Does International Public Health News Compel Us to Cheer Enthusiastically?
Everyone wants drugs to cure diseases. Everyone wants vaccines to prevent them. And in a world of urgent international public health problems, what is more publicly urgent then developing solutions for AIDS or malaria? Positive news on this front is always welcome, and in line with that, you don't win popularity points by sticking pins in up-beat public health reports, results, or clinical trial data. Popular science journalists generally talk about cool, politically neutral science, or slick technology, or brilliant research successfully advanced to save lives; they write about winning clinical trials that will end scourges, any scourge - cancer, AIDS, Hepatitis, obesity... Good news!
Cheerful news, like recent headlines highlighting research showing a vaccine for malaria that may be 55.1% effective. NPR headlines enthused "Vaccine Slashes Infection Risk By Half", whereas a more cautions USA Today said: "Malaria Vaccine May Have Potential to Save Millions".
The RTS,S/AS01 vaccine is a decades long effort, now a collaboration between The Gates Foundation funded PATH Malaria Vaccine Inititive (MVI) and GlaxoSmithKline (GSK). The partners recently published interim results in the New England Journal of Medicine (NEJM)2 and presented their results to the media. By all accounts, the Phase III trials delivered very good news.
The Mosquito Drawing by M. R. Villarreal can be found at Wikipedia 1
But What Does "May" Mean, in "May Save Millions"?
No one could say that Bill and Melinda Gates haven't changed the face of international public health. Mr. Gates leads a relentless campaign pushing the power of vaccines; he berates governments that don't vaccinate enough people; and he effectively leverages the media to deliver his messages. Last year the Gates Foundation held a fund-raiser hoping to collect $3.7 billion from governments and instead received $4.3 billion. As Global Alliance for Vaccination & Immunization's (GAVI) chief executive put it, "Bill was a little like a poker player who put a lot of chips on the table and scared everyone else off." Perhaps Gates is more a bridge guy, but point taken.
Given this, who would write-up the newest Gates Foundation news as, "a vaccine shown to be at best 44.9% ineffective in a half-done clinical trial"? No one. With the intense drive for upbeat news, I credit USA Today for their cautious "may save millions". But if you look more closely, for instance read the editorial accompanying the NEJM report3, or listen to scientists around the web and in journals like The Lancet 4, or pay attention the malaria researchers interviewed by "Nature News5, the caveats of this recent malaria study grab your attention:
First, there's the announcement itself. The data released is interim data; the full results of the malaria trial will be released in three years. Interim data releases are not unprecedented but past experiences, for instance with an AIDS vaccine, caution us against overly enthusiastic receptions for incomplete trials.
The interim results were reported for children aged 5-17 months, but the target age group is infants aged 6-12 weeks. In other words, these results don't address efficacy of the vaccine for the target group.
NEJM reported that at 12 months, the vaccine reduced episodes of malaria by 55.1%. However a US military scientist working with Sanaria, a competing vaccine maker, told Nature News that RTS,S actually offered only 35-36% protection 12 months after the vaccine. It appears that the efficacy of the vaccine might wane over time.
Although the reports noted reduced mortality, another scientist emphasized to Nature News that the data didn't support that announcement. Scientists hypothesize that the vaccine may just delay infection.
Although the vaccine reportedly cut severe disease in older kids by 47%, combining that data with the available data of the younger kids gave only a 34.8% decrease. This suggests the data for the target group of younger kids might turn out lower than reported in these interim results.
In addition, incidents like convulsions and meningitis might be more frequent in the vaccinated group.
These might not be showstoppers. For instance researchers hope that booster shots will improve efficacy. But what if in the end the much touted vaccine turns out not to be a vaccine but just another shot? Scientists and public health workers concern themselves with such non-trivial caveats. What's behind the apparently waning efficacy? How is the adjuvant effecting immunity? Science is exacting even when media reports are not. People also have underlying concerns about what's driving policy, science or the press releases?
Is Marginal Progress, "Success"?
Two of the people interviewed by Nature News are affiliated with Sanaria, a company that is also developing a malaria vaccine. Sanaria just released their own news of a Phase I malaria vaccine study testing the safety of a live attenuated virus. Nature interviewed the first author on the Sanaria study published by Science, as well as the CEO and last author on the Science study. They were complementary of the RTS,S effort, if somewhat critical on some points.6
It's worth noting the history of the Sanaria vaccine, to give context to the executives' comments and perspective. Like the RTS,S vaccine, Sanaria's vaccine is an extremely expensive, tricky, and laborious endeavor. The underlying idea for seems promising, but for starters technicians must painstakingly dissect out the salivary glands of mosquitoes in order to develop the vaccine.7 It's unclear how this can scale.
On top of the laboriousness of vaccine development, once the vaccine was made it didn't seem to work. In their first clinical trial, Sanaria injected 44 subjects. 42 people got malaria and 2 didn't, a 4.5% "success" rate. These subjects might have been better protected from malaria lounging in a malaria endemic region in mosquito-infested huts, but the Sanaria execs quickly pointed out that it wasn't the stunning failure it looked like, rather, it was a trial that "yielded positive results" -- as their press release put it (without including relevant numbers). The company is buoyed by such "success" and primed for the next controversial7 phase.
Because vaccines promise a silver bullet solution to disease, at the moment, every possible vaccine holds promise, since we have no viable one.
Sanaria's position as competitors doesn't invalidate their commentary on RTS,S (complementary as well as critical), since Sanaria executives voiced reservations shared by many others. An editorial in last week's "The Lancet indicated that the release of unorthodox partial results seemed to be more politically than scientifically driven. Diplomatically, The Lancet editors wrote: "although the latest findings are encouraging, we look forward to the full results of the RTS,S/AS01 trial in 3 years time."5
When There is No Treatment, What Does A More Effective "Treatment" Look Like?
Will the upcoming younger cohort data meet World Health Organization (WHO) goals of 'Protective efficacy of more than 50% against severe disease and death lasting longer than one year'? 5 This is an important question. Vaccine experts usually aim for 80% or more efficacy, and representatives for PATH say they hope to get there eventually. So then, does that make this vaccine a beta version?
Is all this media hoopla deserved for a beta version vaccine? A physician working in Africa distributing bed-nets warned against statements that might mislead people "to overestimate the impact of any single new intervention", in a comment at NEJM. Acknowledging this commenter also has vested interests doesn't detract from his message. 75% of the MVI/GSK study participants used bed-nets. But would people in real-life discontinue the more cumbersome bed-net efforts with a vaccine on the horizon? Will bed-nets still be funded with a 50% effective vaccine? A 30% effective vaccine? If you're a mom and your kid gets a vaccine that is 50% effective, what precautions do you then take to prevent infection? Does a 50-50 vaccine make your life better?
The tremendous investment in vaccines, both in terms of money and expectations, shouldn't slow other prevention and treatment efforts. But realistically, we don't have unlimited resources. It would be naive to think that the prolonged difficulty of vaccine development, the immense investment, and lack of a viable alternative don't influence funding and policy decisions.
Some of the problems scientists identified with this vaccine trial have persisted for years. In this 2006 book chapter recently released online, an economist analyzes RTS,S vaccine data of previous trials (PDF) (HT Nature News5). He reports on waning efficacy; and questions how the public health community decides which vaccine candidates merit further investment. 5 years later, as the latest trial barely noses over the 50% bar, we grapple with the same issues and questions he raised back then, but billions more dollars have been invested.
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? As more and more money gets invested, do decision makers begin to act less rationally?
Media reports may boost stocks, may raise money and may discourage competitors, but in the end, the science behind the vaccine, the science that's supposed to underpin public health decisions, is fussy and complicated -- caveats matter. After all, you're asking people and governments to donate tens of billions of dollars, and you're promising 7 billion people that your vaccine will keep millions safe.
Tough Economy for an IPO?
Can we push for an end to malaria as if we were trying to put a computer on every desktop? Does this big money, big marketing, big media approach to public health that some find so jarring actually work? I'm not saying it doesn't. Perhaps it will become a more accepted way of developing medicines and vaccines. Maybe public health needs exactly this kind of paradigm shift.
But even if a 40% or 50% effective vaccine is acceptable from a public health perspective, once this vaccine is developed, governments will still need to consider costs. In this economy, some ask, how much will governments shell out for a vaccine with a 50% efficacy rate? Can you and should we market vaccine with lots of pre-release fanfare to push governments towards buying the vaccine?
Asked about cost per vaccine, GSK wouldn't answer directly, but stressed how the company will reinvest all the proceeds to improve the vaccine. Shares of GSK rose slightly on the RTS,S vaccine news, and shares of biotech company Agenus which makes the RTS,S vaccine adjuvant rose from $.48 prior to the announcement, to $2.80 (which got Agenus re-listed by the SEC). All things that may influence decisions. However when questioned about the unconventional data release, PATH's MVI director didn't mention politics, billions of invested dollars, stakeholder expectations, or the saved Massachusetts biotech companies. He said: "we felt it was our scientific and ethical duty to make the results public when they become available."5
1 The mosquito drawing is by Mariana Ruiz Villarreal. It is the anatomy of a Culex pipiens, a vector for malaria. This image was selected as Wikipedia's Picture of The Day for 10 September 2010.
The RTS,S Clinical Trials Partnership; First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Children, October 18, 2011 10.1056/NEJMoa1102287
3White, N. F.R.S.; A Vaccine for Malaria October 18, 2011 10.1056/NEJMe1111777
4Editorial: The Lancet, Volume 378, Issue 9802, Page 1528, 29 October 2011, doi:10.1016/S0140-6736(11)61659-0
5Butler, D.; Malaria Vaccine Results Face Scrutiny: Published online 26 October 2011, Nature 478, 439-440 2011, doi:10.1038/478439a
6Epstein et al: "Live Attenuated Malaria Vaccine Designed to Protect Through Hepatic CD8+ T Cell Immunity": September 8 2011 Science 28 October 2011: Vol. 334 no. 6055 pp. 475-480
7 Kappe1, S., and Mikolajczak1, S.; "Another Shot at a Malaria Vaccine". Science 28 October 2011: Vol. 334 no. 6055 pp. 460-461 DOI: 10.1126/science.1213934
8 Farlow, Andrew.; "A Review of Malaria Vaccine Candidate RTS,S/AS02A", Chapter Three of The Science, Economics, and Politics of Malaria Vaccine Policy, a report written in 2005 and 2006 and published 14 April 2006 and January 2010. Department of Economics, and Oriel College, University of Oxford.
We previously wrote about Phase II Clinical Trials of the RTS,S vaccine here. We
wrote about US funding for malaria here and here; vaccine strategy here; malaria prevention here and here. We've also written frequently on international public health, including the development of a AIDS vaccine, here and here.