By Philip R. Fischer, MD, DTM&H
Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; Department of Pediatrics, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
SYNOPSIS: Malaria vaccination with the RTS,S/AS01 vaccine is safe and effective. Implementation of the four-dose vaccination regimen for young children in areas of moderate- and high-intensity malaria transmission is in progress — with the expectation that hundreds of thousands of lives could be saved each year.
SOURCE: Björkman A, Stabell Benn C, Aaby P, Schapira A. RTS,S/AS01 malaria vaccine—proven safe and effective? Lancet Infect Dis 2023;23:e318-e322.
Björkman and colleagues from Scandinavia, Guinea-Bissau, and the Philippines acknowledged the strong safety profile and high impact record of RTS,S/AS01 malaria vaccine. They noted that the vaccine now is recommended, based in part on data from widespread implementation of this vaccine in three African countries. Nonetheless, they called for caution and further data as vaccine programs are rolled out.
First, there are concerns about the mortality data in previous studies of the RTS,S/AS01 vaccine. Results of Phase III trials of this new vaccine were published in 2015. Cases of malaria dropped by 39% with vaccination, and episodes of severe malaria decreased by 29%. However, they noted a “tendency” toward increased all-cause mortality following vaccination, a reported 22% “increase” but with the 95% confidence interval spreading from -13 to 71. They also highlighted “safety signals” about increased meningitis (P = 0.02) and cerebral malaria (P = 0.04) following vaccination. Vaccinated girls reportedly had higher mortality by 22% (95% confidence interval, 13-118).
Second, Björkman and co-authors pointed out that the implementation program was slated for follow-up of four years, but that data were disseminated after just two years. They raised concerns that the study might not be adequately powered to identify male-female differences in post-vaccination outcomes, as compared to the originally planned four-year study. They were particularly concerned since the seemingly increased mortality seen in girls during the Phase III study took place after the first year following initiation of the vaccine series. While there was 30% less severe malaria during the two years following the start of vaccination, Björkman and colleagues were concerned that the non-significant 7% (95% confidence interval, -3 to 16) reduction in all-cause mortality that was identified in the implementation surveillance study might be inaccurate because of the shortened duration of pre-publication data collection.
Third, Björkman and colleagues pointed out that vaccine doses in study patients came with instructions about bednet use and management of febrile illnesses. These interventions were not included in the control areas/subjects. Thus, the authors expressed concern that a perceived benefit of vaccination might have been from side benefits (such as reminders to implement other means of malaria prevention) rather than from the vaccination.
Thus, Björkman and colleagues lauded the effectiveness of the RTS,S/AS01 malaria vaccine, but they think the optimism for the safety of this vaccine might have been overextended in World Health Organization (WHO) press releases. They suggested that careful safety and mortality data collection continue throughout the full four years originally planned for the implementation study, that all data be made available for independent analysis, and that male-female data be analyzed carefully.
COMMENTARY
Despite scientific advances and public health interventions involving environmental control, insecticide use, intermittent malaria chemoprophylaxis, diagnostic testing, and effective therapeutic treatment, malaria still is a major problem. Worldwide, there are approximately 250 million cases of human malaria each year and approximately 600,000 deaths resulting from malaria each year, with 80% of those deaths in pre-school-age children in sub-Saharan Africa. With four major life stages of Plasmodium occurring in humans (sporozoite between the mosquito bite and arrival in the liver, hepatic schizonts in the liver, and circulating merozoites becoming erythrocytic schizonts; the contagious gametocyte forms also circulate in red cells) and with complex multifactorial anti-malaria immune responses, vaccine development has been time-consuming, yet, finally, productive.
The RTS,S/AS01 vaccine targets the pre-erythrocytic circumsporozoite protein of P. falciparum. Early formulations of this vaccine were tested in humans in the 1990s, and vaccine formulations were further refined. Since 2009, studies have been done in children in Africa, with variations in dosing regimens. Beginning in 2019, favorable effects of RTS,S/AS01 were demonstrated in pilot implementation programs in Kenya, Ghana, and Malawi. In 2021, the WHO reviewed Phase I, Phase II, Phase III, and implementation program data and recommended that RTS,S/AS01 be used in a four-dose schedule beginning at 5 months of age in children in areas of moderate and high P. falciparum malaria transmission.1 So far, more than 4.5 million vaccine doses have been administered to children in Africa.2 In July 2023, the WHO announced that 18 million vaccine doses are being distributed in 12 African countries during the next two years; global partners are working with national health departments to make even more vaccine available.2
Data collection continues in Kenya, Ghana, and Malawi to further characterize the effects of the fourth dose and to monitor long-term consequences of vaccination.2 A second malaria vaccine, R21/Matrix-M, is under consideration by the WHO; having that option available would allow for more rapid availability of vaccine for more children.2 Pending approval of the R21/Matrix-M sporozoite vaccine, production capabilities already are in place with potential to produce 200 million vaccine doses per year.3
While development of COVID-19 vaccines took a couple of years, development of malaria vaccines has required several decades. Scientific inquiry and discussion around COVID-19 vaccines were associated with conspiracy theories and wild claims of danger. Fortunately, the development of malaria vaccines has not been associated with such wildly unfounded speculations. Thus, the “dissenting” views of Björkman and colleagues are scientifically based and welcomed. These views serve as a clarion call to remain scientifically vigilant, but they need not slow current progress that could, with widespread vaccination, save the lives of half a million children per year.
A systematic review of 35 RTS,S vaccine safety studies concluded that serious adverse events were not more common in vaccine recipients as compared to controls.4 They also referred to the WHO paper about the initially observed male-female differences in mortality, agreeing with the conclusion that those statistical differences likely were “chance findings.”5 (Of course, a P value < 0.05 indicates that there is up to a 5% chance that the findings between the two groups actually are not different.)
Björkman and colleagues carefully reviewed data of many studies and identified several good reasons for ongoing vigilance and careful analysis of emerging data as RTS,S/AS01 vaccine use is broadly implemented. This makes sense, also because widespread malaria vaccination presumably will reduce the transmission of malaria; with altered incidence rates as malaria becomes less common, the vaccine might demonstrate less markedly favorable effects on outcomes.6
Thus, the RTS,S/AS01 malaria vaccine is not dangerous, even though ongoing post-marketing surveillance is warranted. The claims of the efficacy of this vaccine are not dubious, having been confirmed in many countries in Africa. And, to save lives of the 500,000 African children dying of malaria each year, ongoing vaccination of children residing in areas of moderate- and high-intensity malaria transmission definitely is warranted.
REFERENCES
- Sinnis P, Fidock DA. The RTS,S vaccine—a chance to regain the upper hand against malaria? Cell 2023;185:750-754.
- World Health Organization. RTS,S vaccine. Published July 7, 2023. https://www.who.int/news-room/questions-and-answers/item/q-a-on-rts-s-malaria-vaccine
- Gavi: The Vaccine Alliance. Five things you need to know about the new R21 malaria vaccine. April 5, 2023. https://www.gavi.org/vaccineswork/five-things-you-need-know-about-new-r21-malaria-vaccine
- Yihunie W, Kebede B, Tegegne BA, et al. Systematic review of safety of RTS,S with AS01 and AS02 adjuvant systems using data from randomized controlled trials in infants, children, and adults. Clin Pharmacol 2023;15:21-32.
- World Health Organization. Malaria vaccine: WHO position paper – March 2022. Weekly Epidemiol Rec 2022;97:61-80.
- Bell GJ, Goel V, Essone P, et al. Malaria transmission intensity likely modifies RTS,S/AS01 efficacy due to a rebound effect in Ghana, Malawi, and Gabon. J Infect Dis 2022;226:1646-1656.
