Phenotyping of Human Immune Responses in Vaccination

Transcription

1 Phenotyping of Human Immune Responses in Vaccination Charles J. Hackett, Ph.D. National Institutes of Health National Institute of Allergy and Infectious Diseases February 9, 2012 Topics to be Covered Scientific constraints on testing of alternative immunization schedules What is immune phenotyping? Key questions Is there a relationship between acute vaccine adverse events and long-term health issues? Can immune phenotyping be used to inform potential changes in the practice of childhood immunization? 1

2 Infeasibility of Randomized Clinical Trials of Alternative Childhood Immunization Schedules Medical ethics/equipoise require that the current schedule be met Precludes a prospective, randomized, blinded, scientifically well-designed clinical trial Non-randomized/non-blinded studies have potential for inherent biases, poor data quality, and lack of confidence in conclusions Studies based on large national patient databases difficult or impossible to design or repeat e.g. Canadian study of DPT and asthma (McDonald et al, 2008, JACI 121:626) Question of Vaccine Adverse Events and Long-term Health What are the long-term health concerns? Examples raised include allergy, asthma, autoimmune diseases, neurological No clear epidemiologic relationship as evidence for causality No convincing mechanistic relationship between shortterm adverse events and development of long-range health problems 2

3 Requirements for Immunological Analyses of Acute Vaccine Adverse Events System to obtain quality samples from individuals experiencing a specific adverse event Informed consent Timeframe Clinical history and access to health records Sample types /sequential samples Biorepository/database Systems biology analyses in context of normal, expected signatures model development Tools for interpretation and dissemination of results, and development of follow-on studies Vaccine Responses Occur in Context of Large Number of Antigens in Daily Life Neonatal immune system development requires exposure to an evolving microbiome Number of antigens/epitopes encountered in common childhood infections Strep throat ~2000 antigens Otitis media, bacterial causes ~1700 antigens In current vaccines antigens for 12 vaccines Immune system develops memory to a large number of antigens Analysis requires highly advanced approaches 3

4 NIAID Human Immunology Project Consortium Purpose to profile human immune responses FY initiative, ~$20 M per year Awardee institutions Stanford University, Palo Alto, CA Yale School of Medicine, New Haven, CT Emory University School of Medicine, Atlanta, GA Dana Farber Cancer Institute, Boston, MA Mayo Clinic College of Medicine, Rochester, MN Baylor University, Dallas, TX Immune responses to vaccines against influenza, S. pneumoniae, and others 4

5 Yellow Fever Vaccination Stimulates Multiple Arms of the Immune System Gaucher D et al. J Exp Med 2008;205: What We Need to Know Criteria for a normal immune response in broad populations Age-dependent effects Genetics of responses Effects of past environmental and infectious exposures Nutrition, obesity, medications, lifestyle effects, many confounding variables 5

6 Potentially Confounding Variables in the Practice of Systems Vaccinology Populational (age, gender, ethnicity, diet, pathogen exposure, commensals) Individual (family genetic history, prior vacination, infection, stress, nutritional status, diseases) Cellular (frequency of cell subsets) Molecular (stochastic events in transcription, translation, post-translation) Technical (errors and biases in technologies, differences in data generation, acquisition, normalization, analyses) Nakaya, H. & Pulendran, B. Current Opinion in HIV & AIDS. 7(1):24-31, January Potential to Obtain Knowledge Relevant to Immunization Safety Rational design of vaccines New insights into recommendations related to vaccine usage Biomarkers of acute adverse responses Underlying signaling pathways Specific signatures 6

7 Example: Modular Analysis of Genes Active in a Viral Neurological Disease Tattermusch et al PLoS Pathogens Jan Needed to Move Forward Sample sparing assays Bioinformatics improvements Access to important cohorts and samples Medical ethics 7

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