Archive for October, 2011

What was the best time and place to be alive?

In the recent More Intelligent Life, a panel of writers take a stab at answering the question; if you could travel back in time, what would be your destination?

Eras and periods romanticized by those that were not fortunate enough to live through them. Including, London in the 1690s, pre-revolutionary Russia, or the Japanese Heian era. For those writers it’s about lifestyle, ideas, peoples, cultures and to witness something we can only read about.

I am reminded of Woody Allen’s last film Midnight in Paris — a life different from your own will always seem better. Owen Wilson’s character laments:

“I was trying to escape my present the same way you’re trying to escape yours. To a golden age… Look at these guys, to them their golden age was the renaissance. They’d trade belle Époque to be painting alongside Michelangelo. And those guys probably imagined life was a lot better when Kubla Khan was around. I’m having an insight now… it’s a minor one…”

Leading on to the realisation that in the 1920s (the era that he has inexplicably time travelled back to) they have no antibiotics.


How the malaria vaccine works…

March 2009 — 15,460 children are enrolled in a unique vaccine study. The study, encompassing seven African countries, was the first of its kind to test the efficacy of a vaccine against a parasitic-borne disease. That in itself was something many thought would never be seen.

Yesterday — October 18th — the results of that study, the largest ever malaria study, was published in the New England Journal of Medicine, spelling out new hope for fighting a disease that accounts for 800,000 lives lost on a yearly basis – most of them children under the age of 5.

The vaccine, that has been in development for the better part of two decades — the interestingly titled RTS,S – provided protection against both clinical and severe malaria in African children. RTS,S was designed as a vaccine to prevent malaria infection, but it has proven to prevent clinical and severe disease. The trial was a randomized, controlled, and doubleblind designed to evaluate vaccine efficacy, safety, reactogenicity, and immunogenicity in children up to 32 months after the administration of the first dose.

From the abstract:

“In the 14 months after the first dose of vaccine, the incidence of first episodes of clinical malaria in the first 6000 children in the older age category was 0.32 episodes per person-year in the RTS,S/AS01 group and 0.55 episodes per person-year in the control group, for an efficacy of 50.4% (95% confidence interval [CI], 45.8 to 54.6) in the intention-to-treat population and 55.8% (97.5% CI, 50.6 to 60.4) in the per-protocol population. Vaccine efficacy against severe malaria was 45.1% (95% CI, 23.8 to 60.5) in the intention-to-treat population and 47.3% (95% CI, 22.4 to 64.2) in the per-protocol population. Vaccine efficacy against severe malaria in the combined age categories was 34.8% (95% CI, 16.2 to 49.2) in the per-protocol population during an average follow-up of 11 months. Serious adverse events occurred with a similar frequency in the two study groups. Among children in the older age category, the rate of generalized convulsive seizures after RTS,S/AS01 vaccination was 1.04 per 1000 doses (95% CI, 0.62 to 1.64).”

It should be stressed that no one is viewing this new vaccine as the miracle drug or the silver bullet for this disease. Far from it. Researchers are right to point out “A malaria vaccine, deployed in combination with current malaria-control tools, could play an important role in future control and eventual elimination of malaria in Africa”.

Just another weapon in the armoury in the fight against the disease. Indeed, none of the malaria vaccines in various stages of the development process have shown anywhere near 100% efficacy.

RTS,S is the most advanced vaccine candidate against malaria to date, and the story of RTS,S is not just a story of how much we know and understand disease, but also how much we don’t know. The landmarks and feats that went in to getting a workable vaccine for malaria is one done in spite of the gaps in our knowledge. The questions left unanswered offer an important starting point and challenge in the quest to understand the protection afforded by RTS,S and to build a more efficacious second generation vaccine against malaria.

The malaria parasite has a complex life cycle. One that is needed to be understood to understand the vaccine.The life cycle of the malaria parasite starts with the bite of an infected mosquito (female anopholese), inoculating sporozoites into the human host. Within the host it is complex, consisting of  an asymptomatic liver stage (pre-erythrocytic) infection followed by a symptomatic blood stage (erythrocytic) infection. Sporozoites infect liver cells and mature into schizonts. The liver cell ruptures releasing merozoites, which infect red blood cells.

The parasite’s life cycle within the liver is very short. At one point it was thought that a vaccine against the liver stage would prove too ineffective, as immune responses induced by vaccination against liver stage parasites could not act quickly enough to destroy the infected liver cells (hepatocytes) and to prevent the release of liver-stage parasites (merozoites) into the blood.

“During its remarkable journey from conception and design in the early 1980s to the multicenter Phase 3 trial currently underway across sub-Saharan Africa, RTS,S has overcome tremendous challenges and disproved established vaccine paradigms.”

For the sake of brevity, the story of a malaria vaccine begins its life in the 1960s. Researchers at New York University demonstrated that immunization of animals with the bites of irradiated-attenuated infected mosquitoes could protect against infectious sporozoites (the form of the parasite the mosquito injects when it bites). It was this demonstration that led to the identification of the Plasmodium falciparum circumsporozoite (CS) protein expressed on sporozoites  and liver stage schizonts – the basis of the RTS,S vaccine we have today.

The CS protein is present in large amounts on the surface of sporozoites and is also expressed by liver schizonts. The modestly sized CS protein is one involved in sporozoite invasion of mosquito salivary glands as well as in binding to hepatocytes prior to invasion of the liver cells.

The pertinent question is how the vaccine confers immunity, given the very small window of opportunity in which the parasite is exposed.

“immunity conferred by the RTS,S vaccine could act by attacking sporozoites during the short time in which they are in the circulation, disabling them and preventing them from invading liver cells, or by attacking liver schizonts.”

The short answer is we don’t really know. The even shorter answer is that we may never really know, as identification of an immunological measurement that provides a reliable measure of clinical protection in RTS-vaccinated individuals from all populations might never be possible.

RTS,S candidate malaria vaccines induce very high titres of anti-circumsporozoite antibodies as well as a strong CD4 T-cell response (characterised by the production of inflammatory cytokines such as interferon γ), which could contribute to the killing of the liver schizonts.

The chemistry of the vaccine itself is more concrete. The vaccine antigen consists of 19 copies of the central tandem repeats and C-terminal region of the CS protein fused to hepatitis B surface antigen (HBsAg), and co-expressed with unfused HBsAg in Saccharomyces cerevisiae cells.

In order to prevent allergic reactions and autoimmunity, the immune system is generally tolerant to antigens, unless antigens trigger “danger signals” that mobilize the immune system to react aggressively. This is the basis of adjuvant systems. Adjuvants have been long known for their ability to trigger danger signals and have been widely used for immunization purposes. The RTS,S adjuvant comes in two flavours (out of 11 possible different formulations tested) — AS02 and AS01.

The general requirement for an adjuvant formulation (among others) is to stabilize antigen and slow its release to the immune system. AS02 is a squalene-in-water emulsion containing MPL (monophosphoril lipid A), and a saponin (triterpene glycoside) derived from the bark of the plant Quillaja saponaria (QS21). QS21 is thought to function to trap components of the vaccine formulation through hydrophobic interactions and thereby slows their release to the immune system. MPL is a derivative of a lipopolysaccharide that triggers danger signals in macrophages and dendritic cells, and promotes secretion of pro-inflammatory cytokines.

AS01b was developed to increase immunogenicity, in which the oil-in-water emulsion of AS02 was replaced by liposomes. The liposomes replacement meant that RTS,S is delivered to the trans-Golgi in antigen-presenting cells, where the RTS,S is efficiently processed and enhances MHC class I and class II antigen presentation to T cells.

The protection conferred by RTS,S vaccine does not seem to be strain specific. A valid concern is that there is a possibility that RTS,S vaccination could lead to the emergence of a P. falciparum parasite strains carrying polymorphisms in the CS protein. However, some recent trials have shown no increase in the frequency of genetically variant parasites in vaccinated groups.

All in all the RTS,S vaccine is the spark of promise and hope in controlling a disease that causes so much human death and suffering. But it is by no means that last word. As it’s often said, the miracle drug will always be a hard pill to swallow. In the case of diseases of the world’s poorest, there is the problem that the miracle drug will always be one too expensive. More funding will be needed to understand more about this vaccine’s efficacy, the duration of protection, and how best to implement this vaccine to most effectively to control malaria.

The RTS,S malaria vaccine
First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Children
Immunological correlates of protection for the RTS,S candidate malaria vaccine

Traditional media is no longer required for science communication…

If you’re reading this here – on a blog – then you’ve come to the right place. Let’s start with a bold statement – a statement, not a question: traditional media is no longer required for science communication. In fact, its time to draw a line underneath it all and say so long and thanks for all the fish.

In light of this bold new statement I propose a change to the antiquated term “science communication”. Let’s keep it untitled and just call it “science” for now. On the face of it, the term “science communication” seems so pedestrian. What does it actually mean? As term it’s a bit of a misnomer. The way traditional media communicates science sometimes bears no similarity to how science is discussed and debated within academic circles. The same way a three-tiered wedding cake bears no resemblance to eggs, flour, milk and butter. Science isn’t conducive to a journalistic style of reporting. Compare and contrast this and this. Same story, but one more informative than the other. One is science, the other is a wedding cake.

In the UK, recent months have called into question the accuracy of science reported in the media. From time to time, we all like to bemoan the state of science communication by traditional media… climate change, vaccines, not being able to tell the difference between a peptide and a protein, or a virus and a parasite (the original version of this article referred to malaria as a virus – I know because I emailed in to get it corrected). All this is nothing new. We’ve been bemoaning it for a long time. But now there’s some interesting examples. There was Ben Goldacre’s co-authored study into the quality of newspaper reports advocating dietary intake in terms of scientific accuracy. The authors coming to the conclusion that their results indicated that most claims made in UK newspapers had no credible scientific basis, with the broadsheets getting off only slightly better than the tabloid papers with their share of the blame.

July saw the release of a report into the BBC’s science coverage – being deemed not as impartial or accurate as it could be – giving too much weight to fringe opinions and not taking heed to distinguish opinion from well established scientific consensus. That was what most news outlets got from the report, and what most reported. But a distinct lack in ability to communicate science as science communicates itself was probably the most interesting part that no one talked about. Namely, that the corporation’s lack of knowledge on the basics of the scientific inner-workings like using free online peer-reviewed journals, or at the very least citing them. Putting it another way – providing context.

The public looks primarily to the media for its science information. As true as this is, perhaps it’s time for a change. As the internet is doing its best to get rid of newspapers and journalism once and for all, it seems to be doing wonders for the scientific community (albeit with one or two problems); mainly by cutting out the middle man.

The abundance of blogs, blogged by active scientists, science writers, and open-access publishing offers a portal into the scientific world that anyone can access. If we are to raise the level of scientific literacy we should boldly wade into the deep end. Cautionary tales of the scientific world being too opaque should be left at the door. Steering away from the grander themes, big technical words, and towards over-simplification leads to misleading outcomes.

The “cult of irrelevance” among the academic elite is slowly becoming a thing of the past. The gap between scientific consensus in published papers and policy changes from that consensus is bridging at an unprecedented rate. Stephen M Walt’s essay on how academics in the international arena should drive to play their part in public discourse can be applied for any and all academics.

“If scholars working on global affairs are content with having little to say to their fellow citizens and public officials and little to contribute to solving public problems, then we can expect even less attention and fewer resources over time (and to be frank, we won’t deserve either). By contrast, if the academic community decides to use its privileged position and professional expertise to address an overcrowded global agenda in a useful way, then it will have taken a large step toward fulfilling its true social purpose. ”

Scientists are involving themselves more and more in matters that concern them on the public landscape, if for no other reason that our science is bleeding more and more into public life. The scientific elite can start and steer the conversation, debate, and discourse on science – the science that is actually happening, not the science that happens below the fold. In fact, in economic circles, it has already begun. “…blogs are doing more than just providing a new source of procrastination for writers and readers.” Changing the world, one abstract at a time.

The same boat that brought Christianity also brought the guns…

In Ghana there is a saying: “the same boat that brought Christianity is also the same boat that brought the guns”. I cannot remember the exact phrasing, so I paraphrase a little; it was told to me many years ago by a collegue.

This phrase came to mind while reading Chris Blattman’s blog on the new film Machine Gun Preacher. The story of Sam Childers, a former drug-dealing biker tough guy who found God and became a crusader for hundreds of Sudanese children who’ve been forced to become soldiers. The narrative is familiar, and one that irks so many. Framing of global poverty as a tool to keep funds replenished is probably something that should change and — for lack of a better word — be modernised.

As Blattman puts it: “The aid bloggers have been derisive and angry, for pretty good reason. If the “it takes a white man to save Africa” narrative doesn’t piss you off, the narcissistic model of armed humanitarianism just might.”

Blattman continues with some shocking stats on the matter: “Basically, if you were an adolescent boy living in the war region, there was a 2 in 5 chance that a rebel would snatch you in the middle of the night, and probably kill a family member in the process. Assuming he didn’t make you do it yourself. If you were a girl, especially one under 13, your chances were 1 in 5 of getting carted off where you would promptly become the fourth wife of some killer commander leading some a miserable mobile unit through the bush.”

One Day On Earth…

One day with the United Nations Development Programme

What had I twaught…

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