Protective Immunity to HIV:What Animal Models of HIV Infection Can and Cannot Teach Us

Models of Protective Immunity to HIVXVI International AIDS ConferenceAugust 13 18, 2006Toronto, Canada

Ruth Ruprecht, M.D., Ph.D. Dana-Farber Cancer InstituteHarvard Medical School, Boston

What Are the Correlates of Protection?

What Are the Correlates of Protection?

Immune

Vaccine-induced Protection Could be Due to

acquired immunity

Vaccine-induced Protection Could be Due to

acquired immunityinnate immunity

Vaccine-induced Protection Could be Due to

acquired immunityinnate immunityboth acquired and innate immunity

Vaccine-induced Protection Could be Due to

acquired immunityinnate immunityboth acquired and innate immunityviral interference (in the case of live attenuated SIV or SHIV)

Passive Immunization = Tool to Assess Correlates of Protection

Because rhesus monkeys are outbred and twin gestations are very rare, adoptive transfer of immune T cells is not feasible. Only the humoral arm of the immune system can be tested by passive immunization.

Passive Immunization: Cross-clade Protection

SHIV1157ip: Summarybuilt from the SHIV-vpu+ backbone env was derived from an HIV clade C strain, HIV1157i, a primary R5 strain isolated from a six-month old Zambian infant who was HIV positive at birth

replicates in rhesus macaque PBMC

uses only CCR5 as coreceptor

was adapted to rhesus monkeys by rapid animal-to-animal passage in five animals

results in high peak viral RNA levels and persistent infection in infant and adult macaques

was titrated orally in neonatal rhesus monkeys

shows signs of pathogenicity in rhesus macaques: persistent viremia, depletion of memory T cells, loss of absolute numbers of CD4+ T cells, AIDS, thrombocytopenia

oralSHIV-1157ipmAbs1hrcontrol (n=4)treatment with 4x mAbs i.v. (n=4) 12 4 12 4d8 0 0 oralSHIV-1157ip100 weeks100 weeksmAbsExperimental Design

log plasma viral RNA load (copies/ml)13570306090Weeks after inoculationRPj-9RTj-9RWk-9RZk-9RPk-9RSj-9RTk-9RVj-9Week 40Passive Immunization: 1h Post-Exposure Prophylaxis

The Correlates of Immune ProtectionThe human anti-HIV mAbs used in the quadruple combination completely protected monkeys against mucosal virus challenge.These nmAbs, which recognize conserved epitopes and are active across clades, were the sole immune protective mechanism.

IgG1b12:anti - CD4 binding site (b12) 2G12:complex epitope on gp120 dependent on correct N-linked glycosylation 2F5:linear gp41 epitope, ELDKWA

4E10:linear gp41 epitope,NWFDIT

Epitope Specificity

Correlates of Immune ProtectionIgG1b12:anti - CD4 binding site (b12) 2G12:complex epitope on gp120 dependent on correct N-linked glycosylation 2F5:linear gp41 epitope, ELDKWA

4E10:linear gp41 epitope,NWFDIT

Causes of Immune ProtectionIgG1b12:anti - CD4 binding site (b12) 2G12:complex epitope on gp120 dependent on correct N-linked glycosylation 2F5:linear gp41 epitope, ELDKWA

4E10:linear gp41 epitope,NWFDIT

Protective EpitopesIgG1b12:anti - CD4 binding site (b12) 2G12:complex epitope on gp120 dependent on correct N-linked glycosylation 2F5:linear gp41 epitope, ELDKWA

4E10:linear gp41 epitope,NWFDIT

Passive immunization with nmAbs is a tool to identify protective epitopes

AIDS Vaccine Development and Challenge Viruses in Primates Getting Real

In order to be as predictive as possible, vaccine efficacy studies in non-human primate models should reflect the biology of HIV-1 transmission among humans as closely as possible.

HIV-1 Transmission Among Humans90% of all HIV-1 transmissions occur via mucosal exposure; this includes sexual transmission and mother-to-child transmissionmucosal HIV-1 transmission involves R5 viruses almost exclusively, even if the source person harbors predominantly X4R5 and X4 strainsrecently transmitted strains of HIV-1 may be more sensitive to neutralization and encode shorter Env molecules than quasispecies that predominate in the source person (shown for clade C)11 Derdeyn et al., Science 2004; 303:2019-22; Li et al., J Virol 2006; 80:5211-8

Vaccine Challenge Studies in Primates: Getting Realmucosal route (intrarectal, intravaginal, oral) R5-tropic virusrepeated low-dose vs. standard high-dose challengesneutralization-sensitive virusvirus lacking overwhelming, acute pathogenicityheterologous virus (with regard to vaccine)

Vaccine Challenge Studies in Primates: Getting Realmucosal route (intrarectal, intravaginal, oral) R5-tropic virusrepeated low-dose vs. standard high-dose challengesneutralization-sensitive virusvirus lacking overwhelming, acute pathogenicityheterologous virus (with regard to vaccine)

Mucosal Challenge in Primates: Virus Dose MattersThe standard single high-dose virus challenge, designed to yield > 95% chance of infecting unvaccinated controls, does not reflect the HIV-1 inocula during sexual transmission

High-dose challenge may overrun host defenses and set the bar for achieving protection too high

Repeated Low-dose Challenge: Lowering the HurdleExample: using an R5 SHIV, Kim et al.1 performed weekly intravaginal challenges at low doses (10 TCID) in monkeys. Group 1 received the vaginal microbicide CAP 15 min prior to each virus inoculation; controls remained untreated. Whereas all controls became systemically infected after 3 to 4 weekly exposures, 3 out of 4 monkeys given CAP microbi-cide remained uninfected after 12 exposures (p = 0.015).

CAP microbicide efficacy was 66% when tested against a single high-dose virus challenge; when tested against repeated low-dose challenges, efficacy was 92%.

1 J Med Primatol 2006; 35: 210-6 CAP = cellulose acetate phthalate.

Vaccine Challenge Studies in Primates: Getting Realmucosal route (intrarectal, intravaginal, oral) R5-tropic virusrepeated low-dose vs. standard high-dose challengesneutralization-sensitive virusvirus lacking overwhelming, acute pathogenicityheterologous virus (with regard to vaccine)

Neutralization Sensitivity: Avoid Stealth Envelopes Late-stage viruses that have undergone multiple rounds of neutralizing antibody (nAb) selection followed by repeated escape develop more compact, hard-to-neutralize envelopes.Using viruses with such impenetrable envelopes in primates may set the bar for achieving vaccine protection unrealistically high. Neutralization resistance is an issue for SIVmac239 and primary SIVmac251 grown in rhesus monkey PBMC. Essentially, nAb-based vaccines cannot be evaluated for efficacy with these challenge strains.

Vaccine Challenge Studies in Primates: Getting Realmucosal route (intrarectal, intravaginal, oral) R5-tropic virusrepeated low-dose vs. standard high-dose challengesneutralization-sensitive virusvirus lacking overwhelming, acute pathogenicityheterologous virus (with regard to vaccine)

The chance of a human AIDS vaccine recipient to be exposed to an HIV-1 strain that exactly matches his/her vaccine approaches zero

Given the many HIV-1 quasispecies and their increasing divergence with time, human AIDS vaccine recipients will not encounter viruses exactly matched to their vaccine.

Vaccine efficacy testing in primates should reflect this reality. Exactly matching vaccine and challenge virus may overestimate the potential of new vaccines and raise unjustified expectations.

Success with homologous virus challenges may also stimulate the development of vaccine strategies that yield highly protective but only narrowly focused immune responses that fail to protect against divergent viruses. Heterologous Virus Challenge: Reflecting Viral Complexity in Real Life

SHIV Challenges: Closer to the Real Thing SHIV chimeras allow efficacy testing of HIV-1 Env-based vaccines. SHIV chimeras allow testing of neutralizing antibodies isolated from HIV-1-infected individuals. As such, vaccine development could be significantly accelerated because primate-tested reagents can be directly used in clinical trials. In contrast, SIV challenges only allow the evaluation of active or passive immunization concepts but not the actual vaccines or antibodies intended for human use.

Summary AIDS vaccine efficacy studies in primate models should focus on mucosal challenge with R5 strains

SHIVs have the added advantage of directly testing anti-HIV-1 Env responses

SHIVs allow development of passive immunization with human anti-HIV-1 Env nmAbs in primates

Challenge viruses should encode neutralization- sensitive, primary envelopes

Summary, continuedTo reflect HIV heterogeneity, vaccine and challenge virus should not exactly match. Ideally, primate vaccine efficacy studies should employ fully hetero-logous virus, rather than one differing in env only. Replacing single high-dose viral challenges with repeated low-dose mucosal exposures has shown promise. Ultimately, efficacy data generated in primate models need to be compared directly to phase III clinical vaccine trials for validation.

AcknowledgementsDFCI / Harvard Medical SchoolRuijiang SongRobert RasmussenAgns Chenine

Mila Ayash-RashkovskyLauren GoinsRicky GrissonPei-lin LiChantelle McCannSaied MirshahidiHelena OngClaudia RuprechtEla Shai-KobilerTao WangJames WhitneyW. XuL.-Y. Yeh

Beth-Israel Deaconess Medical CenterLisa CavaciniMarshall PosnerInstitute of Applied Microbiology, Vienna, AustriaHermann KatingerGabriela StieglerHarvard School of Public HealthJanet AndersenMemorial Sloan-Kettering Cancer CenterTing Chao ChouYerkes National Primate Research CenterHarold McClureJames Else Elizabeth StrobertCenters for Disease ControlW. Evan SecorUniversity of NebraskaCharles Wood H. ZhangUniv. Teaching Hospital, Lusaka, ZambiaGanapati BhatChipepo KankasaUniversity of WashingtonShiu-lok HuPatricia Polacino

NIAIDHIV-RAD P01: Nancy Miller