Rotavirus is a leading cause of acute gastroenteritis (AGE) in young children globally, contributing significantly to severe diarrhea-related morbidity and mortality [1, 2]. Rotavirus vaccines have been highly effective in reducing hospitalizations and deaths in high-income countries. In the absence of specific antiviral treatments, the World Health Organization (WHO) recommends rotavirus vaccination as the most effective preventive strategy against rotavirus gastroenteritis (RVGE) [3].

Several rotavirus vaccines are currently available in different parts of the world, including the monovalent Rotarix, the monovalent Rotavac, the pentavalent Rotasiil, the pentavalent RotaTeq (RV5) [3], and the monovalent Lanzhou Lamb Rotavirus (LLR) vaccine [2]. Three rotavirus vaccines are currently licensed for use in China: the monovalent LLR developed by the Lanzhou Institute of Biological Products, the pentavalent human–bovine reassortant vaccine (RV5) produced by MSD, and a trivalent live human–lamb reassortant rotavirus vaccine (LLR3) also produced by the Lanzhou Institute [4]. Among these, LLR and RV5 were marketed in 2000 and 2018 in China, respectively, whereas LLR3 was not licensed until December 2023 [2, 4]. Despite their absence in the National Immunization Program, the uptake of RV5 and LLR has been increasing in recent years [2, 5].

Clinical trials have demonstrated the efficacy of RV5 in preventing rotavirus gastroenteritis caused by various genotypes. A pivotal trial reported a vaccine efficacy of 74% against any severity of RVGE and 98% against severe RVGE [6]. In China, a phase III trial showed that RV5 had an efficacy of 67.4% and 88.3% against any severity and severe RVGE caused by the predominant G9 genotype, respectively [7].

Post-marketing studies have further evaluated the real-world effectiveness of RV5, with estimates ranging from 58 to 94% against rotavirus-related hospitalizations and emergency department visits [8,9,10]. However, data on the post-marketing effectiveness of RV5 in China remain limited, with only a small study from Shanghai reporting a vaccine effectiveness (VE) of 85% against mild to moderate RVGE in children aged 14 weeks to 4 years [5].

For LLR, most post-marketing studies have reported a VE of 35–53% against any severity of RVGE and 52–88% against severe RVGE after at least one dose [11,12,13]. The VE against severe RVGE caused by the G3 and G9 genotypes was estimated to be 52% and 40%, respectively [11, 12].

However, the effectiveness of these vaccines in real-world settings can vary depending on factors such as vaccine type, vaccination schedule, population characteristics, and circulating rotavirus strains. Notably, the predominant rotavirus genotypes have been shifting in many regions, with G8P[8] emerging as a one of the most prevalent strains in recent years [14, 15]. In China, G8P[8] has been increasingly detected in the most populous cities such as Shanghai, Beijing, and Guangzhou [16,17,18]. RV5 consisted of genotypes G1, G2, G3, G4, and P1A[8] [19], whereas LLR consisted of genotype G10P[12] [20], neither of which was originally devised to prevent the G8 genotypes.

To date, no study has evaluated the real-world effectiveness of RV5 and LLR in the same population head-to-head, particularly against the G8P[8] genotype. Such data are crucial for informing vaccination policies and strategies in China. As new genotypes of rotavirus continue to pose a significant health burden on children in China, regional and national immunization programs are increasingly considering the inclusion of rotavirus vaccines [21]. However, the non-negligible cost differences across rotavirus vaccine types necessitate a careful analysis of their effectiveness before widespread implementation [22]. Furthermore, since the eligible ages of the vaccine types do not fully overlap, evidence of their effectiveness can help optimize coverage by broadening the reach of rotavirus protection. Even more, whereas the label of RV5 clearly indicates a three-dose immunization schedule for children aged 6–32 weeks, the label of LLR only states “one dose per year for children between 2 months and 3 years of age”, which renders the immunization schedule of the latter ambiguous [23]. It is typically perceived that the maximum possible number of doses is three, but the minimum number of doses to create protection is unknown [23].

To fill these knowledge gaps, the current test-negative case–control study aimed to evaluate the effectiveness of RV5 and LLR in preventing RVGE of any severity and severe RVGE, including cases caused by the G8P[8] genotype among children in China. Given the access barrier to new vaccines due to relatively high costs, a lack of clear evidence on the effectiveness of existing vaccines could undermine the credibility of their use and exacerbate vaccine hesitancy among parents. By providing real-world evidence on the VE of RV5 and LLR against the emerging G8P[8] genotype, the current study may serve as a crucial piece of evidence to inform immunization planning decisions and optimize resource allocation. LLR3 was not investigated in the current study because it was not regulatorily approved in China until December 2023 such that the accrual of data remained insufficient for a reliable evaluation [23].