Estimating typhoid incidence from community-based serosurveys: A multicohort study in Bangladesh, Nepal, Pakistan and Ghana
Authors: Aiemjoy Kristen , Seidman Jessica C. , Saha Senjuti , Munira Sira Jam , Sajib Mohammad Saiful Islam , Al Sium Syed Muktadir , Sarkar Anik , Alam Nusrat , Jahan Farha Nusrat , Kabir Md. Shakiul , Tamrakar Dipesh , Vaidya Krista , Shrestha Rajeev , Shakya Jivan , Katuwal Nishan , Shrestha Sony , Yousafzai Mohammad Tahir , Iqbal Junaid , Dehraj Irum Fatima , Ladak Yasmin , Maria Noshi , Adnan Mehreen , Pervaiz Sadaf , Carter Alice S. , Longley Ashley T. , Fraser Clare , Ryan Edward T. , Nodoushani Ariana , Fasano Alessio , Leonard Maureen , Kenyon Victoria , Bogoch Isaac I. , Jeon Hyon Jin , Haselbeck Andrea , Park Se Eun , Zellweger Raphael , Marks Florian , Owusu-Dabo Ellis , Adu-Sarkodie Yaw , Owusu Michael , Teunis Peter , Luby Stephen P. , Garrett Denise O. , Qamar Farah Naz , Saha Samir K. , Charles Richelle C. , Andrews Jason R. 
Published: October 2021

AbstractBackgroundThe incidence of enteric fever, an invasive bacterial infection caused by typhoidal Salmonellae, is largely unknown in regions lacking blood culture surveillance. New serologic markers have proven accurate in diagnosing enteric fever, but whether they could be used to reliably estimate population-level incidence is unknown.MethodsWe collected longitudinal blood samples from blood culture-confirmed enteric fever cases enrolled from surveillance studies in Bangladesh, Nepal, Pakistan, and Ghana and conducted cross-sectional serosurveys in the catchment areas of each surveillance site. We used ELISAs to measure quantitative IgA and IgG antibody responses to Hemolysin E (HlyE) and S. Typhi lipopolysaccharide (LPS). We used Bayesian hierarchical models to fit two-phase power-function decay models to the longitudinal antibody responses among enteric fever cases and used the joint distributions of the peak antibody titers and decay rate to estimate population-level incidence rates from cross-sectional serosurveys.FindingsThe longitudinal antibody kinetics for all antigen-isotypes were similar across countries and did not vary by clinical severity. The seroincidence of typhoidal Salmonella infection among children <5 years ranged between 58.5 per 100 person-years (95% CI: 42.1 - 81.4) in Dhaka, Bangladesh to 6.6 (95% CI: 4.3-9.9) in Kavrepalanchok, Nepal, and followed the same rank order as clinical incidence estimates.InterpretationThe approach described here has the potential to expand the geographic scope of typhoidal Salmonella surveillance and generate incidence estimates that are comparable across geographic regions and time.FundingThis work was supported by the Bill and Melinda Gates Foundation (INV-000572).Research in contextEvidence before this studyPrevious studies have identified serologic responses to two antigens (Hemolysin E [HlyE] and Salmonella lipopolysaccharide [LPS]) as promising diagnostic markers of acute typhoidal Salmonella infection. We reviewed the evidence for seroepidemiology tools for enteric fever available as of November 01, 2021, by searching the National Library of Medicine article database and medRxiv for preprint publications, published in English, using the terms “enteric fever”, “typhoid fever”, “Salmonella Typhi”, “Salmonella Paratyphi”, “typhoidal Salmonella”, “Hemolysin E”, “Salmonella lipopolysaccharide”, “seroconversion”, “serosurveillance”, “seroepidemiology”, “seroprevalence” and “seropositivity.” We found no studies using HlyE or LPS as markers to measure the incidence or prevalence of enteric fever in a population. Anti-Vi IgG responses were used as a marker of population seroprevalence in cross-sectional studies conducted in South Africa, Fiji, and Nepal, but were not used to calculate population-based incidence estimates.Added value of this studyWe developed and validated a method to estimate typhoidal Salmonella incidence in cross-sectional population samples using antibody responses measured from dried blood spots. First, using longitudinal dried blood spots collected from over 1400 blood culture-confirmed cases in four countries, we modeled the longitudinal dynamics of antibody responses for up to two years following infection, accounting for heterogeneity in antibody responses and age-dependence. We found that longitudinal antibody responses were highly consistent across four countries on two continents and did not differ by clinical severity. We then used these antibody kinetic parameters to estimate incidence in population-based samples in six communities across the four countries, where concomitant population-based incidence was measured using blood cultures. Seroincidence estimates were much higher than blood-culture-based case estimates across all six sites, suggestive of a high incidence of asymptomatic or unrecognized infections. Still, the rank order of seroincidence and culture-based incidence rates were the same, with the highest rates in Bangladesh and lowest in Ghana.Implications of all the available evidenceMany at-risk low- and middle-income countries lack data on typhoid incidence needed to inform and evaluate vaccine introduction. Even in countries where incidence estimates are available, data are typically geographically and temporally sparse due to the resources necessary to initiate and sustain blood culture surveillance. We found that typhoidal Salmonella infection incidence can be estimated from community-based serosurveys using dried blood spots, representing an efficient and scalable approach for generating the typhoid burden data needed to inform typhoid control programs in resource-constrained settings.