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HVTN 080

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					              HVTN 080 Update


                               Rochester
                            UPenn
                    Vanderbilt
                                Inovio
                                Profectus


Spyros Kalams, M.D. Vanderbilt University Medical Center
CELLECTRA Pulse Generator and components for
      intramuscular delivery of vaccines




                                                2
           HVTN 080 schema
A phase 1 clinical trial to evaluate the safety and
immunogenicity of PENNVAX™-B (gag, pol, env)
  vaccine, with or without IL-12 DNA plasmid,
 delivered via electroporation in healthy, HIV-1–
          uninfected adult participants
 HVTN 080 Discontinuation of Vaccinations and
          Early Study Termination

Discontinuation of vaccinations (n=3)
DNA only:    1 exacerbation of pre-existing spinal
             stenosis (not related to vaccine)
DNA+IL-12: 1 participant refused
             1 mild arm pain/tenderness after 1st vac

Early study terminations (n=2)
DNA only:     1 unable to adhere to schedule
DNA+IL-12: 1 unable to contact (same person that
              dropped out after 1st vaccination)
HVTN 080 Pain Assessment (scale 0-10)
      All vaccinations combined
                               HVTN 080 ICS Responses Against
                             ANY Global PTE Peptides: CD4+ T Cells




     Time Point:       Placebos        2wks post 2wks post 6mo post               2wks post 2wks post        6mo post
                       & Day 0           VAC2      VAC3      VAC3                   VAC2      VAC3             VAC3
Treatment Group:                                   T1: PV-B DNA (EP)                   T2 & T3: PV-B DNA + IL-12 (EP)

       Positive Response       Negative Response            Visit 5 (D42): 2wks post VAC2       Visit 10 (D273): 6mo post VAC3   1
     EP= Electroporation via VGX CELLECTRA                      0
                                                            Visit 7 (D98): 2wks post VAC3
                               HVTN 080 ICS Responses Against
                             ANY Global PTE Peptides: CD8+ T Cells




     Time Point:       Placebos        2wks post 2wks post 6mo post               2wks post 2wks post        6mo post
                       & Day 0           VAC2      VAC3      VAC3                   VAC2      VAC3             VAC3
Treatment Group:                                   T1: PV-B DNA (EP)                   T2 & T3: PV-B DNA + IL-12 (EP)

       Positive Response       Negative Response            Visit 5 (D42): 2wks post VAC2       Visit 10 (D273): 6mo post VAC3   5
     EP= Electroporation via VGX CELLECTRA                      0
                                                            Visit 7 (D98): 2wks post VAC3
     HVTN 080 ICS Responses Against
ANY Global PTE Peptides: CD4+ T Cells by BMI




                                               1
     HVTN 080 ICS Responses Against
ANY Global PTE Peptides: CD8+ T Cells by BMI




                                               1
       HVTN 080 summary
• HIV DNA+/- IL-12 delivered via EP is
  safe and well tolerated
• High levels of cellular immune
  responses
  – CD4+ 80%
  – CD8+ 52%
  – CD4+ or CD8+    90% overall response
          HVTN 070 vs. 080

• HVTN 070
  – 4 vaccinations (0, 1, 3, 6 months)
  – 2 injections per visit
  – 6 mg PennVAXB
  – 1.5 mg IL-12
  – IM, no electroporation
         HVTN 070 and 080 CD4+ T-cell Responses
             PVB+IL−12 arms; ANY Peptides
                                         P < 0.0001
                                                                       P=0.005
                              P=0.0004




       Time Point:   2wks post   2wks post VAC4            2wks post VAC2 2wks post VAC3
                       VAC3
        Protocol :          HVTN 070                                  HVTN 080
Positive response                 M0 (VAC1)             M1(VAC2)        M3(VAC3)       M6(VAC4)
                        070       PV-B+ IL-12          PV-B+ IL-12     PV-B+ IL-12    PV-B+ IL-12
Negative response
                        080      PV-B+ IL-12 +        PV-B+ IL-12 +   PV-B+ IL-12 +      N/A        1
          HVTN 070 vs. 080 CD8+ T-cell Responses
             PVB+IL−12 arms; ANY Peptides
                                           P = 0.0003
                                                                   P<0.0001
                              P=0.01
                                                  P =0.005




       Time Point:   2wks post   2wks post VAC4         2wks post VAC2 2wks post VAC3
                       VAC3
        Protocol :          HVTN 070                              HVTN 080
Positive response                M0 (VAC1)         M1(VAC2)        M3(VAC3)       M6(VAC4)
                        070      PV-B+ IL-12      PV-B+ IL-12     PV-B+ IL-12    PV-B+ IL-12
Negative response
                        080     PV-B+ IL-12 +    PV-B+ IL-12 +   PV-B+ IL-12 +      N/A        5
        HVTN 080 vs. 070

• HVTN 080 higher response rate despite
  half the dose of DNA, and only 3
  vaccinations
       HVTN 080 other results

• Antibody results:
  – P55 binding 1/10 T1, 6/25 Group (T2+T3)
  – Env binding 1/10 T1, 0/25 group (T2+T3)
• Neut ab results:
  – Low titer <1:20 responses to MW965.26 only (5
    others negative)
  – T1 Post 2nd vaccination 6/10; post 3rd 2/10
  – (T2+T3) 2nd vaccination 2/27; post 3rd 3/27
    Acknowledgements 080 protocol team

Co-Chair Srilatha Edupuganti          Rochester CRS
                                        Mike Keefer
Protocol team leader Marnie Elizaga
                                        Deb Dunbar
Statistician Barbara Metch            UPenn CRS
Medical Officer Adam Sherwat           Ian Frank
                                       Cathy Bunce
Vaccine Developer: David Weiner       Vanderbilt CRS
                                         Kyle Rybczyk
Electroporator: Inovio                   Katie Crumbo
                                         Shawan Carr
        Niranjan Sardesai
                                         Rita Smith
        Amir Khan
                                         Frances Robinson
IL-12 Adjuvant: Profectus (formerly      Gwendolyn Reese
        Wyeth/Pfizer)
        Michael Egan
        John Eldridge
                             HVTN 080 ICS Responses Against
                         Any ENV Global PTE Peptides: CD4+ T Cells




     Time Point:       Placebos        2wks post 2wks post 6mo post               2wks post 2wks post        6mo post
                       & Day 0           VAC2      VAC3      VAC3                   VAC2      VAC3             VAC3
Treatment Group:                                   T1: PV-B DNA (EP)                   T2 & T3: PV-B DNA + IL-12 (EP)

       Positive Response       Negative Response            Visit 5 (D42): 2wks post VAC2       Visit 10 (D273): 6mo post VAC3   2
     EP= Electroporation via VGX CELLECTRA                      0
                                                            Visit 7 (D98): 2wks post VAC3
                             HVTN 080 ICS Responses Against
                         Any ENV Global PTE Peptides: CD8+ T Cells




     Time Point:       Placebos        2wks post 2wks post 6mo post               2wks post 2wks post        6mo post
                       & Day 0           VAC2      VAC3      VAC3                   VAC2      VAC3             VAC3
Treatment Group:                                   T1: PV-B DNA (EP)                   T2 & T3: PV-B DNA + IL-12 (EP)

       Positive Response       Negative Response            Visit 5 (D42): 2wks post VAC2       Visit 10 (D273): 6mo post VAC3   6
     EP= Electroporation via VGX CELLECTRA                      0
                                                            Visit 7 (D98): 2wks post VAC3
                Matched Env peptide results
                                       ENV ICS ASSAY                              STANDARD ICS ASSAY - PTEG
pub_id    arm    tcellsub   PVB resp PVB mag PTEG resp PTEG mag    Env resp Env mag Gag resp Gag mag Pol resp Pol mag
080-008   T3     CD4+               1    0.067       0     0.023           0    0.030       0     0.031      1    0.058
080-008   T3     CD8+               0    0.020       0     0.017           0    0.000       0     0.000      0    0.001
080-010   T2     CD4+               0    0.000       0     0.003           0    0.008       1     0.122      1    0.126
080-010   T2     CD8+               1    0.135       0     0.030           0    0.002       0     0.000      1    0.293
080-018   T3     CD4+               0    0.028       0     0.023           0    0.016       1     0.125      1    0.067
080-018   T3     CD8+               1    0.168       0     0.059           1    0.089       0     0.020      1    0.104
080-021   T3     CD4+               0    0.007       0     0.017           0    0.017       1     0.125      1    0.079
080-021   T3     CD8+               1    0.888       0     0.048           1    0.106       0     0.000      1    0.243
080-028   T3     CD4+               0    0.037       0     0.004           0    0.029       1     0.264      1    0.173
080-028   T3     CD8+               1    0.078       0     0.001           0    0.034       0     0.011      0    0.051
080-035   T2     CD4+               0    0.031       0     0.044           0    0.037       1     0.066      1    0.077
080-035   T2     CD8+               0    0.046       1     0.223           1    0.113       0     0.006      0    0.011
080-046   T3     CD4+               0    0.026       0     0.014           0    0.016       1     0.192      1    0.077
080-046   T3     CD8+               1    0.105       0     0.000           0    0.005       0     0.014      0    0.022
080-048   T2     CD4+               0    0.007       0     0.011           0    0.010       0     0.015      0    0.040
080-048   T2     CD8+               0    0.030       0     0.036           1    0.051       0     0.007      1    0.275



                 5/27 responders (CD8+)                                 4/27 responders (CD8+)
   Matched Env peptide results
• CD4 original 0/27; CD4 matched 1/27
• CD8+ Original Env PTE 4/27 (14.8%)
• On repeat, only 1 of these 4 was positive with
  PTE (low level responses to begin with)
• CD8 repeat 1/27 with PTE; 5/27 with matched
            Future directions
• Consider 4th dose as a “boost”-in macaques
  DNA is able to boost itself
• Possibly combine with other approaches as
  part of a prime-boost, or head to head
  comparisons
• Next generation devices (ID, next gen IM)

				
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