A group of key opinion leaders represented the voice of the diagnostic user by describing and predicting scenarios faced by STH programs, creating a series of problem statements and decisions that each can be addressed by a hypothetical diagnostic. Each solution is further detailed in a TPP as a list of technical characteristics, such as type of measurement and implementation requirements.
One practical use of a TPP is to provide an objective framework for evaluating existing technologies and innovations to determine opportunities for product development Table 2. The breakdown of an STH program into diagnostic use-cases also ensures that research and product development resources are aligned with program time lines by considering global progress of STH programs and goals controlling morbidity, interruption of transmission , maturity of technology landscape, and time lines when technologies will be needed.
This framework is not intended to prevent the development of a single technology that addresses multiple use-cases; however, a platform must meet the requirements described in each of the various TPPs. Previous works by Solomon et al.
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This report builds on these efforts by providing a more comprehensive framework that links program decision points to detailed use-cases and TPPs. The diagnostic end user is the STH program manager who requires a population-wide diagnostic assessment to determine the transition of a program to the next planned phase. This introduces a unique challenge for developing diagnostic TPPs for population-based intervention programs, as performance requirements for individual-level assays are in context of decisions informed by population-level indicators.
Following previous work [ 22 ], four broad decision points were used to categorize each use-case against a hypothetical reduction in population-level infection resulting from program intervention, as shown in Fig 1. Those decisions that are hypothetically guided by diagnostic test results are described in the algorithm shown in Fig 2 and form the basis of the use-case categories:. Dashed box indicates a decision not described under current WHO guidelines for controlling STH morbidity but that may be important for a program aiming to eliminate transmission of STH.
An additional level of detail is provided in the spreadsheet within the supplementary materials of this article S1 File. Several factors were considered in prioritizing a diagnostic that confirms a break in transmission use-case 3.
There is strong interest in leveraging the successes of increased MDA coverage to further reduce STH transmission beyond the level of morbidity control toward interruption of transmission [ 2 , 3 ]. Achievement of this goal would allow programs to stop regular MDA with minimal risk of recrudescence, but there currently lacks a reliable tool to confirm this end point. However, as discussed later, evidence from research is needed to develop a rigorous TPP for such a diagnostic. On the shorter term, there may be opportunities to strengthen STH programs by providing access to technologies that are superior to the Kato-Katz method Table 1 for monitoring impact on transmission use-case 2 [ 24 ].
The development of a TPP for use-case 4 was felt to be premature and not to be pursued until evidence demonstrates that a strategy for sustained interruption of transmission is feasible and can be scaled for STH programs.
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The biomarker landscape that would meet this context of use is also at its early stages, and resources required to implement the scale and coverage for this type of surveillance infrastructure need to be further defined [ 25 ]. Across all use-cases is an option to integrate and leverage the resources of other public health programs. For instance, many STH programs are integrated with schistosomiasis control efforts due to co-endemicity [ 8 , 26 ], with the Kato-Katz method also able to detect infection by Schistosoma mansoni and S.
Non—stool-based biomarkers may provide opportunities for simultaneous detection of infection by S. Post-elimination surveillance would likely leverage multiple disease surveillance programs through centralized laboratory analysis. The assay described in this use-case provides results that identify populations that warrant MDA and determines the frequency of MDA and the frequency of future monitoring. These decisions are currently based on measurements of two parasitological indicators in school-aged children: overall prevalence of any STH infection and proportion of individuals harboring an infection of moderate to heavy intensity [ 27 ].
To meet the needs of the second indicator, a test provides individual-level quantitative results that are combined to estimate the proportion harboring moderate to heavy intensities of infection by any STH, thresholds currently based on species-specific FEC Table 3 , [ 1 ]. These test results also provide a baseline measurement for monitoring the impact of an intervention, as described in latter use-cases.
This use-case applies to STH programs that have initiated intervention and seek to evaluate progress in reducing prevalence and intensity of infection [ 28 ]. By comparing population-level results from previous or baseline measurements, programs that meet their milestones would continue the intervention strategy as planned.
However, an under-performing program would conduct additional evaluations to determine potential causes, such as assessments of population migration, environment, workforce, drug quality, treatment adherence, and anthelmintic drug resistance. Decisions made from these quantitative tests are dependent on the type of program and this use-case was divided into two.
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Morbidity control programs are initiated in moderate- to high-prevalence settings and rely on two indicators, overall prevalence of infection by any STH and the proportion of individuals with moderate and heavy infections e. An STH program targeting interruption of transmission would initiate or continue efforts in lower transmission settings and would be focused solely on monitoring the reduction of overall prevalence e.
The Kato-Katz method provides sufficiently reliable analytical data to meet use-case 2A and is suitable for morbidity control programs focused on moderately to heavily infected individuals, but improvements to FEC measurements that address reproducibility and throughput challenges Table 1 would enhance program efficiency as well as create opportunities for programs to proceed beyond morbidity control [ 30 , 31 ]. Technologies that meet the needs of use-case 2B can also be used in moderate and high transmission settings by STH control programs but offer greater value in lower transmission settings, where the Kato-Katz method fails to provide reliable data.
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For practical considerations, a preferred technology would be a platform that addresses multiple use-cases by meeting the requirements described in each of the associated TPPs. This use-case applies to programs aiming to interrupt transmission of any STH in low- to very-low- prevalence settings. Diagnostic results that confirm a break in transmission with minimal risk of recrudescence would transition program goals from active intervention to surveillance for recrudescence use-case 4 or, in the event of discordant results, would initiate additional assessments.
The low- to very-low-prevalence threshold that describes the transmission breakpoint is species specific and has yet to be established, although it can be approximated through mathematical and animal models [ 32 ]. Based on studies with A. Nonmicroscopy biomarkers with a linear relationship to low worm burden, detectable within a dynamic range relevant to the transmission breakpoint, are needed.
Table 4 provides a high-level overview of desired characteristics for any biomarker meeting this use-case.
This use-case applies to programs that have successfully interrupted STH transmission use-case 3 and seek to verify sustained elimination of transmission [ 34 ] or have reason to believe that there may be a risk of recrudescence. A program would investigate the potential causes of unexpected results if qualitative test results indicate ongoing transmission. Ideally, the test detects other diseases under surveillance and requires a specimen that is easier to collect than stool, such as urine, saliva, or blood, to encourage participation in screening events, with analysis performed in a centralized laboratory.
The aspirational list of biomarker characteristics described in Table 4 are similar for use-cases 3 and 4, and stricter definitions warrant further discussion. Similar tests for other diseases have relied on detecting host-response antibodies of infection [ 35 ], a class of biomarker convenient for integrated surveillance. These biomarkers of host response should ideally be specific for active infection, not exposure.
Alternatively, exposure-based biomarkers could be measured within indicator subpopulations born after transmission has been broken, as these groups should not have been exposed to STH infection in geographies remaining absent of transmission [ 36 ]. Although species-specific detection is listed in Table 4 , it remains unclear if a pan-STH biomarker would suffice for this use-case.
Each requirement is defined in a TPP as minimal or optimal criteria, reflecting a consensus of accepted compromises. To reduce risks and time lines for developing a product and accelerating adoption, criteria should consider the capacity, resources, and diagnostic workflows of STH programs in the context of existing research, methodology, and technology landscape. Requirements for technology performance and implementation are linked and criteria consider trade-offs for supporting a new test within an existing diagnostic system versus costs for adapting or creating infrastructure.
Implementation considerations include: survey design population targeted for testing, sampling size , available workforce, workflow specimen collection and transportation, sample preparation and analysis , throughput and turnaround time for test results, data requirements, and criteria for reimbursing test costs.
Other considerations include external quality assurance requirements and regulatory pathway as well as program recommendations, policies, and guidelines. Because diagnostics only approximate a true state of infection, mathematical models can be used to further inform performance requirements by estimating the impact of different levels of uncertainty on the accuracy of program decision-making and ultimately on health outcomes [ 37 ].
Models can also provide a health economics framework to justify performance requirements by weighing the predicted health outcomes against costs incurred by a program to conduct a survey as well as resources deployed in the event of an incorrect decision [ 3 ]. Minimum criteria describe performance characteristics that must be achieved for a test to be used by most STH programs. Optimal criteria describe attributes that expand the value of the assay but would not be required by most STH programs. In addition to setting targets for technology development, these requirements are also criteria for clinical and field trials and should consider availability and access to patient specimens from geographies representing the epidemiological and individual context of intended-use populations.
These specimens must naturally represent the diversity and range of biomarkers to validate the performance claims of a prototype assay, with appropriate analytical and clinical benchmarks.
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Excessive technical complexity beyond actual program needs should be avoided, as each claim needs to be validated with available patient samples. In this instance, the minimum requirement listed in a TPP would be a qualitative test result, for interpretation by a program manager. It is important to differentiate the presentation of a test result from the method of analysis, as this qualitative output could be derived from the quantitative analysis of aggregated individual-level data or pooled specimens.
If some programs have the resources and capacity to also act on test results that provide species-specific intensities of infection, then quantitation could be listed as optimal criteria. However, validating that a test reliably provides quantitative test results for each STH species also requires access to statistically powered quantities of accessible patient specimens that contain the natural dynamic range of intensities for each STH. As mentioned earlier, the use-case for monitoring program impact was divided into two similar use-cases, 2A and 2B, to address programs that intend to reduce transmission beyond morbidity control S1 File.
However, a TPP for use-case 2B was not developed, as a lower limit of detection LOD would approximate the transmission breakpoint, a species-specific indicator that requires further definition. At these lower transmission settings, a program manager might be solely interested in prevalence, unlike morbidity control programs, in which intensities of infection are an additional program metric.
Use-cases 1 and 2A were combined because there is little demand for a diagnostic dedicated to use-case 1, with the current pace of coverage by STH programs S2 File. Diagnostic tools that address both use-cases would likely be similar, given the current landscape of coproscopy technologies. There was agreement on current WHO recommendations for using the Kato-Katz method in morbidity control programs, but this technique would not meet all requirements described in this new TPP.
The second TPP described a tool to confirm a sustained break in transmission, a use-case that only requires a qualitative test result S3 File. Conceptually, a platform that meets the needs of use-case 3 might also satisfy use-case 1— 2 if the test offered quantitative test results with appropriate upper limits of quantitation, but this warrants further discussion in the context of this type of multi-parametric test result.
The complete TPPs are available as supplemental materials that accompany this article, with key sections for use-case 3 discussed below. This diagnostic confirms that transmission of each STH has been sustainably suppressed below its breakpoint, a qualitative population-level test result provided by statistical analysis of pooled specimens or data aggregated from multiple individual-level tests.
A negative test result confirms the decision to wind down an active intervention and transition program goals to surveillance for recrudescence use-case 4. A positive test result indicates that transmission has not been broken, requiring the program to investigate causes of confounding results. An STH program manager would use this test when other metrics indicate that the intervention has likely met its end point and seeks confirmation with a diagnostic survey of a targeted population.
These nondiagnostic indicators to initiate testing have yet to be defined and will be clarified through ongoing research assessing the strategy for interrupting transmission [ 38 ]. The minimum detection requirement is species-level infection by A. Hookworm differentiation is not required because interventions are the same for the two species. Interestingly, a recent serological study on VZV-specific antibody titres as a function of age also implied that chronic CMV infection could lead to more frequent VZV reactivation and subsequent boosting termed endogenous boosting Both hypotheses CMV as an activator of immunity versus CMV as a depressor of immunity could explain the observations made in this study.
The results from this study are of importance beyond the realm of fundamental immunology, as the exogenous boosting hypothesis is considered to be an obstacle for the implementation of universal chickenpox vaccination 6. Many cost-effectiveness studies have concluded that the decrease of contacts with chickenpox patients after the implementation of universal chickenpox vaccination would lead to a significant increase of herpes zoster incidence, which could overshadow the positive effects on the reduction of chickenpox 7 , 8 , These simulation models were based on the deterministic modelling estimation that re-exposure to chickenpox would lead to a duration of protection against herpes zoster for 20 years However, a recent individual-based model for VZV estimated the duration of exogenous boosting to last for 1—2 years 9.
Our experimental study supports the latter modelling estimation through our findings that average boosting of cellular immunity was not noticeable by one year after re-exposure vs. This means that our data suggest that the cost-effectiveness analyses for chickenpox vaccination should be redone using the new experimental results, potentially leading to a policy in favour of universal chickenpox vaccination. Our pilot study encountered several limitations, including the modest sample size, the exclusive focus on grandparents and the exclusive use of peptide mixes for the stimulation of PBMCs.
We note that differences in exposure characteristics might also have had an effect on boosting potential as more infectious children more than 50 vesicles have been estimated to have mildly increased infectivity Furthermore, more frequent sampling during the first weeks after re-exposure could also give more insights into boosting dynamics, as recent studies on T-cell dynamics and TCR dynamics following VZV vaccination highlighted a peak in VZV-specific T-cells about one week after vaccination 19 , Future larger studies should also encompass both parents and grandparents so that the effect of immunosenescence could receive more attention.
These larger studies will be more suitable for the mathematical classification of boosted and non-boosted individuals. Indeed, we noted that the formal classification of boosting did not correlate with our visual classification in all instances.
In conclusion, we have found empirical evidence for short-lasting boosting of the cellular immune response against VZV in a minority of grandparents after re-exposure to chickenpox. The error has been fixed in the paper. Arvin, A. J Infect Dis , — Ogunjimi, B. Exploring the impact of exposure to primary varicella in children on varicella-zoster virus immunity of parents. Viral immunology 24 , — Clinical and vaccine immunology: CVI 21 , — Vossen, M.
J Infect Dis , 72—82 Hope-Simpson, R. Proc R Soc Med 58 , 9—20 PloS one 8 , e Bilcke, J. Childhood varicella-zoster virus vaccination in Belgium: cost-effective only in the long run or without exogenous boosting? Brisson, M. Modelling the impact of immunization on the epidemiology of varicella zoster virus.