Novel Heterologous Prime-Boost Vaccine Strategies for HIV Dan Barouch April 18, 2012
Desired Features of a Next Generation HIV-1 Vaccine Candidate The RV1 study suggests that an HIV-1 vaccine is possible However, improved vaccine regimens will likely be required, and a diversity of concepts needs to continue to be explored Key features desired in a next generation HIV-1 vaccine include: Vectors that avoid high levels of vector-specific NAbs and can be combined into a heterologous prime-boost regimen Antigens that elicit both humoral and cellular immunity and that optimize immunologic coverage of global virus diversity
Biological Differences Among Ad5, Ad26, and Ad5 Vaccine Vectors Ad5 Ad26 Ad5 Virus Subgroup Group C Group D Group B Seroprevalence 1 High Intermediate Low NAb Titers 1 High Low Low Cellular Receptor 2 CAR CD6 CD6 Tropism Hepatic Non-hepatic Non-hepatic DC Maturation Low Intermediate High Innate Profile 5 Proinflammatory Type I IFN Type I IFN Adaptive Phenotype 6 IFN-g Polyfunctional Polyfunctional Immunologic Potency High High Intermediate NHP Protective Efficacy + ++ + Human Safety 8? (phase 2b) + (phase 1) + (phase 1) Human Immunogenicity 8 ++ ++ + References: 1 Thorner et al. J. Clin. Microbiol. 2006 :81-8, Abbink et al. J. Virol. 200 81:65-66, Mast et al. Vaccine 2010 28:950-95, Barouch et al. submitted; 2 Vogels et al. J. Virol. 200 :826-821, Abbink et al. J. Virol. 200 81:65-66; Waddington et al. Cell 2008 12:9-09; Lore et al. J. Immunol. 200 19:121-129; 5 Barouch et al. unpublished; 6 Liu et al. J. Virol. 2008; 82:8-852, Ahmed et al. unpublished; Liu et al. Nature 2009; 5:8-91; 8 Buchbinder et al. Lancet 2008 2:1881-189, Catanzaro et al. J. Infect. Dis. 2006 19: 168-169, Barouch et al. AIDS Vaccine 2009, Paris, France
International Seroepidemiology of Ad5, Ad26, Ad5, and Ad8 in Pediatric and Adult Populations (N=,81) Barouch et al. Vaccine 2011; 29:520-5209
Immunogenicity and Protective Efficacy of Adenovirus/Poxvirus Regimens in Rhesus Monkeys IPCAVD-MHRP Collaboration 0 rhesus monkeys immunized with the following vectors expressing SIVsmE5 Gag, Pol, Env (N=8/group) DNA/MVA MVA/MVA Ad26/MVA MVA/Ad26 Sham Prime at week 0 (or week 0,, 8 for DNA) Boost at week 2 Low-dose, heterologous, neutralization-resistant IR SIVmac251 challenges at week 52 No vaccine regimen has previously been reported to afford protection in this highly stringent challenge model Barouch et al. Nature 82: 89-9 (2012)
% Uninfected Heterologous Vector Regimens Partially Resist Heterologous, Repetitive, IR SIVmac251 Challenges 100 80 60 0 20 DNA/MVA MVA/MVA Ad26/MVA MVA/Ad26 Sham 0 0 2 6 8 Number of IR Challenges
Heterologous Vector Regimens Partially Resist Heterologous, Repetitive, IR SIVmac251 Challenges
Log SIV RNA Log SIV RNA Ad26/MVA and MVA/Ad26 Regimens Lower Setpoint Viral Loads Following SIVmac251 Infection 9 8 6 5 2 Sham * * 9 DNA/MVA 9 MVA/MVA 8 18-08 8 28-08 * 19-08 0-08 * 20-08 1-08 5.85 6 22-08 6-08 * * 5.6 5 2-08 5 6-08 * 2-08 25-08 5-08 -08 8-08 9-08 2 MEAN 2 MEAN 0 50 100 150 200 250 9 0 50 100 150 Ad26/MVA 200 250 9 0 50 100 150 MVA/Ad26 200 250 8 8 09-08 * death 10-08 11-08 6 6 12-08 5 5 1-08 1-08.5 16-08 1-08 2 N= 2 MEAN 6.9. 0 50 100 150 200 2500 50 100 150 200 250 * * N=1 M M Days Following Infection
Immunogenicity and Protective Efficacy of Ad5/Ad26 Regimens in Rhesus Monkeys We next evaluated directly whether Env was required for vaccine-mediated protection against SIVmac251 acquisition 0 rhesus monkeys immunized with Ad5 prime, Ad26 boost regimens expressing the following antigens SIVsmE5 Gag-Pol (N=16) SIVsmE5 Gag-Pol-Env (N=16) Sham (N=8) Ad5 Prime at week 0 Ad26 Boost at week 2 Low-dose, heterologous, neutralization-resistant IR SIVmac251 challenges at week 52 Barouch et al. Nature 82: 89-9 (2012)
% Uninfected Ad5/Ad26-SIVsmE5 Gag-Pol-Env Partially Resists Heterologous, Repetitive, IR SIVmac251 Challenges 100 80 60 0 20 GagPol (N=16) GagPolEnv (N=16) Sham (N=8) 0 0 2 6 Number of IR Challenges
Ad5/Ad26-SIVsmE5 Gag-Pol-Env Partially Resists Heterologous, Repetitive, IR SIVmac251 Challenges
Log SIV RNA Log SIV RNA Log SIV RNA Ad5/Ad26 Regimens Lower Setpoint Viral Loads Following SIVmac251 Infection 9 8 6 5 2 Gag-Pol 9 8 6 5.15 2 0 50 100 150 Gag-Pol-Env 9 90-0 92-0 8 162-0 16-0 6 16-0 5 1-0.55 1-0 19-0 181-0 2 182-0 0 50 100 150 28-0 19-0 152-0 192-0 21-0 25-0 2-0 281-0 19-0 Sham 21-0 0 50 100 150 * 6. 29 298 0 09 10 18 19 20 ME Days Following Infection PEAK (DAY 1) SETPOINT (DAY 8) * death 9 8 6 5 2 P=0.065 P=0.00051 P=0.0016 Gag-Pol Gag-Pol-Env Sham 9 8 6 5 2 P=0.02 P=0.00022 P=0.00060 Gag-Pol Gag-Pol-Env Sham
Protective Efficacy of Heterologous Ad26/MVA and Ad5/Ad26 Regimens in Rhesus Monkeys Ad26/MVA and Ad5/Ad26 regimens afforded protection against acquisition of stringent, heterologous, neutralization-resistant SIVmac251 challenges with per-exposure VE=80% Ad26/MVA and Ad5/Ad26 regimens also resulted in 2 log reductions in setpoint viral loads in infected animals Env (when added to Gag-Pol) appears critical for acquisition effect against SIVmac251 Different immune correlates for blocking acquisition of infection compared with virologic control Clinical studies evaluating Ad26/MVA regimens expressing HIV-1 mosaic antigens planned
What are Mosaic Antigens? Algorithm to Generate a k=-valent Mosaic Vaccine Input: Single clade or M group Iterations improve the populations, improve the cocktail Fischer et al. Nat. Med. 200; 1:100-106
Expanded Breadth by Mosaic Compared with Consensus or Natural Gag/Pol/Env Antigens in Rhesus Monkeys The Ad26 mosaic vaccine yielded many more Gag, Pol, and Env (A) epitopespecific T lymphocyte responses as well as (B) numbers of epitope response regions to PTE peptides than did the Ad26 M consensus, clade B + clade C, or optimal natural clade C vaccines P = 1 x 10-11, Poisson regression P = 2 x 10 -, Poisson regression Barouch et al. Nat. Med. 2010; 16:19-2
Ad Vectored Mosaic Env Antigens Elicit Noninferior ELISA and NAb Responses Compared with Consensus or Natural Sequence Env Antigens in Rhesus Monkeys The mosaic vaccine elicited comparable ELISA and Tier 1 C (MW965.26) NAb titers (P = NS) and increased Tier 1 B (SF162.LS) NAb titers compared with the M consensus and optimal natural C clade vaccine (P = 0.02) Barouch et al. Nat. Med. 2010; 16:19-2
HIV-1 Vaccine Clinical Development Strategy 1. Develop prototype novel Ad vectors expressing a single test antigen (VRC EnvA) for a rapid assessment of vector safety and immunogenicity in humans 2. Develop complete vaccine products involving optimal heterologous prime-boost regimens expressing multiple HIV-1 antigens (mosaic Gag/Pol/Env) for clinical development
Conclusions Ad26/MVA regimens afford partial protection against acquisition and virologic control following heterologous, neutralizationresistant SIVmac251 challenges in rhesus monkeys Stable Env gp10 trimers induce substantially higher NAb responses than corresponding gp120 monomers in guinea pigs Preclinical studies are in progress to assess whether Env trimer protein boosts augment protective efficacy A prototype Ad26.ENVA.01 vector has proven safe and immunogenic in humans in both the U.S. and sub-saharan Africa We propose clinical development of Ad26/MVA expressing HIV-1 mosaic antigens, with or without a stable Env trimer boost
Acknowledgements Beth Israel Deaconess, Harvard Medical School Peter Abbink Kara Brandariz Rebecca Dilan Justin Iampietro Hualin Li Jinyan Liu Diana Lynch Lori Maxfield Lauren Peter Elizabeth Rhee Raphael Dolin Michael Seaman New England Primate Research Center Angela Carville Keith Mansfield Brigham & Women s, Harvard Medical School Lindsey Baden Jane Kleinjan Kathleen Krause Alka Patel Robert Tucker Stephen Walsh Daniel Worrall Safety Monitoring Committee Paul Goepfert Michael Keefer Peter Wright NIAID Vanessa Hirsch LANL Bette Korber Children s Hospital Boston, Harvard Medical School Bing Chen Crucell Holland BV Jaap Goudsmit Sandra Kik Maria Grazia Pau Jerry Sadoff MHRP Jerome Kim Mary Marovich Nelson Michael Merlin Robb Ragon Institute Bruce Walker CAVD, Gates Foundation Nina Russell Hanneke Schuitemaker DAIDS, NIAID, NIH Mo Weijtens Alan Fix Gerrit Jan Weverling Michael Pensiero Jort Vellinga