Human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS, currently infects approximately 35 million people worldwide. The pandemic continues to spread, with ~1.5 million new infections occurring annually, emphasising the need for effective prophylactic HIV vaccines. Combination antiretroviral therapy (ART) is highly effective in preventing disease progression and onward transmission but fails to eradicate infection, necessitating lifelong treatment. A safe, effective, accessible vaccine against HIV-1 infection is therefore key to sustained control of the AIDS epidemic even in the context of a broader prevention landscape. There is also a need for improved therapeutic strategies, including therapeutic vaccines, to induce long-term control of infection or contribute to its eradication.
There is a consensus that for prophylactic vaccines stimulation of both arms of the response would be optimal, with antibody responses aimed at preventing initial infection and CD8+ T cell responses present as a back-up to control any infection that breaks through the antibody barrier. Although both antibody and T cell-based strategies have had their disappointments, with initial phase IIb and III trials showing no efficacy, the observation of a modest level of short-term protection in the most recent phase III trial of an antibody-inducing vaccine, together with the demonstration that CD8+ T cell responses induced by a persisting rhesus cytomegalovirus vector were able to eradicate infection with a pathogenic challenge virus provide renewed optimism that generation of effective prophylactic HIV vaccines will be possible. However considerable further work is required to achieve this goal, and to tackle the additional challenges associated with development of therapeutic HIV vaccines.
T cell-based vaccine strategies
Based at the Jenner Institute and NDM Research Building, this programme has two main phases: preclinical vaccine design and development and clinical trials. This work is complemented by human immunology studies that aim to define the immunological correlates of virus control.
Preclinical vaccine design
In collaboration with other experts in the field, we explore novel approaches and emerging technologies to induce protective T-cell and neutralizing antibody responses. The programme includes conception, construction and stepwise improvements of new vaccine candidates in an iterative process from mouse to non-human primate models, followed by clinical studies in humans.
Our central hypothesis is that CD8+ (killer) T cells focused from the very onset of infection on conserved regions of the HIV-1-proteome, together with binding/neutralizing antibodies to Env, will control early the transmitted/founder viruses, slow or stop their replication, prevent damage to the immune system and control any breakthrough infections without the need for antiretroviral drugs.
Phase I/IIa prophylactic and therapeutic clinical trials have been undertaken at various sites in order to evaluate safety and immunogenicity of some of the vaccine strategies that we have developed. These are ongoing.
A reliable immune correlate of protection against infection or disease would facilitate evaluation of vaccine candidates at an early stage of development and enable prioritisation of promising candidates for further testing. Through observational studies in HIV-infected individuals and recipients of HIV vaccine candidates we have identified some of the characteristics of CD8+ T cells that potently suppress HIV replication and are developing new assays that may be used to predict vaccine efficacy.
B cell-based vaccine strategies
Based principally at the Sir William Dunn School of Pathology, this programme is funded by the Medical Research Council and The Bill and Melinda Gates Foundation. The programme has two main goals:
1. To design novel envelope glycoprotein (Env)-based antigens for eliciting HIV-1 neutralising antibodies
2. To discover and characterise novel adjuvants for vaccine use
Design of novel envelope glycoprotein (Env)-based antigens
We are interested in designing new immunogens to elicit neutralizing antibodies to conserved regions on the HIV-1 envelope glycoprotein (Env) spike. Env has evolved numerous antibody evasion mechanisms that make antibody-based vaccine design a formidable task. Amongst these mechanisms are structural and conformational instability, both of which render Env a difficult target for B cell recognition, and the immunodominance of highly variable regions, facilitating viral escape from antibody attack. We have adopted several parallel strategies to overcome these immune evasion mechanisms. Firstly, we are using chemical cross-linking to ‘lock’ the Env into a stable conformation that should extend in vivo lifespan and facilitate B cell recognition of conserved surfaces. Second we are using post-translational targeted addition of synthetic glycans to mask proteins surfaces with undesirable immunogenicity. Third, we are investigating appropaches to mimic small conserved glycopeptide epitopes of Env using synthetic glycopeptides, to focus the antibody response to these areas.
Discovery of novel adjuvants
As with most other subunit vaccines, HIV-1 Env is relatively weakly immunogenic in its own right, requiring an adjuvant to elicit a potent immune response.
The Dunn School group has been involved in adjuvant discovery, and has two candidates. One is the polycation PEI which is currently undergoing extensive preclinical evaluation as a potent mucosal adjuvant, the other is carbopol™ a variant of polyacrylic acid, which drives s strong Th1-type immune response making it compatible with both antibody and cytotoxic T cell induction. It is hoped that either or both of these new classes of adjuvant may be useful not only in HIV vaccine design but also for other vaccines in which high titre antibody and robust T cell responses are required.