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Future Directions of IAVI's R_D Program - HIV Vaccine Trials Network

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Future Directions of IAVI's R_D Program - HIV Vaccine Trials Network Powered By Docstoc
					Broadly Neutralizing Antibodies for HIV
         Immunoprophylaxis




                    Frances Priddy MD MPH
       Senior Director, Medical Affairs, Research and Development
               HVTN Full Group Meeting- November 2010
  IAVI R&D Program

• The modest level of protection in ALVAC +gp120 (RV-144), coupled with the
  lack of efficacy of Ad5 (gag-pol-nef/STEP) and gp120 (VaxGen), suggests that
  improved responses will be needed for successful HIV vaccine development


             Neutralizing Abs                Cell Mediated
                                            Immunity (CMI)
  Towards a Vaccine to Elicit Broadly
  Neutralizing Antibodies
                                                       Human
                                                       broadly neutralizing
                                                       mAb




                                                                Antigen


 Immune / Infected individual                          Molecular characterization
                                                       of Ab- Ag interaction




                                                                Immunogen design
                                                                and testing


         Combination of several immunogens
                     = vaccine

adapted from Burton, Nat. Rev. Immunol., 2:706, 2002
Questions for rational design of an HIV vaccine
eliciting bnAbs

•   Can vaccine-induced bnAbs protect humans
    from HIV infection?

•   What titer/concentration is required for
    protection?
    •   In plasma
    •   At the mucosa

•   What are the characteristics of viruses that
    are able to elude a mixture of bnAbs and
    still cause infection?
    Broadly neutralizing antibodies for HIV
    immunoprophylaxis

•    Rationale

     •   To help answer some major questions in
         rational HIV vaccine design
         •    Proof of concept
         •    Concentration
         •    Breadth of protection

     •   To develop a new biomedical HIV
         prevention method for specific
         populations
         •   Discordant couples
         •   MTCT
         •   Other populations?
Examples of antibody immunoprophylaxis for other
viral infections

 Rabies (HRIG)
 •  Human rabies IgG given with vaccine for post-exposure prophylaxis
 •  Polyclonal antisera
 •  IM injection
 •  Monoclonal antibodies under development

 Hepatitis B (HBIG)
 •  Post-exposure prophylaxis for occupational exposure; sexual
    exposure; infants born to HBsAg+ mothers
 •  Polyclonal antisera
 •  5ml IM injection for adults

 RSV
 •  Palivizumab
 •  Prophylaxis against RSV in high-risk infants <2 years
 •  Monthly 1-2ml IM injection
Evidence from human studies – mAbs for HIV
treatment

mAbs that bind HIV envelope glycoproteins
• 2G12, 2F5, 4E10
    • Anti-gp120, anti-gp41 mAb
    • Delay in viral rebound after treatment interruption
    • First direct evidence that bnAbs can suppress HIV virus in humans
        • High doses, viral escape

• PRO 542
   • CD4-Ig fusion protein, binds to gp120

Humanized mAbs to host cell receptors
• PRO 140
   • Anti-CCR5 mAb, binds to CCR5

• Ibalizumab
    • Humanized IgG, binds to CD4
    • Currently in phase 2b                  Trkola Nat Med 2005; Jacobsen AAC 2004; Jacobsen
                                             AAC 2008; Jacobsen AAC 2009
Evidence for HIV immunoprophylaxis from animal
studies

bnAbs can prevent SHIV infection in rhesus macaques, but high
concentrations required

• 2F5, 2G12, HIV IgG

• b12
    • 90% protection against high-dose vaginal challenge
    • Required high concentration (75X the IC50 in PBMC assay)
    • Lower dose of b12 successful in low-dose SHIV mucosal challenge model

Sterilizing immunity in NHP models requires roughly 20-50 times the IC90 in
PBMC assay with previously characterized, less potent bnAbs such as b12.

2G12
• Repeat low dose SHIV mucosal challenge model        Mascola J Virol 1999;
• Titers of 1:1 (IC90) protected 3/5 animals          Mascola Nat Med 2000;
                                                      Parren J Virol 2001; Hessel
                                                      Nat Med 2009; Hessell PLoS
                                                      Path 2009
Requirements for HIV immunoprophylaxis


•   Safe

•   Highly potent

•   Breadth

•   Long half-life

•   Feasible formulation for repeated delivery

•   Affordable

•   Accessible
    Broadly neutralizing monoclonal antibodies, binding to highly
    conserved regions on the native Env trimer, have been identified




                     PGV04,




Schief, W.R. et al.. Curr Opin HIV AIDS. 2009 Sep;4(5):431-40.
       IAVI Protocol G: elite neutralizers-score ≥ 2.5
                               Clade A       Clade B             Clade C      CRF01_AE

Rank    Score     Country      94UG103   92BR020   JRCSF IAVI C22 93IN905     92TH021
 1       3.67   Ivory Coast      900       900      2700   2700     2700        2700
 2       3        Zambia        300        300         2700    300     2700     2700
 5      2.83    Ivory Coast     300        300          900    300     2700     2700
 5      2.83    Ivory Coast     300        900         2700    900     2700      100
 5      2.83       Kenya        300        900          900    900     2700      300
 5      2.83    South Africa    300        900          900   2700     2700      100
 5      2.83      Rwanda        300       2700          900   2700     2700     <100
 8      2.69      Zambia        345        345         1190   1190     1190      345
 10     2.67        UK          300        900          900   2700      900      100
 10     2.67      Zambia        900        900          900    300     2700      100
 10     2.67      Uganda        900        900          900   2700      900     <100
 15     2.5     Ivory Coast     300        900          300    900      900      300
 15     2.5     South Africa    100        300          300   2700      900      900
 15     2.5     South Africa    300        300          300   2700     2700      100
 15     2.5         UK          300        900          300    900      900      300
 15     2.5     South Africa    2700       100          300   2700     2700     <100
 15     2.5       Uganda        900        900          900    900      900     <100
 15     2.5       Zambia        300       <100          900    300     2700     2700

                                                       (IC50 values)
     Identification of broadly neutralizing monoclonal
     antibodies PG9/PG16 & new target on HIV for bnAbs

Insights for Immunogen Design from Protocol G: PG9 & PG16

 •    Potently neutralize a high proportion of a cross-clade panel of 162 viruses
      and identify a new target for vaccine design

 •    PG9: 127/162 viruses neutralized
      (median IC50=0.22 µg/ml)

 •    PG16: 119/162 viruses neutralized
      (median IC50=0.15 µg/ml)

 •    PG9 and PG16 bind to conserved parts of
      V2/V3 loop (new target for vaccine design)
      and are trimer specific




Walker et al, Science, 2009, 326:285-9
PG9 and PG16 - Neutralization potency


                          Median IC50 (µg/mL) against viruses neutralized
                                       with an IC50 <50 µg/mL

  Cladea    # viruses   b12      2G12      2F5     4E10      PG9     PG16
    A          27       6.98     17.10    5.70      6.20     0.16     0.11
    B          31       0.80     0.82     2.41      5.22     0.43     0.70
    C          27       6.46     2.93     31.51     2.97     0.22     0.25
    D          25       1.47     7.71     3.17      4.60     0.10     0.02
 CRF01_AE      10       21.53    >50      0.26      0.51     0.08     0.03
 CRF_AG        10       10.40    0.95     0.64      1.42     0.80     0.03
    G          15       3.07     31.03    1.24      1.44     0.29     1.21
    F          15       >50      9.23     1.78      2.30     0.09     0.08
   Total      162       2.82     2.43     2.30      3.24     0.22     0.15
PG9 and PG16-Neutralization breadth

                            % viruses neutralized with an IC50 <50 µg/mL
  Cladea    # viruses   b12     2G12       2F5       4E10        PG9      PG16
   A            27       30       37        74         96         85        85
   B            31       58       71        68         97         74        74
   C            27       33       11        7          96         78        78
   D            25       48       24        56         96         76        60
CRF01_AE        10       30       0         89        100        100       100
 CRF_AG         10       30       50        80        100         80        60
   G            15       13       20        80        100         87        73
    F           15       0        21        87        100         67        64
  Total        162       35       32        60         98         79        73
                            % viruses neutralized with an IC50 <1.0 µg/mL
   Clade    # viruses   b12     2G12       2F5       4E10        PG9      PG16
     A          27       0        4         4          0          70        63
     B          31       32       39        23         0          45        42
     C          27       7        0         0          11         56        48
     D          25       12       8         12         8          48        44
 CRF01 AE       10       11       0         88         80         70        70
  CRF AG        10       10       30        60         30         40        50
     G          15       0        0         27         0          60        33
     F          15       0        14        13         28         80        79
   Total       162       11       12        19         12         57        51
                      New bnAbs from elite neutralizers
                      (Protocol G) identify novel and
                      conserved epitopes on the HIV
                      spike




VRC01, PGV04, HJ16
        b12 (CD4BS)
Neutralizing activity of novel MAbs isolated from
4 Protocol G elite neutralizers




Poignard, AIDS Vaccine 2010
Potential development plan

 •   Manufacturing

 •   Preclinical toxicology

 •   Phase 1 trial of a single or multiple bnAbs
     •  Safety
     •  Pharmacokinetics
        •    Serum concentration and half-life
        •    Mucosal concentration and half-life
     •  Serum concentrations several fold higher than IC90

 •   Additional trials
     •  Integrate multiple bnAbs, enhancements in half-life
        engineering and IM/SC formulation

 •   Phase 2b test-of-concept trial to evaluate safety and
     protection against HIV infection in at-risk population
Potential pitfalls
 •   For rational vaccine design

     •   bnAb activity may not mirror biologic activity
         of vaccine-induced bnAb
     •   Test of concept trial may not be able to
         determine precisely what concentration is
         required for efficacy


 •   For HIV immunoprophylaxis

     •   Can half life be extended to make repeated administrations
         feasible?
     •   Will volume be suitable for administration, if multiple bnAbs are
         used?
     •   Will 2 or 3 bnAbs have enough breadth to cover circulating viruses?
     •   As in NHP studies, bnAbs may offer partial, not complete protection
         if titers not sufficient
     •   Cost, acceptability, feasibility of delivery
Conclusions

•   Recently described very potent and broad neutralizing antibodies
    could be developed for HIV immunoprophylaxis



•   bnAbs for HIV immunoprophylaxis could inform rational HIV
    vaccine design




•   IAVI’s focus is on development of a safe and effective vaccine
    that prevents and controls HIV infection
    o   Our hypothesis is that this will require induction of bnAbs and cell mediated
        immunity


•   IAVI is collaborating with others on early clinical development of
    bnAbs for immunoprophylaxis
Acknowledgements

Protocol G collaborators       IAVI                IAVI at Scripps
and volunteers
                               Wayne Koff          Laura Walker
KAVI, Kenya
                               Pat Fast            Pascal Poignard
AFRIMS, Univ Mahidol,          Sanjay Phogat
Thailand                                           Dennis Burton
                               Melissa Simek
University of Cape Town,       Pervin Anklesaria
South Africa
                               Eddy Sayeed
UVRI, MRC, Uganda
                               Jennifer Lehrman    Monogram
Natl Serology Lab, Australia
                                                   Biosciences
WIHS, 5 US cities
Imperial College, UK
                                                   Theraclone
Rwanda Zambia HIV Research
Group (PSF and ZEHRP)
CeDReS, Ivory Coast
Institute of Human Virology,
Nigeria

				
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