4/14/2016. HIV Vaccines and Immunoprotection: Where Are We? Learning Objectives. After attending this presentation, participants will be able to:

Transcription

1 HIV Vaccines and Immunoprotection: Where Are We? Mark J. Mulligan, MD, FIDSA Distinguished Professor of Medicine Emory University School of Medicine Atlanta, Georgia FINAL: 04/01/16 Atlanta, Georgia: Friday, April 8, 2016 Financial Relationships With Commercial Entities Dr Mulligan has served on the safety monitoring committee for VaxInnate, Inc, and has received funding for public education with regard to HIV prevention from Gilead Sciences, Inc. (Updated 04/8/16) Slide 2 of 39 Learning Objectives After attending this presentation, participants will be able to: Describe the challenges in HIV vaccine development List the correlates of infection risk identified in the RV144 Thai HIV vaccine efficacy trial Summarize the objectives of the HIV Vaccine Trials Network (HVTN) and the HIV Prevention Trials Network (HPTN) Antibody-Mediated Protection (AMP) studies Slide 3 of 39 1

2 Outline History Challenges RV144 - Thai HIV Vaccine Efficacy Trial Antibody-Mediated Protection (AMP) Studies Prevention conclusions Slide 4 of 39 Slide 5 of 39 Which of the following is true and provide rationale for HIV vaccine development? 1. UNAIDS estimated that there were 2.1 million new infections in Vaccines are historically the primary public health intervention for prevention of a wide range of infectious diseases and thus would provide the most cost-effective, durable, and accepted approach to reduce HIV-1 infection. 3. In an HIV vaccine efficacy trial in >16,000 persons, the first-year vaccine efficacy (VE) approached 60%, but efficacy waned with time and overall VE for the 3.5 year trial was 31.2%. 4. All of these are true and provide rationale. 5. These are all false and you should rethink your rationale. UNAIDS estimated that there... In an HIV vaccine efficacy trial i... Vaccines are historically the pr... 2% 11% 5% 2% These are all false and you shou.. All of these are true and provid... 81% History 1970s illness 1981 description 1984 blood test 1987 first ARV 1991 second ARV 1996 HAART 2012 Tx as Prevention 2012 Oral PrEP (TDF/FTC) licensed in US 1988 first HIV vaccine trial 2003 gp120 in alum 2007 rad5-gag-pol-nef 2009 Cpox-gag-progp120 + gp120 in alum 2012 DNA-g-p-n-envABC + rad5-g-p-envabc 2016 Antibody-mediated protection (AMP) studies Slide 6 of 39 2

3 1988 first HIV vaccine trial 2003 gp120 in alum 2007 rad5-gag-pol-nef 2009 Cpox-gag-progp120 + gp120 in alum 2012 DNA-g-p-n-envABC + rad5-g-p-envabc 2016 Antibody-mediated protection (AMP) studies History Slide 7 of 39 Which of the following is false regarding the six HIV vaccine efficacy trials completed to date? 1. Protection against HIV infection has not been observed in any trial. 2. The reactogenicity of the vaccines has been acceptable. 3. Risk compensation (increase in HIV risk behaviors) has not been observed. 4. In the Step and Phambili studies, certain participant sub-groups had increased acquisition of HIV after vaccine relative to placebo. Protection against HIV infectio... 46% The reactogenicity of the vacci... 20% 20% Risk compensation (increase in... 13% In the Step and Phambili studie.. Slide 8 of 39 Challenges The Virus Transmission as free virions or cell-associated virus Retrovirus: integration Long latency RNA virus variability Clades - geography Strains - escape We don t know what the protective antigens & epitopes are No animal model that predicts vaccine protection of humans against HIV Slide 9 of 39 3

4 Challenges The Host The virus is not eliminated in natural infection failure of T cell immunity Immunologically privileged sanctuaries Immunodominant response to variable epitopes - decoys Host genetic variability class 1 alleles - HLA-A, -B, -C; class 2 alleles; SNPs We don t know how to induce a BNAb with a vaccine Human correlates of immune protection unknown A vaccine must do better against virus than natural infection Slide 10 of 39 The Changing Landscape Combination prevention, or HAARP Adherence-based biomedical approaches - PMTCT, Behavioral EBIs, ABCs, CVTC, Test & Treat (treatment as prevention), PrEP Other approaches Circumcision, Caesarean section, Vaccination Combine partially effective interventions to maximize prevention an individualized prevention tool-box Slide 11 of 39 The challenges for HIV vaccine developers include all of the following except: 1. The high degrees of both viral and host genetic variability. 2. The immunologic correlates of vaccine protection are well established. 3. The key viral epitopes & antigens for a protective vaccine are unknown. 4. Required sample sizes for efficacy trials will likely increase with roll out of PrEP. The high degrees of both viral... 3% The immunologic correlates of... 63% The key viral epitopes & antige.. 20% 14% Required sample sizes for effic... Slide 12 of 39 4

5 The Thai Trial RV144 ALVAC + AIDSVAX Community-based, randomized 1:1, placebo controlled, double blinded efficacy trial does the vaccine protect? 16,402 healthy men and women - 3 years of follow-up two priming injections of a recombinant canarypox vector vaccine (ALVAC-HIV [vcp1521]) Gag, Pro, gp120 plus two booster injections of a recombinant canarypox and gp120 in alum (AIDSVAX B/E) Primarily at heterosexual risk for HIV infection Rerks-Ngarm et al., New Engl J Med, 2009 Slide 13 of 39 Kaplan-Meier Cumulative Rate of Infection A first, modest (energizing) success. Analysis N Vaccine Efficacy 95% CI (P value) In the first year, 60% protection was observed. MITT 16, % 1.1 to 51.2 (P=0.04) Rerks-Ngarm S et al. N Engl J Med 2009 Slide 14 of RV144 Trial - First Efficacy Signal and Immunological Correlates of Risk Corey, Sci Transl Med, 2015 Slide 15 of 39 Corey et al. Science Translational Medicine. Vol 7 (310); Oct

6 RV144 Trial Immunologic Correlates of Infection Risk 84% of participants developed IgG to V1V2 loop higher magnitude lower risk of infection Non-neutralizing antibodies IgG3 to V1V2 loop Antibody Dependent Cellular Cytotoxicity (ADCC) Higher IgG avidity to gp120 Higher frequency of neutralizing antibodies to Tier 1 viruses Polyfunctional CD4+ T cell responses against Env Haynes, New Engl J Med, 2012; Corey, Sci Transl Med, 2015 Slide 16 of 39 After RV144: Pox-Protein Public-Private Partnership (P5)* Two efficacy trials planned Sub-Saharan Africa, clade C, population at higher risk 1: Cpox C-gag-pro-gp120 + bivalent C/C gp120 + MF59 2: (DNA +) NYVAC + bivalent C/C gp140 trimer in alum or in MF59 or in AS01B (liposomal MPL + QS21) Multiple early phase trials ongoing US, South Africa, Thailand *NIAID/HVTN, US Army, SAAVI, Thai Government, Sanofi, Novartis, GSK, BMGF Corey, Sci Transl Med, 2015 Slide 17 of 39 Ongoing early phase trials Other Candidates Electroporation of DNA prime followed by MVA boost Molecular adjuvants: IL-12 rad26 vector; replicating rad4 vector; mosaic gene inserts Other novel vectors Experimental work on induction of BNAbs Slide 18 of 39 6

7 The RV144 Thai HIV vaccine efficacy trial identified immunological direct correlates of infection risk which included all of the following except: 1. The magnitude of IgG against V1V2 loop of gp CD8+ T cell responses targeting the Gag protein. 3. IgA against the C1 region of gp ADCC The magnitude of IgG against... 6% CD8+ T cell responses targeting... 29% 22% IgA against the C1 region of gp... 43% ADCC Slide 19 of 39 October, 2016 Community Engagement! Slide 20 of 39 Antibody-mediated Protection (AMP) Studies HVTN 704/HPTN 085: MSM and TG in Americas HVTN 703/HPTN 081: Women in sub-saharan African Slide 21 of 39 7

8 There is a long history of using antibodies to prevent viral infections VIRUS PRODUCT DESCRIPTION INDICATION Measles Concentrated human gamma globulin Prevention Polio Concentrated human gamma globulin Prevention CMV Cytomegalovirus Immune Globulin Prevention Hepatitis A Immune serum globulin (ISG) Prevention (travel) Hepatitis B Hepatitis B Immune Globulin Post Exposure Rabies Rabies Immune Globulin Post Exposure RSV mab (palivizumab) for prophylaxis of Prevention in High Risk Infants high risk infants VZ Varicella Zoster Immune Globulin Post Exposure And, most effective vaccines induce antibodies that neutralize the pathogen. Thanks to John Mascola for this slide. Slide 22 of 39 The Main Hypotheses of the AMP Trials Administration of this BNAb will reduce acquisition of HIV in these higher risk populations The levels of VRC01 Ab required for protection will vary by type of sexual exposure and not by clade The concentration of Ab in serum will be directly associated with the rate of protection Breakthrough isolates will have greater resistance to neutralization and will have specific molecular signatures Slide 23 of 39 VRC01 - Antibody being tested in the AMP Study to prevent acquisition of HIV infection Discovered in an individual who was HIV infected for a long time (>15 years), who maintained virologic control on no ART --IgG1 Ab Developed by John Mascola & colleagues at the Vaccine Research Center of the NIH Gray: gp120 Red: CD4 binding site (CD4bs) Purple & Green: VRC01 attached to the CD4bs Photo: NIAID/NIH Vaccine Research Center (VRC) Slide 24 of 39 8

9 Unique features of HIV BNAbs Long Complementarity determining regions Long heavy chain CDR3 region, as in VRC01 High levels of somatic hypermutation Due to a complex evolutionary process over many years which leads to higher avidity Autoreactivity with host antigens Limited production -- B cells clonally deleted Development of BNAbs is disfavored in the host Slide 25 of 39 VRC01 Binds gp120 CD4bs and Blocks Viral Attachment to CD4 gp41 trimer gp120 trimer CD4 binding site on gp120 is functionally conserved: All viruses must bind CD4 CD4 CCR5 Target Cell Slide 26 of 39 A Broadly Neutralizing Antibody Slide 27 of 39 Wu, Science, 2010; Zhou, Science,

10 AMP Study: Antibody Mediated Prevention Slide 28 of 39 Ledgerwood, Clin Exp Immunol, 2015 VRC01 Antibody Dosing in the AMP Studies REGIMEN MSM & TG in the Americas Women in sub-saharan Africa TOTAL N VRC01 10 mg/kg VRC01 30 mg/kg Control (normal saline) infusions total & Infusions every 8 weeks Total Study duration: ~22 months Slide 29 of 39 What Happens With Success? Best case We find that low doses (e.g., producing concentrations of 5-10 mcg/ml) can protect against acquisition Translate that into: a) immunogen that achieves this level of neutralization b) develop product that allows dosing interval by subcutaneous or IM administration c) move to genetic immunization to provide long term low dose concentrations Slide 30 of 39 10

11 Which of the following is true for the VRC01 antibody? 1. It is an IgG3 antibody that mediates ADCC. 2. Infusion reactions have been seen in phase 1 studies. 3. No effect on viral load was observed in a phase 1 trial in HIV-infected study participants. 4. It is a BNAb with a median IC 50 of 0.3 mcg/ml against a panel of 190 HIV isolates from all clades. It is an IgG3 antibody that med... 0% 0% 0% 0% Infusion reactions have been se.. No effect on viral load was obs... It is a BNAb with a median IC50... Slide 31 of 39 Conclusions Burden of HIV disease and history of vaccine effectiveness against infectious diseases drive the HIV vaccine mandate Challenges virus, host, prevention landscape Thai efficacy result provided many leads Discovery research new vectors, induction of BNAb, new technologies (systems biology, omics) Antibody-mediated protection (AMP) Studies Proof of principle inform vaccine design Slide 32 of 39 Acknowledgements Hope Clinic Faculty and Staff Emory-CDC HIV/AIDS CTU Emory CFAR Action Cycling Atlanta Georgia Research Alliance Sri Edupuganti, MD, MPH Barney Graham, NIAID/VRC Larry Corey, HVTN Myron Cohen, HPTN Slide 33 of 39 11

12 Funding Slide 34 of 39 HIV-1 Diversity Worldwide HIV-1 group M: 9 subtypes & several circulating recombinant forms Subtype A B C D F, G, H, J, K CRF01_AE CRF02_AG CRF03_AB other HIV genomes differ by 10-30% Human genomes differ by about 0.1% Hemelaar et al WHO/UNAIDS. Slide 35 of 39 VRC01: Safety and Tolerability Studied in 3 Phase 1 trials: VRC601, VRC602, HVTN104 VRC 601: dose escalation and PK study of IV and SC in HIV infected individuals VRC 602: dose escalation and PK study of IV and SC in HIV uninfected individuals (Ledgerwood, Clin Exp Immunol, 2015) HVTN 104: safety and PK study of VRC01 in HIV uninfected individuals Overall, safe and well-tolerated Slide 36 of 39 12

13 Intravenous infusion, minutes Infusions every 8 weeks Monthly study visits CASI administration Medical emergency management capacity Trial Design Aspects for Clinic Consideration Slide 37 of 39 How to determine efficacy? Other Challenges Can t do human challenge studies after vaccination - unethical Vaccine field trials cost >$100M each How decide which vaccines to move into efficacy trials? New prevention technologies (e.g., PrEP, vaginal rings) may increase the sample sizes (and costs) Slide 38 of 39 HIV Vaccines - Practicalities Can t acquire HIV from the vaccines Safe and well tolerated to date* Must be HIV negative to enroll Vaccine-induced sero-reactivity (VISR) may occur Volunteers are reimbursed Challenges of enrolling those most affected by HIV/AIDS Risk compensation - not observed Slide 39 of 39 *Step and Phambili enhanced acquisition some groups 13