A staged clinical development and evidence-generation framework for Group A Streptococcus vaccines

Abstract

Group A Streptococcus (Strep A) causes substantial global morbidity and mortality, yet vaccine development faces scientific, regulatory, and strategic challenges. We propose a platform-agnostic, staged clinical development and evidence-generation framework aligning trial feasibility with public health priorities. Laboratory-confirmed symptomatic pharyngitis could provide a feasible pivotal efficacy endpoint for initial licensure, subject to regulatory agreement. Complementary efficacy, effectiveness, and implementation studies could then generate evidence across diverse populations and outcomes.

Introduction

Group A Streptococcus (Streptococcus pyogenes, Strep A) remains a major global cause of morbidity and mortality, responsible for a broad spectrum of diseases ranging from common infections such as pharyngitis and impetigo to severe invasive syndromes, including necrotizing fasciitis and streptococcal toxic shock syndrome. In addition to its acute manifestations, Strep A infection can trigger immune-mediated complications such as acute rheumatic fever (ARF) and rheumatic heart disease (RHD), which continue to impose a disproportionate burden on low- and middle-income countries (LMICs) and on vulnerable populations in some high-income countries (HICs)^1–5. It is estimated that Strep A–associated diseases account for more than 500,000 deaths annually, a burden that has led the World Health Organization (WHO) to prioritize Strep A both as a vaccine target and as a contributor to antimicrobial resistance (AMR)^2,6,7.

Despite decades of research and preclinical evidence supporting several vaccine candidates, progress toward a licensed Strep A vaccine has been slow. Only a small number of candidates have advanced into early clinical development. Historical concerns regarding vaccine safety, particularly the theoretical risk of autoimmune sequelae, have contributed to a cautious regulatory environment and have influenced the opportunities for vaccine development in the field⁶. At the same time, the substantial genetic diversity of Strep A strains and the absence of well-established correlates of protection have complicated antigen selection and progression to clinical development⁸. While recent years have seen renewed investment and a diversification of vaccine approaches, including targeting both M protein–based and non–M protein antigens, and the utility of various delivery platforms such as mRNA, along with advances in adjuvant technology, no single strategy has yet emerged as clearly dominant⁸.

Beyond the scientific challenges, Strep A vaccine development faces a fundamental strategic and clinical problem: severe invasive disease and immune-mediated sequelae, including ARF and RHD, account for major mortality and long-term disability, yet are difficult to evaluate directly in conventional efficacy trials. RHD may evolve over the years following repeated Strep A infections, while ARF is incompletely ascertained in many LMICs. Invasive Strep A disease has high case-fatality but lower incidence than uncomplicated infections and affects a broad age range, although targeted studies in higher-risk groups, including older adults with comorbidities, may be more feasible and warrant evaluation. Superficial skin and skin-structure infections, including impetigo, are highly prevalent in many tropical and resource-limited settings and may contribute to immune-mediated sequelae; their epidemiology and ascertainment may also be influenced by comorbid conditions such as scabies. Conversely, symptomatic Strep A pharyngitis is common, represents a major driver of antibiotic prescribing, and is an established antecedent of ARF. We therefore consider it a feasible and clinically meaningful candidate endpoint for pivotal efficacy evaluation, while recognizing that acceptability for licensure will require prospective agreement with relevant regulators and cannot be presumed. This tension between feasible efficacy endpoints and the outcomes that matter most for global health has long complicated Strep A vaccine development.

Here, we propose a staged clinical development framework in which prevention of laboratory-confirmed symptomatic pharyngitis can serve as an initial pivotal endpoint, while complementary efficacy, effectiveness, and implementation studies generate evidence across diverse populations and clinically important outcomes.

Development of the proposed framework

This Perspective presents a conceptual framework developed iteratively through discussion among the authors, drawing on the published Strep A vaccine literature, WHO R&D roadmap and Preferred Product Characteristics, and ongoing developments in the field. It was not derived through a systematic review, Delphi process, formal stakeholder consultation, or regulatory consensus procedure, and it should therefore be interpreted as an author-proposed strategy intended to stimulate discussion and prospective testing. Where the framework addresses potential regulatory pathways or endpoints, these are proposals rather than statements of regulatory acceptance. Recent initiatives in the field, including the Coefficient Giving Strep A Vaccine Fund, independently emphasize parallel candidate advancement, human challenge studies, early regulatory and policy engagement, and evaluation of early RHD as a potential endpoint, illustrating convergence around several of the development needs addressed here⁹.

The Strep A vaccine landscape and persistent development challenges

The development of vaccines against Strep A has been pursued for over 100 years, yet a combination of biological complexity, historical safety concerns, uncertainty about correlates of protection, regulatory challenges, lack of consensus around feasible clinical efficacy endpoints, and funding constraints has repeatedly hampered progress. Strep A is characterized by extensive genetic and antigenic diversity, creating a major challenge for achieving broad and durable strain coverage. Consequently, vaccine development has focused on either highly conserved antigens or strategies capable of eliciting broadly protective immune responses, although no single approach has yet resolved the balance between breadth of coverage and robust protection^8,10.

Current vaccine candidates fall broadly into two categories: M protein–based and non–M protein–based approaches^8,11,12. To date M protein–based vaccines are the only strategies to have demonstrated protection in human studies^8,11,13–24. Contemporary M-protein-based vaccine constructs differ substantially from earlier candidates by focusing on conserved or engineered regions designed to minimize theoretical autoimmune risks while maintaining broad strain coverage^6,25,26. In parallel, numerous non–M protein candidates, including Group A Carbohydrate (GAC), Streptolysin O (SLO), Streptococcal C5a peptidase (ScpA), Streptococcus pyogenes Cell Envelope Protease (SpyCEP), Streptococcus pyogenes Adhesion and Division protein (SpyAD) and other conserved antigens²⁷, aim to achieve broad protection independent of M protein diversity^{8,11,25,28–42}. Although these approaches differ biologically, both have shown encouraging preclinical results and protection against S. pyogenes challenge in animal models^8,12. Recent experimental evidence has also helped alleviate historical concerns regarding autoimmune responses to GAC-based vaccines⁴³. Representative vaccine candidates are summarized in Supplementary Tables S1 and S2.

Despite increasing diversification of the pipeline, several critical obstacles remain. First, there are still no established correlates of protection, complicating candidate selection, immunobridging, and clinical development^8,44. Second, historical safety concerns, based on a single poorly characterized M-protein extract vaccine study associated with cases of ARF, continue to influence regulatory expectations despite the absence of comparable findings with modern vaccine candidates and more than 200,000 vaccinated individuals across multiple clinical programs⁴⁵. Third, and perhaps most importantly from a strategic perspective, the clinical outcomes responsible for the greatest global burden, particularly ARF and RHD, are not readily amenable to evaluation within conventional Phase III efficacy trials because of their prolonged natural history and the very large sample sizes that would be required^2,6,7,46. This challenge has also been recognized in recent international discussions involving the Strep A Vaccine Global Consortium (SAVAC) and the WHO aimed at defining practical clinical development strategies and feasible pathways for vaccine evaluation (WHO and SAVAC engagement meetings; manuscript in preparation).

The clinical endpoint problem: reconciling feasibility and public health impact

Unlike some bacterial vaccine targets for which a single, well-defined clinical endpoint can anchor clinical development, such as invasive pneumococcal disease for pneumococcal vaccines, Strep A presents a uniquely complex challenge. The pathogen causes a broad spectrum of diseases ranging from mild pharyngitis and impetigo to life-threatening invasive infections and immune-mediated sequelae, including ARF and RHD. However, the outcomes responsible for the greatest mortality and long-term disability are also those that are least amenable to evaluation in conventional clinical efficacy trials, creating a fundamental misalignment between the endpoints that are feasible to measure and those that matter most from a public health perspective (Supplementary Table S3).

This misalignment lies at the heart of Strep A vaccine development. While ARF typically occurs within weeks of infection, RHD can emerge after one or more episodes of RF and progressive valvular damage over years. Demonstrating vaccine efficacy against clinically significant RHD would therefore require long follow-up and, depending on background incidence, potentially very large trials. By contrast, symptomatic Strep A pharyngitis is common and can be evaluated within conventional efficacy-study timelines. WHO estimates a global incidence of approximately 22.1 episodes of Strep A sore throat per 100 child-years among children aged 5–14 years, although incidence varies substantially by population and trial eligibility⁴⁷. This frequency supports the practical feasibility of event-driven efficacy studies, but definitive sample size will depend on local incidence, the prespecified case definition, expected vaccine efficacy, follow-up duration, and loss to follow-up. Pharyngitis is also a major driver of healthcare utilization and antibiotic prescribing and an established antecedent of ARF^3,48–50.

Importantly, efficacy against symptomatic pharyngitis should not be interpreted as a validated surrogate for prevention of ARF or RHD. The vaccine-preventable fraction of these sequelae will depend on whether vaccination also affects asymptomatic infection, carriage and transmission; protection against skin and skin-structure infections as well as throat infection; the cumulative effect of repeated exposures; age-dependent immune responses; geographic differences in infection patterns; and the breadth and durability of protection across antigenically diverse strains. Potential changes in strain distribution after vaccination will also require surveillance. These uncertainties are a central reason for the staged evidence-generation approach proposed here.

Accordingly, symptomatic pharyngitis has direct clinical and public-health value as an endpoint in its own right, independent of any unproven effect on downstream sequelae. Prevention would reduce symptomatic illness and could reduce healthcare use and antibiotic prescribing. We propose it as a potential basis for initial licensure in settings where an adequately specific endpoint can be ascertained, subject to regulator agreement; complementary evidence would then be needed to characterize vaccine effects on other manifestations and on the pathways leading to ARF and RHD.

Rather than seeking a single endpoint to address all public health objectives, we propose an incremental, staged strategy in which specific evidence targets are defined for each development phase, population and intended indication.

A staged clinical development and evidence-generation framework for Strep A vaccines

Shared early clinical development with population-specific evaluation

Regardless of the eventual regulatory or implementation strategy, clinical development would generally begin with first-in-human studies in healthy adult volunteers followed by Phase 2 studies to further evaluate safety, immunogenicity, dose and regimen selection, and age de-escalation toward target pediatric populations. Standard clinical-trial safety monitoring should remain the foundation. Given historical concerns in the field, additional cardiac or immunological investigations for theoretical autoimmune risk may be considered on a candidate-specific and regulator-agreed basis, but should not be treated as universally required because nonspecific testing may generate false-positive findings and very rare adverse events may only become detectable in substantially larger studies or post-authorization surveillance.

At this stage, development should remain largely vaccine-agnostic. Both M protein–based and non–M protein–based candidates can be evaluated within a common framework. Advancement to Phase 2b and pivotal evaluation should use prespecified, candidate-specific stage-gates that integrate an acceptable safety/reactogenicity profile, evidence of biologically meaningful immunogenicity, dose and regimen selection, manufacturability, anticipated breadth of coverage, and, where available, preliminary efficacy or proof-of-concept evidence from field or human challenge studies. Because no validated correlate of protection or universal efficacy threshold exists, numerical go/no-go criteria should be defined prospectively for each program with regulators, funders and other decision-makers rather than imposed as a single field-wide threshold. The overall framework is summarized in Fig. 1.

Fig. 1. A staged clinical development and evidence-generation framework for Group A Streptococcus vaccines.

Evidence is tailored to the needs and disease burden of different populations, generated in parallel and refined over time to accelerate impact: Clinical development of Strep A vaccines begins with a shared, vaccine-agnostic pathway to establish safety, immunogenicity, and optimal regimens. A Phase 2b proof-of-concept study provides expanded safety data and a preliminary efficacy signal to inform a go/no-go decision for pivotal Phase 3 evaluation. Subsequent clinical evaluation is tailored to population-specific disease burden and public health needs, with complementary studies across different settings. All populations may pursue studies of pharyngitis and other relevant outcomes; licensure may initially be sought for pharyngitis and/or impetigo in any setting. Multiple lines of efficacy and effectiveness evidence are generated in parallel, with prespecified opportunities to refine later evidence-generation priorities as data accumulate, with early planning for implementation and impact studies to accelerate policy uptake and equity. ^*CHIM Controlled Human Infection Model.

Pivotal efficacy against pharyngitis as a licensure pathway

For initial licensure, we propose that pivotal Phase III efficacy trials could be conducted in settings where laboratory-confirmed symptomatic pharyngitis can be evaluated efficiently, including HICs and selected LMICs as appropriate, subject to agreement with relevant regulatory authorities. For vaccine trials, the endpoint should represent clinically significant disease rather than detection of Strep A alone: a prespecified symptomatic pharyngitis syndrome should be accompanied by microbiological confirmation from a throat specimen using culture or a validated molecular or antigen-based assay, with active case ascertainment and blinded endpoint adjudication where feasible. WHO identifies throat culture as the current diagnostic gold standard and notes that the performance of alternative tests can vary by setting⁴⁷. Because asymptomatic carriage can yield a positive microbiological result in a patient whose symptoms have another cause, trial protocols should prespecify symptom criteria, sampling windows, diagnostic methods and analytic approaches to minimize misclassification. Local surveillance should inform event-rate assumptions and sample size. Pivotal trials should also prospectively collect immunological samples to explore correlates of risk and protection and to support future immunobridging hypotheses.

Protection against laboratory-confirmed symptomatic pharyngitis would constitute a direct clinical benefit and could support a licensure application if the totality of evidence is judged adequate by the relevant regulator. This endpoint need not be justified solely as an intermediate step toward RHD: reducing pharyngitis can decrease symptomatic illness, healthcare utilization and antibiotic prescribing^3,48. Evidence of downstream complications strengthens the broader public-health rationale, but efficacy against pharyngitis alone should not be taken as evidence of protection against ARF or RHD. In high-burden settings, asymptomatic carriage, transmission intensity and co-circulating strains may complicate endpoint interpretation, reinforcing the need for context-specific trial design and standardized case definitions.

The role of controlled human infection models

Controlled human infection models (CHIMs) for Strep A pharyngitis can provide an experimental setting for early proof-of-concept and mechanistic studies⁵¹. At present, however, no vaccine efficacy result from a Strep A CHIM has been shown to predict protection in field efficacy trials. CHIM findings should therefore be considered hypothesis-generating and supportive rather than a validated surrogate for field efficacy or a stand-alone basis for licensure.

CHIMs are conducted using carefully selected wild-type strains, standardized inoculation protocols, intensive clinical monitoring, and predefined early antibiotic treatment criteria to minimize risk to participants. These studies have demonstrated the feasibility and safety of experimentally induced pharyngitis in healthy adult volunteers⁵¹.

Within this framework, CHIMs may help compare or prioritize candidates, characterize immune responses under controlled exposure, and contribute to the development of candidate correlates of protection. Their future role on the critical development pathway will depend on demonstrating reproducibility across studies and, importantly, concordance between CHIM and field efficacy results. Until such validation is available, pivotal evidence should continue to rely on appropriately designed clinical studies in the intended populations.

Generating evidence for public health impact in high-burden settings

While pharyngitis-based efficacy trials may provide one potential pathway toward initial licensure, they do not by themselves establish vaccine impact on severe invasive disease or immune-mediated sequelae such as ARF and RHD in high-burden populations^2,6,7,46. In many LMICs, recurrent Strep A exposure and RHD remain important causes of long-term morbidity and socioeconomic burden. Complementary studies in high-burden settings are therefore essential to determine whether protection extends beyond symptomatic pharyngitis and to quantify population-level impact.

Direct efficacy trials against established RHD are unlikely to be practical within conventional development timelines because of its long natural history. ARF and invasive disease may be measurable in selected populations with sufficiently high incidence and robust surveillance, but feasibility should be established empirically rather than assumed. For invasive disease, targeted evaluation in higher-risk populations, including older adults and people with relevant comorbidities, may reduce required sample sizes. We therefore propose a portfolio of setting-specific efficacy and effectiveness studies, intermediate outcomes, and longer-term observational follow-up, potentially extending into the post-licensure period. In early-adopter LMICs or high-incidence populations in HICs, these studies could simultaneously inform local policy and the broader evidence base.

Echo-detected early RHD is a promising candidate outcome for evaluating vaccine impact⁵², but it is not currently an established vaccine efficacy or licensure endpoint. The 2023 World Heart Federation criteria provide standardized echocardiographic diagnostic definitions, and the 2024 WHO guideline recommends echocardiographic screening for early detection of RHD among children and adolescents aged 5–19 years in populations with moderate/high RHD prevalence^47,53. WHO also recommends antibiotic prophylaxis for children and adolescents meeting minimum RHD criteria on echocardiographic screening, supporting the clinical relevance of detecting early disease⁴⁷. These recommendations concern diagnosis, screening and secondary prevention, however, and do not constitute regulatory validation of early RHD as a vaccine endpoint.

A validation pathway for use in vaccine evaluation would therefore need to establish: standardized acquisition and interpretation using accepted criteria; reproducibility and blinded adjudication across sites; background incidence and natural history in the intended trial population; sensitivity to a vaccine effect within a feasible follow-up period; and a sufficiently well-characterized relationship between prevention of incident or progressive echo-detected disease and outcomes that are meaningful to patients and policy-makers. Prospective engagement with regulators and WHO would be required to determine whether and under what circumstances such data could support an efficacy claim, expanded indication, policy recommendation, or post-licensure effectiveness assessment.

In parallel, well-designed population-based effectiveness studies can evaluate vaccine impact on clinically apparent disease, healthcare utilization, and antibiotic use under real-world conditions. Selected early-adopter LMICs and middle-income countries with established research infrastructure could generate critical evidence to inform global policy recommendations. Planning and funding for these studies should begin alongside Phase IIb/III efficacy trials to avoid delays between initial licensure and broader policy recommendations, consistent with lessons learned from the RTS, S malaria vaccine implementation pathway⁵⁴.

Managing safety and autoimmune risk in Strep A vaccine development

Safety considerations have shaped Strep A vaccine development because natural infection can lead to autoimmune sequelae and because a historical study of a poorly characterized vaccine was temporally associated with cases of ARF⁴⁵. The causal interpretation and relevance of that experience to modern candidates remain uncertain, so safety statements should distinguish theoretical concerns from observed vaccine-attributable risk.

Modern candidates use defined antigens and contemporary preclinical and clinical evaluation. Available studies have not established a signal of vaccine-induced autoimmune pathology, but the relatively small size and limited duration of most clinical studies mean that very rare or delayed risks cannot be excluded^8,25,55,56.

Safety should be addressed through standard, phase-appropriate clinical monitoring, with additional investigations driven by the biology of the candidate, preclinical findings, emerging clinical data and regulatory advice. Exploratory cardiac assessments or assays of tissue cross-reactivity may be useful in selected programs, but routine use should be justified because low-specificity testing can create false-positive signals. Larger efficacy studies and post-authorization pharmacovigilance will remain necessary to characterize uncommon or delayed adverse events.

The use of pharyngitis as the initial efficacy endpoint does not lessen the need for rigorous safety evaluation in populations at risk of immune-mediated disease. Instead, it reflects a staged evidence-generation strategy in which a feasible clinical endpoint supports licensure while progressively larger and more diverse studies continue to strengthen the safety evidence base. Ultimately, confidence in vaccine safety will derive from the cumulative evidence generated across preclinical studies, clinical trials, and real-world use rather than from any single study.

The role of preclinical models and correlates of protection

Preclinical models play an essential but inherently limited role in the development of Strep A vaccines. A variety of small-animal (mice, rat, rabbit) and non-human primate models have been used to explore immunogenicity, mechanisms of protection, and, in some cases, disease-specific outcomes, and these systems have contributed substantially to the identification and prioritization of candidate antigens and formulations^8,39–41. However, no available model fully recapitulates the complex natural history of human Strep A infection or the long, multistep pathway leading to immune-mediated sequelae such as ARF and RHD.

One of the most important unmet needs remains the identification and validation of correlates of protection. Candidate correlates should be distinguished from validated correlates or surrogate endpoints. Discovery requires paired immune and clinical outcome data, ideally across more than one vaccine, population and epidemiological setting. Candidate readouts include opsonophagocytic killing, antigen-specific binding antibodies, bactericidal activity, adherence-inhibition assays and other functional or cellular measures^8,44. Any proposed correlate would require prespecified analytical validation, reproducibility across laboratories, demonstration of an association with clinical protection, and, before use as a surrogate for efficacy, evidence that vaccine-induced changes in the marker reliably predict vaccine effects on the clinical endpoint. CHIM studies may contribute mechanistic and exploratory data, but cannot by themselves establish surrogacy until their relationship to field protection is known.

From a safety perspective, preclinical studies continue to play a critical role in screening, particularly regarding the theoretical risk of autoimmune cross-reactivity. Contemporary development programs routinely incorporate in vitro tissue cross-reactivity assays and in vivo assessments designed to detect pathological immune responses before candidates enter clinical testing^25,55. While such studies cannot exclude extremely rare or delayed adverse events, they provide an essential layer of risk mitigation and support rational candidate selection.

In the context of the staged clinical development framework proposed here, preclinical models should therefore be viewed primarily as tools for hypothesis generation, candidate prioritization, and early risk reduction, rather than as definitive predictors of clinical efficacy or long-term safety.

Regulatory considerations and pathway to licensure

Early engagement with regulatory authorities will be important to seek agreement on clinical endpoints, safety requirements, target populations and the evidence needed for a marketing authorization and specific indication. Regulatory licensure and the wording of an indication are distinct from WHO prequalification, which assesses products for procurement after appropriate regulatory review and from WHO or national policy recommendations, which additionally consider disease burden, benefit–risk, programmatic feasibility, economics and equity. Implementation is a further step requiring financing, delivery systems, surveillance and country-level adoption. The WHO R&D roadmap and Preferred Product Characteristics provide strategic guidance for Strep A vaccine development but do not pre-empt decisions by regulators, WHO prequalification or policy bodies⁶.

Implications for policy, access, and global impact

From a development perspective, demonstration of efficacy against laboratory-confirmed symptomatic pharyngitis could provide a practical basis for an initial licensure application, but adequacy of the evidence and the resulting indication would be determined by the relevant regulator. Subsequent evidence may support expanded indications, policy recommendations, prequalification and implementation, each of which involves distinct decision criteria. Continued engagement with regulators, WHO, national immunization programmes and affected communities will be important so that complementary studies are designed to answer these different questions⁶. Staged evidence generation has precedents in other vaccine fields, although the evidentiary pathway for Strep A will need to be established prospectively rather than inferred from analogy.

Equity should be operationalized throughout development rather than treated only as an implementation objective. This includes selecting trial and surveillance sites that represent populations bearing the greatest disease burden; ensuring age de-escalation and evidence generation in intended pediatric populations; investing in local laboratory, echocardiography, pharmacovigilance and trial capacity; engaging communities and national decision-makers in endpoint and implementation planning; and anticipating affordability, supply, delivery requirements and post-trial access. Evidence packages intended to support global policy should include data from diverse epidemiological settings rather than relying solely on HIC efficacy studies^2,6,7,46.

The potential contribution of Strep A vaccination to reducing antibiotic use should also be recognized. Pharyngitis remains a major driver of antibiotic prescribing worldwide, much of it unnecessary, and reductions in disease incidence could contribute meaningfully to efforts to mitigate antimicrobial resistance^3,48. Although this alone does not justify vaccine development, it represents an important additional public health benefit that further strengthens the rationale for widespread vaccination.

Ultimately, successful implementation of a Strep A vaccine will depend not only on antigen design but also on coordinated strategies for generating, integrating and applying evidence across diverse epidemiological settings. The staged clinical development and evidence-generation framework proposed here is intended to contribute to that objective.

Limitations of the proposed framework

This framework has several limitations. It is a Perspective developed through iterative discussion among the authors rather than a formal consensus process or systematic evidence review, and it has not been endorsed by regulators or policy bodies. Several central assumptions remain unvalidated, including the extent to which prevention of symptomatic pharyngitis predicts effects on infection, carriage, transmission, skin disease, ARF or RHD; the generalizability of endpoints across ages and geographies; and the feasibility of early RHD or invasive disease endpoints in specific high-risk populations. The Strep A vaccine pipeline and relevant WHO guidance are also evolving. Accordingly, the framework should be treated as a testable development strategy that requires prospective refinement through epidemiological studies, clinical trials, regulatory dialogue and engagement with affected countries and communities. The recent Coefficient Giving Strep A Vaccine Fund illustrates external convergence on several priorities, i.e., parallel candidate advancement, CHIM development, early regulatory engagement and investigation of early RHD endpoints, but does not validate the specific pathway proposed here⁹.

Conclusion

The development of safe and effective Strep A vaccines has reached an important turning point. Scientific advances have generated an increasingly diverse pipeline of promising vaccine candidates, yet progress toward licensure and implementation remains constrained by the challenge of generating evidence that is both regulatorily feasible and relevant to global public health priorities.

The staged clinical development and evidence-generation framework proposed here aims to address this challenge by aligning evidence generated at different stages with distinct decisions by regulators, policymakers and public-health authorities. Rather than relying on a single endpoint to address all objectives, the framework proposes initial evaluation against feasible, clinically meaningful outcomes such as symptomatic pharyngitis, followed by progressively broader evidence generation across populations and disease manifestations to inform expanded indications, policy and implementation.

This platform-agnostic strategy could be applied across the current and future Strep A vaccine pipeline. Its value will depend on prospective testing and refinement through collaboration among developers, regulators, policymakers, researchers and affected communities. Such an approach may help translate scientific progress into evidence packages that are both feasible to generate and relevant to reducing the global burden of Strep A disease.

Author contributions

A.C. conceived the manuscript and developed the proposed framework. A.C. and A.K. prepared the initial draft and figures. T.A.W., A.S., J.C., A.F. and J.H.K. contributed to the development and refinement of the concepts and framework presented in the manuscript. All authors critically reviewed and revised the manuscript and approved the final version.

Funding

This work was funded by the International Vaccine Institute Europe Regional Office through investment from the Swedish Ministry for Foreign Affairs grant UD2022/000123.

Data availability

No datasets were generated or analyzed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Supplementary information

The online version contains supplementary material available at https://doi.org/10.1038/s41541-026-01607-5.