Efficacy of inactivated SARS-CoV-2 vaccination in pediatric hematology/oncology patients: a real-world study

Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) has been spreading globally since its initial outbreak in 2019. Substantial evidence has revealed that children who are receiving antitumor therapy or hematopoietic stem cell transplantation (HSCT) present higher rates of severe illness and mortality [1]. It is important to identify infected children with hematology and oncology diseases who have the tendency to develop worse outcomes of coronal virus disease 2019 (COVID-19) during the early stage of COVID-19. Recent studies have demonstrated that vaccination against SARS-CoV-2 in adults can reduce the likelihood of infection and reduce the severity and mortality of COVID-19 when SARS-CoV-2 breakthrough infection occurs [2–4]. However, the effectiveness of SARS-CoV-2 vaccination in children with hematology and oncology diseases is poorly defined due to the lack of relevant data, which might lead to vaccine hesitancy [5, 6]. This retrospective study enrolled a total of 190 pediatric hematology and oncology patients with clear vaccination status who were infected with SARS-CoV-2 between December 1, 2022, and January 19, 2023. All of these children had received specialty treatment in the Department of Hematology & Oncology, Children's Hospital of Zhejiang University School of Medicine. Detailed baseline and outcome data were obtained through clinical medical records, attending physicians, and guardians. Laboratory data within three days after SARS-CoV-2 infection and at the peak of the disease were collected. The patient was diagnosed with COVID-19 by viral nucleic acid or antigen testing. COVID-19 was classified into four categories based on disease severity according to guidelines published by the National Health Commission of China on March 14, 2022: (1) mild: symptomatic infection of the upper respiratory tract (URT) without any pneumonia manifestations in radiology; (2) moderate: radiological proof of pulmonary involvement but oxygen saturation > 93% without any oxygen support; (3) severe: any one of the following signs: shortness of breath, oxygen saturation ≤ 93%, dyspnea, convulsion or disturbance of consciousness, food refusal or feeding difficulties accompanied by signs of dehydration, high-resolution computed tomography (HRCT) of chest showing bilateral or multiple lobular infiltration, > 50% lung imaging progress in a short period, or pleural effusion; and (4) critical: any one of the following signs: shock, respiratory failure requiring mechanical ventilation, or organ failure requiring intensive care unit. This study protocol was reviewed and approved by the Ethics Committee of Children's Hospital, Zhejiang University School of Medicine (2023-IRB-0032-P-01) as a retrospective study. Informed consent was obtained from the guardians. The baseline characteristics are summarized and the comparison is presented in Table 1. The median age of the population included in this study was 6.7 years, including 65 females (34.2%). Among them, 140 children (73.7%) were diagnosed with acute leukemia, and 24 (12.6%) had received HSCT. One hundred thirteen children (59.5%) were receiving ongoing active chemotherapy. The median value of the presumed incubation period (the time from the first exposure to a symptomatic patient to the first onset of symptoms) was three days. There were 144 children (75.8%) who developed mild illness, 40 (21.1%) with moderate illness, and 6 (3.2%) with severe or critical diseases, among whom one child died of acute respiratory distress syndrome. * Xiao-Jun Xu xuxiaojun@zju.edu.cn

The patient was diagnosed with COVID-19 by viral nucleic acid or antigen testing. COVID-19 was classified into four categories based on disease severity according to guidelines published by the National Health Commission of China on March 14, 2022: (1) mild: symptomatic infection of the upper respiratory tract (URT) without any pneumonia manifestations in radiology; (2) moderate: radiological proof of pulmonary involvement but oxygen saturation > 93% without any oxygen support; (3) severe: any one of the following signs: shortness of breath, oxygen saturation ≤ 93%, dyspnea, convulsion or disturbance of consciousness, food refusal or feeding difficulties accompanied by signs of dehydration, high-resolution computed tomography (HRCT) of chest showing bilateral or multiple lobular infiltration, > 50% lung imaging progress in a short period, or pleural effusion; and (4) critical: any one of the following signs: shock, respiratory failure requiring mechanical ventilation, or organ failure requiring intensive care unit. This study protocol was reviewed and approved by the Ethics Committee of Children's Hospital, Zhejiang University School of Medicine (2023-IRB-0032-P-01) as a retrospective study. Informed consent was obtained from the guardians.
The baseline characteristics are summarized and the comparison is presented in Table 1. The median age of the population included in this study was 6.7 years, including 65 females (34.2%). Among them, 140 children (73.7%) were diagnosed with acute leukemia, and 24 (12.6%) had received HSCT. One hundred thirteen children (59.5%) were receiving ongoing active chemotherapy. The median value of the presumed incubation period (the time from the first exposure to a symptomatic patient to the first onset of symptoms) was three days. There were 144 children (75.8%) who developed mild illness, 40 (21.1%) with moderate illness, and 6 (3.2%) with severe or critical diseases, among whom one child died of acute respiratory distress syndrome.
All 190 children were categorized into vaccinated and unvaccinated groups. A total of 107 children had never been vaccinated against SARS-CoV-2, while 83 children had received at least one dose of vaccine, all of whom were immunized with inactivated vaccines. All the patients in the vaccinated group had received SARS-CoV-2 vaccination before they developed hematology and oncology diseases. There were no significant differences in age, sex, height, weight, body mass index, hematologic malignancy types, or active chemotherapy status between the two groups (for all, P > 0.05). However, there was a higher rate of non-mild cases in the unvaccinated group than in the vaccinated group [risk ratio (RR): 2.79, 95% confidence interval (CI) 1.47-5.29, P = 0.001], while there was no significant difference in the hospitalization rate (P = 0.678) (Fig. 1a). Furthermore, Spearman analysis was performed, and negative correlations were observed between the number of vaccinations and the severity of COVID-19 (correlation coefficient: − 0.244, P = 0.001).
Laboratory data at the peak of the disease and presumed incubation period were also analyzed, and the results showed that there were no significant differences in the presumed incubation period and levels of white blood cell, lymphocyte, neutrophil, platelet, C-reactive protein (CRP) and hemoglobin (P > 0.05) ( Table 1).
Previous studies showed that nearly 20% of parents were hesitated about vaccination, which was related to ignorance about vaccine efficacy [5,8,9]. Our findings filled a gap in the study of the effectiveness of vaccines and might enhance the confidence in vaccination in children with hematology and oncology diseases. Vaccination against SARS-CoV-2 can significantly reduce the incidence of shortness of breath and headache or dizziness and significantly reduce the severity of COVID-19 in children with hematologic diseases, Fig. 1 Relative risk (RR) of COVID-19-related symptoms and outcomes and risk factors for non-mild COVID-19. a The RR of COVID-19-related symptoms and outcomes in the vaccinated and unvaccinated groups; b The results of univariable logistic regression analysis between the mild COVID-19 group and the non-mild COVID-19 group. The continuous variables were recategorized as dichotomous variables: age, ≤ 12 years vs. < 12 years; body mass index, ≤ 15 vs. 15; platelet, < 300 × 10 9 /L vs. ≥ 300 × 10 9 /L; neutrophil, < 0.6 × 10 9 /L vs. ≥ 0.6 × 10 9 /L; lymphocyte, < 2 × 10 9 /L vs. ≥ 2 × 10 9 /L; hemoglobin, < 130 g/L vs. ≥ 130 g/L; white blood cell, < 4 × 10 9 /L vs. ≥ 4 × 10 9 /L; C-reactive protein, < 1 mg/L vs. ≥ 1 mg/L. c The results of multivariable logistic regression analysis between the mild COVID-19 group and the non-mild COVID-19 group. The continuous variables were recategorized as dichotomous variables: lymphocytes, < 2 × 10 9 /L vs. ≥ 2 × 10 9 /L; C-reactive protein, < 1 mg/L vs. ≥ 1 mg/L. COVID-19 coronavirus disease 2019, RR risk ratio, OR odds ratio which is similar to the data in adult cancer patients [2,10,11]. Moreover, a trend of severity reduction was observed as the number of vaccinations increased. These findings suggest that we can reduce the severity and mortality of COVID-19 in children with hematologic diseases through booster vaccination during the Omicron pandemic [12].
In this study, vaccination did not reduce hospitalization rates, which is different from other studies [13]. This might be related to the fact that most of the children included in this study were undergoing active chemotherapy, and chemotherapy-related hospitalizations interfered with the results. In addition, vaccination seemed not to affect the incubation period of COVID-19 in children with hematologic diseases.
There are some limitations in this study. It is a singlecenter retrospective study and is prone to recall bias and admission bias. This study only assessed limited laboratory data (the levels of blood cells and CRP), possibly overlooking the impact of other factors. Finally, the protective effects of different vaccination brands were not compared.
In conclusion, vaccination against SARS-CoV-2 can significantly improve clinical outcomes related to COVID-19 in children with hematology/oncology diseases. SARS-CoV-2 vaccination and booster doses were recommended for children with hematologic diseases. Children with elevated CRP at the early stage of COVID-19 are significantly more likely to develop non-mild COVID-19 as the disease progresses.
Author contributions MJ contributed to conceptualization, methodology, data curation, formal analysis, and writing-original draft; ZJY was involved in conceptualization, methodology, data curation, and supervision; LJ performed methodology, data curation, and supervision; ZFY and SH performed validation, data curation, and supervision; XWQ performed data curation and supervision; TYM contributed to conceptualization, methodology, and supervision; XXJ was involved in conceptualization, methodology, data curation, formal analysis, and writing-review and editing; QS was involved in conceptualization, writing-review and editing.
Funding None.

Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations
Conflict of interest Qiang Shu is the Editor-in-Chief for World Journal of Pediatrics and Xiao-Jun Xu is a member of the Editorial Board for World Journal of Pediatrics. This paper was handled by the other Editor and has undergone rigorous peer review process. Qiang Shu and Xiao-Jun Xu were not involved in the journal's review of, or decisions related to, this manuscript.
Ethical approval This study protocol was reviewed and approved by the Ethics Committee of Children's Hospital Zhejiang University School of Medicine (2023-IRB-0032-P-01) as a retrospective study. Consent was obtained from the guardian and assent was obtained from each child.
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