90% of which were subclinical. By analysing imputed infections, we found that individual antibody titres, household composition and antibody titres of other members in the same household affect an individual's risk of DENV infection. Those individuals living in households with high average antibody titres, or households with more adults, had a reduced risk of infection. We propose that herd immunity to dengue acts at the household level and may provide insight into the drivers of the recent change in the shifting age distribution of dengue cases in Thailand.

A systematic review of the data, methods and environmental covariates used to map Aedes-borne arbovirus transmission risk.

BACKGROUND: Aedes (Stegomyia)-borne diseases are an expanding global threat, but gaps in surveillance make comprehensive and comparable risk assessments challenging. Geostatistical models combine data from multiple locations and use links with environmental and socioeconomic factors to make predictive risk maps. Here we systematically review past approaches to map risk for different Aedes-borne arboviruses from local to global scales, identifying differences and similarities in the data types, covariates, and modelling approaches used. METHODS: We searched on-line databases for predictive risk mapping studies for dengue, Zika, chikungunya, and yellow fever with no geographical or date restrictions. We included studies that needed to parameterise or fit their model to real-world epidemiological data and make predictions to new spatial locations of some measure of population-level risk of viral transmission (e.g. incidence, occurrence, suitability, etc.). RESULTS: We found a growing number of arbovirus risk mapping studies across all endemic regions and arboviral diseases, with a total of 176 papers published 2002-2022 with the largest increases shortly following major epidemics. Three dominant use cases emerged: (i) global maps to identify limits of transmission, estimate burden and assess impacts of future global change, (ii) regional models used to predict the spread of major epidemics between countries and (iii) national and sub-national models that use local datasets to better understand transmission dynamics to improve outbreak detection and response. Temperature and rainfall were the most popular choice of covariates (included in 50% and 40% of studies respectively) but variables such as human mobility are increasingly being included. Surprisingly, few studies (22%, 31/144) robustly tested combinations of covariates from different domains (e.g. climatic, sociodemographic, ecological, etc.) and only 49% of studies assessed predictive performance via out-of-sample validation procedures. CONCLUSIONS: Here we show that approaches to map risk for different arboviruses have diversified in response to changing use cases, epidemiology and data availability. We identify key differences in mapping approaches between different arboviral diseases, discuss future research needs and outline specific recommendations for future arbovirus mapping.

Transplacental transfer efficiency of maternal antibodies against influenza A(H1N1)pdm09 virus and dynamics of naturally acquired antibodies in Chinese children: a longitudinal, paired mother-neonate cohort study.

BACKGROUND: The 2009 pandemic H1N1 influenza A virus (A(H1N1)pdm09 virus) evolves rapidly and has continued to cause severe infections in children since its emergence in 2009. We aimed to characterise the kinetics of maternally and naturally acquired antibodies against historical A(H1N1)pdm09 strains and to assess the extent to which the response to heterologous strains following infection or vaccination affects observed A(H1N1)pdm09 strain-specific antibody titres in a Chinese paediatric population. METHODS: In this retrospective study, we used residual serum samples from 528 mother-neonate pairs from a non-interventional, longitudinal cohort study in southern China conducted from Sept 20, 2013, to Aug 24, 2018, from six local hospitals in Anhua County, Hunan Province, China. Mother-neonate pairs were eligible for inclusion if the neonates were born after Sept 20, 2013, and their mothers had resided in the study sites for at least 3 months. We tested samples with a haemagglutination inhibition (HAI) assay to measure antibody levels against three historical A(H1N1)pdm09 strains that were antigenically similar to the strains that circulated during the 2009 pandemic (A/Hunan-Kaifu/SWL4204/2009 [SWL4204/09 strain], A/Hunan-Daxiang/SWL1277/2016 [SWL1277/16 strain], and A/Hunan-Yanfeng/SWL185/2018 [SWL185/18 strain]). We also determined the seroprevalence, geometric mean titres (GMTs), transfer ratio of maternal antibodies, and the dynamics of maternally and naturally acquired antibodies in children, from birth to 3 years of age. FINDINGS: 1066 mother-neonate pairs were enrolled in the original cohort between Sept 20, 2013, and Oct 14, 2015. Of these, 528 pairs (523 mothers, 528 neonates) were selected for the present study. The median age of the mothers was 25 years (IQR 23 to 29). 291 (55%) of 528 children were boys and 237 (45%) were girls, and most children (452 [86%]) were breastfed before the age of 6 months. The GMTs and the seroprevalence for the SWL4204/09 strain were higher than those for the SWL1277/16 and SWL185/18 strains among mothers (GMTs: 10·4 [95% CI 9·8 to 11·1] vs 9·3 [8·7 to 9·8] vs 8·0 [7·5 to 8·4], p<0·0001; seroprevalence: 11·1% [95% CI 8·5 to 14·1] vs 6·9% [4·9 to 9·4] vs 4·6% [3·0 to 6·8], p=0·0003) and among neonates (GMTs: 10·7 [10·0 to 11·5] vs 9·4 [8·8 to 10·0] vs 8·1 [7·6 to 8·6], p<0·0001; seroprevalence: 13·4% [10·7 to 16·7] vs 8·7% [6·5 to 11·5] vs 6·1% [4·2 to 8·5], p=0·0002). Regardless of the A(H1N1)pdm09-specific strain, maternal antibodies could be transferred efficiently via the placenta (mean transfer ratios: 1·10 for SWL4204/09 vs 1·09 for SWL1277/16 vs 1·06 for SWL185/18; p=0·93). The A(H1N1)pdm09 strain-specific antibodies waned below the protective threshold of 1:40 within 2 months after birth. After maternal antibody waning, there were periodic increases and decreases in HAI antibody titres against three A(H1N1)pdm09 strains, and such increases were all significantly associated with a higher immune response to heterologous strains. Vaccination against the SWL4204/09 strain was associated with a poor response to the SWL185/18 strain (ß-0·20, 95% CI -0·28 to -0·13; p<0·0001). INTERPRETATION: Our findings suggest low pre-existing immunity against influenza A(H1N1)pdm09 virus among unvaccinated Chinese adult female and paediatric populations. This evidence, together with the rapid decay of maternal antibodies and the observed cross-reactivity among different A(H1N1)pdm09 strains, highlights the importance of accelerating maternal and paediatric influenza vaccination in China. FUNDING: The Key Program of the National Natural Science Foundation of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Marginal effects of public health measures and COVID-19 disease burden in China: A large-scale modelling study.

China had conducted some of the most stringent public health measures to control the spread of successive SARS-CoV-2 variants. However, the effectiveness of these measures and their impacts on the associated disease burden have rarely been quantitatively assessed at the national level. To address this gap, we developed a stochastic age-stratified metapopulation model that incorporates testing, contact tracing and isolation, based on 419 million travel movements among 366 Chinese cities. The study period for this model began from September 2022. The COVID-19 disease burden was evaluated, considering 8 types of underlying health conditions in the Chinese population. We identified the marginal effects between the testing speed and reduction in the epidemic duration. The findings suggest that assuming a vaccine coverage of 89%, the Omicron-like wave could be suppressed by 3-day interval population-level testing (PLT), while it would become endemic with 4-day interval PLT, and without testing, it would result in an epidemic. PLT conducted every 3 days would not only eliminate infections but also keep hospital bed occupancy at less than 29.46% (95% CI, 22.73-38.68%) of capacity for respiratory illness and ICU bed occupancy at less than 58.94% (95% CI, 45.70-76.90%) during an outbreak. Furthermore, the underlying health conditions would lead to an extra 2.35 (95% CI, 1.89-2.92) million hospital admissions and 0.16 (95% CI, 0.13-0.2) million ICU admissions. Our study provides insights into health preparedness to balance the disease burden and sustainability for a country with a population of billions.

Maternally derived antibody titer dynamics and risk of hospitalized infant dengue disease.

Infants less than 1 y of age experience high rates of dengue disease in dengue virus (DENV) endemic countries. This burden is commonly attributed to antibody-dependent enhancement (ADE), whereby concentrations of maternally derived DENV antibodies become subneutralizing, and infection-enhancing. Understanding antibody-related mechanisms of enhanced infant dengue disease risk represents a significant challenge due to the dynamic nature of antibodies and their imperfect measurement processes. Further, key uncertainties exist regarding the impact of long-term shifts in birth rates, population-level infection risks, and maternal ages on the DENV immune landscape of newborns and their subsequent risks of severe dengue disease in infancy. Here, we analyze DENV antibody data from two infant cohorts (N = 142 infants with 605 blood draws) and 40 y of infant dengue hospitalization data from Thailand. We use mathematical models to reconstruct maternally derived antibody dynamics, accounting for discretized measurement processes and limits of assay detection. We then explore possible antibody-related mechanisms of enhanced infant dengue disease risk and their ability to reconstruct the observed age distribution of hospitalized infant dengue cases. We find that ADE mechanisms are best able to reconstruct the observed data. Finally, we describe how the shifting epidemiology of dengue in Thailand, combined with declining birth rates, have decreased the absolute risk of infant dengue disease by 88% over a 40-y period while having minimal impact on the mean age of infant hospitalized dengue disease.

Integration of population-level data sources into an individual-level clinical prediction model for dengue virus test positivity.

The differentiation of dengue virus (DENV) infection, a major cause of acute febrile illness in tropical regions, from other etiologies, may help prioritize laboratory testing and limit the inappropriate use of antibiotics. While traditional clinical prediction models focus on individual patient-level parameters, we hypothesize that for infectious diseases, population-level data sources may improve predictive ability. To create a clinical prediction model that integrates patient-extrinsic data for identifying DENV among febrile patients presenting to a hospital in Thailand, we fit random forest classifiers combining clinical data with climate and population-level epidemiologic data. In cross validation, compared to a parsimonious model with the top clinical predictors, a model with the addition of climate data, reconstructed susceptibility estimates, force of infection estimates, and a recent case clustering metric, significantly improved model performance.

Antigenic diversity and dengue disease risk.

Many pathogens continuously change their protein structure in response to immune-driven selection, resulting in weakened protection. In addition, for some pathogens such as dengue virus, poorly targeted immunity is associated with increased risk of severe disease, through a mechanism known as antibody-dependent enhancement. However, it remains a mystery whether the antigenic distance between an individual's first infection and subsequent exposures dictate disease risk, explaining the observed large-scale differences in dengue hospitalisations across years. Here we develop an inferential framework that combines detailed antigenic and genetic characterisation of viruses, and hospitalised cases from 21 years of surveillance in Bangkok, Thailand to identify the role of the antigenic profile of circulating viruses in determining disease risk. We find that the risk of hospitalisation depends on both the specific order of infecting serotypes and the antigenic distance between an individual's primary and secondary infections, with risk maximised at intermediate antigenic distances. These findings suggest immune imprinting helps determine dengue disease risk, and provides a pathway to monitor the changing risk profile of populations and to quantifying risk profiles of candidate vaccines.

The genetic diversity of Nipah virus across spatial scales.

Nipah virus (NiV), a highly lethal virus in humans, circulates silently in Pteropus bats throughout South and Southeast Asia. Difficulty in obtaining genomes from bats means we have a poor understanding of NiV diversity, including how many lineages circulate within a roost and the spread of NiV over increasing spatial scales. Here we develop phylogenetic approaches applied to the most comprehensive collection of genomes to date (N=257, 175 from bats, 73 from humans) from six countries over 22 years (1999-2020). In Bangladesh, where most human infections occur, we find evidence of increased spillover risk from one of the two co-circulating sublineages. We divide the four major NiV sublineages into 15 genetic clusters (emerged 20-44 years ago). Within any bat roost, there are an average of 2.4 co-circulating genetic clusters, rising to 5.5 clusters at areas of 1,500-2,000 km2. Using Approximate Bayesian Computation fit to a spatial signature of viral diversity, we estimate that each genetic cluster occupies an average area of 1.3 million km2 (95%CI: 0.6-2.3 million), with 14 clusters in an area of 100,000 km2 (95%CI: 6-24). In the few sites in Bangladesh and Cambodia where genomic surveillance has been concentrated, we estimate that most of the genetic clusters have been identified, but only ~15% of overall NiV diversity has been uncovered. Our findings are consistent with entrenched co-circulation of distinct lineages, even within individual roosts, coupled with slow migration over larger spatial scales.

Accounting for assay performance when estimating the temporal dynamics in SARS-CoV-2 seroprevalence in the U.S.

Reconstructing the incidence of SARS-CoV-2 infection is central to understanding the state of the pandemic. Seroprevalence studies are often used to assess cumulative infections as they can identify asymptomatic infection. Since July 2020, commercial laboratories have conducted nationwide serosurveys for the U.S. CDC. They employed three assays, with different sensitivities and specificities, potentially introducing biases in seroprevalence estimates. Using models, we show that accounting for assays explains some of the observed state-to-state variation in seroprevalence, and when integrating case and death surveillance data, we show that when using the Abbott assay, estimates of proportions infected can differ substantially from seroprevalence estimates. We also found that states with higher proportions infected (before or after vaccination) had lower vaccination coverages, a pattern corroborated using a separate dataset. Finally, to understand vaccination rates relative to the increase in cases, we estimated the proportions of the population that received a vaccine prior to infection.

The spatial signature of Plasmodium vivax and Plasmodium falciparum infections: quantifying the clustering of infections in cross-sectional surveys and cohort studies.

BACKGROUND: Over the last decades, enormous successes have been achieved in reducing malaria burden globally. In Latin America, South East Asia, and the Western Pacific, many countries now pursue the goal of malaria elimination by 2030. It is widely acknowledged that Plasmodium spp. infections cluster spatially so that interventions need to be spatially informed, e.g. spatially targeted reactive case detection strategies. Here, the spatial signature method is introduced as a tool to quantify the distance around an index infection within which other infections significantly cluster. METHODS: Data were considered from cross-sectional surveys from Brazil, Thailand, Cambodia, and Solomon Islands, conducted between 2012 and 2018. Household locations were recorded by GPS and finger-prick blood samples from participants were tested for Plasmodium infection by PCR. Cohort studies from Brazil and Thailand with monthly sampling over a year from 2013 until 2014 were also included. The prevalence of PCR-confirmed infections was calculated at increasing distance around index infections (and growing time intervals in the cohort studies). Statistical significance was defined as prevalence outside of a 95%-quantile interval of a bootstrap null distribution after random re-allocation of locations of infections. RESULTS: Prevalence of Plasmodium vivax and Plasmodium falciparum infections was elevated in close proximity around index infections and decreased with distance in most study sites, e.g. from 21.3% at 0 km to the global study prevalence of 6.4% for P. vivax in the Cambodian survey. In the cohort studies, the clustering decreased with longer time windows. The distance from index infections to a 50% reduction of prevalence ranged from 25 m to 3175 m, tending to shorter distances at lower global study prevalence. CONCLUSIONS: The spatial signatures of P. vivax and P. falciparum infections demonstrate spatial clustering across a diverse set of study sites, quantifying the distance within which the clustering occurs. The method offers a novel tool in malaria epidemiology, potentially informing reactive intervention strategies regarding radius choices of operations around detected infections and thus strengthening malaria elimination endeavours.

Geographic migration and vaccine-induced fitness changes of Streptococcus pneumoniae.

Streptococcus pneumoniae is a leading cause of pneumonia and meningitis worldwide. Many different serotypes co-circulate endemically in any one location. The extent and mechanisms of spread, and vaccine-driven changes in fitness and antimicrobial resistance (AMR), remain largely unquantified. Using geolocated genome sequences from South Africa (N=6910, 2000-2014) we developed models to reconstruct spread, pairing detailed human mobility data and genomic data. Separately we estimated the population level changes in fitness of strains that are (vaccine type, VT) and are not (non-vaccine type, NVT) included in the vaccine, first implemented in 2009, as well as differences in strain fitness between those that are and are not resistant to penicillin. We estimated that pneumococci only become homogenously mixed across South Africa after about 50 years of transmission, with the slow spread driven by the focal nature of human mobility. Further, in the years following vaccine implementation the relative fitness of NVT compared to VT strains increased (RR: 1.29 [95% CI 1.20-1.37]) - with an increasing proportion of these NVT strains becoming penicillin resistant. Our findings point to highly entrenched, slow transmission and indicate that initial vaccine-linked decreases in AMR may be transient.