RV144 The Thai Prime-boost HIV Vaccine Trial – Past, Present and by lse16211

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									RV 144




             RV144: The Thai Prime-boost HIV Vaccine Trial – Past,
             Present and Future

             Merlin L Robb, MD
             Deputy Director (Clinical Research), US Military HIV Research Program (MHRP)
             Walter Reed Army Institute of Research


             IMPAACT Leadership Meeting
              7 December 2009




         0                                                                            December 7, 2009
         A Phase III Trial of Aventis Pasteur Live Recombinant ALVAC-HIV (vCP1521) Priming
          With VaxGen gp120 B/E (AIDSVAX® B/E) Boosting in HIV-uninfected Thai Adults
RV 144


         Sponsor: US Army                   Funder: NIH and US Army

         Execution: Thai MOPH, RTA and Mahidol University
                Prevent acquisition of HIV infection
                 • Study sized to detect true vaccine efficacy (VE) of 50%
                Slow disease progression by decreasing viral load
                 • Study sized to detect a true VL difference of 0.4 Log10




         1                                                                   December 7, 2009
                   Vaccination and Follow-up Schedule
RV 144


                   Community-based, randomized, double-blind, placebo-controlled
                    trial (vaccine: placebo 1:1)

                   Healthy Volunteers: HIV negative, 18-30 years of age
                                                  HIV test,
                                      risk assessment and counseling




                              0.5       1                    2                    3     (time in years)



             6-month vaccination
                                             3 years of follow-up (every 6 mo.)
                  schedule

                             ALVAC®-HIV (vCP1521) priming at week 0, 4, 12, 24

         2
                             AIDSVAX® B/E gp120 boosting at week 12, 24               December 7, 2009
                                 Baseline Demographics
RV 144



         Balanced by arm for self-reported risk factors, self-perception of risk

          Gender                                    Age


             70                                        70                                       Vaccine
                   5033   5031
             60                                        60                                       Placebo
             50                                        50               3633 3708
                                    3164   3167
             40                                        40
         %                                         %
                                                  Vaccine   2297 2246               2267 2244
             30                                        30
                                                  Placebo
             20                                        20

             10                                        10

             0                                          0
                     Male            Female                  18-20       21-25       26-30




         3                                                                               December 7, 2009
                        Baseline Demographics
RV 144



             Risk Behavior

                 70                                 Vaccine

                 60                                 Placebo


                 50   3865   3924


                 40
             %
                                    2369   2292
                 30
                                                  1963   1982

                 20

                 10

                 0
                         Low         Medium          High
         4                                                      December 7, 2009
                  Breakdown of high risk group
RV 144




                    risk          vaccine #(%)   placebo # (%)

               self-percieved     801 (9.8%)      819 (10%)

              2-4 sex partners    520 (6.3%)      514 (6.3%)

              >4 sex partners      99 (1.2%)      196 (1.3%)

             no condom - casual   497 (6.1%)      439 (5.4%)

              no condom-same
                                    79 (1%)       90 (1.1%)
                    sex
               needle sharing      68 (0.8%)      65 (90.8%)

                   CSW             42 (0.5%)      44 (0.5%)
         5                                              December 7, 2009
             Condom use during trial
RV 144




         6                             December 7, 2009
                         Endpoint Accrual Timeframes
                                                                                                   
RV 144



                                                              PP – 12,542
                                                       mITT – 16,395
                                                       ITT – 16,402
                        Randomization
         Screening

             Up to 45
              days


                                   0.5           1                   2                    3   (time in years)



                           6-month
                          vaccination                3 years of follow-up (every 6 mo.)
                           schedule

                                         ®
                                  ALVAC -HIV (vCP1521) priming at week 0, 4, 12, 24
                                             ®
                                  AIDSVAX B/E gp120 boosting at week 12, 24
         7                                                                                December 7, 2009
                     Modified Intent-to-Treat (mITT)
RV 144



                Examines all HIV-uninfected subjects who were
                 randomized

                This was a pre-specified analysis in the Statistical Analysis
                 Plan
                    Primary analysis for DSMB examinations throughout the
                     trial




         8                                                            December 7, 2009
             Efficacy (mITT)
                                                        
RV 144




                               52,985 person-years

                               125 infections

                               Vaccine infections: 51
                               Placebo infections: 74

                               VE: 31.2%
                               p=0.04
                               95% CI: 1.1, 52.1
                               (O’Brien-Fleming-adjusted)




         9                                      December 7, 2009
              Efficacy (ITT)
                                                        
RV 144




                               52,985 person-years

                               132 infections
                               (7 prevalent)

                               Vaccine infections: 56
                               Placebo infections: 76

                               VE: 26.4%
                               p=0.08
                               95% CI: -4.0, 47.9




         10                                     December 7, 2009
                                Per Protocol (PP)
RV 144



                 12,542 subjects analyzed

                 Excludes 3,853 subjects who were included in the mITT
                     2,422 who did not receive all six study injections
                     1,412 who received any injection “out of window”
                     19 for other protocol violations

                 Excludes first 6 months (14%) of the 42-month trial period

                 Excludes 39 HIV-infected subjects (15 vaccine, 24
                  placebo), reducing the number of endpoints by 31%




         11                                                                December 7, 2009
              Efficacy (PP)
                                                      
RV 144




                              36,720 person-years

                              86 infections

                              Vaccine infections: 36
                              Placebo infections: 50

                              VE: 26.2%
                              p=0.16
                              95% CI: -13.3, 51.9




         12                                   December 7, 2009
                                       Early Viremia Endpoint
RV 144




                                  6   Vaccine                                   6
                                      Placebo

                                  5                                             5
              Log 10 Viral Load




                                                                      XX
                                  4                                             4


                                  3                                             3


                                  2   Mean Viral Load                           2
                                      Vaccine recipients: 4.3 log10
                                      Placebo recipients: 4.2 log10
                                      p = NS
                                  1                                             1
                                                        VACCINE       PLACEBO

                                        Dx        3 wks      6 wks    Average
         13                                                                         December 7, 2009
              No difference in post-infection CD4+ T cell count
RV 144




                               Mean CD4 T cell count @ notification and
                               verification visits
                               Vaccine: 554.7/ul (SE = 38.0)
                               Placebo:            567.5/ul (SE = 27.2)
                               p = NS




         14                                                        December 7, 2009
              Risk-stratified Treatment Effects (mITT)
RV 144




                               Vaccine                         Placebo                 Treatment Effect
                        N      Endpoints   PY Rate %    N      Endpoints   PY Rate %   Efficacy    95% CI
                                                                                                    -8.5,
              Low     3,865       17        0.135      3,924      29        0.227      40.4%        67.2
                                                                                                    -6.0,
         Medium       2,369       12        0.157      2,292      22        0.299      47.6%        74.0
                                                                                                    -72.7,
              High    1,963       22        0.349      1,982      23        0.364      3.7%          46.3

                     VE for each risk category was statistically similar




         15                                                                                  December 7, 2009
                  Exploratory Risk-stratified Analysis
RV 144



                 The point estimate of VE in high-risk volunteers was very
                  low with very large confidence intervals
                     Of the 125 infections
                      •   12 infections were seen in same-gender sex risk
                      •   2 infections were seen in CSW
                      •   Zero infections were seen in IDU
                     Of these 14 events, half occurred in each treatment group

                 The point estimates of VE in lower risk, heterosexual
                  volunteers were higher with very large confidence
                  intervals
                 These observations are exploratory and hypothesis-
                  generating

         16                                                                 December 7, 2009
RV 144
              Vaccine efficacy may decrease over time
                           Vaccine                 Placebo
                                 % HIV-1                    % HIV-1
                                                                         Vaccine
          Time     Cumulative   infection     Cumulative   infection
                                                                         Efficacy
          (mo)     Infections      rate       Infections      rate
                                                                           (%)
                                 (95% CI)                  (95% CI)

                                   0.15                       0.38
              12      12                         30                           61
                                (0.07,0.24)                (0.24,0.52)

                                   0.41                       0.64
              24      32                         50                           36
                                (0.27,0.55)                (0.46,0.82)

                                   0.58                       0.84
              36      45                         65                           31
                                (0.41,0.75)                (0.63,1.04)

                                   0.68                       0.96
              42      51                         74                           31
                                (0.49,0.87)                (0.74,1.18)
         17                                                          December 7, 2009
                        RV144 Immunogenicity – Study Flow
                    RV144 Immunogenicity – Study Flow
RV 144



                                           Randomized list (EMMES)
                                      Laboratory blinded to vaccine status
                                     3 Vaccine recipient: 1 Placebo recipient
                      200 participants         200 participants                 200 participants



                       IFN-γ ELISpot             IFN-γ/IL-2 ICS
                                                                           LPA         gp120/p24 BAb


          Months          0 and 12                 0 and 12                         0 and 6.5



         Antigens      gp160 (92TH023) - 162 peptide pool               A244 and            A244 and
                          p24 (LAI) - 120 peptide pool                  MN gp120            MN gp120
                                                                         IIIB p24           BH10 p24

         Match                   ALVAC (vCP1521)                                   AIDSVAX/ALVAC

           18                                                                             December 7, 2009
RV 144
                     ELISpot responses – Vaccinees
                                   6 months post-final vaccination



              Antigen(s) Frequency (%)
                                                                  ENV     GAG
              Env Only        17/152 (11)*




                                                    SFC/106PBMC
              Gag Only           6/148 (4)

              Env + Gag          3/151 (2)

               Any HIV       26/152 (17)**


         * P<0.05;**P<0.01 versus Placebo (N=38)
         19                                                             December 7, 2009
RV 144
                                          IFN-/IL-2 ICS
                                 6 months post-final vaccination


                                                  Frequency (%)
                                            CD4                          CD8

              Antigen               V                P          V                  P

              Env Only       45/142 (32) *        1/54 (2)   5/133 (4)         4/52 (8)

              Gag Only           0/144             0/56      3/136 (2)         1/53 (2)

              Env + Gag         2/142 (1)          0/54       0/131              0/51

               Any HIV        47/142 (33)*        1/54 (2)   8/131 (6)         5/51 (10)


         *P <0.0001 compared to placebo
         20                                                                    December 7, 2009
RV 144
                   Ag-Specific Lymphoproliferation
                              2 weeks post-final vaccination- FINAL DATA


                                                            Frequency (%)
                    Antigen                      Vaccinee              Placebo

                 gp120 E (A244)                  115/130 (88)              4/50 (8)



                  gp 120 B (MN)                   96/116 (83)              4/44 (9)



                        p24                       59/114 (52)              9/48 (19)



         P<0.001 compared to placebo group - all Antigens
         21                                                                      December 7, 2009
RV 144
                                     Binding Antibody
                                  2 weeks post-final vaccination



                                             Frequency             Reciprocal
                   Antigen
                                                (%)                  GMT

                      B gp120                                     31207 (800-204800)

                                                140/142 (99)

                      E gp120                                     14558 (200-204800)



                       B p24                     74/142 (52)        138 (50-1600)


              P<0.0001 compared to placebo group - all Antigens
         22                                                                  December 7, 2009
                                    Conclusions
RV 144



              The observed vaccine efficacy in the mITT analysis was 31.2% [p
               = 0.04, 95% CI (OBF) 1.1, 52.1].
                  A modest, statistically significant protective effect supported
                   by the trends observed in the ITT and PP populations

              There is no difference in early viremia by treatment arm.

             The vaccine regimen is safe and well tolerated.

             The regimen produced binding antibody, lymphoproliferative
              responses (env >gag) at high frequency

             IFN-g ELISPOT and IFN-g/IL-2 ICS responses were present in
              17% and 33% (CD4 only) respectively

             Self-reported behavioral risk was the same in vaccine and placebo
              groups.

         23                                                                December 7, 2009
                      Major Hypotheses Generated
RV 144


             Which vaccine component is working?
                 Unable to distinguish in RV 144
                 Power to detect in RV 144 limited
                  •   8 million PBMC at 2 week and 16 million PBMC at 6 month post 4th
                      vaccination
                  •   51 infections among vaccine recipients /Case-control subset
                      reserved
                 Non-human primate models – acquisition & low dose challenge

             Would a boost extend and improve efficacy?
               What boost: ALVAC, AIDSVAX, both?

             Would a better CD8 response add a viral load benefit?

             What is the nature of interaction between risk and efficacy?
         24      Methods to better estimate route and frequency of risk events
                                                                       December 7, 2009
                Organization of the Post-trial Effort
RV 144


                         ADVISORY GROUPS
                                                                   PA H Steering Committee
              Implications for future       Product
              clinical development        Development
              of this product            Advisory Group
                                                                    MHRP - DAIDS Steering
                                                                        Committee
                 Humoral &
              Innate Immunity

                  Cellular                                        RV144 Steering Committee
                 Immunity                    Scientific
                                             Steering
               Host Genetics                Committee
                                        Implications for future   Investigators may submit
                                        scientific inquiry into   proposals for research to
              Animal Models
                                        the result and
                                                                  our web site
                                        evaluation/design of
                 Scientific             other candidates and      <www.hivresearch.org>
              Advisory Groups           studies
         25                                                                      December 7, 2009
                                    Next Steps
RV 144


             Intensive characterization of immune response profile

             Evaluation of potential correlates based upon biological
              feasibility and frequency of response in RV 144
                 Rare and high frequency responses unrewarding
                 Only substantial effects will be detected

             New studies under consideration
                 Intensive immunogenicity assessment
                  •   Separate arms for each product and prime boost
                  •   Add later boost
                  •   Large blood collections
                  •   Mucosal collections

             Both products must have new lots produced
         26                                                            December 7, 2009
                                   Acknowledgements
RV 144



                 RV144 volunteers and community members

                 Participants in Phase I/II ALVAC and AIDSVAX B/E trials



                 AFRIMS – US and Thai Component

                 Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH

                 Faculty of Tropical Medicine, Mahidol University

                 Global Solutions for Infectious Diseases

                 Henry M. Jackson Foundation for the Advancement of Military Medicine

                 Ministry of Public Health, Thailand

                 sanofi pasteur

                 U.S. Military HIV Research Program, Walter Reed Army Institute of Research; U.S.
                  Army Medical Research and Materiel Command
         27                                                                                 December 7, 2009

								
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