hiv vaccine

HIV Vaccine Research : 

HIV Vaccine Research By Dr Ashish J PG Dept of Microbiology

History of HIV : 

History of HIV HIV 2009

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HIV Virion Structure

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HIV Lifecycle T Cell CD4

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Course of HIV Infection

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Global HIV infections, Dec 2009

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X X Reverse Transcription Inhibitors Protease Blockers HIV Treatment: Anti-virals

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What Might a Successful Vaccine Do? • Antibodies Bind virus; neutralize or stop virus from infecting cells; eliminate virus • Cytotoxic T lymphocytes (CTL) Recognize cells infected with virus and kill those cells

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HIV Vaccine Approaches

Classification : 

Classification Phase I: Free state Phase II: Attachment Phase III: Penetration Phase IV: Uncoating Phase V: Replication Phase VI: Assembling Phase VII: Releasing

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Challenges in HIV Vaccine Research Viral Genetic Diversity: Immune Protection: Neutralizing Antibody: Vaccine Testing:

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…but on the Brightside… Precedent from other systems: Success against other viral infections Precedent from animal studies: Long-term control of infection in vaccinated monkeys Immune control of HIV-1: Infected individuals control infection Vaccine Trials: In progress

The first wave 1983-1994 : 

The first wave 1983-1994 Hep B vaccine as model. Mainly vaccine against gp 120 and gp 41 env. Goal was to create sterilizing immunity. Dependent on strong humoral response.

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Specifically candidate vaccine that induce one or more of the following are being sought Neutralizing antibody Cytotoxic T cell response Strong mucosal immune response

Why was there failure : 

Why was there failure Polyspecific and auto reactive antibody generation Viral heterogeneity Natural limits of humoral immunity in HIV

Second phase : 

Second phase 1990’s Vaccine’s which activated CMI. T cells inhibit HIV from replicating 34 AIDS vaccine All failed. Merck vaccine carrying the adenovector

T cell vaccine goals : 

T cell vaccine goals Decrease in window of vulnerability Smaller burst of viremia with less dissemination. Less seeding and destruction of gut associated lymphoid tissue. Smaller HIV reservoir established.

Benefits of limiting early viremia : 

Benefits of limiting early viremia Preserve mucosal and lymph node T cells. Decrease the viral set point. Lengthen time before starting HAART Reduce transmission of virus Limit viral spread into non CD4 cells.

Merck vaccine failure : 

Merck vaccine failure STEP study: Phase IIb “proof—of concept” trial –– 3000 volunteer study in America, Caribbean Stopped 9/2007 at 1st interim analysis –– Futility in primary end--points

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Step HIV trial -Adenovirus as vector failed Vaccine failed to protect adenovirus seronegative individuals

Phase III : 

Phase III Back to basics Rational vaccine development Create mucosal immunity Generate combine humoral and cellular immunity

Phase III : 

Phase III RV 144 16 years of research showing 31 % efficacy. Co-relates with study in Duke university 35 investigation from 20 institutes and 32 test were done on 4000 blood samples

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Important Milestones

Study Vaccines : 

Study Vaccines ALVAC®-HIV (vCP1521) Recombinant canarypox vector vaccine genetically engineered to express HIV-1 gp120 (subtype E: 92TH023) linked to the transmembrane anchoring portion of gp41 (subtype B: LAI), and HIV-1 gag and protease (subtype B: LAI). AIDSVAX® B/E Bivalent HIV gp120 envelope glycoprotein vaccine containing a subtype E envelope from the HIV-1 strain CM244 and a subtype B envelope from the HIV-1 strain MN.

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6 injections for 6 months High concentration of antibodies that bind V1 and V2 region of the co-relates that keeps changing having a reduction in infection rate by 43% but high plasma IgA envelope indicated 54% increase in infection rate.

Status of HIV Vaccine Development : 

Status of HIV Vaccine Development Over 60 Phase I/II trials of 30 candidate vaccines United States, Thailand, South Africa, Brazil One Phase III trial RV 144

Vaccine Vector Platform : 

Vaccine Vector Platform Vaccine Approach: Engineer, characterize and optimize a viral vector system that can be used to deliver HIV antigen(s) to antigen presenting cells (APCs) and that could also improve immune responses to induce long-term immunological memory Viral Vectors HSV-based Amplicon Vector Recombinant Adenovirus Type 5 Vector Bacteriophage Lambda Vector

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In vivo expression of a luciferase reporter gene delivered by Amplicon vectors K. Santos

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Inoculation of Amplicon particles expressing HIV-1 gp120 results in the production of gp120-specific cytotoxic T cells Percent Killing P. Hocknell

Adenovirus Biology : 

Adenovirus Biology Non-enveloped, DNA virus Primary cell surface receptor: Coxsackie and Adenovirus Receptor (CAR) Expressed on many cells types

Planned trials on : 

Planned trials on Modified vaccinia Ankarra Adeno associated vaccine Venezuelan equine encephalitis replicon Codon optimized DNA

Reverse Engineering a Vaccine : 

Reverse Engineering a Vaccine Isolate monoclonal antibodies from non—progressers Targets conserved regions of virus