The Kitchen Sink. Glenda Gray AIDS vaccine at the cross roads: how to adapt to a new preven9on age? Monday 7 th October, 2013, Barcelona

Transcription

1 The Kitchen Sink Glenda Gray AIDS vaccine at the cross roads: how to adapt to a new preven9on age? Monday 7 th October, 2013, Barcelona

2 The only important slide of my presentation. All efficacy trial in humans are important and they give us huge amounts of information o o It is possible to develop a vaccine regimen that will prevent acquisition of HIV. It is also possible to develop a vaccine regimen that may increase the acquisition of HIV. o It is possible that many HIV vaccine regimens will need to balance these factors associated with increased acquisition (e.g. a strong but only partially effective mucosal T cell response) with the factors associated with protection from acquisition (a partially effective antibody response).

3 Ad5 HIV-1 Vaccines o Three HVTN efficacy studies using Ad 5 vectors have been tested Each one has somewhat different results and messages albeit one common agreed upon message o No efficacy against HIV acquisition or post acquisition viral load Step and Phambili are common in that, overall time periods acquisition rates in vaccine recipients are greater than placebo recipients

4 Merck Vaccine: Step and Phambili Schema N Week 0 Week 4 Week rad5 (1.5 x 1010 Ad vg) rad5 (1.5 x 1010 Ad vg) rad5 (1.5 x 1010 Ad vg) 1500 Placebo Placebo Placebo Vaccine: 1:1:1 admixture of 3 Ad5 vectors Encoded transgenes: codon- op9mized, near- consensus clade B HIV sequences Placebo: vaccine dilu9on buffer without Ad5

5 It rocked as far as immunogenicity was concerned Protein Total % (# positive/# tested)* 90.4% (498/551) Gag Pol 82.2% (453/551) 79.3% (437/551) Nef 75.0% (413/551) *analysis by IFN-γ ELISpot in PBMC at week 8 in male vaccinees After 2 immunizations with MRKAd5 HIV-1 vaccine, 90% of vaccinees had detectable HIV-specific T cells

6 Cumulative incidence of HIV by Subgroups over 48 months of follow up in HVTN 502/504

7 HVTN 503/Phambili: Cumulative HIV Incidence Over Entire Study Follow-up Period of blinded follow- up

8 HIV Infection Rates Phambili > Step 505 Step Phambili 505 Number of HIV infecions

9 BUT..It is also possible to develop a vaccine regimen that prevents HIV acquisition

10 RV144 Trial Kaplan-Meier Cumulative Rates of Infection Modified Intent to Treat Rerks-Ngarm, et al. NEJM, 2009;361

11 P5 idea was to improve on this Efficacy Potent Priming Immunogen (PPI)

12 The P5 Strategy for the ALVAC/Protein Phase 3 program Construc9on of ALVAC- HIV- C (vcp2438) Construc9on of bivalent gp 120/MF59 Op9mise regimen by increasing potency & durability Booster at 12 months

13 Strategy for the Licensure Track HVTN 097 Designed to evaluate RV144 vaccine regimen in RSA and compare immunogenicity to that in Thailand HVTN 100 A standard phase 1 trial of the clade C products to decide whether to proceed to phase 3 HVTN 702 A Classic phase 3 RCT assessing efficacy and safety aimed at licensure

14 Study Schema: HVTN 100 N (total 240) Primary Vaccine Regimen Booster Month 0 Month 1 Month 3 Month 6 Month ALVAC- HIV (vcp2438) ALVAC- HIV (vcp2438) ALVAC- HIV(vCP2438 )+gp120 Env (with MF59) ALVAC- HIV (vcp2438)+g p120 Env (with MF59) ALVAC- HIV (vcp2438)+g p120 Env (with MF59) 40 Placebo Placebo Placebo +Placebo Placebo +Placebo Placebo +Placebo Products: ALVAC- HIV (vcp2438) expressing HIV- 1 env (clade C gp120), clade B (gp41), gag (clade B) & protease (clade B) (Dose: >1 X 10 6 CCID 50 ) Bivalent subtype C gp120/mf59 containing 100mcg TV1.Cgp120 & 100mcg 1086.Cgp120 Immunogenicity evaluation to be applied to this study to inform advancement into phase 3

15 HVTN 100 immunological evaluation Head-to-head comparisons are complicated by the issue that the C scaffolded V1V2 antigen targets differ from the AE scaffolded V1V2 antigen targets Immunological Assessments Ab Take : binding Ab to vaccine strains Response Rate : binding Ab to V1V2 Ab Potency : magnitude of binding Ab to vaccine strains Adequate CD4+ T cell take : CD4+ T cell responses

16 Study Schema: HVTN 702 N (total 5400) Primary Vaccine Regimen Booster Month 0 Month 1 Month 3 Month 6 Month ALVAC- HIV (vcp2438) ALVAC- HIV (vcp2438) ALVAC- HIV(vCP2438 )+gp120 Env (with MF59) ALVAC- HIV (vcp2438)+g p120 Env (with MF59) ALVAC- HIV (vcp2438)+g p120 Env (with MF59) 2700 Placebo Placebo Placebo +Placebo Placebo +Placebo Placebo +Placebo Es9mated Study dura9on: Total Study duraion 72 months Stage 1: 60 months 918 months for enrolment, 24 months of follow- up for HIV- 1 uninfected individuals, 18 months follow up for HIV- 1 infected individuals) Stage 2: an addi9onal months

17 Phase 3 Trial Design (HVTN 702): One Vaccine Regimen vs. Placebo o Primary Objectives: Safety& Efficacy Sequential monitoring for potential harm, non-efficacy, and high efficacy VE will be assessed at 24 months [VE (0-24)] o Secondary objectives: n n Immune correlates Durability of VE out to 36 months n Evaluate vaccine effects on HIV-1 disease progression for 18 months post-diagnosis

18 Correlates Program o A key point post RV144 need reliable biomarkers of vaccine efficacy: n n n n n Bridge efficacy conclusions to novel populations Assess surrogates of vaccine protection in Phase1-2a Support basic science research on mechanisms Optimize NHP challenge studies Refine formulation when the regimen is complex or the vaccine is only partially efficacious o A key to designing a correlates program is to select vaccines with differing immunogenicity profiles n A biomarker increases in importance if vaccines with different immunological profiles lead to similar predictive biomarkers.

19 P5 Strategy for the Correlates Program Construc9on of DNA Construc9on of bivalent Clade C gp 120/Adjuvant 1 Formula9on of bivalent Clade C gp 120/Adjuvant 2 Construc9on of NYVAC Increase potency, durability & diversity Booster at 12 months

20 How Will Potent Priming and Adjuvants Impact HIV Vaccines? o The different vaccine regimens demonstrate promising immunological profiles n Sufficient to support search for immune CoP. o Inclusion and study of different adjuvants to the proteins will further diversify the vaccine responses and the number of potential biomarkers for evaluation as CoPs.

21 HVTN 701: Research Phase 1-2b Trial Schema (Part A+B version) o Design with 4 vaccine regimens vs. a shared placebo group Part A Group N Month 0 Month 1 Month 3 Month 6 Month NYVAC NYVAC DNA DNA NYVAC NYVAC DNA DNA NYVAC + gp 120/ adj A NYVAC + gp 120/ adj A NYVAC + gp 120/ adj B NYVAC + gp 120/ adj B NYVAC + gp 120/ adj A NYVAC + gp 120/ adj A NYVAC + gp 120/ adj B NYVAC + gp 120/ adj B NYVAC + gp 120/ adj A NYVAC + gp 120/ adj A NYVAC + gp 120/ adj B NYVAC + gp 120/ adj B Placebo Placebo Placebo Placebo Placebo Part B Same as in Part A, or down- selected number of ac9ve arms Placebo Placebo Placebo Placebo Placebo o HIV negative subjects enrolled and tested for HIV bimonthly for a maximum of 36 months

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23 Stanley Plotkin, Review in CVI, 2010 "Correlates of protection induced by vaccination" o After the administration of nearly all vaccines, prevention of infection correlates with the induction of specific antibodies o It is likely that vaccines of the future, such as those for HIV, will obey the same paradigm

24 Lynn Morris slide 4 sites of vulnerability on the HIV-1 envelope defined by neutralizing mabs PGT128 V3/glycan >25 mabs PG9 V2/glycan >12 mabs Long CDRH3 (>25 aa) to penetrate glycan shield Heavily mutated (30%) Bind lipids, VRC01 autoreactive CD4bs >25 mabs MPER 2F5/4E10 >5 mabs Modified from Burton et al., Science 2012

25 RV144 elicited mabs (Liao, Haynes et al Immunity 2013) o Bind residues in V2 that overlap PG9 (and CAP256-VRC26) mabs o Not neutralizing o Do not bind glycans o Low-levels of somatic hypermutation and short CDRH3s o Show ADCC and other functional activities Are these antibodies on the pathway to developing neutralization breadth?

26 o We must evaluate the effectiveness of humanized broadly reactive monoclonal antibodies given by infusion, as well as via persistent vectors in Test of Concept Efficacy Studies. o Test in infants as well as adults o Test as active/passive vaccination

27 Actually this is the most important slide Participants are the most valuable components of clinical trials as they teach us everything

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29 Concluding in Larry s words o New defining principles are emerging; largely from efficacy studies: n n n Enough vectorology More insertology Less conservatism in envelope immunogen design o Use DNA and protein platforms more o Nothing replaces working in the human system: n n n We must diversify the types of envelope immunogens we get into humans We must measure a wider scope of functional antibodies in these studies We must evaluate how to manipulate these functional antibodies by either adjuvants, vectors or DNA priming

30 Acknowledgments HVTN Larry Corey Julie McElrath, Georgia Tomaris ; Bart Haynes ; Jim Kublin, David Montefiore. Peter Gilbert Scott Hammer, Susan Buchbinder, Banks Warden, Zoe Moodie, Barb Metch, Carter Bentley, Nicole Grunenberg Site PIs, Investigators, Clinic Staff Recruiters, Community Educators MHRP Nelson Michael Jerome Kim Merlin Robb Mark De Sousa CHAVI-IDs Bill & Melinda Gates Foundation Lynn Morris Sanjay Phogat Susan Barnett Nina Russell NIH DAIDS P. D Souza Libby Adams Mary Marovich Vaccine Sponsors Merck GeoVax PENNVAX SAAVI Sanofi Novartis NIH VRC