RTS,S Malaria Vaccine: An Imperfect Vaccine that Will Save Thousands of Lives

The COVID-19 pandemic has reminded us all of the importance and impact of vaccines. In less than a year since the World Health Organization (WHO) declared the pandemic, several COVID-19 vaccines had already received emergency authorizations for their use in a large number of countries. The unprecedented –and maybe unexpected– fast development of these vaccines contrasts with the lack of vaccines for many deadly infectious diseases and the many years of research and testing required for many vaccine candidates. Malaria is one of these diseases.

Malaria kills one child every two minutes and more than 260,000 African children under the age of five every year. The reasons why a malaria vaccine has taken so long to develop include limited resources, the fact that affected populations belong to low income countries, and the high complexity of the pathogen. Because of this, the WHO’s recommendation of the first generation malaria vaccine for widespread use in African children at risk is a historic milestone.

The World Health Organization (WHO)’s recommendation of the first generation malaria vaccine for widespread use in African children at risk is a historic milestone

RTS,S/AS01E vaccine (Mosquirix^TM) has been in development for more than 30 years and was licensed in 2015 after showing an efficacy of only 39% against clinical malaria after a four-dose regimen in a Phase 3 clinical trial in African children. Despite a modest vaccine efficacy, the impact was high, as thousands of malaria cases had been adverted and, according to estimates, one life was saved for every 200 vaccinated children. However, it raised some concerns regarding safety, as higher mortality in girls than boys and more cases of meningitis and cerebral malaria were detected in vaccinated children. In addition, the feasibility was questioned due to the need to administer four doses, to the existence of other health interventions and malaria control measures, and also because of its relatively high cost compared to other routine vaccines administered in low income countries. Therefore, at that time, the WHO recommended a series of pilot implementation studies that started in 2019 in three African countries, with the goal of gathering additional evidence on feasibility, safety, and impact.

Photo: BMGF (2007), Manhiça (Mozambique).

An Evidence-Based Recommendation

WHO support has arrived after reviewing and discussing all the evidence from the ongoing pilot studies in a joint meeting of the WHO top advisory committees for malaria (MPAG) and immunization (SAGE). Despite these difficult times, more than 800,000 children have received at least one vaccine dose and 2.3 million doses have been administered since 2019 in those pilot studies, and have provided solid evidence for policy recommendation.

First, it seems that vaccine introduction is feasible, as it has good coverage of the first three doses through the expanded programme of immunization and routine systems. The community demand is high. Crucially, the administration of the vaccine does not impact the uptake of other vaccines or negatively affect the use of other malaria control measures such as insecticide-treated bed nets or care-seeking behavior. Indeed, it increases access to malaria prevention tools.

For the first time ever, we have a recommended malaria vaccine, but its efficacy is moderate, far from where we want it to be. We need to better understand the protective immunity elicited by RTS,S. This is precisely what we are working on.

Secondly, the vaccine has proven to be safe. Importantly, the data from the pilot has alleviated aforementioned concerns raised in the Phase 3 trial and demonstrated that the safety issues were not related to the vaccine. Finally, the impact of the vaccine was confirmed. RTS,S/AS01E resulted in a 30% reduction in hospitalization due to severe malaria and a 21% reduction of hospitalization with malaria infection. The study has no power yet to detect the effect on overall mortality, but the pilot is ongoing till 2023 and will also assess the added value of the 4^th vaccine booster dose. In addition, the vaccine is estimated to be highly cost-effective.

For the first time ever, we have a recommended malaria vaccine, but its efficacy is moderate, far from where we want it to be. We need to better understand the protective immunity elicited by RTS,S and why some children are not protected, in order to rationally design the new generation of malaria vaccines with higher efficacy.

Photo: Immunology Group at ISGlobal (Barcelona).

This is precisely what we are working on. Our group is studying the immune mechanisms of the RTS,S vaccine, identifying the responses that contribute to protection and those that are counterproductive. We are also working on how the status of the immune system before vaccination influences vaccine responses and protection in order to identify those children that may not be protected despite vaccination, and learn how to make vaccines work for all. If we can modulate the immune system before vaccination, then we may be able to increase protection. We hope our work will contribute to future improved vaccines to end malaria.

This is an historic milestone for global health and child health in Africa, and a step forward against health inequities, which have been made even more visible ty the the COVID-19 pandemic

This is an historic milestone for global health and child health in Africa, and a step forward against health inequities, which have been made even more visible ty the the COVID-19 pandemic. The addition of this vaccine to the currently available tools for malaria prevention makes the world more equitable. However, many challenges have yet to be overcome. It is unclear for example, with the limited resources available, how widely will the vaccine be administered, and vaccine doses will likely have to be prioritized. Nevertheless, we will make it happen, just as we managed to achieve this milestone in the fight against malaria: with a mass effort of many actors, namely African and worldwide researchers, including ISGlobal and Manhiça Health Research Centre (CISM) colleagues, policy makers, communities, funders, NGOs… all those that have been involved in the design, testing, and development of this vaccine and to whom we are so grateful.

More information

WHO Recommends the First Malaria Vaccine for Children at Risk