[In The News] Modest protection conferred by malaria vaccine in phase 3 trial

Image: PD/NIH

Key study points: 

1. In infants 6 to 12 weeks of age, the RTS,S/AS01 vaccine was 31.3% effective in preventing clinical malaria and 36.6% effective in preventing serious malaria. This was lower than expected based on previous studies. 

Primer: The malaria parasite has a complex life cycle with a mosquito stage and a human stage. Parasites in the sporozoite form enter the human host through the bite of an infected mosquito. In the liver phase of the infection, the parasite reproduces within hepatocytes. Subsequently, the parasites enter the blood stream and initiate the erythrocytic phase of the life cycle.

The RTS,S/AS01 vaccine, which is being developed by GlaxoSmithKline with support  from the PATH Malaria Vaccine Initiative and the Bill and Melinda Gates Foundation, targets the pre-erythroctic phase of the parasite life cycle in humans. The key antigen in the vaccine is the circumsporozoite protein, which is expressed by sporozoites and liver forms of the parasite.

This phase 3 trial had previously reported that in children 5 to 17 months of age at time of vaccination, vaccine efficacy against clinical malaria was 55.8%; and vaccine efficacy against severe malaria was 47.3%. These results were consistent with phase 2 studies that had reported vaccine efficacies of 60-65%.

The present report looks at the efficacy of the vaccine when administered to infants in the 6 to 12 week age range. In this age group (but not the 5 to 17 month age group), the study vaccine was delivered together with vaccines in the Expanded Program on Immunization (EPI). The authors envision RTS,S/AS01 ultimately being added to the EPI package of vaccines, so the results in this age cohort are of particular interest. 

Background reading:

1. Article in the New York Times

2. Results from older (5 to 17 months) children in the same study

3. Phase 2 trials of the vaccine reporting efficacy and safety: 1, 2, 3, 4

4. A 2009 overview of the development of RTS,S/AS01 

This [randomized, controlled, double-blind] study enrolled 6,537 infants 6 to 12 weeks of age. 4,358 infants were randomized to receive the vaccine. 2,179 infants received a meningococcal vaccine as a control. The full course for RTS,S/AS01 involves 3 monthly doses

In the 12 months following vaccination, the incidence of clinical malaria was 0.37 per person-year in the RTS,S/AS01 group and 0.48 per person-year in the control group; vaccine efficacy was 31.3% (97.5% CI, 23.6 to 38.3). 1.5% of the infants in the RTS,S/AS01 group had at least one episode of severe malaria, compared to 2.3% of infants in the control group. In this respect, vaccine efficacy was 36.6% (95% CI, 4.6 to 57.7).

Adverse events between the two groups were similar, suggesting that the vaccine was well- tolerated. No deaths were attributed to the study vaccine.

In sum: The efficacy of RTS,S/AS01 in infants 6 to 12 weeks of age is less than in infants 5 to 17 months old. The efficacy observed here is also less than in a smaller phase 2 trial with a similar protocol that involved 3 of the same trial sites.

The authors propose several explanations for this discrepancy. They note that the younger infants generated lower titers of antibodies to the circumsporozoite antigen compared to the older infants (209 EU/mL vs. 621 EU/mL), but they also acknowledge that this does not necessarily correlate with protection. Vaccination earlier in life and co-administration with the EPI vaccines can also present other issues. For example, maternal antibodies may “protect” the infant from the vaccine antigens, reducing the infant’s immune response to the vaccine. The authors also suggest that there may be site-specific differences related to the malaria transmission intensity at each site.

Taking this and previous results into account, it appears that the RTS,S/AS01 vaccine does have a protective effect. However, since this effect is modest and varies between some populations, more work is needed to determine how to maximize its efficacy and how best to employ it in malaria control efforts.

Click to read the study in [NEJM]

By [TJ] and [MP]

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