By Philip R. Fischer, MD, DTM&H

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; Department of Pediatrics, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates

SYNOPSIS: Globally, there are hundreds of millions of cases of malaria each year and nearly half a million deaths due to malaria. Current preventive strategies are only partially effective. New data suggest that combining vaccination with chemoprophylaxis is better than either intervention alone, and a small pilot study suggests that a monoclonal antibody infusion is effective in preventing malaria infections.

SOURCES: Gaudinski MR, Berkowitz NM, Idris AH, et al. A monoclonal antibody for malaria prevention. N Engl J Med 2021;385:803-814.

Chandramohan D, Zongo I, Sagara I, et al. Seasonal malaria vaccination with or without seasonal malaria chemoprevention. N Engl J Med 2021;385:1005-1017.

Malaria still is incompletely controlled, especially in sub-Saharan Africa where tens of millions of people get malaria each year and about 400,000 (mostly women and young children) die of malaria. Preventive efforts have been very helpful in reducing the morbidity and mortality rates to these levels, but further improvements have stalled. Thus, additional interventions are needed.

CIS43 is a human monoclonal antibody against the circumsporozoite protein of the sporozoite stage of Plasmodium falciparum. Pre-clinical studies showed that it was protective against mouse malaria. CIS43 was modified to the CIS43LS form to prolong its plasma half-life. Gaudinski and a group of colleagues in America studied the safety, side effects, pharmacokinetics, and protective efficacy of intravenously or subcutaneously administered CIS43LS in 40 healthy malaria-naïve adult humans. No significant safety concerns were identified, although individual patients had dizziness, asymptomatic neutropenia, or mild elevation of the creatinine level. Antibody levels were dose-dependent, since doses varied from 5 mg to 20 mg to 40 mg per kg of body weight; levels rose during the first week after subcutaneous administration. Antibodies still were detectable 24 weeks after administration, and the half-life of antibodies was 56 days.

Fifteen patients underwent controlled malaria infection with bites from infected Anopheles mosquitoes at least four weeks after antibody administration; of these, none developed parasitemia (even up to 36 weeks after receiving CIS43LS), but five of six untreated controls developed parasitemia eight to nine days after the mosquito bites. These early data suggest that monoclonal anti-circumsporozoite antibody injection protects malaria-naïve adults from developing malaria infection for up to 36 weeks after bites from infected mosquitoes. Another study is underway in Mali, where exposure happens naturally during the rainy season instead of with controlled bites from infected mosquitoes.

Meanwhile, Chandramohan and a group of colleagues in Europe and Africa studied the effectiveness of a combination of newer (vaccination) and more established (chemoprophylaxis) means of preventing malaria. Chemoprophylaxis can be effective for individuals when it is used regularly. Vaccination with an RTS,S/AS01 vaccine has been shown to reduce the incidence of malaria in children in Africa, but with waning protection over time. With 5- to 17-month-old children in areas of Mali and Burkina Faso where malaria incidence varies seasonally, Chandramohan and colleagues compared the malaria-preventing value of vaccination (an RTS,S/AS01 vaccine) to chemoprophylaxis (sulfadoxine-pyrimethamine and amodiaquine, known to still be effective in the study areas) and to both interventions in a randomized, blinded, controlled study. A total of 6,781 children began the study, and 88% completed the three-year study.

The efficacy of vaccination was statistically similar to the efficacy of chemoprophylaxis, with approximately 30 bouts of symptomatic malaria per 100 child-years. The combination of vaccination and chemoprophylaxis was significantly better than either intervention alone, with 11 malaria events per 100 child-years. Overall, the combination treatment provided 61% protective efficacy as compared to either intervention alone. Combination treatment also was associated with fewer malaria-induced deaths, blood transfusions, and hospitalizations. Five (< 0.1) vaccinated children had fever-associated seizures within a day of vaccination but did not have any lasting sequelae. Vaccination was not inferior to chemoprophylaxis, and the combination of both interventions was significantly more effective than either intervention alone.

COMMENTARY 

The incredible complexity of the life of Plasmodium parasites makes the prevention of malaria extremely challenging. Multiple approaches targeting a reduction in the incidence and severity of malaria infection have focused on various aspects of the parasite’s life cycle. As demonstrated by these two papers, new strategies to prevent malaria can be novel or combined.

Malaria parasites rely on mosquito vectors to sustain their existence. Anopheles breed near water, bite from dusk to dawn, and live for several weeks. Reduction of standing water around residences reduces the number of breeding mosquitoes near where people sleep. However, large puddles are not required, and even a few drops of water between the leaves and stalks of plants can support insect breeding. Screened windows, air conditioning, and bed nets (especially those impregnated with an insecticide such as permethrin) block access of mosquitoes to sleeping humans. DEET and picaridin in concentrations of 20% to 30% are effective as topical repellents on exposed skin for four to six hours (but not usually all night). Genetically altered and Wolbachia-infected mosquitoes can, to some degree, displace malaria-transmitting mosquitoes in some areas.1

Decades ago, DDT (dichloro-diphenyl-trichloroethane) was dispersed widely to kill mosquitoes; this was somewhat effective, but resistance developed (of mosquitoes to DDT and of societies to the adverse ecological effects of widespread application of DDT). Now, application of DDT and related compounds on the walls of homes provides some safe and lasting local reduction in mosquito populations.

In humans, there are four main stages of Plasmodium’s life: sporozoites, hepatic schizonts, blood schizonts, and gametocytes; each has been targeted by various medications and vaccines. Sporozoites travel from the site of a mosquito bite through the bloodstream to the liver and are cleared from the blood within 30 to 60 minutes of the bite. Sporozoites are targeted by some prospective malaria vaccines, including the RTS,S/AS01 vaccine used in Chandramohan et al’s study. The monoclonal antibody used in Gaudinski et al’s study targeted a sporozoite protein that is needed for sporozoite motility and hepatocyte invasion.

Hepatic schizonts develop in the liver and then disperse short-lived merozoites from the liver into the bloodstream a week or so later (or much longer, such as with the dormant hypnozoites of P. vivax). Hepatic schizonts are attacked by a limited number of malaria medications, including primaquine and atovaquone-proguanil. After being released from hepatic schizonts into the blood, merozoites invade red cells to form blood schizonts. For days, with repeated rupture and release and reinfection, parasitemia builds and persists — and is responsible for the clinical symptoms of acute malaria. Some candidate vaccines target merozoites to prevent them from penetrating red blood cells, and most anti-malarial medications (including the amodiaquine and sulfadoxine-pyrimethamine used in Chandramohan et al’s study) target blood stages of malaria.

Finally, some parasites in the blood become gametocytes, the fertile forms of the parasite that then are taken up by another Anopheles mosquito with a subsequent blood meal to continue the life cycle through mosquitoes. “Transmission-blocking vaccines” are those that attack gametocyte function; new data offer hope that monoclonal antibodies also can block gametocytes from transmitting infection back to mosquitoes.2

Clearly, multifaceted approaches to the prevention of malaria still are required. Vaccines and chemoprophylaxis can help many children, but more children can be helped by combining these interventions. Novel monoclonal antibody therapy holds great potential for the prevention of malaria in travelers and, with repeated doses, for residents of malaria-endemic areas. With implementation of all available as well as emerging interventions, there is potential to save the lives of the 400,000 women and children currently dying of malaria each year.

REFERENCES

  1. Wang GH, Gamez S, Raban RR, et al. Combating mosquito-borne diseases using genetic control technologies. Nat Commun 2021;12:4388.
  2. de Jong RM, Meerstein-Kessel L, Da DF, et al. Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes. NPJ Vaccines 2021;6:101.