Malaria Vaccines Development

Tieng Viet

Status Update

Many thanks to David Trent of the World Animal Foundation for reminding me to update data on the burden of the disease in the world. According to information published by the WHO as of December 11, 2024, the number of malaria cases in 2023 was 263 million compared to 252 in 2022. So, there is a slight increase in incidence. Fortunately, the estimated malaria deaths decreases to 597,000 in 2023 compared to 600,000 in 2022. I am not sure if the decrease is statistically meaningful. Clearly, the need for improving the vaccines and access to vaccines is still great, in addition to other preventive measures.

​Updated 3/4/2025 11:29 AM

After 60 long years of R&D the first-ever routine childhood malaria vaccinations, part of the regular immunization schedule, were administered to infants and toddlers in Cameroon on  January 22, 2024. They received  RTS,S (Mosquirix) made by GlaxoSmithKline and approved in 2021 by the World Health Organization (WHO).

Cameroon begins routine malaria shots in global milestone
Reuter
January 22, 20245:59 PM EST

Tieng Viet

Introduction
 
Most of us don’t think about malaria until we decide to travel to areas of the world where it is endemic and prevalent. The first thought is to get vaccinated. Unfortunately, no vaccines have been approved by the FDA and there are no pending reviews of applications for approval. This also holds true for most Western countries. Traveling to endemic areas still requires seeing a doctor for prescriptions of prophylactic antimalarials [1] such as Atovaquone-proguanil (Malarone), Chloroquine phosphate (Aralen), Mefloquine, Primaquine, Tafenoquine (ArakodaTM), or Doxycycline, just to name a few. These drugs are mechanism specific, have different spectrum of potential side effects, different dosage, and mode of administration, and are prescribed to match the patient health status. Precautionary measures such as the use of mosquito repellent during the day and netting at bedtime are also standard recommendations. All the above notwithstanding, there are two malaria vaccines that have been recommended by the World Health Organization (WHO) for broader use among children in sub-Saharan Africa and other regions with moderate to high malaria transmission. They are the crowning achievements of a long and arduous research and discovery process [2], and one can only hope soon they will meet the rigorous standards of the FDA and other country regulatory agencies for wide use among travelers.

Disease Background
 
Malaria is a mosquito-borne parasitic disease that causes high fever, severe chills and sweating, and can be fatal if not treated promptly. Malaria is endemic and prevalent in many tropical and subtropical regions of the world, especially in Africa, Asia, and Latin America. According to data published by the World Health Organization (WHO) in December 2022, there were an estimated 247 million cases of malaria and 619,000 deaths in 2021, with 95% of the cases and 96% of the deaths occurring in the WHO African Region [3]. Malaria transmission can vary depending on climatic factors, such as temperature, humidity, and rainfall, as well as the presence and behavior of the Anopheles mosquitoes that carry the malaria parasites (mostly Plasmodium falciparum and vivax). Malaria can also be reintroduced or eliminated in some areas through effective control or prevention measures, such as insecticide-treated nets, indoor residual spraying, and antimalarial drugs. Therefore, it is important to check the latest malaria risk information for your destination before traveling, and to take appropriate precautions to avoid mosquito bites and malaria infection. World distribution of the regions or countries where malaria is endemic, is available from the CDC’s malaria distribution map [4] and WHO’s malaria threat map [5].

Two vaccines under development
 
RTS,S/AS01 and R21/Matrix-M malaria vaccines have been approved by the WHO for use in children in sub-Saharan Africa and other regions with moderate to high malaria transmission.
 
RTS,S/AS01 (commercial name Mosquirix) is the first malaria vaccine to be approved and in current use. It was developed by the Walter Reed Army Institute of Research and GlaxoSmithKline [6], and it received a WHO recommendation7 in 2021. It requires four doses and has been shown to prevent about 4 in 10 cases of malaria and 3 in 10 cases of severe malaria over four years [7]. The malarial antigen used in Mosquirix is a portion of the Plasmodium falciparum circumsporozoite protein (CSP), which is found on the surface of the malaria parasite. The CSP antigen triggers the production of antibodies that can block the parasite from infecting the liver cells. The vaccine also contains a part of the hepatitis B virus surface antigen, which enhances the immune response and provides protection against hepatitis B infection. Mosquirix is a recombinant protein-based vaccine that is produced in yeast cells by genetic engineering [8,9].
 
R21/Matrix-M is the second malaria vaccine to be recommended by the WHO and was developed by the University of Oxford and the Serum Institute of India, using Novavax’s adjuvant technology. It received a WHO recommendation [10] in 2023, and it is the first malaria vaccine to meet the WHO’s target of 75% efficacy. It requires three doses and has been shown to reduce symptomatic cases of malaria by 75% during the 12 months following vaccination [11]. The antigen employed in R21/Matrix-M is like that of RTS,S/AS01 except for the Matrix-M adjuvant component which was successfully deployed by Novavax in its Covid-19 vaccine.
 
Vaccines Applications
 
As stated previously, neither of these vaccines has been authorized or approved by the FDA for use in the US. The FDA has a different regulatory process and standards for approving vaccines, and it may require more data and evidence from clinical trials before deciding. The FDA also considers the public health need and benefit of a vaccine in the US, where malaria is not endemic, and cases are rare. Both vaccines are intended for use in countries and regions where malaria is a major public health problem, especially for children and pregnant women. At least 28 countries in Africa plan to introduce a WHO-recommended malaria vaccine as part of their national immunization programs. Gavi, the Vaccine Alliance, with backing from the Bill & Melinda Gates Foundation has approved providing support to roll out malaria vaccines to 18 countries [12]. The RTS,S vaccine will be available in some African countries in early 2024 and the R21 vaccine is expected to become available to countries in mid-2024, according to the WHO.
 
 Prospects
 
The development of a completely effective malaria is still pending. Current research efforts are directed towards improving RTS,S/AS01 and R21/Matrix-M, developing new antigen and adjuvant combinations, targeting attenuated sporozoites, and considering the parasite potential for mutations [13]. Ultimate success remains an open proposition. It is important to note with optimism that further progress will be achieved as the Bill & Melinda Gates Foundation has the vision of eradicating malaria [14] by 2040 whereas the WHO more aggressively wants to end the global malaria threat [15] by 2030.

References
 
[1] CDC-Choosing a Drug to Prevent Malaria
[2] Amal A. El‑Moamly and Mohamed A. El‑Sweify. Malaria vaccines: the 60‑year journey of hope and final success—lessons learned and future prospects. Trop. Med. & Health (2023) 51:29. https://doi.org/10.1186/s41182-023-00516-w.
[3] World Malaria Day 2023/ Malaria by numbers: global and regional burden
[4] CDC-Where Malaria Occurs
[5] WHO-Malaria Threats Map: tracking the spread of biological threats to malaria
[6] WHO grants prequalification to GSK’s Mosquirix – the first and only approved malaria vaccine
[7] CDC-Malaria vaccine recommended for broader use by WHO: “Best thing since bed nets”
[8] Matthew B. Laurens. RTS,S/AS01 vaccine (Mosquirix™): an overview. Human Vaccines & Immunotherapeutics (2020) 16, 480-489. https://doi.org/10.1080/21645515.2019.1669415
[9] Yahiya Y. Syed. RTS,S/AS01 malaria vaccine (Mosquirix®): a profle of its use. Drugs & Therapy Perspectives (2022) 38:373–381. https://doi.org/10.1007/s40267-022-00937-3
[10] WHO recommends R21/Matrix-M vaccine for malaria prevention in updated advice on immunization
[11] Mehreen S Datoo, Magloire H Natama, et al. Efficacy of a low-dose candidate malaria vaccine, R21 in
adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: a randomised controlled trial. The Lancet (2021) 397, 1809-1818. https://doi.org/10.1016/S0140-6736(21)00943-0
[12] Gavi outlines plans to build sustainable supply of malaria vaccines
[13] Wikipedia> Malaria vaccine
[14] Report by UN and Gates Foundation presents vision for eradicating malaria by 2040
[15] “A great day for science”: WHO recommends second vaccine against malaria