The Omicron variant is the dominant strain circulating globally, and studies have shown that Omicron cases have milder symptoms than Delta cases. This study aimed to analyze the factors that affect the clinical severity of Omicron and Delta variants, evaluate and compare the effectiveness of COVID-19 vaccines with different technological platforms, and assess the vaccine effectiveness against different variants. We retrospectively collected the basic information of all local COVID-19 cases reported by Hunan Province to the National Notifiable Infectious Disease Reporting System from January 2021 to February 2023, including gender, age, clinical severity, and COVID-19 vaccination history. From 1 January 2021 to 28 February 2023, Hunan Province reported a total of 60,668 local COVID-19 cases, of which, 134 were infected with the Delta variant and 60,534 were infected with the Omicron variant. The results showed that infection with the Omicron variant (adjusted OR (aOR): 0.21, 95% CI: 0.14–0.31), getting vaccinated (booster immunization vs. unvaccinated aOR: 0.30, 95% CI: 0.23–0.39) and being female (aOR: 0.82, 95% CI: 0.79–0.85) were protective factors for pneumonia, while old age (≥60 years vs. <3 years aOR: 4.58, 95% CI: 3.36–6.22) was a risk factor for pneumonia. Being vaccinated (booster immunization vs. unvaccinated aOR: 0.11, 95% CI: 0.09–0.15) and female (aOR: 0.54, 95% CI: 0.50–0.59) were protective factors for severe cases, while older age (≥60 years vs. < 3 years aOR: 4.95, 95% CI: 1.83–13.39) was a risk factor for severe cases. The three types of vaccines had protective effects on both pneumonia and severe cases, and the protective effect on severe cases was better than that on pneumonia. The recombinant subunit vaccine booster immunization had the best protective effect on pneumonia and severe cases, with ORs of 0.29 (95% CI: 0.2–0.44) and 0.06 (95% CI: 0.02–0.17), respectively. The risk of pneumonia from Omicron variant infection was lower than that from Delta. Chinese-produced vaccines had protective effects on both pneumonia and severe cases, with recombinant subunit vaccines having the best protective effect on pneumonia and severe pneumonia cases. Booster immunization should be advocated in COVID-19 pandemic-related control and prevention policies, especially for the elderly, and booster immunization should be accelerated.