1. HIV Vaccine Research & Development
Prof. Omu Anzala
KAVI
Department of Medical Microbiology
School of Medicine
University of Nairobi

2. A DECADE OF VACCINES

3. 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

4. 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)

5. 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

6. 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.
The vaccine regimen consisted of two components. The prime, ALVAC-HIV, is a recombinant canarypox vector expressing HIV-1 gp120 subtype E linked to gp41, as well as HIV-1 gag and protease subtype B. The boost, AIDSVAX B/E, is a bivalent HIV-1 gp120 envelope glycoprotein containing both subtype B and E components. 6

7. 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

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

9. New and exciting discovery
Broadly neutralizing antibodies.
Revealed vulnerable targets on the virus that are now being exploited for
vaccine design.

10. Antibody Attack on Targets: What we knew and what’s NEW
Viral Membrane
CD4bs
“b12”
MPER
“2F5” and 4E10”
Glycan
shield
“2G12”
NEW
gp41
gp120
“Trimer”
“PG9” and “PG16” V3
CD4
CCR5
target
Wyatt and Sodroski Science 1998
Huang et al Science 2005
Phogat, Wyatt Curr Pharm Design
Cell Membrane 10

11. HIV Life Cycle & Vaccine Design
Cell Mediated
Immunity
Neutralizing Antibodies

12. HIV Vaccine Clinical Research
IAVI 002
(2001)
IAVI 004
(2002)
IAVI 008
(Roll over)
IAVI 010
(2003)
V001
(2006)
Candidate vaccine
DNA
MVA
DNA+MVA
Multi-clade
DNA/Ad5
Sample Size 18 10 70 57
Enrolled
15:3
(M:F)
16:2
58:12
36:21
Recruitment rate (no/month)
4.5 12 14
Retention rate
94.4%
(17/18)
100%
98.6%
(69/70)
98.2%
(56/57)

13. Vaccine Research
On going Vaccine trials at KAVI

14. Ongoing Phase 1 clinical trials
PaedVac
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

15. Ongoing Phase 1 clinical trials
Protocol 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 yrs
Low risk, healthy, HIV –ve, Ad35 antibodies -ve
Multisite study – Kenya, Uganda, Zambia

16. Ongoing Phase 1 clinical trials
Protocol 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

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

18. Vaccines: Death Exposure Infection Disease Recovery
Mechanism of Action
Vaccines:
Death
Exposure Infection Disease
Recovery

19. Balancing safety and efficacy in HIV vaccine design

20. Would an HIV vaccine be useful if it was less than 100% effective?
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?
The study aimed at answering the following three questions:
Would a 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?

21. Vaccines can take decades to develop
INFECTIOUS AGENT (Disease)
AGENT LINKED TO DISEASE IN …
VACCINE LICENSED IN U.S. IN …
YEARS ELAPSED 10 16
12-25 33 42 47 92
105
116 28
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)
1953
1963
1965
1981
Early ’80s to mid-’90s
2006
1973
2006
1953
1995
1906
1948
1908
1955
1889
1981
1884
1989
1893 —
1983 —