PROJECT SUMMARY/ABSTRACTInfection with SARS-CoV-2 and its associated disease state COVID-19 has resulted in over 374000 deaths inthe United States to date. Vaccines protecting against COVID-19 have recently received FDA emergency useauthorization and are being administered to high-risk individuals with wider dissemination to follow. Exposure toper- or polyfluoroalkyl substances (PFAS) is associated with reduced immune response following vaccinationagainst other infections but its effect on COVID-19 vaccine effectiveness is not known. We have a time-sensitiveopportunity to determine the effect of serum PFAS on response to COVID-19 vaccination building on a uniquestudy in ~2000 healthcare workers first responders and other essential workers in Arizona without prior COVID-19 infection many of whom have either recently been vaccinated or will be vaccinated in the coming monthssupplemented by ~700 additional participants from a similar study in both Arizona and Florida. Our objective inthis application is to determine the effects of PFAS exposure levels on COVID-19 vaccine effectiveness. Ourcentral hypotheses are that increased PFAS serum concentrations will: 1) reduce initial SARS-CoV-2 antibodytiters following COVID-19 vaccination; 2) increase the rate of longitudinal decline in antibody titers; and 3)increase the frequency of COVID-19 during a nine-month period following vaccination. The rationale for thisresearch is that successful completion can be expected to provide new data about the immune effects of PFASexposure. We will test these hypotheses through two regular and one exploratory specific aims: 1) Evaluate theassociation of serum PFAS with initial SARS-CoV-2 antibody titers following COVID-19 vaccination; 2) Evaluatethe association of serum PFAS with longitudinal decline in SARS-CoV-2 antibody titers following COVID-19vaccination; and 3) Evaluate the association of serum PFAS concentrations with frequency of COVID-19following vaccination. For aims 1 and 2 we will select 600 of our Arizona study participants for measurement ofserum PFAS following COVID-19 vaccination. As part of the study these participants will also provide serum formeasurement of SARS-CoV-2 antibodies every three months for at least nine months and provide respiratorysamples weekly for PCR testing to identify SARS-CoV-2 infection. For the exploratory aim we will identify allCOVID-19 cases following vaccination in both the Arizona and Florida study populations and for each caseselect five matched controls who received COVID-19 vaccination but were not infected with SARS-CoV-2. SerumPFAS levels will be compared across the cases and controls. At study completion we will have documented theeffects of PFAS exposure on SARS-CoV-2 antibodies following COVID-19 vaccination and the frequency ofCOVID-19 cases following vaccination. The proposed research is significant given the potential for PFASexposure to reduce the effectiveness of COVID-19 vaccines. The proposed research is innovative as it is thefirst to our knowledge to determine the association between serum PFAS levels and measures of COVID-19vaccine effectiveness.