Developmental Clinical Study - UK HVC 003 DMP Phase I Prime-Boost-ReBoost HIV vaccine trial

Lead Research Organisation: Imperial College London
Department Name: Research Office

Abstract

The global health burden associated with HIV continues to grow with 33 million people estimated to be living with HIV in 2009 and 2.7 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 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 the UK HIV Vaccines Consortium (UK HVC) 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 UK HVC 001DMP trial is based on an immunisation regimen similar to that used in the only HIV vaccine trial to demonstrate partial efficacy (RV144, which showed a 31% reduction in HIV infection in Thailand). The study will explore both the safety and immunogenicity of this novel combination of HIV vaccine candidates and will formally explore the immunological impact of a prime, boost and re-boost strategy using different vaccine candidates provided by the UK HVC. It will also explore the effectiveness of combining vaccines candidate together with the added advantage of minimising the length of 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 one of the highest priorities for international public health. Despite slow progress, a recent phase III trial (RV144) demonstrated significant protection against HIV infection through a prime-boost strategy with a canary-pox viral vector (ALVAC), followed by an ENV (GP120) protein boost. The immune correlates of protection remain obscure, but consensus is that both antibodies to HIV and a strong cellular immune response are required. The UK HIV Vaccine Consortium (UK HVC) has developed a series of HIV immunogens with freedom to undertake clinical research, so that diverse combinations of viral vectors, DNA, protein and adjuvant can be directly compared to define the most immunogenic vaccine immunisation strategy. By building on our previous vaccine studies, we believe that the HVC 003 DMP immunisation strategies will be more immunogenic than the partially successful RV144. The UK HVC 003 DMP trial proposes to study two prime-boost strategies using GMP products. The priming will be done with DNA followed by modified pox (MVA) and boost with rGP140 protein adjuvanted with GLA. The study will compare 3X DNA followed by 2X MVA and 2X rGP140/GLA, versus 3X DNA, followed by concurrent MVA/rGP140/GLA, with a primary end-point of ENV antibody titre and secondary end-points of neutralisation and cellular immunity. If safe and highly immunogenic, we would wish to optimise the immunisation schedule through another comparative study and proceed with a phase II/III study in East and Southern Africa, as a university-based and led public-private partnership, based on the Microbicides Development Programme model.
 
Title INFORM ORACLE 
Description INFORM database captured trial participant information for analysis. 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact This database has allowed statistical evaluation of primary data from the trial. 
 
Description Clinical Trial Site 
Organisation University of Surrey
Country United Kingdom 
Sector Academic/University 
PI Contribution This collaboration was set up in order to facilitate and speed up the recruitment into the clinical trial. It will also allow for harmonising protocols, SOPs and other trial-related activities across institutions. Our team provided training and SOPs.
Collaborator Contribution The partner is providing access to a large database of volunteer as well as to clinical facilities for the purpose of completing the study.
Impact This collaboration will significantly increase the recruitment of volunteers into the study contributing to its timely completion. It will also be a springboard for future collaborations.
Start Year 2013
 
Description Dr. Sarah Joseph collaboration with Chriss Geldmacher: Epitope mapping project 
Organisation UK HIV Vaccine Consortium (UKHVC)
Country United Kingdom 
Sector Academic/University 
PI Contribution Jointing drafted the application and contributed to the design of the study. UKHVC supplied samples for cross comparison studies between other trials.
Collaborator Contribution Expert in the technology needed for the project. Major financial contribution to the project.
Impact Preliminary results presented data to UKHVC - analysis ongoing
Start Year 2014
 
Description TRANSVAC 
Organisation Braunschweig University of Technology
Department Helmholtz-Zentrum für Infektionsforschung
Country Germany 
Sector Academic/University 
PI Contribution Sarah Joseph was a lead applicant on an application made to TRANSVAC for access to deep sequencing technology.
Collaborator Contribution Unversity of Munich supplied man power and also access to samples from vaccinated and chronically infected individuals for deep sequencing. The facility at Helmholtz supplied access to deep sequencing technology and expertise.
Impact Bioinformatice Analysis is ongoing and will lead to publication and strengthening of infrastructure and expertise within the consortium.
Start Year 2012
 
Description TRANSVAC 
Organisation Ludwig Maximilian University of Munich (LMU Munich)
Department Institute of Immunology
Country Germany 
Sector Academic/University 
PI Contribution Sarah Joseph was a lead applicant on an application made to TRANSVAC for access to deep sequencing technology.
Collaborator Contribution Unversity of Munich supplied man power and also access to samples from vaccinated and chronically infected individuals for deep sequencing. The facility at Helmholtz supplied access to deep sequencing technology and expertise.
Impact Bioinformatice Analysis is ongoing and will lead to publication and strengthening of infrastructure and expertise within the consortium.
Start Year 2012
 
Description UK HVC Spoke 003 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We will be providing clinical data to the UK HVC which will help them adapting their research strategy
Collaborator Contribution The UK HVC is providing vaccine candidates for the trial as well as clinical trial and lab support.
Impact Design of CRF Preparation of Investigator Brochure for the clinical study Study design and Protocol writing
Start Year 2010
 
Title Spoke 003 Study 
Description The Spoke 003 study is the first trial of all the UK HVC candidate vaccines used in combination. This is a major phase I to determine the safety, immunogenicity and comparison of sequential versus simultaneous MVA/rgp140 boosting. This Phase I trial is funded by a DCS Award form the MRC with support from the Wellcome Trust Funded UK HVC Four different products have been trialled and data is currently being analysed. DNA A two parts product including one plasmid encodes ZM96 Clade C gag-pol-nef derived from the 96ZM651-8 clone construct developed by B.H. Hahn, G.M. Shaw and F. Gao at the University of Alabama at Birmingham. The other encodes CN54 Clade C env derived from the HIV-1 97CN54 coding sequences (Geneart). Both sequence optimised inserts were introduced into the VRC8400 CMV/R vector (NIAID/NIH) for GMP manufacture. Vaccines have been manufactured by Althea Technology, Inc (USA). MVA-C The MVA-C 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. Volunteers will receive 1.10e8 TCID50 in a volume of 0.5mls. Vaccine has been manufactured by Bavarian Nordic (Denmark). CN54rgp140 The CN54rgp140 is a recombinant GP140 derived from the HIV-1 CN54 coding sequence and has been manufactured by Polymun, Austria. CN54rGP140, is a trimeric recombinant C-clade ENV protein, derived from the 97CN54 Chinese viral isolate. GLA-AF In the current trial we will use a completely synthetic aqueous monophosphoryl lipid A (MPL®) like molecule GLA-AF,. MPL is a component of human vaccines including Cervarix which is used to prevent certain types of human papilloma virus infection associated with cervical cancer and is licensed for use in the European Union. The manufacture of these products has been paid for by a Wellcome Trust Award. This study is conducted in collaboration with the University of Surrey (Dr David Lewis). As of November 2014 all participants have been enrolled and have completed their immunisation schedule. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2012
Development Status Closed
Clinical Trial? Yes
Impact The global health burden associated with HIV continues to grow with 35 million people estimated to be living with HIV in 2014. Despite a huge expansion of access to ART with an estimated 12.9 million people on ART by the end of 2013, leaving others in urgent need of therapy whilst 2.1 million new infections were identified in the same year. With the exception of male circumcision and the challenging Pre-Exposure prophylasis there has been disappointing outcomes from most other prevention strategies on HIV incidence. 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 a 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. The Manufacturing process was documented and formed the basis for an online tool for researchers willing to take vaccine candidates from the bench to the clinic. http://www.vaccineenterprise.org/Benchtoclinic From Bench to Clinic is a webtool to help researchers most efficiently move their candidate vaccines into first-in-human trials. With a focus on the practical steps that need to be accomplished before a clinical trial can be initiated, this tool is intended to acquaint researchers, funders and advocates, with the processes, costs and timelines involved in the first phase of product development. 
URL http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=14173
 
Description Invited Lecture for World AIDS Day Event - The Francis Crick Institute - Talk entitled - Eradicating HIV 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact My talk was around clinical perspectives of HIV and the London story at this event. The programme included leading HIV/AIDS researchers and associations.
Year(s) Of Engagement Activity 2017
 
Description Newspaper Interview (CJ) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Media (as a channel to the public)
Results and Impact Trial clinician met with a local journalist to discuss public participation in clinical research.

This interview led to an article in a local media that draw attention to the research and led a number of people to enroll in the study.
Year(s) Of Engagement Activity 2013
URL http://www.getwestlondon.co.uk/news/west-london-news/volunteers-wanted-ground-breaking-trials-612154...
 
Description Talk at HIV scientific conference R4P (Chicago, October 2016) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Presentation at the R4P conference in Chicago, Ocober 2016 to present findings from the Phase I study UK-HVC 003: A Phase I Clinical Trial Exploring a Strategy to Maximise HIV Antibody Responses using Subtype C DNA, MVA and GLA adjuvanted gp140.
Year(s) Of Engagement Activity 2016