HIV Vaccine Research & Development Prof. Omu Anzala KAVI Department 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. 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

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

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.

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 2007 Cell Membrane 10

HIV Life Cycle & Vaccine Design Cell Mediated Immunity Neutralizing Antibodies

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)

Vaccine Research On going Vaccine trials at KAVI

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

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 18-40 yrs Low risk, healthy, HIV –ve, Ad35 antibodies -ve Multisite study – Kenya, Uganda, Zambia

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

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

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

Balancing safety and efficacy in HIV vaccine design

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?

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 —