ANIMAL MODELS FOR HIV VACCINES

Girish N. Vyas, Ph.D.UCSF School of Medicine, San Francisco (UCSF)

A quote from the keynote Address at the January, 2008 Congress of the Intl Soc Cell and Gene Therapy applicable to HIV Vaccine?

“Mice tell lies and monkeys do not tell the truth. Human clinical trials alone provide the proof”

WEAA03 Session, Aug 6, ‘08, International AIDS Conference, Mexico City

Live Attenuated Whole inactivated

HIV peptide Recombinant protein subunit

DNALive virus vector Live bacterial vector

PREMISE FOR AN HIV VACCINE MODEL

• Vaccines are aimed at producing a potent antibody response protective against a pathogen without producing an infection.

• Lessons learnt from HBsAg vaccine against HBV appear applicable to fruitful HIV vaccine development.

• Antibody response in HIV-infected persons has more than 10 distinct specificities to HIV-gp 41/120 but together they fail to protect against HIV-1 infection.

• Essential to elicit antibody response broader than that in HIV-1 infected persons.

• For effective protection a vaccine must induce antibody response to both envelope proteins, HIV-gp41 and -120.

• Monoclonal antigens/antibodies have apparently proven inadequate.

• Genetic diversity of population-prevalent HIV-1 may be necessary for developing an effective polyvalent HIV vaccine

Geographic Distribution of HIV-1 SubtypesMost Animal Work Done with HIV-1 Subtype B

BB,A,D,E,A,D,E

B,B,EE,,F,CF,C

BB,A,C,D,E,F,G,H,A,C,D,E,F,G,H

A,C,DA,C,D,,E,F,G,HE,F,G,H

BB

EE,B,B

CC,B,E,B,E

Adapted from U.S. Military HIV Research ProgramAdapted from U.S. Military HIV Research ProgramAdapted from U.S. Military HIV Research ProgramAdapted from U.S. Military HIV Research Program

ANIMAL MODELS USEFUL IN HIV VACCINE R&D

NONHUMAN PRIMATES (NHP)• Chimpanzee: Useful model for HIV-1 infection and immunity but

not pathogenesis; expensive and available with difficulty. • Macaques: SIV and SHIV, a chimeric analogue of HIV, used as

model for immunization/challenge.• Baboons: Though not susceptible to infection with HIV-1, it is a

useful nonhuman primate model for phylogenetically relevant anti-HIV response.

SMALL ANIMALS• SCID-hu mouse: A heterochimeric small animal model

improved upon by hollow-fiber SCID model used for evaluation of antivirals. Intrathymic injection of 4XTCID-50 infected 15/16 animals (Stoddard, personal communication, August 2008)

• Cats: Vaccine against Feline Immunodeficiency Virus (FIV) may provide a biological paradigm.

Non-human Primate Models for AIDS Vaccine Research

Critical component of AIDS vaccine research effort for foreseeable future

Discovery and applied evaluation

Proof of concept prior to efficacy testing (exceptions)

Resources, infrastructure inadequate to expanding demands

Non-human Primate Models for AIDS Vaccine Research

Multiple models available; none perfect

Model = NHP species, challenge virus, route/dose, predictable outcome

Viruses in vivo adapted/selected

Match model to research question

Non-human Primate Models for AIDS Vaccine Research

Standardization

Comparative evaluation of vaccine candidates

Model(s)

Challenge stocks (homolog, heterolog)

Laboratory analysis (virology, immunology)

Two edged sword absent “perfect” model

Dangers of standardization for its own sake

Match model to research question

Non-human Primate Models for AIDS Vaccine Research

New model development

Other SIVs (breadth, heterolog, in vivo)

R5 SHIVs

Minimally chimeric HIV-1’s

In vivo manipulations

Attenuated SIV StrainsAttenuated SIV Strains

gag

pol

vif

vpx tat

env

revvpr

nef

LTR LTRSIVmac239∆nef

gag

pol

vif

vpx tat

env

revvprLTR LTR

nef

SIVmac239∆3

SIVmac239∆4

gag

pol

vif

vpx tat

env

revvprLTR LTR

nef

Marie-Claire Gauduin, Ph.D.

101033

00

101011

101022

101044

101055

101066

101077

101088

Wild-type SIVWild-type SIV

Live, attenuated strainsLive, attenuated strainsnefnef

3 (3 (nef, nef, vpr, vpr, US)US)4 (4 (nef, nef, vpr, vpr, vpx, vpx, US)US)

Duration of infectionDuration of infection

SIV

Pla

sma

RN

A (

cop

ies/

ml)

SIV

Pla

sma

RN

A (

cop

ies/

ml)

Limit ofLimit ofDetectionDetection

Adapted from R. Desrosiers et al.Adapted from R. Desrosiers et al.

Replication of Attenuated SIV in Vivo

Summary of Scientific Issues and Questions

Animal models:Lack of good models and understanding of mechanisms of protection

Animal models:Lack of good models and understanding of mechanisms of protection

Vaccine designs to generate broad

neutralizingab to circulating strains

(primary) isolates

Vaccine designs to generate broad

neutralizingab to circulating strains

(primary) isolates

Correlates of immunityNeutralizing ab vs CTL or bothWhat are the best strategies to achieve both?

Correlates of immunityNeutralizing ab vs CTL or bothWhat are the best strategies to achieve both?

HIV pathogenesis(latency) and virus immune escape

mechanisms

HIV pathogenesis(latency) and virus immune escape

mechanisms

Viral Diversity/Different Clades

Viral Diversity/Different Clades

Sterilizing immunity vs disease

modulation?

Sterilizing immunity vs disease

modulation?

Trial designsLaboratory Methods

Trial designsLaboratory Methods