The Long Quest for AIDS Vaccines

Dr. Simon Noble

Senior Director of Scientific Communications
International AIDS Vaccine Initiative
29 July 2008
Part I: Why an AIDS Vaccine?

Part II: What makes it so challenging?

Part III: Where is the field now?

Part IV: Where are we going?

 AIDS is still devastating much of the World

58 million infected

6,800 new infections daily

25 million deaths to date

Women bear the brunt of the

epidemic, representing half of all
HIV-infected adults worldwide and
almost 60 percent in Africa

Without significant prevention

improvements, HIV infections could
double from around 5 million a year
in 2005 to 10 million a year by 2030

Source: UNAIDS 2007, John Stover, Modeling the Impact of AIDS Vaccines
 The Impact Of AIDS On Life Expectancy
for a Child Born In 2010
years

Rwanda

South
Africa

Swaziland

Zimbabwe
Zambia
Namibia
Kenya
Botswana

Data source: The AIDS Pandemic in the 21st Century, Karen A. Stanecki, U.S. Census Bureau
 A Comprehensive Response

Deliver for today – better use of tools

Prevent further spread of the virus
Treat with antiretrovirals (ARVs) those already infected
Mitigate social impacts

Develop better tools for the future

Invest in innovation for new technologies (drugs, diagnostics,
microbicides, vaccines)

Better prevention – particularly AIDS vaccines - is

critical for the affordability and sustainability of our
commitments to universal access to ARV treatment
Source: UNAIDS 2006
The Price of Universal Access

July 2005 Gleneagles Summit of

G8 countries:

“…to develop and implement a package for

HIV prevention, treatment and care, with the
aim of moving as close as possible to universal
access to treatment for all those who need it
by 2010”

Universal access will cost

$54 billion/year by 2015
 Donor Spending for HIV and AIDS could Consume a Third of
all Development Assistance by the End of the Decade

10%
33%
Share for
AIDS

67%
90%
Other aid

2007 2010
(net ODA = $97b) (net ODA = $130b)

Source: OECD-DAC Secretariat simulation for DAC members’ net ODA volumes, 2000-2010
UNAIDS Financial Resources Report, 2007
 An AIDS Vaccine Could Have a Significant Impact
New adult HIV infections in low- and middle-income countries
5

4
Vaccine introduction Total new infections
averted by an AIDS
New Infections (Millions)

Base vaccine between

3 2015-2030
30% efficacy,
Low scenario 20% coverage 5.5 million
2

50% efficacy,
Medium scenario 30% coverage 17 million
1

70% efficacy,
High scenario 40% coverage 28 million
0
2000 2005 2010 2015 2020 2025 2030
 An AIDS Vaccine is Possible

Immune control is possible:

Majority of HIV-infected individuals initially

suppress viral load

Populations resistant to HIV infection

Highly exposed, uninfected: CSWs, MSMs

Children of infected mothers

Long-term non-progressors control infection

for many years

Experimental candidates:
SIV infection by live attenuated in Macaques

Human broadly neutralizing antibodies in Macaques

 AIDS Vaccine Designs

Env / gp120
 Part II
What Makes it so Challenging?
Scientific Challenge #1: HIV Genetic Diversity:
Rapid Replication, High Mutation, Recombination

Sequence divergence of HIV gp120 (V2-C5) as compared to influenza A

 Scientific Challenge #2:
Eliciting Broadly Neutralizing Antibodies
Viral
membrane

MPER (4E10, 2F5, Z13e1)

CD4bs (b12)

Glycan shield (2G12)

D. R Burton, R.L Stanfield, I.A. Wilson, 2005, PNAS 102:14943-8.
C. C. Huang, et al., 2005, Science 310:1025-8.
 Scientific Challenge #3:
Brief Window of Opportunity
Early Events:
Vaginal Transmission

“Lenti” in Lentiviruses = misnomer

Initial stage of infection = rapid!

Systemic
Infection
Production
Persistence
Pathology

A Haase et al
 Scientific Challenge #4: Which HIV Antigens to
Include in the Vaccine to Control HIV (CMI)

LTR gag pol vif/vpr/tat/vpu env rev nef LTR

LTR p17 p24 PR RT IN tat gp120 gp41 rev nef LTR

Assays:
Cohorts: Clues to
Develop Clinical
Elite Guide Immunogen
to Trials
Controllers; Immunogen Design
Quantify To Test
Acute Design
Efficacy of Hypotheses
Infection
Responses

Control of HIV: Clinical Research Consortia

Clinical research will be needed to identify the HIV immunogens

required for control of HIV
 An AIDS Vaccine is Possible, but to do what?

AIDS vaccines might be able to:

Protect against HIV infection against all routes of transmission

Against intravenous transmission

Against mucosal transmission

Protect against progression to disease

Reduction of the viral load

Reduce transmission
Infected vaccines likely to be lower or non–transmitters
Scientific Challenges #5
No Ideal Animal Model; No Immune Correlates
Phase I/II Phase II Screening Test of
SIV
Safety & Concept (STOC) Trials
Protection
Immunogenicity Preliminary Efficacy
• ELISPOT, ICS • Systematic analysis • Small trials (30 incident HIV
• Poly-functional of vectors and infections) to detect
analysis antigens suppression of viral loads of
1 log or greater
What do they mean?? SIV is not HIV and Preliminary indications of
monkeys are not potential efficacy will help
people? guide product development

Efficacy Trials
Finding a Vaccine is therefore very challenging

• We need sustained political

support
• Long term effort requires long term, high level
global commitment - leading to action • We need to build private sector
engagement
• Market incentives for industry activity lacking
• We need to optimize the
• Ethical, regulatory, IP issues
environment for safe, ethical
• Health systems challenges trials
We Must Persevere - Vaccines are powerful tools,
but can take decades to develop
Agent linked Vaccine licensed Years
Infectious agent (disease) to disease in U.S. elapsed
Pertussis (whooping cough) 1906 1948 42
Polio 1908 1955 47
Measles 1953 1963 10

Hepatitis B 1965 1981 16

Haemophilus influenza 1889 1981 92

Typhoid 1884 1989 105

Varicella zoster (chicken pox) 1953 1995 42

Rotavirus (diarrheal disease) 1973 2006 33

Human papilloma virus (cervical Early ’80s-

2006 12-25
cancer) mid ‘90s
Malaria 1893 - 112+
Human immunodeficiency virus
1983 - 25+
–HIV (AIDS)
 PART III:
Where Are We ?
The State of the AIDS Vaccine Field Today
 Three “Waves” of AIDS Vaccine Development
1983 - 1994 Hepatitis B Model
Identify the Antigen which elicits Neutralizing Antibodies
Significant infrastructure investment (manufacturing, primates, reagents)
VaxGen: gp120

1995 - 2007 Cell Mediated Immunity / Public Private Partnerships

More than 30 vaccines focused on CMI
Lack of validated preclinical model → Large-scale efficacy trials
Merck: Ad-5 Gag-pol-nef

2008 - Harnessing Innovation

Addressing the key scientific challenges: NAbs and CMI
Iterative, adaptive clinical development and smaller efficacy trials
Harnessing innovations and clinical research
Investments in next generation of scientists
State of The Global R&D Effort Today
Advances Limitations
More candidates in the pipeline… …yet only two fully tested for efficacy, all
current candidates focused on one
hypothesis = cellular immunity

More countries and scientists are …but response is still insufficient in some
involved… countries and from industry

Developing countries are becoming

more active partners… …yet we need to invest in their capacity
to stay the course over the long run

…but scientific challenges remain a

Scientific knowledge is growing…
major impediment to progress
Political Commitment is Improving

"Whether it takes us 15 years,

20 years, 25 years to get an
AIDS vaccine, it is what will
break the back of the disease."

- Melinda Gates
Non-commercial* sector investments in AIDS
vaccine R&D (2000-2006)

*Commercial sector investments were not collected for all years.

However, between 2003-2006, they accounted for 8-10% of the global total.

Source: HIV Vaccines and Microbicides Resource Tracking Working Group (2007)
The Good News: Scientific engagement is now global;
26 countries currently conduct AIDS vaccine trials
The Bad News: The Current Pipeline is Inadequate

Only hypothesis currently tested in pipeline is cell-mediated immunity

The AIDS Vaccine Pipeline: June 2008

• Efficacy Trials Completed

VaxGen gp 120: NO EFFICACY
Merck: Ad 5-gag-pol-nef: NO EFFICACY

• Efficacy Trial Ongoing

Sanofi + VaxGen: ALVAC + gp120 (Data 2009)

• Other Candidates Currently in Clinical Trials

Phase II: DNA + Ad5; DNA + MVA; DNA + NYVAC
Phase I: Multiple DNA, Pox, Adeno vectors, Env protein(s)
Our Assessment: - Screening Test of Concept (STOC) Phase II
trials will determine if any of these approaches provide advances
over candidates above.
 Vector Based AIDS Vaccines in Clinical Trials – June 2008
DNA vectors Viral Vectors- Adenovirus
Clade C, electroporation IAVI-ADARC Ad-5 (Clade B) Merck

Clade B, MVA* Epimmune Ad-5 (Clades A,B,C), [DNA] NIH-VRC

Clade B, MVA* GeoVax Ad-6 (Clade B) Merck

Multiclade-A,B,C, Ad5* NIH-VRC Ad-26 (Clade A) Harvard-NIAID

Multiclade-ABC, MVA* Karolinska Adenovirus-35 (Clade A) Ad5* NIH-VRC GenVec

Clade C Johns Hopkins Viral Vectors- Pox

Clade B/C Changchun Baike Canarypox (Clade B/E), gp120* Aventis
Clade C, NYVAC* EuroVac MVA* (Clade C) IAVI-India
Clade B- IL12, IL-15, peptide* Wyeth MVA (Clade B),[DNA] GeoVax
Clade C, MVA* SAAVI MVA (Clade A/E), [DNA] WRAIR/Karolinska
Clade B U. Penn MVA (Clade B/C) Changchun Baike
Clade A, FPV* HNATRC NYVAC (Clade C)[DNA] EuroVac
Vaccinia (Cocktail) St. Jude’s
[ ] = prime FPV Clade A,E, [DNA] HNATRC
* = boost
MVA [DNA ] Bavarian Nordic
 Merck Ad5-HIV vaccine: Phase IIb Summary

Safe and immunogenic

Failed to prevent HIV or suppress viral load

Not a terrible surprise (SIV predicted), yet very
disappointing

Potential enhancement of infection in volunteers with

pre-existing Ad5 immunity; non-circumcision
May be due to demographics of population or other
variable, not necessarily Ad5 immunity

Major implications for the AIDS vaccine field

Immediate Impact: PAVE 100 (DNA +Ad5) on hold
Why did the Merck vaccine fail to suppress viral load in
subjects who subsequently became HIV infected??
What we know:
Analogous SIV vaccine also failed to significantly suppress viral load
75% of subjects who received the vaccine responded positively by
validated ELISPOT assay.......beckons for better, more predictive assays
Responses were to multiple epitopes

What we don’t know:

Whether antigen targets matched sequences of transmitted virus: Studies
ongoing
Whether the failure is due to:
Vector: Non-replicative, too weak?
Antigenic inserts: gag-pol-nef are they the right ones?
Combination of vector + inserts?
Concept: Can any CMI-based vaccine suppress viral load?
Post - Merck HIV Vaccine: Impact on the Field

Large pharma cutting back

NIH likely to redirect funds from Development to Discovery

Enterprise to review the issues and impact

Greater focus on Neut Ab problem and SIV model

AIDS Vaccines: Global Update- June 2008
Vaccine Development:
Merck/STEP trial (Ad5-gag-pol-nef) : Comprehensive effort launched by
Merck and NIH to determine mechanism for apparent increased acquisition of
HIV infection in subjects with pre-existing Ad5 immunity

VRC (DNA+ Ad5, gag-pol-nef, Env): PAVE 100A test of concept protocol
downsized from 8500 to 2400 subjects- go/no-go decision expected this
summer
Go at 2400: Endpoints- prevent infection; no harm; viral load
suppression
No-Go
Further Downsize: STOC trial at 800-1000- to only look at viral load
New Adeno-vector based trials:
Ad 26 (Env): D Barouch
Ad35 (Env) + Ad5 (Env): NIH-VRC
State of the AIDS Vaccine Field

No Candidate Currently in
Clinical Trials that:

Elicits broadly neutralizing

antibodies against HIV

Controls HIV as well as live

attenuated SIV protects
against pathogenic SIV
challenge
 Part IV
Future Direction of AIDS Vaccine Research
Next Major Advances in AIDS Vaccine Development

Demonstration of protection in humans by an

HIV vaccine

Design, develop and advance to efficacy trials

a vaccine candidate that:

Elicits broadly neutralizing antibodies against

HIV;

Controls HIV infection as well as live

attenuated SIV protects against pathogenic
SIV challenge;

Candidates that trigger mucosal immunity

Replicating viral vectors capable of

persistent and long-term protection
Future Direction of AIDS Vaccine Research

To achieve this we need:

1. Better understanding of HIV and immune responses

2. To elicit Neutralizing Antibodies

3. To elicit durable CMI Responses

4. To explore other areas

5. Innovation
1. Better Understanding of HIV Virus

More research is needed on pathogenesis and early

events in HIV infection, including mucosal immunity
Genetic bottleneck during transmission of HIV
Transmission Re-emergence of
viral diversity

Diverse virus
population in
chronically infected
“donor” E. Hunter, et al.
2. How to Elicit Neutralizing Antibodies to HIV
There won’t be an AIDS vaccine without a solution
to the HIV Neutralizing Antibody Problem

Broadly neutralizing antibodies

against HIV exist in humans …
Research Consortia focus on Key Challenges
e.g. Neutralizing Antibody Consortium
Broadly neutralizing
High thru-put immunogen
antibodies design

Determining structure
Assays to rapidly screen immunogens
of novel antigens

Characterize
Sera and
Structural Immunogen Immunogen Clinical
Identify
Biology Design Screening Dev.
BN-Mabs

Proteins
Major Block
High Peptides
Slow
Protocol G thru-put Sugars
Immunogen
Robot “needle in
Screen
haystack”
 Protocol G: Neutralization Activity of Top 5 Samples

Sample Score 92BR020 92TH021 93IN905 94UG103 IAVIC22 JRCSF

1 3.67 900 2700 2700 900 2700 2700

2 2.83 300 2700 2700 300 300 900

3 2.43 900 100 2700 900 300 900

4 2.52 900 300 900 300 900 300

5 2.37 2700 0 2700 300 2700 900

3. How to Elicit Durable CMI Immune Responses

CMI responses will likely be needed to “mop up”

breakthrough infection and will require:

Vectors that elicit persistent immune responses

Determine which antigens to include in a vector

Assays to measure predictive immune responses

Case for Live Replicating Vectors :
Improvements Over Vectors in the Current Pipeline
Live Attenuated
Virus
‘Jennerian’ - related,
nonpathogenic animal virus

Majority of candidates
in preclinical and
clinical testing Live Viral Vector

Nucleic Acid Vaccines

Nonpropagating Viral
Subunit Vectors

Virus-Like Particles Inactivated Virus

Vector Discovery:
Prioritization and Key Milestones
Many candidates are selected for viability
Ad ND
V
V
based on scientific hypothesis.
V V CD
HS VS Candidates are advanced based on:

Technical Feasibility

Small animal models

Safety Immunogenicity

SIV/macaque Model
Safety Efficacy

Clinical Candidate
Antigens to elicit CMI responses

Goal:

Elicit effective cellular immune responses to control HIV

infection

Challenge:

To identify and design the requisite antigens which must be

included in a vaccine to confer control of HIV infection
4. Other Areas to Explore

• Basic mechanisms of B-cell biology, including B-

cell memory

• Greater understanding of innate responses,

including adjuvants to elicit them

Toll-like receptors
Chemokines
Molecular
Liposomal
5. Innovation

Innovation will be essential to solve the challenges

in AIDS vaccine development as it will likely require:

Cross fertilization across functional areas

The next generation of HIV researchers

Engagement of Biotechs
IAVI Innovation Fund Launched August 2007

Partnership with the BMGF

Identify and test novel, unproven technologies and
pioneering ideas from outside the AIDS vaccine field

Catalyze untapped potential of small and mid-sized biotechs

Proactively recruit technologies for AIDS vaccine discovery

Success could
transform the pipeline
Innovation Fund Completed Grants June 2008
VaxDesign (US)
In vitro mimic of human immune system for rapid vaccine
evaluation

Spaltudaq (US)
Human B cell screening technology for identification of new
bnMAbs

Lipoxen (UK)
Liposome delivery technology for antigen presentation

Strand (India)
In silico protein structure modeling to design immunogens
mimicking the 4E10 epitope
What is not accurate about the HIV/AIDS
vaccine field today?

• The recent STEP trial was a failure

• We have spent a lot of money and have gotten
nowhere
• We cannot develop a preventive vaccine
• The private sector has withdrawn from the field
• It is a choice between treatment vs. prevention vs.
new prevention technology research
• We are giving up on clinical research
• There is no role for developing countries in R&D
What is accurate about the field?

• The STEP trial was a disappointment

• We learned more about a CMI approach
• Reaffirmed need to increase work on neutralizing
antibodies
• Raised difficult and challenging issues about pre-
existing immunity
• We need innovation from in and outside of the field
• We must continue to pursue incentives to further
engage industry
• We must conduct clinical research and clinical trials
more efficiently
• There is a critical role for the developing world in
global R&D
 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 everyday people 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
The World Needs an AIDS Vaccine
IAVI Gratefully Acknowledges
the support of our Donors
IMAGINE a World
Without AIDS