HIV-VACCINES

HIV - Vaccines

Vaccine development remains priority of AIDS research

Best hope for protection against HIV infection

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.

How vaccines work against viruses

What Might a Successful Vaccine Do?

• AntibodiesBind virus; neutralize or stop virus from infecting cells; eliminate virus

• Cytotoxic T lymphocytes (CTL)Recognize cells infected with virus and kill those cells

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.

HIV Vaccine Approaches

Protein subunit

Synthetic peptide

Naked DNA

Inactivated Virus

Live-attenuated Virus

Live-vectored Vaccine

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

Live recombinant vaccines

genes of HIV molecularly cloned into micro-organisms; immune response develop to both (HIV product +vector)

Problem: preexisting immunity

Live-vaccine vectors

Adeno-associated viruses Several avian and mammalian poxviruses Rhabdoviruses Alphaviruses Replication-defective adenoviruses Herpesviruses Picornaviruses

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)

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

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

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

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

Future prospectives

Vaccines based on Lipopeptides

Mucosal immunization

Stimulation of CTL

Prevention of CD4+ T-cell loss

Monoclonal antibodies

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

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

…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

THANK YOU