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

Lead Research Organisation: Imperial College London
Department Name: Infectious Disease

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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Title EAVI2020 Photo Exhibition Barcelona 
Description A photo exhibition involving the EAVI2020 consortium partners showcasing the development of an HIV vaccine in photos 
Type Of Art Artistic/Creative Exhibition 
Year Produced 2017 
Impact The photo exhibition was held in a large cafe in Barcelona open to the general public and anyone interested in the development of a HIV vaccine. Impacts included requests for further information on HIV clinical trials, including how to participate in clinical trials. Members of the general public had questions on HIV vaccines and clinical trials that were answered by leading HIV researchers. This exhibition also helped members of the public gain a better understanding of how different funding bodies are supporting HIV research efforts and the impressive levels of funding invested in HIV vaccine research. 
URL http://www.eavi2020.eu/news/
 
Description Developing a Chlamydia Trachomatis Vaccine
Amount € 6,674,498 (EUR)
Funding ID 733373 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2017 
End 12/2021
 
Description European AIDS Vaccine Initiative
Amount € 22,948,515 (EUR)
Organisation European Commission 
Department Horizon 2020
Sector Public
Country European Union (EU)
Start 11/2015 
End 10/2020
 
Description European AIDS Vaccine Initiative
Amount € 22,948,515 (EUR)
Funding ID 681137 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2015 
End 12/2020
 
Description Future Vaccine Manufacturing Research Hub
Amount £9,947,570 (GBP)
Funding ID EP/R013764/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 12/2017 
End 03/2021
 
Description SBRI Vaccines for Global Epidemics - Preclinical Stage 1
Amount £494,303 (GBP)
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 04/2017 
End 03/2018
 
Description SynbiCITE: Development of an oral Chlamydia trachomatis vaccine using an attenuated Salmonella synthetic biology chassis
Amount £256,783 (GBP)
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 08/2015 
End 07/2017
 
Description PaxVax 
Organisation PaxVax, Inc.
Country United States 
Sector Private 
PI Contribution The primary objective of this project is to conduct a phase I trial of the safety and immunogenicity of oral Ad4 prime followed by MPLA adjuvanted CN54rgp140 boosts with and without MVA-C to maximise mucosal and systemic antibody responses to HIV-1 Envelope. The proposed study wil provide critical data needed to support and inform the further exploration of immunisation regimen based on Ad4 vectors for HIV vaccines in a phase II/III trial. Imperial College London will sponsor the clinical trial and will be responsible for its conduct in accordance to ICH-GCP as well as performing all the immunoassays. Imperial will also provide the MVA-C and CN54rgp140/MPLA component of the study through the Imperial-led UK HIV Vaccine Consortium and will oversee the GMP manufacture of the Ad4-EnvCN54 vaccine to EU GMP.
Collaborator Contribution PaxVax will provide expertise related to the manufacture and use of the Adenovirus 4 serotype. PaxVax will assemble the Ad4 vector and CN54 envelope insert into a construct prior to performing the manufacture of the starting material and then the manufacture of the Ad4-EnvCN54. This collaboration is unique as the Ad4 serotype is only available from PaxVax and the other vaccine only available from an existing Imperial-led research programme (UK HVC).
Impact Manufacture of Ad4-EnvCN54 encoding CN54 is complete.
Start Year 2015
 
Description Polymun Scientific 
Organisation Polymun Scientific GmbH
PI Contribution The primary objective of this project is to conduct a phase I trial of the safety and immunogenicity of oral Ad4 prime followed by MPLA adjuvanted CN54rgp140 boosts with and without MVA-C to maximise mucosal and systemic antibody responses to HIV-1 Envelope. The proposed study wil provide critical data needed to support and inform the further exploration of immunisation regimen based on Ad4 vectors for HIV vaccines in a phase II/III trial. Imperial College London will sponsor the clinical trial and will be responsible for its conduct in accordance to ICH-GCP as well as performing all the immunoassays. Imperial will also provide the MVA-C and CN54rgp140/MPLA component of the study through the Imperial-led UK HIV Vaccine Consortium and will oversee the GMP manufacture of the Ad4-EnvCN54 vaccine to EU GMP.
Collaborator Contribution The manufacture of CN54gp140 / MPLA
Impact The manufacture of CN54gp140 / MPLA is complete.
Start Year 2015
 
Title Ad4-EnvCN54 
Description The vaccine vector virus, designated as Ad4-EnvCN54 , is a recombinant, replication-competent Ad4, encoding the full length of a HIV-1 membrane expressed trimeric envelope protein (CN54gp160) that will be administered orally as a lyophilized powder in a capsule. CN54gp160 is a subunit of a C-clade, comprising a sequence of 634 amino acids. This subunit has been shown to be immunogenic, raising high titre antibodies when given systemically in B6D2F1 mice, and intra-vaginally in New Zealand white rabbits. The recombinant Ad4 virus was derived from the US Military Ad4 vaccine virus which had been originally isolated from a military recruit with acute respiratory disease before being passaged in WI-38 cells (Lyons et al, Vaccine. 2008). Funded by the Ad4HIV MRC grant. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2016
Development Status Under active development/distribution
Impact None at this stage 
 
Title CN54gp140/MPLA 
Description The CN54gp140 is a recombinant gp140 derived from the HIV-1 97CN54 coding sequence and will be manufactured by Polymun, Austria. CN54rgp140, is a trimeric recombinant C-clade envelope protein. The protein comprises a sequence of 670 amino acids, and has been shown to be immunogenic in humans. MucoVac 1 (EudraCT number 2007-000781-20) was the first human clinical trial to have used the trimeric CN54gp140 although the protein was not administered systemically but topically. To date Mucovac 2 (EudraCT number 2010-019103-27) is the only completed trial to have generated safety data on the systemic administration of the CN54gp140 in GLA-AF in healthy participants. 100 and 20?g of protein was administered I.M after bedside mixing with GLA-AF (an aqueous formulation of synthetic MPLA). Analysis of the (presumed) peak antibody responses measured after the last immunisation demonstrated induction of robust antibody responses, with moderate neutralization activity against easy to neutralize tier 1 viral isolates. Funded by the Ad4HIV MRC grant. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2016
Development Status Under active development/distribution
Impact None at this stage 
 
Title MVA-C 
Description MVA-C encoding CN54 gp120: The MVA-CN54 has been developed by M. Esteban at the Centro Nacional de Biotecnologia of CSIC and expresses the HIV-1 protein gp120 and the fusion protein gag-pol-nef from HIV-1 97CN54. Ad4HIV trial participants will receive 1.4 x 108 TCID50 (or matching placebo) in a volume of 0.5mls. MVA-CN54 will be injected into the left deltoid muscle at the 2nd and 3rd immunisation visits. The vaccine has been manufactured by Bavarian Nordic (Denmark). 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier UKHVC Consortium
Impact None at this stage 
 
Description BBC Radio 4 Today Programme 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Interviewed by BBC Radio 4 hosts to provide information to the general public on Vaccine Manufacture
Year(s) Of Engagement Activity 2017
URL http://www.bbc.co.uk/programmes/b09jqtb1
 
Description BBC Radio 4 Today Programme 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact To publicise the start of patient recruitment to the Ad4HIV trial
Year(s) Of Engagement Activity 2017
URL http://www.bbc.co.uk/programmes/b099v33m
 
Description Financial Times Article 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Article describing Professor Shattock's research efforts to tackle viral epidemics worldwide
Year(s) Of Engagement Activity 2017
URL https://www.ft.com/content/afdc493e-e716-11e7-97e2-916d4fbac0da
 
Description Times Higher Education Article 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact To describe the establishment of a new hub to help UK scientists to respond quickly to emerging infectious diseases
Year(s) Of Engagement Activity 2017
URL https://www.timeshighereducation.com/news/new-hub-puts-scientists-front-line-against-disease-outbrea...