HIV research at St George's

St George’s scoops $21 million

St George’s has been selected, as part of the Grand Challenges in Global Health Initiative to receive one of 43 international grants for groundbreaking research projects to improve health in developing countries.

The research group led by Professor Robin Shattock of the Centre for Infection, which includes Professor Martin Cranage and Professor Julian Ma of the Division of Cellular and Molecular Medicine, has received a grant for $19.7 million jointly from the Bill and Melinda Gates Foundation and the Wellcome Trust. This will provide a significant opportunity for the development of new interventions in the fight against HIV and AIDS through the development of novel vaginal vaccines.

Everyday more than 14,000 people become infected with HIV, 95% of these people are from developing countries and over 40 million people have already been infected world-wide. Globally almost 50% of those infected are women, but strikingly 76% of young people infected in sub-Saharan Africa (aged 15 — 24) are female. Currently women have no means to protect themselves if their partners do not use male condoms or do not allow female condoms to be used.

To contain the global HIV/AIDS epidemic, it is essential to develop an HIV vaccine that stimulates an effective immune system response. This project will work to develop an HIV vaccine that stimulates immune responses in the lining of the vagina, which serves as the entry point for HIV for most women. The research team will work with collaborators in the UK and South Africa to design an HIV vaccine that would be time-released into the vaginal lining through low-cost gels or silicone rings that would be inserted into the vagina. To date, vaccine candidates have not specifically targeted entry point in the body, for example, the linings of vagina and cervix. However, direct vaccination of these vulnerable surfaces can stimulate both whole body and local responses, possibly providing the most potent form of protection. This five year project is designed to take this approach into early human trials.

Professor David Lewis of the St George’s Vaccine Institute has also been awarded $1.3 million as part of a consortium of researchers receiving a grant of $8.7 million from the Foundation for the National Institutes of Health (FNIH) as part of the Grand Challenges Initiative. Professor Brett Finlay of the University of British Columbia will lead the international consortium looking at “Novel therapeutics that boost innate immunity to treat infectious diseases”, which will develop new medicines that activate innate defences against devastating bacterial and parasitic infections of the developing world.

They will do this by exploring new ways to combat drug resistance by developing medicines that, rather than targeting specific disease-causing organisms, seek to boost the body’s general defences against infectious agents. Because the medicines would act on the human body and not the microbes themselves, the researchers expect that it will be more difficult for the microbes to develop resistance to this approach. This concept has already been demonstrated in animal studies.

Professor Lewis and the Vaccine Institute will continue to work in health human volunteers using the novel oral vaccines against tuberculosis and typhoid to work out the way in which the immune system responds to these pathogens. Once the mechanisms have been defined, this model of infection will be used to select and characterise novel molecules to enhance or reduce immune responses as appropriate.

Professor Lewis has also been awarded funding to carry out clinical trials for Professor Shattock’s project bringing the total awards to the Vaccine Institute under the Grand Challenges in Global Health Initiative to $5.8 million.

The Grand Challenges in Global Health Initiative is a major international effort to achieve scientific breakthroughs against diseases that kill millions of people each year in the world’s poorest countries. It is funded with a $450 million commitment from the Bill and Melinda Gates Foundation, $27.1 million from the Wellcome Trust, and $4.5 million from the Canadian Institutes of Health Research and the Foundation for the National Institutes of Health (FNIH).

For more information on either of these projects please contract either Professor Robin Shattack — r.shattock@sgul.ac.uk or Professor Lewis — d.lewis@sgul.ac.uk



St George’s unites HIV vaccine and microbicide research

With the recent EUROPRISE announcement, four St George’s researchers, led by Professor Robin Shattock of the Centre for Infection, will be leading the fight against HIV transmission with a new European consortium dedicated to HIV vaccine and microbicide research.

Research teams within the Centre for Infection are currently studying the early pathogenesis and transmission of HIV infection. Professor Shattock’s team have been instrumental in elucidating several aspects of the early mechanism of HIV transmission using novel tissue explant systems. This work is being used to develop safe and effective vaccines and microbicides designed to prevent HIV infection at the site of transmission.

At present, Professor Shattock’s Group is focusing on the pre-clinical evaluation of microbicides and their effectiveness in other compounds such as gels or creams as well as possible vaccine delivery systems. The team, along with the Hotung Molecular Vaccinology Group, led by Professor Martin Cranage, are investigating how HIV interacts with the body’s mucosal surfaces that are the principal sites of virus entry, in particular the female genital tract, the male genital tract and the rectum. The teams are particularly interested to determine if candidate vaccines administered at the sites of virus entry either alone or in combination with other antiviral substances stimulate innate and adaptive arms of the body’s immune system thereby reducing, or preferably eliminating, susceptibility to infection with the virus.

The Hotung Molecular Vaccinology Group is especially interested in how HIV is recognised by the immune system at mucosal portals of entry. Specialised cells known as antigen presenting cells are present within mucosal tissues and are believed to be critically important for the generation of primary immunity. Members of the group are working on novel strategies to target these cells with candidate vaccine antigens in a way that causes minimal inflammation and at the same time allows access across the mucosal barrier. Other members of the group, comprising the Immunology Core Team, are developing, refining and standardising immunoassays for the measurement of HIV-specific immunity. This is a particularly challenging job when it comes to the evaluation of immunity at mucosal surfaces and the team work in close collaboration with clinical colleagues within the Vaccine Institute.

Professor Julian Ma heads the Hotung Molecular Immunology Group, also within the Centre for Infection. His team is focused on the expression of recombinant pharmaceuticals in transgenic plants. The use of plants as a scalable, low cost expression system is a potential means for delivering modern high tech medicines on a global scale, and particularly to developing countries. His group was among the first to demonstrate the potential of plant-derived monoclonal antibodies, and the assembly of engineered antibodies, leading to the first monoclonal secretory antibody. They conducted the first human trial of a monoclonal antibody purified from transgenic plants, thereby establishing the proof of concept that plant-derived antibodies could be used safely for passive immunisation in humans. More recently, the focus has expanded to the expression of vaccines, microbicides and a range of monoclonal antibodies in transgenic plants.
Professor David Lewis leads the Vaccine Institute, within the Centre for Infection, a state of the art unit that was opened in 1996. It is focused on the evaluation of novel vaccines in humans, principally after mucosal delivery and involving subunit, live recombinant and other vaccine strategies. It has conducted over 15 Phase 1-3 clinical trials and has unique inpatient isolation facilities for managing GMO (genetically modified organisms) vaccines, as well as laboratory and outpatient facilities to obtain mucosal and other clinical specimens.

Professor David Lewis is currently the clinical coordinator for the EU Framework 6 integrated project MUVAPRED to develop mucosal vaccines against HIV and TB, Principal Investigator in the EU Framework 6 integrated project RMHIV to develop recombinant measles-HIV vaccines against HIV, and subgrantee in a Grand Challenges award to the University of British Columbia to investigate human models of innate immunity.

“These teams form an integral part of the Cellular and Molecular Medicine wider portfolio of infection research which includes groups of international stature working on infectious diseases including Mycobacterium tuberculosis, Malaria, Cryptococcus, and MRSA.” says Professor George Griffin, Head of Cellular and Molecular Medicine at St George's.



GM The plants that save lives

Work on turning tobacco plants into factories for making new medicines has been hailed “a perfect example of why research in genetic engineering and modification must go on” by a Channel 4 documentary.

Biologist Dr Olivia Judson, presenter of Channel 4’s Animal Pharm, visited St George’s earlier this year to film Professor Julian Ma’s work on genetically modified tobacco plants, which produce a compound that kills HIV/Aids on contact.

The three-part series, questioned the ethics behind manipulating nature for the sake of food and medicine, covering controversial experiments from pigs that glow in the dark to the creation of human organs inside a laboratory.

But Professor Ma’s Pharma-Planta project was highlighted as one of many examples of how the biotech revolution has the potential to save the lives of millions.

His GM tobacco plants contain a compound called cyanovirin, which destroys the HIV virus. Normally, cyanovirin is only produced by a small alga, in tiny quantities. Professor Ma’s team took a gene from the alga and put it in the tobacco plants so that they can produce cyanovirin, too.

At a vast contained greenhouse in East Malling, Kent, hundreds of the plants are being grown, each one producing up to 10,000 seeds that can be shipped anywhere in the world. In developing countries, local farmers can cultivate acres of these plants and harvest cyanovirin from them.

With each plant potentially providing 20 doses of an anti-HIV drug - enough to protect a woman from infection for up to three months — an affordable means to combat the pandemic could soon be available to millions.

Professor Ma said: “HIV/Aids is a huge problem around the world, but particularly in developing countries, where there are millions or people who need this kind of protection but are too poor to pay for this kind of medicine.

“Plants are cheap to grow. Once you get to this stage you’re actually in very low-tech technology — anyone can build a greenhouse very cheaply, even a contained greenhouse, and grow a number of plants. If you really want to address global access to new technologies, that’s where I think plants come in.”

The clear advantages of the method win over even Dr Judson’s skeptical food critic co-presenter, Giles Coren. As the documentary sums up: “It’s just a perfect example of why research in genetic engineering and modification must go on. The work of scientists like Professor Ma could end up saving the lives of millions.”



Eavesdropping on molecules

A robotic machine that analyses samples with soundwaves is helping scientists at St George’s develop vaccines for HIV.

St George’s is the first medical and healthcare school in Britain to get the Akubio — which uses soundwaves emitted by vibrating crystals to examine how molecules interact in samples such as serum, urine and cell cultures.

The Akubio analyses molecules by pasting them on to the surface of the crystal. Changes in the frequency of the crystal’s vibrations reveal how quickly they interact, how strongly they bind and the amount of active molecule present in each solution.

The process, known as resonant acoustic profiling (RAP), has been dubbed “eavesdropping on molecular interactions”.

The new machine can be programmed to analyse hundreds of samples automatically using a robotic arm. It will be used by St George’s to examine the immunoglobulin make-up of patients with immunodeficiency disorders.

It was funded by grants won by three different groups. Professor Robin Shattock’s group, working on the development of microbicides, will use the technology to investigate the interactions between HIV and cells to help design HIV vaccines.

The machine will also help the Molecular Immunology Group, headed by Professor Julian Ma, which is looking at ways of developing novel recombinant vaccines. It will allow them to assess the functional integrity of recombinant proteins produced in plants with a view to manufacturing them on a large scale so that they can be incorporated into vaccines.

The Molecular Vaccinology group, headed by Professor Martin Cranage, will primarily use this new technology in multiplex assays to measure immunogenicity — the ability of a particular substance to provoke an immune response — in phase one HIV vaccine trials.

Senior Postdoctoral Research Fellow Dr Lea Cope said: “The Akubio is extremely versatile as well as being fully automated for almost 300 samples. This allows us to put on a run over night and collect data the following morning — a huge labour-saver.”



St George’s Heads EC Consortium on HIV/AIDS Prevention

A €15.5 million European Commission award under the Sixth Framework Programme has placed St George’s, University of London firmly at the centre of European efforts to halt the AIDS pandemic. The grant represents another resounding endorsement of the high international standing in HIV/AIDS research enjoyed by the Centre for Infection and the Vaccine Institute.

In 2005, the Centres attracted the second largest grant in the world that year under the Gates Grand Challenges in Global Health Initiative and won a total of $21 million in funding for two HIV/AIDS programmes. Funding is provided jointly by the Bill and Melinda Gates Foundation and the Wellcome Trust.

The EUROPRISE consortium funded by the EC grant is an unprecedented, integrated approach to HIV-1 prevention that will bring together researchers at 33 institutions in 10 European countries working in microbicide and vaccine research.

St George’s international profile in HIV/AIDS research in both the microbicide and vaccine fields made them a natural choice to head the first organisation in both Europe and internationally to deliberately bring these two groups together.

The consortium plans to develop an integrated network that facilitates the sharing of information, identification of new candidates, establishment of clinical development pathways and scientific training development to maximize research synergy in the development of effective protection against HIV-1 transmission.

Heading the Europe-wide consortium is Professor Robin Shattock, who along with Professors Martin Cranage, and Julian Ma, also from the Centre for Infection, and Professor David Lewis of the Vaccine Institute have received over 50 grants, totalling £14.8 million in the last 5 years for their respective work.

The UNAIDS/WHO estimates that at the end of 2004, 40 million people globally were living with HIV, of which 610,000 were in Western Europe and 28.5 million were in Sub-Saharan Africa. Globally, there are 14,000 new HIV infections per day, 80% of which are now heterosexual, and 95% of which are in developing countries. In some countries, public health programmes encouraging the use of condoms have achieved modest results in reducing HIV infection rates but it is clear that other preventative strategies are needed.

“Although therapeutics for HIV/AIDS continue to improve, ultimately the development of safe and effective strategies of blocking and preventing HIV transmission will be key to combating this pandemic.” says Professor Shattock.

Unlike many common vaccines, HIV vaccines do not contain the live virus and at present cannot induce sufficient immune response and immunological memory to protect against infection. In contrast, while it may be technically easier to develop microbicides that prevent transmission, their duration of protection is likely to be short lived and they are critically dependent on user compliance.

In the past, the two fields have been slow to work together in the development of products that provide multiple levels of protection. This network is focused on the premise that microbicides and vaccines that target stages of the virus’ life cycle will have the best chance of success. And since both fields study and target the transmission of HIV, there is clear overlap between the two fields.

The EUROPRISE consortium has 6 main objectives for this project:

1. Standardization and harmonization of research tools.

2. Identification of new HIV/AIDS vaccine and microbicide candidates and combinations to prevent HIV/AIDS.

3. Establishment of clinical development pathway for vaccines and microbicides within a European framework.

4. Provision of Scientific training in microbicide and vaccine development

5. To facilitate access to information relevant to HIV-1 microbicides and vaccines

6. Provision of a single focus for European HIV-1 microbicide and vaccine research

“A large part of our success in HIV research has been due to our extensive research in both the vaccine and microbicide fields. We look forward to leading the development of an integrated research network in Europe." says Professor George Griffin, Head of Cellular and Molecular Medicine at St George's.



HIV on the BBC

A UNIQUE project linking the laboratories of St George’s to London’s African communities is now the subject of a BBC film.
A TV crew from BBC1’s Inside Out show spent three days following St George’s scientists Martha Stefanidou and Dr Trish Fletcher, who are researching microbicides — a gel women can use discreetly to protect themselves against the transmission of HIV. In the film, screened earlier this month, 600,000 viewers saw the pair showing community workers from the UK African Microbicides Working Group around the labs, explaining the science behind the gel development, and hearing how the products might be received in the community.
Dr Fletcher described her involvement with the HIV Science In Action project as ‘motivational’. She said: ‘You always believe that what you do in the lab can have an effect on people’s lives, but to actually meet them and discover first hand that this is true is fantastic.
‘It actually gave the disease we’re working on a face.’
BBC researcher Amelia Vale, who worked closely on the show, said: ‘We enjoyed the programme and feel we have learnt so much from it from the community and scientific perspective.’
The film about the launch of HIV Science In Action can be viewed online at www.bbc.co.uk/insideout/ until September 27. n


For more information on the ongoing project, or to get involved, visit our website at www.sgul.ac.uk