Elsevier

Vaccine

Volume 28, Issue 29, 23 June 2010, Pages 4539-4547
Vaccine

Conference report
Utilization of serologic assays to support efficacy of vaccines in nonclinical and clinical trials: Meeting at the Crossroads

https://doi.org/10.1016/j.vaccine.2010.04.094Get rights and content

Abstract

In May 2009 the National Institute of Allergy and Infectious Diseases hosted a workshop on serologic assays that support vaccine efficacy evaluations. The meeting promoted exchange of ideas among investigators from varying disciplines who are working on anti-infectious agent vaccines at different stages of development. The presentations and discussions at the workshop illustrated the challenges common across various pathogens with recurring themes: (1) A thorough understanding of the science regarding the pathogen and the host response to disease and immunization is fundamental to assay selection. (2) The intended use of the immunoassay data must be clearly defined to ensure appropriate specificity, accuracy, and precision; a laboratory must also commit resources to assure data quality and reliability. (3) During vaccine development, an immunoassay may evolve with respect to quality, purpose, and degree of standardization, and, in some cases, must be changed or replaced as data are accumulated. (4) Collaboration on standardized reagents and methods, harmonization efforts, and multidisciplinary teams facilitate consistent generation of quality data. This report provides guidance for effective development and utilization of immunoassays based on the lessons learned from currently licensed vaccines. Investigators are encouraged to create additional opportunities for scientific exchange, noting that the discussed themes are relevant for immunoassays used for other purposes such as therapeutics and diagnostics.

Introduction

On May 5–6, 2009, in Bethesda, MD, the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID) hosted a workshop on the use of serologic assays to support vaccine efficacy in clinical studies. The purpose of this meeting was to provide a forum for the exchange of ideas among researchers and clinicians and to identify some common themes across pathogens and technologies regarding the development and use of immunoassays. Participants in the meeting were those involved in vaccine or immunotherapeutic development programs that have been evaluated in clinical trials as well as those that are expected to enter Phase I clinical trials in the near future. Also attending were regulatory reviewers involved in evaluation of clinical and nonclinical assay data.

Generation of clinical data demonstrating efficacy and safety remains the gold standard for assessing candidate vaccines protecting against infectious diseases; however, efficacy studies for some products may be unfeasible because of statistical limitations (e.g., disease incidence is too low or variable) or because of ethical considerations (e.g., alternative vaccines or therapeutics are available). The primary purpose of this meeting was to review some vaccines that have been licensed recently and to extract some of the lessons learned which could facilitate the use of serologic assays to evaluate current and future candidate vaccines. The serologic data and experiences associated with vaccine evaluations were presented in three sessions (Table 1): (1) general concepts when using immunoassays to evaluate efficacy, (2) specific vaccines for which humoral correlates have been used for vaccine licensure, and (3) evolving issues related to humoral correlates of protective immunity with respect to new vaccine evaluations. The final session was a panel discussion with participation from the audience that addressed issues and questions raised during the meeting. This summary represents a distillation of the presentations and discussions, uniting the common themes and issues that appeared throughout the meeting.

One issue raised early in the meeting was the lack of clarity of terminology. For many terms, no definitions are universally accepted; this lack of clarity can itself hinder effective communication. In order to facilitate interpretation, we have defined our usage; however, these should not be considered consensus definitions. “Correlate” is a variable that is statistically related to a clinical endpoint, while a “protective correlate” or “predictive correlate” is a correlated variable that, based on additional evidence, is reasonably likely to predict the clinical endpoint [1], [2], [3]. We avoid using the term “surrogate”, as its definition indicates that the measured variable (serologic data, in our case) can totally explain and replace a defined clinical endpoint [1]. “Immunoassays” is a broad term representing measurement of any number of biologic processes associated with immune function. The scope of this meeting was limited to serologic assays which identify and quantify antibodies, rather than assays that assess the cellular activities and functions. Serologic assays include both binding assays (e.g., enzyme linked immunosorbent assays (ELISAs) and hemagglutination inhibition (HI) assays) and functional assays (e.g., bactericidal, opsonophagocytic, neutralization assays). Assay “standardization” is defined as the establishment of an assay methodology within and across laboratories that utilizes a common standard operating protocol (SOP), defining reagent requirements as well as procedures, and generates comparable data sets. Assay “harmonization” is defined as the identification, through an iterative experimental process, of critical parameters that affect assay performance, and the development of related SOPs that conform in those critical variables, leading to the generation of comparable data sets within and across laboratories.

Several common themes emerged and are the focus of this report.

  • 1.

    Clinical and laboratory testing strategies aimed at defining a protective correlate should be based on an understanding of the biology of a pathogen, the host interactions, and the natural protective responses. This knowledge can lead to the selection of relevant assays which are the most likely to be predictive of clinical benefit.

  • 2.

    The intended use of the assay needs to be clearly defined before selecting and optimizing the methodology. The assay must be designed to yield data appropriate for the question being asked. Assays need to be of sufficient quality and perform reliably to yield usable data, and the assay format must be practical. “Data are only as good as the quality of the assay used to generate them.” (D.L. Burns presentation).

  • 3.

    Changes in immunoassays are expected during the vaccine development process. For any particular assay, there is an evolution in the quality, purpose, and degree of standardization. The most rigorous requirements are for assays where the resultant data will be used to consider vaccine licensure and to define correlates of protection. Additionally, the assay itself sometimes must be changed or replaced as the knowledge base increases, the experience with the candidate vaccine matures, and new technologies are developed.

  • 4.

    Effective identification and utilization of available collaborative resources promote assay evolution, improve testing efficiency, and facilitate generation of comparable data over time. Among these resources are standardized critical laboratory reagents and methods, inter-laboratory harmonization efforts, and multidisciplinary teams that include statistical expertise.

Section snippets

Understanding the pathogen and the immune response to vaccines

Ideally, vaccine developers formulate a product that elicits a protective immune response specific for the target pathogen. Rational vaccine design requires the best possible understanding of the nature of the immune response to the pathogen and the cascade of immunological events that culminate in protection [4]. Identification of the important types of response (e.g., humoral or cellular, specific isotype or subclass of immunoglobulin) and the kinetics of response to the initial and

Cell-mediated immunoassays and other assays

Although the meeting focused on antibody assays, immunological assays to measure cell-mediated immune (CMI) responses are also critically important to the assessment of many vaccines. Elkins noted that the state of knowledge related to CMI assays is less mature than for serum antibody assays. Analogous to the discussion above comparing functional and binding assays, many investigators believe that CMI-related assays are inherently better than antibody assays for many products; however, direct

Summary and conclusions

This meeting was organized to bring together investigators from diverse disciplines who are working with different pathogens at various stages of vaccine development. The goal was to encourage communication and explore common experiences with the development, implementation, and potential interpretation of data from serologic assays. One of the overarching goals of the meeting was to facilitate efficient immunoassay development for candidate vaccines by learning lessons from more mature

Acknowledgements

This meeting was funded by the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, and National Institutes of Health.

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    Margaret C. Bash and Drusilla L. Burns, US Food and Drug Administration, Rockville, MD 20852, United States; Jan Callahan, Callahan Associates, La Jolla, CA 874 92037, United States; James B. Dale, University of Tennessee Health Science Center, Memphis, Memphis, TN 38104, United States; Morven S. Edwards, Baylor College of Medicine, Houston, TX 77030, United States, United States; Karen L. Elkins, US Food and Drug Administration, Rockville, MD 20852, United States; Carl E. Frasch, Frasch Biologics Consulting, Martinsburg, WV, United States; Steven W. Hildreth, Sanofi Pasteur, Swiftwater, PA 18370, United States; Katrin Jansen, Pfizer Inc., Pearl River, NY 10965, United States; Robert C. Kohberger, Blair and Associates, Greenwich, CT 06831, United States; Michael Kalos, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, United States; Karen C. Meysick, US Food and Drug Administration, Rockville, MD 20852, United States; ChrisAnna M. Mink, Harbor-UCLA Medical Center, Torrance, CA 90502, United States; Moon Nahm, University of Alabama, Birmingham, AL 35294, United States; Brian D. Plikaytis, Centers for Disease Control and Prevention, Atlanta, GA 30333, United States; David S. Stephens, Emory University School of Medicine, Atlanta, GA 30322, United States; Kanta Subbarao and Christopher Taylor, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, United States; Edward E. Walsh, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, United States.

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