Embedding research capacity strengthening in multi-country studies in low-and middle-income countries: learnings from sexual and reproductive health research.

Research capacity strengthening (RCS) can empower individuals, institutions, networks, or countries to define and prioritize problems systematically; develop and scientifically evaluate appropriate solutions; and reinforce or improve capacities to translate knowledge into policy and practice. However, how to embed RCS into multi-country studies focusing on sexual and reproductive health and rights (SRHR) is largely undocumented. We used findings from a qualitative study, from a review of the literature, and from a validation exercise from a panel of experts from research institutions that work on SRHR RCS. We provide a framework for embedded RCS; suggest a set of seven concrete actions that research project planners, designers, implementers, and funders can utilise to guide embedded RCS activities in low- and middle-income countries; and present a practical checklist for planning and assessing embedded RCS in research projects.

Paper ContextMain findings: Building on findings from a primary qualitative study, a literature review, and a consultation with experts on capacity strengthening in LMICs, we propose a systematic approach to embedded RCS.Added knowledge: We present a framework for embedding RCS in multi-country studies and propose seven action points and a checklist for the implementation of RCS in multi-country research projects with considerations for sexual and reproductive health and rights research.Global health impact for policy and action: An easy-to-use checklist can enable global health researchers and policymakers to ensure RCS is an integral component of multi-country research.

Strengthening capacity for community and public engagement (CPE): a mixed-methods evaluation of the 'DELTAS Africa CPE seed fund' pilot.

Background: The 'DELTAS Africa CPE seed fund' was a pilot scheme designed to strengthen capacity in community and public engagement (CPE) via a 'learn by doing' approach.   The scheme supported a total of 25 early career researchers and research support staff belonging to the DELTAS Africa network to design and implement a variety of CPE projects between August 2019 and February 2021.  We examine recipient experiences of the DELTAS Africa CPE seed fund initiative, changes in their CPE attitudes, knowledge and proficiency and their CPE practice and/or practice intentions post-award. Methods: A mixed-methods process and performance evaluation drawing on three data sources: An anonymous, online knowledge, attitude and practice survey completed by CPE seed fund awardees pre- and post-project implementation (N=23); semi-structured interviews completed with a sub-sample of awardees and programme implementors (N=9); and 'end-of-project' reports completed by all seed fund awardees (N=25).  Results: All awardees described their seed fund experience in positive terms, despite invariably finding it more challenging than originally anticipated.  The combined survey, interview and end of project report data all uniformly revealed improvement in awardees' self-reported CPE knowledge, attitudes and proficiency by completion of their respective projects.   Commitment to continued CPE activity post-award was evident in the survey data and all interviewees were adamant that they would integrate CPE within their respective research work going forward. Conclusion: The DELTAS Africa CPE seed fund appeared to work successfully as a CPE capacity strengthening platform and as a vehicle for fostering longer-term interest in CPE activities.

Development of an international sexual and reproductive health survey instrument: results from a pilot WHO/HRP consultative Delphi process.

Population health surveys are rarely comprehensive in addressing sexual health, and population-representative surveys often lack standardised measures for collecting comparable data across countries. We present a sexual health survey instrument and implementation considerations for population-level sexual health research. The brief, comprehensive sexual health survey and consensus statement was developed via a multi-step process (an open call, a hackathon, and a modified Delphi process). The survey items, domains, entire instruments, and implementation considerations to develop a sexual health survey were solicited via a global crowdsourcing open call. The open call received 175 contributions from 49 countries. Following review of submissions from the open call, 18 finalists and eight facilitators with expertise in sexual health research, especially in low- and middle-income countries (LMICs), were invited to a 3-day hackathon to harmonise a survey instrument. Consensus was achieved through an iterative, modified Delphi process that included three rounds of online surveys. The entire process resulted in a 19-item consensus statement and a brief sexual health survey instrument. This is the first global consensus on a sexual and reproductive health survey instrument that can be used to generate cross-national comparative data in both high-income and LMICs. The inclusive process identified priority domains for improvement and can inform the design of sexual and reproductive health programs and contextually relevant data for comparable research across countries.

Assessing Gender Identity and Sex in Diverse Low-, Middle-, and High-Income Settings: Findings from a WHO/HRP Consultative Process.

ABSTRACT: Obtaining detailed data on gender identity and sex in population-based sexual health studies is important. We convened a group to develop consensus survey items. We identified 2 items to capture data on gender identity and sex that can be used in diverse settings.

Effective supervision of doctoral students in public and population health in Africa: CARTA supervisors' experiences, challenges and perceived opportunities.

The quality and success of postgraduate education largely rely on effective supervision. Since its inception in 2008, the Consortium for Advanced Research Training in Africa (CARTA) has been at the forefront of providing training to both students and supervisors in the field of public and population health. However, there are few studies on supervisors' perceptions on effective doctoral supervision. We used a mostly descriptive study design to report CARTA-affiliated doctoral supervisors' reflections and perceptions on doctoral supervision, challenges and opportunities. A total of 77 out of 160 CARTA supervisors' workshop participants responded to the evaluation. The respondents were affiliated with 10 institutions across Africa. The respondents remarked that effective supervision is a two-way process, involving both supervisor and supervisee's commitment. Some reported that the requirements for effective supervision included the calibre of the PhD students, structure of the PhD programme, access to research infrastructure and resources, supervision training, multidisciplinary exposure and support. Male supervisors have significantly higher number of self-reported PhD graduates and published articles on Scopus but no difference from the females in h-index. We note both student and systemic challenges that training institutions may pursue to improve doctoral supervision in Africa.

SARS-CoV-2 seroprevalence in three Kenyan health and demographic surveillance sites, December 2020-May 2021.

BACKGROUND: Most of the studies that have informed the public health response to the COVID-19 pandemic in Kenya have relied on samples that are not representative of the general population. We conducted population-based serosurveys at three Health and Demographic Surveillance Systems (HDSSs) to determine the cumulative incidence of infection with SARS-CoV-2. METHODS: We selected random age-stratified population-based samples at HDSSs in Kisumu, Nairobi and Kilifi, in Kenya. Blood samples were collected from participants between 01 Dec 2020 and 27 May 2021. No participant had received a COVID-19 vaccine. We tested for IgG antibodies to SARS-CoV-2 spike protein using ELISA. Locally-validated assay sensitivity and specificity were 93% (95% CI 88-96%) and 99% (95% CI 98-99.5%), respectively. We adjusted prevalence estimates using classical methods and Bayesian modelling to account for the sampling scheme and assay performance. RESULTS: We recruited 2,559 individuals from the three HDSS sites, median age (IQR) 27 (10-78) years and 52% were female. Seroprevalence at all three sites rose steadily during the study period. In Kisumu, Nairobi and Kilifi, seroprevalences (95% CI) at the beginning of the study were 36.0% (28.2-44.4%), 32.4% (23.1-42.4%), and 14.5% (9.1-21%), and respectively; at the end they were 42.0% (34.7-50.0%), 50.2% (39.7-61.1%), and 24.7% (17.5-32.6%), respectively. Seroprevalence was substantially lower among children (<16 years) than among adults at all three sites (p≤0.001). CONCLUSION: By May 2021 in three broadly representative populations of unvaccinated individuals in Kenya, seroprevalence of anti-SARS-CoV-2 IgG was 25-50%. There was wide variation in cumulative incidence by location and age.

Cognitive testing of a survey instrument to assess sexual practices, behaviours, and health outcomes: a multi-country study protocol.

BACKGROUND: Population level data on sexual practices, behaviours and health-related outcomes can ensure that responsive, relevant health services are available for all people of all ages. However, while billions of dollars have been invested in attempting to improve sexual and reproductive health (including HIV) outcomes, far less is understood about associated sexual practices and behaviours. Therefore, the World Health Organization embarked on a global consultative process to develop a short survey instrument to assess sexual health practices, behaviours and health outcomes. In order for the resulting draft survey instrument to be published as a 'global' standard instrument, it is important to first determine that the proposed measures are globally comprehensible and applicable. This paper describes a multi-country study protocol to assess the interpretability and comparability of the survey instrument in a number of diverse countries. METHODS: This study will use cognitive interviewing, a qualitative data collection method that uses semi-structured interviews to explore how participants process and respond to survey instruments. We aim to include study sites in up to 20 countries. The study procedures consist of: (1) localizing the instrument using forward and back-translation; (2) using a series of cognitive interviews to understand how participants engage with each survey question; (3) revising the core instrument based on interview findings; and (4) conducting an optional second round of cognitive interviews. Data generated from interviews will be summarised into a predeveloped analysis matrix. The entire process (a 'wave' of data collection) will be completed simultaneously by 5+ countries, with a total of three waves. This stepwise approach facilitates iterative improvements and sharing across countries. DISCUSSION: An important output from this research will be a revised survey instrument, which when subsequently published, can contribute to improving the comparability across contexts of measures of sexual practices, behaviours and health-related outcomes. Site-specific results of the feasibility of conducting this research may help shift perceptions of who and what can be included in sexual health-related research.

'We always find things to learn from.' Lessons from the implementation of the global maternal sepsis study on research capacity: a qualitative study.

BACKGROUND: Research capacity strengthening could be an indirect outcome of implementing a research project. The objective of this study was to explore the ability of the global maternal sepsis study (GLOSS), implemented in 52 countries, to develop and strengthen sexual and reproductive health research capacity of local participants in low- and middle- income participating countries. METHODS: We carried out a qualitative study employing grounded theory in sixteen countries in Africa and Latin America. We used inductive and deductive methods through a focus group discussion and semi-structured interviews for the emergence of themes. Participants of the focus group discussion (n = 8) were GLOSS principal investigators (PIs) in Latin America. Interviewees (n = 63) were selected by the country GLOSS PIs in both Africa and Latin America, and included a diverse sample of participants involved in different aspects of study implementation. Eighty-two percent of the participants were health workers. We developed a conceptual framework that took into consideration data obtained from the focus group and refined it based on data from the interviews. RESULTS: Six themes emerged from the data analysis: recognized need for research capacity, unintended effects of participating in research, perceived ownership and linkage with the research study, being just data collectors, belonging to an institution that supports and fosters research, and presenting study results back to study implementers. Research capacity strengthening needs were consistently highlighted including involvement in protocol development, training and technical support, data analysis, and project management. The need for institutional support for researchers to conduct research was also emphasised. CONCLUSION: This study suggests that research capacity strengthening of local researchers was an unintentional outcome of the large multi-country study on maternal sepsis. However, for sustainable research capacity to be built, study coordinators and funders need to deliberately plan for it, addressing needs at both the individual and institutional level.

Strengthening research capacity through regional partners: the HRP Alliance at the World Health Organization.

BACKGROUND: Improvements in health cannot occur without cutting-edge research informing the design and implementation of health programmes and policies, highlighting the need for qualified and capable researchers and institutions in countries where disease burden is high and resources are limited. MAIN BODY: Research capacity strengthening efforts in low- and middle-income countries have included provision of training scholarships for postgraduate degrees, often in high-income countries, internships at research universities/centres, short courses, as well as involvement with research groups for hands-on experience, among others. The HRP Alliance provides opportunities for developing local research capacity in sexual and reproductive health and rights through institutions based in low- and middle-income countries linked with ongoing and past collaborative studies. It is a network of HRP research partner institutions, World Health Organization (WHO) country and regional offices, WHO special programmes and partnerships, and WHO collaborating centres. CONCLUSION: It is through the HRP Alliance that HRP seeks to improve population health by strengthening local research capacity in sexual and reproductive health across the globe, with focus in low- and middle-income countries, in alignment with WHO's quest of promoting healthier populations.

CARTA fellows' scientific contribution to the African public and population Health Research agenda (2011 to 2018).

BACKGROUND: Since its inception in 2009, the Consortium for Advanced Research Training in Africa (CARTA) program has focused on strengthening the capacity of nine African universities and four research centres to produce skilled researchers and scholars able to improve public and population health on the continent. This study describes the alignment between CARTA-supported doctoral topics and publications with the priorities articulated by the African public and population health research agenda. METHODS: We reviewed the output from CARTA PhD fellows between 2011 and 2018 to establish the volume and scope of the publications, and the degree to which the research focus coincided with the SDGs, World Bank, and African Development Bank research priority areas. We identified nine key priority areas into which the topics were classified. RESULTS: In total, 140 CARTA fellows published 806 articles in peer-reviewed journals over the 8 years up to 2018. All the publications considered in this paper had authors affiliated with African universities, 90% of the publications had an African university first author and 41% of the papers have CARTA fellows as the first author. The publications are available in over 6300 online versions and have been cited in over 5500 other publications. About 69% of the published papers addressed the nine African public and population health research agenda and SDG priority areas. Infectious diseases topped the list of publications (26.8%), followed by the health system and policy research (17.6%), maternal and child health (14.7%), sexual and reproductive health (14.3%). CONCLUSIONS: Investments by CARTA in supporting doctoral studies provides fellows with sufficient training and skills to publish their research in fields of public and population health. The number of publications is understandably uneven across Africa's public and population priority areas. Even while low in number, fellows are publishing in areas such as non-communicable disease, health financing, neglected tropical diseases and environmental health. Violence and injury is perhaps underrepresented. There is need to keep developing research capacity in partner institutions with low research output by training more PhDs in such institutions and by facilitating enabling environments for research.

Gender responsive multidisciplinary doctoral training program: the Consortium for Advanced Research Training in Africa (CARTA) experience.

Doctoral training has increasingly become the requirement for faculty in institutions of higher learning in Africa. Africa, however, still lacks sufficient capacity to conduct research, with just 1.4% of all published research authored by African researchers. Similarly, women in Sub-Saharan Africa only constitute 30% of the continent's researchers, and correspondingly publish little research. Challenging these gendered inequities requires a gender responsive doctoral program that caters for women's gender roles that likely affect their enrollment in, and completion of, doctoral programs. In this article, we describe a public and population health multidisciplinary doctoral training program - CARTA and its approach to supporting women. This has resulted in women's enrollment in the program equaling men's and similar throughput rates. CARTA has achieved this by meeting women's practical needs around childbearing and childrearing and we argue that this has produced some outcomes that challenge gender norms, such as fathers being child minders in support of their wives and creating visible female role models.

Antigenic cartography of immune responses to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1).

Naturally acquired clinical immunity to Plasmodium falciparum is partly mediated by antibodies directed at parasite-derived antigens expressed on the surface of red blood cells which mediate disease and are extremely diverse. Unlike children, adults recognize a broad range of variant surface antigens (VSAs) and are protected from severe disease. Though crucial to the design and feasibility of an effective malaria vaccine, it is not yet known whether immunity arises through cumulative exposure to each of many antigenic types, cross-reactivity between antigenic types, or some other mechanism. In this study, we measured plasma antibody responses of 36 children with symptomatic malaria to a diverse panel of 36 recombinant proteins comprising part of the DBLα domain (the 'DBLα-tag') of PfEMP1, a major class of VSAs. We found that although plasma antibody responses were highly specific to individual antigens, serological profiles of responses across antigens fell into one of just two distinct types. One type was found almost exclusively in children that succumbed to severe disease (19 out of 20) while the other occurred in all children with mild disease (16 out of 16). Moreover, children with severe malaria had serological profiles that were narrower in antigen specificity and shorter-lived than those in children with mild malaria. Borrowing a novel technique used in influenza-antigenic cartography-we mapped these dichotomous serological profiles to amino acid sequence variation within a small sub-region of the PfEMP1 DBLα domain. By applying our methodology on a larger scale, it should be possible to identify epitopes responsible for eliciting the protective version of serological profiles to PfEMP1 thereby accelerating development of a broadly effective anti-disease malaria vaccine.

Biomarkers of post-discharge mortality among children with complicated severe acute malnutrition.

High mortality after discharge from hospital following acute illness has been observed among children with Severe Acute Malnutrition (SAM). However, mechanisms that may be amenable to intervention to reduce risk are unknown. We performed a nested case-control study among HIV-uninfected children aged 2-59 months treated for complicated SAM according to WHO recommendations at four Kenyan hospitals. Blood was drawn from 1778 children when clinically judged stable before discharge from hospital. Cases were children who died within 60 days. Controls were randomly selected children who survived for one year without readmission to hospital. Untargeted proteomics, total protein, cytokines and chemokines, and leptin were assayed in plasma and corresponding biological processes determined. Among 121 cases and 120 controls, increased levels of calprotectin, von Willebrand factor, angiotensinogen, IL8, IL15, IP10, TNFα, and decreased levels of leptin, heparin cofactor 2, and serum paraoxonase were associated with mortality after adjusting for possible confounders. Acute phase responses, cellular responses to lipopolysaccharide, neutrophil responses to bacteria, and endothelial responses were enriched among cases. Among apparently clinically stable children with SAM, a sepsis-like profile is associated with subsequent death. This may be due to ongoing bacterial infection, translocated bacterial products or deranged immune response during nutritional recovery.

Cerebrospinal fluid markers to distinguish bacterial meningitis from cerebral malaria in children.

Background. Few hospitals in high malaria endemic countries in Africa have the diagnostic capacity for clinically distinguishing acute bacterial meningitis (ABM) from cerebral malaria (CM). As a result, empirical use of antibiotics is necessary. A biochemical marker of ABM would facilitate precise clinical diagnosis and management of these infections and enable rational use of antibiotics. Methods. We used label-free protein quantification by mass spectrometry to identify cerebrospinal fluid (CSF) markers that distinguish ABM (n=37) from CM (n=22) in Kenyan children. Fold change (FC) and false discovery rates (FDR) were used to identify differentially expressed proteins. Subsequently, potential biomarkers were assessed for their ability to discriminate between ABM and CM using receiver operating characteristic (ROC) curves. Results. The host CSF proteome response to ABM ( Haemophilusinfluenza and Streptococcuspneumoniae) is significantly different to CM. Fifty two proteins were differentially expressed (FDR<0.01, Log FC≥2), of which 83% (43/52) were upregulated in ABM compared to CM. Myeloperoxidase and lactotransferrin were present in 37 (100%) and 36 (97%) of ABM cases, respectively, but absent in CM (n=22). Area under the ROC curve (AUC), sensitivity, and specificity were assessed for myeloperoxidase (1, 1, and 1; 95% CI, 1-1) and lactotransferrin (0.98, 0.97, and 1; 95% CI, 0.96-1). Conclusion. Myeloperoxidase and lactotransferrin have a high potential to distinguish ABM from CM and thereby improve clinical management. Their validation requires a larger cohort of samples that includes other bacterial aetiologies of ABM.

Differential Plasmodium falciparum surface antigen expression among children with Malarial Retinopathy.

Retinopathy provides a window into the underlying pathology of life-threatening malarial coma ("cerebral malaria"), allowing differentiation between 1) coma caused by sequestration of Plasmodium falciparum-infected erythrocytes in the brain and 2) coma with other underlying causes. Parasite sequestration in the brain is mediated by PfEMP1; a diverse parasite antigen that is inserted into the surface of infected erythrocytes and adheres to various host receptors. PfEMP1 sub-groups called "DC8" and "DC13" have been proposed to cause brain pathology through interactions with endothelial protein C receptor. To test this we profiled PfEMP1 gene expression in parasites from children with clinically defined cerebral malaria, who either had or did not have accompanying retinopathy. We found no evidence for an elevation of DC8 or DC13 PfEMP1 expression in children with retinopathy. However, the proportional expression of a broad subgroup of PfEMP1 called "group A" was elevated in retinopathy patients suggesting that these variants may play a role in the pathology of cerebral malaria. Interventions targeting group A PfEMP1 may be effective at reducing brain pathology.

Prime-boost vaccination with chimpanzee adenovirus and modified vaccinia Ankara encoding TRAP provides partial protection against Plasmodium falciparum infection in Kenyan adults.

Protective immunity to the liver stage of the malaria parasite can be conferred by vaccine-induced T cells, but no subunit vaccination approach based on cellular immunity has shown efficacy in field studies. We randomly allocated 121 healthy adult male volunteers in Kilifi, Kenya, to vaccination with the recombinant viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia Ankara (MVA), both encoding the malaria peptide sequence ME-TRAP (the multiple epitope string and thrombospondin-related adhesion protein), or to vaccination with rabies vaccine as a control. We gave antimalarials to clear parasitemia and conducted PCR (polymerase chain reaction) analysis on blood samples three times a week to identify infection with the malaria parasite Plasmodium falciparum. On Cox regression, vaccination reduced the risk of infection by 67% [95% confidence interval (CI), 33 to 83%; P = 0.002] during 8 weeks of monitoring. T cell responses to TRAP peptides 21 to 30 were significantly associated with protection (hazard ratio, 0.24; 95% CI, 0.08 to 0.75; P = 0.016).

Translating the immunogenicity of prime-boost immunization with ChAd63 and MVA ME-TRAP from malaria naive to malaria-endemic populations.

To induce a deployable level of efficacy, a successful malaria vaccine would likely benefit from both potent cellular and humoral immunity. These requirements are met by a heterologous prime-boost immunization strategy employing a chimpanzee adenovirus vector followed by modified vaccinia Ankara (MVA), both encoding the pre-erythrocytic malaria antigen ME-thrombospondin-related adhesive protein (TRAP), with high immunogenicity and significant efficacy in UK adults. We undertook two phase 1b open-label studies in adults in Kenya and The Gambia in areas of similar seasonal malaria transmission dynamics and have previously reported safety and basic immunogenicity data. We now report flow cytometry and additional interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) data characterizing pre-existing and induced cellular immunity as well as anti-TRAP IgG responses. T-cell responses induced by vaccination averaged 1,254 spot-forming cells (SFC) per million peripheral blood mononuclear cells (PBMC) across both trials and flow cytometry revealed cytokine production from both CD4(+) and CD8(+) T cells with the frequency of CD8(+) IFN-γ-secreting monofunctional T cells (previously shown to associate with vaccine efficacy) particularly high in Kenyan adults. Immunization with ChAd63 and MVA ME-TRAP induced strong cellular and humoral immune responses in adults living in two malaria-endemic regions of Africa. This prime-boost approach targeting the pre-erythrocytic stage of the malaria life-cycle is now being assessed for efficacy in a target population.

Discovery and validation of biomarkers to guide clinical management of pneumonia in African children.

BACKGROUND: Pneumonia is the leading cause of death in children globally. Clinical algorithms remain suboptimal for distinguishing severe pneumonia from other causes of respiratory distress such as malaria or distinguishing bacterial pneumonia and pneumonia from others causes, such as viruses. Molecular tools could improve diagnosis and management. METHODS: We conducted a mass spectrometry-based proteomic study to identify and validate markers of severity in 390 Gambian children with pneumonia (n = 204) and age-, sex-, and neighborhood-matched controls (n = 186). Independent validation was conducted in 293 Kenyan children with respiratory distress (238 with pneumonia, 41 with Plasmodium falciparum malaria, and 14 with both). Predictive value was estimated by the area under the receiver operating characteristic curve (AUC). RESULTS: Lipocalin 2 (Lpc-2) was the best protein biomarker of severe pneumonia (AUC, 0.71 [95% confidence interval, .64-.79]) and highly predictive of bacteremia (78% [64%-92%]), pneumococcal bacteremia (84% [71%-98%]), and "probable bacterial etiology" (91% [84%-98%]). These results were validated in Kenyan children with severe malaria and respiratory distress who also met the World Health Organization definition of pneumonia. The combination of Lpc-2 and haptoglobin distinguished bacterial versus malaria origin of respiratory distress with high sensitivity and specificity in Gambian children (AUC, 99% [95% confidence interval, 99%-100%]) and Kenyan children (82% [74%-91%]). CONCLUSIONS: Lpc-2 and haptoglobin can help discriminate the etiology of clinically defined pneumonia and could be used to improve clinical management. These biomarkers should be further evaluated in prospective clinical studies.

CD4+ T cell responses to the Plasmodium falciparum erythrocyte membrane protein 1 in children with mild malaria.

The immune response against the variant surface Ag Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a key component of clinical immunity against malaria. We have investigated the development and maintenance of CD4(+) T cell responses to a small semiconserved area of the Duffy binding-like domain (DBL)α-domain of PfEMP1, the DBLα-tag. Young children were followed up longitudinally, and parasites and PBMCs were isolated from 35 patients presenting with an acute case of uncomplicated malaria. The DBLα-tag from the PfEMP1 dominantly expressed by the homologous parasite isolate was cloned and expressed as recombinant protein. The recombinant DBLα-tag was used to activate PBMCs collected from each acute episode and from an annual cross-sectional survey performed after the acute malaria episode. In this article, we report that CD4(+) T cell responses to the homologous DBLα-tag were induced in 75% of the children at the time of the acute episode and in 62% of the children at the following cross-sectional survey on average 235 d later. Furthermore, children who had induced DBLα-tag-specific CD4(+)IL-4(+) T cells at the acute episode remained episode free for longer than children who induced other types of CD4(+) T cell responses. These results suggest that a wide range of DBLα-tag-specific CD4(+) T cell responses were induced in children with mild malaria and, in the case of CD4(+)IL-4(+) T cell responses, were associated with protection from clinical episodes.