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New developments in the search for an HIV/AIDS vaccine
Medical Research Council (MRC UK)Uganda Virus Research Institute (UVRI)
Pontiano KaleebuUVRI
Uganda Virus Research Institute
Summary1. The need for a vaccine2. The types of vaccines3. On-going trials4. Three exciting advances in vaccine
research– How RV 144 trial is advancing vaccine research– Advancing broadly neutralizing antibodies to
vaccine design– Highly protective vaccines in NHP
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45k
35k
25k
15k
2010 2015 2020 2025 2030 2035
30,685
18,892
14,440
3,2115k
New prevention technologies will reduce HIV incidence… but only a vaccine will end the epidemic
38%
53%
90%
Source: Imperial College and BMGF, 2010. *Assumed efficacy of 60% and uptake of 50%
Microbicides/PrEP
Vaccine*
Scaled Interventions
Status Quo
Ann
ual N
ew H
IV In
fect
ions
Rural Zimbabwe
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Long term goals for a prophylactic AIDS vaccine
Primary– Prevent the
establishment of persistent HIV infection
Secondary– Control HIV infection/
progression to AIDS
Tertiary– Reduce HIV
transmission (public health vaccine)
Cell Mediated Immunity
Neutralizing Antibodies
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Antigens for induction Neutralizing antibody
First candidatevaccines
Recombinant proteins
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DNA: Naked, replicon, adjuvants (CMI)
Type of Vaccine
Second approach
Viral vectors:Canarypox, Adeno5, MVA, AAV (CMI)
Brief History of HIV Vaccines
87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13
gp160/gp120 subunits
Poxvirus vector + protein
rAd5-gag/pol/nef
DNA/rAd5-Env/gag/pol/nef
Rela
tive
focu
s on
vac
cine
eff
ecto
r mec
hani
sms
CD8 T cells
Antibody
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On-going trials-IAVI report Oct 2012
Globally: 36 phase I/IIa and one IIb efficacy trial• 19 of these USA• Most prime-boost - DNA + Viral vector (Pox
and Adeno)Pox mostly MVA; various adeno, 5,26, 35 etc)
• Improved DNA delivery e.g electroporation
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Title Phase Strategy Product Organizer/Developer Country073E/SAAVI 102 I Protein Sub C gp140 SAAVI, HVTN South AfricaHVTN 073 I DNA/Viral Vector-
PoxSAAVI DNA-C2/SAAVI MVA-C
HVTN South Africa, USA
HVTN 086, SAAVI 103
I Viral Vector Pox/DNA/Protein
SAAVI MVA-C/SAAVI DNA-C2/Oligomeric gp140/MF59
SAAVI, HVTN South Africa
IAVI B002 I Protein/Protein/Viral Vector-Adeno
Adjuvanted GSK products and Ad35-GRIN
IAVI Kenya, Uganda, Zambia
IAVI B003 I Viral Vector-Adeno/Viral-Adeno
Ad26, EnvA01-Ad35-ENV
IAVI Kenya, Rwanda, South Africa, USA
IAVI B004 I DNA/Viral Vector-Adeno
HIV-MAG/Ad35-GRIN/ENV
IAVI Kenya, Rwanda, Uganda
PedVacc001 and PedVacc002
I Viral Vector Pox MVA.HIVA Oxford University Gambia, Kenya
RV262 I DNA/Viral Vector-Pox Pennvax-G/MVA-CMDR
USA DoD Kenya, Tanzania, Uganda, USA
TAMOVAC-01MZ I DNA/Viral Vector-Pox HIVIS-DNA/MVA-CMDR
Karolinska, USA DoD Mozambique
HIVS06 I/II DNA/Viral Vector-Pox HIVIS-DNA/MVA-CMDR
Karolinska, USA DoD Tanzania
On-going trials in Africa IAVI report by October 2012
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RV144 Trial- Renewed hope
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Case Control Study
1. Measured immune responses from:• 41 Infected Vaccinees• 205 Uninfected Vaccinees• 40 Placebo Recipients
Question: What are the immunologic measurements in vaccinees that predict HIV-1 infection over 3 year follow-up?
• Sample Time point: Peak Immunogenicity (2 weeks after final vaccination) • Cryopreserved specimens
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Two Correlates of Infection Risk Found (Haynes, NEJM 366: 1275, 2012)
1. IgG antibodies that bind to a V1V2 recombinant fusion protein correlated inversely with infection rate. (Higher V1V2, lower infection rate)
2. Env binding plasma (monomeric) IgA correlated directly with infection rate. (Higher IgA to Env, higher infection rate).
CH58 CH59 PG9
Jason McLellan, Peter Kwong
Plans to move RV144 forwardPox-Protein Public-Private Partnership (P5)Seeks to advance and ultimately licence HIV pox-protein vaccine candidatesPlans:
1) Improving the vaccine regimen2) Conduct other trialsRV 305 trial in Thailand- evaluating re-boosting of volunteers who participated in RV144Other trials in Thailand and S. Africa
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Infected individual Broadly neutralizing (protective) antibodies
Ag
Molecular characterizationof interaction of
antibodywith pathogen antigen
Modified antigen
Immunogen designand testing
Combination of several immunogens
= vaccine
Source: Adapted from Burton, Nat. Rev. Immunol., 2:706, 2002
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Retrovaccinology: From antibody to antigen
Vaccine volunteer
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An innovative approach: Passive Immunity
THE FINDMultiple broadly neutralizing antibodies against HIV
THE GOALElicit those antibodies through vaccination
INTERIM STEPSProve concept through …
Passive immunizationby injecting antibodies
Gene transfer through a vector that produces the antibodies
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Progress
1. AAV 1 vector expressing gene for PG9 antibody has been developed (IAVI and NIAID) will be tested in phase 1 soon
2. Passive immunotherapy infants- GHVI consultative workshop using VRC01 held 22-23 Jan 2013-Entebbe
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Correlates of protection against acquisition of infection and virological control with Adeno/pox vaccines
1. T cell responses to gag (core proteins)
2. Antibodies to V2
Trial design challenges
1. Future efficacy trials- large and expensive– Kublin J. et al It will require 5100 volunteers in S. Africa
at 20 sites to observe a 50% efficacy with 4% incidence in a setting of male circumcision, increased ART uptake, possible PreP
– Most cohorts have much lower incidence
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We need to continue to support HIV vaccine research
and development
24Major International funders of HIV Vaccine Research and development in Uganda
Conclusion
1. There is some progress in understanding correlates of risk and mechanisms in RV144 relevant for vaccine design
2. There is progress in moving bNab to vaccine design
3. Optimised HIV vaccines can block acquisition in heterologous neutralization resistant SHIV in NHP
4. Future efficacy trials will be more complicated and expensive to design 25
Thank you
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