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HIV VACCINES What does an HIV vaccine need to do immunologically and clinically? What have we learned so far in vaccine clinical trials and where are we going? Neutralization Binding Antibodies What Does an HIV Vaccine Need to Do? Bind up free virions in infected secretions CTL CTL Kill

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HIV VACCINES

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HIV VACCINES

  • What does an HIV vaccine need to do immunologically and clinically?

  • What have we learned so far in vaccine clinical trials and where are we going?


Neutralization

BindingAntibodies

What Does an HIV Vaccine Need to Do?

  • Bind up free virions in infected secretions


CTL

CTL

Kill

HIV Infected Cell

Apoptotic Death

What Does an HIV Vaccine Need to Do?

  • Produce T cell memory to eliminate HIV infected cells


Localized Infection in Mucosal Tissue 1-3 days

Regional Spread

and Latency

3-5 days

Systemic Dissemination

6-9 days

What is the Time Frame for These Immune Responses?


HIV VACCINE

TRIALS NETWORK

Why Has It Been Difficult to Construct an HIV Vaccine?


Scientific Reasons Why an HIV Vaccine Has Been Difficult to Develop

  • No definitive marker of protection exists, even among long term non-progressors

  • HIV employs several immune evasion strategies

    • HIV proteins mask their neutralizing sites

    • HIV-1 proteins down regulate T cell immune response to the virus

    • Antigenic diversity results in escape from both neutralizing antibodies, as well as CD8+ and CD4+ T cell responses


Economic Issues Affecting HIV Vaccine Development

  • Economic incentives for large scale development of vaccines is miniscule compared to those for therapeutic drugs

  • Vaccines require high efficacy and negligible toxicity

    • Vaccines need to be inexpensive

    • Vaccines are not administered chronically

  • Development of an HIV vaccine is a high risk venture, requiring a diversion of resources from programs with a perceived higher degree of success


Fortunately These Economic Perceptions are Starting to be Altered

  • Global Fund and Gates Foundation have given confidence that if there are useful vaccine(s) there will be a mechanism to buy them

  • Government funding in U.S. and European Communities for HIV-1 vaccine development has increased

  • NGO support has also increased (IAVI)


Political Recognition of the Importance of an HIV Vaccine

  • Recognition that poor health leads to poor economies

  • Recognition at the presidential/ cabinet level that an HIV vaccine is essential to the control of the HIV pandemic


Ideal Pipeline for HIV Vaccine Development

Vaccine

Concepts

Vaccine

Constructs

Vaccine

Clinical Trials

  • Money

  • People

  • Laboratory and animal resources

  • Money

  • People

  • Resources

  • Regulatory approval


HIV Vaccines: Current Pipeline Situation

Vaccine Constructs in Concept Stage

66

# GMP

lots made

25

# Entered

Phase I

25

# Entered

Phase II

5

# Entered

Phase III

2


HIV Vaccines

The road so far traveled


HIV Vaccines 1987-2000: The First Wave

  • Between 1987 and 2000 over 20 different HIV vaccine products tested

  • Trials involved over 5,000 subjects

  • Trials conducted in U.S., Thailand, China, Kenya, and Europe

  • Vaccines extremely safe

    • Only local side effects

    • No immunosuppressive effects

    • No long or short term toxicities

    • One subunit vaccine advanced to phase 3 trials


HIV Vaccines 1995-2000:The Second Wave

  • In mid 1990’s recognition of the importance of CD8+ T cell responses in abrogating HIV-1 viremia

  • Initiation of clinical trials of recombinant vectors to deliver HIV-1 genes into class I pathway

    • Poxvirus vector major prototype

  • Development of DNA vaccines


Second Wave Vaccines

  • Clinical trials of viral vector vaccines demonstrate CD8+ T cell responses after vaccination

    • Replication defective canary pox virus vectors (ALVAC)

    • Vaccinia/MVA vectors


HIV Vaccine Clinical Trials in 2002

  • Near completion of phase 3 trials of gp120 VaxGen trials in U.S. and Thailand

    • Taught us that doing clinical trials of HIV vaccine in different regions of the world can be done and done well

  • Thailand proposal to move into a phase 3 clinical trial - a Clade E ALVAC vector in combination with gp120


HIV Vaccines 2002:The Third Wave

  • Use of combination vaccines to increase T cell responses after vaccination

    • Adjuvanted DNA vaccine to prime

    • Viral vector vaccine (adenovirus replicon or MVA vector) to boost

  • Enhanced efficacy of such vaccines in primate models in controlling HIV-1 viremia after experimental inoculation


107

DPeak

106

105

RNA copies/ml

104

DSet-pt

103

102

101

0

1

2

3

4

5

HIV VACCINE

TRIALS NETWORK

Years

Vaccines that do not prevent infection but modify viral replication after acquisition of HIV infection


Localized Infection in Mucosal Tissue 1-3 days

Regional Spread

and Latency

3-5 days

Systemic Dissemination

6-9 days

Mechanism of Action of T Cell Vaccine Directed at gag Gene Products


HIV VACCINE

TRIALS NETWORK

T Cell Directed Vaccines Bring with them Several New Scientific and Policy Issues


Vaccines That Modify Viral Replication

  • It is conceptually “easy” to see that a vaccine that reduces viral setpoint would help the individual

    • Increase time to AIDS

    • Reduce need for or number of antivirals

    • Improve efficacy of antiretrovirals, reduce frequency of resistance


HIV VACCINE

TRIALS NETWORK

Vaccines Designed to Modify Replication Offer New Challenges in Clinical Trial Design

  • What level and duration of set point viremia would be adequate for use of such a vaccine regimen?

    • Durability of viremic control is the major determinant in clinical as well as epidemiological effects of such vaccines

  • Late breakthroughs associated with low grade replication and escape mutations from CTL control have been documented in non-human primate experiments


HIV VACCINE

TRIALS NETWORK

Would such a vaccine reduce transmission?


Relationship to Viral Load and Heterosexual Transmission(Rakai Discordant Couple Trial, n=415)

Quinn et al, NEJM 342(13):921-9, 2000 Mar 30

Annual Frequency

of Transmission

RNA Viral Load in HIV+ Source Partner


Population Based Effects of Vaccines that Control Viremia

  • Vaccines that control viremia can potentially impact the epidemic spread of HIV in a community.


Mathematical Model of Impact of a Vaccine That Reduced Viral Load Over Time(Ira Longini, Emory University)

Prevalence of HIV in Population

Years


HIV VACCINE

TRIALS NETWORK

Determining the Effectiveness of Vaccines that Control Viremia

  • Effective mathematical models require data

  • We must generate such data concomitant with phase 3 trials of these vaccines

  • Design clinical trials to directly measure the effects on transmission

    • Partner studies

    • Community level randomized controlled trials


HIV VACCINE

TRIALS NETWORK

T Cell Based Vaccines also Raise the Issue of Whether Clade-Specific Vaccines are Needed


Clades and T Cell Vaccines

  • Strain/clade typing is largely based on envelope sequence and antibody diversity

  • Cross clade T cell responses are well documented in both natural infection and after ALVAC vaccination or DNA/adenovirus vaccination


Cross-Clade CTL Responses After Receipt of Clade B ALVAC Vaccination(vCP205 - HVTN Protocol 022)

% Specific Lysis

Primary Isolate Targets (HIV-1 Clades)

Ferrari et al. PNAS 1997:94


Clade A

Clade B

Clade C

10 / 13

13 / 13

10 / 13

77%

100%

77%

Frequency of T cell Responses by ELISPOT to Clade A, B and C Prototype Peptides After Receipt of Ad5-gag Clade B Vaccine

Shiver and Emini - 5/7/2002


Message Number 1

  • Momentum and progress in HIV-1 vaccine development is picking up

    • more vaccine candidates are entering clinical trials

    • more novelty in the scientific approach

    • more T cell immunogenicity


HIV VACCINE

TRIALS NETWORK

T cell based vaccines are approaching the immunogenicity that we feel is needed for effectiveness


700

Vesicle Formation

No Vesicle Formation

600

500

400

Interferon-g-Producing Cells

(per 106 PBMC)

300

200

100

0

-100

Undiluted

1:10

1:100

Dilution

Dilution

Elispot Responses After Vaccinia Vaccine(Frey, et al; NEJM 4/25/02)


Anti-gag T Cell ELISPOT Responses After DNA Priming and Adenovirus Boosting at 108 vp Dose

Immunizations at Weeks 0, 4 and 26

Weeks Post Boosting

4

8

16

Subject #

1

2

3

4

5

6

7

359

418

-

230

618

461

69

398

333

729

141

1739

230

241

-

-

898

243

1038

180

-

Response = # HIV-1 gag-specific SFC / 10^6 PBMCs in a -IFN ELISPOT assay

Emini, Shiver, et al


Message Number 2

  • While we still lack approaches that give the breadth and magnitude of neutralizing antibodies we feel are needed for an effective vaccine that prevents acquisition of HIV , it is likely we can achieve a reduction in transmission of HIV-1 with T cell based vaccines.


Message Number 3

  • Cross clade T cell responses to HIV are being achieved at high frequency with many vaccines currently in clinical trials

  • The scientific rationale to study clade mismatched T cell vaccines exists


Why Should one Conduct non Clade Matched HIV Vaccine Trials?

  • Many vaccines, especially recombinant viral vectors, are technically difficult to manufacture, even for large scale clinical trials.

    • The resources and technical support to manufacture country-specific vaccines are very limited

    • speed of regulatory approval and manufacturing scale up of novel vector based vaccines is not commensurate with the needed pace of vaccine development


Corollary of Message 3

  • Cross clade responses to a potent vaccine may provide greater efficacy than clade specific responses to a less potent vaccine


Message Number 4

  • Evaluation of HIV-1 vaccines requires international cooperation between agencies involved in HIV vaccine development and testing

  • Combination vaccines are likely to be needed

    • This increases the complexity of preclinical and clinical development

    • This requires coordination and cooperation among developers and clinical trial sites


HIV VACCINE

TRIALS NETWORK

An International Program to Test HIV Vaccines

New York, NY

Baltimore, MD

Boston, MA

Washington, DC

Port-au-Prince, Haiti

Chicago, IL

Rochester, NY

Providence, RI

Fairfax, VA

St. Louis, MO

Nashville, TN

Seattle, WA

*Yunnan, China

Nanning, China

San Francisco, CA

Birmingham, AL

*Kingston, Jamaica

Chiang Mai, Thailand

*Tegucigalpa,

Honduras

*Santo Domingo, Dominican Republic

*Pune, India

San Juan, Puerto Rico

Blantyre, Malawi

Port of Spain, Trinidad & Tobago

Gaborone, Botswana

Lima, Peru

Soweto, South Africa

Sao Paulo, Brazil

Rio de Janeiro, Brazil

Durban, South Africa

*Capetown, South Africa

*Potential Expansion Sites


Message Number 5

  • Global development means investment of international scientists and organizations earlier in vaccine development than any previous vaccine effort

  • Development of a National HIV vaccine plan is critical for facilitating participation in this global vaccine effort


HIV VACCINE

TRIALS NETWORK

Message Number 6

  • HIV-1 vaccines need to be developed in the context of a larger prevention effort

    • This is a marathon - not a sprint

    • Initial vaccines partially effective

    • Community education is critical not only in trials, but to continue safe sex and safe injection behaviors

    • ART therapy is complementary and not competitive with HIV vaccine development


HIV VACCINE

TRIALS NETWORK

ART and Vaccine Trial Participation

  • International investigators in the HVTN believe that ART should be available for its trial participants when they need it.

  • Communities who participate in vaccine research should be provided ART, but if this is not possible, then individuals who participate in vaccine trials and develop HIV while on the trials should be eligible for ART when they and their physician feel it is needed.

  • HVTN is committed to utilize its expanding global network to bring these messages to HIV vaccine development.


  • Delays in the scientific, regulatory and political process of developing and evaluating HIV vaccines are the most egregious error that we now encounter in the HIV vaccine field.


HIV VACCINE

TRIALS NETWORK

The HIV vaccine field should be a model for science and medicine ; a world that values rich and poor, north and south, women and men, young and old alike.

A world that speeds vaccine development to all in need.


The virus recognizes the similarity among people on the planet - scientists, policy makers, and communities must act similarly.


Judy Wasserheit

Peggy Johnston

Ed Tramont

Jorge Flores

Julie McElrath

Kent Weinhold

Steve Self

Steve Wakefield

Emilio Emini, Jeff Chodokowitz, Jerry Sadoff, John Shiver and Scott Thaler of Merck Research Labs

Jim Tartaglia, Sanjay Gurunathan of Aventis Pasteur

Debbie Birx and John McNeal of WRAIR

Jose Esparza, UNAIDS

Contributors


Special Thanks

Tony Fauci


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