Age-structured serosurveys can provide information about age-specific immunity gaps for vaccine-preventable diseases that result from missed vaccination or waning immunity (7,20). For example, immunizing reproductive-age women through antenatal care visits is needed for boosting tetanus seroprotection and preventing neonatal tetanus in lower-income countries. Serologic data from Cambodia revealed the success of that country’s maternal and neonatal tetanus elimination program and identified that additional effort is still needed to reach young, first-time mothers (Figure 1, panels A, B) (25). This example illustrates how analyses of single antibodies can reveal public health program gaps, but the most novel and synergistic opportunities will most likely emerge from concurrent measurement of antibody responses to a broad pathogen panel.

The simultaneous measurement of antibody responses to multiple pathogens could uncover populations with high exposure to multiple infectious diseases and potentially multilayered health disparities. This, in turn, should create opportunities to integrate program delivery rather than relying on multiple vertical programs separately delivering interventions, a paradigm shift that aligns with calls for integrated global health systems (26). High pairwise correlation (r>0.5) of mean antibody responses to different antigens across geographic clusters in the Cambodia serosurvey suggests overlap in disease exposure and transmission (Figure 2, panel A). Cluster-level mean antibody responses reveal regional differences in exposure but also provide multilayered information that could help identify opportunities for coordinated response. For example, clusters in the western and northern regions of Cambodia with the highest Plasmodium falciparum antibody levels also have high antibody levels to the causative agent of lymphatic filariasis (Wuchereria bancrofti) and Strongyloides stercoralis but low antibody levels to tetanus toxoid (Figure 2, panel B, far right columns under West and North).

The Cambodia survey illustrates how a relatively small panel of antigens in a multiplex assay can extend the value of blood collection, and including a broader panel (Technical Appendix Table) could provide even more information in future surveys. Similar measurements among young children would more accurately reflect recent exposure than measurement in adults, which would reflect both short-term and long-lived antibody responses (27). For pathogens with exposure that begins at birth, measurements in young children capture the key period of age-dependent antibody acquisition that differentiates transmission across populations (24). High-resolution maps of overlapping serologic responses estimated through geostatistical predictive algorithms could contribute information to integrated surveillance-and-response systems (discussed later) (27,28). If extended in this way, multiplex serologic testing could create new opportunities for coordinated and appropriate response across diverse diseases.

Integrated serosurveillance would dramatically expand our knowledge of pathogens that are not currently part of routine surveillance in low- and middle-income countries. Serologic data combined with mathematical models were critical to developing global burden of disease estimates for rubella and hepatitis (7). Similar efforts could augment burden of disease estimates for enteric pathogens, NTDs, and other pathogens that have well-defined antigen targets but lack population-based information about incidence. For example, including antibody responses to diverse enteric pathogens in population-based surveys could improve burden of disease estimates and provide an objective indicator through which we could view progress toward achieving related United Nations sustainable development goals 3.3 (improving health and well-being target 3, which includes reducing waterborne diseases) and 6 (universal access to clean water and sanitation) (11,29).

Integrating multiplex assays into geolocated, population-based surveys would enable an unprecedented characterization of population-level, multipathogen immunologic profiles. Large-scale studies drawing on this resource could lead to new biological insights about how disease occurrence is interrelated and provide clues for future experimental studies to examine mechanisms of immune modulation (19,30). For example, helminths infect >800 million persons worldwide, and growing evidence suggests these pathogens influence malaria infection, HIV infection, vaccine effectiveness, and even fecundity through complex immunoregulatory pathways (31–34). As another example, studies have linked seasonal El Niño atmospheric conditions to profound shifts in environmentally mediated infections, such as regional-scale cholera epidemics and mosquitoborne pathogen transmission (e.g., malaria, arboviruses) (35,36). Antibody titers in young children are a sensitive measure of recent pathogen exposure and have even been shown to fluctuate with seasonal changes in malaria transmission (24). Because antibody levels reflect symptomatic and asymptomatic infections, measuring antibody responses could reveal a more complete picture of seasonally driven changes in transmission compared with case-based surveillance.

Serum samples and dried blood spots are already collected for programs such as the Demographic and Health Surveys, Malaria and AIDS Indicator Survey, and NTD transmission assessment surveys. With small changes in protocol, samples from these platforms could be used for routine multiplex testing. In most cases, protocol changes will amount to ensuring adequate consent to enable broad-based serologic testing and sending specimens to regional or national laboratories with the capacity for multiplex testing. Broader multiplex testing of routine clinical samples could supplement the information available through these population-based surveys, and expanded testing within other focused serologic surveys could contribute as well (16,25,37). In all cases, adequate safeguards for participant privacy and biosafety will be essential and should follow similar protocols already in place for existing periodic serosurveys (e.g., Malaria and AIDS Indicator Surveys) and global laboratory testing networks (38). Dried blood spots collected on filter paper from finger or heel pricks are easy to collect, transport, and preserve, and antibody results from dried blood spot eluates are comparable with those obtained directly from serum samples for malaria, some helminths, and a broad range of viral pathogens, including vaccine-preventable diseases and dengue (39–42). Additional validation studies would help ensure that field protocols are adequate for the broad set of antigens envisioned in an integrated platform (Technical Appendix Table).

A challenge to integrated serosurveillance is that different diseases have different ideal populations for monitoring, governed by disease-specific transmission dynamics. For example, children are a focus of most NTD and vaccine-preventable disease monitoring, but teens and adults are most relevant in surveillance of HIV, tetanus protection, and in some cases malaria (e.g., forest workers). Enteric pathogen transmission is often so intense in low-income settings that most population-level heterogeneity in antibody response occurs in the first few years of life (24), an age range that is only partly represented in population-based samples. Moreover, HIV surveillance programs have demonstrated that sampling methods that extend beyond population-based surveys and passive clinical surveillance are needed to capture the highest risk groups, and similar methods will probably be necessary for malaria and other pathogens in elimination settings (43). Aligning optimal sampling methods across diseases is a substantive challenge, but adaptive geostatistical design methods (44) could potentially start with the information collected during the initial integrated, population-based serosurvey and then augment the information needed for disease-specific control priorities through follow-on, enrichment sampling of persons in ideal age ranges and with high-risk characteristics.

From a large set of potential antigens (Technical Appendix Table), each survey could include a subset tailored to specific disease monitoring objectives, while new antigens could be added in response to emerging threats. For example, including a recombinant chikungunya virus antigen in multiplex testing of an existing filariasis surveillance cohort tracked the virus’s introduction to Haiti during 2013–2014 (16). Technologic advances on bead-based platforms, such as Luminex, will further extend the number of antigens included in a single assay, and new antigen discovery through high-throughput screening studies will further enrich integrated platforms (45). A current limitation of the technology is that individual antigen-coupled beads are generally not yet commercially available; future commercial development of these reagents would enable better standardization across laboratories. Bead-antigen coupling and bead degradation can introduce variability into multiplex assays, so the use of standardized operating procedures and a consistent bead preparation for each survey are essential. Another limitation is that global reference serum standards to translate arbitrary units in serologic assays into international unit values are mainly limited to vaccine-preventable diseases. Reference standards for other pathogens, such as non–P. falciparum malarias and NTDs, would add immense value because they would enable direct comparison of quantitative results across surveys and laboratories. Finally, antibody measurements will be most useful if they are integrated into a coordinated repository and testing platform, such as the recently proposed World Serology Bank (19), which could further streamline laboratory protocols, accessibility to reagents, and funding. Surveillance laboratory networks for vaccine-preventable diseases provide a model for how globally standardized testing can work in practice (38).

Integrated serosurveillance will only reduce infectious disease transmission if it translates into actionable information and triggers a response by effective programs. In this context, information must be timely, accurate, and high resolution to be actionable from a programmatic perspective. Generating actionable information at spatial scales much smaller than national or district levels is commonplace in high-income countries and should be a near-term, attainable goal for the rest of the world (1). Efforts in precision global health exemplify how information could be integrated across serosurveys in space and time; high-resolution estimates of child growth failure, measles immunization gaps, and malaria mortality rates show how advances in computation, modeling, and data science have accelerated the development of new pipelines for processing, analysis, and visualization to support precision public health that spans from village to continental scales (46–48). Integrated serosurveillance will be best positioned to contribute to this endeavor if serology measurements flow into efficient data pipelines and analysis methods are general enough to accommodate diverse pathogens. The breadth of antigens incorporated into multiplex assays (Technical Appendix Table) means that a single integrated serosurveillance platform could potentially generate spatially explicit estimates of vaccine immunity, malaria transmission, NTD transmission, and HIV incidence.

For antigenically stable pathogens, force of infection can be estimated from cross-sectional surveys with general methods that range in approach from mathematical modeling to nonparametric survival analyses (20). For infections that lead to partial or transient immunity, it might be possible to extend existing approaches to estimate force of infection among young children, provided that antibody levels remain sufficiently elevated for multiple years. The distribution of infectious disease transmission in populations is often highly heterogeneous in space, and for this reason, malaria and NTD elimination efforts have led to the development of sophisticated data pipelines that aggregate, analyze, and map surveillance data with rapid updates (49,50). Mapping antibody response is a relatively underexploited opportunity, and existing platforms could be extended to include multiplex serologic data. Combining antibody levels, seroprevalence, or force of infection estimates with geospatial prediction algorithms could lead to high-resolution, richly layered maps of infectious disease exposure and immunity that would be an immense resource for precision guidance of global public health programs.

Integrated serosurveillance will generate information that is a global public good (26), and international financing will be essential to support coordination across programs for specimen storage, testing, analysis, and reporting. Coordinated financing would also help ensure harmonization across each step in the collection, testing, and analysis pipeline. As the global community prepares for a world after polio eradication, extending the polio surveillance infrastructure and integrating surveillance across vaccine-preventable diseases has been proposed (38). World Health Organization reference laboratory networks for vaccine-preventable diseases already support serologic testing for measles, rubella, yellow fever, and Japanese encephalitis and have the technical capacity to support high-throughput serologic assays. Additional financial support that builds from this existing laboratory infrastructure could reinforce investments that are already in place and extend the serologic testing platform beyond vaccine-preventable diseases. In an analogous example, the World Health Organization’s Global Rotavirus Laboratory Network tests fecal specimens for the presence of >20 enteric pathogens other than rotavirus using multiplex molecular assays (38). For data analysis and synthesis, the Institute for Health Metrics and Evaluation’s Local Burden of Disease Project provides an example of how coordinated financing can be used to aggregate, analyze, and disseminate information through sophisticated data pipelines to support diverse precision public health efforts (http://www.healthdata.org/lbd).