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.

“Malaria drugs fail for first time on patients in UK”

A recent news article by the BBC reported that four cases of malaria in the UK failed to respond to artemether-lumefantrine treatment, the current front-line drug combination recommended by the WHO. Drug resistance to older antimalarial drugs, like chloroquine, is already widespread in many countries with endemic malaria. It spreads faster in areas where treatments have been dispensed inappropriately, because this fosters selection for resistant strains, similarly to antibiotic resistance. WWARN (worldwide antimalarial resistance network) has an excellent series of interactive maps that you can use to explore the available data on antimalarial resistance.

Of particular concern is resistance to artemisinins – a group of drugs which are the key component in the artemisinin-combined therapies recommended by the WHO. These are well tolerated therapies with high effectiveness, assuming the full course of treatment is taken. However, in certain areas where healthcare has not been well managed, or access to drugs is available without appropriate medical advice, artemisinin resistance has spread rapidly and pervasively. This is shown well in the map produced by Ashley et al., which demonstrates the prevalence of a certain cause of resistance in South East Asia.

A map produced by Ashley et al., showing prevalence of PfKelch13-associated artemisinin resistance in S.E. Asia, and the limited spread of PfKelch13-independent resistance in Africa.

The exact mechanism of resistance to artemisinin is still contested, with several ideas proposed so far but no consensus has yet been achieved. Part of the reason for this is that we still don’t really know how artemisinin kills the parasite in the first place… What we do know however, by using Genome Wide Association Studies of parasite genomes, is that mutations in the “Kelch-propeller domain” of Plasmodium falciparum Kelch13 are strongly associated with cases of artemisinin resistance. Kelch-propeller domains are used for protein:protein interactions, and can be very specific. K13 belongs to a superfamily of proteins known to mediate ubiquitin-regulated protein degradation and oxidative stress-responses, which plays into some theories suggesting that artemisinin acts by generating reactive oxygen species, thereby causing oxidative stress.

While mutations in PfK13 are certainly common in resistant cases (again, particularly in S.E. Asia), they aren’t constant. As seen in the map above, African cases of artemisinin-resistance are mostly not found to have any mutations in PfK13. Instead, variable artemisinin efficacy appears to be linked to multi-locus genotypes involving other resistance-associated proteins such as PfMDR1 (a multi-drug resistance pump) and PfCRT (a chloroquine resistance-associated transporter protein), along with less well understood proteins such as PfUBP1 and PfAP2MU. Worryingly, the diverse causes of artemisinin resistance suggest multiple, independent evolutions of resistance in isolated Plasmodium populations.

Going back to the original point of this post, the BBC article “Malaria drugs fail for the first time on patients in the UK”, we should look at the source of this information. This is a brief report of four case histories of patients with imported malaria that were initially treated with artemether-lumefantrine but presented with recurrent parasitaemia within 6 weeks of treatment with no intervening travel to malaria-endemic areas. In English, this means patients that caught malaria outside of the UK were treated to the point where they seemed healthy, but were then readmitted at a later date with the same symptoms without an opportunity to catch it again. Two patients had been to Uganda, one to Liberia and one to Angola – all in Africa. As you might be able to guess, when profiled for resistance markers, none of the parasites these patients were infected with had any PfKelch13 mutations. Instead, they had a variety of mutations in other loci known to be associated with resistance, shown in table 1.

Ultimately all patients were successfully treated with alternative drug combinations such as atovaquone/proguanil, quinine/doxycycline or artemether/lumefantrine with doxycycline so the initial headline may be slightly exaggerated when you take the full picture into account. However, this is still an important news story as it is the first time artemisinin resistance has been seen in the UK. As resistance spreads throughout Africa these cases will only become increasingly common, so finding appropriate alternatives is a necessary task. 

The BBC article includes an interview with Dr Sutherland, the lead researcher, who stresses that while this is not yet a national health crisis it is important for doctors to be aware that drugs may not work and says drug guidelines should be reviewed. He also suggested that large scale studies of drug efficacy need to be urgently undertaken in Africa to determine the severity and scale of the problem we could be facing very soon.

Personally, I feel that while this is a very important news story, the fact that just four UK cases made headlines while thousands occur every year abroad is telling of people’s attitudes in the UK. The spread of drug resistant malaria is very real and a very serious concern to people living in malaria endemic areas, causing death on a huge scale, but is not on the radar for most people until it directly concerns them. I think awareness needs to be raised about this as an issue that faces other countries, not just ours. I’d like to know if you agree or disagree, and if you have any ideas about ways we could achieve this goal – let me know in the comments.