Virus Panels for Assessing Vaccine-Elicited Neutralizing Antibodies

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1 Virus Panels for Assessing Vaccine-Elicited Neutralizing Antibodies Michael Seaman, Ph.D. Center for Virology and Vaccine Research Beth Israel Deaconess Medical Center Harvard Medical School

2 J. Virol. 2005, 79(16): 10103

3 First Generation Clade B and C Reference Panels Clade B Panel (n=12) J. Virol. 2005, 79(16): Clade C Panel (n=12) Southern Africa J. Virol. 2006, 80(23): Clade C Panel (n=12) India Virology 2009, 385: 505

4 CA-VIMC Standard Virus Panel Consortium: >600 Functional env Clones for Pseudovirus Production Standard Multiclade Panel for Assessing bnab Potency/Breadth SVPC Carolyn Williamson Francine McCutchan Sodsai Tovanabutra Eric Sanders-Buell Jerome Kim Beatrice Hahn Ron Swanstrom Feng Gao Michael Thomson Gama Bandawe Cecilia Rademeyer Ray Dolin Lindsey Baden Subtype Number A 8 A (T/F) 3 B 12 B (T/F) 9 C 16 C (T/F) 15 BC 8 CRF01_AE 11 CRF01_AE (T/F) 4 CRF02_AG 9 G 7 D 4 D (T/F) 1 CD 5 AC/ACD 6 Total 118

5 Neutralization Serotype Discovery Project 205 sera, multiclade 219 viruses, multiclade NAb assay Heatmap SGA gp160 sequence Peptide array binding gp160 sequences Computational Analysis

6 Global Panel of Tier 2 HIV-1 Env Reference Strains Goal: Identify panel of Env pseudoviruses that are representative of the global epidemic Lasso statistical modeling identified 9 isolates that were highly predictive of neutralizing activity seen with larger panel of 219 Additional 3 isolates selected for greater genetic and antigenic diversity (B. Korber) Performed nearly as well as clade-matched panels for prediction of sub-type specific responses Isolate Clade 246_F3_C10_2 AC Ce1176_A3 C CNE55 CRF01_AE X1632_S2_B10 G Ce _B6 C BJOX CRF07_BC C TRO.11 B CH CRF07_BC X2278_C2_B6 B CNE8 CRF01_AE 398_F1_F6_20 A decamp et al., J. Virol. 88(5):2489

7 Neutralization Sensitivity of Global Panel (Prototypic Tier 1A) (Prototypic Tier 1B) Global Panel decamp et al., J. Virol. 88(5):2489

8 Global Panel of Tier 2 HIV-1 Env Reference Strains Applicable to multiple vaccine platforms and clades of HIV-1 in different parts of the world Facilitate cross-protocol comparisons Highly predictive of clade-specific responses Complementary to other panels that may be used, e.g., cladematched to vaccine and geographic region Useful as initial screen to identify and characterize bnabs decamp et al., J. Virol. 88(5):2489

9 Greater Neutralization Potency Within Clade Hraber et al, J. Virol. 88(21):12623 Seaman et al, J. Virol. 84(3):1439

10 Southern Africa Clade C NSDP Project

11 Clade C HIV-1 Env Pseudovirus Panel 200 early infection viruses that are more recent in the epidemic ( ): 130 South Africa (8 provinces) 28 Tanzania 23 Malawi 13 Zambia 6 Botswana Mostly heterosexual transmissions (1 breastfeeding transmission) Isolated within the first 100 days of infection. 67 seronegative (Fiebig I/II) 29 early seroconversion (Fiebig II/IV) 104 seropositive with seronegative test within the previous 100 days (Fiebig V/IV) Viruses phenotyped for Tier classification (global sensitivity to neutralization)

12 Mean log10 ID50 +/- SD Expected Distribution of Tier Phenotypes Each virus assessed for neutralization sensitivity to 30 chronic clade C HIV+ plasma Tier 1A: n=2 (1.3%) Tier 1B: n=17 (8.5%) Tier 2: n=150 (75%) Tier 3: n=31 (15.5%) Rademeyer et al., PLoS Path (in press)

13 Computational Selection of Optimal Tier 2 Clade C Reference Panel Objective: Select 12 Envs from larger panel of 200 that will be optimal for detecting vaccine-elicited neutralizing antibodies Strategy: Select based on mab IC50s and Env traits (loop length, charge, PNGs); compare with serum ID50 profiles Tier 2 Clade C Isolate Ce _C4 ZM233M.PB _F10_B6 Ce _2B7 So431_C1_1 ZM215F.PB v2.c B _G7.8 CAP D7.19 Ce2103_E8 Ko243_H6.3 Favored more sensitive viruses for detecting low-level Nab activity Captured diversity of known bnab sensitivities Captured diversity of Env properties associated with neutralization sensitivity (Peter Hraber, Bette Korber, manuscript in preparation)

14 Non-Standardized Approach: Rational Tier 2 Virus Panel Selection Select viruses on more sensitive end of spectrum (top quartile of geometric mean serological activity) Viruses that are as close as possible to sequence of vaccine immunogen Viruses that have good glycosylation and variable loop properties Viruses that are highly sensitive to epitope-specific bnabs of interest

15 Sensitivity of 200 C Panel Viruses to bnabs gp120/gp41: Next time gp41 MPER: 10E8** CD4 Binding Site: VRC01*, VRC07, VRC07-523, VRC13, 3BNC117* V2 Glycan: PGT145, PGDM1400**, PG9, CAP256-VRC26.08, CAP256-VRC26.25** V3 Glycan: PGT121**, PGT *, V * Phase I/II trials in progress ** Planned phase I trial

16 bnab Lineage Vaccine Strategies: Selection of Isolates with High Sensitivity Profile Wagh et al, PLoS Path (3):e

17 Summary of Points for Consideration Large numbers of Env pseudoviruses with geographic, genetic, and antigenic diversity have been extensively characterized and optimized panels have been developed: Global Panel for standardized assessments of NAb across multiple HIV-1 vaccine platforms in different parts of the world Optimally selected clade matched panels representative of circulating strains in regions in which vaccine trials being conducted Rational selection of isolates based on properties of vaccine immunogen(s) to increase the probability of detecting Tier 2 neutralization Rational selection of isolates based on bnab sensitivities for lineage induction vaccine strategies

18 Acknowledgements Duke University Kelli Greene Hongmei Gao David Montefiori LANL Kshitij Wagh Tanmoy Bhattacharya Alan Lapedes Peter Hraber Bette Korber VISC Allan decamp Raphael Gottardi Steve Self Clade C Panel Carolyn Williamson Cecilia Rademeyer Lynn Morris Jerome Kim Feng Gao Beatrice Hahn Ronald Swanstrom SVPC Carolyn Williamson Francine McCutchan Sodsai Tovanabutra Eric Sanders-Buell Jerome Kim Beatrice Hahn Ron Swanstrom Feng Gao Michael Thomson Gama Bandawe Cecilia Rademeyer Ray Dolin Lindsey Baden