Progress and Challenges for Developing an AIDS Vaccine

Dr Simon Noble Editor, IAVI Report and VAX, International AIDS Vaccine Initiative

The World Needs an AIDS Vaccine……
Over 70 million HIV infections Over 28 million AIDS deaths 39.5 million currently living with HIV/AIDS 11,000 new infections daily, 95% in developing world A comprehensive response: Short term Prevent further spread of the virus Treat those already infected Mitigate social impacts Long term Create the tools necessary to end the epidemic (drugs, diagnostics, vaccines, microbicides)

Source: UNAIDS 2004 Photos: WHO/UNAIDS

Why An AIDS Vaccine?
HIV/AIDS pandemic requires a comprehensive response PREVENTION must be a significant part of that response For each person who starts antiretroviral treatment, at least six people are newly infected with HIV (2006 – 4.3 million new infections - 650,000 newly on ARVs) Current prevention methods are insufficient to end the epidemic Current treatment programs are not sustainable Only an AIDS vaccine can end the epidemic; only historically proven tools to end viral epidemics

What is a vaccine?
A vaccine is a substance that stimulates an immune response that can either prevent an infection or create resistance to an infection It is important to note, no vaccine is 100% effective. In fact, most vaccines are between 70% - 95% effective HERD IMMUNITY

How An AIDS Vaccine Would Work

For people not infected with HIV To elicit immune responses To prevent HIV infection or progression to AIDS

The Ideal Vaccine
One dose, low cost Safe and highly effective Protective in all circumstances

Candidate vaccines are made from synthetic pieces of HIV only Cannot cause HIV infection or AIDS

AIDS Vaccine Development: Scientific Challenges
HIV integrates into the host cell genome – persistent infection, short window of opportunity before integration HIV infects, suppresses, and destroys key cells of the immune system HIV antigens required for protection remain undefined Natural immune responses do not eradicate HIV; Limitations in the animal models for HIV/AIDS; correlates of protective immunity remain undefined HIV isolates worldwide are hypervariable AIDS vaccine efficacy trials very complex and long (4-5 years)

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The Impact Of A Vaccine Could Be Huge
New adult HIV infections in low- and middle-income countries by year and vaccine scenario
4,500,000

4,000,000

3,500,000

Vaccine introduction

Base

3,000,000

Total new infections averted by an AIDS vaccine between 2015-2030

2,500,000 Low effective coverage 2,000,000

30% efficacy, 20% coverage 50% efficacy, 30% coverage 70% efficacy, 40% coverage

5.5 million

1,500,000 Medium effective coverage 1,000,000

17 million

500,000

High effective coverage

0 2000 2005 2010 2015 2020 2025 2030

28 million

Source: Stover 2006. IAVI and the Futures Group

Vaccine R&D
Basic research to identify concepts Applied research to design candidates Preclinical tests in animals Clinical trials in humans Process engineering

The Classical Trial Paradigm
# Volunteers Phase I Phase II Safety Immune responses (and more safety) Dozens Hundreds

Phase IIB and III

Efficacy (and more safety)

Thousands

An AIDS Vaccine is Possible Human immune system can control HIV infection for many years (>10) ‘Elite controllers’ are extreme example Rare individuals are naturally resistant to HIV infection (Exposed Seronegatives) Experimental vaccines have protected monkeys Human antibodies can prevent infection in monkeys

Recent progress towards an AIDS vaccine

Where Does The Global R&D Effort Stand?
Advances
More candidates in the pipeline… More countries and scientists are involved…

Limitations
…yet only one fully tested for efficacy, all candidates focused on one hypothesis = cellular immunity …but response is still insufficient in some countries and from industry …yet we need to invest in their capacity to stay the course over the long run …but scientific challenges remain a major impediment to progress

Developing countries are becoming more active partners… Science knowledge is growing…

Countries Conducting AIDS Vaccine Trials

In 2006, 13 new phase I/II trials of preventive AIDS vaccine candidates were started in 8 countries.

VAX Special Issue – 2006 Year in Review

AIDS Vaccines in Clinical Trials – 2007
Phase I trials – 19 ongoing
Including : ADVAX-DNA TBC-M4 MVA-mBN32 *GENEVAX Gag-2692 DNA Boost ADARC,IAVI IAVI, Therion Bavarian Nordic NIAID, Wyeth

Phase II trials – 3 ongoing
Including : *VRC-HIVDNA-016-00-VP Adeno Boost tgAAC09 NIAID, IAVI, USMHRP IAVI, Targeted Genetics

Phase IIb trials – 1 ongoing
MRKAd5 HIV-1 Merck, NIAID

Phase I/II trials – 3 ongoing
Including : *EnvDNA+- Vaccinia Protein Boost ALVAC-HIV and LIPO 5 NIAID, ANRS St. Jude; NIAID

Phase III trials – 1 ongoing
*ALVAC vCP1521 Boost gp120 DoD, Thailand MOPH, NIAID, TAVEG, Sanofi, VaxGen

* Prime Boost

AIDS Vaccine Designs

AIDS Vaccine Designs, Cont.

Fast forward to 2009-2011
Current Candidates Potential Outcome Response
Need vaccine applicable worldwide—particularly for developing countries and plan for manufacture, licensing and access

High efficacy

• Merck Ad5 – Results Due in 2008-9 • Sanofi Canarypox + gp120 – Results Due in 2009

Low to moderate efficacy

Pursue better engineered candidates to improve upon response

Inadequate or no efficacy

Need to explore other mechanisms such as broadly neutralizing antibody; mucosal responses, etc.

Challenges for Developing an AIDS vaccine

Finding a vaccine is very complicated
Issue
HIV hyper-variability Immune correlates of protection are still unknown

What it means
We are tackling a moving target We have to test in people Success will take time

Scientific

Clades Relevant animal models are lacking Clinical trials are long and costly Long term effort requires long term, high level global commitment - leading to action

We need sustained political support We need to build private sector engagement We need to optimize the environment for safe, ethical trials

Policy & Political

Market incentives for industry activity lacking Ethical, regulatory, IP issues Health systems challenges

The Extensive Genetic Diversity of HIV

The current pipeline is inadequate

Only hypothesis currently tested in pipeline is cell-mediated immunity

The Challenges, However, Are Not Only Scientific
AIDS Vaccine and other new prevention technology research is a marathon and not a sprint Must have Long term commitment & support at ALL levels Long term financing Engagement of Industry, who have been the only ones successful at developing vaccines

Some of the complex, non-scientific challenges
Trial site capacity and developing country research infrastructure Regulatory reform: speed and risk-benefit analysis without any safety compromise Important role of the community and vaccine preparedness activities Real partnership with the South – political as well as scientific

Why should developing countries test vaccines early ?
Vaccines tested in industrialized countries available in developing countries very late Advantages of testing vaccines simultaneously in developing countries
available first where needed most relevant to HIV type in the region safety in local population known early immune response in local population protection known in local population (Development - science & infrastructure)

Why the Media are Vital in the Fight Against AIDS The media have power to bring attention that leads to action Accurate and humanizing coverage helps combat stigma The media connect general public with lifesaving medical information

What the Media Can Do Report on both problems and potential solutions Spread the word in your newsroom to make AIDS visible—it is the story of our time Encourage your peers at other news organizations to do the same You can make a difference in ending the AIDS pandemic

24 February 2003

Large Trial Finds AIDS Vaccine Fails to Stop Infection

24 February 2003

AIDS vaccine appears to work

22 April, 2006

AIDS: Think Again

3 February, 2007

Medical research trial guinea pigs contract HIV

8 Novermber, 2000

Vaccine Patent Duped Kenyan Researchers

15 August, 2006

Future promising for AIDS vaccine: group says

21 March, 2001

India to develop AIDS vaccine

The world can and must do more.
IAVI Mission Statement To ensure the development of a safe, effective, accessible, preventive HIV vaccine for use throughout the world

IAVI – the first “PDPPP”
Political will & finance R&D Clinical trials Production Access & Health & other systems uptake

10 years old 170 staff, 5 offices (Amsterdam, Delhi, Johannesburg, Nairobi, NY), active in 23 countries $84 million annual budget
largest global organization solely focused on HIV vaccine; 2nd largest program 40+ R&D partnerships 6 vaccine candidates into humans, pipeline Trials in 12 countries

‘Integrated industrial-like model’ of R&D
Emphasis on applied research and product development – targeting gaps and promoting rational vaccine design Industrial project management

Policy & advocacy linked (lab bench to the G8) Sustained commitment to developing countries

IAVI Clinical Trial Network

IAVI Laboratory Network in Sub-Saharan Africa
Kyamulibwa Kakira Kenya UVRI Kangemi Masaka Kigali KAVI Kilifi

Uganda

Rwanda

Zambia Lusaka

Medunsa Jo’Burg Durban

South Africa
CapeTown

Site Development: BEFORE
Uganda Virus Research Institute Site of Proposed UVRI-IAVI Lab & Clinic

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AFTER UVRI-IAVI Lab & Clinic Entebbe, Uganda
Lab/Clinic built Laboratory:Validated CMI assays, GLP training Accredited and now BMGF/CAVD reference lab

Clinic: Multiple Phase 1 HIV vaccine trials:
Accelerated approval and accelerated enrolment vs. historical controls

Expansion: Field sites doing incidence
and other clinical studies in preparation for future efficacy trials
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IAVI Clinical Research Studies May 2007
Protocol A: Sero-prevalence Protocol B: Sero-incidence Protocol C: Early infection studies 6532 subjects 5100 at-risk volunteers enrolled 150 of 300 enrolled Completed Ongoing OngoingCollaboration with CHAVI Results to be published 2007 Completed Completed 1st group of donors identified Ongoing Protocol being drafted

Protocol D: Reference values Protocol E: Methods validation Protocol F: Seroepi Adeno, AAV Protocol G: Broadly Neut. Sera Protocol H: Clinical, host and viral outcomes – acute and early HIV infection

2410 subjects

IAVI Satellite Symposium Accelerating the Development of Replicating Viral Vectors for AIDS Vaccines
Sunday, July 22, 2007 8:00 a.m. - 1:00 p.m. The Sydney Convention & Exhibition Centre Room: Bayside 204 A
An overview of the field of replicating viral vectors An assessment of the current viral vectors in development Rationale for the development of replicating viral vectors for AIDS vaccines

Key speakers include:
Dr. Ian Gust, University of Melbourne Dr. Wayne Koff, International AIDS Vaccine Initiative Dr. Christopher Parks, International AIDS Vaccine Initiative Mr. Jim Ackland, Global Biosolutions Dr. Ben Berkhout, University of Amsterdam Dr. Linqui Zhang, Chinese Academy of Medical Sciences Dr. Keith Peden, US Food and Drug Administration Dr. Gary Grohmann, University of Sydney Dr. Helen Rees, Reproductive Health Research Unit, Johannesburg, South Africa

IAVI gratefully acknowledges the support of our donors

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