VISP/R Meeting Summary - Global HIV Vaccine Enterprise

VISP/R Meeting Summary
Robert W Coombs MD PhD FRCPC
University of Washington, Seattle, WA
bcoombs@uw.edu
Introduction
• Mary Marovich (NIH)
• The Vaccine-induced seropositivity/reactivity issue
– Scope: Volunteer participation; Enrollment;
Safety/stigma; Public perception; Diagnosis and study
endpoints
– Magnitude: Will increase with more immunogenic
vaccines; increased testing intensity and follow-up; Cost
escalation with NAT; Monitoring frequency post-study
– Conclusion: All aspects of vaccine research are clearly
affected by VISP/R!
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Vaccine candidate pipeline
• Barney Graham (NIH VRC)
• Back to the future…an historical HIV vaccine perspective with
evolution of outcome from antibody to cellular response to
antibody response
• Conclusions:
– Antigen content of vaccines more complex; as such VISP/R will
increase
– Commonly used serological tests can’t distinguish suppressed HIV
infection from vaccine-induced response
– Peptide-based serological testing helps to discriminate vaccineassociated antibody responses from infection but requires
collaboration between kit manufactures, vaccine developers and
the various regulatory agencies
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HIV Diagnostic Algorithms
• Sheila Peel (US Military HIV Research Program)
• Overview of US Military HIV-testing algorithm
• Emphasis on testing for HIV DNA and RNA given that RNA may be
suppressed for a number of reasons
• Symantec clarification of “misclassification” from “false-positive”
serological testing results
• Orthogonal testing adds to algorithm specificity but also redraw
and retest is important
• No FDA-approved HIV-1 DNA or HIV-2 NAT assays are available for
the next-generation HIV diagnostic algorithm
• The appropriate HIV diagnostic algorithm for resource limited
settings will be driven by what testing platforms are available
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HVTN VISP/R Practices
• John Hural (UW HVTN)
• HVTN has a long-term commitment to providing VISP/R services, which
influences
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Kit selection for each protocol
Algorithm design
Endpoint adjudication (Web-based; results in 24 hours)
End of study seroreactivity (EOS)
VISP protocol (HVTN 091)
• Post study testing
• VISP Registry
• Conclusion: Need for “less sensitive” FDA-approved serological kits for
protocols; When does cost of testing algorithm exceed cost of running NAT
PCR on all vaccine recipients for diagnosis of infection? Still need to deal with
community level HIV testing algorithms for post-study testing.
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HVTN Post-study testing services
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Carissa Karg (UW HVTN)
Testing service in place for 2.5 years (HVTN 910)
Objective is to mitigate social harm from VISP/R
Challenges: providing local phlebotomy service;
State guidelines for consent/testing/reporting;
confirm prior study participation (hence, registry);
• 3 hours administrative time per participant at a cost
of $500;
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HVTN VISP Registry (cont’d)
• Secure web-based data base (ATLAS)
• Projected to have >8000 registrants
• Registry will facilitate
– More efficient post-study testing services
– Identify specimens for test optimization
– Study vaccine breakthrough infection
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Current VISP/R practice overview
• Mary Allen(DAIDS, Vaccine Clinical Research Branch)
• Participants 14 question survey of 9 vaccine research
groups
• Inconsistencies in some VISP/R-related services:
– Awareness of social impact of VISP/R; collect data on
durability of VISP; publish experience; long-term contact
with post-study participants; offer remote HIV testing;
information about effect of study participation and
VSIP/R on blood donations
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Best practices discussion
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Pat Fast (International AIDS Vaccine Initiative)
Informed consent
IRB/Ethical/Regulatory concerns
Effect of VISP/R on recruitment
Social harms
Long-term follow-up
Public health interference
Vaccine design
Several issues raised during discussion
– Cyber security of VISP/R data bases
– Self-testing and implications for blinding; participation in overlapping studies;
participation in VISP/R registries associated with some complexities for vaccine
subjects in different countries
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Pipeline of diagnostic tests
• Mark Ware (Clinton Health Access Initiative)
• Number of emerging near-patient tests with following characteristics:
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Small and portable
Decreased turn-around-time for results
Low throughput
High limit of detection
Small sample size
Whole blood (Early infant diagnosis)
Integration of sample preparation & detection
Quantitative/qualitative flexibility
Connectivity to internet and 3G for data transmission to central data bases
Ease of use and training
Seeking regional approval, WHO prequalification and CE Mark
Need blinded head-to-head comparisons and participation in EQA programs
• A standardized regulatory approach to assay approval in resource-limited countries
would assist with assay development and deployment
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Challenges in developing & commercializing
HIV test that differentiate VISP
• Chris Bentsen (Bio-Rad Laboratories)
• Overview of FDA regulatory complexities and why
developing VISP/R-specific HIV antibody tests is not
cost-effective for large diagnostic companies
• Bio-Rad has only 10/39 diagnostic assays in US
• Summarized four FDA-approved HIV tests (WB, Plus
O, Multispot, Combo Ag/Ab 4th generation assay)
• Described Geenius HIV1/2 as eventual replacement
for Multispot assay
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Developing a commercial VISP test:
SELECTEST experience
• Andrew Levin (Immunetics, Inc.)
• Application of antigen discovery and peptide design
to develop a specific assay for VISP, based on gp41
peptides not found in vaccines
• In population with prevalence of 0.7%, SELECTEST
has a PPV of 58%; NPV 99.9%; in combination with
WB, PPV of 98.5%
• Fewer misclassifications (VSIP/SR) in HIV vaccine
trials thus far compared to commercial platforms
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Simple AMplification Based Assay (SAMBA)
• Helen Lee (University of Cambridge, UK)
• Isothermal HIV-1 2LTR target amplification with
signal amplification
• Comparable to Roche COBAS AMP/COBAS TM v2.0
• Whole blood (EID) and plasma (monitoring
treatment); combined specimen preparation and
amplification
• POC test: No cold chain; requires AC power source;
deployed for evaluation trials internationally
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Roundtable on VISP/SR & diagnostic tests
• Bob Coombs, Helen Lee, Michele Owen, Marco Schito, Mark Ware
• Potential for decreased VSIP/SR by using orthogonal tests that can
interrogate the vaccine-associated immunoblot profile (e.g.,
Geenius)
• Need data on vaccine performance of 4th generation EIA/CLIA
• Complex HIV seroreactivity patterns arising from complex env-gag
vaccine regimens and requirement for complementary HIV-1
nucleic acid testing in testing algorithms but limitations noted in
absence of FDA-approved HIV DNA test and labeling restrictions on
some commercial HIV RNA assays
• Potential attenuating effects of pre- and/or post-exposure
antiretroviral prophylaxis on detection of HIV infection -- antibody,
RNA and DNA -- in vaccine trials requires further study
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VISP/R Terminology
• Helene Zinszner (Global HIV Vaccine Enterprise)
• A community focus group was conducted to
evaluate the use of the term “VISP/SR”
• Outcome: A kindler and gentler phrase/acronym to
replace the VISP/SR “phenomenon” that also confers
a more positive message is needed…
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