THE ROLE OF NON-IMMUNE VACCINE RESPONSES IN PROTECTION CONFERRED BY LIVE ATTENUATED SIV

Lead Research Organisation: Nat Inst for Bio Standards and Control
Department Name: Division of Virology

Abstract

The World Health Organisation recognises HIV/AIDS as the number one infectious disease in the world. Doctors and scientists know that the best way to stop this disease would be to develop a vaccine to stop the 14,000 new infections with AIDS virus that occur each day worldwide.

The difficulty is that scientists do not know whether an AIDS vaccine needs to stimulate the production of antibodies, molecules in the blood that recognise the virus and stop it from infecting new cells, or killer T cells that eliminate virus infected cells before the infection can spread further. Alternatively the vaccine may need to do something different to be fully effective.

The team at NIBSC are studying an animal model of HIV and have found that animals vaccinated with a disabled form of the virus first are resistant to disease causing strains. This group think that events that occur within 3 weeks of vaccination are critical for the vaccine and that many of these occur in and around the gut. As a result, they will focus on unravelling these early events to enable a better AIDS vaccine to be designed and developed in the future.

Technical Summary

In the quest for a safe, effective vaccine against HIV, many scientists believe that the potent protection conferred by live attenuated simian immunodeficiency virus (SIV) will provide pertinent insight into the responses that an AIDS vaccine will need to generate. Published work from the group at NIBSC, as well as the reports of others, have been unable to demonstrate unequivocal evidence that responses of adaptive immunity correlate with protection conferred by live attenuated SIV. Passive transfer of immune serum does not transfer protection to na?ve macaques and profound depletion of CD8+ve (cytotoxic) T cells throughout the course of vaccination does not abrogate protection. We propose to investigate whether responses apart from adaptive immunity are involved in this vaccine protection. We will characterise changes in lymphocyte subsets, activation status, and gene expression to determine, in detail, the pathogenesis of infection with a live attenuated virus SIVmacC8 in na?ve juvenile cynomolgus macaques and compare it with the pathogenesis of infection with a vigorous wild-type virus SIVmacL28 in na?ve juvenile macaques. Then we will characterise the pathogenesis of infection with SIVmacL28 in macaques that have been vaccinated with attenuated SIVmacC8 for three weeks at a time when we know that responses of adaptive immunity do not play a part in protection. For each part of the study, we will determine the kinetics of virus replication, establish the distribution of virus infected cells in 5 lymphoid tissues by in situ based techniques and determine the properties of purified infected and uninfected cells by immuno-staining and flow cytometric analysis of disaggregated tissues. The purpose of these studies will be to evaluate whether vaccination results in (i) the depletion of target cells (ii) the alteration of target cells so they are no longer capable of being infected (iii) the induction of anti-viral resistance mechanisms in infected or bystander cells not infected with the vaccine virus that prevent productive infection by wild-type virus (iv) the induction of anergy in potentially susceptible cells. As a result, we will establish the role of responses that exclude adaptive immunity in this potent vaccine protection and thus identify approaches to develop an AIDS vaccine that reproduces this protection in a safe and effective manner.

Publications

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Corrigan GE (2006) Reverse transcriptase viral load correlates with RNA in SIV/SHIV-infected macaques. in AIDS research and human retroviruses

 
Description MRC Project Grant
Amount £830,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2007 
End 09/2009
 
Description MRC Project Grant
Amount £116,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 09/2010
 
Description MRC Project Grant
Amount £500,000 (GBP)
Funding ID G0801172 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2009 
End 03/2012
 
Title Biological materials from SIVmacC8 time-course 
Description Early time-course studies of attenuated SIVmacC8, wild-type SIVmacL28 and wild-type SIVsmE660 performed has provided multiple blood and tissue samples for viral and cellular analyses 
Type Of Material Biological samples 
Year Produced 2009 
Provided To Others? Yes  
Impact Impact of viral and cellular gene expression changes at critical sites post-infection following vaccination with live attenuated SIV. Distribution and host responses following LAV vaccination. These data are providing novel insights into the mechanism by which live attenuated virus vaccination is operating, particularly early responses to viral infection/vaccination. The role of the innate immune response has been studied and evaluated in relation to this study; the materials generated remain an invaluable study aid and have led to series of novel insights into the acute-phase responses and vaccine efficacy. 
 
Title Refinement of SIV model 
Description Refinements and improvements have been made to the model system as a result of this funding. Detailed analyses of gut-associated lymphoid tissue and other tissues have been deployed with novel extraction and cell purification protocols established. 
Type Of Material Improvements to research infrastructure 
Year Produced 2009 
Provided To Others? Yes  
Impact In particular the GALT analyses will allow the detailed description of the impact of attenuated and wild-type SIV replication on cell population distribution. Detailed analyses of innate responses and gene expression in this study have been highly informative in elucidating early vaccine responses. 
 
Title SIV RNA reference materials 
Description A bulk volume of high titre SIV + plasma was generated by in vivo studies providing a basis for a panel of SIV RNA reference materials 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact The first international multi-centre collaborative study was performed between centres in Europe and the USA characterising a panel of SIV RNA reference standards. Provision of these to the scientific community will facilitate the comparison of data generated between different centres in pre-clinical HIV/SIV vaccine / intervention studies. The study has been published in J Clin Micro (PMID 20427693). These materials are now widely available to the scientific community via CFAR/NIBSC (AIDS reagent repository). 
 
Description Conditionally live attenuated SIV 
Organisation Academic Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution Hosting of the first non-human primate study to investigate the in vivo properties of novel conditionally live attenuated SIV vaccine (SIVrtTA IAVI study)
Collaborator Contribution Productive 2-way collaborative research with internationally recognised molecular virology broupOur collaborators have provided a novel SIV vaccine which has been trialled and evaluated at NIBSC. This has resulted in 2 distinct studies which are nearing completion and will be reported on in 2011.
Impact A subsequent MRC grant has been awarded based around collaborations with this group: The role of vaccine persistence in protection conferred by live attenuated SIV (G0601201).
 
Description Conditionally live attenuated SIV 
Organisation Academic Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution Hosting of the first non-human primate study to investigate the in vivo properties of novel conditionally live attenuated SIV vaccine (SIVrtTA IAVI study)
Collaborator Contribution Productive 2-way collaborative research with internationally recognised molecular virology broupOur collaborators have provided a novel SIV vaccine which has been trialled and evaluated at NIBSC. This has resulted in 2 distinct studies which are nearing completion and will be reported on in 2011.
Impact A subsequent MRC grant has been awarded based around collaborations with this group: The role of vaccine persistence in protection conferred by live attenuated SIV (G0601201).
 
Description HIV vaccines 
Organisation Guy's and St Thomas' NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution Hosting of the NHP arm of an NIH funded study leading to novel observations into innate immune responses in an SIV/HIV model system
Collaborator Contribution Collaboration in a novel area of SIV/HIV vaccine research
Impact Description of innate immune responses after immunisation : Publication PMID number: 19084567
Start Year 2006
 
Description Hepatitis C research 
Organisation Pfizer Ltd
Country United Kingdom 
Sector Private 
PI Contribution New initiatives and research projects undertaken as result of the collaborations through the MRC Industrial partnerships scheme
Collaborator Contribution Facilitation of industrial/academic collaborative research into the immunological and virological parameteres of HCV infection
Impact As part of the MRC Industrial partnership scheme a grant was awarded allowing distinct avenues of research to be undertaken.: Grant title: Restoration of pathways implicated in T cell exhaustion following HCV infection (G 0900861).
Start Year 2009
 
Description Mucosal immunity / virology / vaccines 
Organisation St George's University of London
Department Department of Cellular and Molecular Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual and practical support in hosting non-human primate studies to further clinical and pre-clinical vaccine trials for HIV/AIDS
Collaborator Contribution As part of the Gates foundation network of scientists partners within this international consortium have contributed both intellectually and financially with novel ideas, strategies and access to novel reagents and materials to further research initiatives Collaborative interactions on related virus research projects.
Impact Collaboration on NIH grant relating to pre-exposure prophylaxis of SIV /anti-HIV microbicide and vaccine studies leading to publication PMID 18684007
 
Description Mucosal immunity / virology / vaccines 
Organisation St George's University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual and practical support in hosting non-human primate studies to further clinical and pre-clinical vaccine trials for HIV/AIDS
Collaborator Contribution As part of the Gates foundation network of scientists partners within this international consortium have contributed both intellectually and financially with novel ideas, strategies and access to novel reagents and materials to further research initiatives Collaborative interactions on related virus research projects.
Impact Collaboration on NIH grant relating to pre-exposure prophylaxis of SIV /anti-HIV microbicide and vaccine studies leading to publication PMID 18684007
 
Description Next Generation Sequencing 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Provision of HIV-1 RNA reference materials as a template for NGS, genome assembly and computational analysis
Collaborator Contribution Experts in NGS, assemblies and analyses
Impact Publication in J Clin Micro PMID: 22993180
Start Year 2010
 
Description Vaccines and reference materials 
Organisation Centers for Disease Control and Prevention (CDC)
Department Office of Infectious Diseases
Country United States 
Sector Public 
PI Contribution Organising centre of an international multi-centre study to develop and evaluate a panel of reference materials for the quantification of SIV RNA in plasma.
Collaborator Contribution A number of distinct strands of collaborative research, including developement of international standards for SIV RNA quantification and as part of the 'Europrise' network of labs and scientists. The CDC is a key, internationally recognised laboratory in the USA which has played a central role in the collaborative study laeding to development of the SIV RNA reference panel. A key role in the collaborative study of SIV RNA reference materials
Impact Publications: PMID 16989619 and another study recently accepted for publication in the Journal of Clinical Microbiology, describing the results of the international SIV RNA study
 
Description Vaccines and reference materials 
Organisation Government of Sweden
Department Swedish Institute for Infectious Disease Control
Country Sweden 
Sector Public 
PI Contribution Organising centre of an international multi-centre study to develop and evaluate a panel of reference materials for the quantification of SIV RNA in plasma.
Collaborator Contribution A number of distinct strands of collaborative research, including developement of international standards for SIV RNA quantification and as part of the 'Europrise' network of labs and scientists. The CDC is a key, internationally recognised laboratory in the USA which has played a central role in the collaborative study laeding to development of the SIV RNA reference panel. A key role in the collaborative study of SIV RNA reference materials
Impact Publications: PMID 16989619 and another study recently accepted for publication in the Journal of Clinical Microbiology, describing the results of the international SIV RNA study
 
Description Vaccines and reference materials 
Organisation Government of Sweden
Department Swedish Institute for Infectious Disease Control
Country Sweden 
Sector Public 
PI Contribution Organising centre of an international multi-centre study to develop and evaluate a panel of reference materials for the quantification of SIV RNA in plasma.
Collaborator Contribution A number of distinct strands of collaborative research, including developement of international standards for SIV RNA quantification and as part of the 'Europrise' network of labs and scientists. The CDC is a key, internationally recognised laboratory in the USA which has played a central role in the collaborative study laeding to development of the SIV RNA reference panel. A key role in the collaborative study of SIV RNA reference materials
Impact Publications: PMID 16989619 and another study recently accepted for publication in the Journal of Clinical Microbiology, describing the results of the international SIV RNA study
 
Description Virus/ host interactions 
Organisation University College London
Department Division of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution The initial study funded by this reported grant (ie G0600007) enabled MRC funding of a further grant to analyse early gene expressions changes following live attenuated SIV vaccination. Research activities are on-going.
Collaborator Contribution Collaboration with an internationally recognised expert in the field of retroviral restriction factors
Impact MRC grant awarded: . 'Correlating gene expression changes and innate immune responses with protective SIV vaccination in cynomolgus macaques (G 0801172). This additional award is a direct result of the reporting grant allowing a detailed analysis of materials collected as part of this study
Start Year 2007