14 December 2010

Malaria vaccine almost a reality

After 23 years of painstaking lab work and a programme of major trials in seven countries, biologist Joe Cohen says the clinical case for the malaria vaccine is almost proved.


Joe Cohen, a scientist tantalisingly close to delivering the world's first malaria vaccine, is on the stump.

After 23 years of painstaking laboratory work and a programme of major trials in seven countries, the 67-year-old biologist says the clinical case for the vaccine is almost proved.

It's a breakthrough moment that could save hundreds of thousands of lives, but when it comes to public health in the developing world, Cohen knows hard science is only half the job.

That's why the softly spoken US-Italian researcher found himself one chilly December evening pitching his life's work to rich-world politicians whose voters will have to foot the bill, and fielding questions over festive mince pies and wine in a leather and oak-clad room in London's Houses of Parliament.

Many questions

How cost-effective will the vaccine be compared to tried and tested low-tech approaches like mosquito nets and insecticides, one inquirer asks. Is there any evidence that it will bring down the spread of the disease in general, helping those who haven't been vaccinated? How long is a shot likely to stay effective?

Is there a danger it might foster a false sense of security? As the session goes on, it's clear that enthusiasm for Cohen's work is coupled with wariness among the experts and well-informed lawmakers.

The bottom-line question: is the vaccine - and the global health community's aim of completely eradicating a disease that kills a child every 45 seconds - really worth the money?

It may seem an absurd thing to ask. Malaria threatens half the people on the planet and kills around 800,000 people a year, many of them too young to have even learned to walk. The death rate has come down in the last decade, but full-scale eradication will cost billions and drag funds away from other equally, or possibly even more urgent health efforts.

As governments in poor countries and donors from wealthy ones weigh up where to put their money, experts have begun a quiet but fundamental debate about whether wiping out malaria is realistic or even makes economic sense.

"With all of the money and human capacity in the world, there is very little doubt that we could eliminate malaria. The question is: What is the best value for our dollar? And this is an increasingly pressing question as we look at the global economic climate," says malaria expert Oliver Sabot, who works at the Clinton Health Access Initiative in Boston.

Targeting the parasite

What is the best value for our dollar? The answer to that question seems obvious to someone like Loyce Dama Karisa, a Kenyan woman who recently gave birth to her seventh child, a girl called Rehema. Karisa has come in a minibus full of other mothers and babies to a clinic in the mud-and-thatch village of Madamani in the Kilifi district on Kenya's south coast.

GlaxoSmithKline, the British-based drug-maker Cohen works for, is using the clinic as part of Africa's biggest ever medical experiment, giving the vaccine to babies and young children in a trial designed to assess its efficacy.

"I wanted my child to get this vaccine," Karisa says. "Malaria is a very bad disease."

In the Kilifi District Hospital, the children's high- dependency unit is full of malaria patients. Listless babies and toddlers lie motionless in adult-sized beds, tangles of tubes taped to their nostrils, arms and legs. One boy has his hands bandaged into stumps to stop him pulling a tube out of his nose.

He screams and thrashes about as a drip is attached to a vein in his foot. Mothers in mint green hospital gowns watch silently. One cradles her tiny sleeping baby's hand in her own while a ceiling fan chops slowly through the hot air, doing nothing to reduce the draining heat.

Vaccine attacks parasite

Families in Kilifi, which despite its lush green vegetation has poor soil for growing crops and high levels of poverty, are almost numb to the ravages of malaria. It's a similar story across the continent: around 90% of malaria's victims live in sub-Saharan Africa; most of those are under five.

The disease is caused by a parasite carried in the saliva of mosquitoes. GSK's vaccine goes to work at the point the parasite enters the human bloodstream after a mosquito bite.

By stimulating an immune response, it can prevent the parasite from maturing and multiplying in the liver. Without that response, the parasite re-enters the bloodstream and infects red blood cells, leading to fever, body aches and in some cases death.

The vaccine Cohen and his colleagues have developed combines technology from GSK's hepatitis B shot with pieces of the malaria parasite, and adds in a chemical known as an adjuvant to boost the body's immune response further.

The result - the first ever vaccine against a human parasite, as opposed to simple bacteria or viruses - is a product that could be given alongside standard infant vaccines and has been shown in a Phase II, or mid-stage, clinical trial to reduce the risk of clinical episodes of malaria in young children by 53% over eight months.

Success rate of 80% expected

The pivotal Phase III programme, the one baby Rehema is part of, will inject the last of 16,000 African children by February. If all goes according to plan, the vaccine could be licenced and rolled out as soon as 2015.

GSK's chief executive Andrew Witty says the trials are going well and he's looking forward to bringing the vaccine to market -- something he says won't make shareholders in his company any money, but will make them proud. "This is the first vaccine that has any effect at all against a parasite-borne infection. If we went back 20 or 25 years, people would have said it was impossible," he said.

An efficacy rate of around 50% means the vaccine will be no panacea. Scientists and health experts normally like a success rate of at least 80% before a vaccine is accepted for widespread use. There are concerns that the availability of shots could instil a false sense of protection, leading people to neglect other measures like mosquito nets.

But added to the already extensive range of nets, insecticides and anti-malarial drug treatments, the vaccine - known as RTS,S or Mosquirix - could prove a powerful new tool.

"There are not many scientists who have this incredible opportunity to work on a project and see the realisation of that work being transformed into a vaccine that could save hundreds of thousands of lives," says Cohen, who with his baggy cords, beard and mop of grey hair strikes a contrast with Witty's clean-cut corporate look.

"My worst nightmare is that it sits on the shelf for years." 

Convincing the funders

Whether that happens will depend on securing funding and, crucially, how much the vaccine costs - a figure health care experts and donors would love to know. GSK has promised it will be cheap, with a profit margin of 5% over the cost of making it to be reinvested in new vaccines for malaria and other neglected diseases.

"The last thing in the world we want to do is get to 2014 or 2015, have something that is the world's first vaccine to work against a parasite ? and then say I'm sorry we couldn't figure out a way to make it cheap enough for people in Africa to actually get it," says CEO Witty.

But the company has yet to give an exact figure to enable direct comparison with, say, the cost of insecticide-treated mosquito nets -- currently available for around $5 each. Witty points out that mosquito nets typically last around 20 washes, or three to four years, while a vaccine may last a lot longer.

"We want a safe and effective vaccine ? that complements, rather than replaces all the other things that are going on, and that will be priced in that kind of world."

The uncertainty on price is one of the reasons for the debate about how, where and on what scale the new vaccine -- designed exclusively for children in Africa - should be used.

Cost-benefit analysis

The cost-benefit analysis that donors must make when they work out where to spend their money is sure to be a lot more complex with this vaccine than with those targeting other diseases such as polio and smallpox.

For those diseases, vaccines virtually guarantee (or guaranteed, in the case of smallpox, which was eradicated in 1979) people won't get sick. With malaria, the picture is more complex, given its transmission cycle via mosquitoes and the practical steps that can already be taken to reduce the risk of infection.

"This is not the elimination or eradication vaccine," says David Brandling-Bennett, deputy director for malaria at the Bill & Melinda Gates Foundation, which said last January it planned to spend $10 billion over the next decade researching new vaccines and bringing them to poor countries.

"And obviously the situation with malaria is very different from the situation with smallpox which relied on a single tool - a highly effective vaccine that provided solid protection to essentially everyone who had it. We don't have that yet for malaria, and we're under no illusion that we do."

Other vaccines in the pipeline are 10 years away or more. PATH Malaria Vaccine Initiative (MVI), a non-profit organisation based just outside Washington DC that has channelled more than $200 million in grants from the Gates Foundation into the GSK vaccine (alongside more than $300 million from the drug-maker itself), has a long-term goal of developing a vaccine that is at 80 percent effective by 2025.

Vaccinate mosquitoes?

One candidate could be an amended version of the current GSK shot, which the drug-maker has started work on with Dutch biotech company Crucell (now the target of a $2.3 billion takeover bid from Johnson & Johnson).

This would use a common cold virus to "prime" the immune system to get a stronger response, but it is still a year or so away from starting clinical trials. MVI has also just signed a deal with Merck & Co for a new vaccine project designed to stop the malaria parasite from entering the liver.

Experience shows it won't be easy. Sanaria, a start-up biotech company with funding from MVI, recently found its experimental vaccine protected only five out of 80 volunteers in its first clinical trial. The Maryland-based firm is not giving up but its disappointing results demonstrate the scale of the challenge.

Another, very different approach - which at first sight looks off the wall - is to try to vaccinate not humans but mosquitoes. Such a transmission-blocking vaccine would still be injected into people but with the aim of preventing the mosquitoes that bite them from subsequently spreading the malaria parasite.

Researchers at John Hopkins University believe they have found a way of doing this, and the good news is it could protect against both the type of malaria common in Africa, and the variant that is widespread in Asia. GSK's vaccine only works against the African form.

These are promising leads for the future, but some experts fear the race for smart technology may risk sidelining the effective tools that already exist.

Every death could be prevented

"We worry a lot about the science of this, but the reality is that every death from malaria today could be prevented, either by avoiding the malaria case in the first place or treatment at an early stage, using existing tools all costing less than a pint of beer," says Chris Whitty, who works at the London School of Hygiene and Tropical Medicine, advises the British government on malaria, and was one of those at Cohen's appearance in parliament.

"The fact is our biggest problem with malaria at the moment is that we are not getting the technologies we know work and are already there to the people who need them."

The snowy streets of Swiss ski resort Davos are a long way from the palm trees and mangrove-fringed creeks of Kilifi. But if a malaria vaccine does get into widespread use across Africa, it will in large part be thanks to a novel project to fund vaccines for poor countries that was launched 11 years ago at the World Economic Forum, the annual talk-fest of the rich and powerful.

Back in January 2000, the inauguration of the Global Alliance for Vaccines and Immunisation (GAVI) left many in Davos scratching their heads. The venture sounded worthy, but hardly set the world alight. Media covering Davos were more excited by the Internet stock bubble, which would soon burst.

A few months later, billionaire Bill Gates, who was just embarking on his transformation from software tycoon to philanthropist and who had pledged an initial $750 million for GAVI, complained that their presentation in Davos was "one of the least inspirational, least informative panels I've seen".

A decade on, though, the alliance can claim remarkable success. It has paid for the immunisation of 288 million children against diphtheria, tetanus, whooping cough, hepatitis B and Haemophilus influenzae type b (known as Hib), saving more than 5 million lives in the process.

If it wants to beat malaria, the GAVI Alliance will have to up its game even further. It is already $3.7 billion short on donor money to fund its work through 2015, and that's before any new malaria vaccine.

Nina Schwalbe, its managing director for policy and performance, says the alliance wants to be ready for the malaria vaccine and is already working on the sums. "We are very enthusiastic about working on this and we are beginning to factor it into our financial projections," she says.

"But this vaccine cannot come at any price. In order to be taken on it has to be cost effective."

What that means is clearly defined by the World Bank: interventions are considered cost-effective if they save a year of healthy life for less than a country's average gross domestic product per head.

In simple cash terms that means the difference between a vaccine priced at $5 and $15 can be hugely significant, especially at the scale the GAVI Alliance works on: it aims to immunise more than 40 million children a year. "For any vaccine that's introduced, we're looking for less than $10 per course - and ideally significantly less," Schwalbe said.

Christian Loucq, director of PATH MVI, says that even with a new vaccine in 2015, wiping out malaria is going to be extremely difficult to achieve, and very pricey. - (Reuters, December 2010)


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