immune strategies for hiv prevention dr l stranix-chibanda uz-ucsf annual research day 17 april 2015
TRANSCRIPT
Immune Strategies for HIV Prevention
Dr L Stranix-ChibandaUZ-UCSF Annual Research Day
17 April 2015
Outline Active immunisation
Recent history of HIV vaccine development – RV144 trial
The P5 initiative and Uhambo
Passive immunisation Monoclonal antibodies against HIV
Immunoprophylaxis by gene transfer
Active Immunisation
Administer an antigen and wait for the immune system to respond Requires immune system capable of
responding Takes some time for response to develop If successful, results in long term protection Generally results in both antibody and T cell
responses
Thailand,>16,000 healthy, heterosexual, HIV negative adults
Intervention 2004-2006, 3-year follow-up concluded 2009
Tested 2 HIV vaccines Prime: ALVAC HIV (vCP1521) pox Boost: AIDSVAX B/E (gp120)protein
RV144 – study design
RV144 – proof of concept/2009
P5 &Uhambo – a journey of hope Identify a product submitted for
regulatory approval and eventual public health introduction.
Graphic: AVAC Report 2014/5
P5 &Uhambo – a journey of hope Correlates of protection – AB & T-cell
Graphic: AVAC Report 2014/5
Passive Immunisation
Administer pre-formed antibodies Does not require intact immune system Immediate levels of antibodies detectable Only lasts as long as the antibodies last
Passive immunisation is used to prevent a variety of infections Polyclonal
Rabies Immune Globulin (RIG) Hepatitis B Immune Globulin (HBIG) Varicella Zoster Immune Globulin (VZIG) Tetanus Immune Globulin
Monoclonal Respiratory Syncitial Virus (Paluvizimab) Anthrax
Monoclonal AB against HIV Developed a few in 1990’s Explosion in AB development >2008
next-generation sequencing advances in in vitro B cell clonal amplification high-throughput neutralisation assays
Identification of monoclonal antibodies from HIV-infected patients with broad and potent neutralisation potential
Sites of Vulnerability for HIV Neutralisation
membrane proximal domain2F5, 4E10, CAP206-CH12, 10E8
V3/glycan2G12, PGT125-128, PGT131-
135, 10-1074
CD4 binding siteB12, VRC01-03, PG04, HJ16 CH30-34, NIH45-46, 12A12,
VRC07, 3BNC17
V1V2PG9/16, CH01-04, PGT 141-145
Haynes et al. (2012) Nat.Biot. 5: 423-433Kwong and Mascola et al. (2012) Immunity. 37: 412-425
Possible Roles for Monoclonals Strong pre-clinical evidence that potent
monoclonal antibodies (like VRC01) could be important for prevention and treatment of HIV. Prevention of vertical transmission Augment therapy in treated children and
adults Early treatment of infected infants Strategy for cure
Barin, Jourdain, Brunet et al. JID 2006
Antibody therapy Advantages
Single or intermittent injection, does not require daily meds, adherence
Could prevent disease or modify disease in those already infected
If it works, it provides critical data to inform the entire vaccine field
Disadvantages Requires monthly injection Currently expensive
bnAB clinical trials VRC/NIH Phase 1 trial US, S Africa, Zim
Single dose of SC VRC01 to high-risk newborns at birth (0-72hr)
In addition to the standard-of-care HIV prevention regimens
Verify safety Determine PK profile of 20mg/kg dose Proceed to 40mg/kg dose, if safe
VRC601/602 in adults, ?pregnancy
Antibody summary Potent and broadly neutralizing
monoclonal antibodies provide a new opportunity for HIV prevention (also treatment / cure)
If effective, antibody production can be scaled up and altered to increase duration of effect (> 1 month)
Immunoprophylaxis by gene transfer (IGT) A form of gene therapy to modify the
DNA of patients to enable them to produce antibodies that deactivate HIV
Pre-clinical studies in monkeys/mice identify the genes that produce powerful
antibodies against disease create artificial versions of these genes insert them into viruses inject muscle transfer the genetically engineered DNA to
the muscle cells alter programming
In conclusion, Various immune approaches are being
explored against HIV infection Advancements in laboratory
techniques mean that the knowledge base is expanding rapidly
None are yet ready for clinical use Immune strategies are required to
guarantee a sustained end to the AIDS pandemic
Acknowledgements UZ College of Health Sciences UZ-UCSF Collaborative Research
Programme HIV Vaccine Trials Network IMPAACT Network Dr C Cunningham and VRC