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

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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

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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

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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)

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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

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Prevention of HIV:

A vaccine that elicits broadly neutralizing antibodies

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Challenges of Developing a Vaccine

• Pathogen -Physical Compositions

-Life Cycle

•Pathogen Interactions - Nature of Infection

(disease, immunity<>protection)

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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

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CD4

CCR5

Env trimer spike(gp120)3 (gp41)3

Host cell

Virion

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Neutralizing Antibody

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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?

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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

**

Retrovaccinology: From antibody to antigen

Vaccine volunteer

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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)

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How do we get broadly neutralizing antibodies?

ANTIBODY MATURATION IN HIV INFECTION

Weeks to Months

Years

VACCINE

Weeks to Months

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Control of infection:

A vaccine that elicits cellular immune responses

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∆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

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What are replicating vectors?

Time post vaccinationTime post vaccination

Single cycle vector (current vectors: Ad35, Ad26)

Replication competent (coming vector)

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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

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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

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• 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

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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

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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

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BOO2BOO3BOO4

Current HIV vaccine research at KAVI-ICR

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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

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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

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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

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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

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,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

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To Zero

An HIV vaccine is our best hope

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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Electroporation Mediated DNA Vaccine Delivery

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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.