A framework for assessing immunological correlates of protection in vaccine trials.

A central goal of vaccine research is to identify a vaccine-induced immune response that predicts protection from infection or disease. The term "correlate of protection" has been used to refer to at least 3 distinct concepts, which has resulted in confusion surrounding this topic. We propose precise definitions of these different concepts of immune correlates, using the nomenclature "correlate of risk," "level 1 surrogate of protection," and "level 2 surrogate of protection." We suggest a general framework for assessing these 3 levels of immune correlates in vaccine efficacy trials. To demonstrate the proposed principles, we analyze data from a 1943 influenza vaccine field trial, supporting Weiss strain A-specific antibody titers as a level 1 surrogate of protection. Other real and simulated examples are also discussed.

[1]  J. Heyse,et al.  Use of statistical models for evaluating antibody response as a correlate of protection against varicella , 2002, Statistics in medicine.

[2]  R J Carroll,et al.  On meta-analytic assessment of surrogate outcomes. , 2000, Biostatistics.

[3]  Michael G Hudgens,et al.  Correlation between immunologic responses to a recombinant glycoprotein 120 vaccine and incidence of HIV-1 infection in a phase 3 HIV-1 preventive vaccine trial. , 2005, The Journal of infectious diseases.

[4]  A. Fauci,et al.  The AIDS epidemic--considerations for the 21st century. , 1999, The New England journal of medicine.

[5]  P. Peduzzi,et al.  Immunity to influenza in older adults with chronic obstructive pulmonary disease. , 2004, The Journal of infectious diseases.

[6]  M. Hudgens,et al.  What constitutes efficacy for a human immunodeficiency virus vaccine that ameliorates viremia: issues involving surrogate end points in phase 3 trials. , 2003, The Journal of infectious diseases.

[7]  H. Hallander,et al.  Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis. , 1998, Vaccine.

[8]  Thomas R. Fleming,et al.  Surrogate Endpoints in Clinical Trials , 1996 .

[9]  P. Anderson.  The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. , 1984, The Journal of infectious diseases.

[10]  T R Fleming,et al.  Surrogate markers in AIDS and cancer trials. , 1994, Statistics in medicine.

[11]  R. Prentice.  Surrogate endpoints in clinical trials: definition and operational criteria. , 1989, Statistics in medicine.

[12]  D. Rubin.  Causal Inference Using Potential Outcomes , 2005 .

[13]  Geert Molenberghs,et al.  Statistical challenges in the evaluation of surrogate endpoints in randomized trials. , 2002, Controlled clinical trials.

[14]  M J Daniels,et al.  Meta-analysis for the evaluation of potential surrogate markers. , 1997, Statistics in medicine.

[15]  P. Mäkelä,et al.  Haemophilus influenzae type b capsular polysaccharide vaccine in children: a double-blind field study of 100,000 vaccinees 3 months to 5 years of age in Finland. , 1977, Pediatrics.

[16]  Siber Gr.  Methods for estimating serological correlates of protection. , 1997 .

[17]  R. Schneerson,et al.  Correlation between pertussis toxin IgG antibodies in postvaccination sera and subsequent protection against pertussis. , 2000, The Journal of infectious diseases.

[18]  Tuofu Zhu,et al.  Persistence of Extraordinarily Low Levels of Genetically Homogeneous Human Immunodeficiency Virus Type 1 in Exposed Seronegative Individuals , 2003, Journal of Virology.

[19]  N. Day,et al.  Surrogate markers in AIDS and cancer trials. , 1995, Statistics in medicine.

[20]  M. Halloran,et al.  Design and interpretation of vaccine field studies. , 1999, Epidemiologic reviews.

[21]  Wayne C Koff,et al.  HIV vaccine design and the neutralizing antibody problem , 2004, Nature Immunology.

[22]  D. Rubin,et al.  Principal Stratification in Causal Inference , 2002, Biometrics.

[23]  Dean Follmann,et al.  Augmented Designs to Assess Immune Response in Vaccine Trials , 2006, Biometrics.

[24]  Anthony S. Fauci,et al.  Toward an Understanding of the Correlates of Protective Immunity to HIV Infection , 1996, Science.

[25]  C. Glymour,et al.  STATISTICS AND CAUSAL INFERENCE , 1985 .

[26]  T. Francis,et al.  A CLINICAL, EPIDEMIOLOGICAL AND IMMUNOLOGICAL EVALUATION OP VACCINATION AGAINST EPIDEMIC INFLUENZA , 1945 .

[27]  M. Alter,et al.  A Comprehensive Immunization Strategy to Eliminate Transmission of Hepatitis B Virus Infection in the United States , 2006, Pediatrics.

[28]  D. DeMets,et al.  Considerations in the evaluation of surrogate endpoints in clinical trials. summary of a National Institutes of Health workshop. , 2001, Controlled clinical trials.

[29]  Andrew J Dunning.  A model for immunological correlates of protection. , 2006, Statistics in medicine.

[30]  D. Bernstein,et al.  Antibody-Mediated Neutralization of Pertussis Toxin-Induced Mitogenicity of Human Peripheral Blood Mononuclear Cells , 2004, Infection and Immunity.

[31]  D. Ruppert,et al.  Measurement Error in Nonlinear Models , 1995 .

[32]  P. Villari,et al.  Methodological quality of studies and patient age as major sources of variation in efficacy estimates of influenza vaccination in healthy adults: a meta-analysis. , 2004, Vaccine.

[33]  M. Hughes.  Evaluating surrogate endpoints. , 2002, Controlled clinical trials.

[34]  M. L. Clements-Mann.  Lessons for AIDS vaccine development from non-AIDS vaccines. , 1998, AIDS research and human retroviruses.

[35]  G. Siber.  Methods for estimating serological correlates of protection. , 1997, Developments in biological standardization.