Influenza viruses are constantly evolving, resulting in vaccine strains being selected for reformulation every season. Annual estimates of influenza vaccine effectiveness (VE) in preventing influenza-related morbidity are essential in evaluating the protection provided by annual, nationwide vaccination programs. Our long-term goal is to advance the understanding of the epidemiology of viral respiratory infections while measuring the public health impact of immunization on reducing the overall burden of illness and on improving the health of the population. We plan to systematically evaluate the influenza VE with the CDC ACIP recommended annual universal immunization strategy in the Baylor Scott & White Health, Central Texas (BSWCTX) patient population. The objective is to obtain reliable vaccination information for the enrolled population and provide accurate estimates of annual VE to prevent influenza-associated medically-attended acute respiratory illness (MAARI) in the vaccine age-eligible population. Our central hypothesis is that timely and efficient measurement of annual VE and burden of illness due to seasonal/pandemic influenza, RSV and other respiratory viruses is sustainable. The rationale is that by assessing the mid-season VE, ACIP can recommend antiviral chemoprophylaxis and treatment for high risk groups, as needed. To accomplish the overall objective, the following specific aims will be pursued: 1) Assess influenza VE against laboratory-confirmed influenza among at least 1,000 children and adults, including at least 333 persons from each of three age groups (6 months ? 17 years, 18-49 years and ?50 years) with MAARI in ambulatory settings during each of 5 seasons from 2016-17, with at least 100 among young children aged 6 months ? 8 years and with at least 100 among adults aged ?65 years. 2) Evaluate disease burden due to seasonal influenza (during each of 5 seasons from 2016-17), RSV and other respiratory viruses (during seasons 3-5) among children (ages 6 months ? 17 years), adults (ages 18-64 years) and older adults (ages ?65 years). 3) Develop influenza pandemic preparedness operational plan and pilot research methods (during seasons 3-5) to describe the epidemiology of the novel influenza virus infection, beginning whenever the next influenza pandemic is imminent anywhere in the world, estimate MAARI incidence of pandemic influenza, estimate VE of seasonal and pandemic influenza vaccines for prevention of pandemic influenza-associated MAARI, and evaluate the use and effectiveness of antiviral agents for treatment of pandemic influenza. To accomplish these goals, we will estimate real-time VE for the enrolled population in the ambulatory setting using a test-negative design, estimate burden of illness of seasonal/pandemic influenza, RSV and other respiratory viruses in the BSWCTX source population, and examine factors associated with VE. The proposed research is innovative in that it will generate new knowledge in the methods used to aptly measure influenza VE in different healthcare settings and measure burden of illness of influenza, RSV and other respiratory viruses in the West South Central region of the U.S.