Development of therapeutic vaccination strategies for the treatment of HIV-1 infection

Lead Research Organisation: University of Oxford
Department Name: Unknown

Abstract

The only effective treatment for infection with the human immunodeficiency virus (HIV), the cause of AIDS, is a combination of three anti-HIV drugs taken for life. Less than one in six people living with HIV and in immediate need of treatment are actually receiving it. We are exploring the possibility of using vaccines to boost the body?s immune defences against HIV: the aim is to see whether the immune system can keep the virus at low levels in the bloodstream without continuous drug treatment. We have already seen excellent immune boosting effects with a new HIV vaccine (a modified smallpox vaccine carrying a fragment of HIV, called ?MVA.HIVA?) when it is given to HIV-positive people who are taking anti-HIV drugs. We now need to find out how well vaccinated patients control their virus when their treatment is stopped temporarily. In order to do this we will carry out detailed tests measuring patients? immune responses before, during and after vaccination and then measure HIV levels in the bloodstream while they are off treatment. We will also investigate whether there is greater benefit from using MVA.HIVA together with another vaccine, ?MVA.RENTA?, which carries additional fragments of HIV. If these small studies are successful, we will design a larger study which will aim to test whether vaccination combined with intermittent drug treatment is a realistic alternative to continuous drug treatment. This could have significant benefits for people with HIV as the overall cost and harmful effects of treatment would be reduced.

Technical Summary

Lifelong treatment with antiretroviral drugs (highly active antiretroviral therapy or HAART) is currently the only means to halt or prevent progression to AIDS but has several limitations, including cost and complexity of treatment regimens, drug toxicity and potential for drug resistance. Exhaustive exploration of drug-sparing treatment strategies which can limit HIV-1 replication is warranted. Enhancement of host cellular immunity by therapeutic vaccination during HAART may potentiate HIV-1 control after drug withdrawal. We have observed significant boosting of virus-specific CD8+ and CD4+ T cell responses in HIV-1-infected patients given a recombinant modified vaccinia virus Ankara (MVA) / HIV-1 gag vaccine (MVA.HIVA) during HAART. Peak responses after vaccination were ten- to 100-fold greater than in HIV-uninfected individuals given the same vaccine. We propose to extend our preliminary findings by conducting a series of experimental studies investigating the potential of MVA.HIVA and another new vaccine, MVA.RENTA (expressing HIV-1 reverse transcriptase, nef, tat and gp41) to stimulate a broad T cell response with the capacity to suppress viral rebound in HIV-1-infected patients undergoing a supervised HAART interruption. These studies will aim to investigate the relationship between breadth, quality and evolution of the immune response, the timing of the treatment interruption and subsequent viral rebound kinetics. These questions have not been adequately addressed by other therapeutic vaccination studies to date, yet are crucial to the design of phase I randomised trials. They may also yield insights into immune correlates of viral containment which could advance prophylactic vaccine development.

Publications

10 25 50
publication icon
Borthwick N (2014) Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV-1. in Molecular therapy : the journal of the American Society of Gene Therapy

publication icon
Dorrell L (2006) Therapeutic immunization for the control of HIV-1: where are we now? in International journal of STD & AIDS

 
Description Gene Therapy Advisory Committee training day
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact Delegation of ethics review of low risk clinical trial applications to NHS ethics committees has helped to accelerate and simplify review process.
 
Description Treatment Action Group / AIDS Vaccine Advocacy Coalition
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
 
Description British HIV Association Research Award
Amount £5,411 (GBP)
Organisation British HIV Association (BHIVA) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2010 
End 12/2010
 
Description European Commission FP7 Health 2012 Innovation 1
Amount € 4,388,000 (EUR)
Funding ID 305632 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 02/2013 
End 01/2017
 
Description HEFCE Senior Clinical Lectureship
Amount £270,994 (GBP)
Organisation Higher Education Funding Council for England 
Sector Public
Country United Kingdom
Start 05/2008 
End 04/2013
 
Description John Fell Fund
Amount £7,500 (GBP)
Organisation University of Oxford 
Department John Fell Fund
Sector Academic/University
Country United Kingdom
Start 01/2012 
End 12/2012
 
Description MRC PhD Studentship
Amount £42,300 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2008 
End 03/2012
 
Description MSc Integrated Immunology, Nuffield Department of Surgery / Medicine
Amount £3,000 (GBP)
Organisation University of Oxford 
Department Nuffield Department of Medicine
Sector Academic/University
Country United Kingdom
Start 04/2010 
End 07/2010
 
Description NIHR Oxford Biomedical Research Centre
Amount £517,780 (GBP)
Organisation Oxford University Hospitals NHS Foundation Trust 
Department NIHR Oxford Biomedical Research Centre
Sector Public
Country United Kingdom
Start 04/2007 
End 03/2012
 
Description Oxford NIHR Biomedical Research Centre
Amount £651,669 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2012 
End 03/2017
 
Title HIV inhibition assay 
Description Assay to quantify CD8 cell-mediated suppression of HIV-1 replication in vitro, using flow cytometry to detect cells stained with an HIV-1 p24 antibody. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Assay has been evaluated in a chronic HIV infection cohort and subsequently in an acute HIV infection cohort. Assay predicts rate of CD4 cell decline in HIV infection. A manuscript has been published and replication studies in collaboration with internationally renowned research groups have been completed. Further manuscripts have been submitted. 
 
Description Investigation of killing of HIV-infected cells using ImmTAC reagents 
Organisation Immunocore Ltd
Country United Kingdom 
Sector Private 
PI Contribution Collaboration exploits assay which I and my research team have developed. I demonstrated proof-of-concept that the ImmTACs (ImmTAVs) mediate killing of HIV reservoir cells ex vivo from patients on antiretroviral therapy.
Collaborator Contribution Provided reagents that have enabled additional experiments for ongoing research project. Provided intellectual input into further work with the ImmTAVs.
Impact Manuscript published. Further collaborations ongoing.
Start Year 2011
 
Description Irsicaixa-HIVACAT ChAd-MVA.HIVconsv-BCN01 EudraCT: 2011-000846-39 
Organisation HIVACAT Program IrsiCaixa Institute for AIDS Research
Country Spain 
Sector Multiple 
PI Contribution Drafting of clinical trial protocol and advice on regulatory applications and study design. Lead applicant on research funding application.
Collaborator Contribution Principal investigator / local investigators for the clinical trial.
Impact Clinical trial application approved and trial is ongoing.
Start Year 2010
 
Description Pathophysiology of HIV Cardiovascular Disease 
Organisation University of Oxford
Department Oxford Centre for Functional MRI of the Brain (FMRIB)
Country United Kingdom 
Sector Academic/University 
PI Contribution Study design, review of drafts of funding applications and clinical protocol. Recruited patients for the study. Provided training for junior clinical investigator. Assisted with data analysis and manuscript preparation.
Collaborator Contribution Provided clinical samples from patients with HIV infection and data which will inform future studies and funding applications.
Impact Recruitment, MR imaging and blood samples of patients and control subjects for initial study (n = 100) completed. Manuscript published (PMID:23817574) and highlighted in Nature Reviews Cardiology 10, 489 (September 2013). Other manuscripts published since (in publications list). We have applied for funding to support a 5-year follow-up study.
Start Year 2010
 
Title HIV-CORE 002 pTHr.HIVconsv, MVA.HIVconsv, ChAdV63.HIVconsv 
Description pTHr.HIVconsv, MVA.HIVconsv, ChAdV63.HIVconsv are HIV vaccine candidates that have been tested in 3 different prime-boost combinations in healthy HIV-negative volunteers. Safety evaluations have been completed. Immunogenicity analyses are ongoing. This work is funded by an MRC Experimental Medicine award for which I am a co-applicant. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2012
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Immunogenicity data have been published (PMID: 24166483). Other phase I studies are ongoing and funding has been obtained. 
URL http://clinicaltrials.gov/ct2/show/NCT01151319
 
Title Therapeutic immunomodulation in HIV-1 infection 
Description MVA.HIVconsv - a vaccine comprising an attenuated poxvirus vector and a novel immunogen based on highly conserved sequences in the HIV-1 proteome. The aim is to induce T cell responses with specificity for diverse viral strains. 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier CSP Ref. 3087
Impact HIV-CORE 001 - a phase I clinical trial in HIV-seropositive subjects completed in 2013. Safety and immunogenicity data analysis complete. Manuscript has been peer reviewed and revised and final decision is awaited. A phase I clinical trial in HIV+ subjects initiating antiretroviral therapy during primary HIV infection testing MVA.HIVconsv in combination with chimpanzee adenovirus vectored HIVconsv vaccines in prime-boost regimens is ongoing. 
URL http://clinicaltrials.gov/ct2/show/NCT01024842
 
Description Emergent Biosolutions visit to Oxford University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Updated industry representatives on HIV vaccine field and novel vaccine approach in development at Oxford University

Industry representatives expressed interest in our work. Potential partners identified.
Year(s) Of Engagement Activity 2009
 
Description One-to-one meeting with venture capitalist 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Presentation of our HIV vaccine programme, past present and future. Discussion with venture capitalist and Oxford University Head of International Development re potential for future funding.

Raised profile of our research - ongoing discussions with potential funders.
Year(s) Of Engagement Activity 2010
 
Description Oxford Biomedical Research Centre open day 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Open day to present research funded wholly / in part by Oxford Biomedical Research Centre to the general public and NHS Trust staff. I presented a poster outlining research which is partly funded by MRC.

None as yet, other than progression of research through joint funding. Proposals to increase impact were discussed afterwards.
Year(s) Of Engagement Activity 2010
 
Description Radio Interview (BBC Radio 4 Today) 
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 Interviewed for a radio package - awaiting broadcast

Not yet able to assess
Year(s) Of Engagement Activity 2012
 
Description Scientists on the Sofa 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Panel discussion re vaccine development to members of public at Oxford venue, Science Oxford. Positive feedback received.

None known
Year(s) Of Engagement Activity 2007
 
Description Thames Valley HIV group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact Gave a research presentation to clinicians, nurses, community workers with interest in HIV.
A colleague gave a separate research presentation for another study for which I am a co-investigator.

Clinicians expressed interest and willingness to expedite recruitment to research studies.
Year(s) Of Engagement Activity 2011
 
Description Therapeutic HIV Vaccine Development 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Intensive discussion among scientists, patient / community representatives and funders on how to advance the therapeutic vaccine field.

A feedback symposium was convened at AIDS Vaccine 2013 conference, in which I participated as a panel member.
A report on the Workshop is being prepared for publication.
Year(s) Of Engagement Activity 2013
 
Description Therapeutic HIV vaccines: prior setbacks, current advances, and future prospects. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Report published, describing the achievements of the event, in Vaccine 2014 Sep 29;32(43):5540-5. doi: 10.1016/j.vaccine.2014.06.066.


Subsequent publication by NIH program officer, recommending investment in and strategies to advance therapeutic HIV vaccine development.
Shapiro SZ. AIDS Res Hum Retroviruses. 2014 Nov 11. [Epub ahead of print]
Year(s) Of Engagement Activity 2013
 
Description Training day, Department of Health 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Health professionals
Results and Impact Presented and discussed research experience to assist lay members of ethics committee in decision making regarding assessment of applications for clincal gene therapy trials.

Triage protocol has been developed and implemented by GTAC to enable delegation of assessment of low risk proposals to local research ethics committees.
Year(s) Of Engagement Activity 2008
 
Description Weatherall Institute of Molecular Medicine Science Week 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Open evening attended by ~100 members of public including Year 11-13 students during which I presented an update on my research.

Very positive feedback with requests for more public lectures of a similar kind, including letter from teacher at one of the local schools.
Year(s) Of Engagement Activity 2011