Malaria

The theme for World Malaria Day 2024 is “Accelerating the fight against malaria for a more equitable world’’. For this reason, we took the opportunity to review our Infectious Disease R&D Tracker to uncover new vaccines, innovative drugs, cutting-edge diagnostics, and next-generation vector control products in development for malaria. We analyze how the pipeline has evolved since 2015 and explore the technologies that will accelerate the progress for a more equitable fight against malaria.

While progress in reducing malaria cases and deaths has stagnated since 2015, there is optimism fuelled by the growing number of pipeline candidates and the emergence of innovative and promising products and technologies. To advance towards a malaria-free world, research and investment across all product areas are imperative. Critical gaps such as a more effective, widely applicable vaccine that can prevent infections at community level, new antimalarials to combat emerging drug resistance, rapid diagnostic tests (RDTs) that have better performance to the widely used Plasmodium falciparum histidine-rich protein 2 (PfHRP2) antigen-based tests and more safe chemopreventive options for pregnant women underscore the urgency of continued efforts.

Malaria research and innovation: a vital element of the global technical strategy for malaria 2016–2030

Nearly 50% of the world population is at risk of malaria infection. In 2022, there were an estimated 249 million cases and 608 000 deaths globally, with the majority of the burden in sub-Saharan Africa. Children under 5 years accounted for about 80% of all malaria deaths in this region. WHO's Global Technical Strategy for Malaria targets a 90% reduction in global malaria mortality and incidence rates by 2030. Key interventions include maintaining the efficacy of artemisinin-based therapies, developing new non-artemisinin combinations, and vector control tools addressing emerging drug/insecticide resistance and intervention gaps like outdoor biting. They also include enhancing diagnostics for asymptomatic infections and point-of-care G6PD tests.

At least 151 different malaria countermeasures are in development as of December 2023. Vaccines constitute nearly half (43%) of the active pipeline, taking over from drugs (27%), which held a substantial share of over one-third of the pipeline (36%) in 2015. The remaining pipeline is composed of diagnostics (19%), biologics (5%) and vector control products (6%).

Second-generation malaria vaccine

The introduction of malaria vaccines like RTS,S and R21/Matrix-M has demonstrated significant potential in reducing the burden of malaria. RTS,S, rolled out in 2019, has led to a 13% decrease in malaria-associated deaths. Similarly, R21/Matrix-M, recommended by WHO in 2023, reduced clinical malaria cases by 75%, underscoring the substantial impact future vaccines could have.

The malaria vaccine pipeline is not just growing; it's thriving. We now have twice as many candidates in clinical development as in 2015. Even more promising is that these candidates are not just entering clinical development but progressing. We've seen a near double in the number of candidates in phase II compared to 2019. Three-quarters of the candidates target P. falciparum, with less than a fifth target P. vivax. Regarding the life cycle, an almost equal number of candidates target the pre-erythrocytic (39%) and blood stages (38%).

As with the two approved vaccines, over half of the pipeline is based on a sub-unit approach. This approach involves using a specific part of the malaria parasite to stimulate an immune response. Candidates approaching late-stage development use various parasite antigens to target different stages of the parasite's infectious cycle. These include a whole parasite pre-erythrocytic vaccine, along with a vaccine for the blood stage and a transmission-blocking candidate. Two mRNA-based vaccines have recently entered the pipeline, including one in clinical trials. The mRNA platform could potentially develop vaccines targeting multiple malaria parasite stages. 

Impressive strides have been made in malaria vaccine development in the past decade. However, it's crucial to recognize that vaccines with current or similar efficacy profiles are only helpful when used as part of a comprehensive malaria control strategy, which must also include vector control measures. An ideal malaria vaccine would reduce infection and clinical malaria by 90% and block community transmission. To achieve this, it must target multiple stages of the parasite’s lifecycle with the potential to impact transmission. We have made progress and recently approved two malaria vaccines; now, we need to channel efforts into developing the second generation of malaria vaccines that can fulfil these WHO strategic goals.

Next-generation antimalarials: providing radical cure, chemoprevention and fighting drug resistance

Artesunate-based combination therapy (ACT) has significantly decreased malaria-related deaths in the last twenty years. Now, imagine the impact of newer antimalarials that can achieve a single-dose radical cure, mitigate emerging drug resistance, deliver prophylactic effects, and are safe to use during pregnancy. The most promising solution to tackle emerging drug resistance is a novel non-artemisinin combination therapy. However, it will take some years, with ongoing phase III trials projected for completion by 2027. Achieving a single-dose cure will hinge on a candidate with a long half-life and those being explored for this indication are still undergoing safety studies. The next-generation antimalarials in the pipeline hold immense promise in our fight against drug resistance, giving us hope for a future where malaria is no longer a major global health threat.

Currently, 48 antimalarials, including 41 small molecules and seven biologics, are in development. The vast majority (88%) of the small molecules are new chemical entities, and over four-fifths (88%) of these new compounds have the potential to cure multiple plasmodium species and most (27%) of the remaining target plasmodium falciparum. The biologics pipeline continues to expand, with seven monoclonal antibody (mAbs) candidates currently in active development. Leading the pack are two phase II candidates based on the PfCSP antigen, but more than half of the mAb candidates (four) target the circumsporozoite protein.

Vector control products: genetically modified mosquitoes, dual-action insecticide-treated nets and more

Before the wider programmatic use of seasonal chemoprophylaxis and the more recent introduction of the malaria vaccine, vector control in the form of insecticide-treated nets (ITNs) and indoor residual spray (IRS) was, for a long time, the only arsenal for controlling malaria. The impact of introducing vector control products in the various malaria control programs worldwide has been phenomenal. In Africa, an estimated 663 million malaria cases were averted between 2000 and 2015. ITNs were responsible for over two-thirds (68%), a testament to the high-impact role of vector control products (VCPs). An increase in insecticide resistance is a threat that could undo some of the progress made in the last two decades, especially knowing that a malaria vaccine on its own, is currently not enough as a preventive tool.

Currently, at least nine novel VCPs are in development, of which over three-quarters are based on chemical control and the remaining use biological control strategies. The chemical-based products include dual-insecticide nets, non-pyrethroid-based IRS, and tools that are entirely novel and have never been used before, such as attractive toxic sugar baits. The biological control strategies currently being explored include the gene drive approach. Leveraging CRISPR-Cas9 genome editing, the gene-drive approach modifies mosquito genomes to boost the inheritance of desired traits in successive generations. Strategies being employed include decreasing mosquito populations by reducing female mosquito numbers and genetically modifying Anopheles mosquitoes so that their offspring cannot transmit the malaria parasites to humans.

Novel diagnostics for asymptomatic infections and overcoming malaria parasite mutation

Rapid diagnostic tests (RDTs) have been a boon as a companion tool for timely and accurate malaria diagnosis. Before the introduction of RDTs, diagnosing malaria relied on microscopy, a resource-intensive and time-consuming process.

Currently, 29 novel diagnostics to detect various forms of malaria are in development. Close to a quarter are being developed for HRP2 replacement and detecting asymptomatic low parasitemia. Over half (59%) of these diagnostics tests are immunoassay-based; most of the remaining are novel immunoassay-based platforms such as biosensors and molecular platforms such as PCR and LAMP. 

P. falciparum RDTs primarily rely on detecting PfHRP2; parasite mutations involving PfHRP2 deletion have recently been reported, making HRP2-based tests unsuitable. Similarly, these RDTs are not recommended for areas with low transmission or sub-clinical infection. For malaria diagnostics to remain pertinent, research is needed to develop PfHRP2 replacement tests and tests to diagnose asymptomatic infections, an essential tool for regions nearing elimination targets. Additional unmet diagnostics needs include a point-of-care G6PD deficiency companion test for P. vivax relapse cases requiring treatment with primaquine and tafenoquine and tests that can detect multiple malaria species.

Conclusion

The WHO's Global Technical Strategy for Malaria aims to reduce malaria mortality and incidence by 90% by 2030. Novel tools, including medicines, diagnostics, vaccines, and vector control interventions, are crucial. The expanding malaria pipeline across all product areas offers renewed hope for significant progress. The drug pipeline has remained steady, with the influx of new clinical candidates replacing dropouts and promising late-stage antimalarial combination therapies to address existing needs, including emerging drug resistance. The vaccine landscape has grown significantly, with over a dozen candidates, including advancing mRNA vaccines. However, more efforts are required to propel the development of second-generation candidates that align with WHO strategic goals for malaria vaccines.  Meanwhile, as novel chemical and biological vector control products are progressing to late-stage trials, the malaria diagnostics pipeline is expanding, featuring tests to address current unmet needs such as those that can diagnose varying forms of malaria infections and multi-species detection.

While we spotlight the flourishing malaria pipeline, especially in vaccines and vector control, we must also acknowledge the ongoing efforts to develop an expanded set of effective countermeasures against malaria. Sustaining the remarkable progress in vaccine development and maintaining momentum in other areas is essential for reducing mortality and morbidity among vulnerable populations worldwide.