HIVVaccine Research & Development

Prof. Omu Anzala

KAVIDepartment of Medical Microbiology

School of Medicine University of Nairobi

A DECADE OF VACCINES

What is a “Vaccine”• The term vaccine derives

from Edward Jenner's 1796 use of the term cow pox (Latin) variola vaccinæ, adapted from the Latin vaccīn-us, from vacca cow), which, when administered to humans, provided them protection against smallpox

A Decade of Vaccines

Global Commitment to:• Increase uptake of the current childhood vaccines.• Increase the use of underused vaccines • Accelerate research & development of 6 new vaccines( diarrhea & pneumonia, TB, Malaria and HIV vaccines)

Is the discovery of an HIV vaccine possible?

Basic and Epidemiology research in HIV/AIDS has been pointing to this fact.

RV144 trial in Thailand demonstrated for the first time modest protection against HIV infection.(Canary-pox-vector prime plus protein-subunit boost)

Discovery of potent and broadly neutralizing antibodies

RV 144 Study Vaccines

• ALVAC®-HIV (vCP1521) • Recombinant canarypox vector vaccine genetically

engineered to express HIV-1 gp120 (subtype E: 92TH023) linked to the transmembrane anchoring portion of gp41 (subtype B: LAI), and HIV-1 gag and protease (subtype B: LAI).

• AIDSVAX® B/E• Bivalent HIV gp120 envelope glycoprotein vaccine

containing a subtype E envelope from the HIV-1 strain CM244 and a subtype B envelope from the HIV-1 strain MN.

RV 144 The Analyses

• - the intention-to-treat and per-protocol analyses,

• showed vaccine efficacies of 26.4% (P = 0.08)• and 26.2% (P = 0.16), respectively. • a possible, albeit modest,protection

TARGET CELLEFFECTOR CELL

antigen

antibody

Fcreceptors (CD16, CD32, CD64)

granules

TARGET CELLEFFECTOR CELL

antigen

antibody

Fcreceptors (CD16, CD32, CD64)

granules

The ADCC mechanism: bridging the gap between innate and adaptive immunity

New and exciting discovery• Broadly neutralizing antibodies.• Revealed vulnerable targets on the virus that

are now being exploited for vaccine design.

CD4bs“b12”

MPER“2F5” and

4E10”

Glycan shield

“2G12”Cell Membrane

V3

Viral Membrane

gp41

gp120

CD4

Wyatt and Sodroski Science 1998Huang et al Science 2005Phogat, Wyatt Curr Pharm Design 2007

CCR5 target

Antibody Attack on Targets: What we knew and what’s NEW

“Trimer”“PG9” and “PG16”

NEW

HIV Life Cycle & Vaccine Design

Cell Mediated Immunity

Neutralizing Antibodies

HIV Vaccine Clinical ResearchIAVI 002(2001)

IAVI 004(2002)

IAVI 008(Roll over)

IAVI 010(2003)

V001(2006)

Candidate vaccine

DNA MVA DNA+MVA DNA+MVA Multi-cladeDNA/Ad5

Sample Size 18 18 10 70 57

Enrolled 15:3(M:F)

16:2(M:F)

10 58:12(M:F)

36:21(M:F)

Recruitment rate (no/month)

4.5 4.5 10 12 14

Retention rate

94.4%(17/18)

94.4%(17/18)

100% 98.6%(69/70)

98.2%(56/57)

Vaccine Research On going Vaccine trials at KAVI

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Ongoing Phase 1 clinical trialsPaedVac • Funded by EDCTP• MVA + EPI vaccination vs EPI vaccination (alone)• Safety, immunogenicity & interference with EPI

vaccines• Infants vaccinated at 20 weeks - single IM injection• Immunogenicity - ELISPOT & Cultured ELISPOT• Gambia trial over (48 infants) - data being analyzed• Nairobi trial (63/72 infants randomized)• Both sites, no vaccine related SAE• Immunogenicity data not yet out• Antibody titres to EPI being conducted

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Ongoing Phase 1 clinical trialsProtocol B002• Recombinant Fusion protein (F4co) in adjuvant

(ASO1B or ASO1E) + replication incompetent Ad35-GRIN

• F4co [p24-RT-Nef-p17 of HIV-1clade B Gag, Pol, Nef)]• Ad35-GRIN [with HIV-1 clade A gag, RT, integrase, nef)• Phase 1, double blind, randomized placebo controlled • 140 participants (112 vaccine/28 placebo)• Ages 18-40 yrs• Low risk, healthy, HIV –ve, Ad35 antibodies -ve• Multisite study – Kenya, Uganda, Zambia

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Ongoing Phase 1 clinical trialsProtocol B003

Different combinations of recombinant Ad26 vector & recombinant Ad35 (HIV-1 sub-type A env gene)

Heterologous or homologous 212 to be enrolled Multi-centre – Boston (USA), Rwanda, S/Africa KAVI-Kangemi recruiting Screened 85 Enrolled 34

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What are the challenges• The virus impairs the immune systems• Viral diversity • The correlates of immunity or protection not fully

Mechanism of ActionVaccines:

Death Exposure Infection Disease

Recovery

Balancing safety and efficacy in HIV vaccine design

The Questions ??

Would an HIV vaccine be useful if it was less than 100% effective?

Would a vaccine still be needed if current prevention programs and antiretroviral therapy (ART) are significantly expanded while the vaccine is still being developed?

Would a vaccine result in cost-savings?

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

28