The Roll Back Malaria Partnership talks confidently of elimination—many others question if this is possible without new interventions. The recent publication of the first Phase 3 clinical trial for a malaria vaccine shows promise, but is it actually good enough?

REVIEW OF:

• Roll Back Malaria Partnership, “Eliminating Malaria: Learning from the Past, Looking Ahead”, Progress & Impact Series, vol 8, October 17^th, 2011
• RTS,S Clinical Trials Partnership, “First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Children”, New England Journal of Medicine, October 18^th, 2011

This past week has been a busy one in the world of malaria research and control. On Monday, the Roll Back Malaria Partnership (a joint enterprise between the World Health Organisation, UNICEF, UNDP and the World Bank) released the 8^th volume in its Progress & Impact Series, entitled, “Eliminating Malaria: Learning from the Past, Looking Ahead”. The report summarizes RBM’s malaria eradication and elimination efforts to date, and outlines action plans and on-going progress in all malaria-endemic countries around the world. The overall tone of the document is highly positive, emphasizing the various success stories of countries achieving or nearing elimination of malaria in different parts of the world.

This is nowhere more obvious than in Chapter V’s regional summary of the WHO African Region, where no mention is made of the countries that are struggling the most with malaria control, but instead the focus is entirely on congratulating the 4 countries that have already achieved elimination, and praising those 12 countries with existing or imminent plans to move towards elimination. The document as a whole is a comprehensive overview of the status of malaria control, although somewhat light on epidemiological specifics. I was also dismayed to see at least two large photographs of fingerprick blood samples being taken without protective gloves being worn, against all standard diagnostic protocol!

But that’s an aside. In their conclusion, the authors primarily support “existing interventions”, and caution against waiting for “better options” to become available, given the measurable successes already being achieved in many settings using already-available control strategies such as bednet distribution, improved access to diagnosis and treatment and vector control.

It is not perhaps without a touch of irony then that on Tuesday, the first comprehensive analysis of an on-going Phase 3 clinical trial for one of the most promising malaria vaccine candidates was published, in the New England Journal of Medicine. The quest for a malaria vaccine has been protracted, expensive and, thus far, basically unsuccessful, yet to many, global elimination of malaria will not succeed without an intervention that gives lasting protection against re-infection, given the extraordinarily high rates of transmission of malaria in some parts of the world.

The paper reports a reduction of clinical malaria and severe malaria by 56% and 47% respectively, although protection seemed to decay over time; further evaluations will be analysed in 2012 and at the conclusion of the trial in 2014. The authors of the paper are careful to note that the trial was conducted in a cohort with generally good access to medical care, well-supplied health facilities and widespread usage of bednets and other control interventions. As such, mortality from malaria was low even in the control group, and so conclusions about the impact of the vaccine on malaria-related deaths may be difficult to draw.

Moreover, the paper did not directly analyse the relationship between the antibody titers (levels of immune protection to malaria in the blood) conferred by the vaccine and if the patient got malaria or not. In previous studies (for example, Bejon et al.’s 2008 paper also in the NEJM), this relationship was weak, suggesting that the vaccine itself was not contributing strongly to levels of protection against infection, and that other factors were at play. One suggestion is that the adjuvant, a non-specific immune-response enhancer included in the vaccine, may itself play a role, and given that the control groups received vaccines with a different adjuvant, this may partially account for the variations in malaria prevalence seen between the children studied. However, these early data still show potential at least for reducing clinical cases of malaria in a highly-endemic African setting.

It should be noted that these findings do not come entirely as a surprise; there were early signs of potential, at least partial, protection from this vaccine (the results of the Phase 2b trials were published in The Lancet back in 2004). Despite this, the word “vaccine” is mentioned but twice in the latest RBM report. I have a deep admiration for the RBM and all that the partnership has achieved thus far in the struggle to control malaria throughout the world. Without a doubt, the scale of the problem is immense, and they are right to emphasise the enormous achievements many countries have realized, and particularly in reducing malaria mortality in the last 10 years. Nor would I advocate for countries to latch onto the promise of a vaccine too quickly; clearly more research is needed to evaluate the long-term efficacy of the vaccine, as well as its impacts specifically on mortality as opposed to morbidity; hopefully we will have some of these answers in a year, at the conclusion of the Phase 3 trial.

However, in the meantime, there is clearly a huge opportunity for using these preliminary findings to determine what role there might be, if any, for the vaccine in its existing form as part of new and improved control strategies. For example, if the vaccine is not fully protective, might it, perhaps counter-intuitively, actually be more effective in areas which are already well on their way to successful control, by reducing transmission below that which is viable for the persistence of malaria? Or will its role in reducing incidence of severe disease be equally well utilized in extremely high prevalence and low health infrastructure areas, where access to diagnosis and treatment is the limiting step in effecting control? To its credit, RBM has acknowledged this since the publication of the vaccine trial results, with the following statement from the CDC: “These promising vaccine trial results add to the hope that adding an effective vaccine to current malaria interventions will move us closer to that goal.” Perhaps the “better option” wasn’t so long in coming after all.