Health literacy (HL) plays a crucial role in navigating the coronavirus disease 2019 (COVID-19) pandemic, especially with the abundance of conflicting information from unauthorized sources. This study aims to measure COVID-19 vaccine acceptability, COVID-19 HL, and COVID-19 infodemic and their predictors in Iranians. A cross-sectional study was conducted on the general population in Iran between August 20, 2021 to October 29, 2021. Data were collected using a valid questionnaire with four parts. Univariable and multivariable logistic regression models, generalized linear models, and ordinal regression with the Polytomous Universal Model were performed using SPSS version 26. The study revealed that 68.6% of the participants were willing to accept the COVID-19 vaccine, 45% had sufficient knowledge about COVID-19, and 52.2% were confused by false information during the pandemic. The results showed that having sufficient COVID-19 HL was significantly associated with higher acceptance of the vaccine (adjusted odds ratio = 1.52, 95% confidence interval (CI): 1.02, 2.12). Additionally, higher COVID-19 HL scores were associated with a higher adjusted odds of confusion by false information with an odds ratio of 1.12 (95% CI: 1 .11, 1 .13). This study exhibits low levels of COVID-19 HL in Iran, and the fact that higher COVID-19 HL is associated with higher vaccine acceptance. Because vaccination is an essential preventive measure to stop the COVID-19 pandemic, factors associated with low vaccine acceptance need to be addressed by public health strategies. [HLRP: Health Literacy Research and Practice. 2024;8(4):e184-e193.].
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