The Lancet July 04, 2015

Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial

RTS,S Clinical Trials Partnership

Bottom Line

The final results of a landmark Phase 3 trial demonstrated that the RTS,S/AS01 malaria vaccine, when administered with a four-dose schedule, provided significant albeit modest protective efficacy against clinical malaria in African children over nearly four years of follow-up.

Key Findings

1. Among children aged 5-17 months, vaccine efficacy against clinical malaria was 36.3% (95% CI 31.8-40.5) in the group receiving 3 initial doses plus a booster (R3R), compared to 28.3% (95% CI 23.3-32.9) in the group without a booster (R3C).

2. Among young infants aged 6-12 weeks, vaccine efficacy against clinical malaria was lower: 25.9% (95% CI 19.9-31.5) with a booster and 18.3% (95% CI 11.7-24.4) without.

3. Vaccine efficacy against severe malaria in children 5-17 months was 32.2% (95% CI 13.7-46.9) in the booster group, whereas the non-booster group showed no significant protection (1.1%, 95% CI -23.0 to 20.5).

4. Despite modest relative efficacy, the absolute impact was substantial: the booster regimen averted 1,774 cases of clinical malaria per 1,000 children (95% CI 1,387-2,186) aged 5-17 months, and 983 cases per 1,000 infants (95% CI 592-1,337) aged 6-12 weeks.

5. Safety analyses identified an increased risk of febrile convulsions within 7 days of vaccination, as well as an unexplained higher incidence of meningitis and cerebral malaria in the older children group receiving the RTS,S vaccine.

Study Design

Design

Randomized Controlled Trial

Double-Blind

Sample

15,459

Patients

Duration

38-48 mo

Median

Setting

7 African countries

Population African infants aged 6-12 weeks (N=6,537) and children aged 5-17 months (N=8,922) at the time of first vaccination.

Intervention RTS,S/AS01 malaria vaccine administered as 3 initial doses at months 0, 1, and 2, with or without a booster dose at month 20.

Comparator Control vaccine regimen (rabies vaccine for children 5-17 months, or meningococcal C conjugate vaccine for infants 6-12 weeks).

Outcome Vaccine efficacy against clinical malaria (illness with fever ≥37.5°C and P. falciparum parasitemia >5,000 parasites/μL) over the entire study duration.

Study Limitations

• Vaccine efficacy is modest overall and wanes noticeably over time, necessitating a booster dose to maintain clinically meaningful protection against severe malaria.

• Efficacy was substantially lower in the 6-12 week age group, complicating its potential integration into the standard early-life Expanded Programme on Immunization (EPI) schedule.

• An unanticipated safety signal concerning increased rates of meningitis and cerebral malaria in the older cohort could not be fully explained by the trial and required extended pharmacovigilance and pilot implementation studies.

• Because of the high standard of care provided during the trial and the resulting low overall mortality, the study was underpowered to demonstrate a statistically significant reduction in all-cause or malaria-specific mortality.

Clinical Significance

This trial provided the definitive data for RTS,S/AS01 (Mosquirix) to become the world's first approved malaria vaccine. Although the relative efficacy was lower than traditional childhood vaccines and waned over time, the tremendous baseline burden of malaria meant that the absolute number of cases averted was exceptionally high. The trial established the necessity of the four-dose regimen and paved the way for real-world pilot implementation programs, ultimately leading to the WHO's historic recommendation for its broad use in sub-Saharan African children.

Historical Context

Development of the RTS,S vaccine, which targets the circumsporozoite protein of Plasmodium falciparum, began in the 1980s through a collaboration between GlaxoSmithKline and the Walter Reed Army Institute of Research, later joined by the PATH Malaria Vaccine Initiative. Following promising Phase 2 data, this Phase 3 trial was launched across 7 African nations and was the largest clinical trial ever conducted in Africa at the time. Its 2015 final publication marked a massive milestone in a decades-long effort, prompting a positive scientific opinion from the European Medicines Agency (Article 58) and reshaping global malaria prevention strategies.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the RTS,S/AS01 vaccine target the Plasmodium falciparum parasite, and why is this specific stage of the life cycle chosen for vaccine development?

Key Response

RTS,S targets the circumsporozoite protein (CSP) of the P. falciparum sporozoite. This aims to neutralize the parasite immediately after the mosquito bite and before it infects hepatocytes, preventing the blood stage infection which is responsible for clinical symptoms.

Resident

Given the modest efficacy of the RTS,S vaccine (around 30-40 percent over 4 years with a booster), how should clinicians counsel parents regarding concurrent malaria prevention strategies like insecticide-treated nets?

Key Response

The vaccine does not provide sterilizing immunity. It is crucial to emphasize that RTS,S is a complementary tool, not a replacement. Residents must know to strongly advocate for continued use of insecticide-treated nets, indoor residual spraying, and prompt antimalarial treatment for febrile illnesses.

Fellow

The trial evaluated both a 3-dose schedule and a 4-dose booster schedule. What is the immunological basis for the waning efficacy seen in the 3-dose group, and why is the booster dose considered critical for long-term protection?

Key Response

Anti-CSP antibody titers wane rapidly following the primary series, correlating directly with a loss of clinical protection against malaria. The booster dose is necessary to restore protective antibody thresholds and memory B-cell responses, which are essential for maintaining efficacy in high-transmission settings.

Attending

In areas with highly seasonal malaria transmission, how might the timing of the RTS,S vaccine administration be optimized compared to the standard age-based schedule to maximize its modest efficacy?

Key Response

Seasonal administration of the vaccine or its booster just prior to the peak transmission season, akin to seasonal malaria chemoprevention, can align the highest antibody titers with the highest risk period. This substantially increases the practical clinical impact and reduces severe malaria morbidity.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The trial utilized an individually randomized, controlled design across 11 sites with varying malaria transmission intensities. How does this heterogeneity affect the interpretation of vaccine efficacy, and what statistical models best account for transmission intensity as an effect modifier?

Key Response

Vaccine efficacy against clinical malaria tends to be lower in higher transmission settings due to the larger cumulative force of infection overcoming the vaccine-induced barrier. Analyzing this requires transmission-stratified models, such as Cox proportional hazards or Poisson regression adjusting for site-specific incidence, to understand where the vaccine has the highest public health impact.

Journal Editor

The trial reported a potential safety signal regarding an increased rate of meningitis and cerebral malaria in the RTS,S groups. How should a peer reviewer evaluate whether this is a causal relationship or a statistical artifact of multiple testing, and what post-market data would resolve it?

Key Response

Editors must scrutinize unexpected safety signals. The reviewer would flag the need to assess biological plausibility, temporal relationships, and background rates. Resolving this requires large-scale Phase 4 pharmacovigilance studies or cluster-randomized pilot implementations to rule out chance findings due to the sheer number of adverse events tracked.

Guideline Committee

Based on the modest efficacy and the requirement for a 4-dose schedule, how should the WHO integrate RTS,S/AS01 into current malaria control guidelines for Sub-Saharan Africa, particularly concerning the allocation of limited public health resources?

Key Response

The guideline committee must weigh the cost-effectiveness of RTS,S against expanding existing interventions like seasonal malaria chemoprevention. The recommendation should stipulate RTS,S as an addition to standard core interventions in moderate-to-high transmission settings, requiring a strong health system infrastructure to deliver the crucial fourth booster dose at 2 years of age.

Clinical Landscape

Noteworthy Related Trials

2004

RTS,S Phase 2b Trial in Mozambique

n = 2,022 · Lancet

Tested

RTS,S/AS02A malaria vaccine

Population

Children aged 1-4 years in Mozambique

Comparator

Control vaccines (pneumococcal or Hib)

Endpoint

Time to first clinical episode of P. falciparum malaria

Key result: The vaccine reduced clinical malaria episodes by 29.9% and severe malaria by 57.7% over a 6-month observation period.

2021

SMC plus RTS,S Trial

n = 6,861 · NEJM

Tested

RTS,S/AS01 combined with seasonal malaria chemoprevention

Population

Children aged 5-17 months in highly seasonal transmission areas

Comparator

Seasonal malaria chemoprevention alone or RTS,S alone

Endpoint

Incidence of uncomplicated clinical malaria

Key result: Combining RTS,S with seasonal malaria chemoprevention resulted in a significantly lower incidence of clinical malaria and severe malaria than either intervention alone.

2024

R21/Matrix-M Phase 3 Trial

n = 4,800 · Lancet

Tested

R21/Matrix-M malaria vaccine

Population

African children aged 5-36 months

Comparator

Rabies vaccine (control)

Endpoint

Incidence of clinical malaria over 12 months

Key result: The R21/Matrix-M vaccine demonstrated 75% efficacy against clinical malaria, meeting the WHO target for malaria vaccines.

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