Vital Surveillances: Post-Marketing Surveillance of Adverse Events Following Recombinant Zoster Vaccine — China, 2020–2023

The study obtained data on RZV doses administered and all AEFI reports related to RZV from CNIIS, with vaccination dates between January 1, 2020 and December 31, 2023, and downloaded on March 7, 2025.

An AEFI case is defined as a reaction or event occurring after vaccine administration that is suspected to be related to the vaccination. AEFIs are reported and investigated according to the National AEFI Surveillance Guidelines first released in 2010 (6) and revised in 2022.

Through causality assessment, AEFIs are categorized into adverse vaccine reactions, vaccine quality defect-related reactions, program errors-related reactions, coincidental events, and psychogenic reactions. Adverse vaccine reactions refer to reactions caused by inherent characteristics of the vaccine, unrelated to the purpose of vaccination, with individual variations in response. Adverse vaccine reactions can be common vaccine reactions (usually minor), which are transient, mild reactions, or rare vaccine reactions (possibly serious), which result in damage to organs or their function.

AEFIs are also classified as serious or non-serious. Serious AEFIs are adverse events that result in death, are life-threatening, cause permanent or significant disability/incapacity, lead to hospitalization or prolonged hospitalization, or are congenital abnormalities or birth defects suspected to be caused by maternal vaccination during pregnancy according to the national AEFI surveillance guideline in 2022.

In China, all AEFI cases following RZV are classified, and with the exception of common vaccine reactions, all are investigated. Serious AEFIs are classified by expert groups organized by CDCs. Should there be an objection to the conclusion of an expert group, the local Medical Association is requested to resolve classification. Non-serious AEFIs can be classified by vaccination clinics, county CDCs, or by an expert group.

Data were organized and collated with Excel (version 2016, Microsoft, Washington, USA). We determined distributions of age, dose number, and clinical diagnosis and calculated AEFI reporting rates per 100,000 doses administered. Calculations were performed using SAS (version 9.4, SAS Institute, Cary, NC, USA).

During 2020−2023, 1.99 million doses of RZV were administered with 10,525 AEFI cases reported, yielding a reporting incidence of 527.76 per 100,000 doses. Among these AEFI reports, 10,334 cases (98.19%) were classified as common vaccine reactions, 81 cases (0.77%) as rare vaccine reactions, 106 cases (1.01%) as coincidental events, and 4 cases (0.04%) as psychogenic reactions, with reporting incidences of 518.19, 4.06, 5.32, and 0.20 per 100,000 doses, respectively. There were no vaccine quality defect-related reactions or program errors-related reactions reported.

Eleven serious AEFI cases were reported (0.10% of all reports), for a reporting incidence of 0.55 per 100,000 doses. Five of these serious cases were classified as rare vaccine reactions, with a reporting incidence of 0.25 per 100,000 doses. All serious cases recovered, and no deaths were reported. There were no clusters for serious AEFIs with the same dignosis by vaccine lot number.

The annual AEFI reporting incidences were 1,927.98, 587.89, 358.60, and 526.41 per 100,000 doses administered from 2020 to 2023. Similarly, the annual incidences of common vaccine reactions were 1,891.54, 576.42, 349.65, and 519.12 per 100,000 doses during the same period. The annual incidences of both rare vaccine reactions and coincidental events decreased from 2020 to 2023 (Table 1).

RZV AEFI reports included 2,749 male vaccinees and 7,776 female vaccinees, yielding a male-to-female ratio of 1∶2.83. Only 16 cases (0.15%) were reported after co-administration of RZV with either influenza vaccine or 23-valent pneumococcal vaccine; all other reports followed the administration of RZV alone.

By age group, AEFI reports were distributed among 50–59, 60–69, and ≥70-year-olds at proportions of 54.66%, 35.01%, and 10.33%, with corresponding incidences of 505.38, 571.77, and 528.78 per 100,000 doses administered. Incidences of common vaccine reactions in these respective age groups were 497.03, 561.68, and 513.70 per 100,000 doses, while rare vaccine reactions occurred at rates of 3.34, 4.81, and 5.84 per 100,000 doses. The 60–69 year age group demonstrated the highest incidences of both overall AEFI and common vaccine reactions, while the incidence of rare vaccine reactions increased with age.

Regarding dose number, 75.87% of AEFIs occurred after the first dose, with an incidence of 729.17 reports per 100,000 doses, including common vaccine reactions and rare vaccine reactions at incidences of 715.02 and 6.21 per 100,000 doses, respectively. Incidences of all AEFI categories were higher following the first dose compared to the second dose.

By geographic distribution, eastern provincial-level administrative divisions (PLADs) accounted for 76.95% of RZV AEFIs, with an incidence of 720.67 per 100,000 doses. Within eastern PLADs, common vaccine reactions and rare vaccine reactions occurred at incidences of 707.68 and 6.05 per 100,000 doses administered, respectively. Eastern PLADs demonstrated the highest reporting incidences across all AEFI categories (Table 2).

Fever (6,656 cases; 64.41% of reports) and local redness and swelling (4,258; 41.20%) were the most frequently reported common vaccine reactions, with incidences of 333.76 and 213.51 per 100,000 doses, respectively (Table 3). Other commonly reported reactions included fatigue (1,759 cases; 88.20 per 100,000 doses), myalgia (1,702 cases; 85.34 per 100,000 doses), local induration (1,605 cases; 80.48 per 100,000 doses), headache (628 cases; 31.49 per 100,000 doses), gastrointestinal symptoms including loss of appetite, nausea, vomiting, stomachache, and diarrhea (487 cases; 24.42 per 100,000 doses), and dizziness (404 cases; 20.26 per 100,000 doses).

The incidences of fever, fatigue, and induration differed significantly across age groups. The incidences of fever, redness and swelling, induration, fatigue， and myalgia were all higher following the first dose compared to the second dose.

Allergic reactions constituted the most frequently reported rare vaccine reactions (83.95%), with allergic rash accounting for 88.24% of these cases, yielding an incidence of 3.01 per 100,000 doses. Other conditions were rarely reported, with none exceeding an incidence of 1 per 100,000 doses (Table 3). Five serious cases classified as rare vaccine reactions included Henoch-Schonlein purpura (HSP), thrombocytopenia (TP), acute myelitis, acute kidney injury, and brachial plexus neuritis.

No significant differences in diagnosis incidences were observed across age groups. The incidence of allergic rash was significantly higher following the first dose, incidences of other conditions showed no significant differences by dose number.

Among the 106 cases classified as coincidental events, the top five were herpes zoster (34 cases; 32.08% of coincidental events), respiratory infection (8; 7.55%), gastroenteritis (6; 5.66%), facial nerve palsy (5; 4.72%), and dizziness (5; 4.72%). Six serious cases classified as coincidental events included encephalitis, vestibular neuronitis, monoclonal B lymphocytosis, cerebral infarction, postherpetic neuralgia, and chronic urticaria.

98.35% of common vaccine reactions and 82.72% of rare vaccine reactions occurred within 72 hours after vaccination, corresponding proportions occurring within 24 hours were 80.61% and 56.79%. Among common vaccine reactions, 99.19% of fever, 97.46% of redness and swelling, 98.35% of fatigue, 98.53% of myalgia, and 96.39% of induration occurred within 72 hours after vaccination; corresponding proportions occurring within 24 hours were 85.59%, 72.24%, 84.08%, 82.84%, and 70.65%. Among rare vaccine reactions, 85.00% of allergic rash occurred within 72 hours, and 58.33% occurred within 24 hours; 80.00% of other allergic reactions occurred within 72 hours， and 60.00% occurred within 24 hours. Cases of angioedema, Arthus reaction, brachial plexus neuritis all occurred within 24 hours, one case of HSP occurred during 24–48 hours, and one case of TP occurred >7 days after vaccination.

The study found that during 2020–2023, most AEFIs following RZV administration were common vaccine reactions. The incidences of AEFI reports and common vaccine reactions were significantly higher than corresponding reporting rates for other vaccines used in China (7–8). The greater reactogenicity of RZV may be attributed to the AS01 adjuvant used in the vaccine. Adjuvants enhanced the immune response to antigens, while increasing reactogenicity (9). Additionally, reporting sensitivity may have been higher for RZV since it was newly marketed during the study period. The incidence of RZV AEFI reports in our study is higher than that reported in the United States’ post-marketing surveillance data (136 reports per 100,000 doses) (10) and in the GlaxoSmithKline (GSK) safety database (404.33 reports per 100,000) (11). However, the incidence of serious AEFI reports in our study was lower than in the US and GSK safety databases (4.0 and 12.42 per 100,000 doses, respectively) (10–11). Moreover, the AEFI incidence in our study was substantially lower than those reported in clinical trials (12–13).

In this study, more cases were reported for women than men, and few cases were reported after vaccine co-administration, consistent with US findings (10). Most AEFI reports originated from eastern provinces of China, possibly due to greater vaccine uptake and higher AEFI surveillance sensitivity in these regions — a phenomenon observed with AEFI reports for other vaccines in China (7–8). The AEFI reporting incidence was significantly higher for the first dose compared with the second dose, which differs from post-hoc studies of clinical trials that found similar incidences by dose number (12–13). Potential explanations include decreased reporting sensitivity for second doses or that individuals who experienced adverse events after the first dose may have opted not to receive a second dose. The incidence of rare vaccine reactions was higher in older age groups, similar to results from clinical trials (13).

This study found that the most reported adverse vaccine reactions were common and minor — primarily fever and local redness and swelling — most of which occurred within 72 hours after vaccination and resolved within 2–3 days. These findings are consistent with clinical trials (12–13) and other post-marketing safety study results (10–11).

Allergic rash was the most frequently reported rare vaccine reaction, which is unlikely to cause serious consequences. Incidences of other rare vaccine reactions were very low and did not raise safety concerns. Increased risk of Guillain-Barré Syndrome (GBS) following RZV administration was reported among community dwelling Medicare beneficiaries aged 65 years or older during 2017-2020 (14). However, no GBS cases were reported in our study, and the risk of GBS caused by RZV was not identified in active post-licensure safety surveillance in the US during 2018–2019 (15).

A strength of this study is that it provides national post-marketing AEFI results for RZV in China based on comprehensive surveillance data, filling an information gap due to the absence of licensure RZV clinical trials conducted in China. Another strength is that all serious AEFIs undergo investigation for causality assessment.

This study has several limitations. First, the AEFI surveillance system in China is passive, which may lead to underestimation of AEFI rates. Second, the quality of causality assessment for AEFIs varies across regions, potentially influencing classification accuracy.

In summary, post-marketing national AEFI surveillance data in China from 2020–2023 demonstrate that the incidence of RZV AEFIs is higher than incidences for other vaccines used in China, consisting mostly of common vaccine reactions such as fever and local redness and swelling, consistent with adverse events found in clinical trials. The incidence of rare vaccine reactions is very low, predominantly allergic rash, which is manageable and does not present a safety concern. Considering its high protective efficacy, RZV will likely become more widely recommended for people aged 50 and above to prevent shingles and PHN in China. Continued AEFI surveillance and analytical evaluation should be maintained.

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