Reshaping the Scientific Agenda of the HVTN

1
Reshaping the Scientific Agenda of the HVTN

• James Kublin
• Director, HVTN

2
Top Priorities 2006-2007

• Conduct multiple test-of-concept trials for
  T-cell-based vaccines.
• In 2005-06 the HVTN also developed a process for
  increased efficiency
• Need to be able to move more products through
  early phase testing at time of increasingly
  constrained resources
• Need to be able to weed out non-promising vaccine
  candidates before large investment in volunteer,
  site personnel and dollar costs is made
• This implies accepting low risk of rejecting a
  candidate that may eventually show promise
• Revise phase1A design for not only safety
  evaluation but also as an immunogenicity screen

3
19th September Stopping the HVTN503 steam train

• 801 enrolled (45 female)
• 1 vaccination 400
• 2 vaccinations 288
• 3 vaccinations 29

• Age range
• 18-20yrs 30
• 21-30yrs 60
• 31-35 10

4
Top Priorities Today

• As a result of the STEP outcome in 2008 the top
  priorities in the scientific agenda have shifted,
  to account for new information and to meet new
  challenges. These priorities are
• To better understand the outcome of data from
  STEP and Phambili, and to use these data to help
  define and evaluate conceptual improvements in
  T-cell-based vaccines.
• To foster an iterative process between human and
  nonhuman primate studies that should allow the
  field to define such conceptual improvements.

5
Specific priorities include

• To fully analyze STEP and Phambili samples to
  define potential association between
  post-vaccination and post-infection immune
  responses and viral load set point and disease
  progression.
• To use genomic and proteomic technologies to more
  fully explore the leads that ELISpot responses
  have shown with viral load post acquisition.
• To determine if increased HIV acquisition in STEP
  and Phambili is associated with Ad5 serology
  and/or circumcision status.
• To continue follow-up of the STEP and Phambili
  cohorts to define if increased risk from HIV
  acquisition alters over time.
• To follow up subjects who acquired HIV on trial
  to determine if vaccination altered course of
  infection.
• Additional analyses of data on HSV-2 status, HLA
  typing, and sexual network clustering

6
Timeline
Who ever crawled across cut glass to make a
deal.
7
Update

• Finding a vaccine is neither easy nor fast. For
  instance, since World War II, there have been
  more than 20 failed tests for malaria, which has
  no vaccine. The polio vaccine took scientists 47
  years to find measles, 42. HIV was discovered
  only 25 years ago. There's still much that isn't
  known about the virus or AIDS. So what might look
  like a devastating failure to the public could be
  a steppingstone to advanced medications and an
  eventual cure. There was a series of questions
  that the Merck scientists were looking to answer,
  and they answered them. The answers just weren't
  the ones the scientists were hoping for.
• Washington Post, 21 April, 2008

8
Questions for the EAC Feb 08

• Given the current state of the field, what
  types of research studies should the HVTN pursue?
• Should we be more involved in studies of
  immunotherapeutic vaccines for HIV?
• Should we conduct studies of non HIV vaccines?
  If so, what vaccines and what hypotheses do you
  feel we should pursue for such studies?
• Are there opportunities in HIV vaccine development
  that we are missing?
• What types of observational or cohort
  studies would be critical for helping define a
  better understanding of what type of immune
  responses we should be measuring
  for evaluating newer vaccines?
• Do you have ideas on what would be/should
  be criteria for moving to another test of concept
  trial?
• What can we do to improve the types of inserts
  that are used in viral vectors?

9
(No Transcript)
10
Mission

• The mission of the HVTN is to enhance the
  discovery, and drive the development, of a safe
  and globally effective vaccine for the prevention
  of HIV through well-designed clinical research
  which objectively and ethically address the
  critical questions of the field.

11
Major components of our scientific agenda

1. Clinical research in vaccine discovery.
2. Clinical trials platform
3. Efficacy trials

12
Major components of scientific agenda

• Clinical research in vaccine discovery
• Post STEP analyses
• Breadth of T cell response
• Mucosal immune response
• Adjuvants
• Innate immunity
• Antibodies
• Interchange between human and animal research
  models

13
Major components of scientific agenda

• Clinical trials platform. As critical questions
  in HIV vaccine research are modified in the light
  of new data from human testing, the importance of
  a standard infrastructure for such testing is
  evident.
• A. Standard assays
• B. Use of platform to advance candidate
  development
• Efficacy trials.
• A. Trials to address correlates
• 1.Immunity
• 2. Protection
• 3. Risk
• B. Population preparation
• C. Cofactors that affect efficacy

14
(No Transcript)
15
Practices Supporting Scientific Leadership

• We interviewed 25 investigators (2 sites had more
  than one) in March/April
• Interviews (20min-1hr) were taped, transcribed,
  coded and major themes were summarized
• Ellen MacLachlan Rich Shikiar conducted the
  interviews and Ellen analyzed the data

16
Questions for Investigators

• What structures and operations at HVTN support
  and encourage scientific leadership from site
  PIs? Which ones do not?
• What works well at the HVTN in terms of your
  ability to suggest new concepts or ideas and have
  them implemented?
• Are there other groups, networks or
  organizations that you're working with who we
  could learn from?
• Do you have specific recommendations as to how
  best to foster innovation and new scientific
  ideas at HVTN?

17
Major Findings Past HVTN
Examples Site Expansion Sites Clinical
Role Role in New RFA Varied PI Expertise Central
Operations Central Decisions
18
Major Findings Present HVTN
Examples Unclear Processes Current Scientific
Aims Being Protocol Chair Protocol Committee
CWG Who to contact at Core Automation of studies
19
Major Findings Future HVTN

• Examples
• Clear Processes
• Open Communication
• Integrate PIs More
• Topic-based Groups
• Young Investigators
• Internal RFA
• Brainstorming
• Retreats/Workshops
• Mentoring
• Site/Core Reorganized

20
Future Activities Supporting Scientific
Agenda/Leadership
21
Conclusions of Interviews

• We have internal challenges we need to overcome
• We are committed to expanding openness and
  transparency
• We need to better utilize our enormous scientific
  resources
• Providing new opportunities for scientific
  leadership will ultimately move HIV vaccine
  science forward

22
CAB Survey - polyfunctional
23
New NHP Program Goals

• To attract and retain promising early career
  investigators interested in improving non-human
  primate models that support preventive HIV
  vaccine development.
• To provide a framework for ongoing investigator
  mentorship including organized workshops and
  web-based resources for both mentors and mentees

24
DRAFT Methods

• Identifying scientific priorities The HVTN
  Concept Working Group, enriched by a larger
  number of NHP experts and senior investigators
  from CHAVI, will define key priorities. Peer
  review function will be included as part of a
  larger charge to integrate more fully clinical
  and NHP research (i.e., an NHP interest group).
• Recruiting applicants HVTN and NHP center PIs
  will be asked to identify promising individuals
  at their respective centers and institutions
  through personal connections and broad
  advertisement (e.g., CFAR listserves).
• NHP Plenary at HVTN meetings As it is
  anticipated that many of the applicants will be
  utilizing the NHP model, promising applicants
  will be invited to attend a kickoff NHP Plenary
  and symposium at the November 2008 HVTN Meeting
  with the goal of establishing mentor linkages and
  developing proposals.
• Supporting Scholars This program will leverage
  existing resources and expertise within the
  HVTN. The program will be a resource to
  highlight existing NHP centers and ongoing
  research collaborations.

25
Total 2006 Revenues at the Top-Grossing Public
CROs
Shuchman M. N Engl J Med 20073571365-1368
26

• Given the steady dominance of CROs in the
  clinical-trials domain, the current flaws in the
  model will need to be remedied. This will require
  some shift in focus less single-minded
  attention to "deliverables" and "billable hours"
  and greater concern with the discovery of new
  knowledge.

Shuchman M. N Engl J Med 20073571365-1368
Shuchman M. N Engl J Med 20073571365-1368
27
Concepts to New Knowledge

• Immune responses
• Assays
• Breadth
• Mucosal
• Antibodies
• Adjuvants
• Host genetics
• What are the comparative safety and
  immunogenicity of candidate HIV-1 immunogens in
  humans
• Nonhuman primates
• Efficacy
• Biological and behavioral cofactors
• Social sciences, community, and collaboration

28
Are We Prepared?

• Are we adequately preparing ourselves to fully
  engage in the most important scientific debates?
• What then must we do?

29
Acknowledgements

• Artur Kalichman
• Beryl Koblin
• Carmen Zorrilla
• Gavin Churchyard
• Giuseppe Pantaleo
• Glenda Gray
• Jorge Sanchez
• Julie McElrath
• Ken Mayer
• Kris Patterson
• Linda-Gail Bekker
• Lindsey Baden
• Maphoshane Nchabeleng
• Mark Mulligan
• Mauro Schechter

• Mike Keefer, Xia Jin Christine Hay
• Paul Goepfert
• Peter Figueroa
• Rich DAquila Spryos Kalams
• Rick Novak
• Susan Buchbinder
• Yeycy Donastorg
• Ellen MacLachlan
• Rich Shikiar
• Ana Olazabal
• Katie Brooks
• CEU, TU
• NEC
• CABs