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Earlier meetings laid the foundations for Controlled Human Infection Models (CHIMs), also known as human challenge studies and human infection studies, including Good Manufacturing Practice (GMP) production of the challenge agent, CHIM ethics, environmental safety in CHIM, recruitment, community engagement, advertising and incentives, pre-existing immunity, and clinical, immunological, and microbiological endpoints. The fourth CHIM meeting focused on CHIM studies being conducted in endemic countries. Over the last ten years we have seen a vast expansion of the number of countries in Africa performing CHIM studies, as well as a growing number of different challenge organisms being used. Community and public engagement with assiduous ethical and regulatory oversight has been central to successful introductions and should be continued, in more community-led or community-driven models. Valuable initiatives for regulation of CHIMs have been undertaken but further capacity building remains essential., Competing Interests: Declaration of competing interest All authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Many aspects of Controlled Human Infection Models (CHIMs, also known as human challenge studies and human infection studies) have been discussed extensively, including Good Manufacturing Practice (GMP) production of the challenge agent, CHIM ethics, environmental safety in CHIM, recruitment, community engagement, advertising and incentives, pre-existing immunity, and clinical, immunological, and microbiological endpoints. The fourth CHIM meeting focused on regulation of CHIM studies, bringing together scientists and regulators from high-, middle-, and low-income countries, to discuss barriers and hurdles in CHIM regulation. Valuable initiatives for regulation of CHIMs have already been undertaken but further capacity building remains essential. The Wellcome Considerations document is a good starting point for further discussions., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Controlled human infection studies have contributed significantly to the understanding of pathogeneses and treatment of infectious diseases. In malaria, deliberately infecting humans with malaria parasites was used as a treatment for neurosyphilis in the early 1920s. More recently, controlled human malaria infection (CHMI) has become a valuable, cost-effective tool to fast-track the development and evaluation of new anti-malarial drugs and/or vaccines. CHMI studies have also been used to define host/parasite interactions and immunological correlates of protection. CHMI involves infecting a small number of healthy volunteers with malaria parasites, monitoring their parasitemia and providing anti-malarial treatment when a set threshold is reached. In this review we discuss the introduction, development, and challenges of modern-day Plasmodium falciparum CHMI studies conducted in Africa, and the impact of naturally acquired immunity on infectivity and vaccine efficacy. CHMIs have shown to be an invaluable tool particularly in accelerating malaria vaccine research. Although there are limitations of CHMI studies for estimating public health impacts and for regulatory purposes, their strength lies in proof-of-concept efficacy data at an early stage of development, providing a faster way to select vaccines for further development and providing valuable insights in understanding the mechanisms of immunity to malarial infection., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Chronic hepatitis B infection (CHB) is a significant problem worldwide with around 300 million people infected. Ambitious goals have been set towards its elimination as a public health threat by 2030. However, accurate seroprevalence estimates in many countries are lacking or fail to provide representative population estimates, particularly in the WHO African Region (AFRO). This means the full extent of HBV infection is not well described, leading to a lack of investment in diagnostics, treatment and disease prevention. Clinical trials in the WHO AFRO region have been increasing over time and many test for infectious diseases including hepatitis B virus (HBV) to determine baseline eligibility for participants, however these screening data are not reported. Here we review data from six clinical trials completed at the KEMRI-Wellcome Trust Research Programme between 2016 and 2023 that screened for HBV using hepatitis B surface antigen (HBsAg) as part of the trial exclusion criteria. 1727 people had HBsAg results available, of which 60 tested positive. We generated a crude period HBV prevalence estimate of 3.5% (95% CI 2.6-4.5%), and after standardisation for sex and age to account for the population structure of the Kilifi Health Demographics Surveillance System (KHDSS), the prevalence estimate increased to 5.0% (95% CI 3.4-6.6%). The underrepresentation of women in these trials was striking with 1263/1641 (77%) of participants being male. Alanine aminotransferase (ALT) was significantly higher in the HBsAg positive group but was not outside the normal range. We argue that routine collation and publishing of data from clinical trials could increase precision and geographical representation of global HBV prevalence estimates, enabling evidence-based provision of clinical care pathways and public health interventions to support progress towards global elimination targets. We do acknowledge when using clinical trials data for seroprevalence estimates, that local population structure data is necessary to allow standardisation of results, and the point of care tests used here are limited in sensitivity and specificity., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Falciparum malaria remains a global health problem. Two vaccines, based on the circumsporozoite antigen, are available. RTS, S/AS01 was recommended for use in 2021 following the advice of the World Health Organisation (WHO) Strategic Advisory Group of Experts (SAGE) on Immunization and WHO Malaria Policy Advisory Group (MPAG). It has since been pre-qualified in 2022 by the WHO. R21 is similar to RTS, S/AS01, and recently licensed in Nigeria, Ghana and Burkina Faso following Phase 3 trial results., Methods: We conducted a Phase 1b age de-escalation, dose escalation bridging study after a change in the manufacturing process for R21. We recruited healthy adults and children and used a three dose primary vaccination series with a booster dose at 1-2 years. Variable doses of R21 and adjuvant (Matrix-M ™) were administered at 10µgR21/50 µg Matrix-M™, 5µgR21/25µg Matrix-M™ and 5µgR21/50µg Matrix-M™ to 20 adults, 20 children, and 51 infants., Results: Self-limiting adverse events were reported relating to the injection site and mild systemic symptoms. Two serious adverse events were reported, neither linked to vaccination. High levels of IgG antibodies to the circumsporozoite antigen were induced, and geometric mean titres in infants, the target group, were 1.1 (0.9 to 1.3) EU/mL at day 0, 10175 (7724 to 13404) EU/mL at day 84 and (following a booster dose at day 421) 6792 (5310 to 8687) EU/mL at day 456., Conclusion: R21/Matrix-M™ is safe, and immunogenic when given at varied doses with the peak immune response seen in infants 28 days after a three dose primary vaccination series given four weeks apart. Antibody responses were restored 28 days after a 4 th dose given one year post a three dose primary series in the young children and infants., Registration: Clinicaltrials.gov (NCT03580824; 9 th of July 2018; Pan African Clinical Trials Registry (PACTR202105682956280; 17 th May 2021)., Competing Interests: Competing interests: AVSH and KJE are named as coinventors on patent applications related to R21. No competing interests were disclosed for other authors., (Copyright: © 2023 Sang S et al.)

Introduction: Malaria, a devastating febrile illness caused by protozoan parasites, sickened 247,000,000 people in 2021 and killed 619,000, mostly children and pregnant women in sub-Saharan Africa. A highly effective vaccine is urgently needed, especially for Plasmodium falciparum (Pf), the deadliest human malaria parasite., Areas Covered: Sporozoites (SPZ), the parasite stage transmitted by Anopheles mosquitoes to humans, are the only vaccine immunogen achieving >90% efficacy against Pf infection. This review describes >30 clinical trials of PfSPZ vaccines in the U.S.A., Europe, Africa, and Asia, based on first-hand knowledge of the trials and PubMed searches of 'sporozoites,' 'malaria,' and 'vaccines.', Expert Opinion: First generation (radiation-attenuated) PfSPZ vaccines are safe, well tolerated, 80-100% efficacious against homologous controlled human malaria infection (CHMI) and provide 18-19 months protection without boosting in Africa. Second generation chemo-attenuated PfSPZ are more potent, 100% efficacious against stringent heterologous (variant strain) CHMI, but require a co-administered drug, raising safety concerns. Third generation, late liver stage-arresting, replication competent (LARC), genetically-attenuated PfSPZ are expected to be both safe and highly efficacious. Overall, PfSPZ vaccines meet safety, tolerability, and efficacy requirements for protecting pregnant women and travelers exposed to Pf in Africa, with licensure for these populations possible within 5 years. Protecting children and mass vaccination programs to block transmission and eliminate malaria are long-term objectives.

Human Infection Studies (HIS) have emerged as an important research approach with the potential to fast track the global development of vaccines and treatments for infectious diseases, including in low resource settings. Given the high level of burdens involved in many HIS, particularly prolonged residency and biological sampling requirements, it can be challenging to identify levels of study payments that provide adequate compensation but avoid 'undue' levels of inducement to participate. Through this embedded ethics study, involving 97 healthy volunteers and other research stakeholders in a malaria HIS programme in Kenya, and using in-depth interviews, focus group discussions and observations during and after a malaria HIS, we give a grounded account of ethical issues emerging in relation to study payments in this setting. While careful community, national, international scientific and ethics review processes meant that risks of serious harm were highly unlikely, the levels of motivation to join HIS seen could raise concerns about study payments being too high. Particular value was placed on the reliability, rather than level, of study payment in this setting, where subsistence livelihoods are common. Study volunteers were generally clear about the study aims at the point of recruitment, and this knowledge was retained over a year later, although most reported experiencing more burdens than anticipated at enrolment. Strict study screening procedures, regular clinical and laboratory monitoring of volunteers, with prompt treatment with antimalarial at predetermined endpoints suggested that the risks of serious harm were highly unlikely. Ethical concerns emerged in relation to volunteers' attempts to conceal symptoms, hoping to prolong residency periods and increase study payments; and volunteers making decisions that compromised important family relationships and personal values. Our findings support an interpretation that, although study volunteers were keen to join the study to access cash payments, they also paid attention to other features of the study and the general clinical research landscape, including levels of risk associated with study participation. Overall, our analysis shows that the ethical concerns emerging from the study payments can be addressed through practical measures, hinged on reducing burdens and strengthening communication, raising important issues for research policy and planning., (© 2022. The Author(s).)

Human infection studies (HIS) have generally been used as a tool in the pathway for vaccine development in high income settings. Over the last decade, this model has been implemented in LMICs with the aim of accelerating development of next generation vaccines that would perform better in these settings. However, in most LMICs, the ethics and regulatory framework for the conduct of these studies are not in place. In Zambia, these studies are yet to be conducted and thus we conducted a stakeholder engagement workshop in October 2019. We engaged with bioethicists, regulatory authority officials, and scientists from within Zambia and other African countries to anticipate and address foreseeable ethical and regulatory issues when conducting HIS in Zambia for the first time. The workshop largely focused on sensitizing the stakeholders on the benefits of these studies with the following main points for consideration on the implementation of these studies in Zambia: need for in-country legal framework and guidelines; need for adequate informed consent based on comprehensive understanding of the concept of HIS and study requirements; and requirements for heightened vigilance to assure participant safety including good ethical and clinical practice with regulatory, ethical, data safety, and community oversight. Additionally, the workshop emphasized the need for rigorous health screening prior to enrolment; suitable infrastructure for containment; and personnel to provide appropriate treatment including emergency resuscitation and evacuation if indicated. Specific recommendations included compensation for burden of participation; access to care and provision for study related injury (e.g. no-fault insurance); and withdrawal and exit procedures to preserve individual and community safety. Finally, the meeting concluded that researchers should actively engage key gate keepers including civic leaders such as parliamentarians, universities, researchers, potential participants and laypersons to avoid circulation of misinformation., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Kunda-Ng'andu EM et al.)

Background: Human infection studies (HIS) that involve deliberately infecting healthy volunteers with a pathogen raise important ethical issues, including the need to ensure that benefits and burdens are understood and appropriately accounted for. Building on earlier work, we embedded social science research within an ongoing malaria human infection study in coastal Kenya to understand the study benefits and burdens experienced by study stakeholders in this low-resource setting and assess the wider implications for future research planning and policy., Methods: Data were collected using qualitative research methods, including in-depth interviews (44), focus group discussions (10) and non-participation observation. Study participants were purposively selected (key informant or maximal diversity sampling), including volunteers in the human infection study, study staff, community representatives and local administrative authorities. Data were collected during and up to 18 months following study residency, from sites in Coastal and Western Kenya. Voice recordings of interviews and discussions were transcribed, translated, and analysed using framework analysis, combining data- and theory-driven perspectives., Findings: Physical, psychological, economic and social forms of benefits and burdens were experienced across study stages. Important benefits for volunteers included the study compensation, access to health checks, good residential living conditions, new learning opportunities, developing friendships and satisfaction at contributing towards a new malaria vaccine. Burdens primarily affected study volunteers, including experiences of discomfort and ill health; fear and anxiety around aspects of the trial process, particularly deliberate infection and the implications of prolonged residency; anxieties about early residency exit; and interpersonal conflict. These issues had important implications for volunteers' families, study staff and the research institution's reputation more widely., Conclusion: Developing ethically and scientifically strong HIS relies on grounded accounts of volunteers, study staff and the wider community, understood in the socioeconomic, political and cultural context where studies are implemented. Recognition of the diverse, and sometimes perverse, nature of potential benefits and burdens in a given context, and who this might implicate, is critical to this process. Prior and ongoing stakeholder engagement is core to developing these insights., (© 2021. The Author(s).)

Higher academic institutions in the UK need to drive improvements in equity, diversity, and inclusion (EDI) through sustainable practical interventions. A broad view of inclusivity is based on an intersectional approach that considers race, geographical location, caring responsibilities, disability, neurodiversity, religion, and LGBTQIA+ identities. We describe the establishment of a diverse stakeholder group to develop practical grass-roots recommendations through which improvements can be advanced. We have developed a manifesto for change, comprising six domains through which academic institutions can drive progress through setting short, medium, and long-term priorities. Interventions will yield rewards in recruitment and retention of a diverse talent pool, leading to enhanced impact and output., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Wedekind L et al.)

This report of the WHO Working Group for Guidance on Human Challenge Studies in COVID-19 outlines ethical standards for COVID-19 challenge studies. It includes eight Key Criteria related to scientific justification, risk-benefit assessment, consultation and engagement, co-ordination of research, site selection, participant selection, expert review, and informed consent. The document aims to provide comprehensive guidance to scientists, research ethics committees, funders, policymakers, and regulators in deliberations regarding SARS-CoV-2 challenge studies by outlining criteria that would need to be satisfied in order for such studies to be ethically acceptable., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [EJ has received consulting fees from WHO and funding from The Wellcome Trust for research on the ethics of human challenge studies. CW receives consulting income from Cardialen, Eli Lilly & Company, and Research Triangle Institute International. MJS is he has received funding from The Wellcome Trust for previous research on the ethics of human challenge studies. No competing interests: SB,CE,GK,MK,KL,ER,CS,PGS, SS, RU]., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Controlled human malaria infection (CHMI) studies involve the deliberate infection of healthy volunteers with malaria parasites under controlled conditions to study immune responses and/or test drug or vaccine efficacy. An empirical ethics study was embedded in a CHMI study at a Kenyan research programme to explore stakeholders' perceptions and experiences of deliberate infection and moral implications of these. Data for this qualitative study were collected through focus group discussions, in-depth interviews and non-participant observation. Sixty-nine participants were involved, including CHMI study volunteers, community representatives and research staff. Data were managed using QSR Nvivo 10 and analysed using an inductive-deductive approach, guided by ethics literature. CHMI volunteers had reasonable understanding of the study procedures. Decisions to join were influenced by study incentives, trust in the research institution, their assessment of associated burdens and motivation to support malaria vaccine development. However, deliberate malaria infection was a highly unusual research strategy for volunteers, community representatives and some study staff. Volunteers' experiences of physical, emotional and social burdens or harms were often greater than anticipated initially, and fluctuated over time, related to specific procedures and events. Although unlikely to deter volunteers' participation in similar studies in furture, we argue that the dissonance between level of understanding of the burdens involved and actual experiences are morally relevant in relation to community engagement, informed consent processes, and ongoing support for volunteers and research staff. We further argue that ethics oversight of CHMI studies should take account of these issues in deciding whether consent, engagement and the balance of benefits and harms are reasonable in a given context., (© 2020 The Authors. Bioethics published by John Wiley & Sons Ltd.)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Following publication of the original article [1], it was flagged that the name of the author Lisa Ranford-Cartwright had been (incorrectly) given as 'Lisa-Ranford Cartwright.

Malaria infections occurring below the limit of detection of standard diagnostics are common in all endemic settings. However, key questions remain surrounding their contribution to sustaining transmission and whether they need to be detected and targeted to achieve malaria elimination. In this study we analyse a range of malaria datasets to quantify the density, detectability, course of infection and infectiousness of subpatent infections. Asymptomatically infected individuals have lower parasite densities on average in low transmission settings compared to individuals in higher transmission settings. In cohort studies, subpatent infections are found to be predictive of future periods of patent infection and in membrane feeding studies, individuals infected with subpatent asexual parasite densities are found to be approximately a third as infectious to mosquitoes as individuals with patent (asexual parasite) infection. These results indicate that subpatent infections contribute to the infectious reservoir, may be long lasting, and require more sensitive diagnostics to detect them in lower transmission settings.

Background: Large-scale surveillance of mosquito populations is crucial to assess the intensity of vector-borne disease transmission and the impact of control interventions. However, there is a lack of accurate, cost-effective and high-throughput tools for mass-screening of vectors., Methods: A total of 750 Anopheles gambiae (Keele strain) mosquitoes were fed Plasmodium falciparum NF54 gametocytes through standard membrane feeding assay (SMFA) and afterwards maintained in insectary conditions to allow for oocyst (8 days) and sporozoite development (14 days). Thereupon, each mosquito was scanned using near infra-red spectroscopy (NIRS) and processed by quantitative polymerase chain reaction (qPCR) to determine the presence of infection and infection load. The spectra collected were randomly assigned to either a training dataset, used to develop calibrations for predicting oocyst- or sporozoite-infection through partial least square regressions (PLS); or to a test dataset, used for validating the calibration's prediction accuracy., Results: NIRS detected oocyst- and sporozoite-stage P. falciparum infections with 88% and 95% accuracy, respectively. This study demonstrates proof-of-concept that NIRS is capable of rapidly identifying laboratory strains of human malaria infection in African mosquito vectors., Conclusions: Accurate, low-cost, reagent-free screening of mosquito populations enabled by NIRS could revolutionize surveillance and elimination strategies for the most important human malaria parasite in its primary African vector species. Further research is needed to evaluate how the method performs in the field following adjustments in the training datasets to include data from wild-caught infected and uninfected mosquitoes.

Controlled human infection (CHI) models are gaining recognition as an approach to accelerating vaccine development, for use in both non-endemic and endemic populations: they can facilitate identification of the most promising candidate vaccines for further trials and advance understanding of protective immunity. Helminths present a continuing health burden in sub-Saharan Africa. Vaccine development for these complex organisms is particularly challenging, partly because protective responses are akin to mechanisms of allergy. A CHI model for Schistosoma mansoni (CHI-S) has been developed at Leiden University Medical Centre, the Netherlands. However, responses to schistosome infections, and candidate vaccines, are likely to be different among people from endemic settings compared to schistosome-naïve Dutch volunteers. Furthermore, among volunteers from endemic regions who have acquired immune responses through prior exposure, schistosome challenge can be used to define responses associated with clinical protection, and thus to guide vaccine development.  To explore the possibility of establishing the CHI-S in Uganda, a Stakeholders' Meeting was held in Entebbe in 2017. Regulators, community members, researchers and policy-makers discussed implementation challenges and recommended preparatory steps: risk assessment; development of infrastructure and technical capacity to produce the infectious challenge material in Uganda; community engagement from Parliamentary to grass-roots level; pilot studies to establish approaches to assuring fully informed consent and true voluntariness, and strategies for selection of volunteers who can avoid natural infection during the 12-week CHI-S; the building of regulatory capacity; and the development of study protocols and a product dossier in close consultation with ethical and regulatory partners. It was recommended that, on completion, the protocol and product dossier be reviewed for approval in a joint meeting combining ethical, regulatory and environment management authorities. Most importantly, representatives of schistosomiasis-affected communities emphasised the urgent need for an effective vaccine and urged the research community not to delay in the development process., Competing Interests: No competing interests were disclosed., (Copyright: © 2018 Elliott AM et al.)

Background: In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa., Methods: Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15-0.4 mg PQ base/kg for children aged 1-5 years and 0.15-0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6-11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box-Cox transformation power exponential and tested PQ doses of 1-15 mg base, selecting dosing groups based on calculated mg/kg PQ doses., Results: From the Box-Cox transformation power exponential model, five age categories were selected: (i) 6-11 months (n = 39,886, 6.03%), (ii) 1-5 years (n = 261,036, 45.46%), (iii) 6-9 years (n = 20,770, 3.14%), (iv) 10-14 years (n = 12,155, 1.84%) and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12-0.25), (ii) 0.21 (0.13-0.37), (iii) 0.25 (0.16-0.38), (iv) 0.26 (0.15-0.38) and (v) 0.27 (0.17-0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244,537/261,036), 99.6 (20,690/20,770), 99.4 (12,086/12,155) and 99.8% (327,620/328,132), respectively., Conclusions: We plan to test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial (ISRCTN11594437) of uncomplicated falciparum malaria in G6PDd African children aged 0.5 - 11 years. If the regimen is safe and demonstrates adequate pharmacokinetics, it should be used to support malaria elimination.

Background: Malaria control strategies need to respond to geographical hotspots of transmission. Detection of hotspots depends on the sensitivity of the diagnostic tool used., Methods: We conducted cross-sectional surveys in 3 sites within Kilifi County, Kenya, that had variable transmission intensities. Rapid diagnostic test (RDT), microscopy, and polymerase chain reaction (PCR) were used to detect asymptomatic parasitemia, and hotspots were detected using the spatial scan statistic., Results: Eight thousand five hundred eighty-one study participants were surveyed in 3 sites. There were statistically significant malaria hotspots by RDT, microscopy, and PCR for all sites except by microscopy in 1 low transmission site. Pooled data analysis of hotspots by PCR overlapped with hotspots by microscopy at a moderate setting but not at 2 lower transmission settings. However, variations in degree of overlap were noted when data were analyzed by year. Hotspots by RDT were predictive of PCR/microscopy at the moderate setting, but not at the 2 low transmission settings. We observed long-term stability of hotspots by PCR and microscopy but not RDT., Conclusion: Malaria control programs may consider PCR testing to guide asymptomatic malaria hotspot detection once the prevalence of infection falls., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

Transmission blocking vaccines (TBV) which aim to control malaria by inhibiting human-to-mosquito transmission show considerable promise though their utility against naturally circulating parasites remains unknown. The efficacy of two lead candidates targeting Pfs25 and Pfs230 antigens to prevent onwards transmission of naturally occurring parasites to a local mosquito strain is assessed using direct membrane feeding assays and murine antibodies in Burkina Faso. The transmission blocking activity of both candidates depends on the level of parasite exposure (as assessed by the mean number of oocysts in control mosquitoes) and antibody titers. A mathematical framework is devised to allow the efficacy of different candidates to be directly compared and determine the minimal antibody titers required to halt transmission in different settings. The increased efficacy with diminishing parasite exposure indicates that the efficacy of vaccines targeting either Pfs25 or Pfs230 may increase as malaria transmission declines. This has important implications for late-stage candidate selection and assessing how they can support the drive for malaria elimination.