malaria extended essay

London School of Hygiene & Tropical Medicine

Malaria and the brain – what long-term impact does malaria have on brain function.

Dr Sam Wassmer, Associate Professor at the London School of Hygiene & Tropical Medicine, and Dr Sanjib Mohanty, Senior Consultant at the Community Welfare Hospital, India

Malaria infection exerts a tremendous impact on the body, which can have long-term health repercussions, ranging from accrued susceptibility to bacterial infection to cognitive impairment. While some of these nefarious effects are known for the most severe forms of the disease, mounting evidence suggest that this is merely the tip of the iceberg.

Malaria experts will tell you that immunity against the parasite builds up with exposure to the disease, leading to seemingly healthy individuals able to control, but not eliminate, their infection. Because they don’t develop fever anymore, treatment is not sought. The resultant chronic yet silent infection not only helps perpetuate malaria transmission but, over time, also contributes to serious health and developmental impairments . 

At the other end of the disease spectrum, severe malaria occurs when infections are complicated by acute organ failures, abnormal blood cell counts, metabolic dysfunctions – either alone or in combination. Mortality is high, even when appropriate drugs are provided. To muddle things further, this year’s WHO World Malaria Report highlights that defining severe malaria cases reliably is challenging, particularly in settings with limited clinical and laboratory resources.

Cerebral malaria is the most severe neurological complication of malaria infection. Children in sub-Saharan Africa are the most affected, and those who survive often retain life-long disorders which can profoundly affect their quality of life, including cognitive, motor skills, and visual coordination impairment, as well as seizures and attention deficit hyperactivity disorder.

Cerebral malaria has a defining clinical feature – a rapidly progressive coma. This neurological syndrome is diagnosed using age-specific coma scores with different cut-offs for children and adults. It is currently defined by a Glasgow Coma Score of 11 or below in adults (which is classified as moderate to severe brain injury) and a Blantyre coma score of less than 3 in children.

Remarkably, recent studies in Ugandan children showed that some of these long-term neurological effects are also seen in cases without clinically defined cerebral malaria . These surprising new findings indicate that the brain can be affected irrespective of the patient’s state of consciousness. Much less is known in adults however, as fewer studies have been conducted in this age group.

This prompted our team to investigate the occurrence of brain changes in patients without coma, indicative of cerebral malaria. Bridging this knowledge gap was crucial to improve treatment and outcomes for malaria patients.

Our recent study, published in Clinical Infectious Diseases and funded by the US National Institutes of Health suggest for the first time that malaria infection caused by the Plasmodium falciparum parasite often causes undetected brain changes.

These findings suggest many more malaria patients could be experiencing neurological damage which remains undiagnosed as they fall between the current diagnostic cut-offs. This highlights the need for new ways to identify cases with ‘silent’ cerebral malaria and improve their treatment pathways.

Using magnetic resonance imaging (MRI) to scan adult malaria patients in India , we evaluated the impact of P. falciparum infection on the brain of patients who did not fit the diagnostic criteria for cerebral malaria. These included cases of uncomplicated malaria and patients with severe organ dysfunction, excluding the brain. We implemented a novel technique that allows the identification of subtle brain changes, and were surprised to discover that both groups of infected individuals showed various degrees of impact on the brain.

The severe cases without apparent neurological effects had a wide range of brain changes on MRI, with the most pronounced features being similar to the ones we have previously observed in cerebral malaria, despite the absence of coma. We also found this group had higher plasma levels of S100B, a well-recognised marker of brain injury commonly associated with long-term cognitive dysfunction, compared to uncomplicated cases.

These observations have important implications.

First, they challenge our current clinical definition of cerebral malaria, as the cut off of the Glasgow Coma Score of 11 or below does not capture all adult patients with pronounced brain changes seen on MRI.

In this context, it is interesting to note that the WHO already recently increased this cut-off value to define cerebral malaria in adults: it was initially set to 9 and below. Despite this adjustment, many adult patients who do not fall into the strict definition still have cerebral involvement and are, potentially, at risk of developing post-infection neurological disorders.

While MRI scans are much more refined to identify cerebral injury during severe malaria, neuroimaging facilities are seldom available in endemic areas, such as Africa or Southeast Asia. New tools, including biomarkers associated with potentially harmful brain changes detected by MRI are therefore needed to rapidly and reliably identify patients with silent cerebral malaria.

Second, and maybe more importantly, we don’t know yet whether these changes have short- and/or long-term effects on neurological and cognitive functions post-infection. However, the combination of cerebral malaria-like MRI patterns and high plasma levels of a brain injury marker strongly indicate the likelihood of subtle but long-term issues, which have never been assessed in this patient group.

In light of this new report, we urgently need studies assessing the amplitude and impact of brain changes in adult patients with severe P. falciparum infection without coma, in order to inform and develop adequate strategies to identify patients at risk and help their recovery and rehabilitation.

Publication

Sanjib Mohanty et al. Evidence of brain alterations in noncerebral falciparum malaria . Clinical Infectious Diseases. DOI: 10.1093/cid/ciab907

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• Published: 27 May 2022

Reflections on the 2021 World Malaria Report and the future of malaria control

• April Monroe 1 , 7 ,
• Nana Aba Williams 2 , 3 ,
• Sheila Ogoma 4 ,
• Corine Karema 5 , 6 &
• Fredros Okumu 7  

Malaria Journal volume  21 , Article number:  154 ( 2022 ) Cite this article

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The World Malaria Report, released in December 2021, reflects the unique challenges currently facing the global malaria community. The report showed the devastating toll of malaria, with an estimated 627,000 people losing their lives to the disease in 2020. The improved methodological approach used for calculating cause of death for young children revealed a systematic underestimation of disease burden over the past two decades; and that Africa has an even greater malaria crisis than previously known. While countries were able to prevent the worst-case scenarios, the disruptions due to the COVID-19 pandemic revealed how weak health systems and inadequate financing can limit the capacity of the continent to address the malaria challenge. African countries also face a convergence of biological threats that could redefine malaria control, notably widespread pyrethroid resistance and emerging resistance to artemisinin. Despite these challenges, there is cause for optimism in lessons learned from the COVID-19 pandemic, recent acceleration of cutting edge research and development, and new partnerships that encourage leadership from and ownership by affected countries. This article presents key insights from the 2021 World Malaria Report and reflections on the future trajectories: it was informed by an in-depth discussion with leading malaria experts from the World Health Organization (WHO), the Bill & Melinda Gates Foundation, and the U.S. President’s Malaria Initiative (PMI). The discussion took place during the 34th edition of the Ifakara Master Classes, held virtually on December 15th, 2021.

On December 15th, 2021, the 34th edition of the Ifakara Master Classes featured an in-depth discussion on the 2021 World Malaria Report (WMR), released a week earlier [ 1 ]. The discussion unpacked WMR findings and their implications for the future of malaria control. Guest experts included Dr. Pedro Alonso, Director of the Global Malaria Programme (GMP) at the World Health Organization (WHO), Dr. Abdisalan Noor, WHO Head of Strategic Information for Response Unit, Dr. Jennifer Gardy, Deputy Director, Surveillance, Data, and Epidemiology at the Bill & Melinda Gates Foundation, and Dr. Richard Steketee, Deputy Global Malaria Coordinator for the U.S. President’s Malaria Initiative (PMI).

The discussion, which lasted 2 h and 45 min in total, was organized and facilitated by MasterClass hosts Drs. Fredros Okumu (Director of Science, Ifakara Health Institute, Tanzania) and Sheila Ogoma (Technical Director, Clinton Health Access Initiative), and guest hosts, Drs. Corine Karema (Private Consultant and former Director of National Malaria Control Programme, Rwanda) and Nana Aba Williams (Coordinator, MESA Alliance, ISGlobal, Spain). The session began with a brief overview of the 2021 WMR by Dr. Noor, followed by a series of open-ended technical questions posed by the facilitators to the panel of experts about specific aspects of the WMR. The discussion was hosted on Zoom with 320 live participants from the global malaria community, and was live-streamed on YouTube.

A consolidated account of insights and lessons learned from the discussion is presented here. Findings are organized around topics identified a priori by the Master Class facilitators and key themes that emerged through the discussion.

The importance of numbers

The World Malaria Report, released December 2021, reflects the unique challenges facing the global malaria community. The report lays bare the devastating toll of malaria, with an estimated 627,000 people losing their lives to the disease in 2020. The numbers in the report tell two different stories for countries nearing elimination and countries experiencing high burden.

“A growing number of countries with low burden are moving steadily toward elimination, while countries with the highest burden are struggling.” –Dr. Noor

Eleven countries now experience 70% of the world’s malaria burden while 47 now report fewer than 10,000 cases per year. Even before the COVID-19 pandemic, gains against malaria were leveling off, leading to the role out of the High burden, High impact response in 2018 [ 2 ].

Methodological changes

A new statistical method is being used by the WHO, which provides more precise cause-of-death estimates for young children for all diseases, including malaria. In the revised approach, the proportion of childhood deaths attributable to malaria was 7.8%, up from previous estimates of 4.8% [ 3 , 4 ]. The revised approach revealed that there had been a higher number of estimated deaths between 2000 and 2020 than previously recognized and a systematic underestimation across the time series. The revisions also suggest that a higher number of malaria cases (totaling 1.7 billion) and deaths (10.6 million) had been averted in the same period.

The WMR has gotten clearer, and the quality improved consistently since it was first released. However, for most countries, the WHO still relies on modelled estimates derived from verbal autopsies to calculate all-cause mortality and the cause of death fraction for children under-5 to quantify malaria deaths in this age-group before applying a second adjustment to quantify deaths in older children and adults. There is a strong case for improving surveillance as an intervention and investing more heavily in information systems as recommended in the WHO Global Technical Strategy (GTS) 2016–2030 [ 5 ]. These malaria metrics, whether estimates or not, can be powerful advocacy tools and are, therefore, integral for creating compelling narratives of changes over time.

Impact of COVID-19

In addition to increases due to the methodological changes, the COVID-19 pandemic posed significant challenges, and was associated with ~ 47,000 of the ~ 69,000 extra deaths reported in 2020 relative to 2019, [ 1 ]. This includes increases in cases due to disruptions associated with delays in ITN distribution and disruptions in both diagnosis and treatment. Malaria deaths increased by 12% to an estimated 627,000 in 2020, compared to 2019 figures, with more than two-thirds of the additional 69,000 deaths attributable to COVID19-related service disruptions. While the figures are worrying, countries and partners have done well to prevent the worst-case scenarios earlier projected by the WHO and partners [ 6 , 7 , 8 ]; these models had predicted increases in malaria cases and deaths in Africa of as much as two orders of magnitude.

Threats to malaria control in Africa

A range of challenges from biological threats, to preventing severe disease and death in the most remote areas, to fragile and insufficient malaria funding must be addressed to sustain progress.

“ The situation remains precarious, particularly in sub-Saharan Africa where burden remains unacceptably high and a convergence of threats pose added challenges to disease control efforts…Without immediate accelerated action, key 2030 targets of the WHO Global Technical Strategy [ 5 ] for malaria will be missed, and additional ground may be lost.” –Dr. Noor

• Biological threats

While the epidemiology of malaria in Africa is already more challenging and precarious than elsewhere, the situation is compounded by multiple biological and civil threats. Over 122 million people in 21 malaria-endemic countries needed assistance due to health and humanitarian emergencies in 2020–2021 including Ebola outbreaks, armed conflicts, and flooding. Key biological threats in sub-Saharan Africa include anti-malarial drug resistance in the eastern Africa region [ 9 , 10 , 11 ], threats to diagnostics posed by parasite pfhrp2/3 gene deletions (which can cause false negative diagnostic test results) [ 12 , 13 ], resistance of malaria vector mosquitoes to public health insecticides [ 14 , 15 ], and the invasive vector species, Anopheles stephensi in the Horn of Africa [ 16 , 17 , 18 ]. All these factors threaten to undermine malaria control efforts in ways that are not sufficiently understood.

The WHO is tracking biological threats using the WHO threats map [ 19 ]. For pfhrp2/3 gene deletions, there are already new tests, albeit more expensive, which are prequalified by the WHO that can detect these parasites [ 20 ]. Increased investments to improve surveillance of gene deletions is needed and investments in new diagnostics is essential and a cause for optimism. Insecticide resistance remains a significant challenge to be addressed decisively—PBO nets are now recommended, and other new generation nets are being evaluated [ 21 ]. The WHO recognizes A. stephensi as an efficient malaria vector in urban settings [ 22 ], and affected countries and their neighbours should urgently enhance surveillance and deploy novel tools. Given these threats, malaria stakeholders should be open to examining other potentially-transformative approaches such as genetically modified mosquitoes currently in early-stage development [ 23 , 24 ].

Of particular concern is emerging signs of resistance to artemisinin, which is the backbone of current malaria treatment efforts in Africa [ 9 , 10 , 11 ]. Now confirmed in Uganda [ 9 ] and Rwanda [ 10 , 11 ], artemisinin resistance, more accurately described as delayed parasite clearance, is emerging de novo in Africa and does not appear to be linked to the resistance in malaria parasites in south-east Asia, where this problem was first described [ 25 ]. Setting up effective surveillance systems is, therefore, critical to closely track this threat in the region.

Severe malaria and the last mile

Combatting severe malaria is paramount for averting malaria deaths and depends on systems that support prompt treatment, referral for severe disease, and a full course of treatment to clear infection. However, the most severe malaria cases and deaths are often concentrated in areas where health systems are weakest, where prevention practices are most inadequate, and care workers least trained. Effective community-based approaches, particularly training and appropriately compensating community health workers will be key to reaching the unreached and preventing severe disease.

“…This is a Catch 22… if we try to build our health systems to reach the people furthest out, and at the greatest risk, using our least trained, least supplied workers, the system is then going to have to deal with severe malaria because we weren’t able to prevent it in the first place...the question is, how do we take the community outreach, and community health workers on the periphery, and make sure they’re sufficient in scale, have the right skills, and that they are adequately supervised and supplied?” –Dr. Steketee

Funding gap

A consistent feature of global malaria programmes is that less than half of the necessary annual budget is actually available. A total of $3.3 billion was invested in 2020, compared to target of $6.8 billion. Moreover, to reach global targets, investments will need to increase by more than three times by 2030 to 10.3 billion per year. The current system relies on just a small number of major funders and budget needs are unlikely to be met even if these few sources increase their contributions. Further, the relative investment of countries has not increased despite economic growth.

“When you think about what’s stalled, population growth has not stalled, and that will continue, what’s stalled is the money. We’ve been working on efficiencies but there are limits to what we can achieve with efficiency alone.” –Dr. Steketee

The future of malaria control

The malaria situation cannot be effectively tackled using current practices, highlighting the need for a more transformational approach, tailored to different epidemiological contexts. A drastic change in mindset is needed around the disease and its complexities.

“It has not sunk in that we need to do something drastically different. It is a mindset problem, we need to show greater flexibility, and understand we are facing a very complex problem…malaria is a problem to be solved, not simply a task to be performed.” –Dr. Alonso

Lessons learned from the COVID-19 pandemic

There are important opportunities to learn from the COVID-19 pandemic. The pandemic brought the global malaria community together in a way not previously seen, to ensure a buffer against service delivery disruptions.

“It was really heartening to see that when there’s an emergency, we can work effectively across stakeholders to mount an effective response. COVID19 responses have also demonstrated to Ministries of Health that data matters – high-quality real-time data matters.” –Dr. Gardy

The pandemic has also shown that molecular data can provide important information on current and evolving trends over time, and that mathematical models can be valuable for exploring different intervention scenarios, an approach that is now also being utilized in the WHO-backed High burden, High impact response [ 2 ]. Perhaps most promising has been lessons learned from the development of the COVID-19 vaccine.

“...We’ve seen that things like a massive investment in de-risking multiple aspects of the vaccine production pipeline meant that you could very quickly get new products authorized, under Emergency Use Authorizations, and then eventually under full approval for use. We also saw the culmination of decades of work on mRNA vaccines…it’s working better than what we could have imagined. To hear that there’s now an mRNA pipeline for malaria vaccines is very exciting.” –Dr. Gardy

Innovative financing mechanisms will be needed moving forward to ensure sufficient and sustained funding. Resource mobilization seen during the COVID-19 pandemic shows when can be done when a disease is viewed as a global threat.

“COVID-19 may provide an opportunity – when countries in the global north have felt threatened there’s no limit to the money they spend – building on this momentum is a great opportunity to put the health agenda up front. Strengthening health systems is a key issue in the fight against malaria, it may not be considered malaria money, but is key to getting the commodities out.” –Dr. Alonso

RTS,S malaria vaccine

In 2021, the RTS,S malaria vaccine became the first to be approved for widespread use; and the only vaccine currently available for any human malaria parasites. The vaccine is now recommended for children living in areas with moderate to high Plasmodium falciparum transmission. In addition to the modest efficacy demonstrated in earlier clinical trials [ 26 , 27 ] and results of a consensus modelling programme [ 28 ], data from a WHO-backed pilot study in three countries, Kenya, Ghana and Malawi, suggest that the vaccine is feasible to deliver, safe and has a significant public health impact [ 29 ]. When provided in the context of both the expanded programme of childhood immunizations and other malaria control efforts, the vaccine increases access to prevention for vulnerable children—for instance reaching two thirds of children not protected by insecticide-treated nets (ITNs)—and is cost effective in areas with moderate to high transmission. The vaccine programme has already reached more than 900,000 children in three countries and generated among the most robust evidence for a malaria control tool ever.

It will be critical to think comprehensively about malaria control, including the vaccine, to ensure context-appropriate packages of interventions.

“…Putting one tool against another is really unhelpful, it’s bad public health…We have an armamentarium, we have a set of tools, and we need to look at what’s best in a particular circumstance….” –Dr. Alonso

During the evaluation of RTS,S there was a strong partnership between African scientists, the WHO, and several other players working jointly. For example, the Phase III trials were done in 11 different sites across nine African countries [ 26 , 27 ], and the mathematical modelling done to support final decision-making had been conducted jointly by four different research groups [ 28 ]. There is an important opportunity to leverage benefits of such united approaches to improve outcomes for other technologies and malaria control programmes.

“RTS,S forces the malaria community to work with other departments of the ministry of health that are the custodians of the delivery platforms, such as EPI. Therefore, an added benefit of RTS,S is that it will force the malaria community to come out from a siloed space.” –Dr. Alonso

Working across disease portfolios can also maximize efficiencies in health systems.

“The more we can figure out how to work together on delivery platforms, the more we can see benefits across the board and use the limited (funding) envelope more effectively.” –Dr. Gardy

Toward a unified vision and country-led decision-making

Finally, the future of malaria control will require moving toward country-led, unified visions and funding strategies. This includes ensuring evidence-based decisions and centering affected countries in those decisions.

“If a country has the data to show an area would benefit from a fifth round of seasonal malaria chemoprevention, who is anyone on this planet to tell them no? We need to break those attitudes, the lack of empowerment to countries, that lack of evidence-based decision making – only then will we be able to make progress.” –Dr. Alonso

There must also be a more coordinated response from different partners working within countries and a united strategy. This includes movement toward a single national strategic plan, that is costed properly and against which the investments from inside and outside of the country are aligned to achieve the agreed programme goals.

“Let’s get everyone at the table with one single plan, costed, that we all help develop and that we can all invest in. This is truly a partnership.” –Dr. Steketee

The global malaria community is at an inflection point; progress has levelled off and multiple threats confront countries already hardest hit by the disease. A shift in mindset is urgently needed with truly innovative and collaborative approaches to malaria control. Reflecting on the 2021 WMR and its implications for the future, there is a critical opportunity to take-up lessons learned from the COVID-19 pandemic, including what is possible when the world comes together towards a common goal. Cutting edge research and development, as was seen in recent vaccine development, and improved surveillance, can pave the way to more transformational approaches. Finally, and most importantly, the future of malaria control must be led by affected countries, with unified and coordinated support from donors and partners.

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Acknowledgements

We acknowledge all participants for their engagement and for the additional questions raised during the masterclass. We also acknowledge the participants for reviewing the final manuscript and approving it for publication.

There was no funding for this work.

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April Monroe

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Nana Aba Williams

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Sheila Ogoma

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AM and FO drafted the manuscript. NAW, SO and CK reviewed and contributed to the draft. All authors read and approved the final manuscript.

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Monroe, A., Williams, N.A., Ogoma, S. et al. Reflections on the 2021 World Malaria Report and the future of malaria control. Malar J 21 , 154 (2022). https://doi.org/10.1186/s12936-022-04178-7

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This chapter focuses on the epidemiology of malaria. Topics covered include malaria and its life cycle, epidemiology of malaria at the turn of the 20th century, advances in malaria epidemiology after the First World War, progress in the fight against malaria in the years preceding the Second World War, national malaria eradication programmes, and the era of molecular biology.

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• Published: 25 March 2023

Modelling to inform next-generation medical interventions for malaria prevention and treatment

• Narimane Nekkab 1 , 2 ,
• Josephine Malinga 1 , 2   na1 ,
• Lydia Braunack-Mayer 1 , 2   na1 ,
• Sherrie L. Kelly   ORCID: orcid.org/0000-0002-6232-5586 1 , 2 ,
• R. Scott Miller 3 &
• Melissa A. Penny   ORCID: orcid.org/0000-0002-4972-593X 1 , 2  

Communications Medicine volume  3 , Article number:  41 ( 2023 ) Cite this article

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• Computational biology and bioinformatics
• Infectious diseases

Global progress against malaria has stagnated and novel medical interventions to prevent malaria are needed to fill gaps in existing tools and improve protection against infection and disease. Candidate selection for next-generation interventions should be supported by the best available evidence. Target product profiles and preferred product characteristics play a key role in setting selection criteria requirements and early endorsement by health authorities. While clinical evidence and expert opinion often inform product development decisions, integrating modelling evidence early and iteratively into this process provides an opportunity to link product characteristics with expected public health outcomes. Population models of malaria transmission can provide a better understanding of which, and at what magnitude, key intervention characteristics drive public health impact, and provide quantitative evidence to support selection of use-cases, transmission settings, and deployment strategies. We describe how modelling evidence can guide and accelerate development of new malaria vaccines, monoclonal antibodies, and chemoprevention.

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Introduction.

There is an urgent need to accelerate development of novel malaria interventions to prevent infections and severe disease. Progress to reduce the impact of malaria has stalled worldwide alongside disruptions to services during the COVID-19 pandemic. Malaria cases in the African Region increased from 225 per 1000 population at-risk in 2019 to 234 in 2020 and remained similar at 229 cases per 1000 population in 2021 1 , 2 . Estimated malaria deaths in this region rose from 568,000 in 2019 to 625,000 in 2020 and declined marginally to 619,000 deaths in 2021. Moreover, the emergence of partial resistance to treatment with artemisinin in some parts of Africa threatens the efficacy of artemisinin-based combination therapies. Increasing insecticide resistance and invasion of the primary mosquito vector in India, Anopheles stephensi , into Africa may also lead to increasing transmission in urban areas, which could reverse progress made over recent decades 3 .

While the 2021 World Health Organization’s (WHO) recommendation of the first malaria vaccine, RTS,S, was a major milestone, the vaccine took 30 years to develop, test, and pilot, and its availability, acceptance and use has not yet been demonstrated 4 . Furthermore, current malaria prevention measures do not reach all children. For example, seasonal malaria chemoprevention (SMC) is only recommended and deployed in highly seasonal settings with low drug resistance risk. Implementation of intermittent preventive treatment of malaria in pregnancy using sulfadoxine-pyrimethamine (IPTp-SP) is not recommended in low transmission or high SP resistance settings and there is limited guidance on the adverse consequences of drug–drug interactions 5 . Resource constraints, limited access to care, and low chemoprevention adherence in children and pregnant women, who are vulnerable to severe outcomes, continue to be major challenges. The development of novel interventions for malaria prevention must be accelerated to meet current and future needs. Incorporating all forms of evidence to guide decision-making early on during the product development pipeline will be vital in accelerating the process.

Global funders, regulatory agencies, and researchers are expanding their pipelines for next-generation medical interventions for malaria prevention, guided by reference documents for candidate selection and investment decision-making in research and development (R&D). While guidance documents vary, they essentially outline the necessary characteristics required to support development decisions and optimisation of innovative products. The WHO developed Preferred Product Characteristics (PPCs), informed by technical working groups and public consultation, to guide and promote the development of various malaria prevention interventions such as vaccines, chemoprevention, and, recently, for monoclonal antibodies (mAbs) as well as vector control interventions. Medicines for Malaria Venture (MMV) also uses Target Candidate Profiles (TCPs) to support product development partnerships, pipeline development for long-acting injectable drugs, and repurposing, recombining, and developing antimalarials for SMC 6 . The Bill & Melinda Gates Foundation is developing intervention Target Product Profiles (iTPPs) to optimise investment in three next-generation medical interventions for prevention: novel immunological seasonal therapeutics using mAbs and long-acting injectable drugs, multi-seasonal interventions using second-generation malaria vaccines, and novel candidates or repurposed drugs for second-generation oral chemoprevention. In the case of malaria iTPPs for example, the documents define characteristics for development of novel intervention by how they are likely to be used and their indication, product components, target population and setting, safety, formulation, and pre-qualification date targets among other criteria for a base and upside case.

Prioritisation should be given to establishing a comprehensive evidence base to iteratively inform guidance documents and support selection of the most promising candidates, thus accelerating the development of novel medical interventions to prevent malaria. We argue that this evidence base should encompass the full range of quantitative and qualitative findings from clinical trials, modelling, and expert opinion. In the case of malaria prevention, selecting candidates that maximise the potential to achieve high public health impact and accelerate implementation requires decisions based on well-informed product criteria accounting for potential R&D bottlenecks, resources, and timeframes. Importantly, modelling evidence should be incorporated early in the drug development process, as modelling can uniquely link product criteria or properties to likely public health impact, which is not possible before or during clinical trials and is only possible after implementation. In addition to modelling existing interventions, modelling can estimate the potential range of impact on disease burden of a novel intervention to support building a value proposition document used to attract commercial development partners and engage with diverse stakeholders and partners that include those in malaria country programs and health agencies. Such modelling analyses also allow translation of clinical trial evidence to population impact across transmission settings, deployment strategies, or use-cases. Here, we focus our discussion on malaria prevention tools; however, this framework can also be expanded to malaria treatment, vector control, and to other diseases.

Establishing an iterative approach and framework to generate a comprehensive evidence-base

Anecdotally, R&D for malaria interventions seems to take longer than for other diseases. This is due, in part, to higher investment risk since drug and intervention combinations are often needed to demonstrate sufficient effectiveness, on account of malaria’s varied and changing epidemiological landscape. In addition, lack of a dual market dominated by the public sector in malaria endemic settings which are often low and middle-income countries provides little to no financial return as opposed to the travellers market which can be more lucrative 6 , 7 . While increased global investment has helped accelerate development in recent years, candidate selection guidance documents and priority use-cases are mainly informed by expert opinion and results of early stage clinical trials. Guidance documents have an important role to play in shortening R&D timelines and reducing costs, targeting priority use-cases and unmet needs, while ensuring selected candidates have a higher probability of demonstrating high impact for their given use-case. We posit that well informed decision-making along the product development pipeline, from discovery, proof-of-concept, and program implementation to impact, requires the iterative use of a comprehensive evidence-base that includes modelling evidence and allows for decisions to be adapted as new evidence becomes available (Fig.  1 ).

An iterative and collaborative approach between clinical investigators, modellers, and malaria experts to generate evidence to continuously inform guidance documents. Modelling provides evidence on trade-offs between intervention characteristics and minimum criteria informed by predicted public health impact and supported by clinical evidence to define parameter values and generating evidence for priority scenarios defined by experts for different use-cases. Clinical studies provide initial efficacy evidence of first candidates and with improved design and planning informed by modelling evidence to support key evidence for selection criteria of future candidates. Through stakeholder engagement, expert opinions provide well-informed ranking of priorities for the evidence generation process including identifying scenarios to model for different use-cases and intervention feasibility for implementation.

Modelling can inform different priority health targets, as the models can consider both the patient-level benefit of novel prevention products (i.e. the individual-level protection it provides) as well as the population-level benefit of deploying such a product to communities by quantifying the additional public health gains. Pharmaceutical approaches have traditionally prioritised efficacy outcomes at the individual level. For example, pharmacokinetics and pharmacodynamics (PK/PD) modelling support optimisation of drug availability and duration to improve drug efficacy for a particular disease target within the treated individual. In contrast, prevention targets for infectious diseases require considering both the individual-level benefit and an understanding of a product’s public health benefit, including changes to immunity acquisition by delaying infections or via any impact on population-level transmission dynamics. This is essential when we consider medical interventions that impact susceptibility to infection or aim to prevent disease progression to clinically relevant presentations or severe disease.

While clinical trials evaluate the individual-level benefit of products, they do not estimate the total public health benefit over extended time frames or capture any potential benefits of interrupting onward transmission with population-level interventions. Modelling captures these dynamics to link individual and community benefits, allowing clinical trial evidence to be integrated into updated models or public health estimates, and can also support translating clinical trial results into implementation considerations. In early product development stages, population-level modelling can provide quantitative evidence linking an intervention’s minimum key performance criteria, such as efficacy or duration with its projected public health impact and benefit to communities towards meeting health targets, thus contributing to a robust evidence base 8 . While clinical evidence is essential to inform efficacy estimates and eventual registration and funding decisions for products, clinical evidence also informs model parameters, and modelling evidence in turn can improve clinical trial planning and design. For modelling evidence to be integrated within this process, it is essential for experts to be consulted early in the process to design research questions that modelling can address; an iterative loop between clinical trials, modelling, and expert opinion will reshape and transform criteria in guidance documents to support candidate selection.

Developing an accelerated and iterative process for the development of novel malaria prevention interventions should account for the following components.

Identify unmet needs

The first step requires identifying who and where a malaria prevention intervention can meet the health needs of exposed populations. One approach is to consider the WHO-defined high burden high impact (HBHI) settings, ranking communities with mapped under-five mortality as a proxy for need. However, unmet needs can also be defined in communities without current prevention interventions, such as East Africa where SMC is not recommended or settings with perennial malaria transmission, or infants and pregnant women who are more vulnerable to severe outcomes and require higher consideration of drug safety 9 . Addressing health inequity, in particular low access to health services and first line treatment for symptomatic children and low bed net distribution coverage is essential to bridging the gaps of malaria programs and elimination strategies. As social, financial, and epidemiological factors drive change over time, including inequity, unmet needs should be revisited in an iterative manner to anticipate future scenarios. Defining these unmet needs will allow for prioritisation and evaluation of supply requirements for various timeframes and public health goals, such as for elimination.

Define priority use-cases and potential intervention profiles

Once unmet needs have been articulated, the use-case definition is an important driver to prioritise development of a new intervention and should be defined rigorously at each TCP, iTPP, or PPC update to ensure candidates are addressing unmet health needs. A use-case defines the target population(s) who will receive a new malaria prevention intervention (children, pregnant women, all at-risk during an outbreak or humanitarian crisis, travellers to endemic regions), and where and when it should be deployed, ultimately influencing other criteria, including: product properties (mode-of-action, formulation, co-administration), logistic requirements (supply, delivery channel, cost-of-goods), intervention characteristics (protective efficacy, duration of protection, safety), and deployment strategy (deployment coverage, number of rounds). Considering these factors, modelling can evaluate how use-cases influence an intervention’s minimum criteria and vice versa.

Define priority questions through community and expert engagement

In the early stages, shaping novel malaria intervention characteristics in guidance documents should also be guided by community engagement through discussions between global funders, health agencies, researchers, evidence generators (clinical trial investigators and modellers), product developers, local community leaders, and implementation specialists. These discussions should inform the identification of knowledge gaps, potential bottlenecks, and potential additional use-cases to refine the public health value proposition. Developing priority questions that inform modelling scenarios, such as comparing impact in seasonal and perennial settings or optimised number of rounds and timing of deployment, help guide evidence generation by informing clinical trial design and site selection targeting specific epidemiological settings, and the selection of model scenarios for predicting public health impact.

Integrate clinical evidence

Pre-clinical and early clinical evidence of first candidates provides initial profiling of feasibility, safety, and PK/PD relationships. This then informs where, and for which use-cases, a candidate can meet health needs, the expectations of regulatory approval, and implementation factors such as supply, delivery, and deployment strategies. In addition, early clinical evidence for these candidates sets threshold criteria for selection of future candidates that are expected to achieve non-inferiority, and informs model parameterisation to narrow down the exploration space between individual-level effects and population-level impact.

Integrate and refine modelling evidence

Mathematical models of malaria transmission can guide thinking along the entire product development pipeline from clinical trial translation to use-case decisions for implementation. Modelling can initially explore the major drivers of an intervention’s impact across a broad spectrum of scenarios to identify what clinical evidence needs to be generated early. In addition, models can support the clinical evidence generation process by identifying minimum thresholds, linking intervention characteristics to health goals to inform guidance documents to the level of detail required for appropriate candidate selection by product developers. Modelling can provide evidence on where potential candidates would be best implemented to maximise impact and help drive policy and procurement decisions.

Living documents through process reiteration

Modelling can be integrated at each step in the development process to support articulating unmet needs, testing use-cases, translating clinical evidence, and setting achievable health goals to update guidance documents and adapt to new clinical evidence. As a result, evidence-based guidance and decision-making becomes an iterative process where modelling continuously supports the refinement of candidate profiles, rather than a linear process of development.

Building a collaborative framework in practice

The Swiss Tropical and Public Health Institute Disease Modelling group and the Bill & Melinda Gates Foundation have developed a collaborative framework that integrates the process described above to iteratively inform next-generation iTPPs for seasonal, multi-seasonal, and second-generation SMC interventions for malaria prevention. In June 2021, workshops were organised to identify challenges and priority questions and to launch the platform with a broad range of experts and stakeholders, including those based in malaria endemic regions and ensuring gender equity. These discussions focused on the importance of guidance documents during R&D, patient-centred development, community advocacy for target population acceptability, and, when to stop or to continue funding new interventions. Working groups identified the following priorities for modelling: (1) describing trade-offs between intervention and implementation factors; (2) translating clinical trial and modelling evidence to inform policy and investments; (3) informing clinical trial design and identification of standard of care (SOC) comparators; (4) accounting for financial resources and cost-of-goods; and (5) defining burden reduction criteria and timelines for achieving elimination.

The collaborative framework generates modelling evidence using dynamic, individual-based malaria transmission models, such as the OpenMalaria model that was developed over a period of 15 years. Detailed models are coupled with additional analytical and statistical approaches to enable rapid and computationally efficient searches of multi-dimensional parameter spaces spanning a wide range of intervention characteristics and settings 8 . Modelling the mechanisms of individual-level factors and population-level transmission dynamics links predictions of public health burden reduction to key intervention characteristics. By predicting across an entire parameter space of intervention characteristics (for example, ranges for initial efficacy, duration of protection, and deployment coverage), modelling can quantify the importance and level of contribution of each characteristic to health outcomes and identify the minimum value at which intervention characteristics achieve defined health targets to directly inform iTPP criteria for different use-cases. Together with stakeholders from the 2021 convening, priority questions for modelling were ranked by most relevant scenarios to model at a first iteration for each given intervention by accounting for unmet health needs and priority use-cases. Clinical evidence, where and when available, informed parameter ranges to explore trade-offs and minimum criteria comprehensively. We give examples of this process in Table  1 .

Models provide supportive information for decision-making or informing candidate selection, funding, and target product profiles alongside other diverse sources, including clinical evidence and expert opinion. Although not the sole source informing selection criteria, models have a unique role to play before and during clinical trials and as clinical evidence is being acquired. While the additional role of modelling is clear, all models have limitations. To be informative for selection criteria, models must capture essential disease dynamics while remaining simple enough to run. Population model prediction uncertainty comes from model structure and parameter values. For example, assumptions about human behaviour patterns or intervention effect will impact predictions. Some use cases, such as pregnant women or travellers, are more challenging to model due to limited data. Discussions around a model’s limitations in generating evidence to inform TPPs is inherently part of the process itself, which requires stakeholders to formulate specific questions that are fit for purpose. The conversations around models, their limitations, and sources of uncertainty, and how to translate predictions to tangible evidence become the most valuable output.

Modelling to support clinical trial translation

Population-level transmission modelling can translate clinical efficacy outcomes to population-level effectiveness by integrating pharmacological evidence informing individual-level protection. Take, for example, monoclonal antibodies for infection prevention in seasonal settings. Currently very little is known about the PK/PD relationship of monoclonal antibodies. Previous modelling has shown that the protection of an anti-infective malaria monoclonal over time, informed by PK/PD data and models, is an important driver of public health impact 10 . Unlike vaccines, where immune correlates of protection are challenging to define, mAbs offer the potential to provide early PK/PD evidence. While the first-generation candidate CIS43LS has demonstrated high and prolonged protection, sufficient PD evidence from dose de-escalation data are not yet available 11 . Modelling can address this knowledge gap by generating a comprehensive spectrum of PD characteristics from forthcoming early clinical trials to provide a broad range of potential impact predictions that can be refined iteratively as more data is generated.

Modelling to interpret and define public health impact targets required to guide intervention development

For malaria prevention, imperfect tools, such as perennial malaria chemoprevention (PMC), SMC, and RTS,S vaccination, have been deployed in moderate to high transmission settings. The public health and cost-effectiveness targets for novel interventions can be informed by the standard-of-care (SOC) comparators when the use-case is well defined and alternative interventions already exist. In the absence of a comparator, ranges of desired health targets can be iteratively assessed, but comparison of effectiveness to existing prevention technologies is critical to refine the value proposition for further R&D investment. Without population-based modelling before Phase 3 clinical trials, it is challenging to evaluate the effectiveness of candidates with early clinical data alone. Modelling can quantify effectiveness for different intervention characteristics, use-cases, and evaluation periods, as well as easily translate different endpoints to guide policy decisions. For example, the public health impact and cost-effectiveness of the RTS,S malaria vaccine was evaluated by four independent modelling groups using different mathematical models of malaria transmission. This body of work estimated disability-adjusted life years (DALYs) for both a three-dose and four-dose vaccine schedule more than four years prior to the start of the pilot studies. These cost-effectiveness estimates demonstrated that a partially efficacious vaccine could have significant impact at the population level, critical for the WHO’s recent recommendation of RTS,S 12 , 13 .

Modelling to iteratively update guidance documents and readdress use-cases

Guidance documents for mAbs, next-generation chemoprevention, and vaccines in development currently prioritise preventing clinical illness and severe disease in vulnerable populations, including infants, children under five, and pregnant women. When use-cases are uncertain, modelling can simulate scenarios for different age groups, seasonal profiles, and transmission intensities to demonstrate where interventions will be most impactful and reassess when new evidence is onboarded. For example, WHO recommends malaria vaccines for children aged five to 17 months old in perennial settings with potential for seasonal application in children under five years old. However, these target ages and seasonal use-case only came to light as clinical evidence was accrued because the vaccine prevented infections for a shorter duration than hoped during the Phase 3 studies 12 , 14 . Currently, the efficacy profiles of first-generation anti-infective vaccines like RTS,S and, potentially, R21 support their use in seasonal settings. Yet, many questions remain regarding implementation factors, combinations of the vaccine with oral chemoprevention programs, and impact across different epidemiological settings. Modelling can support this by predicting the likely impact of such factors prior to expensive clinical trials and pilot studies and explore the feasibility of these tools to achieve future elimination targets.

The malaria vaccine example described here provides a lesson to heed for novel malaria intervention development. Firstly, use-cases of novel interventions should be re-evaluated with an improved understanding of the limits of an intervention’s efficacy and duration. Thus, understanding the efficacy and duration of novel malaria interventions as early as possible will help not only to select or reject candidates and optimise duration properties, but also assess and reassess appropriate use-cases iteratively. Modelling supports this by demonstrating the trade-offs between deployment factors and intervention characteristics to identify minimum criteria well before Phase 3 trials. In some cases it will provide efficacy and duration cut-offs (clear ‘no-go’ criteria) for candidate use in different uses-cases. However, if early clinical evidence suggests candidates will struggle to ever meet these initial efficacy and duration requirements defined by iTPPs use-cases, the community should not always discard classes of candidates or novel interventions, but critically and discriminately revaluate if there is value of this efficacy and duration profile for another use-case for malaria prevention.

With increasing threats of malaria drug and insecticide resistance, there is now a need for novel malaria prevention interventions to improve public health impact. As the malaria community moves forward to invest in next-generation interventions, guidance documents are crucial to ensure that the best evidence supports the criteria for candidate section and decision-making for implementation. While clinical evidence and expert opinion will initially play an essential role in informing these criteria, mathematical modelling can accelerate this process and provide robust evidence of candidate characteristics and deployment strategies that are likely to lead to a higher public health impact for different use-cases and enhance the value proposition for a given development candidate. Modelling should be incorporated early in the evidence generation process, to improve the translation of clinical trial efficacy estimates and to support use-case and implementation strategy decisions. Public health impact predictions from modelling studies that include detailed intervention dynamics are currently underutilised for setting selection criteria early in development. Thus, including such analytic tools early on provides a unique opportunity to accelerate the development of malaria interventions for optimised use-cases and deployment strategies.

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Acknowledgements

We would like to acknowledge and sincerely thank all stakeholders who participated in the June 2021 convening, who provided input and feedback that shaped the unmet health needs, questions, and modelling approach. This includes global health funders, product developers, academic partners, policy makers, regulators, implementation specialists, community engagement specialists, and public health specialists from both the Global North and Global South. These discussions were essential in guiding our work. This study was funded by the Bill and Melinda Gates Foundation (INV-002562 to MAP), and we wish to thank Jean-Luc Bodmer for his contributions to this modelling framework. MAP acknowledges individual support from the Swiss National Science Foundation (SNF Professorship PP00P3_170702 and PP00P3_203450, to M.A.P.). We sincerely acknowledge all members of the Disease Modelling unit of the Swiss Tropical and Public Health Institute and Dr Lydia Burgert (under SNF Professorship PP00P3_170702) for their advice. We would like to thank Nadja Cerreghetti for project management support (INV-002562).

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These authors contributed equally: Josephine Malinga, Lydia Braunack-Mayer.

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Swiss Tropical and Public Health Institute, Allschwil, Switzerland

Narimane Nekkab, Josephine Malinga, Lydia Braunack-Mayer, Sherrie L. Kelly & Melissa A. Penny

University of Basel, Basel, Switzerland

Gates Medical Research Institute, Cambridge, USA

R. Scott Miller

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N.N. and M.A.P. conceived the study, wrote the first draft of the manuscript, and provided overall guidance. J.M., L.B.M., S.K. and R.S.M. critically reviewed the approach and the manuscript. All authors read and approved the final manuscript.

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Correspondence to Melissa A. Penny .

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Nekkab, N., Malinga, J., Braunack-Mayer, L. et al. Modelling to inform next-generation medical interventions for malaria prevention and treatment. Commun Med 3 , 41 (2023). https://doi.org/10.1038/s43856-023-00274-0

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DOI : https://doi.org/10.1038/s43856-023-00274-0

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Malaria is an acute febrile illness caused by Plasmodium parasites, which are spread to people through the bites of infected female Anopheles mosquitoes. It is preventable and curable.

Malaria is a life-threatening disease primarily found in tropical countries. It is both preventable and curable. However, without prompt diagnosis and effective treatment, a case of uncomplicated malaria can progress to a severe form of the disease, which is often fatal without treatment.

Malaria is not contagious and cannot spread from one person to another; the disease is transmitted through the bites of female Anopheles mosquitoes.  Five species of parasites can cause malaria in humans and 2 of these species –  Plasmodium falciparum  and  Plasmodium vivax  – pose the greatest threat. There are over 400 different species of Anopheles mosquitoes and around 40, known as vector species, can transmit the disease.

This risk of infection is higher in some areas than others depending on multiple factors, including the type of local mosquitoes. It may also vary according to the season, the risk being highest during the rainy season in tropical countries. 

Nearly half of the world’s population is at risk of malaria. In 2022, an estimated 249 million people contracted malaria in 85 countries. That same year, the disease claimed approximately 608 000 lives.

Some people are more susceptible to developing severe malaria than others. Infants and children under 5 years of age, pregnant women and patients with HIV/AIDS are at particular risk. Other vulnerable groups include people entering areas with intense malaria transmission who have not acquired partial immunity from long exposure to the disease, or who are not taking chemopreventive therapies, such as migrants, mobile populations and travellers.  

The first symptoms of malaria usually begin within 10–15 days after the bite from an infected mosquito. Fever, headache and chills are typically experienced, though these symptoms may be mild and difficult to recognize as malaria. In malaria endemic areas, people who have developed partial immunity may become infected but experience no symptoms (asymptomatic infections).

WHO recommends prompt diagnosis for anyone with suspected malaria. If Plasmodium falciparum  malaria is not treated within 24 hours, the infection can progress to severe illness and death. Severe malaria can cause multi-organ failure in adults, while children frequently suffer from severe anaemia, respiratory distress or  cerebral malaria. Human malaria caused by other Plasmodium species can cause significant illness and occasionally life-threatening disease.

Malaria can be diagnosed using tests that determine the presence of the parasites causing the disease. There are 2 main types of tests: microscopic examination of blood smears and rapid diagnostic tests. Diagnostic testing enables health providers to distinguish malarial from other causes of febrile illnesses, facilitating appropriate treatment.  

More information on malaria diagnostic testing

Malaria is a treatable disease. Artemisinin-based combination therapies (ACTs) are the most effective antimalarial medicines available today and the mainstay of recommended treatment for Plasmodium falciparum  malaria, the deadliest malaria parasite globally.

ACTs combine 2 active pharmaceuticals with different mechanisms of action, including derivates of artemisinin extracted from the plant Artemisia annua and a partner drug. The role of the artemisinin compound is to reduce the number of parasites during the first 3 days of treatment, while the role of the partner drug is to eliminate the remaining parasites.

As no alternative to artemisinin derivatives is expected to enter the market for several years, the efficacy of ACTs must be preserved, which is why WHO recommends that treatment should only be administered if a person tests positive for malaria. WHO does not support the promotion or use of Artemisia plant material (whether teas, tablets or capsules) for the prevention or treatment of malaria.

Over the last decade, parasite resistance to antimalarial medicines  has emerged as a threat in the fight against malaria, particularly in the Greater Mekong subregion. WHO is also concerned about more recent reports of drug-resistant malaria in Africa. To date, resistance has been documented in 3 of the 5 malaria species known to affect humans: P. falciparum , P. vivax , and P. malariae . However, nearly all patients infected with artemisinin-resistant parasites who are treated with an ACT are fully cured, provided the partner drug is highly efficacious.

More information about artemisinin resistance

Malaria occurs primarily in tropical and subtropical countries. The vast majority of malaria cases and deaths are found in the WHO African Region, with nearly all cases caused by the Plasmodium falciparum parasite. This parasite is also dominant in other malaria hotspots, including the WHO regions of South-East Asia, Eastern Mediterranean and Western Pacific. In the WHO Region of the Americas, the Plasmodium vivax parasite is predominant.

The threat of malaria is highest in sub-Saharan Africa, and 4 countries in that region accounted for nearly half of all malaria deaths worldwide in 2022: Nigeria (31.1%), the Democratic Republic of the Congo (11.6%), Niger (5.6%) and the United Republic of Tanzania (4.4%).

People who have no partial immunity to malaria are at higher risk of contracting the disease. This includes travellers from non-endemic countries entering areas of high transmission as well as people in malaria-endemic countries living in areas where there is little or no transmission.

As symptoms often do not present for 10 to 15 days after infection, travellers may return to their home country before exhibiting signs of the disease. Doctors in non-endemic areas may not recognize the symptoms, causing potentially fatal delays in diagnosis and treatment. In addition, effective antimalarial drugs may not be registered or available in all countries.

Chemoprophylaxis can be used as a preventive therapy prior to travelling in endemic areas. When combined with the use of insecticide-treated nets and the repeated application of a topical repellent to prevent mosquito bites, it significantly lowers the risk of infection. If a person has taken chemoprophylaxis as a preventive measure, the same medicine should not be used for treatment if infection occurs. 

Travellers are encouraged to consult a doctor or their national disease control centre prior to departure to determine the appropriate preventive measures.

Chapter on malaria in the WHO “International travel and health”

Malaria is a preventable disease. 

1. Vector control interventions. Vector control is the main approach to prevent malaria and reduce transmission. Two forms of vector control are effective for people living in malaria-endemic countries: insecticide-treated nets, which prevent bites while people sleep and which kill mosquitoes as they try to feed, and indoor residual spraying, which is the application of an insecticide to surfaces where mosquitoes tend to rest, such as internal walls, eaves and ceilings of houses and other domestic structures. For travellers, the use of an insecticide-treated net is the most practical vector control intervention. WHO maintains a list vector control products that have been assessed for their safety, effectiveness and quality.  

More information on vector control

2. Chemopreventive therapies and chemoprophylaxis . Although designed to treat patients already infected with malaria, some antimalarial medicines can also be used to prevent the disease. Current WHO-recommended malaria chemopreventive therapies for people living in endemic areas include intermittent preventive treatment of malaria in pregnancy, perennial malaria chemoprevention, seasonal malaria chemoprevention, post-discharge malaria chemoprevention, and intermittent preventive treatment of malaria for school-aged children. Chemoprophylaxis drugs are also given to travellers before entering an area where malaria is endemic and can be highly effective when combined with insecticide-treated nets. 

More information on chemopreventive therapies

In 2021, WHO recommended the RTS,S/AS01 (RTS,S) vaccine to prevent malaria among children living in regions with moderate-to-high P. falciparum malaria transmission. More than 2 million children were reached with at least one dose of the vaccine through the WHO-coordinated Malaria Vaccine Implementation Programme in Ghana, Kenya and Malawi. A rigorous evaluation has shown a substantial reduction in severe malaria and a 13% drop in early childhood deaths in the areas where RTS,S has been administered compared with areas where the vaccine was not introduced. In October 2023, WHO recommended a second safe and effective malaria vaccine, R21/Matrix-M. The availability of 2 malaria vaccines is expected to increase supply and make broad-scale deployment across Africa possible

More information on the RTS,S vaccine and the malaria vaccine implementation programme

The vision of WHO and the global malaria community is a world free of malaria. This vision will be achieved progressively by countries eliminating malaria from their territories and implementing effective measures to prevent re-establishment of transmission.

Malaria-endemic countries are situated at different points along the road to elimination. The rate of progress depends on the strength of the national health system, the level of investment in malaria elimination strategies and other factors, including biological determinants, the environment and the social, demographic, political and economic realities of a particular country. 

Over the last 2 decades, significant progress has been achieved towards malaria elimination. According to the latest World malaria report , 27 countries had fewer than 100 cases of the disease in 2022, up from 6 countries in 2000. 

Countries that have achieved at least 3 consecutive years of zero indigenous cases of malaria (a case contracted locally with no evidence of importation from another endemic country) are eligible to apply for the WHO certification of malaria elimination . Since 2015, 12 countries have been certified by the WHO Director-General as malaria-free, including Maldives (2015), Sri Lanka (2016), Kyrgyzstan (2016), Paraguay (2018), Uzbekistan (2018), Argentina (2019), Algeria (2019), El Salvador (2021), China (2021), Azerbaijan (2023), Tajikistan (2023) and Cabo Verde (2024).

List of countries certified as malaria-free

Malaria elimination refers to the interruption of transmission in a given geographical area – typically a country. Malaria eradication refers to the complete interruption of malaria transmission globally, in all countries.  

More information on malaria eradication

Malaria Prevention, Treatment, and Control Strategies

Malaria is a difficult disease to control largely due to the highly adaptable nature of the vector and parasites involved. While effective tools have been and will continue to be developed to combat malaria, inevitably, over time the parasites and mosquitoes will evolve means to circumvent those tools if used in isolation or used ineffectively. To achieve sustainable control over malaria, healthcare professionals will need a combination of new approaches and tools, and research will play a critical role in development of those next-generation strategies.

Special Populations

Malaria has a significant impact on the health of infants, young children, and pregnant women worldwide. More than 800,000 African children under the age of five die of malaria each year. Malaria also contributes to malnutrition in children, which indirectly causes the death of half of all children under the age of five throughout the world. Fifty million pregnant women throughout the world are exposed to malaria each year. In malaria-endemic regions, one-fourth of all cases of severe maternal anemia and 20 percent of all low-birthweight babies are linked to malaria. Scientists are working to better understand how malaria uniquely affects children and pregnant women and to develop new research tools, methods, and products appropriate for these populations.

Vaccine Development

The development of a safe and effective vaccine against malaria will be critical in malaria control, prevention, and eradication efforts. Currently, no licensed vaccine against malaria (or any parasitic disease that afflicts humans) exists. The complexity of the  Plasmodium  parasite and the lack of understanding of critical processes, such as host immune protection and disease pathogenesis, have hampered vaccine development efforts.

NIAID supports a broad research program to encourage vaccine development. Several candidate vaccines that target various life cycle stages of the malaria parasite are in development. In addition, NIAID is exploring novel vaccine strategies, such as transmission-blocking vaccines, which work by blocking transmission of the malaria parasite to the mosquito vector.

Drug Development

Antimalarial drugs, in combination with mosquito control programs, have historically played a key role in controlling malaria in endemic areas, resulting in significant reduction of the geographic range of malarial disease worldwide. Over the years, however, the emergence and spread of drug-resistant parasites has contributed to a reemergence of malaria, turning back the clock on control efforts. The need for new, effective drugs for malaria has become a critical priority on the global malaria research agenda.

NIAID-supported researchers are seeking to understand the molecular biology of the  Plasmodium  parasite and how it interacts with its human host at each stage in that cycle. Using that information, scientists hope to develop new drugs that block different molecular processes required for parasite survival and identify the mechanisms of emerging drug resistance.

Diagnostics

New and improved diagnostics are essential for the effective control of malaria. Currently, the most reliable technique for diagnosing malaria is, as it was throughout the last century, labor-intensive, relying on highly trained technicians using microscopes to analyze blood smears. Such microscopic analysis is time-consuming, variable in quality, difficult to use in resource-poor field settings, and cannot detect drug resistance. Therefore, NIAID supports research to develop easy-to-use tests that diagnose the malaria parasite causing an infection and identify its drug resistance profile.

Vector Management Approaches

Vector management tools such as insecticides, environmental modification, and bed nets have contributed greatly to successful malaria control efforts historically, but have faced setbacks in recent years due to factors such as the emergence of insecticide resistance in mosquitoes. NIAID is supporting research on new vector management strategies to prevent parasite transmission (from humans to mosquitoes and mosquitoes to humans) and reduce the mosquito population.

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An Essay on Malaria and Its Consequences

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Malaria: Obstacles and Opportunities (1991)

Chapter: 1. conclusions and recommendations, conclusions and recommendations, defining the problem.

The outlook for malaria control is grim. The disease, caused by mosquito-borne parasites, is present in 102 countries and is responsible for over 100 million clinical cases and 1 to 2 million deaths each year. Over the past two decades, efforts to control malaria have met with less and less success. In many regions where malaria transmission had been almost eliminated, the disease has made a comeback, sometimes surpassing earlier recorded levels. The dream of completely eliminating malaria from many parts of the world, pursued with vigor during the 1950s and 1960s, has gradually faded. Few believe today that a global eradication of malaria will be possible in the foreseeable future.

Worldwide, the number of cases of malaria caused by Plasmodium falciparum , the most dangerous species of the parasite, is on the rise. Drug-resistant strains of P. falciparum are spreading rapidly, and there have been recent reports of drug resistance in people infected with P. vivax , a less virulent form of the parasite. Furthermore, mosquitoes are becoming increasingly resistant to insecticides, and in many cases, have adapted so as to avoid insecticide-treated surfaces altogether.

In large part because of the spread of drug and insecticide resistance, there are fewer tools available today to control malaria than there were 20 years ago. In many countries, the few remaining methods are often ap-

plied inappropriately. The situation in many African nations is particularly dismal, exacerbated by a crumbling health infrastructure that has made the implementation of any disease control program difficult.

Malaria cases among tourists, business travelers, military personnel, and migrant workers in malarious areas have been increasing steadily in the last several years, posing new concerns that the disease will be introduced to currently nonmalarious areas. Recent epidemics have claimed tens of thousands of lives in Africa, and there is an increasing realization that malaria is a major impediment to socioeconomic development in many countries. Unless practical, cost-effective strategies can be developed and successfully implemented, malaria will continue to exact a heavy toll on human life and health around the world.

Although often considered a single disease, malaria is more accurately viewed as many diseases, each shaped by subtle interactions of biologic, ecologic, social, and economic factors. The species of parasite, the behavior of the mosquito host, the individual's immune status, the climate, human activities, and access to health services all play important roles in determining the intensity of disease transmission, who will become infected, who will get sick, and who will die.

Gem miners along the Thailand-Cambodia border, American tourists on a wildlife safari in East Africa, villagers living on the central highlands in Madagascar, residents of San Diego County, California, a young pregnant woman in Malawi, Swiss citizens living near Geneva International Airport, children in Africa south of the Sahara, and a U.S. State Department secretary in Tanzania seem to have little in common, yet they are all at risk of contracting malaria. Because of the disease's variable presentations, each will be affected differently, as illustrated below.

For the hundreds of thousands of Thai seasonal agricultural workers who travel deep into the forest along the Thailand-Cambodia border to mine for gems, malaria is the cost of doing business. These young men are exposed to aggressive forest mosquitoes, and within two to three weeks after arriving, almost every miner will get malaria. Many gem miners seek medications to prevent and self-treat mild cases of the disease. But because malaria in this part of the world is resistant to most antimalarial drugs, the few effective drugs are reserved for the treatment of confirmed cases of malaria. To complicate matters, there are no health services in the forest to treat patients, and the health clinics in Thailand are overburdened by the high demand for treating those with severe malaria, most of whom are returning gem miners. A similar scenario involving over 400,000 people exists among gold miners in Rondonia, Brazil.

Each year, over seven million U.S. citizens visit parts of the world

where malaria is present. Many, at the recommendation of their travel agent or physician, take antimalarial medications as a preventive measure, but a significant number do not. Tourists and other travelers who have never been exposed to malaria, and therefore have never developed protective immunity, are at great risk for contracting severe disease. Ironically, it is not the infection itself that poses the biggest danger, but the chance that treatment will be delayed because of misdiagnosis upon the individual's return to the United States. Most U.S. doctors have never seen a patient with malaria, are often confused by the wide array of symptoms, and are largely unaware that malaria in a nonimmune person can be a medical emergency, sometimes rapidly fatal.

Prior to 1950, malaria was the major cause of death in the central highlands of the African island nation of Madagascar. In the late 1950s, an aggressive program of indoor insecticide spraying rid the area of malaria-carrying mosquitoes, and malaria virtually disappeared. By the 1970s, confident of a victory in the battle against malaria, Madagascar began to phase out its spraying program; in some areas spraying was halted altogether. In the early 1980s, the vector mosquitoes reinvaded the central highlands, and in 1986 a series of devastating epidemics began. The older members of the population had long since lost the partial immunity they once had, and the younger island residents had no immunity at all. During the worst of the epidemics, tens of thousands of people died in one three-month period. The tragedy of this story is that it could have been prevented. A cheap antimalarial drug, chloroquine, could have been a powerful weapon in Madagascar, where drug resistance was not a significant concern. Because of problems in international and domestic drug supply and delivery, however, many people did not receive treatment and many died. In the last 18 months, surveillance has improved, spraying against the mosquito has resumed, and more effective drug distribution networks have been established. Malaria-related mortality has declined sharply as a result.

Malaria, once endemic in the southern United States, occurs relatively infrequently. Indeed, there have been only 23 outbreaks of malaria since 1950, and the majority of these occurred in California. But for each of the past three years, the San Diego County Department of Health Services has had to conduct an epidemiologic investigation into local transmission of malaria. An outbreak in the late summer of 1988 involved 30 persons, the largest such outbreak in the United States since 1952. In the summer of 1989, three residents of San Diego County—a migrant worker and two permanent residents—were diagnosed with malaria; in 1990, a teenager living in a suburb of San Diego County fell ill with malaria. All of the cases were treated successfully, but these incidents raise questions about the possibility of new and larger outbreaks in the future. Malaria

transmission in San Diego County (and in much of California) is attributed to the presence of individuals from malaria-endemic regions who lack access to medical care, the poor shelter and sanitation facilities of migrant workers, and the ubiquitous presence of Anopheles mosquitoes in California.

A 24-year-old pregnant Yao woman from the Mangochi District in Malawi visited the village health clinic monthly to receive prenatal care. While waiting to be seen by the health provider, she and other women present listened to health education talks which were often about the dangers of malaria during pregnancy, and the need to install screens around the house to keep the mosquitoes away, to sleep under a bednet, and to take a chloroquine tablet once a week. Toward the end of her second trimester of pregnancy, the woman returned home from her prenatal visit with her eight tablets of chloroquine wrapped in a small packet of brown paper. She promptly gave the medicine to her husband to save for the next time he or one of their children fell ill. The next week she developed a very high malarial fever and went into labor prematurely. The six-month-old fetus was born dead.

Over a two-week period in the summer of 1989, five Swiss citizens living within a mile of Geneva International Airport presented at several hospitals with acute fever and chills. All had malaria. Four of the five had no history of travel to a malarious region; none had a history of intravenous drug use or blood transfusion. Apart from their symptoms, the only thing linking the five was their proximity to the airport. A subsequent epidemiologic investigation suggested that the malaria miniepidemic was caused by the bite of stowaway mosquitoes en route from a malaria-endemic country. The warm weather, lack of systematic spraying of aircraft, and the close proximity of residential areas to the airport facilitated the transmission of the disease.

Malaria is a part of everyday life in Africa south of the Sahara. Its impact on children is particularly severe. Mothers who bring unconscious children to the hospital often report that the children were playing that morning, convulsed suddenly, and have been unconscious ever since. These children are suffering from the most frequently fatal complication of the disease, cerebral malaria. Other children succumb more slowly to malaria, becoming progressively more anemic with each subsequent infection. By the time they reach the hospital, they are too weak to sit and are literally gasping for breath. Many children are brought to hospitals as a last resort, after treatment given for “fever” at the local health center has proved ineffective. Overall, children with malaria account for a third of all hospital admissions. A third of all children hospitalized for malaria die. In most parts of Africa, there are no effective or affordable options to prevent the

disease, so children are at high risk until they have been infected enough times to develop a partial immunity.

A 52-year-old American woman, the secretary to the U.S. ambassador in Tanzania, had been taking a weekly dose of chloroquine to prevent malaria since her arrival in the country the year before. She arrived at work one morning complaining of exhaustion, a throbbing headache, and fever. A blood sample was taken and microscopically examined for malaria parasites. She was found to be infected with P. falciparum , and was treated immediately with high doses of chloroquine. That night, she developed severe diarrhea, and by morning she was found to be disoriented and irrational. She was diagnosed as having cerebral malaria, and intravenous quinine treatment was started. Her condition gradually deteriorated—she became semicomatose and anemic, and approximately 20 percent of her red blood cells were found to be infected with malaria parasites. After continued treatment for several days, no parasites were detected in her blood. Despite receiving optimal care, other malaria-related complications developed and she died just nine days after the illness began. The cause of death: chloroquine-resistant P. falciparum .

These brief scenarios give a sense of the diverse ways that malaria can affect people. So fundamental is this diversity with respect to impact, manifestation, and epidemiology that malaria experts themselves are not unanimous on how best to approach the disease. Malariologists recognize that malaria is essentially a local phenomenon that varies greatly from region to region and even from village to village in the same district. Consequently, a single global technology for malaria control is of little use for specific conditions, yet the task of tailoring strategies to each situation is daunting. More important, many malarious countries do not have the resources, either human or financial, to carry out even the most meager efforts to control malaria.

These scenarios also illustrate the dual nature of malaria as it affects U.S. policy. In one sense, it is a foreign aid issue; a devastating disease is currently raging out of control in vast, heavily populated areas of the world. In another sense, malaria is of domestic public health concern. The decay of global malaria control and the invasion of the parasite into previously disease-free areas, coupled with the increasing frequency of visits to such areas by American citizens, intensify the dangers of malaria for the U.S. population. Tourists, business travelers, Peace Corps volunteers, State Department employees, and military personnel are increasingly at risk, and our ability to protect and cure them is in jeopardy. What is desperately needed is a better application of existing malaria control tools and new methods of containing the disease.

In most malarious regions of the world, there is inadequate access to malaria treatment. Appropriate health facilities may not exist; those that do exist may be inaccessible to affected populations, may not be supplied with effective drugs, or may be staffed inappropriately. In many countries, the expansion of primary health care services has not proceeded according to expectations, particularly in the poorest (and most malarious) nations of the tropical world.

In some countries, antimalarial interventions are applied in broad swaths, without regard to underlying differences in the epidemiology of the disease. In other countries, there are no organized interventions at all. The malaria problem in many regions is compounded by migration, civil unrest, poorly planned exploitation of natural resources, and their frequent correlate, poverty.

During the past 15 years, much research has focused on developing vaccines for malaria. Malaria vaccines are thought to be possible in part because people who are naturally exposed to the malaria parasite acquire a partial immunity to the disease over time. In addition, immunization of animals and humans by the bites of irradiated mosquitoes infected with the malaria parasite can protect against malaria infection. Much progress has been made, but current data suggest that effective vaccines are not likely to be available for some time.

Compounding the difficulty of developing more effective malaria prevention, treatment, and control strategies is a worldwide decline in the pool of scientists and health professionals capable of conducting field research and organizing and managing malaria control programs at the country level. With the change in approach from malaria eradication to malaria control, many malaria programs “lost face,” admitting failure and losing the priority interest of their respective ministries of health. As external funding agencies lost interest in programs, they reduced their technical and financial support. As a consequence, there were fewer training opportunities, decreased contacts with international experts, and diminished prospects for improving the situation. Today, many young scientists and public health specialists, in both the developed and developing countries, prefer to seek higher-profile activities with better defined opportunities for career advancement.

It is against this backdrop of a worsening worldwide malaria situation that the Institute of Medicine was asked to convene a multidisciplinary committee to assess the current status of malaria research and control and to make recommen-

dations to the U.S. government on promising and feasible strategies to address the problem. During the 18-month study, the committee reviewed the state of the science in the major areas of malariology, identified gaps in knowledge within each of the major disciplines, and developed recommendations for future action in malaria research and control.

Organization

Chapter 2 summarizes key aspects of the individual state-of-the-science chapters, and is intended to serve as a basic introduction to the medical and scientific aspects of malaria, including its clinical signs, diagnosis, treatment, and control. Chapter 3 provides a historical overview of malaria, from roughly 3000 B.C. to the present, with special emphasis on efforts in this century to eradicate and control the disease. The state-of-the-science reviews, which start in Chapter 4 , begin with a scenario titled “Where We Want To Be in the Year 2010.” Each scenario describes where the discipline would like to be in 20 years and how, given an ideal world, the discipline would have contributed to malaria control efforts. The middle section of each chapter contains a critical review of the current status of knowledge in the particular field. The final section lays out specific directions for future research based on a clear identification of the major gaps in scientific understanding for that discipline. The committee urges those agencies that fund malaria research to consult the end of each state-of-the-science chapter for suggestions on specific research opportunities in malaria.

Sponsorship

This study was sponsored by the U.S. Agency for International Development, the U.S. Army Medical Research and Development Command, and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

CONCLUSIONS AND RECOMMENDATIONS

A major finding of the committee is the need to increase donor and public awareness of the growing risk presented by the resurgence of malaria. Overall, funding levels are not adequate to meet the problem. The committee believes that funding in the past focused too sharply on specific technologies and particular control strategies (e.g., indiscriminate use of insecticide spraying). Future support must be balanced among the needs outlined in this report. The issue for prioritization is not whether to select specific technologies or control strategies, but to raise the priority for solv-

ing the problem of malaria. This is best done by encouraging balanced research and control strategies and developing a mechanism for periodically adjusting support for promising approaches.

This report highlights those areas which the committee believes deserve the highest priority for research or which should be considered when U.S. support is provided to malaria control programs. These observations and suggestions for future action, presented below in four sections discussing policy, research, control, and training, represent the views of a multidisciplinary group of professionals from diverse backgrounds and with a variety of perspectives on the problem.

The U.S. government is the largest single source of funds for malaria research and control activities in the world. This investment is justified by the magnitude of the malaria problem, from both a foreign aid and a public health perspective. The increasing severity of the threat of malaria to residents of endemic regions, travelers, and military personnel, and our diminishing ability to counter it, should be addressed by a more comprehensive and better integrated approach to malaria research and control. However, overall U.S. support for malaria research and control has declined over the past five years. The committee believes that the amount of funding currently directed to malaria research and control activities is inadequate to address the problem.

Over the past 10 years, the majority of U.S. funds available for malaria research have been devoted to studies on immunity and vaccine development. Although the promise of vaccines remains to be realized, the committee believes that the potential benefits are enormous. At the same time, the relative paucity of funds available for research has prevented or slowed progress in other areas. Our incomplete knowledge about the basic biology of malaria parasites, how they interact with their mosquito and human hosts, and how human biology and behavior affect malaria transmission and control remains a serious impediment to the development and implementation of malaria control strategies. The committee believes that this situation must be addressed without reducing commitment to current research initiatives. The committee further believes that such research will pay long-term dividends in the better application of existing tools and the development of new drugs, vaccines, and methods for vector control.

The committee recommends that increased funds be made available so that U.S. research on malaria can be broadened according to the priorities addressed in this report, including laboratory and field research on the biology of malaria parasites, their mosquito vectors, and their interaction with humans.

The committee believes that the maximum return on investment of funds devoted to malaria research and control can be achieved only by rigorous review of project proposals. The committee further believes that the highest-quality review is essential to ensure that funding agencies spend their money wisely. The committee believes that all U.S.-supported malaria field activities, both research and control, should be of the highest scientific quality and relevance to the goals of malaria control.

The committee recommends decisions on funding of malaria research be based on scientific merit as determined by rigorous peer review, consistent with the guidelines of the National Institutes of Health or the United Nations Development Program/World Bank/ World Health Organization Special Programme for Research and Training in Tropical Diseases, and that all U.S.-supported malaria field projects be subject to similar rigorous review to ensure that projects are epidemiologically and scientifically sound.

Commitment and Sustainability

For malaria control, short-term interventions can be expected to produce only short-term results. The committee believes that short-term interventions are justified only for emergency situations. Longer-term interventions should be undertaken only when there is a national commitment to support sustained malaria surveillance and control.

The committee recommends that malaria control programs receive sustained international and local support, oriented toward the development of human resources, the improvement of management skills, the provision of supplies, and the integration of an operational research capability in support of an epidemiologically sound approach to malaria control.

Surveillance

During the major effort to eradicate malaria from many parts of the world that began in the late 1950s and ended in 1969, it was important to establish mechanisms to detect all malaria infections. As a result, systems were established in many countries to collect blood samples for later microscopic examination for the presence of parasites. Each year, the results from more than 140 million slides are reported to the World Health Organization, of which roughly 3 to 5 percent are positive for malaria. This approach seeks to answer the question posed 30 years ago: How many people are infected with the malaria parasite? It does not answer today's questions: Who is sick? Where? Why? The committee concludes that the mass collection of blood slides requires considerable resources, poses seri-

ous biosafety hazards, deflects attention from the treatment of ill individuals, and has little practical relevance for malaria control efforts today.

Instead of the mass collection of slides, the committee believes that the most effective surveillance networks are those that concurrently measure disease in human populations, antimalarial drug use, patterns of drug resistance, and the intensity of malaria transmission by vector populations. The committee believes that malaria surveillance practices have not received adequate recognition as an epidemiologic tool for designing, implementing, and evaluating malaria control programs.

The committee recommends that countries be given support to orient malaria surveillance away from the mass collection and screening of blood slides toward the collection and analysis of epidemiologically relevant information that can be used to monitor the current situation on an ongoing basis, to identify high-risk groups, and to detect potential epidemics early in their course.

Inter-Sectoral Cooperation

The committee believes that insufficient attention has been paid to the impact that activities in non-health-related sectors, such as construction, industry, irrigation, and agriculture, have on malaria transmission. Conversely, there are few assessments of the impact of malaria control projects on other public health initiatives, the environment, and the socioeconomic status of affected populations. Malaria transmission frequently occurs in areas where private and multinational businesses and corporations (e.g., hotel chains, mining operations, and industrial plants) have strong economic interests. Unfortunately and irresponsibly, some local and multinational businesses contribute few if any resources to malaria control in areas in which they operate.

The committee recommends greater cooperation and consultation between health and nonhealth sectors in the planning and implementation of major development projects and malaria activities. It also recommends that all proposed malaria control programs be analyzed for their potential impact on other public health programs, the environment, and social and economic welfare, and that local and multinational businesses be recruited by malaria control organizations to contribute substantially to local malaria control efforts.

New Tools for Malaria Control

The committee believes that, as a policy directive, it is important to support research activities to develop new tools for malaria control. The

greatest momentum for the development of new tools exists in vaccine and drug development, and the committee believes it essential that this momentum be maintained. The committee recognizes that commendable progress has been made in defining the characteristics of antigens and delivery systems needed for effective vaccines, but that the candidates so far tested fall short of the goal. Much has been learned which supports the hope that useful vaccines can be developed. To diminish activity in vaccine development at this stage would deal a severe blow to one of our best chances for a technological breakthrough in malaria control.

The committee recommends that vaccine development continue to be a priority of U.S.-funded malaria research.

Only a handful of drugs are available to prevent or treat malaria, and the spread of drug-resistant strains of the malaria parasite threatens to reduce further the limited pool of effective drugs. The committee recognizes that there is little economic incentive for U.S. pharmaceutical companies to undertake antimalarial drug discovery activities. The committee is concerned that U.S. government support of these activities, based almost entirely at the Walter Reed Army Institute of Research (WRAIR), has decreased and is threatened with further funding cuts. The committee concludes that the WRAIR program in antimalarial drug discovery, which is the largest and most successful in the world, is crucial to international efforts to develop new drugs for malaria. The benefits of this program in terms of worldwide prevention and treatment of malaria have been incalculable.

The committee strongly recommends that drug discovery and development activities at WRAIR receive increased and sustained support.

The next recommendation on policy directions reflects the committee 's concern about the lack of involvement in malaria research by the private sector. The committee believes that the production of candidate malaria vaccines and antimalarial drugs for clinical trials has been hampered by a lack of industry involvement. Greater cooperation and a clarification of the contractual relationships between the public and private sectors would greatly enhance the development of drugs and vaccines.

The committee recommends that mechanisms be established to promote the involvement of pharmaceutical and biotechnology firms in the development of malaria vaccines, antimalarial drugs, and new tools for vector control.

Coordination and Integration

The committee is concerned that there is inadequate joint planning and coordination among U.S.-based agencies that support malaria research and

control activities. Four government agencies and many nongovernmental organizations in the United States are actively involved in malaria-related activities. There are also numerous overseas organizations, governmental and nongovernmental, that actively support such activities worldwide.

The complexity and variability of malaria, the actual and potential scientific advances in several areas of malariology, and most important the worsening worldwide situation argue strongly for an ongoing mechanism to assess and influence current and future U.S. efforts in malaria research and control.

The committee strongly recommends the establishment of a national advisory body on malaria.

In addition to fulfilling a much needed coordinating function among U.S.-based agencies and between the U.S. and international efforts, the national advisory body could monitor the status of U.S. involvement in malaria research and control, assess the relevant application of knowledge, identify areas requiring further research, make recommendations to the major funding agencies, and provide a resource for legislators and others interested in scientific policy related to malaria. The national advisory body could convene specific task-oriented scientific working groups to review research and control activities and to make recommendations, when appropriate, for changes in priorities and new initiatives.

The committee believes that the national advisory body should be part of, and appointed by, a neutral and nationally respected scientific body and that it should actively encourage the participation of governmental and nongovernmental organizations, industry, and university scientists in advising on the direction of U.S. involvement in malaria research and control.

The increasing magnitude of the malaria problem during the past decade and the unpredictability of changes in human, parasite, and vector determinants of transmission and disease point strongly to the need for such a national advisory body, which can be responsive to rapidly changing problems, and advances in scientific research, relating to global efforts to control malaria.

Malaria Research Priorities

Malaria control is in crisis in many areas of the world. People are contracting and dying of severe malaria in unprecedented numbers. To address these problems, the committee strongly encourages a balanced research agenda. Two basic areas of research require high priority. Research that will lead to improved delivery of existing interventions for malaria, and the development of new tools for the control of malaria.

Research in Support of Available Control Measures

Risk Factors for Severe Malaria People who develop severe and complicated malaria lack adequate immunity, and many die from the disease. Groups at greatest risk include young children and pregnant women in malaria endemic regions; nonimmune migrants, laborers, and visitors to endemic regions; and residents of regions where malaria has been recently reintroduced. For reasons that are largely unknown, not all individuals within these groups appear to be at equal risk for severe disease. The committee believes that the determinants of severe disease, including risk factors associated with a population, the individual (biologic, immunologic, socioeconomic, and behavioral), the parasite, or exposure to mosquitoes, are likely to vary considerably in different areas.

The committee recommends that epidemiologic studies on the risk factors for severe and complicated malaria be supported.

Pathogenesis of Severe and Complicated Malaria Even with optimal care, 20 to 30 percent of children and adults with the most severe form of malaria—primarily cerebral malaria—die. The committee believes that a better understanding of the disease process will lead to improvements in preventing and treating severe forms of malaria. The committee further believes that determining the indications for treatment of severe malarial anemia is of special urgency given the risk of transmitting the AIDS virus through blood transfusions, the only currently available treatment for malarial anemia. Physicians need to know when it is appropriate to transfuse malaria patients.

The committee recommends greater support for research on the pathogenesis of severe and complicated malaria, on the mechanisms of malarial anemia, and on the development of specific criteria for blood transfusions in malaria.

Social Science Research The impact of drugs to control disease or programs to reduce human-mosquito contact is mediated by local practices and beliefs about malaria and its treatment. Most people in malaria-endemic countries seek initial treatment for malaria outside of the formal health sector. Programs that attempt to influence this behavior must understand that current practices satisfy, at some level, local concerns regarding such matters as access to and effectiveness of therapy, and cost. These concerns may lead to practices at odds with current medical practice. Further, many malaria control programs have not considered the social, cultural, and behavioral dimensions of malaria, thereby limiting the effectiveness of measures undertaken. The committee recognizes that control programs often fail to incorporate household or community concerns and resources

into program design. In most countries, little is known about how the demand for and utilization of health services is influenced by such things as user fees, location of health clinics, and the existence and quality of referral services. The committee concludes that modern social science techniques have not been effectively applied to the design, implementation, and evaluation of malaria control programs.

The committee recommends that research be conducted on local perceptions of malaria as an illness, health-seeking behaviors (including the demand for health care services), and behaviors that affect malaria transmission, and that the results of this research be included in community-based malaria control interventions that promote the involvement of communities and their organizations in control efforts.

Innovative Approaches to Malaria Control Malaria control programs will require new ideas and approaches, and new malaria control strategies need to be developed and tested. There is also a need for consistent support of innovative combinations of control technologies and for the transfer of new technologies from the laboratory to the clinic and field for expeditious evaluation. Successful technology transfer requires the exchange of scientific research, but more importantly, must be prefaced by an improved understanding of the optimal means to deliver the technology to the people in need (see Chapter 11 ).

The committee recommends that donor agencies provide support for research on new or improved control strategies and into how new tools and technologies can be better implemented and integrated into on-going control efforts.

Development of New Tools

Antimalarial Immunity and Vaccine Development Many people are able to mount an effective immune response that can significantly mitigate symptoms of malaria and prevent death. The committee believes that the development of effective malaria vaccines is feasible, and that the potential benefits of such vaccines are enormous. Several different types of malaria vaccines need to be developed: vaccines to prevent infection (of particular use for tourists and other nonimmune visitors to endemic countries), prevent the progression of infection to disease (for partially immune residents living in endemic areas and for nonimmune visitors), and interrupt transmission of parasites by vector populations (to reduce the risk of new infections in humans). The committee believes that each of these directions should be pursued.

The committee recommends sustained support for research to identify mechanisms and targets of protective immunity and to exploit the

use of novel scientific technologies to construct vaccines that induce immunity against all relevant stages of the parasite life cycle.

Drug Discovery and Development Few drugs are available to prevent or treat malaria, and the spread of drug-resistant strains of malaria parasites is steadily reducing the limited pool of effective chemotherapeutic agents. The committee believes that an inadequate understanding of parasite biochemistry and biology impedes the process of drug discovery and slows studies on the mechanisms of drug resistance.

The committee recommends increased emphasis on screening compounds to identify new classes of potential antimalarial drugs, identifying and characterizing vulnerable targets within the parasite, understanding the mechanisms of drug resistance, and identifying and developing agents that can restore the therapeutic efficacy of currently available drugs.

Vector Control Malaria is transmitted to humans by the bites of infective mosquitoes. The objective of vector control is to reduce the contact between humans and infected mosquitoes. The committee believes that developments are needed in the areas of personal protection, environmental management, pesticide use and application, and biologic control, as well as in the largely unexplored areas of immunologic and genetic approaches for decreasing parasite transmission by vectors.

The committee recommends increased support for research on vector control that focuses on the development and field testing of methods for interrupting parasite transmission by vectors.

Malaria Control

Malaria is a complex disease that, even under the most optimistic scenario, will continue to be a major health threat for decades. The extent to which malaria affects human health depends on a large number of epidemiologic and ecologic factors. Depending on the particular combination of these and other variables, malaria may have different effects on neighboring villages and people living in a single village. All malaria control programs need to be designed with a view toward effectiveness and sustainability, taking into account the local perceptions, the availability of human and financial resources, and the multiple needs of the communities at risk. If community support for health sector initiatives is to be guaranteed, the public needs to know much more about malaria, its risks for epidemics and severe disease, and difficulties in control.

Unfortunately, there is no “magic bullet” solution to the deteriorating worldwide malaria situation, and no single malaria control strategy will be applicable in all regions or epidemiologic situations. Given the limited available financial and human resources and a dwindling pool of effective

antimalarial tools, the committee suggests that donor agencies support four priority areas for malaria control in endemic countries.

The committee believes that the first and most basic priority in malaria control is to prevent infected individuals from becoming severely ill and dying. Reducing the incidence of severe morbidity and malaria-related mortality requires a two-pronged approach. First, diagnostic, treatment, and referral capabilities, including the provision of microscopes, training of technicians and other health providers, and drug supply, must be enhanced. Second, the committee believes that many malaria-related deaths could be averted if individuals and caretakers of young children knew when and how to seek appropriate treatment and if drug vendors, pharmacists, physicians, nurses, and other health care providers were provided with up-to-date and locally appropriate treatment and referral guidelines. The development and implementation of an efficient information system that provides rapid feedback to the originating clinic and area is key to monitoring the situation and preventing epidemics.

The committee believes that the second priority should be to promote personal protection measures (e.g., bednets, screens, and mosquito coils) to reduce or eliminate human-mosquito contact and thus to reduce the risk of infection for individuals living in endemic areas. At the present time, insecticide-treated bednets appear to be the most promising personal protection method.

In many environments, in addition to the treatment of individuals and use of personal protection measures, community-wide vector control is feasible. In such situations, the committee believes that the third priority should be low-cost vector control measures designed to reduce the prevalence of infective mosquitoes in the environment, thus reducing the transmission of malaria to populations. These measures include source reduction (e.g., draining or filling in small bodies of water where mosquito larvae develop) or the application of low-cost larval control measures. In certain environments, the use of insecticide-impregnated bednets by all or most members of a community may also reduce malaria transmission, but this approach to community-based malaria control remains experimental.

The committee believes that the fourth priority for malaria control should be higher cost vector control measures such as large-scale source reduction or widespread spraying of residual insecticides. In certain epidemiologic situations, the use of insecticides for adult mosquito control is appropriate and represents the method of choice for decreasing malaria transmission and preventing epidemics (see Chapter 7 and Chapter 10 ).

The committee recommends that support of malaria control programs include resources to improve local capacities to conduct prompt diagnosis, including both training and equipment, and to ensure the availability of antimalarial drugs.

The committee recommends that resources be allocated to develop and disseminate malaria treatment guidelines for physicians, drug vendors, pharmacists, village health workers, and other health care personnel in endemic and non-endemic countries. The guidelines should be based, where appropriate, on the results of local operational research and should include information on the management of severe and complicated disease. The guidelines should be consistent and compatible among international agencies involved in the control of malaria.

The committee recommends that support for malaria control initiatives include funds to develop and implement locally relevant communication programs that provide information about how to prevent and treat malaria appropriately (including when and how to seek treatment) and that foster a dialogue about prevention and control.

Organization of Malaria Control

One of the major criticisms of malaria control programs during the past 10 to 15 years has been that funds have been spent inappropriately without an integrated plan and without formal evaluation of the efficacy of control measures instituted. In many instances, this has led to diminished efforts to control malaria.

The committee strongly encourages renewed commitment by donor agencies to support national control programs in malaria-endemic countries.

The committee recommends that U.S. donor agencies develop, with the advice of the national advisory body, a core of expertise (either in-house or through an external advisory group) to plan assistance to malaria control activities in endemic countries.

The committee believes that the development, implementation, and evaluation of such programs must follow a rigorous set of guidelines. These guidelines should include the following steps:

Identification of the problem

Determine the extent and variety of malaria. The paradigm approach described in Chapter 10 should facilitate this step.

Analyze current efforts to solve malaria problems.

Identify and characterize available in-country resources and capabilities.

Development of a plan

Design and prioritize interventions based on the epidemiologic situation and the available resources.

Design a training program for decision makers, managers, and technical staff to support and sustain the interventions.

Define specific indicators of the success or failure of the interventions at specific time points.

Develop a specific plan for reporting on the outcomes of interventions.

Develop a process for adjusting the program in response to successes and/or failures of interventions.

Review of the comprehensive plan by a donor agency review board

Modification of the plan based on comments of the review board

Implementation of the program

Yearly report and analysis of outcome variables

To guide the implementation of the activities outlined above, the committee has provided specific advice on several components, including an approach to evaluating malaria problems and designing control strategies (the paradigm approach), program management, monitoring and evaluation, and operational research.

Paradigm Approach

Given the complex and variable nature of malaria, the committee believes that the epidemiologic paradigms (see Chapter 10 ), developed in conjunction with this study, may form the basis of a logical and reasoned approach for defining the malaria problems and improving the design and management of malaria control programs.

The committee recommends that the paradigm approach be field tested to determine its use in helping policymakers and malaria program managers design and implement epidemiologically appropriate and cost-effective control initiatives.

The committee recognizes that various factors, including the local ecology, the dynamics of mosquito transmission of malaria parasites, genetically determined resistance to malaria infection, and patterns of drug use, affect patterns of malaria endemicity in human populations and need to be considered when malaria control strategies are developed. In most endemic countries, efforts to understand malaria transmission through field studies of vector populations are either nonexistent or so limited in scope that they have minimal impact on subsequent malaria control efforts. The committee recognizes that current approaches to malaria control are clearly inadequate. The committee believes, however, that malaria control strategies are sometimes applied inappropriately, with little regard to the underlying differences in the epidemiology of the disease.

The committee recommends that support for malaria control programs include funds to permit a reassessment and optimization of antimalarial tools based on relevant analyses of local epidemiologic, parasitologic, entomologic, socioeconomic, and behavioral determinants of malaria and the costs of malaria control.

Poor management has contributed to the failure of many malaria control programs. Among the reasons are a chronic shortage of trained managers who can think innovatively about health care delivery and who can plan, implement, supervise, and evaluate malaria control programs. Lack of incentives, the absence of career advancement options, and designation of responsibility without authority often hinder the effectiveness of the small cadre of professional managers that does exist. The committee recognizes that management technology is a valuable resource that has yet to be effectively introduced into the planning, implementation, and evaluation of most malaria control programs.

The committee recommends that funding agencies utilize management experts to develop a comprehensive series of recommendations and guidelines as to how basic management skills and technology can be introduced into the planning, implementation, and evaluation of malaria control programs.

The committee recommends that U.S. funding of each malaria control program include support for a senior manager who has responsibility for planning and coordinating malaria control activities. Where such an individual does not exist, a priority of the control effort should be to identify and support a qualified candidate. The manager should be supported actively by a multidisciplinary core group with expertise in epidemiology, entomology, the social sciences, clinical medicine, environmental issues, and vector control operations.

Monitoring and Evaluation

Monitoring and evaluation are essential components of any control program. For malaria control, it is not acceptable to continue pursuing a specific control strategy without clear evidence that it is effective and reaching established objectives.

The committee recommends that support for malaria control programs include funds to evaluate the impact of control efforts on the magnitude of the problem and that each program be modified as necessary on the basis of periodic assessments of its costs and effectiveness.

Problem Solving (Operational Research) and Evaluation

At the outset of any malaria prevention or control initiative and during the course of implementation, gaps in knowledge will be identified and problems will arise. These matters should be addressed through clearly defined, short-term, focused studies. Perhaps the most difficult aspects of operational research are to identify the relevant problem, formulate the appropriate question, and design a study to answer that question.

The committee recommends that a problem-solving (operational research) component be built into all existing and future U.S.-funded malaria control initiatives and that support be given to enhance the capacity to perform such research. This effort will include consistent support in the design of focused projects that can provide applicable results, analysis of data, and dissemination of conclusions.

The committee concludes that there is a need for additional scientists actively involved in malaria-related research in the United States and abroad. To meet this need, both short- and long-term training at the doctoral and postdoctoral levels must be provided. This training will be of little value unless there is adequate long-term research funding to support the career development of professionals in the field of malaria.

The committee recommends support for research training in malaria.

Whereas the curricula for advanced degree training in basic science research and epidemiology are fairly well defined, two areas require attention, especially in the developing world: social sciences and health management and training.

The committee recommends that support be given for the development of advanced-degree curricula in the social sciences, and in health management and training, for use in universities in developing and developed countries.

The availability of well-trained managers, decision makers, and technical staff is critical to the implementation of any malaria prevention and control program. The development of such key personnel requires a long term combination of formal training, focused short courses, and a gradual progression of expertise.

The committee recommends support for training in management, epidemiology, entomology, social sciences, and vector control. Such training for malaria control may be accomplished through U.S.-funded grant programs for long-term cooperative relationships

between institutions in developed and developing countries; through the encouragement of both formal and informal linkages among malaria-endemic countries; through the use of existing training courses; and through the development of specific training courses.

The committee recommends further that malaria endemic countries be supported in the development of personnel programs that provide long-term career tracks for managers, decision makers, and technical staff, and that offer professional fulfillment, security, and competitive financial compensation.

Malaria is making a dramatic comeback in the world. The disease is the foremost health challenge in Africa south of the Sahara, and people traveling to malarious areas are at increased risk of malaria-related sickness and death.

This book examines the prospects for bringing malaria under control, with specific recommendations for U.S. policy, directions for research and program funding, and appropriate roles for federal and international agencies and the medical and public health communities.

The volume reports on the current status of malaria research, prevention, and control efforts worldwide. The authors present study results and commentary on the:

• Nature, clinical manifestations, diagnosis, and epidemiology of malaria.
• Biology of the malaria parasite and its vector.
• Prospects for developing malaria vaccines and improved treatments.
• Economic, social, and behavioral factors in malaria control.

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