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Introduction: Qualitative studies are often inadequately reported, making it difficult to judge their appropriateness for decision making in public health. We assessed the publication characteristics and quality of reporting of qualitative and mixed-method studies from the Structured Operational Research and Training Initiative (SORT IT), a global partnership for operational research capacity building. Methods: A cross-sectional analysis of publications to assess the qualitative component using an adapted version of the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist. Results: In 67 publications involving 18 countries, 32 journals and 13 public health themes, 55 were mixed-methods studies and 12 were qualitative studies. First authorship from low-and-middle-income (LMIC) countries was present in 64 (96%), LMIC last authorship in 55 (82%), and female first authorship in 30 (45%). The mean LMIC institutions represented per publication was five (range 1–11). Sixty-three (94%) publications were open access. Reporting quality was graded as ‘good’ to ‘excellent’ in 60 (89%) publications, ‘fair’ in five (8%) and ‘poor’ in two (3%). Conclusion: Most SORT IT publications adhered to COREQ standards, while supporting gender equity in authorship and the promotion of LMIC research leadership. SORT IT plays an important role in ensuring quality of evidence for decision making to improve public health.

The mRNA vaccine technology platform may enable rapid response to some emerging infectious diseases (EIDs), as demonstrated through the COVID-19 pandemic. Beyond the role it could play in future EID response, mRNA technology also could have an important role in accelerating the development of, and access to, vaccines for some neglected tropical diseases (NTDs), which occur mainly in impoverished regions of the world. Despite their significant disease burden, few vaccines against NTDs have been developed, in part because of the uncertain market and return on investment. In addition, the probability of technical and regulatory success is considered to be low for developing vaccines against multicellular parasites, or organisms that have sophisticated mechanisms for evading immunological surveillance, such as many of the NTD pathogens. The global 2021-2030 road map for neglected tropical diseases sets ambitious targets for the eradication, elimination, and control of NTDs. For some, effective interventions exist but are underutilized. For others, vaccines need to be developed or their use expanded to meet global targets on control and elimination. This article discusses the application of the mRNA technology platform to the development of vaccines for NTDs as well as EIDs, highlights the challenges in bringing these products to the market, and indicates potential areas which could be explored, including leveraging investment for vaccines with a more profitable market potential and enabling local manufacturing in regions where NTDs are endemic. Such regional production could include collaborations with the mRNA vaccine technology transfer hubs that are being established with the support of WHO and COVAX partners.

Children, although at lower risk of poor outcomes from COVID-19 relative to adults, still stand to benefit from therapeutic interventions. Understanding of COVID-19 clinical presentation and prognosis in children is essential to optimize therapeutic trials design. This perspective illustrates how to collectively accelerate pediatric COVID-19 therapeutic research and development, based on the experience of the Global Accelerator for Paediatric Formulations.

To maximise the likelihood of success, global health programmes need repeated, honest appraisal of their own weaknesses, with research undertaken to address any identified gaps. There is still much to be learned to optimise work against neglected tropical diseases. To facilitate that learning, a comprehensive research and development plan is required. Here, we discuss how such a plan might be developed.

The COVID-19 pandemic has put research evidence and its use in health policy-making under a new spotlight.1 Faced with the need for immediate action, as most recently shown with vaccination roll-out strategies,2 many politicians and other leaders have publicly stressed the need to follow the ‘science’. Scientific advisors and advisory bodies have gained unprecedented visibility. At the same time, the conflicts between researchers/health experts and political decision-makers have, now and then, been vividly brought to the fore.3 To bridge the divide, building and strengthening knowledge translation (WHO defines knowledge translation as the exchange, synthesis and effective communication of reliable and relevant research results. The focus is on promoting interaction among the producers and users of research, removing the barriers to research use, and tailoring information to different target audiences so that effective interventions are used more widely.) organisations, which act as institutional bridges between researchers and both decision-makers and communities, is called for.4 More than ever before, countries need to counter misinformation and rapidly mobilise the best available evidence, and present it in userfriendly ways to decision-makers.5 The WHO has been championing the need for research evidence to inform decision-making in the context of COVID-19. Although at times also challenged to provide clear guidance in …

(1) Introduction. The Structured Operational Research and Training IniTiative (SORT IT) supports countries to build operational research capacity for improving public health. We assessed whether health workers trained through SORT IT were (1) contributing to the COVID-19 pandemic response and if so, (2) map where and how they were applying their SORT IT skills. (2) Methods. An online questionnaire survey of SORT IT alumni trained between 2009 and 2019. (3) Results. Of 895 SORT IT alumni from 93 countries, 652 (73%) responded to the survey and 417 were contributing to the COVID-19 response in 72 countries. Of those contributing, 307 (74%) were applying their SORT IT skills to tackle the pandemic in 60 countries and six continents including Africa, Asia, Europe, South Pacific and North/South America. Skills were applied to all the pillars of the emergency response with the highest proportions of alumni applying their skills in data generation/analysis/reporting (56%), situation analysis (55%) and surveillance (41%). Skills were also being used to mitigate the health system effects of COVID-19 on other diseases (27%) and in conducting research (26%). (4) Conclusion. Investing in people and in research training ahead of public health emergencies generates downstream dividends by strengthening health system resilience for tackling pandemics. It also strengthens human resources for health and the integration of research within health systems.

Background: TDR, The Special Programme for Research and Training hosted at the World Health Organization, has long supported Low- and Middle-Income Countries in strengthening research capacity through three training programmes: the Postgraduate Training Scheme (PGTS), the Clinical Research and Development Fellowship (CRDF), and the Structured Operational Research Training InitiaTive (SORT IT). In the advent of the COVID-19 pandemic, we assessed whether those trained through these programmes were involved in the COVID-19 response and if so, in which area(s) of the emergency response they were applying their skills. Methods: From the records for each training programme, we identified the individuals who had completed training during the relevant timespan of each programme: 1999-2018 for the CRDF scheme, 2015-2020 for PGTS, and 2009-2019 for SORT-IT. Between March and April 2020, we sent trainees an online questionnaire by e-mail. Results: Out of 1254 trained, 1143 could be contacted and 699 responded to the survey. Of the latter, 411 were involved with the COVID-19 response, of whom 315 (77%) were applying their acquired skills in 85 countries. With some overlap between programmes, 84% of those trained through CRDF were applying their skills in 27 countries, 91% of those trained through PGTS were applying their skills in 19 countries, and through SORT IT, this was 73% in 62 countries. Skills were being applied in various areas of the emergency response, including: emergency preparedness, situation analysis/surveillance, infection control and clinical management, data generation, mitigating the effect of COVID on the health system, and research. Depending on the type of training programme, 26-74% were involved in implementation, operational or clinical research. Conclusion: Research training programmes build research capacity and equip health workers with transferable core competencies and skillsets prior to epidemics. This becomes invaluable in building health system resilience at a time of pandemics.

Background: TDR, The Special Programme for Research and Training hosted at the World Health Organization, has long supported Low- and Middle-Income Countries in strengthening research capacity through three training programmes: the Postgraduate Training Scheme (PGTS), the Clinical Research and Development Fellowship (CRDF), and the Structured Operational Research Training InitiaTive (SORT IT). In the advent of the COVID-19 pandemic, we assessed whether those trained through these programmes were involved in the COVID-19 response and if so, in which area(s) of the emergency response they were applying their skills. Methods: From the records for each training programme, we identified the individuals who had completed training during the relevant timespan of each programme: 1999-2018 for the CRDF scheme, 2015-2020 for PGTS, and 2009-2019 for SORT-IT. Between March and April 2020, we sent trainees an online questionnaire by e-mail. Results: Out of 1254 trained, 1143 could be contacted and 699 responded to the survey. Of the latter, 411 were involved with the COVID-19 response, of whom 315 (77%) were applying their acquired skills in 85 countries. With some overlap between programmes, 84% of those trained through CRDF were applying their skills in 27 countries, 91% of those trained through PGTS were applying their skills in 19 countries, and through SORT IT, this was 73% in 62 countries. Skills were being applied in various areas of the emergency response, including: emergency preparedness, situation analysis/surveillance, infection control and clinical management, data generation, mitigating the effect of COVID on the health system, and research. Depending on the type of training programme, 26-74% were involved in implementation, operational or clinical research. Conclusion: Research training programmes build research capacity and equip health workers with transferable core competencies and skillsets prior to epidemics. This becomes invaluable in building health system resilience at a time of pandemics.

If research is to have an impact and change health outcomes for the better, the findings of the research should be translated into recommendations and actions that can influence policy and/or practice [...]

Microscopy performed on stained films of peripheral blood for detection, identification and quantification of malaria parasites is an essential reference standard for clinical trials of drugs, vaccines and diagnostic tests for malaria. The value of data from such research is greatly enhanced if this reference standard is consistent across time and geography. Adherence to common standards and practices is a prerequisite to achieve this. The rationale for proposed research standards and procedures for the preparation, staining and microscopic examination of blood films for malaria parasites is presented here with the aim of improving the consistency and reliability of malaria microscopy performed in such studies. These standards constitute the core of a quality management system for clinical research studies employing microscopy as a reference standard. They can be used as the basis for the design of training and proficiency testing programmes as well as for procedures and quality assurance of malaria microscopy in clinical research.

This commentary highlights the value of community-engaged social innovations to advance health care delivery in low- and middle-income countries and to accelerate universal health coverage. It emphasizes the importance of research to guide the innovators on what works, what does not work to make their innovations sustainable and to replicate and scale them up as relevant. It also helps to demonstrate impact and to enhance uptake within the health systems. Electronic supplementary material The online version of this article (10.1186/s40249-019-0586-9) contains supplementary material, which is available to authorized users.

Findings from participants who attended the second post-Ebola SORT-IT course are reported in five short papers on the “legacy of Ebola on health Systems in Sierra-Leone”. After a decline of health service provision and utilisation during the Ebola outbreak, present findings show recovery over time in the post-Ebola period. However, important challenges remain, including an important health workforce gap.

The Global Technical Strategy for Malaria 2016–2030 was adopted by the 68th World Health Assembly in May 2015. It emphasizes the importance of scaling up malaria control responses and moving towards elimination [1]. It is anticipated that such scale-up will help countries reduce and, eventually, eliminate the human suffering caused by malaria as well as contribute more broadly to the achievement of the Sustainable Development Goals. The Global Technical Strategy consists of three main pillars, underpinned by two supporting elements (Fig. 1). The first of the supporting elements, harnessing innovation and expanding research, is also recognized as critical in the global control and elimination of other diseases, such as tuberculosis [2]. It is recognized that operational and implementation research are needed to ensure that existing interventions are applied effectively and efficiently in different contexts and, as new interventions become available, to ensure that innovation is deployed appropriately and to maximum effect. Fig. 1 The World Health Organization Global Technical Strategy for Malaria 2016–2030 In 2011, the malERA Consultative Group on Health Systems and Operational Research published a Research Agenda for Malaria Eradication: Health Systems and Operational Research [3]. The WHO Global Malaria Programme (GMP) has more recently published the report of a multi-partner meeting that discussed operational challenges for malaria elimination, identified priority operational research questions and recommended ways forward [4]. Other organizations have produced similar lists of operational research priorities [5]. There is no shortage of recommendations on the priorities for operational research and most authors consider operational research to be relatively straightforward and, if using routinely-collected data, inexpensive. However, a recent review of the literature on malaria control and elimination between 2008 and 2013 (15,886 articles) revealed that less than 4 % met the definition of operational research. Of these articles only 19 (3.8 %) were related to malaria surveillance [6]. It would seem that operational research, though recognized as critically important to the success of global strategies for malaria control and elimination, is not so commonly undertaken or at least not so commonly published. Indeed, it could be argued that the difference between these two is academic since unpublished research is unlikely to inform widespread scaling up of malaria activities. Why is so little operational research done when much of it would be straightforward and inexpensive and could be done within the context of routine malaria programme activities? It is a long-standing problem. In 2007, a report of the Global Fund’s Technical Review Panel noted that operational research was often absent or inadequately elaborated in proposals [7]. The report further stated that proposals clearly described bottlenecks to progress and that these provide the basis for operational research questions that seem obvious but were not proposed. How can operational research be promoted to support the new Global Technical Strategy for Malaria? A good start would be to look at the recent experiences of other disease control programmes. In 2011, the WHO listed its priorities in operational research to improve tuberculosis care and control. One of the five priority areas for operational research was capacity-building for operational research. Key questions included: what are the existing models of operational health research capacity? What is the impact of existing training models in terms of products, outputs and outcomes? How to ensure sustainable operational research capacity at the national level? 4 years later, its Global Action Framework for TB Research described some of the lessons from this exercise and has provided case studies of how operational research capacity has been built in public health programmes in low-income and middle-income countries [2]. One of these case studies was the Structured Operational Research and Training Initiative (SORT IT) a global partnership-based initiative led by the Special Programme for Research and Training in Tropical Diseases (TDR) based at WHO [8]. Started in 2012, SORT IT aims to support countries to: conduct operational research around their own priorities, build adequate and sustainable operational research capacity within public health programmes; and make evidence-informed improvements to programme implementation. More than 400 health workers in 80 countries have been trained through SORT IT to date. Over the course of 1 year, participating health workers learn the skills required to develop operational research questions, protocols, data capture and analysis instruments and to publish their work. Over 90 % of participants publish their research in the peer reviewed literature and many go on to become facilitators in further SORT IT training courses. The training is currently being delivered in English, Russian and Spanish, with the transition into French underway. The model has been recognized as a reliable way to build the much-needed research capacity in public health programmes in LMICs [9, 10]. Having its roots in a training course run by Medecins Sans Frontieres and the International Union Against Tuberculosis and Lung Diseases, that supported tuberculosis control, SORT IT is now delivering regional and national capacity-building for operational research in all WHO regions and in number of disease areas [11, 12]. In TDR-supported SORT IT Programmes, the core training course is embedded within broader capacity-building activities in knowledge management (research needs assessments and prioritization, dissemination of research findings and evidence-informed policy making). Efforts are also made to consolidate research capacity that has been built through SORT IT by providing participants with further research training and small research grants. In 2014, two research studies related to malaria elimination were supported by SORT IT [13, 14]. In 2015–16, in collaboration with the Global Malaria Programme and the WHO African Regional Office (AFRO), a SORT IT programme supported four malaria-eliminating countries in Southern Africa: Botswana, Namibia, South Africa and Swaziland. A Supplement of Malaria Journal is in preparation to feature research outputs of this SORT IT programme. It is hoped that this Supplement will encourage others to adopt approaches like SORT IT, conduct operational research while building research capacity in malaria programmes and make evidence-informed improvements to policy and practice. On the occasion of the 2016 World Malaria Day the authors would like to highlight both the need for, and the feasibility of, building operational research capacity in malaria programmes in low- and middle-income countries if the ambitions of the Global Technical Strategy for Malaria 2016–2030 are to be achieved.

Background: The Health Product Profile Directory (HPPD), is an online database describing 8-10 key characteristics (such as target population, measures of efficacy and dosage) of product profiles for medicines, vaccines, diagnostics and other products that are intended to be accessed by populations in low- and middle-income countries. It was developed by TDR on behalf of WHO and launched on 15 May 2019. Methods: The contents of the HPPD was downloaded into an ExcelTM spreadsheet via the open access interface and analysed to identify the number of health product profiles by type, by disease, by year of publication, by status, by author organization and safety information. Findings: The HPPD contains summaries of 215 health product profiles published between 2008 and May 2019, 117 (54%) provide a hyperlink to the detailed publication from which the summary was extracted, the remaining 98 provide an email contact for further information. 55 target disease or health conditions are covered with 210 profiles describing a product with an infectious disease as the target. Only 5 product profiles in the HPPD describe a product for a non-communicable disease. Four diseases account for 40% of product profiles in the HPPD: TB 33 profiles (15%), Malaria 31 profiles (14%) HIV 13 profiles (6%) ad Chagas 10 profiles (5%). Interpretation: the HPPD provides a new tool to inform priority setting in global health - it includes all product profiles authored by WHO (51). There is a need to standardise nomenclature to more clearly distinguish between strategic publications (describing R&D priorities or preferred characteristics) compared to target product profiles to guide a specific candidate product undergoing R&D. Combining the analysis from HPPD to a mapping of funds available for R&D and those products in the R&D pipeline would create a better overview of global health priorities and how they are supported. Such analysis and increased transparency should take us another step closer to measuring and improving coordination of efforts in global health R&D. Funding Statement: TDR was funded by the Swiss Agency for Development and Cooperation. Declaration of Interests: No conflict of interest is declared by the authors. Ethics Approval Statement: Not required.

Background The climate variables that directly influence vector-borne diseases’ ecosystems are mainly temperature and rainfall. This is not only because the vectors bionomics are strongly dependent upon these variables, but also because most of the elements of the systems are impacted, such as the host behavior and development and the pathogen amplification. The impact of the climate changes on the transmission patterns of these diseases is not easily understood, since many confounding factors are acting together. Consequently, knowledge of these impacts is often based on hypothesis derived from mathematical models. Nevertheless, some direct evidences can be found for several vector-borne diseases. Main body Evidences of the impact of climate change are available for malaria, arbovirus diseases such as dengue, and many other parasitic and viral diseases such as Rift Valley Fever, Japanese encephalitis, human African trypanosomiasis and leishmaniasis. The effect of temperature and rainfall change as well as extreme events, were found to be the main cause for outbreaks and are alarming the global community. Among the main driving factors, climate strongly influences the geographical distribution of insect vectors, which is rapidly changing due to climate change. Further, in both models and direct evidences, climate change is seen to be affecting vector-borne diseases more strikingly in fringe of different climatic areas often in the border of transmission zones, which were once free of these diseases with human populations less immune and more receptive. The impact of climate change is also more devastating because of the unpreparedness of Public Health systems to provide adequate response to the events, even when climatic warning is available. Although evidences are strong at the regional and local levels, the studies on impact of climate change on vector-borne diseases and health are producing contradictory results at the global level. Conclusions In this paper we discuss the current state of the results and draw on evidences from malaria, dengue and other vector-borne diseases to illustrate the state of current thinking and outline the need for further research to inform our predictions and response. Electronic supplementary material The online version of this article (10.1186/s40249-019-0565-1) contains supplementary material, which is available to authorized users.

Background: The Portfolio-To-Impact (P2I) Model is a novel tool, developed to estimate minimum funding needs to accelerate health product development from late stage preclinical study to phase III clinical trials, and to visualize potential product launches over time. Methods: A mixed methods approach was used. Assumptions on development costs at each phase were based on clinical trial costs from Parexel’s R&D cost sourcebook. These were further refined and validated by interviews, with a wide variety of stakeholders from Product Development Partnerships, biopharmaceutical and diagnostic companies, and major funders of global health R&D. Results: the tool was used to create scenarios describing the impact, in terms of products developed, of different product portfolios with funding ranging from $1 million per annum through to $500 million per annum. These scenarios for a new global financing mechanism have been previously presented in a report setting out the potential for a new fund for research and development which would assist in accelerating product development for the diseases of poverty. Conclusion: The P2I tool does enable a user to model different scenarios in terms of cost and number of health products launched when applied to a portfolio of health products. The model is published as open access accompanied with a user guide. The design allows it to be adapted and used for other health R&D portfolio analysis as described in an accompanying publication focussing on the pipeline for neglected diseases in 2017. We aim to continually refine and improve the model and we ask users to provide us with their own inputs that can help us update key parameters and assumptions. We hope to catalyse users to adapt the model in ways that can increase its value, accuracy, and applications.

Historically, women have been less likely to be supported through higher degree training programmes, and they continue to hold more junior positions in science. This paper reviews the current gender research and gender capacity-building efforts led by the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). Created more than 40 years ago as the only United Nations-based Special Programme dedicated to research and research capacity building on infectious diseases, TDR has a longstanding track record both in supporting research into gender-specific questions and in research capacity strengthening among women scientists. We provide an overview of these approaches, then describe a recent pilot programme on Women in Science, designed to understand and remedy the gender gaps in health research. The programme focused on Africa, but it is hoped that the replication of such schemes in TDR and other international funding agencies will lead to more attention being given to women in infectious diseases research in other continents.This article may not be reprinted or reused in any way in order to promote any commercial products or services.

Despite having the highest Plasmodium vivax burden in the world, molecular epidemiological data from Papua New Guinea (PNG) for this parasite remain limited. To investigate the molecular epidemiology of P. vivax in PNG, 574 isolates collected from four catchment sites in East Sepik (N = 1) and Madang (N = 3) Provinces were genotyped using the markers MS16 and msp1F3. Genetic diversity and prevalence of P. vivax was determined for all sites. Despite a P. vivax infection prevalence in the East Sepik (15%) catchments less than one-half the prevalence of the Madang catchments (27-35%), genetic diversity was similarly high in all populations (He = 0.77-0.98). High genetic diversity, despite a marked difference in infection prevalence, suggests a large reservoir of diversity in P. vivax populations of PNG. Significant reductions in transmission intensity may, therefore, be required to reduce the diversity of parasite populations in highly endemic countries such as PNG.

This paper summarizes our current understanding of the biology of Plasmodium vivax, how it differs from Plasmodium falciparum, and how these differences explain the need for P. vivax-tailored interventions. The article further pinpoints knowledge gaps where investments in research are needed to help identify and develop such specific interventions. The principal obstacles to reduce and eventually eliminate P. vivax reside in 1) its higher vectorial capacity compared with P. falciparum due to its ability to develop at lower temperature and over a shorter sporogonic cycle in the vector, allowing transmission in temperate zones and making it less sensitive to vector control measures that are otherwise effective on P. falciparum; 2) the presence of dormant liver forms (hypnozoites), sustaining multiple relapsing episodes from a single infectious bite that cannot be diagnosed and are not susceptible to any available antimalarial except primaquine, with routine deployment restricted by toxicity; 3) low parasite densities, which are difficult to detect with current diagnostics leading to missed diagnoses and delayed treatments (and protracted transmission), coupled with 4) transmission stages (gametocytes) occurring early in acute infections, before infection is diagnosed.

Today, the World Health Organization recognizes 17 major parasitic and related infections as the neglected tropical diseases (NTDs). Despite recent gains in the understanding of the nature and prevalence of NTDs, as well as successes in recent scaled-up preventive chemotherapy strategies and other health interventions, the NTDs continue to rank among the world's greatest global health problems. For virtually all of the NTDs (including those slated for elimination under the auspices of a 2012 London Declaration for NTDs and a 2013 World Health Assembly resolution [WHA 66.12]), additional control mechanisms and tools are needed, including new NTD drugs, vaccines, diagnostics, and vector control agents and strategies. Elimination will not be possible without these new tools. Here we summarize some of the key challenges in translational science to develop and introduce these new technologies in order to ensure success in global NTD elimination efforts.

Aim To determine the age specific immunity profile for rubella from three discrete study populations in Papua New Guinea, and to inform policy regarding the possible introduction of rubella vaccine. Background In 2005, the Western Pacific Region (WPR), of which Papua New Guinea (PNG) is a member state, declared the goal of regional measles elimination by 2012. Recently, WPR has incorporated an accelerated control goal for rubella and congenital rubella syndrome (CRS). PNG currently recommends two doses of measles vaccination at 6 and 9 months of age with a monovalent measles vaccine, which does not include rubella vaccine. Methods Convenience samples were collected from 1326 eligible participants in PNG and assessed for rubella immunity using the Dade Behring Enzygnost™ Anti-Rubella-Virus enzyme immunoassay. Nearly 34% were collected during an age stratified prospective survey of febrile patients in Madang Province; approximately 49% were collected from women of childbearing age in East Sepik and Milne Bay Provinces. Remaining specimens were collected from 6 to 7-month-old infants in Port Moresby prior to receiving the first dose of measles vaccine. Findings Of all samples tested, 65.2% (95% confidence interval (CI): 62.6–67.8) had evidence of immunity to rubella infection. Of women more than 15 years of age, 91.6% (95% CI: 89.4–93.5) were immune. The force of infection was highest between 5 and 19 years of age. Conclusions Although a population-based sample was not used, our multi-centre study of the population immunity profile suggests that immunity against rubella is extremely high in most women of childbearing age, but women who become pregnant at an early age may be at high risk of rubella infection during pregnancy and potential delivery of an infant with CRS. Routine measles vaccine coverage, a proxy for measles-rubella vaccine coverage, as measured in recently published studies, is well below the WHO target of 80% coverage. Introduction of a child or infant dose of rubella vaccine requires caution and further study.

Despite consistent evidence of a protective effect of alpha(+)-thalassemia against severe Plasmodium falciparum disease, the mechanisms underlying this protection remain unknown. An increase in risk of Plasmodium vivax malaria in early childhood resulting in a cross-species protection against severe P. falciparum malaria has been proposed as a possible mechanism in Melanesian children. The association of alpha(+)-thalassemia genotypes with a risk of P. falciparum and P. vivax infection and uncomplicated illness was reassessed in a cohort of 1,112 Papua New Guinean children, followed from 3-21 months of age. Three hundred and eighty-nine (35.0%) children were homozygous for a(+)-thalassemia (-a/-a), 506 (45.5%) heterozygous (aa/-a) and 217 (19.5%) homozygous for the wild-type allele. No significant differences in the incidence of P. falciparum (Pf) or P. vivax (Pv) malaria were observed between alpha(+)-thalassemia homozygote (Pf: Incidence rate ratio (IRR) = 1.13, CI(95) (0.82,1.56), P = 0.45, Pv: IRR = 1.15, CI(95) (0.9881.56), P = 0.31), heterozygote (Pf: IRR = 0.98, CI(95) (0.71,1.34), P = 0.93, Pv: IRR = 1.14, CI(95) (0.88,1.48), P =0.33) and wild-type children. The prevalence of infection with either species did not differ between alpha(+)-thalassemia genotypes, although densities of P. vivax (but not of P. falciparum) infections were significantly higher in alpha(+)-thalassemia homozygote and heterozygote children. An excessive risk of moderate-to-severe anemia (hemoglobin (Hb) > 8 g/dl) was observed in alpha(+)-thalassemia homozygote children (IRR = 1.54, CI(95)(1.12, 2.11), P = 0.008). This study therefore failed to confirm an increased risk of P. vivax or P. falciparum malaria in very young, alpha(+)-thalassemic children without significant levels of acquired immunity. This confirms the lack of protection by alpha(+)-thalassemia against uncomplicated P. falciparum and challenges the hypothesis of immunological cross-protection between P. falciparum and P. vivax as a mechanism underlying alpha(+)-thalassemia protection against severe P. falciparum disease in Melanesian children