Project Grant F31AI197677

THE EFFECTS OF DYNAMIC POPULATION-LEVEL IMMUNITY ON THE ACCURACY AND INTERPRETATION OF VACCINE EFFECTIVENESS ESTIMATES AND THE EVOLUTIONARY IMPACTS OF VACCINATION - PROJECT SUMMARY/ABSTRACT ACCURATE ESTIMATES OF VACCINE EFFECTIVENESS (VE) AGAINST DISEASE ARE NECESSARY TO EVALUATE THE PERFORMANCE OF VACCINATION CAMPAIGNS AND MOTIVATE UPDATES TO VACCINE STRAINS DUE TO THE PATHOGENS' RAPID EVOLUTION. IN INFLUENZA, VE VARIES SUBSTANTIALLY ACROSS YEARS, LOCATIONS, POPULATIONS, AND SUBTYPES; HOWEVER, EVEN WHEN VACCINE STRAINS ARE CONSIDERED WELL-MATCHED TO CIRCULATING STRAINS, MEASURED VE CAN STILL BE LOW. THE FACTORS UNDERLYING LOW VE, WHICH MAY BE STATISTICAL AS WELL AS BIOLOGICAL, REMAIN UNCERTAIN. THE DIRECT EFFECTS OF VACCINATION ON DISEASE AND INDIRECT EFFECTS OF VACCINATION ON VIRAL EVOLUTION REMAIN UNDERSTUDIED AND AFFECT THE ACCURACY AND INTERPRETABILITY OF VE ESTIMATES. OBSERVATIONAL STUDIES USED FOR VE ESTIMATION GENERATE BIASED ESTIMATES AND MAKE MANY SIMPLIFYING ASSUMPTIONS. CHANGING LEVELS OF IMMUNITY, INCLUDING IMMUNITY FROM PREVIOUS INFECTIONS AND VACCINATIONS, CAN AFFECT INDIVIDUALS' RESPONSE TO AND PROTECTION FROM VACCINATION. SOME STUDIES ATTEMPT TO CONTROL FOR PRIOR IMMUNITY THROUGH STRATIFICATION BY PRIOR-INFECTION STATUS; BUT IT REMAINS UNCLEAR HOW DIFFERENCES IN IMMUNITY BETWEEN VACCINATED AND UNVACCINATED POPULATIONS AFFECTS VE ESTIMATES ACROSS MULTIPLE YEARS AND HOW OBSERVATIONAL STUDIES SHOULD ACCOUNT FOR UNCERTAINTY IN POPULATION IMMUNITY. IN ADDITION TO DIRECT IMPACTS ON DISEASE OUTCOMES, A POSSIBLE EFFECT OF WIDESPREAD VACCINATION IS SELECTION FOR STRAINS THAT ESCAPE VACCINE-INDUCED IMMUNITY-WHICH MAY IMPACT FUTURE ESTIMATES OF VE. FURTHER STUDY IS REQUIRED TO ESTIMATE THE EFFECT THAT INCREASED VACCINATION COVERAGE HAS ON EVOLUTIONARY PRESSURES IN REAL-WORLD SETTINGS. THE PROPOSED WORK AIMS TO EVALUATE THE IMPACTS OF CHANGING LEVELS OF POPULATION IMMUNITY ON THE ACCURACY AND INTERPRETATION OF VE AND THE EVOLUTIONARY IMPACTS OF VACCINATION. AIM 1 WILL INVESTIGATE HOW DISTRIBUTIONS OF PRE- EXISTING IMMUNE PROTECTION, WANING VACCINE PROTECTION, AND CO-CIRCULATING VARIANTS AFFECT VE ESTIMATES ACROSS MULTIPLE YEARS. WE HYPOTHESIZE THAT VE ESTIMATES ARE SENSITIVE TO THE CHANGING DISTRIBUTIONS OF IMMUNITY IN THE VACCINATED AND UNVACCINATED POPULATIONS. IN AIM 2, COMPARTMENTAL MODELS WILL BE FIT TO EPIDEMIOLOGICAL DATA TO RE-ESTIMATE SEASONAL INFLUENZA VE ACCOUNTING FOR UNCERTAINTY IN POPULATION IMMUNITY. WE HYPOTHESIZE THAT TRUE VE ESTIMATES ARE LESS VARIABLE FROM YEAR-TO-YEAR WHEN ACCOUNTING FOR CHANGING POPULATION IMMUNITY. LASTLY, AIM 3 WILL INFER THE FITNESS OF SEASONAL INFLUENZA CLADES THAT ESCAPE VACCINE PROTECTION AND EVALUATE EVIDENCE FOR SIGNALS OF VACCINE-INDUCED SELECTION IN SEASONAL INFLUENZA IN MORE- AND LESS-VACCINATED POPULATIONS. WE HYPOTHESIZE THAT VACCINATION SELECTS FOR MORE ANTIGENICALLY DIVERGED CLADES AND THAT THE STRENGTH OF VACCINE- INDUCED SELECTION IS PROPORTIONAL TO VACCINATION COVERAGE. THROUGH THE PROPOSED RESEARCH TRAINING PLAN, THE CANDIDATE WILL DEVELOP MASTERY OF TECHNICAL AND PROFESSIONAL SKILLS NECESSARY TO INDEPENDENTLY LEAD TRANSLATIONAL RESEARCH IN INFECTIOUS DISEASE DYNAMICS WITH BROADER PUBLIC HEALTH IMPLICATIONS. THE CANDIDATE IS WELL POSITIONED TO EXCEL IN BOTH RESEARCH AND TRAINING ACTIVITIES UNDER DR. SARAH COBEY'S MENTORSHIP AND WITH THE RESOURCES OF THE UNIVERSITY OF CHICAGO.