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Prof. anzala hiv vaccine update
 

Prof. anzala hiv vaccine update

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  • Ongoing Phase IIb : The only HIV vaccine candidate currently being assessed for efficacy is the DNA + Ad5 vaccine from the NIH. Enrollment in the 2200 person trial has been relatively slow, with approximately 1850 of the 2200 enrolled since 2009. It is now expected that data from this trial will be available in late 2013. Next Phase IIb : Phase IIb trials repeating the RV-144 regimen will likely begin in 2014-2015.
  • There has been encouraging data suggesting that A combination of several epitope would probably be used to provide maximum coverage and target as many viruses as possible. We know from the current bNABS isolated that a combination of 2 of them could be sufficient to block over 99% of the virus tested.
  • When discussing vaccine that elicit cellular immunity one has to look at the shift in perspective in the field
  • Replicating vectors would allow a more sustained exposure of the immune system to the HIV antigen, allowing a stronger, longer lasting immune response the be induced.
  • CSF is a gate funded program where IAVI provides support, expertise and skills to help move product to development. We provide helps for investirgators which don ’ t have the experience, know how on how to move their product into development.

Prof. anzala hiv vaccine update Prof. anzala hiv vaccine update Presentation Transcript

  • KAVI-INSTITUTE OF CLINICAL RESEARCH (KAVI-ICR) UNIVERSITY OF NAIROBI Prof .Omu Anzala Update: HIV Vaccine Research
  • 07/11/13 09:07 AM 2 OUT LINE OF PRESENTATION • Introduction • Current global position • Current science in vaccine development
  • 07/11/13 09:07 AM 3 PrEP Clean injecting equipment Cervical barriers: vaginal diaphragms Prevention of vertical transmission Vaccines Voluntary counselling and testing Microbicides Treatment as prevention Male circumcision PEP Comprehensive HIV prevention Male and female condoms ARV
  • 07/11/13 09:07 AM 4 Research at KAVI Protocols A, B, (DBS), C (EIR) , G, J, I Protocols A, B, C, D Protocols 002/4/8/10, V001, B002/3 PrEP,/004 Protocols M, H, LTFU
  • 07/11/13 09:07 AM 5 Public sector, academia Pharmaceutical companies, product-development partnerships Research & Development : Basic research Applied research Preclinical development Clinical development Advanced development Large-scale Efficacy trials R&DR&D R&D Strategy: Address key gaps to improve the pipeline by integrating vaccine discovery and development R&D Strategy: Address key gaps to improve the pipeline by integrating vaccine discovery and development
  • 07/11/13 09:07 AM 6 4 vaccine efficacy trials: What have we learned ? • Vaxgen gp 120 (No efficacy) – Induced weak neutralizing antibodies • STEP Merck Ad5 gag-pol-nef (No efficacy) – Cellular response but not broad and sustained – Evidence of protection against vaccine matched viral strains in vaccine recipients in vivo and in vitro • RV144 Canarypox + gp 120 (31% reduction of HIV-1 acquisition with no viral load effect) – Induced antibody responses – Correlates analysis (V2 specific region antibody binding) • HVTN 505 Ad5 gag-pol-nef and DNA ( No efficacy) - stop due to futility - No evidence of protection - (Similar results as the step and Phambili trial in 2007)
  • 07/11/13 09:07 AM 7 1.AIDS vaccine shows first efficacy in clinical trials 2.Replicating viral vector effective in controlling SIV in animal studies 3.Multiple new antibodies and targets on HIV discovered State of the HIV Vaccine field
  • 07/11/13 09:07 AM 8 Prevention of HIV: A vaccine that elicits broadly neutralizing antibodies
  • 07/11/13 09:07 AM 9 Challenges of Developing a Vaccine • Pathogen -Physical Compositions -Life Cycle •Pathogen Interactions - Nature of Infection (disease, immunity<>protection)
  • 07/11/13 09:07 AM 10 HIV Variability: The major scientific challenge for HIV vaccine Source: Weiss, R.A. (2003) Genetic variability of global influenza A virus (1996) Genetic variability of HIV-1 V2-C5 (Congo, 1996) Size = Extent of HIV variability
  • 07/11/13 09:07 AM 11 CD4 CCR5 Env trimer spike (gp120)3 (gp41)3 Host cell Virion
  • 07/11/13 09:07 AM 12 Neutralizing Antibody
  • 07/11/13 09:07 AM 13 A broadly neutralizing antibody is defined by: •Breadth: how many type of HIV (or strains) can it block? The more the better. •Potency: how well will it inhibit (the less amount of antibody needed the more potent). What are broadly neutralizing antibodies?
  • 07/11/13 09:07 AM 14 Infected individual Broadly neutralizing (protective) antibodies Ag Molecular characterization of interaction of antibody with pathogen antigen Modified antigen Immunogen design and testing Combination of several immunogens = vaccine Source: Adapted from Burton, Nat. Rev. Immunol., 2:706, 2002 * * Retrovaccinology: From antibody to antigen Vaccine volunteer
  • 07/11/13 09:07 AM 15 Targets for HIV Vaccine Design: Major Sites on HIV identified by broadly neutralizing antibodies against HIV membrane proximal domain + lipid Dual glycan, V3 (2G12, PGT 120-135) CD4 binding site (b12, VRC01, PG04, CH31) V1V2 Peptide-glycan (PG9/16, CH01) (2F5, 4E10)
  • 07/11/13 09:07 AM 16 How do we get broadly neutralizing antibodies? ANTIBODY MATURATION IN HIV INFECTION Weeks to Months Years VACCIN E Weeks to Months
  • 07/11/13 09:07 AM 17 Control of infection: A vaccine that elicits cellular immune responses
  • 07/11/13 09:07 AM 18 ∆nef-Vaccinated Single Cycle SIV (sc SIV) Live Vaccines control SIV in monkeys infection better than other approaches PlasmaViralLoad(RNAceq/mL) Weeks Post Challenge 101 102 103 104 105 106 107 108 0 10 20 30 40 50 60 Jia PLOS Pathogens 2009 No Vaccine  Live vaccines are among the most effective (measles, polio, mumps)  Live HIV vaccines will not be developed due to safety considerations  How can we mimic the efficacy of live attenuated vaccines while maintaining safety for global use ?  REPLICATING VECTORS
  • 07/11/13 09:07 AM 19 What are replicating vectors? Time post vaccinationTime post vaccination Single cycle vector (current vectors: Ad35, Ad26) Replication competent (coming vector)
  • 07/11/13 09:07 AM 20 Neutralizing Abs Cell Mediated Immunity (CMI) • Block virus entry: induction of antibody response (likely broadly neutralizing) • Block virus replication post-entry: induction of cellular response (CMI) An effective HIV vaccine will likely need to induce two “types” of immune responses
  • 07/11/13 09:07 AM 21 1. Advance current candidates through clinical trials PROOF OF CONCEPT SAFETY AND IMMUNOGENICITY EFFICACY DATA 2. Advance next generation improved vector candidates 3. Develop candidates to elicit broadly neutralizing antibodies Near term/mode rate impact Longer term/high impact Recombinant vector platform Replicating vectors HIV Envelope Goals for Research & Development MILESTONES BY 2015
  • 07/11/13 09:07 AM 22 • Ad26 + MVA (mosaic antigens) • Chimp Ad 63 + MVA HIVconsv (conserved antigens) • epDNA + IL12+ Ad35 or chAd63 • DNA + MVA (Multiple) • DNA + Tiantian-VV • Electroporated DNA • MVA (multiple) • HIV ENV trimers • Designed Immunogens • AAV –bnAb delivery •Measles virus •Attenuated VSV •Vaccinia virus Tiantan •Sendai •CMV •CDV •VSV •Pox •Adeno Improving RV- 144: CMI + non- neutralizing Ab Improving RV- 144: CMI + non- neutralizing Ab Prime Boost Candidates- improve the breadth of vaccine Prime Boost Candidates- improve the breadth of vaccine Candidates to Elicit bnAbs Candidates to Elicit bnAbs Replicating Vectors- for durable responses to mimic live attenuated Replicating Vectors- for durable responses to mimic live attenuated DNA + Ad5 (gag-pol, nef-Env A,B.C) : Phase IIb Efficacy (HVTN 505) 2009-2014 ALVAC + gp120/MF59 Licensure RSA (planned 2015) DNA + NYVAC + gp120 Test of Concept Trial NYVAC + gp120 (planned 2015) The Global HIV Vaccine Landscape - 2013 ALVAC + gp120 Licensure Trial in Thailand (planned 2015) Basic research Applied researc h Preclinical development Phase I / II Large-scale Efficacy trials
  • 07/11/13 09:07 AM 23 IAVI and Partners in 2013 Immunogen Designs to Elicit bnAbs Replicating Vectors Product Development & Clinical Trials ChAd63/MVAChAd63/MVA eOD; iVSV; JFRL, BG505 eOD; iVSV; JFRL, BG505 VSV CDV VSV CDV AAV-PG9AAV-PG9 Sendai vectorSendai vector 23
  • 07/11/13 09:07 AM 24 IAVI’s most advanced replication competent vector  Sendai virus based vector:  Replication competent vector; naturally infect mice but not pathogenic in humans  Phase-1 due to start by end of 2012 beginning of 2013 would include our partners in:  Kenya  Rwanda  UK  Prime-boost regiment with SeV(Gag) and Ad35(GRIN) vectors  Strong focus on mucosal responses with KAVI as center of excellence for mucosal immunity  Other replicating vectors in development:  Canine Distemper virus (CDV)  CMV partnership with L. Picker as part of the new Central Service Facility
  • 07/11/13 09:07 AM 25 BOO2 BOO3 BOO4 Current HIV vaccine research at KAVI-ICR
  • 07/11/13 09:07 AM 26 On-going or Just-completed Phase 1 studies at KAVI IAVI sponsored Clinical Trials IAVI B002 Ad35-GRIN + Adjuvanted Protein –Kenya, Uganda and Zambia IAVI B003 Ad35- ENV + Ad26- ENV –USA, Kenya, Rwanda and South Africa IAVI B004 DNA IL-12 EP + Ad35-GRIN/ENV –Kenya, Uganda and Rwanda
  • 07/11/13 09:07 AM 27 Summary KAVI’s Experience with Vaccine studies Study title Product [route of administration] Number of volunteers [retention] % women Study Dates Timelines (# days to enrol 1 vol) IAVI 002 DNA [IM1 ] 18 [94%] 17% 2001- 2002 4.9 IAVI 004 MVA [ID] 18 [94%] 11% 2002- 2005 8.5 IAVI 010 DNA + MVA [IM/ID] 70 [99%] 17% 2003- 2005 2.7 IAVI V001 Multi-clade DNA/Ad5 [BJ/IM] 57 [98%] 39% 2006- 2007 2.5 IAVI B002 F4co-AS01/ Ad35 [IM] 40 [100%] 28% 2011 - 2012 3.1 IAVI B003 Ad26/Ad35 [IM] 40 [100%] 33% 2011-2012 2.4 IAVI B004 DNA/Ad35[IM/EP] 25 [96%] 40% 2012-2013 1.1
  • 07/11/13 09:07 AM 28 IAVI PROTOCOL B004 Phase I double blind, randomized, placebo-controlled trial to Evaluate the Safety and Immunogenicity of a Multiantigen HIV (HIV-MAG) plasmid DNA (pDNA) Vaccine co- administered with Recombinant Human IL-12 pDNA (GENEVAX® IL-12) followed or preceded by Recombinant Ad35-GRIN/ENV HIV Vaccine in HIV-Uninfected, Healthy Volunteers
  • 07/11/13 09:07 AM 29 Fresh semen Non-invasive mucosal sampling from among volunteers enrolled in the three vaccine studies Rectal sponge Vaginal/cervical Saliva Semen Mucosal Studies: Development of immune mucosal assays
  • 07/11/13 09:07 AM 30 Vaccines can take decades to develop Measles Hepatitis B Human papilloma virus (cervical cancer) Rotavirus (diarrheal disease) Varicella zoster (chickenpox) Pertussis (whooping cough) Polio Haemophilus influenza Typhoid Malaria Human immunodeficiency virus (HIV/AIDS) INFECTIOUS AGENT (Disease) AGENT LINKED TO DISEASE IN … VACCINE LICENSED IN U.S. IN … 1953 1965 1884 1973 1953 1906 1908 1889 Early ’80s to mid-’90s 1893 1983 1963 1981 2006 2006 1995 1948 1955 1981 1989 — — YEARS ELAPSED 10 16 12-25 33 42 42 47 92 105 116 26
  • 07/11/13 09:07 AM 31 To Zero  An HIV vaccine is our best hope
  • 07/11/13 09:07 AM 32
  • 07/11/13 09:07 AM 33 Rationale for the Protein-based and Prime boost combinations IAVI PROTOCOL B002 Protein-Based Vaccines –Not limited by pre-existing immunity to vectors –When formulated with appropriate adjuvants, can elicit potent and broad-based immune responses (Antibody, CD4+ T cell responses) Recombinant Viral Vector Based Vaccines –Can elicit CD8+ T cells to HIV-1 proteins Prime-Boost (PB) vaccine regimen –Two vaccines could potentially show additive and possibly synergistic priming and boosting effect
  • 07/11/13 09:07 AM 34 What is the B003 trial? Candidate Vaccines consists of  Ad35 ENV- Recombinant replication-incompetent adenovirus serotype 35 expressing HIV-1 subtype A gp140 env gene  Ad26.ENVA.01 is a recombinant replication deficient adenovirus serotype 26 expressing HIV-1 A gp140 env gene Both vectors code for HIV-1 Clade A gp140 Env glycoprotein
  • 07/11/13 09:07 AM 35 Rationale for IAVI Protocol B003 IAVI PROTOCOL B003 Choice of Viral vectors Vector serotypes were chosen due to the low likelihood of past community exposures and pre-existing (serotype) immunity. (Ref. Dan Barouch Havard U) 76% 21% 3% 0% <16 16-200 200-1000 >1000 NAb Titers 76% 21% 3% 0% <16 16-200 200-1000 >1000 N A b T i t e r s 0% 31% 21% 48% 83% 13% 3%1% 79% 17% 4%0% 97% 2% 1% 0% 78% 21% 1%0% Ad5 Ad35 Ad26 Ad48 Ad49 Comparative Adenovirus Seroprevalence in Adults from Sub-Saharan Africa (N=200; 18-65 yrs) 81% 12% 5% 2%Ad50
  • 07/11/13 09:07 AM 36 B003 Trial Schema- Part 1 BOSTON SITE Group Vaccines N Month 0 M3 M6 A Ad26 → Ad35 13 (10/3) Ad26 - Ad35 B Ad35 → Ad26 13 Ad35 - Ad26 C Ad26 → Ad35 13 Ad26 Ad35 - D Ad35 → Ad25 13 Ad35 Ad26 - Total 52 (40/12) Evaluating o Heterologous design o Two different vaccine intervals
  • 07/11/13 09:07 AM 37 B003 Trial Schema- Part II East and South African Sites Group Vaccines N (Each grp) M0 M3 M6 E & I Ad26 → Ad26 13 (10/3) Ad26 Ad26 F & J Ad35 → Ad35 13 Ad35 Ad35 G & K Ad26 → Ad35 13 Ad26 Ad35 H & L Ad35 → Ad25 13 Ad35 Ad26 Total 104 (80/24) Evaluating o Heterologous and homologous design o One vaccine interval
  • 07/11/13 09:07 AM 38 B004 Vaccine Candidates Ad35-GRIN/ENV Vaccine consists of  Ad35-GRIN- Recombinant replication-incompetent adenovirus serotype 35 expressing HIV-1 subtype A gag, reverse transcriptase, integrase, nef genes  Ad35 ENV- Recombinant replication-incompetent adenovirus serotype 35 expressing HIV-1 subtype A gp140 env gene HIV-MAG VACCINE consists of two DNA plasmids  HIV-1 subtype B gag/pol DNA plasmid  HIV-1 subtype B nef/tat/vif, env (gp160)
  • 07/11/13 09:07 AM 39 Special Features of IAVI Protocol B004 IAVI PROTOCOL B004 GENEVAX® IL-12 pDNA (naturally occurring) as molecular adjuvant • Adjuvant: to improve the immunogenicity of DNA vaccines • HIVMAG vs HIVMAG + IL12 • 2 dosage levels of IL12 Route: Intramuscular by electroporation (IM/EP) to improve efficiency of delivery of DNA vaccine
  • 07/11/13 09:07 AM 40 Rationale for IAVI Protocol B004 IAVI PROTOCOL B004 HIV DNA Vaccines Not limited by pre-existing immunity to vectors Safe and well tolerated, BUT weakly immunogenic in humans  to improve the immunogenicity/efficiency of delivery -Adjuvants (e.g.; molecular such as IL-12) -Electroporation Recombinant Viral Vector Based Vaccines (Ad35) Elicit CD8+ and CD4+ T cells to HIV-1 antigens Ad35 tested in previous vaccine studies and safe to date Prime-Boost (PB) vaccine regimen DNA vaccines no stand-alone vaccines Improve cellular and humoral (Ab) immune responses
  • 07/11/13 09:07 AM 41 B004 Study Design Months 0, 1, 2 Month 6 Study Groups N vaccine / placebo Prime Vaccine (dosage, delivery) Boost Vaccine (dosage, delivery) 1 12/3 HIV-MAG (3,000mcg) (IM/EP*) Ad35-GRIN/ENV (2x1010 vp, IM) 2 12/3 HIV-MAG (3,000mcg) + GENEVAX® IL-12 (100mcg) (IM/EP*) Ad35-GRIN/ENV (2x1010 vp, IM) 3 12/3 HIV-MAG (3,000mcg) + GENEVAX® IL-12 (1000mcg) (IM/EP*) Ad35-GRIN/ENV (2x1010 vp, IM) Month 0 Month 4 4 12/3 HIV-MAG (3,000mcg) + GENEVAX® IL-12 (1000mcg) (IM/EP*) Ad35-GRIN/ENV (2x1010 vp, IM) 5 12/3 Ad35-GRIN/ENV (2x1010 vp, IM) HIV-MAG (3,000mcg) + GENEVAX® IL-12 (1000mcg) (IM/EP*) Total 75 (60/15) *HIVMAG +/- IL12: Each EP vaccination time point requires 2 administrations
  • 07/11/13 09:07 AM 42 42 Electroporation Mediated DNA Vaccine Delivery Intracellular delivery of DNA inducing expression of the encoded antigen by the recipient’s own cells DNA vaccine Somatic cells Endogeneous antigen production Key Considerations: • Intracellular uptake of DNA essential for antigen expression • Conventional injection of DNA results in low efficiency uptake •EP disturbs phospholipid layer of membrane causing transient increase cell membrane permeability • Enhances DNA potency by 2-3 orders of magnitude •DNA doses of up to 4.0mg (bilateral administration)
  • 07/11/13 09:07 AM 43 Electroporation Mediated DNA Vaccine Delivery
  • 07/11/13 09:07 AM 44 IAVI B002 Trial Study Design Phase I double blinded, placebo-controlled, randomized trial with F4co adjuvanted with AS01B or AS01E (1/2 strength of AS01B) administered with Ad35-GRIN (1011 vp ) in African Collaborating Research Centers • . Months N Vaccine/ Placebo 0 1 3 4 A 32/8 F4co10 ug / AS01E F4co 10 ug / AS01E Ad35-GRIN 1011 vp B 32/8 F4co 10 ug / AS01B F4co 10 ug / AS01B Ad35-GRIN 1011 vp C 32/8 Ad35-GRIN 1011 vp F4co 10 ug / AS01E F4co 10 ug / AS01E D 32/8 Ad35-GRIN 1011 vp F4co 10 ug / AS01B F4co 10 ug / AS01B vp: viral particles
  • 07/11/13 09:07 AM 45 B002 HIV vaccine Candidates Vaccine candidate: F4co/AS01 Recombinant fusion protein to target conserved regions of HIV comprised of p24-RT-Nef-p17 Adjuvant System AS01 Two immunostimulants (Glycoside from Quillaja saponaria 21 & 3-D monophosphoryl lipid A) Ad35-GRIN- Recombinant replication-incompetent adenovirus serotype 35 expressing HIV-1 subtype A gag, reverse transcriptase, integrase, nef genes F4co: Fusion protein of p24/RT/Nef and p17 (Clade B HIV-1) RT (mutation Trp464Lys) 560a.a. p24 232 a.a. p17 132 a.a. Nef 206 a.a. hinge 2 a.a. hinge 2 a.a. hinge 2 a.a.