Streptococcus pneumoniae is the most common cause of community-acquired pneumonia, bacterial meningitis, bacteremia, and otitis media. As normal flora of human upper respiratory tract of human, it is often found in the nasopharynx of healthy people, and about 20 to 50% of people carry them (1, 2). When a human body lies under immunocompromising conditions, colonized pneumococcal is likely to develop into invasive disease (2). In recent years, pneumococcus has developed varying degrees of resistance to antibiotics, making the treatment of pneumonia more difficultly (3). In 2019, there were an estimated 13.7 million infection-related deaths globally of which more than 500,000 deaths were associated with pneumococcal infections (4, 5). Among the countries with the highest burden of pneumococcal diseases in children under 5 years of age, China ranks 4th,which accounts for about 3% of the total number of cases in the world (4, 6). Considering the infection rate, morbidity, mortality rate, the resistance of Streptococcus pneumonia, and cost-effectiveness of prevention and treatment of the disease, there is an urgent need to control pneumococcal disease using vaccines (3, 6–8).

The World Health Organization (WHO) recommends that all countries, especially those with a mortality rate of >50‰ for children under 5 years old, include the pneumococcal conjugate vaccine (PCV) in their National Immunization Programs (NIP) (9). As of 2023, China has not integrated PCVs into her NIP (10). At present, there are two kinds of products of the 13-valent pneumonia conjugate vaccine (PCV13) worldwide. One is PCV13 conjugated with cross-reactive material 197 (CRM197), and the other is PCV13 conjugated with tetanus toxoid (TT). The latter is China’s first PCV-13, which has been licensed by China National Medical Products Administration (NMPA) in December 2019 for all children aged 2 months to 5 years (4).

In view of the high number of serotypes and complex mechanism of PCV vaccines, manufacturers have been looking for suitable carrier proteins and combinations. Before the launch of TT-carrier protein PCV13, there were some doubts about the safety of the vaccine with TT as the carrier protein (11). According to the previous researches on TT, this carrier protein is the inactivated tetanus toxin manipulated with formaldehyde, which may suffers from formaldehyde residuals and the incomplete detoxification of tetanus toxin in vaccine products (11, 12). In other words, TT carrier protein is an inactivated tetanus toxin, whose safety depends on whether it is inactivated completely during production process. TT-based conjugate vaccine may show high rates of irritability, crying, and fever (11). Therefore, whether the post TT-carrier protein PCV13 is really affected by its carrier protein is still unclear. The study aimed to assess the safety of PCV13. Specifically, a comparison was conducted between the CRM197-carrier protein PCV13 and the TT-carrier protein PCV13. This study might help policy-makers in their decisions to continue adjusting its vaccination schedule or integrating it into NIP.

Widespread use of 23-valent pneumococcal polysaccharide vaccine (PPV23) and PCV13 has significantly decreased invasive pneumococcal disease (IPD) in children (14, 15). The significant reduction in the burden of pneumococcal disease in children worldwide over the last decade underscores the public health value of infant immunization with pneumonia vaccine (16–18). Although the 13-valent pneumonia vaccine is not included in China’s National Expanded Programme on Immunization, Chinese parents are highly motivated to vaccinate their children against pneumonia.

Previous study shows that no significant differences on AEFIs were observed between PHiD-CV + MenC-TT and PHiD-CV + MenC-CRM, which is accordance with our results on PCV13-CRM197 and PCV13-TT (19). In addition, our results showed that the reported incidence of AEFI associated with these two kinds of vaccines was higher than that of many other vaccines reported in the national AEFI monitoring system (20). As one of the most expensive category II vaccines for children to be vaccinated at present, which is mainly administrated among children whose parents with good economic status and educational level (4, 21, 22). These parents often pay more attention to the situation of their children after vaccination than others, accompanying with the increasing active reporting rate and sensitivity of AEFI.

We observed no significant difference in reported AEFI incidence between boys and girls, which is generally consistent with previous reports (23, 24). We found that the reported incidence of AEFI in 2020 was highest from 2019 to 2022. Since February 2021, population-wide immunization of COVID-19 vaccine programme was carried out, more efforts and manpower were put in to strengthen AEFI surveillance linked to COVID-19 vaccination in many provinces. It could cause indirectly that the reported incidence of AEFIs except COVID-19 vaccine declined, and this phenomenon lasted from 2021 to 2022. Nonetheless, the reduction in reported AEFIs was mainly focused on general response induced by vaccine. Our results indicated that the reported incidence of AEFI after inoculating the fourth dose of PCV13 is highest whatever for CRM197 or TT conjugated vaccine. Which is distinct from some previous studies which showed that the reported incidence of AEFI after inoculating the first dose is highest (25, 26). Their argument is the recipients and their guardians pay more attention to the reaction after the first dose of vaccine (25, 26). However, there are some studies that support our conclusions (24, 27). The view they take is the subsequent dose was more likely to cause allergic reactions due to the body sensitization by the early dose. No significant difference on the reported incidence of AEFIs was observed among three geographical regions in Jiangsu Province, which was in accordance with our previous studies (13, 25).

AEFI in PCV13 occurs mainly within 2 days after vaccination and generally lasts about 72 h in previous studies (23–25). This is basically consistent with the conclusion of our results. The main clinical symptoms of AEFI caused by PCV13 are general reactions such as fever, redness or scleroma, which usually occur in 2–5 days after vaccination. Guardians’ awareness of reporting AEFI often wanes over time. Even though some minor adverse reactions occur after 5 days, they are often neglected by guardians because they think it is only mild presentation. Similar phenomena have been observed in post-marketing studies of other vaccines. This is actually one of the drawbacks of passive monitoring (21).

There are three limitations to this study. (1) Recipients have different tolerance for adverse events from domestic vaccine (developed and produced in China) and imported one (developed and produced outside China). Some recipients may subconsciously believe that imported vaccines have fewer adverse effects. Even if there is an adverse reaction, they get used to attribute it to personal physique. However, we do not think it will have a significant impact on the conclusions given the nearly 2 million doses. (2) Reporting bias and information bias cannot be well controlled, for the passive monitoring system. This may affect the accuracy of the results to some extent. Active surveillance study in the future may be a way to solve this problem. (3) The AEFI data associated with TT-carrier protein PCV13 in 2019 was unavailable. So we compare reported AEFI incidence between various years, only the data collected during 2020–2022 were used to conduct statistical analysis.

In conclusion, our findings demonstrated that most AEFIs caused by both PCV13 vaccines were mild and belonged common reactions. No significant differences in rare reactions were observed between TT-carrier protein PCV13 vaccine and CRM197-carrier PCV13. Which was broadly consistent with the safety data from the previous pre- or post-licensure trials. Our results is helpful to reduce the concern from parents for the safety of TT-carrier protein PCV13 vaccine and increase the coverage of PCV13 vaccine in Chinese children.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

RH: Conceptualization, Data curation, Formal analysis, Writing – original draft, Investigation, Supervision. YL: Investigation, Methodology, Data curation, Software, Visualization, Validation, Writing – review & editing. LZ: Data curation, Methodology, Resources, Writing – review & editing. GK: Investigation, Project administration, Validation, Data curation, Formal analysis, Writing – review & editing. BX: Investigation, Methodology, Validation, Visualization, Writing – review & editing. ML: Data curation, Methodology, Formal analysis, Investigation, Writing – review & editing. JY: Data curation, Methodology, Investigation, Visualization, Writing – review & editing. YZ: Investigation, Data curation, Validation, Visualization, Writing – review & editing. HG: Data curation, Conceptualization, Formal analysis, Writing – original draft, Writing – review & editing. ZW: Data curation, Conceptualization, Methodology, Writing – original draft.