VIR201 : Therapeutic HIV Vaccine

VIR201 Program: Therapeutic HIV Vaccine

Background

Acquired immunodeficiency syndrome (AIDS) was first recognized in 1981 with the human immunodeficiency virus (HIV) being identified as the causative agent in 1983.  It has become the fourth largest cause of death globally.  Worldwide about 40 million individuals are infected with the disease with Sub-Saharan Africa remaining the region most devastated by the epidemic.

Reference
1. AID Epidemic Update 2007, WHO Press Release, 20 Nov 2007

In the United States of America (USA) and Europe, the current treatment for HIV is highly active antiretroviral therapy (HAART).  While effective in controlling HIV replication and delaying HIV-related morbidity and mortality, these regimens are not without cost.  Chronic use requires strict adherence to often-complex regimens that impact upon daily life through special dietary and scheduling requirements.  Ultimately, even minor breakdowns in adherence are likely to result in the development of drug-resistant HIV that can have a negative impact upon the efficacy of sequential antiretroviral therapies.

The concept of therapeutic vaccination for HIV relies on the notion that administration of exogenous antigen(s) can modify the natural history of disease either by:

1. enhancing existing anti-HIV immune responses; or
2. generating new anti-HIV immune responses.

This assumes that the host's immune response to the virus is, in some way, inadequate or compromised through infection, and can be improved. The ultimate goal of a therapeutic vaccine would be to generate sufficient anti-HIV immune responses to allow the infection to be cleared either alone or in combination with other novel therapies.  A more immediate, reasonable and pragmatic objective is to generate sufficient immune responses to allow individuals to cease using antiretroviral drugs or to defer their use.

Therapeutic vaccines could be of particular value in some countries of the developing world where the provision of long term antiretroviral therapies to large numbers of infected persons is severely constrained by resources.  In countries such as the Republic of South Africa, a vaccine that could reduce the need for antiretroviral use may greatly contribute towards a significant reduction in the burden of disease.

The immunopathogenesis of HIV disease has not been completely delineated.  Central to current dogma is evidence that suggests that cell-mediated immunity plays a significant, if not central role in controlling HIV replication.

HIV Development Program Overview

The Candidate Vaccine VIR201

Virax's candidate therapeutic vaccine is known as VIR201.  VIR201 utilises Australian developed co-expression technology, Co-X-Gene^TM, to harness the body's own immune system to fight infection.  The Co-X-Gene^TM platform technology attempts to direct the immune system to develop the right range of immune responses, in the right place, at the right time.  VIR201 is a recombinant fowl pox virus that co-expresses genes for immunogenic but highly conserved parts of the HIV-1 virus in conjunction with a human cytokine (interferon gamma).  It is designed to preferentially stimulate T cell-mediated immune responses against conserved regions of HIV-1 (HIV gag/pol).  The objective is to both amplify the cell-mediated (T-cell) response of the human immune system to the HIV virus and overcome the Th2 bias associated with HIV infection.

Prior Human Experience with VIR201

To date, two Phase I/IIa clinical trials have been conducted at St Vincent's Hospital, Sydney and the Alfred Hospital, Melbourne, Australia.  In these studies the influence of IFN-γ co-expression in VIR201 was assessed by comparison with rFPV expressing gag/pol alone (PC or Partial Construct).

The first trial (protocol VIR-NCHR-01) was a phase I/IIa controlled evaluation of the safety and biological activity of fowlpox virus expressing HIV gag/pol and Interferon-gamma in HIV‑1 infected subjects (ITV Study).  Thirty-five patients were recruited from May 2001 to March 2002.  Patients were randomized to receive placebo, Partial Construct (PC) or VIR201 (FC) vaccine on day 0, week 4 and week 12.

Neither of the candidate vaccine constructs evaluated in this protocol appeared to possess any T-cell mediated anti-HIV immunogenic properties in this protocol using the assays employed.  However, given the effects of vaccination on viral load in the context of treatment interruption (see protocol VIR-NCHR-02 below) it is postulated that there may be some stimulation that has not been detected in the assays employed. Administration of candidate vaccines in this protocol was not associated with any significant toxicity or safety concerns.

The second trial (protocol VIR-NCHR-02) was an extension study to protocol VIR-NCHR-01 to assess the anti-retrovirological properties of candidate therapeutic HIV vaccines based on recombinant fowlpox virus (FPV) (ITV Extension Study).  At day 0 of VIR-NCHR-02, one additional vaccination was administered according to the original randomly assigned vaccine schedule.  One week later, all patients ceased combination antiretroviral therapy (ART) for analytical treatment interruption (ATI) of up to 20 weeks.  During this ATI, volunteers underwent frequent virological and immunological monitoring to assess whether vaccination had any impact upon ongoing virus replication.

A total of 25 patients consented to participate in the extension phase study VIR-NCHR-02.  Based upon this limited sample size, the study had insufficient power to be definitive and therefore, in terms of both safety and efficacy analyses should be regarded as an exploratory proof of concept study.  The primary endpoint was a time-weighted mean area under the curve change in log plasma HIV-RNA viral load (pVL) from baseline (day 0) until reintroduction of ART.  

All 25 subjects completed the scheduled assessments as planned and have contributed data to all analyses.  There were no serious adverse events (SAEs) during the conduct of VIR-NCHR-02.  Other than injection site reactions and mild to moderate discomfort at the time of vaccination, there were no clinical or laboratory abnormalities that occurred more frequently in recipients of either the VIR201 or PC vaccines than placebo.  The time weighted mean change (SD) from baseline plasma HIV RNA was 1.8 (0.72), 1.78 (0.91) and 0.96 (0.91) log10 copies/mL for placebo, PC and VIR201 recipients respectively (p= 0.06, mean differences between placebo and VIR201).  Laboratory evaluations did not reveal differences in anti-HIV specific immune responses between study arms.  No difference between treatment arms for host genetic factors known to affect pV_L was demonstrated.

Further Developments in Immunology (post trial)

Virax has (with collaborators) undertaken additional immunological analyses of samples from the previous Australian trials of VIR201. The results of this analysis were presented in July 2009 by our collaborators led by Professor Martyn French from Royal Perth Hospital in a paper to the International AIDS Society conference in Cape Town, South Africa. The presentation detailed the outcome of additional immunological testing of clinical samples from the Australian trials of VIR201 which noted a novel mechanism of action - namely antibody isotype switching (IgG1 to IgG2). Importantly, this vaccine-induced IgG2 antibodies to a vaccine-encoded antigen (p24) were associated with lower HIV replication and could provide the mechanism as to how VIR201 suppressed viral load in the Australian trials.

A significant gap in the previous Australian clinical trial data was the ability to relate the viral load suppression to an immune readout potentiated by VIR201. This data fills this gap. In order to further build on this data, the antibody isotyping assays developed by Professor French will be done in the ongoing trial in South Africa as a major immune read out.
 

Conclusions

In summary, VIR201 was demonstrated to be safe and well tolerated in patients with HIV-1 infection, when administered as an initial three dose series, with a booster vaccination at 12 months.  Results suggest that VIR201 causes an approximately 1 log decrease in time weighted mean change from baseline plasma HIV RNA.

VIR201 may have the potential to control viral replication during ATI.  It is noted that these studies have been conducted in small patient numbers and that further study of these constructs is required in broader populations with HIV disease.

The full details of the two studies are published in:

(1)  Emery S, Workman C, Puls RL, Bloch M, Baker D, Bodsworth N, Anderson J, Crowe SM, French MAH, Hoy J, Aichelburg A, Ward LD, Boyle DB, Law MG, Kelleher AD and Cooper DA (2005) Randomized, Placebo-Controlled, Phase I/IIa Evaluation of the Safety and Immunogenicity of Fowlpox Virus expressing HIV gag-pol and Interferon-γ in HIV-1 Infected Subjects. Human Vaccines 1, 232-238

(2)  Emery S, Kelleher AD, Workman C, Puls RL, Bloch M, Baker D, Anderson J, Hoy J, Ip S, Nalliah K, Ward LD, Law MG, Cooper DA (2007) Influence of IFN-γ co-expression on the safety and antiviral efficacy of recombinant fowlpox virus HIV therapeutic vaccines following interruption of antiretroviral therapy.  Human Vaccines; 3(6): 260-267

Articles are linked to Scientific Published Papers

Current Clinical Testing
I.  Product Development for the Developing World

South African Clinical Trial of VIR201

The devastating impact of HIV on African society, both culturally and economically has been well documented.  Existing highly active anti-retroviral treatments have significantly reduced the toll of this disease in Australia, the United States and Europe.  These drugs are already providing some benefit in parts of Africa, but will not provide more than a partial solution for emerging countries.  Not only is the cost of anti-retroviral treatment prohibitive for widespread distribution in Africa, but the resource-limited medical infrastructure is unable to support the comprehensive programs required to control the HIV pandemic.  Furthermore, the effects of anti-retroviral treatment are not well tolerated by people in situations where poor nutritional status and lack of access to clean water is often accompanied by other disease burdens like TB or malaria.

VIR201 is one of  the only therapeutic vaccine based on stimulating the immune system known to have shown a positive effect in suppressing virus levels in HIV infected patients in fully controlled, gold standard, clinical trials.

Non-dilutive Funding Model

In an innovative drug development strategy, Virax has formed a South African non-profit organization for corporate donors with significant operations and interests in South Africa and other African countries where HIV/AIDS is endemic to provide funding for a phase I/IIa trial in an emerging country environment.  In effect, this has seen the formation of a global coalition of corporations to fight AIDS with contributions from four nations - Australia, Japan, South Africa and the United Kingdom.

Twelve global mining companies have joined the consortium led by BHP Billiton to fund the first emerging country trials of Virax's VIR201 HIV/AIDS therapeutic vaccine, currently being undertaken in South Africa.

The consortium now includes:

The project funding is non-dilutive to Virax and will contribute its intellectual property.  The international contract research organization (CRO), Quintiles, are engaged to implement the trial and provide project management in South Africa under Virax's management control.  Dr Des Martin, Immediate Past President, Southern African HIV Clinicians Society, is the National Principal Investigator for the trial.

Clinical Trial Design

The trial involves 140 HIV positive subjects in 4 well established HIV clinics across 4 provinces in South Africa and will be carried out as a Phase I/IIa double-blind, randomised, placebo controlled, parallel group study.  There are two groups to this study: 1, study participants that have not received anti-retroviral therapy (ART naive) and 2, study participants that are on anti-retroviral therapy (ART experienced).  Participants in each of the two groups will be vaccinated with either placebo or VIR201.  In order to enhance the immune response a higher dose of VIR201 than that used in the Australian Phase I/IIa trials will be utilised.  Major endpoints of the study are safety, tolerability and immunogenicity.

A promising application of a successful HIV therapeutic vaccine, particularly in the developing world setting would be the lengthening of time between primary HIV infection and the need to commence ART.

Virax has received regulatory approval from the South African Medicines Control Council to conduct the trial of VIR201.  

Key Dates of the Trial  

Future Clinical Testing

I.  Planned Product Development of VIR201 in the Developed World

Phase II Clinical Trial in Australia, Europe and United States

Virax has an open US IND to conduct a Phase II study of VIR201.  A major objective of the trial, which involves an Analytical Treatment Interruption, is to monitor the anti-retrovirological effects of VIR201 in a broader patient population to that used in the Australian trials.  Upon successful completion of the South African trial Virax will attempt to attract further non-dilute funding to complete this trial.

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