For a study, it was determined that West Nile virus (WNV) was the leading cause of arboviral disease in the United States and was related with morbidity and mortality. The analysis found that a vaccination program with people aged older or equal to 60 years was more cost-effective than universal vaccination, but costs remained high. Researchers used the mathematical Markov model to calculate the cost-effectiveness of age- and incidence-based WNV vaccination programs. The study grouped states and large countries (≥100,000 persons aged ≥60 years) by median annual WNV incidence rates from 2004 to 2017 for persons aged older or equal to 60 years. Further, defined WNV incidence thresholds, in increments of 0.5 cases per 100,000 persons older or equal to 60 years. Calculation of potential cost per WNV vaccine-prevented case and quality-adjusted life-years (QALYs) saved was done. Vaccinating people aged older or equal to 60 years in states with an annual incidence of WNV neuroinvasive disease of more than or equal to 0.5 per 100,000 resulted in half the cost per health outcome compared to vaccinating persons aged older or equal to 60 years in the contiguous United States. This approach could potentially prevent 37% of all neuroinvasive disease cases and 63% of WNV-related deaths nationally. Improvement in cost-effectiveness ratios while preventing 19% and 30% of WNV-related neuroinvasive disease cases and deaths, respectively, was seen. According to the study, age and incidence-based WNV vaccination program was a more cost-effective strategy than an age-based program while still impacting lowering WNV-related morbidity and mortality.