Malaria vaccines: A first for parasitic diseases
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In the last few years, major strides have been made in the fight to control malaria, including the first two malaria vaccines ever recommended for use.
"As a malaria researcher, I used to dream of the day when we would have a safe and effective vaccine against malaria. Now we have two,” WHO Director-General Tedros Adhanom Ghebreyesus, PhD, MSc, said during a press briefing in October after WHO recommended the second vaccine.
Although the successful development and subsequent rollout of these vaccines is seen as a major advancement in the fight against malaria, experts cautioned that there is still much left to do to achieve the goal of significantly reducing the burden of a disease that kills more than 600,000 people globally each year.
We checked in with some experts to get their feedback on the vaccines and where the world stands in its fight against malaria.
‘An incredible moment’
In October 2021, WHO recommended the widespread use of a malaria vaccine for the first time for children in sub-Saharan Africa and other areas heavily impacted by the mosquito-borne disease.
The vaccine, RTS,S/AS01, protects against Plasmodium falciparum — the most deadly of the five species of malaria parasites that infect humans, and the most common cause of the disease in Africa.
The announcement was a long time coming since researchers first determined that a malaria vaccine was biologically possible, said Ashley Birkett, PhD, global head for malaria vaccines and biologics at PATH.
“It took about 50 years,” Birkett told Healio | Infectious Disease News.
WHO’s recommendation was based on data from a pilot program called the Malaria Vaccine Implementation Program, which has delivered the vaccine to nearly two million children in Ghana, Kenya and Malawi since 2019. As part of the program, children received four doses of the vaccine — the first three between age 5 to 9 months, and the fourth dose around age 2 years.
According to WHO, the program demonstrated that the vaccine was safe and feasible to deliver and reduced severe malaria by 30% and all-cause deaths by 13%, even in areas where insecticide-treated bed nets are widely used and people have good access to malaria care.
Additional data from a phase 3 study published in The Lancet Infectious Diseases this past August demonstrated that seasonal vaccination with RTS,S/AS01, in combination with seasonal chemoprevention with sulfadoxine-pyrimethamine plus amodiaquine, reduced hospitalizations and deaths from malaria by around two-thirds among children in two African countries, Burkina Faso and Mali.
Rollout of the vaccine has continued to expand. In July, WHO announced that 12 African countries — Benin, Burkina Faso, Burundi, Cameroon, the Democratic Republic of the Congo, Ghana, Kenya, Liberia, Malawi, Niger, Sierra Leone and Uganda — will receive 18 million doses of the vaccine beginning in the last quarter of this year, with the first doses to be prioritized for children who are at the highest risk for dying from malaria.
WHO, UNICEF and Gavi, the Vaccine Alliance said they expect GSK to produce approximately 15 million doses of the vaccine per year from 2026 through 2028.
WHO recommended the second vaccine — R21/Matrix-M — in October after clinical trial data showed it reduced symptomatic cases of malaria by 75% during the 12 months following a three-dose series in areas with high seasonal malaria transmission. A fourth dose given a year after the third maintained that efficacy, study data published in September 2022 showed, making it the first vaccine to meet WHO’s Malaria Vaccine Technology Roadmap goal of a vaccine with at least 75% efficacy.
However, because the vaccines were studied in different populations, it is not clear if one is more effective than the other, according to Philip J. Rosenthal, MD, professor of medicine at the University of California, San Francisco. In fact, RTS,S has demonstrated a similar effectiveness to the R21 vaccine in similar settings, according to PATH.
“We’ve been hoping for a malaria vaccine for many decades. In fact, the path to these vaccines started in the 1960s with the initial basic research that led to our understanding of the value of this vaccine approach,” Rosenthal told Healio | Infectious Disease News. “It’s very exciting that we have vaccines for any parasitic disease. However, as is much discussed, the efficacy is much lower than what we see for most vaccines.”
According to Stephen Sosler, PhD, MPH, an epidemiologist and head of vaccine programs at Gavi, the next step for R21/Matrix-M is WHO prequalification, which will allow for it to be distributed on a large scale globally. (GSK’s vaccine received prequalification last year.) Once that happens, national immunization programs can decide on its use, enabling organizations such as Gavi to help them acquire and roll out the vaccine.
According to Sosler, it is estimated that malaria vaccines could prevent one death for every 200 children who are vaccinated.
“This is an incredible moment in the fight against malaria,” Sosler said. “We are close to unleashing not one, but two vaccines against a disease that kills half a million children in Africa each year. This is a game-changer for the continent, which has 96% of the global disease burden.”
The vaccines are unique because they protect against a parasite — “a complex organism with a lifecycle of its own” — rather than a virus or bacterium, Birkett said.
“The malaria parasite has more than 5,000 genes, which makes identifying the disease-causing gene or protein very difficult,” he said. “[These] are the first vaccines against a human parasite. There are many vaccines against viruses, far fewer against bacteria, but when it comes to parasites, the only success in terms of a vaccine for people has been against malaria.”
The two vaccines are similar, but not identical, according to Rosenthal, who explained that both use the same surface antigen — the circumsporozoite protein — but different adjuvants to boost immune responses.
“There is so far no evidence that one vaccine is much better than the other,” Sir Brian Greenwood, CBE, FRS, FMedSci, professor of clinical tropical medicine at the London School of Hygiene & Tropical Medicine, told Healio | Infectious Disease News. “However, the advantage that R21 has over RTS,S is that it is manufactured by the Serum Institute of India, which can produce it rapidly at scale whilst GSK, the manufacturer of RTS,S, can only produce limited supplies.”
That advantage was also noted by Kate O’Brien, MD, MPH, director of WHO’s Department of Immunization, Vaccines and Biologicals, during the press conference after WHO announced that it was recommending the second vaccine.
“We have only 18 million doses of RTS,S through the end of 2025, with work going on to increase that supply,” O’Brien said. “With R21 coming in and commitments from the manufacturer [to have] over 100 million doses per year, this is a very big step toward access.”
R21 will cost $2 to $4 per dose, keeping its cost-effectiveness in line with other recommended malaria interventions and other childhood vaccines, WHO said. According to UNICEF, the GSK vaccine is expected to cost more than $9 per dose from 2023 to 2025.
Sosler said R21 has the chance to “significantly alleviate supply constraints, enabling us to meet high demand in malaria-endemic countries.”
“The availability of the two vaccines will necessitate a strategic shift,” he said. “The addition of R21 allows for new approaches — smaller countries might exclusively scale up with RTS,S, whereas populous nations like Nigeria could opt for R21.”
The total cost of vaccination programs may be complicated by questions about dosing. Greenwood noted that the vaccines provide a relatively short period of high protection without the addition of a booster or repeat doses and that it is not yet known how frequently someone might need these.
“One might say this is like a polio vaccine, but the polio vaccine, I think, was much more important for the control of polio than the malaria vaccines are going to be in controlling malaria,” Rosenthal said. “This is one important tool, but it’s probably not a game-changer.”
‘Not a silver bullet’
It will be important to deploy vaccines in conjunction with other proven prevention methods, experts agreed.
“Vaccination is not a silver bullet. It must be used alongside existing malaria interventions such as insecticide-treated nets, indoor residual spraying, intermittent preventive treatment in pregnant women, use of antimalarials, plus effective case management and treatment,” Sosler said. “The wide range of nonvaccine interventions deployed since 2000 have helped reduce deaths by a third and their importance cannot be overstated.”
Indeed, some of the most effective tools against malaria have been the ones used to control the mosquitoes themselves, including insecticide-treated bed nets.
A 2-decade study published earlier this year found that the benefits of using treated bed nets for malaria control early in childhood persisted into adulthood, assuaging concerns that malaria control in early childhood with treated bed nets “might delay the acquisition of functional immunity and shift child deaths from younger to older ages,” researchers wrote in The New England Journal of Medicine.
Results from the 22-year cohort study, which was conducted in Tanzania, found that participants who reported during at least half of community outreach visits early in their life that they used treated nets had a 43% lower risk for death compared with participants who reported using treated nets at less than half the visits.
This “suggests that the survival benefits of insecticide-treated nets were large and persisted to adulthood given a moderate level of community coverage,” the researchers wrote.
“Before the evidence came in, many doubted that [treated bed nets] could have such a tremendous impact on malaria, but they did,” Birkett said.
More than 2 billion bed nets have been distributed worldwide since 2005. Over the years, however, mosquitoes have become resistant to pyrethroids, the primary insecticide used to treat the nets. In response, in 2017, WHO recommended also treating them with piperonyl-butoxide, a chemical that enhances the potency of pyrethroids against resistant mosquitoes.
New recommendations published by WHO earlier this year included two new classes of dual-ingredient bed nets — pyrethroid-chlorfenapyr nets to enhance the killing effect of the net, and pyrethroid-pyriproxyfen nets, which disrupt mosquito growth and reproduction.
“These new types of nets were designed to have a greater impact against pyrethroid-resistant mosquitoes,” Jan Kolaczinski, PhD, head of the Vector Control and Insecticide Resistance unit of WHO’s Global Malaria Program, said at the time. “By including two active ingredients in an [insecticide-treated net], the likelihood of mosquitoes being resistant to both is greatly reduced.”
Additionally, drugs to prevent malaria have been routinely prescribed for travelers. Recommendations for which drug to choose depends on where a person is traveling, the CDC notes. The drugs include atovaquone/proguanil, chloroquine, doxycycline, mefloquine, primaquine and tafenoquine.
For decades, the only cases of malaria treated in the United States were related to travel. That changed this year when Florida and Texas — and then Maryland and Arkansas — reported the first locally acquired cases since 2003.
IV artesunate has been the first-line treatment for severe malaria in the U.S. since 2019 and is the only drug available in the U.S. to treat severe malaria. A study published in 2021 in Clinical Infectious Diseases found that it was safe and effective in treating severe malaria in U.S. adults.
‘Very exciting’ mAbs
Another approach that could help curb malaria is the use of monoclonal antibodies.
Although no mAbs are currently approved for malaria, data published in The New England Journal of Medicine and presented at a medical conference last year demonstrated that one dose of an mAb called CIS43LS safely protected healthy adults from malaria infection during the 6-month malaria season in Mali.
The trial — which was conducted in two parts — evaluated the safety and efficacy of a one-time IV infusion of CIS43LS given to 369 healthy, nonpregnant adults aged 18 to 55 years. The first part of the trial assessed the safety of three different doses — 5 mg, 10 mg and 40 mg per kg of body weight — in six participants per dose level, and the second assessed the efficacy of two different doses compared with a placebo.
In all, 300 participants were randomly assigned in a 1:1:1 ratio to receive either the 10 mg/kg or 40 mg/kg dose or a placebo by IV infusion. The researchers followed participants for 24 weeks, testing their blood for P. falciparum weekly for the first 28 days and then every 2 weeks after that.
Over the 24-week study period, testing detected P. falciparum infections in 35.5% of participants who received a 10 mg/kg dose, 18.2% who received a 40 mg/kg dose and 78.2% who received placebo. The researchers calculated the efficacy of a 40 mg/kg dose of CIS43LS at 6 months to be 88.2% (adjusted 95% CI, 79.3%-93.3%) and the efficacy of a 10 mg/kg dose to be 75% (adjusted 95% CI, 61%-84%) compared with placebo.
The NIH said researchers are testing a second, more potent antimalarial mAb that is given subcutaneously in smaller doses and has shown promise in adults in early-stage testing. It is being assessed in two phase 2 trials in infants, children and adults in Mali and Kenya.
“It will be some time before we learn whether this approach will make sense, but monoclonal antibodies are really another vaccine,” Rosenthal said. “It's another immunologic approach to controlling malaria and the initial results are very exciting.”
‘Beginning of another journey’
According to Sosler, all these advancements against malaria are not the end of the road.
“We see this as the beginning of another journey,” he said. “Now that we have the first generation of malaria vaccines, what’s next? How can we improve efficacy and have a simpler dose regimen? How can we further diversify manufacturing, particularly in Africa?”
Regardless of what questions are left to answer, Sosler emphasized the importance of having the two vaccines.
“This is a first in global health,” he said.
References:
- Abanyie F, et al. Clin Infect Dis. 2021;doi:10.1093/cid/ciab570.
- Bigira V. PLoS Med. 2014;doi:10.1371/journal.pmed.1001689.
- Chandramohan D, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2026330.
- Cissé B, et al. PLoS Med. 2016;doi:10.1371/journal.pmed.1002175.
- Datoo M, et al. Lancet Infect Dis. 2022;doi:10.1016/S1473-3099(22)00442-X.
- Dicko A, et al. Lancet Infect Dis. 2023;doi:10.106/S1473-3099(23)00368-7.
- Fink G, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2112524.
- Kayentao K, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2206966.
- Kayentao K, et al. Testing the safety and efficacy of anti-malaria monoclonal antibodies in African adults and children. Presented at: American Society of Tropical Medicine & Hygiene Annual Meeting; Oct. 30-Nov. 3, 2022; Seattle.
- Krezanoski PJ, et al. Am J Trop Med Hyg. 2019;doi:10.4269/ajtmh.19-0032.
- UNICEF. Malaria vaccine: Questions and answers on vaccine supply, price and market shaping. https://www.unicef.org/supply/media/13396/file/Malaria-Vaccine-Supply-Price-Market-Questions-Answers-August2022.pdf. Published August 2022. Accessed Oct. 26, 2023.
- WHO publishes recommendations on two new types of insecticide-treated nets. https://www.who.int/news/item/14-03-2023-who-publishes-recommendations-on-two-new-types-of-insecticide-treated-nets. Published March 14, 2023. Accessed Oct. 13, 2023.
- WHO recommends R21/Matrix-M vaccine for malaria prevention in updated advice on immunization. https://www.who.int/news/item/02-10-2023-who-recommends-r21-matrix-m-vaccine-for-malaria-prevention-in-updated-advice-on-immunization. Published Oct. 2, 2023. Accessed Oct. 25, 2023.
For more information:
Ashley Birkett, PhD, can be reached at psingh@burness.com.
Sir Brian Greenwood, CBE, FRS, FMedSci, can be reached at brian.greenwood@lshtm.ac.uk.
Philip J. Rosenthal, MD, can be reached at philip.rosenthal@ucsf.edu.
Stephen Sosler, MD, PhD, can be reached at media@gavi.org.
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