Malaria vaccines have been in development since the 1960’s, with substantial progress in the last decade. October 6, 2021, marks an historic day in the development of malaria vaccines, with release of the World Health Organization (WHO) recommendation for widespread use of the RTS,S/AS01 (RTS,S) malaria vaccine among children living in sub-Saharan Africa and other regions with moderate to high P. falciparum malaria transmission.
Barriers to Developing a Malaria Vaccine
The development of a malaria vaccine has faced several obstacles: the lack of a traditional market, few developers, and the technical complexity of developing any vaccine against a parasite.
Malaria parasites have a complex life cycle, and there is poor understanding of the complex immune response to malaria infection. Malaria parasites are also genetically complex, producing thousands of potential antigens. Unlike the diseases for which we currently have effective vaccines, exposure to malaria parasites does not confer lifelong protection. Acquired immunity only partially protects against future disease, and in many cases people still become infected with the parasite; malaria infection can persist for months without symptoms of disease.
More than a dozen vaccine candidates are now in clinical development, and one, GlaxoSmithKline Biologicals’ RTS,S/AS01, completed Phase III clinical testing, and on October 6, 2021, following a large scale pilot implementation, became the first malaria vaccine to receive a WHO recommendation for widespread use among children living in areas of moderate to high malaria transmission.
The vaccine has been in development since the mid-1980s and has advanced thanks to a unique public-private partnership of GSKBio, the PATH Malaria Vaccine Initiative, and African and other research organizations, with funding support from the Bill and Melinda Gates Foundation.
From 2009–2011, children ages 6–12 weeks and 5–17 months were enrolled in the trial at 11 sites in seven African countries. CDC, in collaboration with the Kenya Medical Research Institute, led the trial at one site in western Kenya.
The trial’s final results, made available in 2015external icon, were a promising advance in development of a malaria vaccine for African children. The RTS,S vaccine reduced clinical and severe cases of malaria by about one-third in 5–17-month-old children over four years who received the three-dose vaccine series plus a booster dose. The vaccine was less effective in children in the young infant group. The vaccine was generally found to be safe, but there were a few safety signals that warranted further study, including febrile convulsions, meningitis, and cerebral malaria.
Notably, the vaccine provided this protection in settings with ongoing use of other effective malaria prevention and treatment interventions: bed nets, antimalarial drugs for disease treatment, indoor residual insecticide spraying to prevent mosquito-borne transmission, and drugs to protect pregnant women and their newborns from malaria’s adverse effects.
In July 2015, the European Medicines Agency (EMA) gave a positive regulatory assessment of the RTS,S/AS01 vaccine for 5–17-month-olds, but WHO recommended in October 2015 that the vaccine be further evaluated in large-scale pilot studies before recommending it. Large-scale pilots of the vaccine began in Ghana, Kenya, and Malawi in 2019, including several hundreds of thousands of infants. CDC, in collaboration with KEMRI and several other organizations, is leading the evaluation of the large-scale RTS,S/AS01 pilot in western Kenya. The goal of these pilot evaluations is to assess the feasibility of delivering the three-dose vaccine series plus booster through routine health systems, carefully examine the relationship of the vaccine to specific adverse events (febrile seizures, meningitis, cerebral malaria), and also evaluate its impact on all-cause mortality. CDC, in collaboration with KEMRI and several other organizations, will lead the evaluation of the large-scale RTS,S/AS01 pilot in western Kenya.
While the pilots are still on-going until 2023, sufficient data on safety and efficacy have been collected to allow for a broader recommendation for the use of the vaccine to take place.
Key findings from the malaria vaccine pilots include:external icon
- Feasible to deliver: Vaccine introduction is feasible, improves health and saves lives, with good and equitable coverage of RTS,S seen through routine immunization systems. This occurred even in the context of the COVID-19 pandemic.
- Reaching the unreached: RTS,S increases equity in access to malaria prevention.
- Data from the pilot programme showed that more than two-thirds of children in the 3 countries who are not sleeping under a bednet are benefitting from the RTS,S vaccine.
- Layering the tools results in over 90% of children benefitting from at least one preventive intervention (insecticide treated bednets or the malaria vaccine).
- Strong safety profile: To date, more than 2.3 million doses of the vaccine have been administered in 3 African countries – the vaccine has a favorable safety profile.
- No negative impact on uptake of bednets, other childhood vaccinations, or health seeking behavior for febrile illness. In areas where the vaccine has been introduced, there has been no decrease in the use of insecticide-treated nets, uptake of other childhood vaccinations or health seeking behavior for febrile illness.
- High impact in real-life childhood vaccination settings: Significant reduction (30%) in deadly severe malaria, even when introduced in areas where insecticide-treated nets are widely used and there is good access to diagnosis and treatment.
- Highly cost-effective: Modelling estimates that the vaccine is cost effective in areas of moderate to high malaria transmission.
Next steps include funding decisions from the global health community for broader rollout, and country decision-making on whether to adopt the vaccine as part of national malaria control strategies.Further research into ways to maximize efficacy of the RTS,S/AS01 vaccine, including assessing alternative dosing schedules such as a fractionated third dose, is underway. CDC is leading one of these studies, in collaboration with KEMRI, in infants in western Kenya.
Whole Sporozoite Vaccines
Another promising malaria vaccine candidate includes whole sporozoites, the sexual form of the parasite extracted from mosquito salivary glands, which have either been made non-infectious through irradiation or are administered along with chemoprophylaxis. Recent trials have shown that the irradiated whole sporozoite PfSPZ Vaccine made by Sanaria® is safe and well tolerated and had promising protection against malaria when administered intravenously. A collaborative CDC and KEMRI trial in western Kenya has shown that the PfSPZ Vaccine is safe and well tolerated in infants and young children. Unfortunately, the vaccine did not provide significant protection against P. falciparum infection at 6 months, precluding further evaluation in this age groupexternal icon, although other studies are currently evaluating the efficacy of the PfSPZ Vaccine in different populations in Mali, Gabon, Tanzania, and Equatorial Guinea. This study did, however, provide important information on the immune response to the vaccine; this information will aid researchers in developing a more effective vaccine for young children.
Malaria Vaccines: The Way Forward
The RTS,S/AS01 vaccine and the PfSPZ vaccine products are two of the most promising malaria vaccine candidates to date. Another pre-erythrocytic vaccine candidate, R21, recently showed good efficacy in an early trial testing it among children 5 – 17 months of age in Burkina Faso.external icon Other malaria vaccine candidates are in development or trial phases, including transmission-blocking vaccines that target the sexual stage of parasite development in the mosquito, and mRNA vaccines against malaria. The world’s leading global health organizations have developed the Malaria Vaccine Technology Roadmap for accelerating development of a highly effective malaria vaccine.
The roadmap includes the following strategic goals for malaria vaccines by 2030:
- Develop and license malaria vaccines with protective efficacy of at least 75% against clinical malaria for areas with ongoing malaria transmission.
- Develop malaria vaccines that reduce transmission and human malaria infection, enabling elimination in multiple settings through mass vaccination campaigns.