Vital Surveillances: Post-Marketing Surveillance of Adverse Events Following Immunization with Haemophilus Influenzae Type b Conjugate Vaccine — China, 2010–2021

AEFI cases with the Hib vaccine, reported between 2010 and 2021, were sourced from the CNIIS AEFI surveillance module. Data on the number of Hib vaccine doses administered during the study period were obtained from the CNIIS vaccination surveillance module.

Hib vaccines, authorized by various marketing authorization holders (MAHs), are approved for administration in children aged 2 months to 5 years. The standard immunization schedule includes three primary-series doses, administered monthly beginning at 2–3 months, followed by a booster dose at 18 months. Infants initiating Hib vaccination between 6–12 months receive two doses, while children who begin their vaccination between 1–5 years receive a single dose.

AEFI surveillance is conducted in compliance with applicable laws, regulations, and guidelines (2–3). Various entities, including medical institutions, vaccination providers, MAHs, CDCs, and medical associations, have distinct roles in the reporting, investigation, and causality assessment of AEFIs. AEFIs are categorized into reactions related to vaccine products, reactions due to vaccine quality defects, reactions suspected to be caused by immunization errors, coincidental events, and psychogenic reactions. Among these, vaccine product-related reactions, or vaccine reactions, are adverse events that are either confirmed to be caused by the vaccine or cannot be definitively ruled out as being caused by the vaccine. These reactions are further subdivided into common reactions, which are usually minor, and rare reactions, which could be serious. Specific symptoms such as fever (axillary temperature ≥38.6 °C), redness and swelling at the injection site (diameter >2.5 cm), and induration at the injection site (diameter >2.5 cm) are mandated to be reported. Serious AEFI encompasses events that are life-threatening, may result in death, or may lead to substantial or permanent disability or significant impairment of organ function. Serious rare vaccine reactions primarily encompass those serious AEFIs that are suspected to be vaccine-related.

Data were analyzed utilizing Microsoft Office Excel (version 2016, Microsoft, Washington, USA) and R (version 4.2.1, R Foundation for Statistical Computing, Vienna, Austria). Descriptive statistics were employed to elucidate the distributions, characteristics, and reported incidences of AEFI with the Hib vaccine. The incidence of AEFI was calculated by taking the number of reported AEFI cases, multiplying it by 100,000, and then dividing it by the total number of administered doses of the Hib vaccine.

From 2010 to 2021, a total of 52,910 AEFIs with the Hib vaccine were reported in China. Of these, 58.01% involved male recipients and 41.99% female recipients, yielding a male-to-female ratio of 1.38∶1. The distribution of AEFI reports by age group showed that 51.01% were in children under 1 year, 36.65% in 1-year-olds, and 12.35% in children aged 2 years or older. Geographically, 60.66% of the reports originated from the eastern regions, 27.53% from the central regions, and 11.81% from the western regions of China. Seasonally, AEFI reports varied across the quarters of the year, comprising 17.38% in the first quarter, 34.33% in the second, 32.70% in the third, and 15.59% in the fourth quarter. The analysis of AEFI reports by dose number revealed that 53.91% occurred after the first dose, 18.15% after the second, 14.97% after the third, and 12.97% after the fourth dose. Additionally, 25.76% of AEFI cases involved children who were concurrently vaccinated with other vaccines. The most commonly co-administered vaccines were the acellular DPT vaccine (7,392 cases, 13.97%), the polio vaccine (2,509 cases, 4.74%), and the meningococcal vaccine (1,407 cases, 2.66%). The timing of AEFI onset post-vaccination was predominantly within the first day (58.42%), followed by 2 to 3 days (39.98%), 4 to 14 days (1.14%), and 15 days or more (0.46%), as summarized in Table 1.

Between 2010 and 2021, approximately 138.88 million doses of the Hib vaccine were administered in China. The reported overall rate of AEFIs was 38.10 per 100,000 doses. This rate fluctuated annually, with a low of 18.60 and a high of 50.25 per 100,000 doses. The breakdown of AEFI rates included: common vaccine reactions at 34.71 per 100,000 doses, rare vaccine reactions at 2.78 per 100,000, coincidental events at 0.57 per 100,000, psychogenic reactions at 0.005 per 100,000, suspected immunization error-related reactions at 0.004 per 100,000, and non-classifiable events at 0.02 per 100,000 doses. No event of vaccine quality defect-related reactions was reported. Incidence rates for serious AEFIs were 0.31 per 100,000 doses, for non-serious AEFIs were 37.79 per 100,000 doses, and for serious rare vaccine reactions were 0.16 per 100,000 doses, as detailed in Table 2.

The study identified 48,203 cases of common vaccine reactions. Fever (axillary temperature ≥38.6 ℃), injection site redness and swelling (diameter >2.5 cm), and injection site induration (diameter >2.5 cm) represented 34.38%, 27.91%, and 9.74% of these reactions respectively, with incidence rates per 100,000 doses of 11.93, 9.69, and 3.38. Additional reported reactions accounted for 4.67% of the total. The five most commonly observed symptoms among these additional reactions were rash (16.80%), crying (11.38%), vomiting (6.71%), pruritus (4.31%), and diarrhea (3.91%), as detailed in Table 3. The majority of the common vaccine reactions occurred within three days post-vaccination, with proportions of 99.08% for fever, 98.75% for injection site redness and swelling, and 97.93% for injection site induration.

Among the rare reactions to vaccination, the incidence of allergic reactions was reported as 2.60 per 100,000 doses; specifically, the rates of allergic rash, angioedema, anaphylactic shock, and laryngeal edema were 2.42, 0.10, 0.01, and 0.004 per 100,000 doses, respectively. Reports of nervous system reactions were 0.07 per 100,000 doses, with specific incidences of febrile convulsion, convulsion, Guillain-Barre syndrome (GBS), and acute disseminated encephalomyelitis (ADEM) at 0.05, 0.01, 0.002, and 0.002 per 100,000 doses, respectively. Local reaction rates, which included sterile abscess, Arthus reaction, lymphangitis and lymphadenitis, were recorded as 0.02, 0.01, and 0.003 per 100,000 doses, respectively. Incidences of thrombocytopenic purpura (TP) and Henoch-Schonlein purpura (HSP) were documented at 0.05 and 0.01 per 100,000 doses, respectively (Table 3). Additionally, there were two reported cases of TP in two distinct vaccine batches.

The proportions of allergic rash, HSP, TP, febrile convulsion, GBS, polyneuritis, and sterile abscess occurring within three days post-vaccination were 98.16%, 85.71%, 65.67%, 98.59%, 33.33%, 50.00%, and 11.11%, respectively. Additionally, laryngeal edema, ADEM, angioedema, anaphylactic shock, convulsion, and Arthus reactions all occurred within this timeframe following vaccination.

The CNIIS serves as the principal platform for AEFI surveillance across Chinese mainland. It compiles comprehensive data on AEFI reports and vaccine doses administered for all post-marketed vaccines, which is pivotal for the quantitative analysis of AEFI. Our study, utilizing data from CNIIS, revealed that AEFIs with the Hib vaccine were more frequently reported in males, within the eastern region, and during the second and third quarters of the year. This distribution mirrors the trend observed in AEFI reports for other vaccines that are market-authorized in China (4). Predominantly, AEFIs with the Hib vaccine occurred in infants, aligning with the typical age for Hib vaccination, and was higher in proportion after the administration of the first dose. Other studies indicate that the AEFI rate was more prevalent following the second and subsequent doses — a trend potentially linked to the cellular immune memory responses (5). Additionally, our analysis showed that 25% of Hib vaccine doses were administered concomitantly with other vaccines. The WHO’s position paper indicates Hib vaccines are safe and effective when given simultaneously with other vaccines (1).

From 2010 to 2021, the incidence of reported AEFI with the Hib vaccine was 38.10 per 100,000 doses. This rate was lower compared to the incidence reported in Australia in 2020, which was 69.4 per 100,000 doses (6). Studies conducted in China indicated higher incidences of AEFI for the combined DTP-IPV/Hib vaccine compared to our findings for the standalone Hib vaccine (4–5,7). Our data showed that annual reported incidences ranged from 18.60 to 50.25 per 100,000 doses, with an initially increasing trend that later stabilized. Notably, the highest incidence of AEFI was recorded in 2019, coinciding with an overall increase in AEFI reports for all post-marketed vaccines that year (8), possibly due to heightened societal concerns and enhanced surveillance of AEFI. The subsequent decrease in the number and incidence of AEFI reports in 2021 may be attributable to the impact on AEFI surveillance and immunization program services amidst the COVID-19 pandemic. In the same year, the incidence of rare reactions also decreased to 1.27 per 100,000. Furthermore, serious AEFIs were reported at a rate of 0.31 per 100,000 doses, and the incidence of serious rare vaccine reactions (0.16 per 100,000) aligned with the average incidences reported for other vaccines in China (4). It is important to note, however, that incidences of AEFI across different countries and regions are not directly comparable due to variations in AEFI reporting systems and methodologies.

The majority (91%) of the AEFI with Hib vaccination were common vaccine reactions. These included local reactions such as redness, swelling, induration, and rash at the injection site, along with systemic reactions such as fever, crying, and vomiting. These findings align with similar observations reported in the United States (9) and various regions of China (5,7). Our analysis indicated that 98% of these common vaccine reactions occurred within three days post-vaccination, consistent with previous national AEFI reports (4). Most of these reactions were either effectively managed with treatment or resolved spontaneously.

Allergic reactions were identified as the most commonly reported rare vaccine reactions, exhibiting a reporting rate of 2.60 per 100,000. This rate was significantly lower compared to that observed in the Yinzhou District of Ningbo City, which stands at 18.4 per 100,000 (10). Among these, allergic rash accounted for 87% of the cases, with the majority being non-serious, of short duration, and resolving favorably. The reported incidence of angioedema, at 0.10 per 100,000, was slightly higher than the incidence of other vaccines in China (4). Cases of anaphylaxis, including manifestations such as anaphylactic shock and laryngeal edema, were exceedingly rare, recorded at 0.01 per 100,000. This incidence was considerably lower than the rates of anaphylaxis reported in the United States, which range from 0.2 to 1.5 per 1,000,000 (11–12). Most anaphylactic reactions occurred within thirty minutes following vaccination and could pose a life-threatening risk if not promptly managed. Consequently, a post-vaccination observation period of 30 minutes is crucial to timely identify and address any cases of immediate anaphylaxis.

AEFI involving the nervous system are a significant concern post-vaccination. The incidence of nervous system events post-Hib vaccination was reported to be relatively low at 0.07 per 100,000 doses. Febrile convulsions, which generally have a favorable prognosis, emerged as the most common nervous system reaction in our study. These were reported at a rate of 0.05 per 100,000 doses, a figure that aligns with the incidences of similar reactions to other vaccines used in China (4) and is notably lower than the rate of febrile convulsions following the DPT-IPV/Hib vaccine in Zhejiang province, which stands at 0.50 per 100,000. The incidence of other neurological events such as GBS and ADEM was exceedingly rare, not exceeding 0.01 per 100,000 doses. Furthermore, no causal link has been established between these neurological conditions and the Hib vaccine. Based on these findings, we advocate for the continuation of vigilant neurological event surveillance following Hib vaccination.

Other rare vaccine reactions have also been reported. In our study, the incidence of TP was 0.05 per 100,000 doses, aligning with the average incidence reported for other vaccines in China (4). Comparatively, a survey in France examining TP cases among individuals under 18 years from 2009 to 2011 identified an incidence of 2.9 per 100,000 person-years, with the highest incidence occurring between ages 1 and 5 (13). However, the diagnostic criteria for TP differ between China and other countries, complicating direct comparisons. The incidence of HSP with Hib vaccine in our study was 0.01 per 100,000, slightly lower than the average incidence observed across other vaccines in China (4). Meanwhile, studies in Sweden and France indicated an annual incidence of HSP in children under 15 years of age ranging from 17.5 to 30 per 100,000 doses (14–15). The WHO position paper on the Hib vaccine has not identified any safety concerns (1).

This study is subject to some limitations. Passive surveillance systems, such as the one used in this research, are inherently vulnerable to underreporting. Additionally, inaccuracies in data entry and variations in the quality of causality assessments, particularly for non-NIP vaccines, may affect the reliability of our findings. Furthermore, we were unable to ascertain the incidence of AEFI among different subgroups due to the lack of available data regarding the number of Hib vaccine doses administered to these subgroups. Our analysis was also confined to the evaluation of AEFI with monovalent Hib vaccines, thereby excluding combination vaccines from our study. Despite these limitations, the extensive administration of monovalent Hib vaccine doses across China lends substantial support to the robustness of our safety evaluation for this vaccine.

In conclusion, the predominant adverse reactions with the Hib vaccine included fever, injection site reactions, and other common vaccine-related symptoms. The incidence of rare adverse reactions was exceedingly low, primarily consisting of allergic rashes. Serious reactions were extremely uncommon. It is imperative to conduct AEFI surveillance and improve the quality of reporting systems. The favorable safety profile of the Hib vaccine advocates for its broader implementation in China.

No conflicts of interest.

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