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Why do novel vector control tools have to be perfect if the RTS,S vaccine isn't?

October 22, 2015 - 21:46 -- Bart G.J. Knols

Last month there was great news for the malaria world: A detailed analysis of the impact of insecticide-treated bednets (LLINs), ACTs, and indoor residual spraying (IRS), showed that some 6.2 million deaths and 700 million cases were averted between 2000-2015, mostly since 2005. Add up the contribution of the vector control components, and it shows that 78% of all the gains originated from just these two tools: LLINs and IRS. Is it safe to draw the conclusion from this that vector control is and shall remain the integral and critical component that will lead us to a world without malaria by 2040? I think the answer to that is 'yes, very much so'.

However, it is also abundantly clear that LLINs and IRS are not sufficient to bring transmission down to zero in many parts of Africa, the hotbed of malaria. So, the logical reasoning then is to come up with additional tools to target the vectors, preferably in harmony with the tools we already have. For years we have read that 'the toolbox needs filling up' and that's going on at present. A variety of new vector control tools as well as novel insecticides are slowly passing through the pipeline.

In spite of this massive success, it also needs to be acknowledged that what we currently have and use on a massive scale isn't perfect: nets are not the silver bullet, nor is IRS. Numerous reports of non-use or misuse of nets have been published, and IRS coverage in many places is far from optimal due to refusals of houseowners to have their houses sprayed. Not to mention the problems with insecticide resistance and changes in vector behaviour we currently witness.

Interestingly, whatever science comes up with these days, it seems that we are no longer satisfied by any of it. New tools have to be absolutely perfect. They need to be dirt cheap, highly effective across the continent, work against all vectors, need to be resistance-breaking, safe, fool-proof, low-tech, and of course accepted by communities that preferably are also willing to pay for them. As vector biologists we are challenged by what may seem the impossible.

Now let's contrast this for a minute with the position of vaccinologists in search of the holy grail: A one-off shot that provides life-long protection against malaria. Not just against falciparum, but against all five species of Plasmodium. If we are faced with similar challenges in our respective disciplines than this is what they are faced with. One shot that provides life-long protection.

So now let's take a look at the RTS,S vaccine. After an investment of USD 565 million by the pharmaceutical company GSK and the Bill and Melinda Gates Foundation, reports from Phase III trials earlier this year showed that protection following vaccination is far from optimal, reaching barely 40% in young children and 26% in infants. Is it a one-off shot? No, it requires 3 shots in the first 3 months and a booster shot in month 18. Does it protect against all Plasmodium species? No, only against falciparum.

This week the New England Journal of Medicine published a paper that appears to shed light on the poor performance of the vaccine. The circumsporozoite protein on which the vaccine is based apparently works well against certain parasite strains but is a 'mismatch' against others. Re-engineering the vaccine to work against more parasite strains could resolve this issue, but, according to Joe Cohen who worked with GSK on the vaccine, when interviewed by Nature, said that this would essentially create a new vaccine that would have to pass through all stages, pushing it into the future by 10-15 years.

As it is, the World Health Organization will soon make a decision to move forward with the RTS,S vaccine or not. The outcome of their deliberations will be extremely interesting. Should a vaccine with a protective efficacy as low as RTS,S has provided become the next big thing in the malaria world? I leave it to you to answer this.

However, if it will, should we then not also start to become more realistic about our expectations from new vector control tools? For example, why do we accept that children need to be vaccinated four times with RTS,S over the course of 18 months but have set the goal that a residual insecticide has to work for a minimum of 6 months (since that is what we got with the golden standard DDT)? Why would 3 or 4 months not be sufficient? If the vaccinologists (rightly so) use the argument that a partially effective vaccine will still save many lives, then why wouldn't the same argument count for an insecticide that works for only 3 months? If 4 vaccinations with RTS,S will cost an estimated USD 20 per child, let's say USD 60-80 for a household with 3 kids, then why does new vector control technology have to cost no more than USD 1 per child per year because that's what an LLIN will cost?

The RTS,S vaccine got this far because those behind it persevered, had faith, maintained a critical mass of support within GSK and the vaccinology community, and stayed pragmatic. Problems were faced and resolved, and albeit not perfect, it is now in the hands of WHO. Maybe the vector control community can learn from all this and take the lesson that even if our solutions are not perfect these will still save many lives. If anything, have we not proven this with nets and indoor spraying?

Comments

Bart G.J. Knols's picture
Submitted by Bart G.J. Knols on

Read about todays views of WHO: http://www.reuters.com/article/2015/10/23/us-glaxosmithkline-malaria-idUSKCN0SH1F220151023

Read the media release from WHO (23 October) here: http://who.int/mediacentre/news/releases/2015/sage/en/

Submitted by Bill Jobin (not verified) on

It is really encouraging to see that WHO Geneva has not been swept away by the drug and vaccine makers, and is justifiably skeptical about the usefulness ( or not ) of this trial vaccine.

Bill Jobin

Graham Small's picture
Submitted by Graham Small on

I totally agree with Bart's point that LLINs and IRS formulations, even when these incorporate actives which are not resisted by locally dominant vectors of malaria, will not offer sufficient vector control if the aim is malaria eradication. Novel vector controls must be developed and implemented which target the control of vectors not controlled by these two interventions. However, I disagree with Bart's suggestion that these novel vector control tools will be expected to be perfect: after all, LLINs and IRS do not perform perfectly. What is required is a consensus on the basic characteristics that these novel tools must have in order for them to be included in the vector control toolbox, i.e. their target product profiles. Once we've defined these TPPs, we can focus research effort on developing novel interventions that meet them.

Bart G.J. Knols's picture
Submitted by Bart G.J. Knols on

Thank you, Graham, for these valuable comments. What's next then is standardised TPP's for the various products that are under development. I know that IVCC and WHO's VCAG ask for such a TPP when submitting new products/ideas, but are you suggesting that these should become more generalised and widely available as 'standards'? And if so, then who should take on this task of developing these TPP's?

Graham Small's picture
Submitted by Graham Small on

Yes, it will be important for TPPs to be developed for all types of novel vector control products for use by researchers, funders and other interested parties. IVCC has developed TPPs for LLINs, IRS formulations and new AIs: a small group composed of experts from different disciplines (biology, chemistry, formulation, etc.) helped IVCC to draft TPPs which were then critiqued and finalised by IVCC's Expert Scientific Advisory Committee (ESAC1). These TPPs are made available to companies/research groups approaching IVCC with possible product development projects in these areas. I'd suggest that a similar process could be used for the drafting of TPPs for novel vector control products. The development of these TPPs is likely to prove much more challenging than for vector control products we already know a lot about. As to who should take on the task of developing these TPPs, it's likely that IVCC is already thinking about how best to move forward with this as it develops its 'new paradigms' project portfolio but I don't know where it has reached in this process.

Bart G.J. Knols's picture
Submitted by Bart G.J. Knols on

Thanks, Graham. I have sent a message to Michael MacDonald and asked him to provide input on this. Let's hope he will comment and shed some light regarding this important matter.

Bart G.J. Knols's picture
Submitted by Bart G.J. Knols on

It describes the (wanted or desired) characteristics of a product, often in relation to other similar products.

Guy Reeves's picture
Submitted by Guy Reeves on

Hi Bart
In response to you original article I do appreciate your point about the downsides of unrealistic expectations and chasing only near universal solutions.

However in pursuing potentially valuable tools which do not meet 'perfection criterion' might it be important to make a clear division between novel tools with
(a) well established properties/tolerances due to a diverse and extensive evidence base,
versus,
(b) those where universal-success is also not guaranteed, in part, because of a limited or inadequate evidence base?

Could failing to make this distinction contribute to unfortunate abandonment and frustration with experimental control techniques?

Cheers Guy

MPI, Plön (Germany)