A malaria vaccine over two decades in the making given to infants in Africa was shown by preliminary data to be 30% effective. Good news or bad news?
It depends on who you talk to. Most scientists and public health workers described the partial phase III clinical trial result of RTS,S/AS01 as disappointing, frustrating, or underwhelming, while trial sponsors, a few scientists, the government of Ghana, and KTN streaming LIVE from Kenya 24/7, remained upbeat, stressing that given the millions of malaria infections, a 30% reduction in would give the vaccine a significant place in malaria prevention.
In 2010 there were an estimated 216 million cases of malaria and 655,000 deaths, 91% of which were in Africa. In the past decade years, the concerted effort to combat malaria has decreased deaths and infections significantly, by 25%. But without a doubt, an effective malaria vaccine would be, if not the end of a horrible scourge, at least be an excellent addition to the arsenal of indoor spraying, bednets, and available treatment options. The question is, given the costs of developing and deploying a vaccine and the current economic climate, what's considered effective?
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This month's 31% results are disappointing compared to last year's results from older kids, 5-17 months, that showed the vaccine to be 55% effective. As well, the newest results from the Phase III trial, show about half the efficacy of those from the previous Phase II trial for the same-aged infants, which seemed to show the vaccine as 62% protective.
Not 55% but 30% Effective
The RTS,S vaccine targets the Plasmodium falciparum and is made with proteins from both the parasite and Hepatitis B virus that serves to enhance the immune response. So why is the vaccine now apparently only 31% effective at preventing infection and 37% effective at preventing severe disease, almost half what it was? Scientists have several hypotheses. It might be the high levels of malaria around the test centers included in this data release, or that increased immunity from mothers in the younger infants blunts the response of the infants' immune systems against the vaccine, or perhaps since the vaccine for the infants was administered with other vaccines the infant immune systems responded less vigorously to the malaria shot. What there's no question about is how tricky it is to make a vaccine that successfully combats infection from an evolving and evasive parasite that moves through different stages of its lifecycle in different parts of the human (host) body.
With the efficacy data so low, scientists were left emphasizing how safe the vaccine is (important, of course, but not exactly the point at this stage). They stress how successful of the logistically complicated and ambitious trial (across 11 centers in 7 countries). Indeed the trial logistics are impressive, important, and a huge inroad to drug testing and public health, but the accomplishment doesn't address the high expectations and promises made during last year's data release.
Glass Now Less Than Half-Full
While the results were discouraging, some scientists weren't surprised. When researchers announced last year's interim results some scientists predicted based on the data that the younger 6-12 week cohort would be less protected by this vaccine. This was one of several caveats scientists pointed out. They also warned against early incomplete data releases, stressed that the older children weren't the target group, and questioned various aspects of the 55% number. We covered some of these questions in a post -- the same caveats and questions apply to this year's data release.
Vaccine development, especially against malaria, is incredibly difficult. Although there are about 30 vaccines in development now, according to the World Health Organization's Rainbow Tables, the closest candidates are 5-10 years behind this one. This fact of course influences the biggest unanswered question: How effective does a vaccine need to be in order to be put into production? There are limits to both attention and money available for urgent public health initiatives, so realistically, funding one initiative can potentially handicap others - but then the argument always swings back -- there is no malaria vaccine right now.
Vaccine Goals - Made To Be Eschewed?
To help guide answers to this question, the World Health Organization, in concert with invested organizations including the public and private sponsors of this vaccine, established in a roadmap(pdf) a "Strategic Goal" to "by 2025, develop and license a malaria vaccine that has a protective efficacy of more than 80% against clinical disease and lasts longer than four years." RTS,S/ASO1 is no where near this. But the WHO also established a "Landmark" Goal, to "by 2015, develop and license a first-generation malaria vaccine that has a protective efficacy of more than 50% against severe disease and death and lasts longer than one year." WHO is currently in the process of updating the roadmap, but warns that the Landmark goal is not being changed.
All scientists acknowledge that only more data analysis from this trial will provide clearer answers. The WHO provides information on vaccine development and its role in assessing the vaccine in 2014-2015. Some scientists predict that the trend of decreasing efficacy after 6 months shown in the data looks ominous: "The results look bad now, but they will probably be worse later", said vaccine expert, researcher for competing vaccines, and deliverer of not-very-upbeat messages Adrian Hill of Oxford University. (But if subsequent data looked somewhat better - the situation of this year's results compared to last year's - the reaction would probably be euphoric.)
Last year when we discussed the vaccine we commented on possible later outcomes that could stem from the incredible hype around interim results releases -
"...which leads us to wonder whether mid-trial fanfare primes us react to whatever future malaria vaccine news comes along with knee-jerk positive determinism? What if the younger data shows only (say, hypothetically) 30% efficacy? Would we ever abandon the effort...?"
Commenting on the latest results, Andrew Witty, GSK CEO told reporters in a conference call "We've been at this for 30 years, and we're certainly not going to give up now".---------------------
In other malaria vaccine news Sanaria, another malaria vaccine maker whose founders have been knee-deep in malaria vaccines for decades, recently hosted 7th graders in an event hosted by Montgomery County universities. The idea was to introduce kids to science and medicine so they don't think of people who work in biosciences as "crazy scientists", said Stephen L. Hoffman, founder and CEO of the company. Hoffman's latest malaria vaccine effort was profiled by Science in "New Hope for Crazy Vaccine", briefed by us last year. Sanaria received $3 million funding for Phase II trials last summer.
In still more malaria news, a program called the Affordable Medicines Facility - Malaria(AMFm) has been radically downsized, killed, and folded into obscurity within the Global Fund. The reasons remain a little mysterious. By all accounts, the program was successful, even "overwhelmingly successful", in lowering the pharmacy prices of drugs called Artemesin Combination Therapies (ACTs). If you contract malaria in Africa you often need to buy your own drugs. Patients will naturally buy the cheapest drugs, which happen to be those that are least effective or most susceptible to antibiotic resistance. The program made the ACTs competitively priced with monotherapies, therefore competitive in the marketplace and helpful to preventing artemisinin resistance and conquering malaria. The strategy was innovative and effective.
However, some critics claimed that this method wasn't getting the drugs to children, and that some people were buying up the drugs without a diagnosis. Defendants said these criticisms moved the goal posts, phase II could have solved some problems. But more scientists aren't at all sure why the program got cut, some suggesting that for some reason Oxfam and the President's Malaria Initiative lobbied hard against it. One contingent that is probably pleased with the outcome has been lobbying vigorously against AMF-m since its inception. The group's members are variously affiliated with pharmaceutical companies, 'free enterprise think-tanks', and target lobby efforts like "Africa Fighting Malaria", they selflessly devote their lives to promoting DDT spraying, and lobbying against generic drugs. One or more have written accounts claiming that the competitive pricing schemes employed by AMF-m used cheaper drug suppliers with inferior services -- a spurious, tedious and surprisingly effective go-to argument for decades by pharmaceutical companies lobbying against generics for the most deadly diseases AIDS, Malaria, etc.