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RV 144. ALVAC®-HIV and AIDSVAX® B/E Prime-Boost HIV-1 Preventive Vaccine Regimen The End of the Beginning. Nelson L. Michael, MD, PhD Colonel, Medical Corps, U.S. Army Director, U.S. Military HIV Research Program (MHRP) HVTN Meeting, Seattle, 18 November 2009. RV 144.

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alvac hiv and aidsvax b e prime boost hiv 1 preventive vaccine regimen the end of the beginning

RV 144

ALVAC®-HIV and AIDSVAX® B/E Prime-BoostHIV-1 Preventive Vaccine Regimen The End of the Beginning

Nelson L. Michael, MD, PhD

Colonel, Medical Corps, U.S. Army

Director, U.S. Military HIV Research Program (MHRP)

HVTN Meeting, Seattle, 18 November 2009

rv 144
RV 144

Primary Population Analyses

Subgroup Analyses

Basic Immunogenicity

Next steps

primary populations statistical analysis plan
Primary Populations (Statistical Analysis Plan)
  • All primary analyses were pre-specified prior to trial unblinding
  • Study design considerations
    • Based on ITT analysis in HIV-uninfected subjects
    • Powered to reduce acquisition during the vaccination period by 25%
    • Powered to reduce post-vaccination acquisition by 50%
  • mITT analysis was used by the independent Data and Safety Monitoring Board to judge trial futility throughout the study and efficacy at the Interim Analysis
intent to treat itt
Intent-to-Treat (ITT)

Examines all subjects, regardless of HIV infection status, who were randomized to either vaccine or placebo arm (16,402 subjects analyzed)

Includes 7 HIV infected subjects (5 vaccine, 2 placebo) discovered to be HIV infected at baseline by look-back analysis

efficacy itt
Efficacy (ITT)

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

per protocol pp
Per Protocol (PP)
  • 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%
efficacy pp
Efficacy (PP)

36,720 person-years

86 infections

Vaccine infections: 36

Placebo infections: 50

VE: 26.2%

p=0.16

95% CI: -13.3, 51.9

modified intent to treat mitt
Modified Intent-to-Treat (mITT)
  • 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
    • Any other outcome scenario (VE > 50%; VL effect only; no VE or VL effect) would have been based on the mITT as the primary analysis
efficacy mitt
Efficacy (mITT)

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)

endpoint accrual timeframes
Endpoint Accrual Timeframes

PP

mITT

ITT

Randomization

Screening

Up to 45 days

0.5

1

2

3

(time in years)

6-month vaccination schedule

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

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

AIDSVAX® B/E gp120 boosting at week 12, 24

summary of analyses
Summary of Analyses

Includes 5 vaccine and 2 placebo recipients who were HIV positive at baseline

Decreased event numbers, lower precision

rv 14413
RV 144

Primary Population Analyses

Subgroup Analyses

Basic Immunogenicity

Next steps

baseline risk stratified treatment effects mitt
Baseline Risk-stratifiedTreatment Effects (mITT)

VE for each risk category was statistically similar

exploratory risk stratified analysis
Exploratory Risk-stratified Analysis
  • 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
efficacy mitt evidence for early waning protective effect
Efficacy (mITT):Evidence for Early, Waning Protective Effect?

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)

cumulative vaccine efficacy over time
Cumulative Vaccine Efficacy Over Time

(Kaplan-Meier-based estimates)

When tested, efficacy did not decrease with time

conclusions
Conclusions
  • The mITT analysis demonstrates a modest, statistically significant protective effect, and this is supported by the trends observed in the ITT and PP populations
  • The mITT analysis is the most clinically relevant analysis as it:
    • Excludes volunteers with prior infection and reflects the study design and protocol
    • Does not assume that all four vaccinations are important
    • Does not assume that timing of all 4 vaccinations is critical
    • Limits bias compared to PP
questions
Questions

Subgroup analyses are provocative but not statistically robust; inferences require caution

  • Was the modest protective effect limited to non-high risk individuals?
  • Was the modest protective effect early and non-durable?
  • As neither ALVAC-HIV nor AIDSVAX was previously tested for efficacy in this population, what is their respective contribution to the observed effect?
rv 14420
RV 144

Primary Population Analyses

Subgroup Analyses

Basic Immunogenicity

Next steps

disclaimer
Disclaimer

I am not Nicole Frahm…….

rv144 immunogenicity study flow
RV144 Immunogenicity – Study Flow

RV144 Immunogenicity – Study Flow

Randomized list (EMMES)

Laboratory blinded to vaccine status

200 participants

200 participants

200 participants

IFN-γ/IL-2 ICS

IFN-γ ELISpot

LPA

gp120/p24 BAb

0 and 12

0 and 6.5

0 and 12

Months

gp160 (92TH023) - 162 peptide pool

p24 (LAI) - 120 peptide pool

Antigens

A244 and

MN gp120

IIIB p24

A244 and

MN gp120

BH10 p24

AIDSVAX/ALVAC

Match

ALVAC (vCP1521)

slide24

ELISpot responses – Vaccinees

6 months post-final vaccination

ENV

GAG

SFC/106PBMC

* P<0.05;**P<0.01 versus Placebo (N=38)

ag specific lymphoproliferation 2 weeks post final vaccination final data
Ag-Specific Lymphoproliferation2 weeks post-final vaccination- FINAL DATA

P<0.001 compared to placebo group - all Antigens

binding antibody 2 weeks post final vaccination
Binding Antibody2 weeks post-final vaccination

P<0.0001 compared to placebo group - all Antigens

immunogenicity summary
Immunogenicity Summary
  • Direct ex vivo cellular immunogenicity assessed by cytokine production at 6 months following completion of immunization was CD4-mediated, but CD8 responses following in vitro stimulation not assessed
  • The vaccine regimen induced robust CMI as measured by LPA responses to HIV subtypes B and E Env and more moderately to p24 at 2 weeks post immunization
  • CI responses overall were predominantly to HIV Env
immunogenicity summary 2
Immunogenicity Summary (2)

vCP1521 induced CD4 and antibody responses to the HIV-1 Gag antigen

Induction of humoral immune responses was robust to both subtypes of HIV-1 gp120 and less so to p24

Both CMI and humoral immune responses were comparable to the earlier phase I/II trial

Future work - Further definition of responding CD4 T cells, neutralizing antibody, ADCC and innate immunity

rv 14431
RV 144

Primary Population Analyses

Subgroup Analyses

Basic Immunogenicity

Next steps

organization of the post trial effort
Organization of the Post-trial Effort

ADVISORY GROUPS

PA H Steering Committee

Product Development Advisory Group

Implications for future clinical development of this product

MHRP - DAIDS Steering Committee

Humoral & Innate Immunity

RV144 Steering Committee

Cellular Immunity

Scientific Steering Committee

Host Genetics

Implications for future scientific inquiry into the result and evaluation/design of other candidates and studies

Animal Models

Scientific Advisory Groups

lessons learned
Lessons Learned
  • “C4”
    • Lines of communication and dissemination of information must be clear, uniform, documentable (minutes, guidance, SOPs)
  • Risk management
    • Initiate damage control before the damage occurs
  • Hire sufficient personnel
  • Community engagement—never enough nor complete
  • Cultural sensitivity ↔ scientific integrity
    • 24 Sep to 20 Oct 2009
churchill address to parliament 10 nov 1942
Churchill address to Parliament, 10 Nov 1942

Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning. Henceforth Hitler's Nazis will meet equally well armed, and perhaps better armed troops. Hence forth they will have to face in many theatres of war that superiority in the air which they have so often used without mercy against other, of which they boasted all round the world, and which they intended to use as an instrument for convincing all other peoples that all resistance to them was hopeless....

acknowledgements
Acknowledgements
  • RV144 volunteers and community members
  • 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