1. HIV-VACCINES

2. HIV - Vaccines  Vaccine development remains priority of AIDS research   Best hope for protection against HIV infection

3. Attributes of an ideal HIV vaccine  AIDS is spread both venereally and by use of contaminated blood products. So, the vaccine should elicit both mucosal and systemic immune response.  HIV is transmitted both as cell-free and cell-associated virus. So, the vaccine should elicit both humoral and cell-mediated immune response.  Should be able to tackle the extraordinary genetic diversity of the virus.

4. How vaccines work against viruses

6. 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

7. Problems in vaccine development 1. Classic vaccines mimic natural immunity against reinfection, seen in patients recovered from infection: no recovered patients. 2. HIV-1 mutates at a very rapid rate; select mutant forms that evade immunity 3. Epitopes of viral envelope are highly variable- Masked by glycosylation, trimerization & receptor induced conormational change so difficult to block with neutralizing antibodies 4. Most effective vaccines: whole killed/live attenuated organisms: killed HIV-1= does not retain antigenicity; live vaccine=safety issues 5. Immune correlates of protection not known 6. Most vaccine protect infection: GI & resp. mucosa. HIV-genital mucosa 7. No suitable animal model for HIV at present.

8. HIV Vaccine Approaches Protein subunit Synthetic peptide Naked DNA Inactivated Virus Live-attenuated Virus Live-vectored Vaccine

9. Organizations involved  HIV Vaccine Trial Network ( HVTN )  International AIDS Vaccine Initiaive ( IAVI )  National institute of Health ( NIH )  Uganda Virus Research Institute ( UVRI )  South African AIDS Vaccine Initiative ( SAAVI )  Walter Reed Army Research Institute (WRAIR )  National Aids Research Agency

10. Live recombinant vaccines  genes of HIV molecularly cloned into micro- organisms; immune response develop to both (HIV product +vector)  Problem: preexisting immunity

11. Live-vaccine vectors  Adeno-associated viruses  Several avian and mammalian poxviruses  Rhabdoviruses  Alphaviruses  Replication-defective adenoviruses  Herpesviruses  Picornaviruses

12. 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  VaxGen gp120 protein subunit vaccine RV144 (Thailand)

13. Summary of HIV-1 vaccine Phase IIb/III efficacy trials.Type of vaccine, Code name and place of trial  Gp120 (B/B orB/E) + alum VAX003 (Americas) VAX004 (Thailand)  Ad5-HIV-1 trivalent vaccine (Gag, Pol,Nef) Step (Americas + Australia)Phambili (South Africa)  Canarypox (ALVAC)-Gag Pol Env E + gp120 B/E + alum RV144 (Thailand)  DNA-Gag, Pol, Env, priming + Ad5-Gag Pol Env (A,B,C) boost HVTN505 (Americas) Results  No protective efficacy observed  No efficacy observed,Enhanced rate of infection in uncircumcised Ad5-seropositive male volunteers  31% protective efficacy against HIV- 1acquisition  On-going Phase IIb trial

14. PROPYLACTIC HIV VACCINES  THE RV 144 TRIAL  This vaccine was designed to elicit cellular immunity and antibodies  It was tested on 16,000 subects ( at low risk of infection ) in Thailand  It proved to protect about 33 % of vaccinated subjects ( 61% after one year )  Offered moderate protection against infection but no significant neutralizing antibody response  The partial success of this vaccine has proven an ideal opportunity to identify correlates of protection

15. Recent trials  Adeno virus recombinant vaccine ( IAVI – 3 Clinical trials ) -IAVI B001 -IAVI B002 -IAVI B003  SAV001: (FDA approved for human clinical trial in Jan 2012) - Based on genetically modified killed whole virus - Early testing shows vaccine stimulate strong immune response & appears to have no adverse effects

16. Indian trials  Prime- boost trial of ADVAX & TBC-M4 (ICMR)  Phase I completed  In NARI, Pune & TRC, Chennai  ADVAC- DNA Vaccine (env, gag, pol, nef, tat)  TBC-M4- vector built from recombinant Mod. Vaccinia Ankara {MVA}, (env, gag, RT, rev, tat,nef)  Initial data- both safe & immunogenic

17. Future prospectives Vaccines based on  Lipopeptides  Mucosal immunization  Stimulation of CTL  Prevention of CD4+ T-cell loss  Monoclonal antibodies

18. Summary & conclusion Mutation in virus causes resistance Drug resistance -Transmitted & Acquired, cross resistance ARVs are ineffective to control resistant mutants Drug resistance data – helps in clinical management of HIV Resistance testing – Phenotypic, Genotypic, Virtual phenotype Best way to prevent resistance – Control HIV by taking strong ARVs, resistance testing & follow up Limitations of resistance testing- Availability, cost, Viral load, new mutations

19. Challenges in HIV Vaccine Research Viral Genetic Diversity: HIV is highly mutable Immune Protection: We don’t know what immune responses are needed, or how strong they need to be. Neutralizing Antibody: Difficult to generate broadly neutralizing antibodies. Vaccine Testing: Slow process, very expensive

20. …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 Focus shifted: To develop vaccines stimulating CTL response

21.  THANK YOU