Hunt for a HIV vaccine
When the first AIDS patient was reported in the 80s, it was believed that a vaccine to prevent HIV would take no longer than two years. However, the scientists underestimated the variability of the AIDS virus, which was unlike any other virus they had ever seen and has continued to befuddle them since the last 25 years. Having tried and tested several vaccine candidates, they are beginning to gain a better understanding of their opponent.
Hits and misses so far
Given the tricky nature of the HIV virus, several approaches have been tried to counteract infection. The first HIV vaccine to enter full-scale efficacy testing (phase III) was the AIDSVAX gp120-based vaccine, VAX004 and VAX003 in 2003. A recombinant subunit protein vaccine(made of bigger pieces of proteins that are on the surface of the HIV virus) was designed to induce neutralising antibodies to inactivate the virus thus aborting infection. However, it produced little or no efficacy. The focus then shifted to T lymphocytes, the cell-mediated arm of the immune system in 2004 under which V520, a modified Adenovirus was used to stimulate the body’s antibody response. Instead the Step trial that ended in 2007 reported an increased instance of infection in vaccinated individuals.
Researchers then shifted to a combination of both these approaches to induce a stronger immune response. Called the prime boost approach, it uses a DNA or vector vaccine to elicit cytotoxic T cells that destroy infected cells followed by a subunit vaccine to induce neutralising antibodies(boost). The 2009 RV144 Thai vaccine trial (phase III) used a combination of two vaccines (Sanofi’s ALVACvCP1521 canarypox vector as the prime and AIDSVAX as the boost). It reduced the risk of infection by 31.2 per cent thus proving that a safe and effective vaccine can indeed be a reality.
Researchers in India too have received better results with the prime boost approach using ADVAX, a DNA-based vaccine, as the prime and a vector, Modified Vaccinia Ankara (MVA) as the boost. The phase I trials conducted by the Tuberculosis Research Centre (TRC), Chennai and the National AIDS Research Institute (NARI), Pune showed a modest immune response as compared to TBC-M4, a vector built from recombinant Modified Vaccinia Ankara (MVA) at TRC and found to be safe.
| ‘A confluence of scientific advances has spurred vaccine development’ |
| The regimen evaluated in the RV144 trial along with the globalisation of efforts to design and develop new vaccine candidates has proved vital to HIV vaccine development. HIV is a global problem, and any solution to the pandemic will have to involve researchers around the world working together to study the virus and its transmission, and to develop and combine new tools and strategies for HIV prevention. A confluence of scientific advances in a variety of fields, a more sophisticated understanding of HIV pathogenesis and the immune response to the virus has spurred the development of new vaccine concepts. Novel vectors and techniques for the study of mucosal immunology are contributing to the design of a new generation of candidates devised to induce immunity in the tissues where sexually transmitted HIV initiates infection. Similarly, the systematic assessment of antibody breadth and potency has helped streamline and speed up the identification of globally relevant broadly neutralising antibodies, and their isolation has been greatly aided by advances in biotechnology. Meanwhile, advances in computational biology and the rapid crystallization and structural analysis of complex protein molecules have dovetailed to boost the design of vaccine candidates that might elicit such antibodies. |
Newer approaches to vaccine design
The success of the RV 144 trial has spurred a number of follow-up trials of vaccine candidates based on it, including the RV 152 study and HVTN 505 trial, that will provide more immunological data for further research. “Experimental data so far suggests that a heterologous prime boost approach is good,” says Dr VD Ramanathan, Former Director, TRC. Prime boost strategy and the use of replicating vectors is a part of the cell-mediated immunity (CMI) strategy wherein infected cells are destroyed. Blocking HIV infection by engaging the body’s antibody response is another. However, novel approaches are being used today, including Broadly neutralising antibodies (bNAbs).
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| Rick King |
Rick King, Vice President Vaccine Design, IAVI said, “bNAbs can neutralise a broad range of HIV strains with an efficacy as high as 90 per cent in laboratory assays. The NAC (Neutralising Antibody Consortium), with partners in nearly every continent has been successful in isolating many bNAbs. Ongoing studies including reverse engineering of the epitope, are likely to give us valuable insights into the structure of the virus.”
bNAbs target regions on the AIDS virus that remain the same, even as it mutates. These sites hold the key to virus replication and thus details on how bNAbs bind to them hold clues to effective vaccines in the future.
 “The empirical application of conventional vaccinology i.e. administering a ‘modified pathogen’ or antigen and hoping that immunity develops has not worked for HIV infection so far.”Guido Silvestri Professor of Pathology and Laboratory Medicine Emory University School of Medicine |
Guido Silvestri, Professor of Pathology and Laboratory Medicine at the Emory University School of Medicine who was one of the key speakers at a recent conference organised by IAVI sums up the ideology behind current approaches. “The empirical application of conventional vaccinology i.e. administering a ‘modified pathogen’ or antigen and hoping that immunity develops has not worked for HIV infection so far. Rather a better understanding of the interaction between HIV and immunogens, process of virus transmission and disease progression including investigating the role of specific immune cell subsets along with structural and functional properties of immunogens designed to interact with these cell types, is the key to HIV immunology,” he said. Silvestri and his team are working upon T cell-based vaccines that will generate memory T cell responses against HIV.
Towards an efficacious vaccine
So, what exactly constitutes an effective vaccine, given that the earlier candidates have failed to do so? An effective AIDS vaccine will likely need to stimulate broad, potent, and durable neutralising antibodies and cell-mediated immunity responses, answers Ramanathan. We are looking at an efficacy of 60-70 per cent, he adds. “About 30 candidates are currently in the pipeline globally. There are also several next-generation candidates testing a number of different vaccine concepts moving through the pipeline with most in the pre-clinical and a few in the phase I testing stage,” informs King.
IAVI is working with its partners to evaluate in clinical trials four distinct vaccine candidates in various combinations and regimens. They include one protein candidate, one DNA vaccine candidate and two adenovirus vector candidates. India is also close on the heels of a HIV-1 DNA vaccine, being developed by a research team at the National HIV Reference Centre, AIIMS, New Delhi, the human trials of which is likely to start as early as 2013.
“The current short-term priority is to build on RV-144 Trial and improve the efficacy seen in in the Thai trial, in the medium term have Heterologous Prime Boost candidates that shall address HIV variability and demonstrate a good efficacy and in the long term have next generation candidates aimed to elicit bNAbs that may be able to substantially bring down the infection,” concludes Dr Ramanathan.
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