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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 monte@duke.edu

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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

monte@duke.edu

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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.

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The Need for HIV-1 Reference Strains

The choice of target viruses has a significant influence on the outcome and interpretation of assay results

slide4

Where they need to be

SPECTRUM OF NEUTRALIZATION-SENSITIVITIES

TCLA & some 1o isolates

Desired reference strains

Where most vaccine-elicited responses are now

Relative abundance

V3 & CD4i sensitive

Low

Average

High

Overall neutralization-sensitivity

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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.
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Need for Standard Panels of HIV-1 Reference Strains

  • 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
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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.
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12 viruses from each clade

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.

J. Virol. 79:10103-10107 (2005)

Multi-Tiered Approach to Assessing Vaccine-Elicited NAb Responses

scientific issues to address
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?
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Initial Panels of 12 Clade B and 12 Clade C HIV-1 Reference Strains

  • 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

J. Virol. 79:10108-10125 (2005) – Clade B panel

J. Virol., in press (2006) – Clade C panel

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Decision Pathway for Prioritizing NAb-Based Vaccine Candidates

  • 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.

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REFERENCES

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. 2005. 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. 79:10103-10107.

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. 2005. Human immunodeficiency virus type 1 env clones from acute and early subtype B infections for standardized assessments of vaccine-elicited neutralizing antibodies. J. Virol., 79:10108-10125.

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. 2006. 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. 2005. 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. 79:6089-6101.

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Dr. Montefiori’s 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)