Beyond the needle: Understanding the safety of life-saving malaria vaccines

Iain Macleod Briongos, PhD

The RTS,S and R21 vaccines represent significant advances in the fight against malaria and are now being deployed with the aim of vaccinating as many children as possible in malarial regions. In this post, we look at the safety profiles of these vaccines and summarize safety information from clinical trials.

Side effects and clinical testing

Vaccines are designed to help the body develop long-lasting resistance to a disease without contracting the illness itself. When a vaccine is administered, it introduces antigens into the body. These antigens, which may be weakened or dead forms of the pathogen or just a specific part of it, mimic an infection. This triggers an immune response similar to that caused by the real pathogen, where a range of immune cells work to defend against a perceived threat. The immune cells clear the introduced antigens and develop a memory response that prepares the body to protect itself against the disease, should it ever be encountered in the future.

This immune response is inherently inflammatory as the immune system creates a less favorable environment for pathogens, causing mild symptoms such as heat, soreness, and more. As the immune response develops, it can lead to systemic versions of these symptoms, such as body aches, fatigue, headache, and fever¹. Vaccines can also contain adjuvants, which support and promote the immune response and can contribute to these mild, short-lived side effects². These symptoms are normal and preferable to the consequences of contracting serious diseases such as malaria. More severe, life-threatening side effects can occur when a vaccine causes the immune system to respond too strongly or causes it to attack an unintended target.

To minimize the risk of life-threatening side effects (SAEs, or serious adverse events), as well as to evaluate ideal dosage, vaccines go through a rigorous, multi-stage, and multi-year process. They are developed in the lab and then tested in animals before undergoing human clinical trials. Human trials start with a small group (Phase I) to assess safety before expanding into larger groups of the target demographic and more diverse populations (Phases II and III). Even after the completion of clinical trials, vaccines follow a post-approval surveillance process where they are monitored for long-term side effects (Phase IV)³. Clinical trials are conducted against control groups who might receive a placebo or an existing approved vaccine with a known safety profile. This comparison helps to differentiate between side effects caused by the vaccine and those that might occur independently of vaccination, such as from other medical conditions or environmental factors. All serious adverse events, regardless of cause, are logged during the trials and generally included in trial publications.

RTS,S

Phase I trials of the RTS,S vaccine were carried out in small groups of adults to compare different formulations and found them to be well tolerated with a low risk of adverse side effects⁴⁵. Different formulations varied in efficacy and side-effect intensity, with some causing mild side effects such as “pain, malaise, feverishness, headache and myalgia.”⁶ None of these formulations caused serious side effects. A promising formulation was selected for subsequent trials when considering both safety and efficacy.

Phase II trials were conducted to first assess safety and efficacy as a standalone vaccine course in 894 infants⁷ and subsequently in 511 infants⁸ integrated into the Expanded Program on Immunization⁹, where it was given along with other well-established childhood vaccines. The former study found fewer SAEs in the RTS,S group when compared to a control vaccine, even when accounting for fewer malaria cases. The latter study found that “The occurrences of serious adverse events were balanced across groups; none were vaccine-related.”

A Phase III trial was conducted from March 2009 to January 2014 involving 8,922 children and 6,537 infants across seven sub-Saharan African countries. The collective data showed that both the three-dose course and a three-dose course plus booster RTS,S vaccine decreased the incidence of malaria significantly when compared to the control group. SAEs were generally balanced across the groups except for meningitis, which was higher in the two RTS,S groups (21 of 22 total cases)¹⁰. When broken down into more specific demographics, follow-up analysis of the same data showed that the RTS,S vaccinated groups had a higher incidence of meningitis and cerebral malaria (43 of 53 cases) in the child age group, as well as a higher all-cause mortality in girls (2.4% vs 1.3% in the control)¹¹. Although the authors considered these findings to be chance due to their low incidence, there was concern among some other researchers.¹² In January 2016, the WHO recognized the public health potential of RTS,S, while also recognizing the need for further assessment.¹³

Started in 2019, the Malaria Vaccine Implementation Program (MVIP) is a vaccination pilot program that was designed by the WHO in part to address these concerns, with final results expected in 2025. Preliminary results up to April 2021, by which point 625,673 children had received one dose and 494,745 children had received three doses of RTS,S, were recently published in a Gavi-funded paper. The data suggest that there is no evidence of excess cases of meningitis or cerebral malaria in areas where the MVIP was implemented compared to areas where it was not. Likewise, the mortality rates of girls and boys were similar, with a mortality ratio of 1.03, contrary to the results of the smaller Phase III trial finding much higher mortality rates for girls. Among children eligible for three doses, there was a 32% reduction in hospital admissions with severe malaria and a 9% reduction in all-cause mortality (excluding injuries).¹⁴ Among children in the target demographic who received three doses plus the booster, there was a 13% reduction in all-cause mortality.¹⁵

These results reinforce the safety of RTS,S, and evaluation will continue so that efficacy and safety can be studied through the booster shot (where some concern remains)¹⁶ and beyond.

R21

Phase I trials for the R21 vaccine had similar results, with one trial involving 28 adults showing that it was generally well tolerated with only mild side effects. Three SAEs were noted, one with serious localized swelling and two with feverishness, with one (unstated) being unrelated to the vaccine.¹⁷ In all cases, the side effects resolved within 48 hours.

Phase II trials were conducted in 2019 in 450 infants aged 5-17 months, comparing two concentrations of R21 in a three-dose course and the rabies vaccine used as a control. There were seven SAEs,¹⁸ although none were deemed to be related to vaccination. In 2020, a follow-up trial including a booster dose one year later was also completed with 409 infants. Here, there were three SAEs, again none related to the vaccine (malaria with pneumonia, severe malnutrition, and bacterial meningitis).¹⁹

Results from the Phase III trial were published earlier this year (2024). 5,139 children participated, 3,434 of whom were allocated to the R21 vaccine.²⁰ There were 88 SAEs in the R21 group and 41 in the control. While the groups did not show significantly different rates of SAEs, the authors reported that six cases, all febrile convulsions, were “considered possibly, probably, or definitely related to study vaccines.”²¹

As with the RTS,S vaccine, monitoring for safety and efficacy will continue through Phase IV.

Conclusion

In October 2023, the WHO updated its recommendations for the RTS,S and R21 vaccines, advocating for their use in endemic regions and stating that “both vaccines are shown to be safe and effective in preventing malaria in children and, when implemented broadly, are expected to have high public health impact.”²² With millions of doses of RTS,S and tens of thousands of R21 administered to date, results suggest that both vaccines are well tolerated, with a low risk of serious side effects. Most side effects experienced are mild, such as soreness, fever, and fatigue, which are also commonly seen in other accepted vaccines. Importantly, recipients of the vaccines had a 9-13% decrease in all-cause mortality compared to control groups.²³²⁴ Continuous monitoring through Phase IV trials ensures that long-term safety concerns are tracked and addressed, helping to counter misinformation and instill trust in these life-saving tools. We will continue to provide updates with the latest results and developments as they become available.