Is RTS,S the malaria vaccine we need?

The World Health Organisation has announced their intention to run three pilot projects within Sub-Saharan Africa for the first malaria vaccine. Due to begin in 2017, the pilots will will answer remaining questioning regarding RTS,S/AS01, which is the result of an enormous 32 years of research from partnerships between GlaxoSmithKline, the PATH Malaria Vaccine Initiative (MVI) and Walter Reed Army Institute of Research. Composed of a viral Hepatitis B surface antigen-like particle, an adjuvant to improve immunogenicity and a section of Plasmodium falciparum circumsporozoite protein, RTS,S represents the only candidate to have completed Phase II trials. 

Despite this success, vaccine efficacy has been found to fall far short of the 75% benchmark. With protection levels reported to be controversially low, what can we really expect from RTS,S?

Development timeline of the RTS,S vaccine shows the path from 1987 to 2014. Since creation of this figure, the vaccine has received a positive opinion from the European Medicines Agency and African countries are applying to national regulatory authorities for vaccine approval. 

The WHO seeks to answer these questions, with the pilot programmes aiming to "evaluate the feasibility of delivering the required 4 doses of RTS,S; the impact of RTS,S on lives saved; and the safety of the vaccine in the context of routine use". The replicability of protection levels has also been queried, with researchers advising four doses to provide maximum efficacy. This in itself could be problematic without comprehensive healthcare infrastructure. Summaries of the available Phase III trail data by Gosling and von Seidlein (2016) found the addition of the fourth booster justified, as in 6 - 12 week infants vaccine efficency rose from 18% to 25%, and in children 5 - 17 months old this rose from 28.3% to 36.3%. 

If RTS,S isn't the answer, where are the other candidates for malaria vaccines? Jack has previously posted regarding the types of malaria vaccine, and the WHO estimates the 20 candidates currently at various stages of the pipeline are all 5 - 10 years behind RTS,S. One of these candidates - PfSPZ, Sanaria - is composed of radiation-attentuated, whole sporozoites and has recently been reported to deliver full protection up to 25 weeks after innoculation. A recent review by Cowman et al (2016) highlights that this candidate lacks the stability of RTS,S, requiring liquid nitrogen to maintain viability which will undoubtedly be a logistical issue. It will be interesting to follow PfSPZ through more extensive trials to see if those statistics hold, but it should also be noted that this vaccine was also using a 4 dose schedule. 

Summarising the benefits and drawbacks of RTS,S, what can we expect from this vaccine? Whilst RTS,S could be integrated into current malaria control schemes, it is easy to be disappointed by the low levels of protection granted. At the beginning of this post I underlined the sheer amount of effort and time funneled into vaccine development, and for it still to fall short is hugely discouraging. Whilst the more cynical among us might argue that RTS,S is no solution in our fight against malaria, I find it important to consider the severity of the disease in sub-saharan Africa. Within this context any new tools are welcome, especially should we wish to continue reducing malarial burden. The WHO's decision to further test RTS,S is prudent but should they not seek to implement vaccination programs after pilot programmes have finalised it would be interesting to see if RTS,S would survive. If nothing else, the public and academic support for malaria vaccines generated by RTS,S should ease the passage of future vaccine candidates.

References

1. Gosling, R., and von Seidlein, L. (2016). The Future of the RTS,S/AS01 Malaria Vaccine: An Alternative Development Plan. PLoS Medicine 13(4) pp. 312-315
   
2. Ishizuka, A.S., Lyke, K.E., DeZure, A., Berry, A.A., Richie, T.L., Mendoza, F.H., Enama, M.E., Gordon, I.J., Chang, L.-J., Sarwar, U.N., et al. (2016). Protection against malaria at 1 year and immune correlates following PfSPZ vaccination. Nature Medicine 6, pp. 614–623.
   
3. Cowman, A.F., Healer, J., Marapana, D., and Marsh, K. (2016). Malaria: Biology and Disease. Cell 167, pp.610–624.