Issues and questions in hiv vaccine trials
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Issues and Questions in HIV Vaccine Trials. Noreen Jack MB.BS, MPH. years-decades. 1-3 yrs. 5-15 yrs. Vaccine Development Process. Application. Concept Exploration. Basic & Exploratory Research. Product Development. Animal Studies. IND. Candidate vaccine. Phase 0. Phase I.

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years-decades

1-3 yrs.

5-15 yrs.

Vaccine Development Process

Application

Concept

Exploration

Basic & Exploratory Research

Product

Development

Animal

Studies

IND

Candidate

vaccine

Phase 0

Phase I

Phase II

Phase III

Virology

Immunology

Molecular

Biology

PLA

5



Overview of AIDS Vaccine Designs

Whole inactivated

Live Attenuated

HIV peptide

Recombinant protein subunit

Live virus vector

DNA

Live bacterial vector


Animal models do not always predict responses in humans

Chimps are not a perfect model

Immunize with HIV-1 surface (env) protein gp120; gp160

Raise neutralizing antibody response

Protect against subsequent infection

1990 Encouraging results in 3 chimps; confirmed in subsequent small studies

But Chimps can clear HIV-1 infection on their own

Macaques is important in current vaccine research

Assessment of safety and immunogenicity in a model closely related to humans

IL2/Ig adjuvanted DNA vaccines or DNA prime followed by MVA boost elicited control over viral replication and protection from CD4 loss

Recently differences in allele (Mamu-A*01) influence immune response and poorer viral control

Animal Models do not always predict responses in humans


Geographic distribution of hiv 1 subtypes 1990 s
Geographic Distribution of HIV-1 Subtypes – 1990’s

B,A,C,D,E,F,G,H

B,A,D,E

C,B,E

A,C,D,E,F,G,H

E,B

B,E,F,C

B

U.S. Military HIV Research Program


Relevance of hiv 1 strains
Relevance of HIV-1 Strains

  • Vaccines that produce CD8-CTLs recognize some HIV strains of other clades

    • Samples from Ugandan volunteers given Clade B based ALVAC 205 responded to Clade A and D peptides

    • Does it lead to cross-protection? Dual infections B/C;B/E and recombinants can occur

  • Vaccines producing Abs; subunit vaccines

    • No neutralization of strains beyond vaccine strain

  • New strategies: combining immunogens from different clades to create “cocktail” vaccines-multiclade vaccines


Advantages for immune escape env
Advantages for immune escape (env)

  • Surface glycosylation obstructs receptor-binding sites and conserved regions are concealed or inaccessible

    • Results in the lack of cross-neutralization within same clades or between different clades

    • Lab-adapted strains don’t neutralize “primary isolates”

  • New approach-designing vaccine immunogens computationally based on consensus or ancestral strains


What arm of immune response correlates with protection from infection or disease
What arm of immune response correlates with protection from infection or disease?

  • Both cellular and humoral responses may be required

  • Humoral responses control early viral replication and prevent viral entry into target cells

  • Cellular immune responses play a role in the control of replication

  • Envelope subunit vaccine (gp160 or gp120) produces better antibody responses

  • Vector vaccines as ALVAC and Ad5 vector produces better cellular immune responses

  • How do we achieve both?


What strategies result in the best immune responses prime boost
What Strategies result in the best immune responses: Prime Boost

  • The administration of one type of vaccine followed or together with another vaccine

    • ALVAC 1452 and gp120 or gp160

    • DNA and MVA

    • DNA and vector Ad5

    • Ad5 and ALVAC 205

  • The purpose is to enhance the immune response and develop both antibody and CTL immune responses enhancing the overall effect


Need for trials in humans
Need for trials in humans Boost

  • Phase I to define safety

  • Phase II to define immunogenicity and safety

  • Phase III to determine efficacy and safety

  • An expanded global trials capacity is required

    • Efficacy trials require large number of volunteers : 5,000 to 15,000

    • Training of staff in the conduct of clinical trials. Retaining staff

    • Infrastructure needs include laboratory supports in country that can meet quality standards

    • Local in-country ethical review board capacity


International and us sites to test hiv vaccines

HIV VACCINE Boost

TRIALS NETWORK

International and US Sites to test HIV Vaccines

New York, NY

Baltimore, MD

Boston, MA

Chicago, IL

Fairfax, VA

Washington, DC

Port-au-Prince, Haiti

Rochester, NY

Providence, RI

  • Global initiative

  • Many sites

St. Louis, MO

Nashville, TN

*Yunnan, China

Seattle, WA

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

*Potential Expansion Sites

*Capetown, SA


Study and operational issues
Study and Operational Issues Boost

  • Eligibility criteria based on US criteria not readily applicable to many international settings

    • Risks criteria

    • Medical criteria especially based on hematology and biochemistries norms for Caucasians

  • This delays recruitment and enrollment

  • Difficulties with shipping samples-often delays. Sites should have the capacity to perform in country sample processing and some laboratory assays


Ethical considerations
Ethical Considerations Boost

  • Prevent social harms

  • Vaccine induced HIV antibodies may lead to an HIV antibody positive result

    • Difficulties include discrimination

    • Problems with immigration and obtaining insurance where an HIV test is required

    • Misdiagnosis during hospitalization or other situations where HIV testing may be needed

  • Mechanisms to prevent social harms include PCR test to distinguish from true infection and providing support for the volunteer as required


Ethical considerations1
Ethical Considerations Boost

  • Legacy of Tuskegee/the term “Guinea Pigs” impacts on community education and recruitment efforts especially in developing countries

  • Is there an obligation to provide antiretroviral treatment for volunteers who become HIV-infected?

  • For a efficacy trial to reach a conclusion, people have to become infected

    • Researchers conducting a vaccine trial must do everything to prevent people from becoming infected: risk reduction counseling

    • Participants in a vaccine trial may believe they are protected


Advocacy community awareness and education
Advocacy, Community awareness and education Boost

  • Develop and maintain Community Advisory Boards (CABs)

  • Increase community awareness of HIV prevention including HIV vaccines.

    • Usually there is misinformation

    • There is distrust of developed countries motives for the development of HIV vaccines

    • Concerns of safety and long term consequences

  • Community awareness assists recruitment providing understanding and support for volunteers


Funding and economic issues
Funding and Economic Issues Boost

  • Adequate resources for infrastructure, to train and fund researchers and increase community awareness to conduct scientifically/ethically sound trials

  • For industry, there is more profit in drugs

    • Preclinical development: $100,000,000

    • Clinical testing: $100,000,000 (NIH)

    • R&D companies may see few incentives given the challenges and uncertainties

  • What are the implications of success? If a HIV vaccine becomes available would it be affordable to developing countries? How will it be distributed?


Summary
Summary Boost

  • HIV Vaccine development is one of the many challenges of the HIV pandemic

  • Since 1980’s the small successes have informed today’s knowledge and the new vaccine designs and strategies

  • Continue efforts require increased resources, commitment and collaboration of many


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