Vital Surveillances: Post-Marketing Surveillance of Adverse Events Following Rotavirus Vaccination — China, 2013–2023

Our observational surveillance study utilized data from the CNIIS, which integrates both the AEFI surveillance database and the vaccination database for China. The CNAEFIS functions as a passive surveillance tool that collects spontaneous reports from all types of reporters. According to the national AEFI surveillance guidelines, AEFI reports are classified into five categories: vaccine product-related reactions, coincidental events, psychogenic reactions, program error-related reactions, and vaccine quality defect-related reactions. Vaccine product-related reactions include common (usually minor) and rare (possibly serious) vaccine reactions. A serious AEFI is defined as one that is life-threatening and results in permanent or significant disability, causes impairment of organ function, or leads to death. In 2022, the revised national AEFI surveillance guidelines expanded this definition to include cases requiring inpatient hospitalization or prolongation of existing hospitalization. To enhance AEFI reporting quality, county surveillance staff review data reporting issues during routine work, and an annual revision and summary of the national AEFI data is conducted.

We extracted data on AEFI reports related to either RV1 or RV5 vaccine from CNIIS for the study period of January 1, 2013 to December 31, 2023. Microsoft Office Excel software (version 2016; Microsoft Corporation, Redmond, Washington, USA) and Python (version 3.12.1) were used for descriptive analysis of RV AEFIs. The AEFI reports per 100,000 doses administered was calculated by dividing the number of AEFI reports by the doses administered and multiplying by 100,000.

During the study period, 77.36 million doses of RV were administered, comprising 49.27 million RV1 doses and 28.09 million RV5 doses. A total of 20,556 AEFI reports for RV were documented; 63.31% were for RV1 and 36.69% for RV5. The overall incidence of RV AEFI was 26.57 per 100,000 doses administered, with similar rates for RV1 (26.42 per 100,000 doses) and RV5 (26.85 per 100,000 doses).

Among RV AEFI reports, 19,668 (95.68%) were classified as vaccine product-related reactions, representing 25.43 reports per 100,000 doses administered. And, 18,192 (88.50%) were common vaccine reactions, and 1,476 (7.18%) were rare vaccine reactions, corresponding to 23.52 and 1.91 reports per 100,000 doses, respectively. In addition, 868 (4.22%) were coincidental events and 6 (0.03%) were psychogenic reactions, with respective incidences of 1.12 and 0.01 reports per 100,000 doses. Serious AEFI reports totaled 222, accounting for 1.08% of all RV reports and representing 0.29 reports per 100,000 doses.

Table 1 shows characteristics of the RV AEFI reports. The majority (63.71%) of RV AEFI reports occurred in infants, with 55.04% in boys. The eastern region accounted for 53.58% of reports, and 31.72% occurred during the third quarter of the year. Most reports (68.14%) followed the first dose of RV, and 97.53% occurred within 3 days after vaccination, with 59.74% on the day of vaccination, 37.79% during days 1–3, 2.12% during days 4–14, and 0.35% more than 15 days after vaccination.

Table 2 shows RV AEFI incidence by vaccine type. There was an overall upward trend in RV AEFI incidence from 2016 to 2019, followed by a downward trend through 2021. The relative proportion of RV5 AEFI increased since 2019. Among all reports, 98.92% were non-serious AEFIs, with serious AEFIs accounting for only a small percentage during the study period. Non-serious AEFI reports per 100,000 doses reported for RV1 and RV5 were 26.22 and 26.39, respectively. Common and rare vaccine reactions were the most frequently reported categories, accounting for 88.50% and 7.18% of all AEFI reports, respectively. Similar AEFI incidences were in RV1 (26.42 per 100,000 doses) and RV5 (26.85 per 100,000 doses).

Table 3 presents the diagnoses and incidences of vaccine product-related reactions. Most vaccine product-related reactions were common vaccine reactions. The most commonly reported common vaccine reactions were fever, gastrointestinal disorders, and rash, with reported incidences of 16.85, 5.84, and 1.28 per 100,000 doses, respectively. Other reported common reactions included sleepiness and fussiness, with incidences of 0.34 and 0.28 per 100,000 doses. The most frequently reported rare vaccine reactions were allergic rash, thrombocytopenic purpura, and febrile convulsion, with incidences of 1.43, 0.07, and 0.03 per 100,000 doses. Other rare reactions were reported at even lower frequencies, including angioedema, Henoch-Schonlein purpura, anaphylactic shock, intussusception, and laryngeal edema, with incidences of 0.02, 0.01, 0.01, 0.01, and 0.001 per 100,000 doses, respectively.

Our study analyzed 20,556 AEFI reports after the administration of 77 million doses of RV during 2013–2023. The overall AEFI reported incidence was 27 per 100,000 doses administered, with similar incidences for both vaccine types: 26 per 100,000 for RV1 and 27 per 100,000 for RV5. During 2019–2023, when both vaccines were licensed and in use, AEFI incidences for RV1 and RV5 were nearly equivalent. The repoted incidence fluctuated throughout the study period, peaking in 2017–2019, possibly reflecting increased reporting sensitivity. Common and rare vaccine reactions constituted 89% and 7% of AEFI reports, respectively. The incidences of both common and rare reactions remained at low levels. Adverse events of special interest, such as intussusception and febrile convulsion, were extremely rare and showed no clustering by vaccine lot number. Based on these findings, both RVs demonstrate favorable safety profiles.

RV1 was licensed in China in 2001, while RV5 received licensure in 2018. Both vaccines are non-program (family-pay) vaccines, meaning they are voluntary and families must cover the cost of the vaccine and its administration. Since these vaccines are not included in the routine vaccination schedule, the timing of vaccination more closely follows the product package insert recommendations. RV1 is indicated for children 2 months to 3 years of age, while RV5 is indicated for infants 6–32 weeks of age. We observed that very few reports documented administration outside the recommended age range specified in the pachage insert. This may remind that vaccination staff should careflly check the age of children before vaccination and vaccinate those who are in an appropriate age. The publicity effors are needed to enable parents to have a better understanding of the benefits of RV and take their children for vaccination at a right time.

The most frequently reported AEFIs were common vaccine reactions, primarily fever and gastrointestinal disorders. Although these reactions do not cause long-term or serious harm, high fever in infants can trigger febrile convulsions, which, while not damaging to the child, can be frightening for parents. As live attenuated oral vaccines, RVs may induce symptoms similar to natural infection, though considerably milder. Allergic rash was the most commonly reported rare vaccine reaction. Nearly all common and rare vaccine reactions occurred within 3 days after immunization, with the majority occurring on the day of vaccination, consistent with the pharmacological properties of the vaccines. Since serious allergic reactions typically manifest immediately, maintaining an observation period of half an hour after vaccination is crucial for promptly identifying and treating potential anaphylaxis in vaccinees.

The first RV licensed globally was withdrawn in 1999, one year after approval, due to a strong and likely causal association with intussusception. Consequently, RV safety has received worldwide attention. Our analysis revealed extremely low reported incidences of intussusception and other gastrointestinal disorders among rare vaccine reactions. Monovalent RVs used internationally, such as Rotarix, showed an increased potential risk of intussusception after vaccination in a post-marketing study in America (8), but no increase was found in self-controlled-case-series studies in sub-Saharan Africa (9). RV5, in its randomized, double-blind, placebo-controlled, multicenter licensure study, demonstrated no risk of intussusception within 42 days of any dose (10); the same result was found in a retrospective birth cohort study in China (11). Other post-marketing studies in several countries, including Australia, New Zealand, and Canada, found no significant change in the overall incidence of intussusception during RV5 use, although some studies suggested intussusception was associated with RV5, especially following the first dose, despite the small risk and short time window (12–15). In 2013, the United States Food and Drug Administration approved the inclusion of new safety information on intussusception risk in the package insert and patient package insert of RV5. RVs apparently influence the gastrointestinal tract as described in their safety profiles, but the risk of increasing intussusception incidence is extremely low. The reported incidence of intussusception following RV immunization is significantly lower than that in general population. Whether RV administration could lead to earlier intussusception in predisposed children remains a topic for further research. Intussusception often occurs in children under 2 years old, with most cases being primary and secondary causes mostly related to infection, intestinal dysplasia, and other factors. Intussusception AEFI should be carefully investigated and classified.

Our study was subject to at least two limitations. First, data reported in CNIIS may be incomplete and contain inaccuracies, including incorrect determination of severity and causality classification. Second, passive reporting systems are prone to underreporting, resulting in underestimation of AEFI incidence. Generally, well-known AEFIs are recognized and reported more easily than unknown AEFIs, and expected minor AEFIs tend to be reported less frequently. Underreporting should be considered when interpreting results. Currently, no other sources provide such extensive AEFI data for vaccines in China. Despite these limitations, passive surveillance helps detect unusual or unexpected patterns of AEFI reporting.

In conclusion, the AEFIs reported for RV were mostly minor and transient, supporting a reasonable safety profile for these vaccines. Given that RVs play an important role in preventing rotavirus-associated severe diarrhea and mortality in children, especially those younger than 5 years old, RV use should continue to be promoted. Parents should be informed of an observation period after vaccination.

We thank the staff at the provincial, prefectural, and county CDCs, as well as all vaccination clinics involved in conducting the adverse event surveillance. We also thank Lance Rodewald, senior consultant at China CDC, for his insightful comments and recommendations on the manuscript.