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KAVI-INSTITUTE OF CLINICAL RESEARCH
(KAVI-ICR)
UNIVERSITY OF NAIROBI
Prof .Omu Anzala
Update: HIV Vaccine Research
04/11/23 10:17 PM 2
OUT LINE OF PRESENTATION
• Introduction
• Current global position
• Current science in vaccine development
04/11/23 10:17 PM 3
PrEP
Clean injecting equipment
Cervical barriers: vaginal diaphragms
Prevention of
vertical transmission
Vaccines
Voluntary counselling and
testing
MicrobicidesTreatment
as prevention
Male circumcision
PEP
Comprehensive HIV prevention
Male and female condoms
ARV
04/11/23 10:17 PM 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
04/11/23 10:17 PM 5
Public sector, academia
Pharmaceutical companies,product-development
partnerships
Research & Development :
Basicresearch
Appliedresearch
Preclinicaldevelopment
Clinicaldevelopment
Advanceddevelopment
Large-scaleEfficacy trials
R&D R&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
04/11/23 10:17 PM 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)
04/11/23 10:17 PM 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
04/11/23 10:17 PM 8
Prevention of HIV:
A vaccine that elicits broadly neutralizing antibodies
04/11/23 10:17 PM 9
Challenges of Developing a Vaccine
• Pathogen -Physical Compositions
-Life Cycle
•Pathogen Interactions - Nature of Infection
(disease, immunity<>protection)
04/11/23 10:17 PM 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 ofHIV-1 V2-C5(Congo, 1996)
Size = Extent of HIV variability
04/11/23 10:17 PM 11
CD4
CCR5
Env trimer spike(gp120)3 (gp41)3
Host cell
Virion
04/11/23 10:17 PM 12
Neutralizing Antibody
04/11/23 10:17 PM 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?
04/11/23 10:17 PM 14
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
**
Retrovaccinology: From antibody to antigen
Vaccine volunteer
04/11/23 10:17 PM 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)
V1V2Peptide-glycan(PG9/16, CH01)
(2F5, 4E10)
04/11/23 10:17 PM 16
How do we get broadly neutralizing antibodies?
ANTIBODY MATURATION IN HIV INFECTION
Weeks to Months
Years
VACCINE
Weeks to Months
04/11/23 10:17 PM 17
Control of infection:
A vaccine that elicits cellular immune responses
04/11/23 10:17 PM 18
∆nef-Vaccinated
Single Cycle SIV (sc SIV)
Live Vaccines control SIV in monkeys infection better than other approaches
Pla
sma
Vir
al L
oad
(R
NA
ceq
/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
04/11/23 10:17 PM 19
What are replicating vectors?
Time post vaccinationTime post vaccination
Single cycle vector (current vectors: Ad35, Ad26)
Replication competent (coming vector)
04/11/23 10:17 PM 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
04/11/23 10:17 PM 21
1. Advance current
candidates through clinical
trials
PROOFOF CONCEPT
SAFETY AND IMMUNOGENICITY
EFFICACYDATA
2. Advance next generation
improved vector candidates
3. Develop candidates to elicit broadly
neutralizing antibodies
Near term/mode
rateimpact
Longer term/high
impact
Recombinant vector platform
Replicating vectors
HIV Envelope
Goals for Research & Development
MILESTONES BY 2015
04/11/23 10:17 PM 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 TrialNYVAC + gp120 (planned 2015)
The Global HIV Vaccine Landscape - 2013
ALVAC + gp120 Licensure Trial in Thailand (planned 2015)
Basicresearch
Appliedresearch
Preclinicaldevelopment Phase I / II Large-scale Efficacy
trials
22
04/11/23 10:17 PM 23
IAVI and Partners in 2013
Immunogen Designs to Elicit bnAbs
Replicating Vectors
Product Development & Clinical Trials
ChAd63/MVAChAd63/MVA
eOD; iVSV; JFRL, BG505eOD; iVSV; JFRL, BG505
VSV CDV VSV CDV
AAV-PG9AAV-PG9
Sendai vectorSendai vector
23
04/11/23 10:17 PM 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
04/11/23 10:17 PM 25
BOO2BOO3BOO4
Current HIV vaccine research at KAVI-ICR
04/11/23 10:17 PM 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
04/11/23 10:17 PM 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
04/11/23 10:17 PM 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
04/11/23 10:17 PM 29
Fresh semen
Non-invasive mucosal sampling from among volunteers enrolled in the three vaccine studies
Rectal spongeVaginal/cervicalSalivaSemen
Mucosal Studies: Development of immune mucosal assays
04/11/23 10:17 PM 30
,z
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 LINKEDTO DISEASE IN …
VACCINE LICENSEDIN U.S. IN …
1953
1965
1884
1973
1953
1906
1908
1889
Early ’80sto mid-’90s
1893
1983
1963
1981
2006
2006
1995
1948
1955
1981
1989
—
—
YEARSELAPSED
10
16
12-25
33
42
42
47
92
105
116
26
04/11/23 10:17 PM 31
To Zero
An HIV vaccine is our best hope
04/11/23 10:17 PM 32
04/11/23 10:17 PM 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
04/11/23 10:17 PM 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
04/11/23 10:17 PM 35
Rationale for IAVI Protocol B003
IAVI PROTOCOL B003
Choice of Viral vectorsVector 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
04/11/23 10:17 PM 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
04/11/23 10:17 PM 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
04/11/23 10:17 PM 38
B004 Vaccine Candidates
Ad35-GRIN/ENV Vaccine consists ofAd35-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 plasmidHIV-1 subtype B nef/tat/vif, env (gp160)
04/11/23 10:17 PM 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
04/11/23 10:17 PM 40
Rationale for IAVI Protocol B004
IAVI PROTOCOL B004
HIV DNA VaccinesNot limited by pre-existing immunity to vectorsSafe 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 antigensAd35 tested in previous vaccine studies and safe to date
Prime-Boost (PB) vaccine regimenDNA vaccines no stand-alone vaccines Improve cellular and humoral (Ab) immune responses
04/11/23 10:17 PM 41
B004 Study Design
Months 0, 1, 2 Month 6
Study GroupsN
vaccine / placeboPrime Vaccine
(dosage, delivery)Boost Vaccine
(dosage, delivery)
1 12/3 HIV-MAG(3,000mcg) (IM/EP*)
Ad35-GRIN/ENV (2x1010vp, 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
04/11/23 10:17 PM 4242
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)
04/11/23 10:17 PM 43
Electroporation Mediated DNA Vaccine Delivery
04/11/23 10:17 PM 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/
Placebo0 1 3 4
A 32/8F4co10 ug
/ AS01EF4co 10 ug / AS01E
Ad35-GRIN 1011 vp
B 32/8F4co 10 ug / AS01B
F4co 10 ug / AS01B
Ad35-GRIN 1011 vp
C 32/8Ad35-GRIN 1011 vp F4co 10 ug
/ AS01EF4co 10 ug / AS01E
D 32/8Ad35-GRIN 1011 vp F4co 10
ug / AS01BF4co 10 ug
/ AS01B
vp: viral particles
04/11/23 10:17 PM 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.
p24232 a.a.
p17132 a.a.
Nef206 a.a.
hinge
2 a.a.
hinge
2 a.a.
hinge
2 a.a.