Issues and Questions in HIV Vaccine Trials

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Issues and Questions in HIV Vaccine Trials

• Noreen Jack MB.BS, MPH

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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
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Scientific Issues and Questions
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Overview of AIDS Vaccine Designs
Whole inactivated
Live Attenuated
Recombinant protein subunit
HIV peptide
Live virus vector
Live bacterial vector
DNA
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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-A01)
  influence immune response and poorer viral control

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Geographic Distribution of HIV-1 Subtypes 1990s
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
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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/CB/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

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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 dont neutralize primary
  isolates
• New approach-designing vaccine immunogens
  computationally based on consensus or ancestral
  strains

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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?

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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

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Need for trials in humans

• 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

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International and US Sites to test HIV Vaccines
New York, NY
Baltimore, MD
Boston, MA
Chicago, IL
Washington, DC
Fairfax, VA
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
Rio de Janeiro, Brazil
Durban, South Africa
Sao Paulo, Brazil
Potential Expansion Sites
Capetown, SA
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Study and Operational Issues

• 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

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Ethical Considerations

• 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

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Ethical Considerations

• 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

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Advocacy, Community awareness and education

• 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

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Funding and Economic Issues

• 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)
• RD 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?

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Summary

• HIV Vaccine development is one of the many
  challenges of the HIV pandemic
• Since 1980s the small successes have informed
  todays knowledge and the new vaccine designs and
  strategies
• Continue efforts require increased resources,
  commitment and collaboration of many