Background

The Human Immunodeficiency Virus (HIV-1) currently infects approximately 40 million people, and the pandemic shown no sign of abating in the absence of a vaccine. There has been debate regarding whether an ideal HIV-1 vaccine would require an immune response focussed predominantly at the T cell or B cell compartment. Most researchers are now of the opinion that 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 backup to control any infection that broke through the antibody barrier. Both B cell and T cell fields have had their disappointments, with the gp20-based VaxGen phase-III trial showing no efficacy, and the Merck phase IIb test of concept trial stopped very recently prematurely because of lack of evidence for efficacy. These setbacks provide the backdrop to renewed efforts in both fields to enhance the vaccine antigens and adjuvants necessary to achieve some level of efficacy.

T cell-based vaccine strategies

Based at the Weatherall Institute for Molecular Medicine, this programme has two main phases: preclinical vaccine design and development and clinical trials.

1. Preclinical vaccine design

We are searching for novel vectors for genetic vaccines used in heterologous prime-boost regimens and designing novel HIV-1-derived immunogens, to which we aim to focus the vaccine-induced T cell responses. The vectors include plasmid DNA, attenuated viruses and attenuated bacteria. The immunogens are derived from individual clades or focus on conserved regions of the HIV-1 proteome.

2. Clinical trials

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 trategies that we have developed. These are ongoing.

B cell-based vaccine strategies

Based at the Sir William Dunn School of Pathology, this programme is funded by the Medical Research Council, The Wellcome Trust, The Bill and Melinda Gates Foundation and the International AIDS Vaccine Initiative. The programme has three main goals:

1. to design novel envelope glycoprotein (Env)-based antigens for eliciting HIV-1 neutralising antibodies
2. to discover and characterise novel adjuvants that are optimal for use with HIV-1 Env antigens for eliciting neutralising antibodies
3. to establish proof of principle that vaginal application of antigen-microbicide formulations can induce mucosal antibody responses to HIV-1

1. Design of novel envelope glycoprotein (Env)-based antigens

The only viral antigens relevant to design of HIV-1 vaccines aimed at eliciting neutralising antibodies are the Env glycoproteins. Early studies demonstated that the monomeric form of HIV-1 gp120 was both weakly immunogenic and a poor inducer of neutralising antibodies. Subsequent studies indicated that gp120 has evolved a range of highly effective immune evasion strategies preventing or reducing B cell recognition of conserved neutralisation epitopes. Subsequent studies have been aimed at engineering the env gene in order to produce recombinant proteins in which:

• Env is presented to the immune system as a trimer, to better represent the native Env viral spike
• The conserved receptor binding sites are constitutively exposed
• The neutralisation-irrelevant surfaces are masked
• The conformational flexibility of the glycoprotein is rigidified.

The Dunn School group has participated in the process of antigen modification and is currently following up a strategy of ‘antigenic silencing’ in which the neutralisation-irrelevant surfaces of the protein are immunologically silenced by addition of polymers such as polyethylene glycol or similar. It is hoped that this approach will focus the B cell response towards towards remaining exposed protein surfaces, corresponding to the conserved receptor binding sites. Further modifications include alteration of the glycans on Env to alter antigenicity and increase immunogenicity. This work is carried out in collaboration with G. Stuart-Jones at the Weatherall Institute of Molecular Medecine and Peter Kwong at the Vaccine Research Centre, National Institute of Health, USA.

2. Discovery of novel adjuvants for use with HIV-1 Env antigens
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. Adjuvants currently licenced for use in man are limited to aluminium salts, virosomes, Novartis’s MF59, and the GSK series of adjuvants. To date none of the adjuvants tested in small animal models has shown the potency required to elicit high-titre neutralising antibody responses to HIV-1. 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, the other is a variant of polyacrylic acid, which is at an earlier stage of development. 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 responses are required.

3. Proof of principle for vaginal application of antigen-microbicide formulations
As part of a Bill and Melinda Gates and Wellcome Trust funded consortium, the Dunn School of Pathology group have been developing model systems for evaluating the use of combinations of vaginal microbicides and HIV-1 Env based antigens as mucosal vaccine formulations. We have developed two in vivo models for vaginal administration, and have demonstrated that combinations of Env and microbicide lead to higher titres of mucosal, Env-specific IgG and/or IgA than antigen alone. If successful, this strategy might lead to the first self-applied mucosal vaccine.