This study aimed to retrospectively assess the cost-effectiveness of various COVID-19 vaccination strategies in Ethiopia. It involved healthcare workers (HCWs) and community participants; and was conducted through interviews and serological tests. Local SARS-CoV-2 variants and seroprevalence rates, as well as national COVID-19 reports and vaccination status were also analyzed. A cost-effectiveness analysis was performed to determine the most economical vaccination strategies in settings with limited vaccine access and high SARS-CoV-2 seroprevalence. Before the arrival of the vaccines, 65% of HCWs had antibodies against SARS-CoV-2, indicating prior exposure to the virus. Individuals with prior infection exhibited a greater antibody response to COVID-19 vaccines and experienced fewer new infections compared to those without prior infection, regardless of vaccination status (5% vs. 24%, p p < 0.001 for unvaccinated). The cost-effectiveness analysis indicated that a single-dose vaccination strategy is optimal in settings with high underlying seroprevalence and limited vaccine availability. This study underscores the need for pragmatic vaccination strategies tailored to local contexts, particularly in high-seroprevalence regions, to maximize vaccine impact and minimize the spread of COVID-19. Implementing a targeted approach based on local seroprevalence information could have helped Ethiopia achieve higher vaccination rates and prevent subsequent outbreaks.
