MICA: Ad4HIV, A Phase I Trial Investigating Ad4, MVA and Protein Immunisation Strategies to Maximise Protective Antibody Responses to HIV-1 Envelope

The global health burden associated with HIV continues to grow with 35 million people estimated to be living with HIV in 2013 and 2.3 million new infections. In absence of a cure, an effective vaccine would be the most sustainable way to prevent new HIV infections. We propose to make the most of what we have learned from a series of previous vaccine trials to design and test an HIV vaccine strategy which we believe will trigger a better immune response than those observed so far and potentially lead to the identification of a successful vaccine and vaccine strategy.

The proposal brings together the scientific, clinical, and technical expertise and a range of vaccine products that are designed around a common HIV virus found predominantly in Southern and East Africa, India and Nepal and which has caused the world's worst HIV epidemics and is responsible for around half of all infections. The study will be conducted in collaboration with an industrial partner, PaxVax, and the UK HIV Vaccines Consortium (UK HVC). PaxVax is a fully integrated vaccine company, whose founders set out to develop and commercialize an innovative vaccine technology in a socially responsible manner for global impact. The UK HVC is a Wellcome Trust funded programme whose mission is to generate a series of candidate vaccines containing similar HIV antigens, such that direct comparison can be achieved to understand most rapidly the most immunogenic strategy for immunization in man.

The design of the Ad4HIV trial is based on an immunisation regimen similar to that used in the only HIV vaccine trial to demonstrate partial efficacy (RV144, which showed an initial 60% reduction in infection rapidly waning to 31% in Thailand) and which builds on an existing MRC DCS funded study (UK HVC Spoke 003) to which it will be comparable. The Ad4HIV study will explore both the safety and immunogenicity of a novel combination of HIV vaccine candidates and will formally explore the immunological impact of a shorter and simpler prime-boost strategy using vaccine candidates provided by the UK HVC and designed to induce sustainable levels of protection form HIV acquisition of more than 60%. It will also explore the effectiveness of different boosting strategies with the added advantage of simplifying the regimen seen as crucial to vaccine feasibility.

A successful and safe HIV vaccine would have considerable benefits across the general populations and high risk groups. It could have the potential to prevent over 70 million infections over the course of 15 years. Should the trial identify promising vaccine constructs or strategies, the research would support the design of the next clinical studies and provide an opportunity to inform and support decisions and policy making in several areas of HIV prevention.

A safe and effective preventive HIV vaccine remains a key priority for global public health. The RV144 Phase IIb efficacy trial showed an estimated efficacy of 31% suggesting that a vaccine to prevent HIV-1 infection may be closer than previously thought.

Although the mechanistic correlates of protection remain obscure, reduced risk of HIV acquisition correlated with a range of functional antibody characteristics. This modest and short-lived immune protection, based on a non-replicating canarypox vector prime and recombinant envelope protein boost regime, suggests the need for much more potent vaccine-induced protective antibody responses at the mucosal portals of viral entry. A mucosal replicating vector system generating local Env antigen persistence could potentially lead to higher levels of protective mucosal and systemic neutralizing antibodies.

We propose a phase I clinical trial based on a replication-competent Adenovirus 4 (Ad4) vectored prime, combined with recombinant trimeric envelope protein boosts administered with or without an attenuated poxvirus (MVA) to identify the most immunogenic strategy for the induction of durable mucosal and systemic protective antibody responses.

Priming will be done with oral replication competent Ad4 encoding membrane expressed HIV-1 envelope gp150 (Ad4-EnvCN54) followed by parentally administered rgp140 protein adjuvanted with synthetic Monophosphoryl Lipid A (MPLA) in an aqueous formulation with or without boost with a modified pox virus (MVA) encoding rgp120. All vaccines are based on the CN54 Clade C HIV.

The primary immunogenicity end-points will be systemic Env antibody titre with a secondary end-point of mucosal (vaginal/rectal) antibody titre. Exploratory endpoints will include a wider panel of immunological assessments including antibody neutralization and cellular immunity. This will facilitate up-selection of the most promising regime to accelerate development towards a phase IIb study in Africa.

The global health burden associated with HIV remains stable with 35m people estimated to be living with HIV in 2012. Despite a huge expansion of access to treatment (ART) with an estimated 9.7m people on ART in low and middle-income countries, a further 18.9m people are in need of ART under new WHO guidelines, whilst 2.3m new infections were identified in the same year. With the exception of a slow roll-out of male circumcision and a costly pre-exposure prophylaxis, there has been disappointing outcomes from other prevention strategies on HIV incidence.

Who will benefit from this research?

A successful and safe HIV vaccine would have considerable benefits across the general populations and high risk groups. It could potentially prevent over 70m infections over the course of 15 years. Should this trial identify a promising vaccine strategy, the research would inform the design of future studies and inform decisions and policy making in several areas of HIV prevention.
The second group to benefit will be the academic community which has been working on the development of a vaccine for 30+ years. The research will also indirectly benefit the private sector and in particular GMP manufacturers and the small biotech sector.

The third group to benefit will be the policy-makers within international and national government who allocate and prioritize funding to research. Non-governmental agencies and health advocates will also benefit.
The fourth group will be the wider public, those living in countries most affected by the epidemics and those amongst the most vulnerable populations. The HIV/AIDS epidemic is a regular feature in the news and media and the public has an interest in finding out and understanding what the scientific community is doing to address it.

How will they benefit from this research?

Academic Community. This proposal is part of the overall strategy of the UK HVC to generating a series of candidate vaccines containing similar HIV antigens so that direct comparison can be achieved to understand most rapidly the most immunogenic strategy for immunization in man. The research represents a technological advance towards an efficient and potent HIV prevention tool. It will lead to a UK contribution in HIV vaccine research which is greater than the sum of its parts in the fastest and most effective manner. The knowledge will allow for the selection of new avenues of research and produce a large body of information available for academic consumption and which will contribute to the effort towards an effective HIV vaccine.

Governmental and non-governmental organisations. The research will provide basis for decision making and policy-making for governments, policy-makers and advocates to develop evidence-based policies and advocacy aiming at prioritising investments in HIV research, allowing for a more efficient use of limited funds, supporting research that has a greater potential to deliver results.

The wider public. The research will contribute to increase public awareness of scientific and clinical research. It will contribute to develop ties and trust between researchers and the public with an aim to increase public participation in clinical research.

Timescales for the benefits to be realised

The results could lead to a Phase II/III Trial to evaluate the best regimen in high incidence settings within 3 years of the completion of the study. This could be achieved in the next 6 years. Impact on governmental and non-governmental organisation and the broader public will be felt by the beneficiaries as the study progresses and results are released.

What research and professional skills will staff working on the project develop which they could apply in all employment sectors?

The collaborators have many years of successful internationally renowned experience in the field of HIV vaccines and prevention. This project will add to the continuation of their expertise, training and development.