Design and Use of HIV-1 Reference Strains for Standardized Assessments of Vaccine-Elicited Neutralizing Antibody Responses David C. Montefiori, Ph.D. Laboratory.

Slides:

Advertisements

Similar presentations

Development of a Panel for Dengue Virus Maria Rios, PhD CBER/FDA Blood Products Advisory Committee Meeting December 14, 2010.

Advertisements

National Institute for Biological Standards and Control Assuring the quality of biological medicines Proposal for a Hepatitis A genotype panel Rob Anderson.

Vaccines and Related Biological Products Advisory Committee 18 February 2009 Topic 2: Considerations and Implications for adding two B Strains to the Seasonal.

Neutralisation with Antisera The neutralisation sensitivity of B-clade primary isolates (3 clones each), isolated at baseline (table on the left) and at.

Evoluzione genetica di HIV ed evoluzione clinica della malattia AIDS: due aspetti correlati? Carlo Federico Perno.

The Path Forward for HIV-1 Vaccine Development

“ The therapeutic effect of FIT- 06, GTU®-Multi-HIVB DNA vaccine, observed in HIV-1 infected people. Results of a Phase II trial”. Prof. Mart Ustav SVP,

Antiviral Immunity and Transmission June 19, 2011 Abst. #: TUAA0105 Maraviroc-resistant subtype B primary HIV-1 induced in vitro selection became highly.

ANIMAL MODELS HIV Cure Research Training Curriculum The HIV CURE training curriculum is a collaborative project aimed at making HIV cure research science.

Designing and Optimizing an Adenovirus Encoded VLP Vaccine against HIV Anne-Marie Andersson PhD Student, University of Copenhagen.

Lab of Immunoregulation

HIV-VACCINES. HIV - Vaccines  Vaccine development remains priority of AIDS research   Best hope for protection against HIV infection.

U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only.

CBER Regulatory Laboratory Planning & Preparedness for SARS-related Biologics Products Kathryn M. Carbone MD Associate Director for Research, Acting, Center.

Monoclonal Antibodies Large scale production and their implications in AIDS research.

Discovery of New Antibodies Against HIV A Case Study of a Global Partnership Prof. Omu Anzala Program Director Kenya AIDS Vaccine Initiative (KAVI) Department.

Influenza Virus Vaccine Strain Selection Vaccines and Related Biological Products Advisory Committee (2/27/2013) Jerry P. Weir, Ph.D., Director.

New Monogram Biosciences Testing Capabilities: Influenza, RSV, Ebola and Other Respiratory and Enveloped Viruses.

Influenza Virus Vaccine Strain Selection Vaccines and Related Biological Products Advisory Committee (2/28/2014) Jerry P. Weir, Ph.D., Director.

Neutralizing Antibody Assays for HIV-1, SIV and SHIV: Recent Advances in Technology David C. Montefiori, Ph.D. Laboratory for AIDS Vaccine Research &

Influenza Virus Vaccine Strain Selection Vaccines and Related Biological Products Advisory Committee (2/25/2011) Jerry P. Weir, Ph.D., Director.

HIV Vaccine Clinical Trials: In Theory and on the Ground Prof. Omu Anzala Program Director Kenya AIDS Vaccine Initiative (KAVI) Department of Medical Microbiology.

Expanding Access to OpenClinica Data via LabKey Server Peter Hussey 2013 OpenClinica Global Conference Founding Partner, LabKey Software June 21, 2013.

NIAID Commitment to Influenza Research and Preparedness F. Gray Handley Associate Director for International Research Affairs National Institute of Allergy.

Characteristics of transmitted viruses in acute and early HIV infection Eric Hunter IAC 2010.

HIV Cellular Pathogenesis III

RV 144: The Thai Phase III Trial and Development of a Globally-Effective, Multi-Clade HIV Vaccine HIV Vaccine: Quo Vadis AIDS July 2010 Dr. Merlin.

Established in late 1999 Scientific/clinical resources Ethics committees Regulatory body TT

Summary Slide Presentation Are subtype differences important in HIV drug resistance? Lessells RJ, Katzenstein DK, de Oliveira T. Are subtype differences.

Conclusions Results show that the mutation at the N-linked glycosylation site N276D has a distinct influence on sensitivity to the HJ16 CD4bs neutralizing.

1 WHO Communicable Diseases, Surveillance & Response SARS Diagnostics and Laboratory Needs: the WHO Perspective C.E. Roth Dangerous and New Pathogens Global.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection DR. S.K CHATURVEDI DR. KANUPRIYA CHATURVEDI.

Molecular genetics of HIV-1 strains spreading in Russia Edward Karamov Ivanovsky Institute of Virology, Moscow 4th World Congress on Virology, 6-8 October.

Lab of Immunoregulation Berkower Lab Weiss Lab -- Angelo Spadaccini -- Russell Vassell -- Yisheng Ni -- Yong He -- Yisheng Ni -- Yong He –Hong Chen --

1 Adaptive, Specific Immunity and Immunization. 2 Specific Immunity – Adaptive Line of Defense The production of specific antibodies by a dual system.

Dr. Jeffrey Dorfman Cellular Immunology ICGEB Cape Town Autoreactivity of anti-HIV-1 neutralizing antibodies does not prevent broad antibody responses.

Determinants of HIV Transmission Eric Hunter Emory Vaccine Center.

HIV Cellular Pathogenesis III Benhur Lee, M.D.. Adult v. infant (IgG v. IgA) CTL response (MHC tetramers) p24 antigenimia Ab response Viral load.

ANIMAL MODELS FOR HIV VACCINES Girish N. Vyas, Ph.D. UCSF School of Medicine, San Francisco (UCSF) A quote from the keynote Address at the January, 2008.

Phenotypic properties influencing HIV-1 transmission fitness IAS Conference on HIV Pathogenesis, Treatment & Prevention Vancouver July 21 st 2015 Katja.

Structural Bioinformatics Section Vaccine Research Center/NIAID/NIH

The Body’s Defenses: The Immune System

1 Approaches to Demonstrate Effectiveness of Vaccines for Prevention of Group B Meningococcal Disease Introduction Vaccines and Related Biological Products.

New Technologies: the Role of the Private Sector Biotech’s Perspectives on Vaccine Development Alliances Peter Young CEO, AlphaVax, Inc.

Towards an antibody-based HIV vaccine

John R. LaMontagne Memorial Symposium on Pandemic Influenza Research April 4-5, 2005 Institute of Medicine Working Group Five: Immunology, Assay Standardization,

Research on killer HIV antibodies provides promising new ideas for vaccine design New discoveries about the immune defenses of rare HIV patients who produce.

Human clinical trial of DNA-MVA HIV vaccine candidate begins A Phase I study, called RV262, recently began to evaluate a combination DNA prime/MVA vector.

Hepatitis Virus. Primary members HAV HBV HCV HDV HEV.

25 Years of HIV Vaccine Research: What have we accomplished? José Esparza MD, PhD Senior Advisor on HIV Vaccines Global Health Program The Search for an.

THE IMMUNE RESPONSES TO VIRUSES

1 IMMUNE CORRELATES OF PROTECTION AGAINST INFLUENZA A VIRUSES IN SUPPORT OF PANDEMIC VACCINE DEVELOPMENT FDA/NIH/WHO Public Workshop, December 10-11, 2007.

1 Assessment of the Effectiveness of Small Pox Vaccines: Immunogenicity Assay Considerations Freyja Lynn Division of Bacterial, Parasitic and Allergenic.

CATEGORY: VACCINES & THERAPEUTICS HIV-1 Vaccines Shokouh Makvandi-Nejad, University of Oxford, UK HIV-1 Vaccines © The copyright for this work resides.

XVII International AIDS Conference 3-8 August 2008, Mexico City, Mexico Abstract Session on: "Molecular Epidemiology and Diversity of HIV" 04 August 2008,

HUMORAL IMMUNE RESPONSES HAVE LITTLE EFFECT ON CONTROLLING VIREMIA DURING SIVagm INFECTION OF AFRICAN GREEN MONKEYS Thaidra Gaufin Division of Microbiology.

HIV & Influenza Figure 2 | Schematic diagram of HIV‑1 and influenza A virus. Both HIV-1 and influenza A virus are approximately 80–120 nm in diameter and.

Anton Sholukh IgG dose dictates outcome for passive immunization of macaques with polyclonal anti-SHIV IgG against challenge with heterologous.

HVTN 702: A pivotal phase 2b/3 multi-site, randomized, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of ALVAC-HIV.

HIV-1 Vaccines Shokouh Makvandi-Nejad, University of Oxford, UK

Monoclonal Antibodies for HIV Prevention

HIV Vaccine Trials Network

? Neutralizing Antibodies: Research pathways in 2013 and beyond

Update on CBER HIV-1 Subtype panel

HIV Immunology Goes Out On a Limb

Volume 18, Issue 3, Pages (September 2015)

Structure of V3-containing HIV-1 gp120 core

Volume 155, Issue 3, Pages (October 2013)

HIV-Host Interactions: Implications for Vaccine Design

Joint work with Holly Janes, Peter Gilbert

Presentation transcript:

Design and Use of HIV-1 Reference Strains for Standardized Assessments of Vaccine-Elicited Neutralizing Antibody Responses David C. Montefiori, Ph.D. Laboratory for AIDS Vaccine Research & Development Duke University Medical Center Durham, NC

Standardization of HIV-1 Reference Strains HIV-1 exhibits an extraordinary degree of genetic variability that has given rise to multiple genetic subtypes and circulating recombinant forms (CRFs) of the virus. Information on the neutralization properties of each major genetic subtype and CRFs will inform vaccine design and will facilitate standardized assessments of vaccine-elicited neutralizing antibody responses.

The choice of target viruses has a significant influence on the outcome and interpretation of assay results The Need for HIV-1 Reference Strains

Overall neutralization-sensitivity Average High Low V3 & CD4i sensitive Where most vaccine-elicited responses are now TCLA & some 1 o isolates Relative abundance SPECTRUM OF NEUTRALIZATION-SENSITIVITIES Desired reference strains Where they need to be

How to Measure HIV-1 Vaccine-Elicited Neutralizing Antibody Responses An effective neutralizing antibody response will need to overcome the genetic variability, structural complexity and many neutralization escape mechanisms of the HIV-1 envelope glycoproteins. These same properties of the virus need to be part of the plan when assessing vaccine-elicited neutralizing antibody responses.

Compare new immunogens based on the potency and breadth of neutralizing antibody responses Prioritize the advancement of candidate vaccine Identify small but significant improvements in immunogen design Facilitate assay standardization and GCLP assay validation for clinical trials Inform new vaccine designs Need for Standard Panels of HIV-1 Reference Strains

Composition of Standard Virus Panels 12 viruses from acute/early sexually acquired infections per panel Not unusually sensitive or resistant to neutralization Genetically and antigenically diverse R5 biologic phenotype Molecularly cloned Env pseudotyped viruses are required for stability, reproducibility, improved GCLP and subsequent epitope analysis Grouping by clade – rational for this purpose: 6 major genetic subtypes: over 90% viruses Clades A, B, C, D, E (CRF01), A/G (CRF02) Need additional panels corresponding to vaccine trial sites Address key scientific questions relating to optimal panel composition and the possible need to modify initial panels to improve their correlative value.

Multi-Tiered Approach to Assessing Vaccine-Elicited NAb Responses Tier 1: Vaccine strain(s) and neutralization-sensitive strains not included in the vaccine. Tier 2: Panel of heterologous viruses matching the genetic subtype(s) of the vaccine; 12 viruses per panel. May include additional strains from vaccine trial sites Tier 3: Multi-clade panel comprised of six tier 2 viruses of each genetic subtype, excluding the genetic subtype(s) evaluated in Tier 2. May include additional strains from the proposed vaccine trial site. 12 viruses from each clade J. Virol. 79: (2005)

Scientific Issues to Address Effect of possible genetic drift – compare recent vs. older isolates Early/acute transmitted isolates vs chronic isolates Clonal viruses vs. virus swarms Plasma viruses vs PBMC coculture viruses Mother-to-child transmission (vaginal, breast milk viruses) Env pseudoviruses vs full-length molecular clones Effect of virus produced in non-lymphoid cells such as 293T compared to primary T- cells Impact of genetically engineered cell lines as target cells What is threshold bar for meaningful neutralization?

Full-length functional Env plasmids – recently donated to the NIH AIDS Research & Reference Reagent Program (B panel cat. #11227; C panel cat. #11326) Sexually acquired, acute/early infections R5 biologic phenotype Neutralization phenotypes represent primary isolates Genetically and antigenically diverse – sequences deposited in Genbank Well-characterized e.g., N-glycans, V-regions, MAb epitopes Transmissions M-M, F-M, M-F Initial Panels of 12 Clade B and 12 Clade C HIV-1 Reference Strains J. Virol. 79: (2005) – Clade B panel J. Virol., in press (2006) – Clade C panel

Emphasis on assays with Tier 2/Tier 3 viruses. Consider the magnitude (e.g., ID50 titer, % neutralization) and breadth (coverage) of the response. Exceed the minimum bar in the Vax004 phase III trial (~10% coverage for 50-80% neutralization; 0% coverage for >80% neutralization). These parameters are only part of a decision pathway that includes other immune responses. Decision Pathway for Prioritizing NAb-Based Vaccine Candidates

COMENTARY: Mascola, J. R., P. D'Souza, P. Gilbert, B. Hahn, N. L. Haigwood, L. Morris, C. J. Petropoulos, V. R. Polonis, M. Sarzotti-Kelsoe, and D. C. Montefiori Recommendations for the design and use of standard virus panels to assess the neutralizing antibody response elicited by candidate human immunodeficiency virus type 1 vaccines. J. Virol. 79: CLADE B REFERENCE PANEL: Li, M., F. Gao, J.R. Mascola, L. Stamatatos, V.R. Polonis, M. Koutsoukos, G. Voss, P. Goepfert, P. Gilbert, K.M. Greene, M. Bilska, D.L. Kothe, J.F. Salazar-Gonzalez, X. Wei, J.M. Decker, B.H. Hahn, and D.C. Montefiori Human immunodeficiency virus type 1 env clones from acute and early subtype B infections for standardized assessments of vaccine-elicited neutralizing antibodies. J. Virol., 79: CLADE C REFERENCE PANEL: Li, M,. J.F. Salazar-Gonzalez, C.A. Derdeyn, L. Morris, C. Williamson, J.E. Robinson, J.M. Decker, Y. Li, M.G. Salazar, V.R. Polonis, K. Mlisana, S.A. Karim, K. Hong, K.M. Greene, M. Bilska, J.T. Zhou, S. Allen, E. Chomba, J. Mulenga, C. Vwalika, F. Gao, M. Zhang, B.T.M. Korber, E. Hunter, B.H. Hahn, and D.C. Montefiori Genetic and neutralization properties of acute and early subtype C human immunodeficiency virus type 1 molecular env clones from heterosexually acquired infections in southern Africa. J. Virol., in press. ADDITIONAL PANELS: Brown, B. K., J. M. Darden, S. Tovanabutra, T. Oblander, J. Frost, E. Sanders-Buell, M. S. DeSouza, D. L. Birx, F. E. McCutchan, and V. R. Polonis Biologic and genetic characterization of a panel of 60 human immunodeficiency virus type 1 (HIV-1) isolates, representing clades A, B, C, D, CRF01_AE, and CRF02_AG, for the development and assessment of candidate vaccines. J. Virol. 79: REFERENCES

Dr. Montefioris laboratory is funded by: Division of AIDS/NIAID/NIH: Primate Core Immunology Laboratory for AIDS Vaccine Research and Development (PCIL) HIV Vaccine Trials Network (HVTN) Center for HIV/AIDS Vaccine Immunology (CHAVI) Bill & Melinda Gates Foundation: Collaboration for AIDS Vaccine Discovery (CAVD)