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