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IAS Durban Talk Lcorey July 19 Final Version Progress in the HIV Vaccine Field Larry Corey, MD Principal Investigator, NIAID supported HIV Vaccine Trials Network (HVTN) Past President and Director, Fred Hutchinson Cancer Research Center Professor, Laboratory Medicine and Medicine, University of Washington Seattle, Washington USA Disclosures • None Acknowledgements • HVTN as an organization, especially my colleagues: Scott Hammer, Glenda Gray, Julie McElrath, Peter Gilbert, Jim Kublin and Susan Buchbinder • The HVTN’s major pharmaceutical and institutional collaborators: Sanofi, GSK, Janssen, VRC, IAVI and CHAVI programs • The HVTN’s community members and advisory boards • Its funders: NIAID and BMGF Special Acknowledgement Tony Fauci, MD HIV: Still the World’s Most Important Global Health Problem • US still over 45,000 new cases yearly • Globally more than 2 million new infections occur per year • Number of people living with HIV increasing yearly • Long way from an AIDS Free Generation Indiana HIV outbreak: geographic distribution Scott County pop. 24,000; Austin, IN pop. 4,200 Adams, NEJM 2015;373:1379-1380 Scott County Commentary on HIV Prevention Strategies • While many prevention strategies have high efficacy in clinical trials, their extended effectiveness requires continuous adherence, which often results in decreased effectiveness over time. • They also require high saturation in a community and hence their long term effects on population based incidence in country’s with generalized epidemics is uncertain: • Condoms; PrEP; vaginal rings; PEP; circumcision, all deserve support and increased uptake • Test and Treat very effective for the individual; eventual population effect will be achieved The Need for an HIV Vaccine • With asymptomatic acquisition, prolonged subclinical infection, and sexual transmission, getting to an AIDS Free Generation will require a vaccine. • Larry’s definition of an AIDS Free Generation; 95% reduction in incident cases annually: • USA < 2,500 incident cases yearly • Globally < 100,000 cases yearly 7/25/16 9 “Ultimately, we believe, the only guarantee of a sustained end of the AIDS pandemic lies in a combination of non-vaccine prevention methods and the development and deployment of a safe and effective HIV vaccine.” The Two Major Scientific Questions Facing the HIV Vaccine Field: • Can non-neutralizing antibodies be potent enough to achieve desirable vaccine efficacy (VE >50%) for at least 2 years? • Can this be achieved by designing better recombinant proteins and adjuvants? • By eliciting better T helper responses to drive higher and more durable antibody production? • Is neutralization, as we currently measure it, associated with vaccine protection and will this protection be of a sufficient magnitude to overshadow other vaccine design approaches? HIV Vaccine Field at the Time of the Durban Conference in July 2000 • HIV vaccines not on the main stage: • No vaccine studies in RSA • HVTN just being organized (1999) • Several phase 1 trials of recombinant proteins were underway, including a phase 1 vaccine study in Uganda • Period of first generation vaccines (1984 – 2004): • Recombinant envelope vaccines all directed at trying to induce neutralizing antibodies • Large number of gp120, gp140, gp145, gp160 manufactured and tested • All immunogenic • Narrow (strain specific) neutralization • Poor durability A Pictorial History of HIV-1 Vaccine Efficacy Trials 1995 2000 2005 2010 2015 IAS Durban 702 VaxGen USA (gp120) 1 year AMP VaxGen IDU Thai Trial (gp120) 1 year Step Trial/Phambili Tria ls (Ad 5 g a g / p o l/ nef) RV144 Thai Trial (ALVAC/gp120) HVTN 505 (DNA/Ad5 env/gag/pol AMP Trial (VRC-01) HVTN 702 (Clade C ALVAC/gp120) Trial star t/end Trial analysis/results Immune correlates Second Generation Vaccines: T Cell Based Vaccines • Post-VaxGen, HIV vaccine field turned to “T cell based” vaccines • CD8+ T cells were what differentiated elite controllers from progression and it was hoped that vaccines that would induce such responses would be effective in either reducing acquisition or post- acquisition viral load. • Hypothesis: the more potent T cell responses, the better the vaccine: • Ad5 vector based vaccine much more effective in inducing CD8+ T cell responses than ALVAC A Pictorial History of HIV-1 Vaccine Efficacy Trials 1995 2000 2005 2010 2015 IAS Durban 702 VaxGen USA (gp120) 1 year AMP VaxGen IDU Thai Trial (gp120) 1 year Step Trial/Phambili Tria l (Ad 5 g a g / p o l/ nef) RV144 Thai Trial (ALVAC/gp120) HVTN 505 (DNA/Ad5 env/gag/pol AMP Trial (VRC-01) HVTN 702 (Clade C ALVAC/gp120) Trial star t/end Trial analysis/results Immune correlates Ad5 HIV Vaccines • Step and Phambili Trials with the MRK Ad5 gag/pol/nef: • No efficacy in either post infection viremia or reduced acquisition despite a high prevalence and reasonable magnitude of CD8+ T cell responses • Increased rate of acquisition of HIV-1 in both trials among men • Step: MSM Ad5 seropositive, uncircumcised men • Phambili: heterosexual men, also Ad5 seropositive • Mechanism of increased acquisition is unclear, especially as the DNA prime Ad5 boost regimen used in HVTN 505 had no evidence of increased acquisition: • The critical difference is the addition of HIV envelope in the DNA/Ad5 regimen • Envelope antibodies may be a factor in eliminating/negating the effects of increased mucosal T cells after Ad5 vaccination The Good News for HIV Vaccine Development – September 2009 and the RV144 Trial • Regimen of ALVAC priming followed by gp120 results in efficacy in large trial in Thailand. • Results met with surprise and skepticism: • ALVAC not as good as Ad vectors for T cell priming • gp120 used had failed in IDU trial • How could these two together all of a sudden produce efficacy? Thai Trial (RV144) Primary Results 1.0 Modified Intention-to-Treat Analysis* 0.9 0.8 Placebo 0.7 0.6 Vaccine 0.5 0.4 0.3 Probability of HIV Infection (%) 0.2 0.1 0.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Post-RV144 • Massive scientific effort to understand how did RV144 work: correlates of risk/correlates of protection. • Pivot in the field from concentrating on novel vectors to understanding that it is the insert (HIV envelope gene ) and structure of the envelope antigen that one puts in the vector that is critical for vaccine design. Concepts from the RV144 Correlates Program 2010 - 2014 • No direct correlation between neutralizing antibodies and HIV-1 acquisition in RV144: • None of the sera from the RV144 vaccinees neutralized a panel of 20 contemporaneous isolates of HIV-1 circulating in Thailand during the course of the trial • The antibody related correlations associated with Vaccine Efficacy in RV144 were in the magnitude and the epitope specificity of non-neutralizing antibodies which exhibited virion binding or infected cell associated functions. Correlation Between Antibodies to the V1V2 Loop and Vaccine Efficacy in RV 144 • Antibodies to the conserved region of V2, previously almost completely ignored by the HIV vaccine field, were highly correlated with efficacy. RV144 Correlates Observations • Sequencing studies of the viral envelope from persons on the trial revealed that distinct immunological pressure was observed in the crown of the V2 loop where vaccine immune responses were directed. • Distracting/inhibitory antibodies could be produced that reduced vaccine efficacy. CD4+ T cell Responses to HIV envelope in RV144 • Polyfunctional CD4+ T cell responses to HIV-1 envelope also independently contributed to VE. • The cytokine patterns of these helper T cell responses suggest that T helper responses that influence antibody development are important. COMPASS: Combinatorial Polyfunctionality Analysis of Single-cell Subsets COMPASS permits the unbiased characterization of polyfunctional subsets Expression of 6 functional markers: CD154, IL-2, IFN-γ, TNF-α, IL-17, IL-4 § 26=64 possible combinations / cell subsets § Many empty combinations → 15 considered Env-specific CD4+ T cell polyfunctionality score is an independent correlate of Vaccine Efficacy The five-function CD4+ T subset remains significant (OR=0.59, p=0.010) when the V1V2 and IgA Ab variables are also included in the model. The effects of the V1V2 IgG correlate and the five-function subset are additive (no evidence of interaction). Variable OR 95% CI P-value 5-function Env-specific CD4+ 0.59 0.40-0.89 0.011 T cell subset V1V2 IgG Ab primary 0.62 0.42-0.94 0.022 IgA Ab primary 1.76 1.2-2.6 0.003 (Lin L. et al, Nat Biotech. 2015 Jun;33(6):610-6.) 2016/2017: 3 Novel Strategies P5 “Clade C” approach using ALVAC & gp120/MF59 (HVTN 702) Multi-clade approach using rAd26/MVA/gp140 trimer (Crucell/Janssen) Neutralizing antibody approach using VRC01 Efficacy Studies Efficacy (AMP Trial: HVTN 703/HPTN 083, HVTN 704/HPTN 085) 2010 Formation of the P5 Partnership Strategy: Purpose: Developed a partnership to extend the To build on RV144 data and RV144 concept to Clade C regions of the ultimately license a pox-protein world. based HIV vaccine with the Use expert committees to select the potential for broad and timely strains and then use company expertise public health impact. to manufacture these vaccines for immunogenicity, safety and efficacy. The Strategy for the ALVAC/Protein Phase 3 Program Construction of Bivalent Subtype C gp120/MF59 Construction of Booster at ALVAC-HIV-C 12 months (vCP2438) Optimize regimen by increasing potency and durability HVTN Strategy for the Phase 3 Program HVTN 097 HVTN 100 HVTN 702 Designed to A standard A Pivotal evaluate RV144 phase 1 trial of Efficacy Trial vaccine regimen the Clade C assessing in RSA and products to efficacy and compare decide whether safety immunogenicity to proceed to to that in phase 3 Thailand LB xxxx Meeting the “Go” Criteria: Immunogenicity from HVTN 100, a phase 1/2 randomized, double blind, placebo-controlled trial of clade C ALVAC- ® (vCP2438) and Bivalent Subtype C gp120/MF59® in HIV-uninfected South African adults.
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