EDCTP Third Forum

PARTNERSHIP AND AFRICAN LEADERSHIP IN VACCINE RESEARCH AND

HIV/AIDS DRUG MBOUP Souleymane

HIV VACCINE IN AFRICA• In 2005, 13 new trials of preventive AIDS vaccine

candidates began in 9 countries around the world. • Two of these involved vaccine candidates that

entered Phase II trials, an intermediate stage of clinical evaluation.

• Several of those newly initiated trials involved novel vaccination strategies

• Participation by Africa in those trials is continuously increasing with

• Rwanda started its first AIDS vaccine and South Africa began the country’s first Phase II AIDS vaccine trial

PROGRESS IN NUMBER OF COUNTRIES PARTICIPATING IN VACCINE TRIALS

2000 2006

1 country 8 countries participating in vaccine trials

CLINICAL TRIAL SITES IN AFRICA PARTICIPATING CLINICAL TRIAL SITES IN AFRICA PARTICIPATING IN HIV VACCINE TRIALSIN HIV VACCINE TRIALS

Cape Town, SA Durban, SASoweto, SA

Gabarone, BotswanaBlantyre, Malawi

KOSH,SA

Dar es Salaam, Tanzania

Entebbe, UgandaMasaka, Uganda

Kericho, KenyaKilifi, KenyaKisumu, Kenya

Kampala, Uganda

Nairobi, Kenya

Lusaka, Zambia Mbeya, Tanzania

Kigali, Rwanda

Medunsa,SA

Kayunga, UgandaMulago, Uganda

ActivePending

PROGRESS IN NUMBER OF COUNTRIES PARTICIPATING IN VACCINE TRIALS

2000 2006

Countries currently involved in vaccine trials

Countries preparing for vaccine trials

COMPLETED TRIALS IN AFRICA*COMPLETED TRIALS IN AFRICA*

*follow-up still ongoing

Phase Trial Name/ Sponsor

Country Status

ALVAC205 (Pasteur Merieux): Gag, pol, env (Subtype B)

Phase I(40)

DAIDS Uganda Complete

DNA Plasmid (Polyepitope Pharmexa – Epimmune): Polyepitope

Phase I (42) HVTN/DAIDS Botswana Complete

DNA MVA (Oxford / IAVI): Gag, polyepitope (Subtypes A)

Phase II (238) IAVI Kenya, Uganda, South Africa Complete

VEE Replicon (AlphaVax): Gag (Subtype C)Phase I (88) HVTN/DAIDS South Africa, Botswana Complete

Ad 5 (Merck): Gag (Subtype B)Phase II (120) HVTN/DAIDS South Africa, Malawi Complete

PREVENTIVE VACCINE CONCEPTSPREVENTIVE VACCINE CONCEPTSIN TRIAL IN AFRICAIN TRIAL IN AFRICA

Phase Trial Name/ Sponsor

Country Status

Adeno Associated (TG, IAVI): Gag-Pr-RT (Subtype C)

Phase II (90) IAVI Uganda, Zambia, South Africa Enrolling

DNA prime/ Ad5 boost (VRC): Gag, Pol, Nef, Env (Subtypes A,B,C)

Phase II (114) IAVI V001, VRC/DAIDS

Rwanda, Kenya Enrolling

Phase II (240) HVTN 204, VRC/ DAIDS

South Africa Enrolling

Phase II (324) RV172,WRAIR VRC/DAIDS

Uganda, Kenya, Tanzania Enrolling

PREVENTIVE VACCINE CONCEPTSPREVENTIVE VACCINE CONCEPTSIN TRIAL IN AFRICAIN TRIAL IN AFRICA

Phase Trial Name/ Sponsor

Country Status

Ad5 (Merck): Gag-Pol-Nef (Subtype B)

IIb (3000) HVTN503,Merck/DAIDS

South Africa Pending

DNA, MVA: Gag, RT, env, pol (Subtype A, E)II (60) SIIDC,

Karolinska, EU,Sida/SARE

C

Tanzania Pending

ALVAC-HIV vCP1521: Gag, Pro, Env (Subtype B, E)

I (50)Perinatal

HPTN027/DAIDS

Uganda Pending

FIRST “TEST OF CONCEPT TRIAL”IN AFRICA (Q4 2006):

MRKAd5 Trivalent Vaccine

ITRL ITRRgaghCMV

ψpA

MRKAd5 HIV-1 gag

ITRL ITRRpolhCMV

ψpA

MRKAd5 HIV-1 pol

ITRL ITRRnefhCMV

ψpA

ΔE1

MRKAd5 HIV-1 nef

1:1:1 mixing of 3 vectors

G. Gray, PHRU, SA

FIRST “TEST OF CONCEPT TRIAL”: HVTN 503

Will subtype B vaccine be efficacious against subtype C heterosexual infection

Markedly enhance the information on efficacy in women

Refine the assessment of the impact of pre-existing Ad5 titers

More than double the number of endpoints to enhance the evaluation of correlates of protection.

A South African Study to test subtype B vaccine (Ad5 gag, pol, nef) in subtype C region (similar to STEP HVTN502 in MSM in USA):

Adapted from G. Gray, PHRU, Soweto

VRC DNA PRIME RAD5 BOOST

Currently largest trial concept being tested in Africa

Enrolling into 3 trials /6 countries in Africa >600 participants

Involving 3 major vaccine initiatives /networks. – HIV Vaccine Trials Network (HVTN)– US Military HIV Research Program (USMHRP) – International AIDS Vaccine Initiative (IAVI)

PAVE 100 (in planning fo 2007/8) will be next proof of concept trial in Africa planning to enrol ~12,000 globally and ~8,000 in Africa

THERAPEUTIC VACCINE CONCEPTS THERAPEUTIC VACCINE CONCEPTS IN TRIAL IN AFRICAIN TRIAL IN AFRICA

Phase Sponsor Country Status

DNA Plasmid: Tat, rev, nef, gag, pol, env (Subtype B)

Phase II (60) FIT Biotech South Africa Enrolling

Tat Protein: (Subtypes B)

Phase II (60) AVIP /ISS South Africa Enrolling

E. Vardus, PHRU, SA

PLANNED VACCINE TRIALS

PAVE 100: DNA /Ad5; ~12 000 participants; 8 000 in Africa; multiple sites; multiple partners.

Mrk Ad5: Adolescent trial in SA (HVTN/DAIDS)

SAAVI DNA /MVA: Phase I trial in SA (SAAVI / HVTN /DAIDS)

EuroVac (NYVAC)

Chiron (Subtype C Env)

Tat Vaccine (AVIP /ISS)

50 volunteers1 country

20002000

400 volunteers8 countries15 trial sites

> 4 000 volunteers? 12 countries

20062006

INCREASING PARTICIPATION BY AFRICAINCREASING PARTICIPATION BY AFRICA

20082008

>10 000 volunteers

20102010

SCIENTIFIC CHALLENGES SPECIFIC TO AFRICA

Vaccine Pipeline is too narrow

Pre-existing immunity to vaccine vector

Genetic Diversity

Osmanov, pers. comm

« ARV therapy in sub saharan Africa : -Complicated combination regimens-Expensive and dangerous-Severe side effects-Rapid development of drug resistancein the community».

Instead of promoting expensive anddangerous ARV therapies…PREVENTION »

Lancet,1998

SHORT TERM EVALUATION ON SHORT TERM EVALUATION ON THE FIRST 175 PATIENTSTHE FIRST 175 PATIENTS

•• VirologicalVirological and and immunologicalimmunological resultsresults similarsimilarto Western countriesto Western countries

•• Excellent Excellent AdherenceAdherence

•• Good Good AccessibiltyAccessibilty and and AcceptabilityAcceptability

CLINICAL TRIALS IN AFRICA• Access to ARV for HIV-infected individuals in

resource-poor settings

• Efficacy ?

• Safety ?

• Adherence ?

• Potent, safe, inexpensive simplified regimen

R.LANDMAN1, R.SCHIEMANN1, S.THIAM2, A.CANESTRI1, M.VRAY4, C.DALBAN4 E. DELAPORTE3, S. MBOUP2, PS. SOW2, MA. FAYE NIANG2, PM. GUEYE2, G. PIEL4, G. PEYTAVIN 1, S. BADIANE2 , PM. GIRARD1, JP. COULAUD1, I. NDOYE2 , AIDS 2003

Once a day DDI/3TC/EFV regimen Once a day DDI/3TC/EFV regimen

in treatmentin treatment

naive HIVnaive HIV--1 infected adults in Senegal 1 infected adults in Senegal

ANRS 12ANRS 12--04 / IMEA 011 study (1999)04 / IMEA 011 study (1999)

-3,2-3,5 -3,5 -3,5

146 142184 199

0

-5

-4

-3

-2

-1

0

1

2

3

4

5

3 months 6 months 12 months 15 months

ΔVL log10 copies/m

l

-300

-200

-100

0

100

200

300

ΔC

D4 cells/m

m3

Evolution Evolution fromfrom baselinebaseline of viral of viral loadload and CD4 countand CD4 count

Once a day HAART regimen in treatment naive HIVOnce a day HAART regimen in treatment naive HIV--1 1 infected adults in Senegal infected adults in Senegal

ANRS 12ANRS 12--04 / IMEA 011 study04 / IMEA 011 study

HIV and non HIV pathologies 1212--04 / IMEA 01104 / IMEA 011

05

1015202530354045

J0 S2 M1 M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12

% Path VIH % Path non VIH

1. First trial in Africa of a simplified regimen

2. effective through treatment period among severely immuno-compromised individuals in resource-poor settings

3. ARV clinical trial in resource-poor settings feasible

4. Introduction et validation of new ARV Drug in SENEGAL

CLINICAL TRIALS in Africa

ONGOING TRIAL

• ANRS 1207/IMEA 025:

Once a dayTenofovir/Emtricitabine/Efavirenz

regimen (3 pills)

Viral loadANRS 1207/IMEA 025

-2,8-3,6

-3,6

-5-4-3-2-101

Série1 0 -2,8 -3,6 -3,6

JO (N=40) M1 (N=39) M3 (N=37) M6 (N=32)

Preliminary results : ANRS 1207/IMEA 025

• Good virological and immunological efficacy• Good adherence to treatment

• More simplified regimen

2 daily pillsTruvada (TDF/FTC)+EFV

1 daily pillTDF/FTC/EFV)

ATRIPLA® : TDF+FTC+EFV 1 daily pillATRIPLA® : TDF+FTC+EFV 1 daily pill

Mathias A., IAC 2006, Abs. TUPE0098

TRUVADA® SUSTIVA® ATRIPLA®+ =

ResearchResearch ClinicalClinical Center, Center, FannFann

HIV LABORATORIES AT LE DANTEC

HIV LABORATORIES AT LE DANTEC

CONCLUSION (1)

Increased African participation in vaccine trials

Increased funding to address scientific questions

Increased partnerships to accelerate the field

Increased success rate at an accelerated pace(Results of first IIb trials in Africa still 3 - 5 years)

CONCLUSION (2)

• ARV scaling up in developing countries• Host, viral,environmental factors (

logistical, operational etc..)• Affordable second line regimen required• Need of incresing African participation in

ARV clinical trials• Impact in developing and developed

countries

ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

WILLIAMSON CDELAPORTE ESOW SALIF