aids vaccines: challenges and opportunities (simon noble)

8/7/2019 AIDS Vaccines: Challenges and Opportunities (Simon Noble)

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The Long Quest for AIDS Vaccines

Dr. Simon NobleSenior Director of Scientific Communications

International AIDS Vaccine Initiative

29 July 2008


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Part I: Why an AIDS Vaccine?

Part II: What makes it so challenging?Part II: What makes it so challenging?

Part III: Where is the field now?Part III: Where is the field now?

Part IV: Where are we going?Part IV: Where are we going?


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AIDS is stilldevastating much of the World

Source: UNAIDS 2007, John Stover, Modeling the Impact of AIDS Vaccines

58 million infected

6,800 new infections daily

25 million deaths to date

Women bear the brunt of theepidemic, representing half of allHIV-infected adults worldwide andalmost 60 percent in Africa

Without significant preventionimprovements, HIV infections coulddouble from around 5 million a yearin 2005 to 10 million a year by 2030


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The Impact Of AIDS On Life Expectancy

for a Child Born In 2010

yea

rs

Botswana

Kenya

Namibia

Rwanda

South

Africa

Zambia

Swaziland

Zimbabwe

Data source: The AIDS Pandemic in the 21stCentury, Karen A. Stanecki, U.S. Census Bureau


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A Comprehensive Response

Deliver for today better use of tools

Prevent further spread of the virus

Treat with antiretrovirals (ARVs) those already infectedMitigate social impacts

Develop better tools for the futureInvest in innovation for new technologies (drugs, diagnostics,

microbicides, vaccines)

Better prevention particularly AIDS vaccines - iscritical for the affordability and sustainability of our

commitments to universal access to ARV treatmentSource: UNAIDS 2006


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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 itby 2010

Universal access will cost$54 billion/year by 2015


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Donor Spending for HIV and AIDS could Consume a Third ofall Development Assistance by the End of the Decade

2007(net ODA = $97b)

2010(net ODA = $130b)

Other aid

Share for

AIDS

10%

90%

33%

67%

Source: OECD-DAC Secretariat simulation for DAC members net ODA volumes, 2000-2010UNAIDS Financial Resources Report, 2007


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New adult HIV infections in low- and middle-income countries

Total new infections

averted by an AIDS

vaccine between

2015-2030

70% efficacy,

40% coverage 28 million

An AIDS Vaccine Could Have a Significant Impact

0

1

2

3

4

5

2000 2005 2010 2015 2020 2025 2030

NewInfections(Millions)

Vaccine introduction

Base

Low scenario

Medium scenario

High scenario

5.5 million30% efficacy,20% coverage

17 million50% efficacy,

30% coverage


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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


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AIDS Vaccine Designs

Env / gp120


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Part II

What Makes it so Challenging?


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Scientific Challenge #1: HIV Genetic Diversity:Rapid Replication, High Mutation, Recombination

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


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Scientific Challenge #2:Eliciting Broadly Neutralizing Antibodies

Viralmembrane

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.

MPER (4E10, 2F5, Z13e1)


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Early Events:Vaginal Transmission

SystemicInfection

Production

Persistence

Pathology

Lenti in Lentiviruses = misnomerInitial stage of infection = rapid!

A Haase et al

Scientific Challenge #3:Brief Window of Opportunity


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Scientific Challenge #4: Which HIV Antigens toInclude in the Vaccine to Control HIV (CMI)

LTR gag pol env nefvif/vpr/tat/vpu LTRrev

nef LTRp17LTR p24 PR RT IN tat gp120 gp41 rev

Control of HIV: Clinical Research Consortia

Cohorts:Elite

Controllers;Acute

Infection

Clinical

TrialsTo Test

Hypotheses

Immunogen

Design

Clues to

Guide

ImmunogenDesign

Assays:

Developto

QuantifyEfficacy of

Responses

Clinical research will be needed to identify the HIV immunogens

required for control of HIV


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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 nontransmitters


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Scientific Challenges #5

No Ideal Animal Model; No Immune Correlates

Phase I/II

Safety &Immunogenicity

SIV

Protection

Phase II Screening Test ofConcept (STOC) Trials

Preliminary Efficacy

ELISPOT, ICS

Poly-functional

analysis

Systematic analysisof vectors and

antigens

Small trials (30 incident HIVinfections) to detect

suppression of viral loads of

1 log or greater

What do they mean?? SIV is not HIV andmonkeys are notpeople?

Preliminary indications ofpotential efficacy will helpguide product development

Efficacy Trials


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Finding a Vaccine is therefore very challenging

We need sustained political

support

We need to build private sector

engagement

We need to optimize the

environment for safe, ethical

trials

Long term effort requires long term, high levelglobal commitment - leading to action

Market incentives for industry activity lacking

Ethical, regulatory, IP issues

Health systems challenges


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We Must Persevere - Vaccines are powerful tools,but can take decades to develop

Infectious agent (disease)

Agent linked

to disease

Vaccine licensed

in U.S.

Yearselapsed

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 (cervicalcancer)

Early 80s-

mid 90s2006 12-25

Malaria 1893 - 112+

Human immunodeficiency virus

HIV (AIDS) 1983 - 25+

PART III:


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PART III:

Where Are We ?The State of the AIDS Vaccine Field Today


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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

Three Waves of AIDS Vaccine Development


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State of The Global R&D Effort Today

Limitations

yet only two fully tested for efficacy, all

current 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

Advances

More candidates in the pipeline

More countries and scientists areinvolved

Developing countries are becomingmore active partners

Scientific knowledge is growing


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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

N i l* t i t t i AIDS


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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;


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The Good News: Scientific engagement is now global;26 countries currently conduct AIDS vaccine trials


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The Bad News: The Current Pipeline is Inadequate

Only hypothesis currently tested in pipeline is cell-mediated immunity


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Efficacy Trials CompletedVaxGen 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 TrialsPhase 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.

The AIDS Vaccine Pipeline: June 2008

Vector Based AIDS Vaccines in Clinical Trials June 2008


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DNA vectors

Clade C, electroporation IAVI-ADARC

Clade B, MVA* Epimmune

Clade B, MVA* GeoVax

Multiclade-A,B,C, Ad5* NIH-VRC

Multiclade-ABC, MVA* Karolinska

Clade C Johns Hopkins

Clade B/C Changchun Baike

Clade C, NYVAC* EuroVac

Clade B- IL12, IL-15, peptide* Wyeth

Clade C, MVA* SAAVI

Clade B U. Penn

Clade A, FPV* HNATRC

[ ] = prime

* = boost

Vector Based AIDS Vaccines in Clinical Trials June 2008

Viral Vectors- Adenovirus

Ad-5 (Clade B) Merck

Ad-5 (Clades A,B,C), [DNA] NIH-VRC

Ad-6 (Clade B) Merck

Ad-26 (Clade A) Harvard-NIAID

Adenovirus-35 (Clade A) Ad5* NIH-VRC GenVec

Viral Vectors- Pox

Canarypox (Clade B/E), gp120* Aventis

MVA* (Clade C) IAVI-India

MVA (Clade B),[DNA] GeoVax

MVA (Clade A/E), [DNA] WRAIR/Karolinska

MVA (Clade B/C) Changchun Baike

NYVAC (Clade C)[DNA] EuroVacVaccinia (Cocktail) St. Judes

FPV Clade A,E, [DNA] HNATRC

MVA [DNA ] Bavarian Nordic


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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 verydisappointing

Potential enhancement of infection in volunteers withpre-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


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Why did the Merck vaccine fail to suppress viral load insubjects 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 assaysResponses were to multiple epitopes

What we dont 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?


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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


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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

summerGo at 2400: Endpoints- prevent infection; no harm; viral loadsuppression

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


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No Candidate Currently inClinical Trials that:

Elicits broadly neutralizing

antibodies against HIV

Controls HIV as well as live

attenuated SIV protects

against pathogenic SIV

challenge

State of the AIDS Vaccine Field

Part IV


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Part IV

Future Direction of AIDS Vaccine Research


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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 liveattenuated SIV protects against pathogenic

SIV challenge;

Candidates that trigger mucosal immunity

Replicating viral vectors capable of

persistent and long-term protection


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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 B tt U d t di f HIV Vi


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1. Better Understanding of HIV Virus

More research is needed on pathogenesis and earlyevents in HIV infection, including mucosal immunity

Transmission

Diverse viruspopulation in

chronically infected

donor

Re-emergence of

viral diversity

E. Hunter, et al.

Genetic bottleneck during transmission of HIV

2 H t Eli it N t li i A tib di t HIV


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2. How to Elicit Neutralizing Antibodies to HIV

There wont be an AIDS vaccine without a solutionto the HIV Neutralizing Antibody Problem

Broadly neutralizing antibodiesagainst HIV exist in humans

Research Consortia focus on Key Challenges


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y ge.g. Neutralizing Antibody Consortium

CharacterizeSera and

IdentifyBN-Mabs

ClinicalDev.ImmunogenScreeningImmunogenDesignStructuralBiology

Protocol GHigh

thru-putRobot

ProteinsPeptidesSugars

needle inhaystack

Major BlockSlow

ImmunogenScreen

Broadly neutralizing

antibodies

Determining structure

of novel antigens

High thru-put immunogendesign

Assays to rapidly screen immunogens

Protocol G: Neutralization Activity of Top 5 Samples


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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


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3. How to Elicit Durable CMI Immune Responses

CMI responses will likely be needed to mop upbreakthrough 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 :


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Improvements Over Vectors in the Current Pipeline

Live Attenuated

VirusJennerian - related,

nonpathogenic animal virus

Inactivated Virus

Live Viral Vector

Nonpropagating ViralVectors

Nucleic Acid Vaccines

Majority of candidatesin preclinical and

clinical testing

Subunit

Virus-Like Particles

Vector Discovery:

P i iti ti d K Mil t


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Prioritization and Key Milestones

Many candidates are selected for viability

based on scientific hypothesis.Candidates are advanced based on:

Technical Feasibility

Small animal modelsSafety Immunogenicity

SIV/macaque ModelSafety Efficacy

HSVA

dCD

VNDV

VSV

Clinical Candidate

Antigens to elicit CMI responses


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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


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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


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5. Innovation

Innovation will be essential to solve the challengesin 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


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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 couldtransform the pipeline

Innovation Fund Completed Grants June 2008


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Innovation Fund Completed Grants June 2008

VaxDesign (US)In vitromimic of human immune system for rapid vaccineevaluation

Spaltudaq (US)

Human B cell screening technology for identification of new

bnMAbs

Lipoxen (UK)

Liposome delivery technology for antigen presentation

Strand (India)In silicoprotein structure modeling to design immunogensmimicking the 4E10 epitope

What is not accurateabout the HIV/AIDSvaccine field today?


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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 accurateabout the field?


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The STEP trial was a disappointment

We learned more about a CMI approach

Reaffirmed need to increase work on neutralizingantibodies

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 furtherengage industry

We must conduct clinical research and clinical trialsmore efficiently

There is a critical role for the developing world in

global R&D

Why should developing countries testvaccines early ?


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vaccines early ?

Vaccines tested in industrialized countries available indeveloping countries very late

Advantages of testing vaccines simultaneously indeveloping 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


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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


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Report on both problems and potential solutions

Spread the word in your newsroom to make AIDS

visibleit is the story of our time

Encourage your peers at other news organizations to

do the same

Youcan make a difference in ending the AIDSpandemic

The World Needs an AIDS Vaccine


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IAVI Gratefully Acknowledgesthe support of our Donors


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the support of our Donors


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IMAGINE a World

Without AIDS

aids vaccines: challenges and opportunities (simon noble)

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