TUBERCULOSIS: A new global strategy for TB vaccines

Michael Regnier
Saturday 24 March, it will be exactly 130 years since Robert Koch identified the cause of tuberculosis (TB) and while there is a vaccine used widely around the world (Bacille Calmette-Guérin, or BCG), it has not proved effective enough to stop this disease killing one and a half million people every year.
Earlier this week, a new Strategic Blueprint for TB vaccines was published in the journal Tuberculosis. Its purpose is to once again draw attention to the need for new TB vaccines to complement or replace BCG, which was first used in humans in 1921. The drive for new tools to prevent, diagnose and treat TB is particularly important in the context of rising reports of drug-resistant TB around the world.
BCG works very well at protecting newborn children against severe forms of TB early in their lives but it is not sufficiently effective against pulmonary TB, which affects adolescents and adults and is now the most common form of the disease. The Blueprint’s authors call for researchers, clinicians, advocates, vaccine manufacturers and governments around the world to work together on creative approaches to vaccine development.
The Blueprint was edited by Dr Jelle Thole, director of the Tuberculosis Vaccine Initiatve (TBVI) and Dr Michael Brennan, senior adviser for scientific and global affairs at Aeras, a non-profit working to develop new TB vaccines. They acknowledge progress in the last decade, which has seen 15 TB vaccine candidates enter clinical trials. The most advanced of those candidates is MVA85A, which has been developed by Dr Helen McShane, a Wellcome Trust Senior Clinical Research Fellow, with funding from Aeras, the Wellcome Trust and other agencies. MVA85A is currently in phase IIb clinical trials, the results from which will determine its safety and effectiveness as a vaccine.
However, we cannot take it for granted that any of the 15 candidate vaccines in the pipeline will prove successful enough to stop TB. Research funded by the Wellcome Trust and many others continues into the basic biology of the mycobacteria that cause TB and possible new ways to fight the infection.

TUBERCULOSIS: vaccines: getting them out of the lab

31 May 2011  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-Guérin (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."

http://www.trust.org/alertnet/news/tb-vaccines-getting-them-out-of-the-lab

TUBERCULOSIS: Oxford-Emergent Tuberculosis Consortium Vaccinates Last Infant In Phase IIb Clinical Trial

 03 May 2011
Emergent BioSolutions Inc. announced today that its joint venture with the University of Oxford (Oxford), the Oxford-Emergent Tuberculosis Consortium (OETC), has vaccinated the last of the 2,784 infants in its Phase IIb efficacy trial evaluating MVA85A, the world's most clinically advanced tuberculosis (TB) vaccine in development. This clinical trial in Worcester, South Africa, is being conducted by the University of Cape Town's South African Tuberculosis Vaccine Initiative (SATVI), in partnership with Aeras, the clinical sponsor of the study, and the Wellcome Trust.
"Emergent BioSolutions joined the fight against TB when it formed OETC with Oxford to further develop MVA85A," said Daniel J. Abdun-Nabi, Chairman of the Board, OETC and President and Chief Operating Officer, Emergent BioSolutions. "We are pleased to complete the vaccination of our targeted 2,784 infants, which is the largest number of infants enrolled in any TB vaccine clinical trial. Our quest to fulfill Emergent's corporate mission - to protect life - will come to fruition when we can bring this vaccine candidate to market and ultimately make an impact in patients' lives."
"We are extremely proud of this achievement and are eager to see the study results, which are expected to be available as early as mid-2012," said Dr. Helen McShane, lead scientist and developer of MVA85A from the University of Oxford. "This milestone brings us a step closer to potentially having a new TB vaccine, from which millions of people around the world would benefit."
This Phase IIb clinical trial was initiated in July 2009 and involves a two-year follow up on the infants vaccinated as part of the trial to evaluate whether the vaccine candidate has conferred protection against TB.
http://www.medicalnewstoday.com/articles/224076.php

TUBERCULOSIS: The BCG World Atlas: a world first in the fight against tuberculosis

March 27, 2011
McGill, RI MUHC researchers launch free online atlas of TB vaccination policies from around the world
Tuberculosis (TB) continues to pose a major global health threat. Someone in the world is newly infected with TB bacteria every second. Every year, more than 9 million people develop active TB and it claims about 2 million lives. In Canada, the overall incidence of TB has declined, but rates remain high among immigrants from endemic countries and among Aboriginal populations. Currently, Nunavut is facing the largest TB outbreak in the territory’s 10- year history.
In the days leading up to World TB Day 2011 on March 24, a team of researchers from McGill University and the Research Institute of the McGill University Health Centre (RI MUHC) is officially launching the BCG World Atlas: a first-of-its-kind, easy-to-use, searchable website that provides free detailed information on current and past TB vaccination policies and practices for more than 180 countries.
“The Atlas is designed to be a useful resource for clinicians, policymakers and researchers alike,” said co-author Dr. Madhukar Pai, who is an assistant professor at McGill’s Dept. of Epidemiology, Biostatistics & Occupational Health and a researcher in the Respiratory Epidemiology and Clinical Research Unit at the Montreal Chest Institute and the RI MUHC. “It has important implications on diagnosing and treating TB and on the research that’s being done on developing a new TB vaccine.”
Pai is a senior author on a paper about the BCG World Atlas that will be published in the March edition of the journal PLoS Medicine.
The Bacille Calmette-Guérin (BCG) vaccine was introduced in 1921 and continues to be the only vaccine used to prevent TB. Despite nearly a century of use, the vaccine remains controversial, with known variations in efficacy, strains, policies and practices across the world. Clinicians need to be aware of the various BCG policies in different parts of the world, as well as changes to those policies over time, especially when dealing with foreign-born adults who were vaccinated as children and who are unlikely to have retained their childhood vaccination records.
Ms. Alice Zwerling, BCG Atlas project leader and PhD candidate in epidemiology at McGill, explained that BCG vaccination can cause false positives in the skin test that’s routinely used to screen for latent TB. “As a clinician, if you’re trying to interpret the skin test in a foreign-born person, you’re going to want to know when the BCG vaccination was given back home and how many times it has been given. The Atlas provides this information and can help doctors decide on when to use the newly available blood tests for TB that are not affected by BCG vaccination,” she added.
“I am pleased that the Public Health Agency of Canada (PHAC) could play a part in such an important project,” said Dr. David Butler-Jones, Canada’s Chief Public Health Officer and the head of PHAC, which provided funding for this project. “The BCG World Atlas will be a vital resource for practitioners across Canada, one that will help us prevent and control the spread of TB here at home.”
The Atlas project began in 2007 with the compilation of detailed information on past and present BCG vaccination policies on as many countries as possible. The data were assembled through respondent-completed questionnaires, published papers, reports, government policy documents and data available from the World Health Organization Vaccine Preventable Diseases Monitoring System. The beta version of the site went live in 2008 and over the past year more than 6,000 visits have been recorded with a steady increase in traffic over time. The Atlas is constantly being updated and its authors welcome input from countries that are currently not covered.
http://www.mednewsafrica.com/2011/03/27/the-bcg-world-atlas-a-world-first-in-the-fight-against-tuberculosis/

TUBERCULOSIS: EspC vaccine

18 March 2011
A protein which could be targeted for a tuberculosis vaccine has been discovered by scientists at Imperial College London.

TB is caused by bacteria and the only vaccine against it, the BCG jab, is not very effective.
The disease of the lungs kills approximately two million people worldwide each year.
The charity, TB Alert, said the research was promising, but a vaccine was a long way off.

A better option
Scientists are aware that the BCG vaccine is not good enough.
Professor Ajit Lalvani, who led the research at Imperial College London, said: "Despite most of the world's population having had a BCG vaccination, there are still nine million new cases of TB every year, so we urgently need to develop a more effective vaccine for TB."
Researchers are trying to find new proteins which can be used in a vaccine to trigger an immune response and provide long-term protection against Mycobacterium tuberculosis.

The study, to be published in Proceedings of the National Academy of Sciences, identifies a new protein called EspC.
Professor Lalvani said: "We've shown that EspC, which is secreted by the bacterium, provokes a very strong immune response, and is also highly specific to Mycobacterium tuberculosis. This makes it an extremely promising candidate for a new TB vaccine that could stimulate broader and stronger immunity than BCG."
Consultant chest physician Dr Peter Davies, who is the secretary of TB Alert, said it was "promising" research.
He told the BBC: "We know of two other targets and the researchers have found a third, which could be useful.
"The trouble is it will take 10 years to find out if it will result in vaccine and whether that vaccine is any better than BCG."

http://www.bbc.co.uk/news/health-12789022

TUBERCULOSIS: Candidate TB vaccines languishing in lab

Mićo Tatalović
27 September 2010
Candidate TB vaccines are ready to be tested but poor resources are keeping them in the lab
Potential tuberculosis (TB) vaccines are languishing in developing country laboratories because there is no money to move them to the clinical trial stage, an international TB vaccine conference has heard.
Some developing country scientists — notably in China and Mexico — have successfully produced vaccine candidates, and are ready to start testing them in clinical trials. But the lack of resources and capacity may hamper their efforts, experts have said.
In Mexico, there are four groups researching candidate vaccines, Bruno Rivas-Santiago, head of one of the groups, and a researcher at the Mexican Social Security Institute, told SciDev.Net. But the government has not provided enough funding, he said, which is slowing progress.
Yolanda Lopéz-Vidal, a professor at the National Autonomous University of Mexico, said her research team has used genomic approaches to identify several vaccine candidates. The results of animal studies are promising but the group lacks funding to take it to the next stage — clinical trials in humans.
Mexico has a history of manufacturing its own BCG (Bacillus Calmette-Guérin) vaccine, the limited vaccine in use today, and has a high incidence of TB. In some areas up to four per cent of people die of the disease. So it would be beneficial — and technically possible because of the availability of a test population — to design and manufacture a new vaccine in Mexico, Lopéz-Vidal said. In general, TB vaccine testing faces a major obstacle because of the low, though widespread, incidence.
In China several vaccine candidates are ready to enter clinical trials following a productive decade with more than 40 published papers on TB vaccines, Douglas Lowrie, a researcher at Fudan University in China told SciDev.Net.
But the country lacks the capacity, he said, including both clinical laboratories and trained staff in the western parts of the country where the disease is most common.
"The government has to resolve to support clinical trials," said Lowrie, arguing that the resulting development of capacity would have broad benefits.
"There would be a tremendous knock-on effect because the quality of healthcare would go up, with motivated people working to a high standard, the healthcare infrastructure would improve and there would be healthcare benefits."
In India, although there is funding available for TB research and the country has the pockets of high TB incidence necessary for clinical trials, so far vaccine research is lacking.
Bindu Dey, an adviser in the department of biotechnology at the Indian Ministry of Science and Technology, said she knew of only one vaccine candidate in clinical trials, and this is aimed only at preventing infection developing into disease.
Institutions from China, Cuba, Malaysia and India all have at least one TB vaccine candidate in the pipeline, according to the Stop TB Partnership's 'Tuberculosis Vaccine Candidate — 2009' report.
http://www.scidev.net/en/news/candidate-tb-vaccines-languishing-in-lab-say-scientists.html

TUBERCULOSIS: Increases despite treatments

More than 36 million patients have been successfully treated via the World Health Organization’s strategy for tuberculosis (TB) control since 1995. Despite predictions of a decline in global incidence, the number of new cases continues to grow, approaching 10 million in 2010. Here we review the changing relationship between the causative agent, Mycobacterium tuberculosis, and its human host and examine a range of factors that could explain the persistence of TB. Although there are ways to reduce susceptibility to infection and disease, and a high-efficacy vaccine would boost TB prevention, early diagnosis and drug treatment to interrupt transmission remain the top priorities for control. Whatever the technology used, success depends critically on the social, institutional, and epidemiological context in which it is applied.
http://www.sciencemag.org/cgi/content/abstract/328/5980/856