The results of the Phase III trial of the malaria vaccine RTS,S/AS01 are greatly disappointing. The efficacy of the vaccine in preventing clinical and severe malaria in infants aged 6 to 12 weeks is much less than what was expected. In fact, the level of protection offered is nearly half of what was reported last year in older children (5 to 17 months).
The vaccine efficacy (in infants aged 6-12 weeks) was about 31 per cent in the case of clinical malaria and 37 per cent in the case of severe malaria. In the case of older children (5 to 17 months), reported last year, the protection offered was nearly 56 per cent in the case of clinical malaria and about 47 per cent for severe malaria. The efficacy against severe malaria in both the groups combined was nearly 35 per cent. Totally, 6,537 infants were studied.
The current data on infants is also lower than what was seen in the Phase II trial results from three of the 11 centres. The protection against clinical malaria was 61.6 per cent. According to Nature, nearly 60 per cent of clinical malaria cases were reported from just two of the 11 sites. The trial is being conducted in 11 centres across seven countries in Africa.
What then could have caused a severe drop in the protection efficacy? One of the possibilities could be the severity of malaria transmission. The Phase II results were from three centres that had only low to moderate malaria transmission. In the case of the Phase III, it also included centres that had high malaria transmission. The real implications of vaccine protection in high malaria transmission areas will be clear when the complete data is analysed in 2014 after a 30-month follow-up.
What is more disappointing is the drastic reduction in efficacy during the 12-month follow-up period. The efficacy was “higher at the beginning than at the end of the follow-up period” found the study, published a few days ago in The New England Journal of Medicine . If the protection efficacy does wane with time, several factors may make younger infants more vulnerable than older children, the paper suggests.
What then could be the possible reasons for the disappointing protection levels seen? One could be the lower protection in areas that had higher malaria transmission. Another could be the difference in immune response between the infants and the older children included in the trial. Evidence favouring this was earlier seen during the trial. The co-administration of other vaccines along with the malaria vaccine could be another. Finally, the presence of maternal antibodies in infants could have played a role in protecting them (both the vaccine and control groups) from malaria, thereby reducing the differences seen in the two groups.
The vaccine has been developed primarily for infants and children in sub-Saharan Africa. The reasons are obvious: of the 216 million cases of malaria and 6,55,000 malaria-related deaths in 2010, a majority of deaths took place in African countries.
Even as many newspapers went overboard last year based on results from the older age group, the 2011 Editorial accompanying the paper in The New England Journal of Medicine explicitly stated: “there does not seem to be a clear scientific reason why this trial has been reported with less than half the efficacy results available.”
The 2011 paper concluded with a rider that the “vaccine has the potential to have an important effect on the burden of malaria in young African children.” The rider was: the “vaccine efficacy among younger infants and the duration of protection will be critical to determining how this vaccine could be used effectively to control malaria.”
In that sense, the latest results do dampen the high spirits seen last year. The last word is yet to be pronounced. One has to wait till 2014 when the complete data is analysed and the outcome is known. Only then can it be said with any certainty if the vaccine will indeed be included for use in the African countries as per WHO recommendations. WHO had taken the unusual decision last year when it had “recommended” its use in the African countries as early as 2015.