Opinion | Man Versus Malaria

“Eeeeee… eeeeee… eeeeee.” The high-pitched whine of an implacable stalker circling your head is bad enough when you’re trying to sleep somewhere that isn’t malarious. But how about when you’re lying in the dark surrounded by whining mosquitoes on the edge of the Indian Ocean?

In 2002, my husband and I and colleagues from Washington D.C. traveled to Tanzania, first to attend a malaria conference in Arusha and to interview experts, then to film rural villagers in a highly-malarious district near Dar es Salaam. On some nights in Mkuranga, the “entomological inoculation rate” — or the per-person toll of malaria-infective bites — was 5 to 10 bites or higher.

The trip left me with indelible impressions and passion for a 2-year project for which I was already an expert consultant. Its ultimate goal? To help move the needle from single-drug to combination antimalarial treatments targeting Plasmodium falciparum, malaria’s deadliest species. Our 350-page report, “Saving Lives, Buying Time — Economics of Malaria Drugs in an Age of Resistance,” offered extensive recommendations and also covered the looming threat of insecticide-resistant anopheline vectors.

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Mothers and children at high risk for P. falciparum malaria, Tanzania, 2002. Photo credit: Claire Panosian Dunavan, MD.

So, where do things stand today? The prospects for controlling malaria are in equal measure hopeful, daunting, and downright scary in light of a mosquito now threatening to enter multiple African cities.

Malaria Then and Now

In the early 2000s, when the U.S. Agency for International Development (USAID) first commissioned our report, malaria was killing more than a million people every year — mostly African children. One reason for its escalating toll? After decades of use, chloroquine had finally lost its clout. Accordingly, a key question our report addressed was how to enable a switch from chloroquine to far more expensive multi-drug regimens including artemisinins, which were powerful new arrows in the antimalarial quiver.

However, as often happens with expert policy recommendations, our panel’s boldest idea — a global subsidy of artemisinin-based combination therapies (ACTs) meant to save lives and delay future resistance — was only partly implemented. Yet, over the next decade, artemisinins plus long-lasting insecticidal bed nets (LLINs) halved malarial deaths (although some would say the first flush of success was followed by a frustrating plateau). Then deaths increased.

Malaria reports confirm this. In 2015, according to WHO, there were an estimated 438,000 malarial deaths — the vast majority in African children. By 2019, the number was 568,000. Then came pandemic disruptions, which led to decreased malaria services in Africa and beyond. As a result, by 2021, malaria deaths were up to 619,000.

Now that COVID is receding, will malaria’s mass annihilation also fall? I certainly hope so. But, at the same time, consider the latest challenge: artemisinin partial resistance. Right now, Asia is far more affected than Africa, but the warning signs for Africa are plain to see. In addition, non-artemisinin partner-drugs have also lost efficacy in Asia’s Greater Mekong region.

(A reminder: a combination treatment that marries an artemisinin with a hobbled partner is essentially mono-therapy, which predicts eventual resistance to both compounds.)

In addition, insecticide resistance now abounds among the roughly 60 anopheline species that transmit malaria to humans. This brings us to LLINs and indoor residual spraying, two practices meant to rebuff malarious mosquitoes. Both largely rely on pyrethrins, nontoxic agents whose overuse (often in agriculture) have triggered new mutations conferring “knock-down resistance” in previously-susceptible mosquitoes.

The good news? Recent cluster-randomized trials in Uganda and Tanzania have shown that treating LLINs with the synergistic duo of a pyrethroid and a second insecticide (piperonyl butoxide) restores LLINs’ benefits.

Now for the bad news.

A New Mosquito Threatens Cities in Africa

In 2012, reports showed that a newly-invasive mosquito entered Djibouti. Before long, Anopheles stephensi had also surfaced in Sudan, Somalia, and Ethiopia, and as recently as last month, in Kenya. A statement from The Kenya Medical Research Institute Entomology Research team stated, “Our surveillance studies indicate that the new vector, unlike the traditional malaria-causing mosquitoes, namely Anopheles gambiae and Anopheles fimfests, is not only invasive and can spread very fast to new areas, but is also adaptive to different climatic and environmental conditions.”

Although malaria sometimes afflicts African cities, it has traditionally plagued rural areas far more. But in India, Pakistan, and the Arabian Peninsula, Anopheles stephensi has been the leading driver of urban malaria. If the vector continues spreading in Africa, the future could be grim. To paraphrase one 2019 forecast: cities like Nairobi, Dar es Salaam, Kinshasa, Lagos, Abidjan, and Dakar (whose populations have all recently doubled) could soon witness malaria epidemics of a scale never before seen.

One more nail in the coffin? Pyrethroids no longer work against A. stephensi in Afghanistan, India, and Iran. Even worse, in Ethiopia, all four insecticide classes (organochlorines, organophosphates, pyrethroids, and carbamates) used to kill malarial vectors are now impotent against the new invader.

The Role of Vaccines and Monoclonal Antibodies

Since the 1970s, the “holy grail” of malaria prevention — a truly effective vaccine — has both excited and eluded scientists. But, in 2021, RTS,S/AS01 (Mosquirix), a four-dose series of shots, 35 years in the making was enough of a win that WHO recommended its widespread use in African infants. But RTS,S/AS01’s 36% protection against clinical malaria after 4 years of follow-up in highly-endemic areas of Kenya, Malawi, and Ghana is far from a home run. Some experts predict that its broader roll-out starting in late 2023 will yield even less-resounding results, especially in low- and middle-risk settings.

In contrast, a vaccine called R21 — which, like RTT,S/AS01, targets a specific protein of the thread-like “sporozoite” stage that mosquitoes inoculate into humans — showed 80% efficacy in 450 children in Burkina Faso, ages 5-17 months, who received an initial 3-dose series followed by a booster. But more real-world data are needed to confirm these results. Furthermore, many experts believe that, for maximal benefit in places where malaria is seasonal, children should receive boosters of RTS,S/AS01 and/or R21 just before the exposure period.

Now for a third vaccine whose proof of concept dates to the 1970s. Its original promise stemmed from the use of whole, irradiated sporozoites laboriously harvested from P. falciparum-infected mosquitoes. But a recent paper in Nature describes an exciting technological breakthrough from vaccine scientists: the in vitro production of whole, infectious sporozoites capable of completing their entire life cycle in a mammalian host. If confirmed, this advance could lead to a genetically-attenuated vaccine requiring fewer shots and producing longer immunity.

Lastly, low-dose subcutaneous or intravenous monoclonal antibodies against P. falciparum malaria now hold promise as a temporary form of protection. Who are the possible candidates for this 3- to 6-month safeguard? A highly-vulnerable African child who needs maximal protection after recovering from a previous bout of life-threatening malaria. A pregnant woman in her first trimester. Or even someone planning a work-related stint in a highly malarious area.

In many ways, the future remains hopeful for tackling malaria as long as we stay the course, continue to accurately monitor its burden and changing variables, and add new antimalarial arrows to our quiver. But no one with in-depth knowledge of this killer that once afflicted a far larger swath of our world ever said it would be easy.

Claire Panosian Dunavan, MD, is a professor of medicine and infectious diseases at the David Geffen School of Medicine at UCLA and a past-president of the American Society of Tropical Medicine and Hygiene. You can read more of her writing in the “Of Parasites and Plagues” column.

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