News (Updated June 5, 2011)

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TB vaccines: getting them out of the lab

31 May 2011

Source: member // SciDev.net - Mico Tatalovic

International tuberculosis (TB) experts are gathering today — World TB Day — in France to discuss advances in research into vaccines.

But the reason there is no effective vaccine to prevent the roughly ten million new cases and two million deaths from TB each year has little to do with the science. There are already 11 vaccines in clinical trials whose progress has slowed or stalled because the funding has dried up.

That is why the TuBerculosis Vaccine Initiative (TBVI), an independent organisation that promotes the development of TB vaccines, is launching a new funding model today.

Joris Vandeputte, senior vice-president of advocacy and resource mobilisation at TBVI, tells SciDev.Net that US$1.5 billion is urgently needed to translate basic research into market-ready vaccines over the next decade. A single TB vaccine can cost up to US$300 million to develop.

Funding gap

Basic research has been adequately funded, he says, resulting in around 40 candidate vaccines because of a huge research effort over the past decade. In addition to the 11 in the faltering trials, a further 30 are languishing in laboratories, some of them in developing countries, waiting to be tested.

But the "second chunk" of funding, needed to get the candidate vaccines through clinical trials, is missing — so vaccine development has effectively stopped, he says.

Under the new funding model, the European Union would provide loans to fill the gaps, possibly through the European Investment Bank. The loans would be administered by the TBVI and paid back once the vaccines start making money.

The model takes into account various logistical difficulties facing the researchers, such as the bottleneck caused by the lack of capacity in clinical trials, by calculating in the costs needed to tackle such issues.

"We will have to look to the east — China , India , Russia — to do more clinical trials," he says, in an attempt to overcome this bottleneck. But he maintains that once there is a new vaccine, it will attract a huge market.

Around 90 per cent of countries currently vaccinate their children against TB with the Bacillus Calmette-Guιrin (BCG) vaccine, using 100 million doses each year. BCG protects children from severe forms of TB but does not protect adults from pulmonary TB — the most common and infectious form of the disease.

A more effective vaccine would save huge amounts on treatment, which costs European countries alone about US$3 billion a year.

Low take-up

But even if the money for trials becomes available and an effective vaccine emerges, further problems may await. Data to be published later this year in a special vaccines issue of the journal Tuberculosis show that some developing countries may be reluctant to accept new TB vaccines.

Several factors seem to determine whether countries are prepared to shoulder the costs of a new vaccine campaign, including whether the vaccine has been tested in their own country.

The study's authors conducted 86 structured interviews with public health clinicians, politicians and senior civil servants from health and finance ministries in countries with the highest burden of the disease: Brazil , Cambodia , China , India , South Africa , Mozambique , Romania and Russia .

Lew Barker, senior medical advisor at the Aeras Global TB Vaccine Foundation in the United States , says their study sought to gauge the opinions of people in high-burden countries who are likely to be involved in making decisions about whether to adopt TB vaccines when they become available.

"None of the respondents, when asked about the most important public health issues and needs of their country, spontaneously mentioned TB," Barker says. Instead, primary, rural and mother-and-child healthcare, as well as HIV/AIDS, were identified as the most pressing issues.

"However, when TB was mentioned [by the interviewer], they uniformly said this is a very serious problem and, by and large, they said it's also a neglected problem that needs and deserves more attention then it gets," Barker adds.

Respondents in the survey welcomed the development of better TB vaccines, but around 20 per cent said it was unlikely that such vaccines would be taken up in their countries, and many more were undecided. In most of the vaccine roll-out scenarios presented, less than half said they were willing to commit to a new vaccine and provide funding. One of the main reasons was that they wanted to see strong efficacy data from clinical trials in their own country.

Political priorities

Vaccine deployment might take 20–30 years to reap healthcare benefits because 95 per cent of cases are latent and may take years to show up, and most vaccines only target people who have not been exposed to TB (around one third of the world's population has been exposed), so there will be a long tail of cases before the hoped-for elimination of TB in 2050, Barker says. This explains why other issues such as HIV are given political priority.

Barker concludes that robust data showing efficacy of 90 per cent, rather than a more realistic 60 per cent, and from studies in the countries concerned, are likely to be needed for the introduction of new TB vaccines.

Opokua Ofori-Anyinam, senior clinical development manager at GSK Biologicals, a vaccine manufacturer, said researchers should engage with policymakers to make sure that, after spending millions of dollars on trials and testing vaccines in thousands of individuals, they end up with vaccines that policymakers will want to deploy.

"These are the things we have to think about ahead of time," Ofori-Anyinam tells SciDev.Net.

Vandeputte says the TB research community must engage with the media and policymakers to put TB onto national political agendas.

But he points out that Aeras' market research, presented by Barker, found a mixed response and that the proportion of decision-makers who would go for a new vaccine is bigger than those who would not. Engagement and advocacy before a new vaccine reaches the market may also help convince the undecided.

Focus on the vaccine

Michel Greco, chair of the working group on new TB vaccines at the Stop TB Partnership, says: "I am not one of those people who think that as soon as we have a good TB vaccine it would be taken up. Countries are very wary of potential problems, so they go slowly."

But he adds that although studies are needed to address uptake issues and pave the way for the future deployment of TB vaccines, the priority should be on designing and testing vaccines rather than worrying about their subsequent uptake.

Helen McShane, a TB vaccine researcher at the University of Oxford, United Kingdom, whose vaccine MVA85A is currently in phase IIb clinical trials, told SciDev.Net: "The more effective a vaccine is, the more likely that it will be taken on. It will also depend on cost — I think if you have a very effective vaccine at affordable prices for the developing areas of the world then it will be taken on."

She adds: "There may be certain countries where you have to do some studies in that country to get some safety data but, although those are all important factors, I don't see them as the biggest challenge — the biggest challenge is that we need to get a vaccine that works."

 

Factbox: HIV/AIDS numbers from ar

Jun 3, 2011

(Reuters) - Here is some new global data on HIV and AIDS from an updated report by the Joint U.N. Programme on HIV/AIDS (UNAIDS).

THE GLOBAL PICTURE:

* More than 34 million people worldwide had the human immunodeficiency virus (HIV) that causes AIDS at the end of 2010, according to the latest figures issued by (UNAIDS). There were 26.2 million in 1999.

* There were an estimated 1.8 million AIDS-related deaths around the world in 2009.

* Since the AIDS pandemic started in the early 1980s, more than 60 million people have been infected with HIV and nearly 30 million have died of HIV-related causes.

* The number of girls aged 10-14 living with HIV grew from about 50,000 in 1999 to more than 300,000 in 2010.

-- Young women aged 15-24 account for 26 percent of all new HIV infections globally.

-- In southern Africa , young women are up to five times more likely to become infected with HIV than young men.

* ANTIRETROVIRAL THERAPY AND PLANNING:

-- An estimated 6.6 million people in low- and middle-income countries were receiving antiretroviral therapy at the end of 2010, a nearly 22-fold increase since 2001.

-- About 9 million people in low- and middle-income countries who were eligible for antiretroviral treatment were not receiving it, as of end-2010.

* Between 2001 and 2009, the global annual rate of new HIV infections declined by nearly 25 percent.

* In 2010, 94 percent of countries (162 of 172 countries reporting) had national HIV strategic plans, up from 87 percent in 2006.

* Despite dramatic gains in treatment access, 9 million people who were eligible for treatment were not receiving it, as of December 2010.

-- Up to 460,000 children were receiving antiretroviral therapy at the end of 2010. Treatment coverage for children (28 percent) was lower than for people of all ages (36 percent) in 2009.

* INVESTMENT AND ACCOUNTABILITY:

-- Between 2001 and 2009, investments in the HIV response in low- and middle-income countries rose nearly 10-fold, from $1.6 billion to $15.9 billion.

-- In 2010, international AIDS resources declined for the first time in a decade. Financial challenges in many countries have put downward pressure on funding sources.

-- A 2011 investment framework proposed by UNAIDS and partners found that a more focused annual investment of at least $22 billion is needed by the year 2015, $6 billion more than is available today.

-- The estimated return on this investment: 12 million more HIV infections averted and 7.4 million more deaths averted by the year 2020.

SOURCE: UNAIDS/Reuters

(Writing by David Cutler, London Editorial Reference Unit)

 

Special Report - An end to AIDS?

Jun 1, 2011

By Kate Kelland

LONDON (Reuters) - For his doctors, Timothy Ray Brown was a shot in the dark. An HIV-positive American who was cured by a unique type of bone marrow transplant, the man known as "the Berlin patient" has become an icon of what scientists hope could be the next phase of the AIDS pandemic: its end.

Dramatic scientific advances since HIV was first discovered 30 years ago this week mean the virus is no longer a death sentence. Thanks to tests that detect HIV early, new antiretroviral AIDS drugs that can control the virus for decades, and a range of ways to stop it being spread, 33.3 million people around the world are learning to live with HIV.

People like Vuyiseka Dubula, an HIV-positive AIDS activist and mother in Cape Town , South Africa , can expect relatively normal, full lives. "I'm not thinking about death at all," she says. "I'm taking my treatment and I'm living my life."

Nonetheless, on the 30th birthday of HIV, the global scientific community is setting out with renewed vigour to try to kill it. The drive is partly about science, and partly about money. Treating HIV patients with lifelong courses of sophisticated drugs is becoming unaffordable.

Caring for HIV patients in developing countries alone already costs around $13 billion (7.9 billion pounds) a year and that could treble over the next 20 years.

In tough economic times, the need to find a cure has become even more urgent, says Francoise Barre Sinoussi, who won a Nobel prize for her work in identifying Human Immunodeficiency Virus (HIV). "We have to think about the long term, including a strategy to find a cure," she says. "We have to keep on searching until we find one."

The Berlin patient is proof they could. His case has injected new energy into a field where people for years believed talk of a cure was irresponsible.

THE CURE THAT WORKED

Timothy Ray Brown was living in Berlin when besides being HIV-positive, he had a relapse of leukaemia. He was dying. In 2007, his doctor, Gero Huetter, made a radical suggestion: a bone marrow transplant using cells from a donor with a rare genetic mutation, known as CCR5 delta 32. Scientists had known for a few years that people with this gene mutation had proved resistant to HIV.

"We really didn't know when we started this project what would happen," Huetter, an oncologist and haematologist who now works at the University of Heidelberg in southern Germany , told Reuters. The treatment could well have finished Brown off. Instead he remains the only human ever to be cured of AIDS. "He has no replicating virus and he isn't taking any medication. And he will now probably never have any problems with HIV," says Huetter. Brown has since moved to San Francisco .

Most experts say it is inconceivable Brown's treatment could be a way of curing all patients. The procedure was expensive, complex and risky. To do this in others, exact match donors would have to be found in the tiny proportion of people -- most of them of northern European descent -- who have the mutation that makes them resistant to the virus.

Dr Robert Gallo, of the Institute of Virology at the University of Maryland , puts it bluntly. "It's not practical and it can kill people," he said last year.

Sinoussi is more expansive. "It's clearly unrealistic to think that this medically heavy, extremely costly, barely reproducible approach could be replicated and scaled-up ... but from a scientist's point of view, it has shown at least that a cure is possible," she says.

The International AIDS Society will this month formally add the aim of finding a cure to its HIV strategy of prevention, treatment and care.

A group of scientist-activists is also launching a global working group to draw up a scientific plan of attack and persuade governments and research institutions to commit more funds. Money is starting to flow. The U.S. National Institutes of Health is asking for proposals for an $8.5 million collaborative research grant to search for a cure, and the Foundation for AIDS Research, or amfAR, has just announced its first round of four grants to research groups "to develop strategies for eradicating HIV infection."

THE COST OF TREATMENT

Until recently, people in HIV and AIDS circles feared that to direct funds towards the search for a cure risked detracting from the fight to get HIV-positive people treated. Even today, only just over five million of the 12 million or so people who need the drugs actually get them.

HIV first surfaced in 1981, when scientists at the U.S. Centers for Disease Control and Prevention discovered it was the cause of acquired immunodeficiency syndrome (AIDS). An article in the CDC's Morbidity and Mortality Weekly Report of that June referred to "five young men, all active homosexuals" from Los Angeles as the first documented cases. "That was the summer of '81. For the world it was the beginning of the era of HIV/AIDS, even though we didn't know it was HIV then," says Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases, who has made AIDS research his life's work.

In the subsequent three decades, the disease ignorantly branded "the gay plague" has become one of the most vicious pandemics in human history. Transmitted in semen, blood and breast milk, HIV has devastated poorer regions, particularly sub-Saharan Africa , where the vast majority of HIV-positive people live. As more tests and treatment have become available, the number of new infections has been falling. But for every two with HIV who get a chance to start on AIDS drugs, five more join the "newly infected" list. United Nations data show that despite an array of potential prevention measures -- from male circumcision to sophisticated vaginal or anal microbicide gels -- more than 7,100 new people catch the virus every day.

Treatment costs per patient can range from around $150 a year in poor countries, where drugs are available as cheap generics, to more than $20,000 a year in the United States .

The overall sums are huge. A recent study as part of a non-governmental campaign called AIDS2031 suggests that low and middle-income countries will need $35 billion a year to properly address the pandemic by 2031. That's almost three times the current level of around $13 billion a year. Add in the costs of treatment in rich countries and experts estimate the costs of HIV 20 years from now will reach $50 to $60 billion a year.

"It's clear that we have to look at another possible way of managing of the epidemic beyond just treating everyone forever," says Sharon Lewin, a leading HIV doctor and researcher from Monash University in Melbourne , Australia .

In some ways, we have been here before. Early AIDS drugs such as AZT came to market in the late 1980s, but within a decade they were overtaken by powerful cocktail treatments known as HAART, or highly active antiretroviral treatment. HAART had a dramatic effect -- rapidly driving the virus out of patients' blood and prompting some to say a cure was just around the corner.

But then scientists discovered HIV could lie low in pools or reservoirs of latent infection that even powerful drugs could not reach. Talk of a cure all but died out.

"Scientifically we had no means to say we were on the way to finding a cure," says Bertrand Audoin, executive director of the Geneva-based International AIDS Society. "Scientists ... don't want to make any more false promises. They didn't want to talk about a cure again because it really wasn't anywhere on the horizon."

GENE THERAPY

The ultimate goal would allow patients to stop taking AIDS drugs, knocking a hole in a $12 billion-a-year market dominated by Californian drugmaker Gilead and the likes of Pfizer, GlaxoSmithKline and Merck.

It's unlikely to happen anytime soon, but Brown's case has opened the door to new ideas. "What it proved was that if you make someone's cells resistant to HIV...then all the last bits of HIV, that hang around for a long time in patients on treatment, did in fact decay and disappear," says Lewin.

Now scientists working on mimicking the effect of the Berlin patient's transplant have had some success. One experimental technique uses gene therapy to take out certain cells, make them resistant to HIV and then put them back into patients in the hope they will survive and spread.

At an HIV conference in Boston earlier this year, American researchers presented data on six patients who had large numbers of white blood cells known as CD4 cells removed, manipulated to knock out the existing CCR5 gene, and then replaced.

"It works like scissors and cuts a piece of genetic information out of the DNA, and then closes the gap," says Huetter. "Then every cell arising from this mother cell has this same mutation."

Early results showed the mutated cells managed to survive inside the bodies of the patients at low levels, remaining present for more than three months in five. "This was a proof of concept," says Lewin. Another potential avenue is a small group of patients known as "elite controllers", who despite being infected with HIV are able to keep it under control simply with their own immune systems. Researchers hope these patients could one day be the clue to developing a successful HIV/AIDS vaccine or functional cure.

Scientists are also exploring ways to "wake up" HIV cells and kill them. As discovered in the late 1990s, HIV has a way of getting deep into the immune system itself -- into what are known as resting memory T-cells -- and going to sleep there. Hidden away, it effectively avoids drugs and the body's own immune response.

"Once it goes to sleep in a cell it can stay there forever, which is really the main reason why we can't cure HIV with current drugs," says Lewin. Her team in Melbourne and another group in the United States are about to start the first human trials using a drug called SAHA or vorinostat, made by Merck and currently used in cancer treatment, which has shown promise in being able to wake up dormant HIV.

WHAT ABOUT PREVENTION?

As scientists begin to talk up a cure, the old question of whether that's the right goal has re-emerged. Seth Berkley, a medical epidemiologist and head of the U.S.-based International AIDS Vaccine Initiative (IAVI) is concerned.

"From a science point of view, it's a fabulous thing to do. It's a great target and a lot of science will be learned. But from a public health point of view, the primary thing you need to do is stop the flow of new infections," says Berkley . "We need a prevention revolution. That is absolutely critical."

Vuyiseka Dubula agrees. The South African activist finds talk of a cure for HIV distracting, almost disconcerting. "This research might not yield results soon, and even when it does, access to that cure is still going to be a big issue," she says. "So in the meantime, while we don't have the answer on whether HIV can be cured or not, we need to save lives."

(Additional reporting by Julie Steenhuysen in Chicago , editing by Sara Ledwith and Simon Robinson )

 


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