Clinical and immune response characteristics among vaccinated persons infected with SARS-CoV-2 delta variant: a retrospective study

Clinical and immune response characteristics among vaccinated persons infected with SARS-CoV-2 delta variant: a retrospective study 新冠疫苗对SARS-CoV-2 Delta感染者临床症状和免疫应答反应的影响:一项回顾性研究 1 2 equal first-author 1 2 equal 3 2 2 4 1 2 1 2 2 5 corresp Yusheng SHU, shuyusheng65@163.com Yusheng SHU, shuyusheng65@163.com shuyusheng65@163.com https://orcid.org/0000-0001-7270-0012 1 2 corresp Ju GAO, gaoju_003@163.com Ju GAO, gaoju_003@163.com gaoju_003@163.com https://orcid.org/0000-0001-7063-7574 Department of Anesthesiology, Northern Jiangsu People’s Hospital, Yangzhou 225001, China Department of Anesthesiology, Northern Jiangsu People’s Hospital, Yangzhou 225001, China 苏北人民医院麻醉科，中国扬州市，225001 苏北人民医院麻醉科，中国扬州市，225001 Clinical Medical College, Yangzhou University, Yangzhou 225001, China Clinical Medical College, Yangzhou University, Yangzhou 225001, China 扬州大学临床医学院，中国扬州市，225001 扬州大学临床医学院，中国扬州市，225001 Department of Neurology, Jiangsu Provincial Corps Hospital, Chinese People’s Armed Police Force, Yangzhou 225000, China Department of Neurology, Jiangsu Provincial Corps Hospital, Chinese People’s Armed Police Force, Yangzhou 225000, China 中国人民武装警察部队江苏省总队医院神经内科，中国扬州市，225000 中国人民武装警察部队江苏省总队医院神经内科，中国扬州市，225000 Department of Traditional Chinese Medicine, Northern Jiangsu People’s Hospital, Yangzhou 225001, China Department of Traditional Chinese Medicine, Northern Jiangsu People’s Hospital, Yangzhou 225001, China 苏北人民医院中医科，中国扬州市，225001 苏北人民医院中医科，中国扬州市，225001 Department of Cardiothoracic Surgery, Northern Jiangsu People’s Hospital, Yangzhou 225001, China Department of Cardiothoracic Surgery, Northern Jiangsu People’s Hospital, Yangzhou 225001, China 苏北人民医院心胸外科，中国扬州市，225001 苏北人民医院心胸外科，中国扬州市，225001 Objective 2 This study aimed to observe the clinical and immune response characteristics of vaccinated persons infected with the delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Yangzhou, China. Methods 2 We extracted the medical data of 129 patients with delta-variant infection who were admitted to Northern Jiangsu People’s Hospital (Yangzhou, China) between August and September, 2021. The patients were grouped according to the number of vaccine doses received into an unvaccinated group: a one-dose group and a two-dose group. The vaccine used was SARS-CoV-2-inactivated vaccine developed by Sinovac. We retrospectively analyzed the patients’ epidemiological, clinical, laboratory, and imaging data. Results 2 Almost all patients with delta-variant infection in Yangzhou were elderly, and patients with severe/critical illness were over 70 years of age. The rates of severe/critical illness ( P =0.006), fever ( P =0.025), and dyspnea ( P =0.045) were lower in the two-dose group than in the unvaccinated group. Compared to the unvaccinated group, the two-dose group showed significantly higher lymphocyte counts and significantly lower levels of C-reactive protein (CRP), interleukin-6 (IL-6), and D-dimer during hospitalization and a significantly higher positive rate of immunoglobulin G (IgG) antibodies at admission (all P < 0.05). The cumulative probabilities of hospital discharge and negative virus conversion were also higher in the two-dose group than in the unvaccinated group ( P < 0.05). Conclusions 2 Two doses of the SARS-CoV-2-inactivated vaccine were highly effective at limiting symptomatic disease and reducing immune response, while a single dose did not seem to be effective. 目的： 2 观察扬州地区疫苗接种对德尔塔（Delta）变异型冠状病毒（SARS-CoV-2）感染者临床和免疫应答特征的影响。 方法： 2 提取2021年8-9月苏北人民医院收治的129例Delta变异株感染患者的病例资料。根据接种疫苗的剂量将患者分为未接种组、一针组和两针组。所用疫苗为北京科兴公司研制的SARS-CoV-2灭活疫苗。我们回顾性分析了患者的流行病学、临床、实验室和影像学资料。 结果： 2 扬州地区Delta变异感染患者多数为老年人，重症/危重患者年龄均在70岁以上。两针组重症/危重症（ P =0.006）患者人数、发热（ P =0.025）和呼吸困难（ P =0.045）发生率均低于未接种组。与未接种组相比，两针组住院期间淋巴细胞计数显著升高，C反应蛋白（CRP）、白细胞介素-6（IL-6）和D-二聚体水平显著降低，入院时免疫球蛋白G（IgG）抗体阳性率显著升高（ P < 0.05）。两针组的累计出院概率和病毒转阴概率也高于未接种组（ P < 0.05）。 结论： 2 接种两针SARS-CoV-2灭活疫苗在减轻新冠肺炎患者症状和降低免疫应答方面效果显著，接种一针疫苗效果不明显。 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant Vaccine Hospitalization Immune response 冠状病毒（SARS-CoV-2） 德尔塔（Delta）变异株 疫苗 住院 免疫反应 1 Introduction 1 Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ( Shi HS et al., 2020 Shi HS et al., 2020 ), has spread to more than 210 countries and territories ( Huang et al., 2020 Huang et al., 2020 ; Haileamlak, 2021 Haileamlak, 2021 ). As of Nov. 8, 2021, the number of people infected worldwide exceeded 250 million and the number of deaths exceeded 5 million. SARS-CoV-2 is an RNA virus with a relatively stable genome, mainly due to its proofreading enzyme ( Wu and McGoogan, 2020 Wu and McGoogan, 2020 ). However, the COVID-19 pandemic has led to large-scale replication events on a global scale, and thus far, approximately 800 SARS-CoV-2 subtypes have been reported ( Lu et al., 2021 Lu et al., 2021 ). The World Health Organization (WHO) has designated the following five variants of SARS-CoV-2 as variants of concern: alpha, beta, gamma, delta, and omicron. These correspond to the Phylogenetic Assignment of Named Global Outbreak (PANGO) lineage designations B.1.1.7, B.1.351, P.1, B.1.617.2, and B.1.1.529, respectively ( Parums, 2021 Parums, 2021 ). During the second wave of global SARS-CoV-2 infection outbreak, the increase in SARS-CoV-2 cases was attributed to the high transmission potential of the delta variant, which was rapidly replacing the alpha variant as the dominant variant in most countries ( Gupta et al., 2021 Gupta et al., 2021 ). The delta variant was first discovered in India in December 2020, and the available evidence suggests that this variant is associated with increased transmissibility, secondary attack rate, hospitalization risk, and immune escape ( Dhar et al., 2021 Dhar et al., 2021 ; Novelli et al., 2021 Novelli et al., 2021 ). In August 2021, there was an outbreak of the delta variant in Yangzhou, China. This outbreak occurred in an urban area and involved the largest number of patients infected with the delta variant in China thus far. The accepted opinion is that the activities of the first few confirmed patients, such as attending crowded public chess and card rooms, led to the rapid spread of the delta-variant virus in China. To date, this outbreak has resulted in more than 500 cases, and most of the patients are over 50 years of age, which has made treatment challenging. In view of the global spread of delta-variant infection, research on the nature, treatment, and especially prevention of this infection is urgently required. Vaccines have been found to be effective in preventing the symptoms of SARS-CoV-2 infection, and their safety and efficacy have been confirmed through clinical trials ( Baden et al., 2021 Baden et al., 2021 ; Skowronski and de Serres, 2021 Skowronski and de Serres, 2021 ; Voysey et al., 2021 Voysey et al., 2021 ). Vaccines were found to be almost as effective against the alpha variant as against the previous virus strains and were found to provide additional protection in COVID-19 patients with severe/critical illness ( Abu-Raddad et al., 2021 Abu-Raddad et al., 2021 ; Hall et al., 2021 Hall et al., 2021 ; Jalkanen et al., 2021 Jalkanen et al., 2021 ). A trial of the NVX-CoV2373 vaccine (Novavax) showed an effectiveness of 51.0% against the beta variant ( Shinde et al., 2021 Shinde et al., 2021 ). Serum samples from patients infected with the P.1 (gamma) variant and treated with the BNT162b2 vaccine (Pfizer BioNTech) were found to show high levels of neutralizing antibodies ( Liu et al., 2021 Liu et al., 2021 ). However, limited data are available on the clinical effectiveness of SARS-CoV-2 vaccines against the delta variant. In this study, we aimed to evaluate the effectiveness of the SARS-CoV-2 vaccine against infections caused by the delta variant. 2 Patients and methods 1 2.1 Participants and study design 2 This single-center, retrospective study involved a group of patients with SARS-CoV-2 delta-variant infection who were treated at Northern Jiangsu People’s Hospital, Yangzhou, China. The diagnosis of SARS-CoV-2 delta-variant infection was confirmed using real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assays of nasopharyngeal and oropharyngeal swabs, followed by sequence analysis. Details of the laboratory confirmation protocol for the delta variant have been described previously ( Ghosh et al., 2021 Ghosh et al., 2021 ). The diagnosis of SARS-CoV-2 delta infection complied with WHO guidelines ( National Health Commission of the People’s Republic of China, 2020 National Health Commission of the People’s Republic of China, 2020 ). In this retrospective study, we categorized patients infected with SARS-CoV-2 delta variant according to their vaccination status into an unvaccinated group, a one-dose group, and a two-dose group. We explored the effects of vaccination status on the patients’ clinical symptoms, laboratory indicators, computed tomography (CT) findings, length of hospital stay, and time until negative conversion of SARS-CoV-2 delta-variant virus. The SARS-CoV-2-inactivated vaccine administered to the studied patients was made by Sinovac in Beijing, China. 2.2 Data collection 2 We queried our electronic medical record database to search for all patients with laboratory-confirmed SARS-CoV-2 delta-variant infection who had been discharged from our hospital on or before Sept. 15, 2021. We recorded the initial symptoms of the patients at admission to our hospital as well as the admission history and physical notes. Then, we collected data on medical history and any chronic diseases via medical records and medical history reviews. Fever was defined as a forehead temperature of >38 ℃, and hypoxemia was defined as a pulse oximetry reading of <90% from a finger oximeter. Hypertension was defined as systolic blood pressure of >140 mmHg and diastolic blood pressure of >90 mmHg; tachycardia was defined as heart rate of >100 beats/min. All laboratory values on the day of admission and during hospitalization were collected from the electronic medical record database. Laboratory values assessed in the study included white blood cell, lymphocyte, and platelet counts. Blood chemistry profiles included levels of liver- and renal-function markers, C-reactive protein (CRP), interleukin-6 (IL-6), creatine kinase, creatine kinase-MB, and D-dimer. Details on nucleic acid test results, chest CT findings, and treatment methods were also extracted. Patients were deemed to have abnormal chest CT findings if this was mentioned in the report from the radiologist. All the data were entered into a computer database and cross-checked twice to ensure their accuracy. 2.3 Study outcomes 2 The primary composite endpoint was discharged from the hospital. According to the Chinese National Health Commission’s SARS-CoV-2 treatment criteria, patients must meet the following three conditions for discharge: (1) body temperature returned to normal for > 3 d and respiratory symptom improvement; (2) improvement of lung involvement demonstrated by chest CT; and (3) two consecutive negative qRT-PCR tests, with a sampling interval of > 1 d. The secondary endpoint was a SARS-CoV-2 delta-variant virus test turning negative (seroconversion). Based on the National Health Commission’s SARS-CoV-2 diagnostic criteria, negative virus conversion was defined as two consecutive negative qRT-PCR tests, with a sampling interval of > 1 d (cycle threshold ( C T ) value of < 40 was defined as a SARS-CoV-2 virus-positive result). 2.4 Statistical analysis 2 Continuous data were presented as means and standard deviations (SDs); categorical data were presented as numbers and percentages, and missing data were not imputed. Our objective was to report the impact of vaccination on the epidemiological and clinical characteristics and outcomes of patients infected with SARS-CoV-2 delta variant. All data from the three study groups were verified for normality and homogeneity of variance using the Kolmogorov-Smirnov and Brown-Forsythe tests before analysis; then, one-way analysis of variance (ANOVA) followed by the Tukey’s post-hoc test was performed for each group. The log-rank method was applied to estimate the change in hospital discharge rates and the probabilities of negative conversion of SARS-CoV-2 delta-variant virus tests. The proportional hazard Cox regression model was used to identify potential factors associated with discharge and negative virus conversion. Hazards ratios (HRs) were calculated with 95% confidence intervals (CIs). Differences were considered statistically significant if P < 0.05. All statistical analyses were performed using SPSS v19.0 (IBM, Beijing, China) and GraphPad Prism v7.0 software (GraphPad, San Diego, USA). 3 Results 1 3.1 Clinical presentation and epidemiological characteristics 2 As of Sept. 15, 2021, a total of 485 people had been infected with the delta virus in Yangzhou, China and no deaths had been reported. In this study, we retrospectively analyzed the chart data of the 129 patients who were diagnosed with SARS-CoV-2 delta-variant infection between Aug. 4, 2021 and Sept. 15, 2021 in Northern Jiangsu People’s Hospital, Yangzhou, China ( Fig. 1 Fig. 1 ). The demographic and baseline characteristics of these 129 patients are summarized in Table 1 Table 1 , which shows the comparison between unvaccinated patients and patients who received one or two vaccine doses. Of the 129 patients, 63 were men and 66 were women. The average age was (60±15) years. The body mass index of all patients was within the normal range. The most common comorbidities were hypertension (60, 46.5%), diabetes (17, 13.2%), and coronary heart disease (10, 7.8%). The most common symptoms were cough (68, 52.7%), fever (35, 27.1%), sore throat (24, 18.6%), fatigue (22, 17.1%), and sputum production (17, 13.2%). Other symptoms such as difficulty breathing (8, 6.2%), headache (3, 2.3%), myalgia (4, 3.1%), diarrhea (6, 4.7%), anosmia (6, 4.7%), and loss of appetite (4, 3.1%) were less common. Age, gender, and complications did not significantly differ between unvaccinated patients and those who had received one or two doses of the vaccine. The incidence rates of fever (11.4% vs. 32.1%, P =0.025, χ 2 test), difficulty breathing (0% vs. 9.4%, P =0.045, χ 2 test), and severe/critical illness (2.4% vs. 25.0%, P =0.006, χ 2 test) were significantly lower in patients who received two vaccine doses than in unvaccinated patients ( Table 1 Table 1 ). Data are expressed as mean±SD or number (percentage). P values of < 0.05 are in bold. SD: standard deviation; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2. 2 Characteristics 2 Entire cohort ( n =129) 2 Unvaccinated ( n =56) 4 Vaccinated ( n =73) One-dose ( n =38) P value (one-dose vs. unvaccinated) Two-dose ( n =35) P value (two-dose vs. unvaccinated) Age (years) 60±15 60±18 60±16 0.802 60±6 0.490 7 Sex Male 63 (48.8%) 27 (48.2%) 22 (57.9%) 0.357 14 (40.0%) 0.444 Female 66 (51.2%) 29 (51.8%) 16 (42.1%) 21 (60.0%) Body mass index (kg/m 2 ) 24.2±3.5 24.5±3.6 23.9±3.3 0.380 24.2±3.6 0.408 Comorbidities Hypertension 60 (46.5%) 30 (53.6%) 18 (47.4%) 0.555 12 (34.3%) 0.073 Hyperlipidemia 2 (1.6%) 1 (1.8%) 0 (0%) 0.408 1 (2.9%) 0.735 Diabetes 17 (13.2%) 11 (19.6%) 4 (10.5%) 0.236 2 (5.7%) 0.065 Chronic obstructivepulmonary disease 2 (1.6%) 0 (0%) 2 (5.3%) 0.083 0 (0%) 1.000 Coronary heart disease 10 (7.8%) 6 (10.7%) 2 (5.3%) 0.353 2 (5.7%) 0.413 Cerebrovascular disease 3 (2.3%) 3 (5.4%) 0 (0%) 0.147 0 (0%) 0.164 Liver disease 1 (0.8%) 1 (1.8%) 0 (0%) 0.408 0 (0%) 0.427 Renal disease 2 (1.6%) 1 (1.8%) 1 (2.6%) 0.780 0 (0%) 0.427 Malignancy 5 (3.9%) 1 (1.8%) 2 (5.3%) 0.347 2 (5.7%) 0.307 Symptoms/signs Cough Fever Difficulty breathing Fatigue 68 (52.7%) 35 (27.1%) 8 (6.2%) 22 (17.1%) 32 (57.1%) 18 (32.1%) 6 (9.4%) 13 (23.2%) 18 (47.4%) 13 (34.2%) 2 (5.3%) 6 (15.8%) 0.351 0.834 0.353 0.379 18 (51.4%) 4 (11.4%) 0 (0%) 3 (8.6%) 0.594 0.025 0.045 0.074 Sputum production 17 (13.2%) 6 (10.7%) 8 (21.1%) 0.167 3 (8.6%) 0.739 Sore throat Headache Myalgia Diarrhea Anosmia 24 (18.6%) 3 (2.3%) 4 (3.1%) 6 (4.7%) 6 (4.7%) 10 (17.9%) 0 (0%) 3 (5.4%) 4 (7.1%) 2 (3.5%) 5 (13.2%) 2 (5.3%) 1 (2.6%) 0 (0%) 3 (7.9%) 0.542 0.083 0.521 0.092 0.359 9 (25.7%) 1 (2.9%) 0 (0%) 2 (5.7%) 1 (2.9%) 0.370 0.203 0.164 0.789 0.853 Loss of appetite 4 (3.1%) 1 (1.2%) 2 (5.3%) 0.347 1 (2.9%) 0.735 Severity Mild/moderate 110 (85.3%) 42 (75.0%) 34 (89.5%) 0.080 34 (97.6%) 0.006 Severe/critical 19 (14.7%) 14 (25.0%) 4 (10.5%) 1 (2.4%) All patients with severe/critical illness were elderly ( > 70 years), including 14 unvaccinated patients, four patients who had received one vaccine dose, and one patient who had received two vaccine doses. We conducted a detailed dynamic evaluation of the clinical evolution of these 19 patients, and found that three patients had abnormal chest CT findings before diagnosis, with patchy shadow as the main CT manifestation. In all 19 of these patients, chest CT abnormality progressed through three stages: patchy shadow occurrence, patchy shadow progression, and patchy shadow absorption. For most patients, the nucleic acid test results during hospitalization underwent dynamic conversion between positive and negative, and ultimately stayed negative (Fig. S1). Analysis of all 129 SARS-CoV-2 delta variant-infected patients revealed similar probability density distributions of the time intervals from symptom onset to admission, symptom onset to diagnosis, and admission to diagnosis among unvaccinated patients and those with one or two vaccine doses (Figs. 2 2 a– 2 2 c). The mean time intervals from symptom onset to admission, symptom onset to diagnosis, and admission to diagnosis were also similar in the unvaccinated, one-dose, and two-dose groups (Figs. 2 2 d– 2 2 f). 3.2 Laboratory findings 2 The laboratory findings for all patients are shown in Table 2 Table 2 . The total white blood cell count did not differ between the unvaccinated ((5.59±2.13)×10 9 L -1 ) and vaccinated groups (one-dose group: (5.89±2.45)‍×10 9 L -1 , P =0.569; two-dose group: (6.39±2.27)‍×10 9 L -1 , P =0.273). Similarly, the platelet count did not differ between the unvaccinated group and one-dose or two-dose group (all P > 0.05). However, the lymphocyte count was significantly higher in the two-dose group than in the unvaccinated group ((1.15±0.41)×10 9 L -1 vs. (0.88±0.40)×10 9 L -1 , P =0.010, one-way ANOVA). The levels of CRP ((14.39±15.61) mg/L vs. (32.41±40.16) mg/L, P =0.043, one-way ANOVA) and IL-6 ((16.77±13.43) pg/mL vs. (31.23±34.21) pg/mL, P =0.048, one-way ANOVA) were significantly lower in the two-dose group than in the unvaccinated group. The D-dimer level at admission was significantly elevated in the unvaccinated group and almost normal in the two-dose group ((0.37±0.21) mg/L vs. (1.26±3.58) mg/L, P =0.040, one-way ANOVA). No significant differences among the three study groups were found in any of the other laboratory indices tested. Patients with SARS-CoV-2 delta-variant infection have been reported to have lymphocytopenia and elevated CRP, IL-6, and D-dimer levels ( Zhang et al., 2020 Zhang et al., 2020 ). Thus, the above changes in the 129 patients at admission are consistent with previous reports. Importantly, we found that completion of two doses of the vaccine limited the decrease in lymphocyte count, reduced the inflammatory response, and lowered the D-dimer level in infected patients. These findings suggest that completion of vaccination may limit the clinical progression of SARS-CoV-2 delta-variant infection. * Data are expressed as mean±SD. P values of < 0.05 are in bold. SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; LDH: lactate dehydrogenase; CK: creatine kinase; CRP: C-reactive protein; IL-6: interleukin-6; SD: standard deviation. 2 Laboratory test 2 Normal range 2 Entire cohort ( n =129) * 2 Unvaccinated ( n =56) * 4 Vaccinated ( n =73) One-dose ( n =38) * P value (one-dose vs. unvaccinated) Two-dose ( n =35) * P value (two-dose vs. unvaccinated) White blood cell count (×10 9 L -1 ) 4.00–10.00 5.88±2.22 5.59±2.13 5.89±2.45 0.569 6.39±2.27 0.273 Lymphocytes (×10 9 L -1 ) 1.20–4.00 1.10±0.51 0.88±0.40 1.00±0.45 0.237 1.15±0.41 0.010 Platelets (×10 9 L -1 ) 115.00–350.00 167.83±60.94 152.93±53.70 162.55±65.74 0.427 183.29±53.59 0.057 Total bilirubin (μmol/L) 5.10–19.00 10.67±5.97 11.03±5.48 11.49±7.82 0.708 9.09±3.90 0.247 LDH (U/L) 109.00–245.00 234.74±92.44 239.66±90.67 232.03±75.52 0.947 229.83±112.22 0.947 Alanine aminotransferase (U/L) 5.00–35.00 27.41±24.45 30.69±22.39 23.88±17.72 0.161 22.25±11.46 0.108 Creatinine (μmol/L) 44.00–106.00 78.13±27.28 80.71±27.71 77.61±23.69 0.832 74.57±30.42 0.657 CRP (mg/L) 0–8.00 26.09±34.90 32.41±40.16 27.56±37.41 0.503 14.39±15.61 0.043 IL-6 (pg/mL) 0.10–2.90 26.45±28.18 31.23±34.21 25.83±26.13 0.354 16.77±13.43 0.048 CK (U/L) 26.00–140.00 231.05±835.73 173.78±198.11 179.24±269.49 0.904 137.97±168.13 0.798 CK-MB (ng/mL) 0.10–500.00 19.40±27.12 22.57±32.98 20.19±29.39 0.677 13.46±3.97 0.321 D-Dimer (mg/L) 0–0.50 0.95±2.50 1.26±3.58 0.71±0.73 0.808 0.37±0.21 0.040 Taking the above results into consideration, we further analyzed the lymphocyte count, as well as CRP, IL-6, and D-dimer levels, at 7 and 14 d after admission. At both time points, lymphocyte counts were significantly higher in the two-dose group than in the unvaccinated group (Day 7, (1.36±0.39)×10 9 L -1 vs. (1.11±0.40)×10 9 L -1 , P =0.033; Day 14, (1.85±0.58)×10 9 L -1 vs. (1.42±0.42)×10 9 L -1 , P =0.002; one-way ANOVA; Figs. 3 3 a and 3 3 e). D-Dimer levels were significantly lower in the two-dose group than in the unvaccinated group (Day 7, (0.43±0.27) mg/L vs. (1.10±0.82) mg/L, P < 0.001; Day 14, (0.47±0.32) mg/L vs. (0.85±0.62) mg/L, P =0.025; one-way ANOVA; Figs. 3 3 d and 3 3 h). Similarly, the CRP and IL-6 levels were lower in the two-dose group than in the unvaccinated group (Figs. 3 3 b, 3 3 c, 3 3 f, and 3g), indicating a reduced inflammatory response in patients who contracted SARS-CoV-2 delta-variant infection after completion of vaccination. Although the CRP, IL-6, and D-dimer levels seemed to be correlated with disease severity, this result should be interpreted with caution. Therefore, we further investigated the correlations between levels of CRP, IL-6 and D-dimer (Fig. S2) and found that CRP and IL-6 levels were highly positively correlated with each other ( r =0.51), while CRP ( r =0.23) and IL-6 levels ( r =0.29) were less strongly correlated with D-dimer level. 3.3 Antibody levels 2 To explore the changes in immune response after SARS-CoV-2 delta-variant infection, we analyzed the levels of immunoglobulin M (IgM) and IgG antibodies at different time points after admission. On the day of admission (Day 0), IgM antibodies were detected in 19.6%, 23.8%, and 20.0% of patients in the unvaccinated, one-dose, and two-dose groups, respectively; the corresponding detection rates for IgG antibodies were 41.1%, 29.0%, and 65.7%. Consistent with our observations, previous studies have found that the positive rate of IgG antibodies is higher than that of IgM antibodies in patients with SARS-CoV-2 infection ( Long et al., 2020 Long et al., 2020 ; Xu X et al., 2020 Xu X et al., 2020 ). Positive rates of IgM and IgG antibodies increased significantly at 7 d after admission, especially in the two-dose group, and reached 100% at 14 d after admission ( Fig. 4 Fig. 4 ). Furthermore, IgG antibody levels were significantly higher in the two-dose group than in the unvaccinated group on Day 0 ((47.30±95.85) vs. (12.39±31.35), P =0.030, one-way ANOVA; Fig. 5 Fig. 5 ). The dynamic changes in antibody levels on Days 0, 7, and 14 in the 19 patients with severe/critical illness are shown in Fig. S3. The above results indicate that completion of vaccination may induce earlier production of antibodies against the SARS-CoV-2 delta-variant virus. 3.4 Radiological findings 2 According to recent data, almost all patients with SARS-CoV-2 delta-variant infection exhibit characteristic CT findings during the course of the disease, such as different degrees of ground-glass opacities with or without the crazy-paving sign, multifocal organizing pneumonia, and architectural distortion in a peripheral distribution ( Hu et al., 2020 Hu et al., 2020 , Lei et al., 2020 Lei et al., 2020 ). Therefore, chest CT is currently used as an important complement to qRT-PCR tests in the diagnosis of SARS-CoV-2 delta-variant infection. We analyzed the chest CT changes in the three study groups. The time interval from the onset of chest CT abnormalities to their progression was approximately 3 d in all three groups, and the probability density distributions of this interval were similar in all groups ( Fig. 6 Fig. 6 a). The time interval from onset to complete absorption of chest CT abnormalities was approximately 15 d, and its probability density distribution was similar in the three groups (Figs. 6 6 b and 6 6 c). 3.5 Clinical outcomes 2 The primary composite endpoint was discharge from the hospital, and the secondary endpoint was a negative SARS-CoV-2 delta-variant virus test. According to the National Health Commission’s SARS-CoV-2 diagnostic and treatment criteria ( National Health Commission of the People’s Republic of China and National Administration of Tranditional Chinese Medicine, 2022 National Health Commission of the People’s Republic of China and National Administration of Tranditional Chinese Medicine, 2022 ), a patient is considered to have turned negative for the virus when two consecutive nucleic acid tests yield negative results. Once negative virus conversion occurs, doctors comprehensively evaluate the patients’ condition to determine if they can be discharged from the hospital. In this study, we retrospectively analyzed the discharge rate and negative virus conversion rate in the three study groups. By Sept. 15, 2021, all 129 patients had been discharged, and none had died. The discharge probabilities in the three groups are shown in Figs. 7 7 a and 7 7 b. According to the results of the log-rank (Mantel-Cox) test, the median discharge time was 15 d in the unvaccinated group, 14.5 d in the one-dose group, and 14 d in the two-dose group. The cumulative probability of hospital discharge was significantly higher ( P =0.014, log-rank test; Fig. 7 Fig. 7 b) and the length of hospital stay was significantly lower ((14.3±3.4) d vs. (16.4±4.6) d, P =0.038, one-way ANOVA; Fig. S4a) in the two-dose group than in the unvaccinated group. We used multivariable Cox regression analysis to investigate the associations of discharge rate with age, sex, fever, and levels of CRP, IL-6, D-dimer, total bilirubin, alanine aminotransferase, and creatinine. It was evident that an elevated creatinine level on admission was an unfavorable factor for discharge (hazard ratio (HR)=0.503, 95% confidence interval (CI): 0.290–0.874, P =0.015; Fig. 7 Fig. 7 c). The probabilities of negative conversion of the SARS-CoV-2 delta-variant virus in the three study groups are shown in Figs. 8 8 a and 8 8 b. According to the results of the log-rank (Mantel-Cox) test, the median time until negative virus conversion was 12.5 d in the unvaccinated group, 13 d in the one-dose group, and 10 d in the two-dose group. The cumulative probability of a positive viral RNA test result ( P =0.032, log-rank test; Fig. 8 Fig. 8 b) and the time until negative viral RNA conversion ((10.6±4.2) d vs. (12.8±4.9) d, P =0.039, one-way ANOVA; Fig. S4b) were significantly lower in the two-dose group than in the unvaccinated group. Multivariable Cox regression analysis was used to investigate associations of the negative virus conversion rate with age, sex, fever, and levels of CRP, IL-6, D-dimer, total bilirubin, alanine aminotransferase, and creatinine. We found no unfavorable factors for negative virus conversion rate ( Fig. 8 Fig. 8 c). By observing the dynamic changes in viral RNA loads in the 19 patients with severe/critical illness, we found that many patients with SARS-CoV-2 delta-variant infection underwent dynamic virus transformation, which increased the difficulty of confirming negative virus conversion (Fig. S5). 3.6 Treatment measures 2 All patients were offered traditional Chinese medicine; 14 patients with severe/critical illness in the unvaccinated group were treated with neutralizing antibodies, and none of the patients were given empirical antiviral drugs, corticosteroids, thymosin, or other therapies. On the day of admission (Day 0), oxygen therapy was administered via nasal cannulas in 87 (67.4%) patients, nasal high-flow therapy in 7 (5.4%) patients, and non-invasive ventilation in 1 (0.8%) patient. No patient required endotracheal intubation on admission. On Day 7, the following methods were used for oxygen delivery: nasal cannula, 36 (27.9%) patients; nasal high-flow therapy, 7 (5.4%) patients; non-invasive ventilation, 3 (2.3%) patients; and endotracheal intubation, 2 (1.6%) patients. On Day 14, 26 (30.6%) patients used a nasal cannula, 6 (7.1%) patients received nasal high-flow therapy, 1 (1.2%) patient received non-invasive ventilation, and 2 (2.4%) patients required endotracheal intubation. The proportion of patients who did not require oxygen therapy did not differ among the unvaccinated, one-dose, and two-dose groups on Day 0, 7, or 14; the selection of oxygen-delivery methods also did not differ among the three groups ( Table 3 Table 3 ). At 0 and 7 d after admission: entire cohort, n =129; unvaccinated group, n =56; one-dose group, n =38; and two-dose group, n =35. At 14 d after admission: entire cohort, n =85; unvaccinated group, n =41; one-dose group, n =24; and two-dose group, n =20. Data are expressed as number (percentage). SARS-CoV-2: severe acute respiratory syndrome coronavirus 2. 2 Time after admission (d) 2 Maximal need for oxygen 2 Entire cohort 2 Unvaccinated 4 Vaccinated One-dose P value (one-dose vs. unvaccinated) Two-dose P value (two-dose vs. unvaccinated) 0 No oxygen 34 (26.4%) 18 (32.1%) 6 (15.8%) 0.074 10 (28.6%) 0.720 Nasal cannula 87 (67.4%) 33 (58.9%) 30 (78.9%) 0.521 24 (68.6%) 0.448 Nasal high-flow therapy 7 (5.4%) 4 (7.1%) 2 (5.3%) 1 (2.9%) Non-invasive ventilation 1 (0.8%) 1 (1.8%) 0 (0%) 0 (0%) Endotracheal intubation 0 (0%) 0 (0%) 0 (0%) 0 (0%) 7 No oxygen 81 (62.8%) 34 (60.7%) 24 (63.2%) 0.683 23 (65.7%) 0.620 Nasal cannula 36 (27.9%) 14 (25.0%) 12 (31.6%) 0.288 10 (28.6%) 0.361 Nasal high-flow therapy 7 (5.4%) 3 (5.4%) 2 (5.3%) 2 (5.7%) Non-invasive ventilation 3 (2.3%) 3 (5.4%) 0 (0%) 0 (0%) Endotracheal intubation 2 (1.6%) 2 (3.6%) 0 (0%) 0 (0%) 14 No oxygen 50 (58.8%) 21 (51.2%) 15 (62.5%) 0.377 14 (70.0%) 0.164 Nasal cannula 26 (30.6%) 13 (31.7%) 8 (33.3%) 0.547 5 (25.0%) 0.765 Nasal high-flow therapy 6 (7.1%) 4 (9.8%) 1 (4.2%) 1 (5%) Non-invasive ventilation 1 (1.2%) 1 (2.4%) 0 (0%) 0 (0%) Endotracheal intubation 2 (2.4%) 2 (4.9%) 0 (0%) 0 (0%) 4 Discussion 1 This retrospective study investigated the first outbreak of the delta variant in China. We enrolled a total of 129 patients with SARS-CoV-2 delta-variant infection who were admitted to our hospital for treatment. Our focus was on the impact of the SARS-CoV-2 vaccine on the immune response and clinical outcomes of patients infected with the delta variant. The principal findings of this study are threefold: (1) by analyzing the laboratory data of patients, we found that compared with unvaccinated patients, patients who completed two doses of vaccination showed higher lymphocyte counts and lower levels of CRP, IL-6, and D-dimer during hospitalization; (2) IgG levels were significantly higher in the two-dose group than in the unvaccinated group at admission, indicating that in patients who had completed vaccination, immune defenses were activated in the early stages of the infection; (3) Completion of two doses of the vaccine reduced the length of hospital stay and increased the negative virus conversion rate of patients with delta-variant infection. Taken together, these findings suggested that the SARS-CoV-2 vaccine was effective against the delta variant in this Yangzhou outbreak, especially in patients who had completed two doses. An epidemiological review showed that almost all patients with delta-variant infection in Yangzhou were elderly people, with an average age of 60 years, and all patients with severe/critical illness were over 70 years of age, which made treatment more challenging. The main reason for this is that the initial source of virus infection was frequent visits to chess and card rooms, which are public places where many older people gather. In addition, the elderly have less knowledge about the transmission routes of SARS-CoV-2 and poor personal protection practices, which led to the rapid spread of the delta variant. Therefore, training the elderly on SARS-CoV-2 transmission routes and personal protection will play an important role in the prevention and control of SARS-CoV-2 infections. The delta variant consists of 41 different sublineages sharing additional T19R, del157/158, T478K, and D950N mutations in the Spike protein and the I82T mutation in M protein, as compared to B.1 ( Baj et al., 2021 Baj et al., 2021 ). The SARS-CoV-2 Spike protein mutation of the delta variant is known to affect transmission and neutralization of the virus ( Kemp et al., 2020 Kemp et al., 2020 ). In addition, the secondary attack rate of the delta variant is higher than that of the alpha variant. At the time of writing, the delta variant was spreading rapidly around the world and had become the main variant in many countries, causing massive numbers of hospitalizations and deaths. According to our data, it took only 3 d, on average, from the onset of symptoms for patients to be diagnosed in the Yangzhou outbreak. Infection with the delta variant of SARS-CoV-2 caused changes in many biological indicators in the blood. By analyzing the laboratory data of the patients, we found that in the early stage of delta-variant infection, the peripheral lymphocyte count was decreased. Studies have confirmed that the main immune response to viral infection is a specific T-lymphocyte immune response ( Beňová et al., 2020 Beňová et al., 2020 ; Wan et al., 2020 Wan et al., 2020 ). The host’s cellular immune response mostly produces a large number of CD8 + lymphocytes specific to the virus in approximately one week after the virus enters the human body ( Wu et al., 2018 Wu et al., 2018 ). To determine why the lymphocyte count decreases in patients infected with the delta variant, we searched the literature. It has been reported that infection with SARS-CoV and Middle East respiratory syndrome (MERS)-CoV, two viruses that are similar to SARS-CoV-2, also cause lymphocyte reduction ( Liang et al., 2020 Liang et al., 2020 ). The mechanism of lymphopenia in COVID-19 patients is a matter of some debate. Both SARS-CoV and SARS-CoV-2 are known to infect host cells by binding to angiotensin-converting enzyme 2 (ACE2) receptors on the cell surface ( Lu et al., 2020 Lu et al., 2020 ; Xu XT et al., 2020 Xu XT et al., 2020 ). Immune cells, including T-lymphocytes, are negative for ACE2 receptors, which suggests that SARS-CoV-2 is unlikely to directly infect lymphocytes and cause their destruction ( Hamming et al., 2004 Hamming et al., 2004 ; Yan and Wu, 2021 Yan and Wu, 2021 ). Another prerequisite for SARS-CoV, SARS-CoV-2, and MERS-CoV to gain entry into host cells is the expression of transmembrane serine protease 2 (TMPRSS2), a cellular serine protease ( Glowacka et al., 2011 Glowacka et al., 2011 ; Kleine-Weber et al., 2018 Kleine-Weber et al., 2018 ; Hoffmann et al., 2020 Hoffmann et al., 2020 ). It is unclear whether lymphocytes express TMPRSS2 or other similar proteases. Thus, the observed lymphopenia in COVID-19 patients is likely to be caused by the redistribution of leukocytes to other tissues due to the inflammatory response to the infection or by the apoptosis of lymphocytes triggered by the activation of the p53 signaling pathway ( Xiong et al., 2020 Xiong et al., 2020 ; Yan and Wu, 2021 Yan and Wu, 2021 ). Therefore, lymphocyte reduction may be an important indicator of disease severity, and lymphocytopenia could be used as a reference index in the diagnosis of SARS-CoV-2 infections in the clinic ( Huang et al., 2020 Huang et al., 2020 ). Inflammatory response or cytokine storm also plays an important role in the progression of SARS-CoV-2 infection, and our findings confirm that delta-variant infection leads to increased levels of CRP and IL-6 ( Li RF et al., 2020 Li RF et al., 2020 ; Wang et al., 2020 Wang et al., 2020 ). Research has shown that levels of CRP and inflammatory cytokines may be related to and serve as an indicator of disease severity ( Chen et al., 2020 Chen et al., 2020 ). Furthermore, infection-induced coagulation dysfunction and secondary hyperfibrinolysis have been found in severe cases of SARS-CoV-2 infection ( Tang et al., 2020 Tang et al., 2020 ), and high levels of D-dimer at admission are associated with poor prognosis for SARS-CoV-2-infected patients ( Wang et al., 2011 Wang et al., 2011 ). Therefore, we continuously monitored the changes in D-dimer levels after admission. We found that patients infected with the delta variant had high D-dimer levels at admission, which is consistent with previous reports ( Wang et al., 2011 Wang et al., 2011 ; Tang et al., 2020 Tang et al., 2020 ). In addition, these patients had bilateral, subpleural, ground-glass opacities on chest CT images, which is consistent with recent radiological reports on SARS-CoV-2 ( Kong and Agarwal, 2020 Kong and Agarwal, 2020 ; Pan et al., 2020 Pan et al., 2020 ; Shi Y et al., 2020 Shi Y et al., 2020 ). We also analyzed the progression of chest CT abnormalities from appearance to aggravation and ultimately absorption. Our results showed that in patients with SARS-CoV-2 delta-variant infection, chest CT abnormalities started to progress approximately 3 d after symptom onset and were completely absorbed by 15 d after symptom onset. Studies have investigated the effectiveness of the SARS-CoV-2 vaccine against COVID-19, but few have investigated whether the vaccine is effective against delta-variant infection ( Sultana et al., 2020 Sultana et al., 2020 ; Malik et al., 2021 Malik et al., 2021 ). Upon comparing epidemiological data between unvaccinated patients and those with one or two vaccine doses, we found that the incidences of fever and difficulty breathing were significantly lower in patients who had completed two doses of vaccination than in those who were unvaccinated. Moreover, a high percentage of severe/critical cases occurred in the unvaccinated group. These findings suggested that the SARS-CoV-2 vaccine could reduce the incidence of severe symptoms after infection, such as fever and breathing difficulty, and reduce the risk of patients developing severe/critical illness. In addition, it was clear that the completion of two vaccine doses limited SARS-CoV-2 infection-related lymphocytopenia, inflammation, and coagulation, which are all important indicators of the transformation of the infection into severe/critical disease. It is generally believed that IgM antibodies provide the first line of defense against viral infection, and that production of IgG antibodies lags behind that of IgM antibodies, but provides long-term immunity and immune memory ( Li ZT et al., 2020 Li ZT et al., 2020 ). Our observations showed that at admission, the total IgG level of anti-SARS-CoV-2 antibodies was already higher in the two-dose group than in the unvaccinated group. In our opinion, possible reasons for this are as follows: on the one hand, antibodies were generated after these patients completed two doses of vaccination, and a certain immune capacity was obtained; on the other hand, the patients in the two-dose group had mild symptoms, so they presented to the hospital later in the course of the disease, by which time some IgG antibodies had already been produced. To further assess the impact of vaccination on the clinical outcomes of patients with delta-variant infection, we assessed the impact of vaccination on patient discharge rates and negative virus-conversion rates. We found that the cumulative probability of hospital discharge was higher in the two-dose group (log-rank test), and the length of hospital stay was significantly lower in the two-dose group than in the unvaccinated group. Predictors of hospital discharge among infected patients were identified using the Cox model. Creatinine levels of > 1×10 6 μmol/L were significantly associated with a lower likelihood of discharge. Studies have shown that acute kidney injury can occur in patients with critical SARS-CoV-2 infections ( Gabarre et al., 2020 Gabarre et al., 2020 ; Hansrivijit et al., 2020 Hansrivijit et al., 2020 ), and patients with renal insufficiency have increased mortality ( Mudatsir et al., 2020 Mudatsir et al., 2020 ), which increases the length of hospital stay. It is important to understand which factors affect the condition of inpatients and their risks during hospitalization because we can use this knowledge to screen and identify high-risk patients at admission. Our study determined that the cumulative probability of positive viral RNA was lower in the two-dose group (log-rank test), and the time until negative viral RNA conversion was significantly lower in the two-dose group than in the unvaccinated group. Thus, completion of two doses of vaccination had a positive effect on the outcomes of patients with SARS-CoV-2 infection. Since most of the patients with delta-variant infection in Yangzhou had mild symptoms, symptomatic treatment, such as oxygen therapy, was administered, and hormone, plasma, or antiviral treatment was not used. Traditional Chinese medicine also played an important role, and all hospitalized patients were administered traditional Chinese medicine decoctions. We acknowledge that our study has some limitations. First, the study included only 129 patients infected with the delta variant from a single hospital in Yangzhou. This limitation may have caused deviation of the epidemiological and clinical characteristics. Second, the retrospective study design may be a confounding factor. Although we performed multivariate analysis, residual bias and lack of adjustments for unmeasured confounding factors may still exist. Third, the time interval between vaccination and disease onset was not included in our admission information, so we could not analyze this factor or determine how it affected the changes in antibody levels in our patients. Fourth, although we found that vaccination status did not affect the timing of CT changes in our patients, we did not observe these changes over a prolonged period of time due to limited medical resources. However, the CT changes were not one of the main outcome measures of this study, and were used solely for the purpose of corroborating the clinical and laboratory findings. Finally, as the study was based on the experience of the delta variant outbreak in China, the results may not be fully applicable to future cases due to differences in race, vaccination rates, and treatments. 5 Conclusions 1 We retrospectively analyzed the cases of 129 patients who were treated for SARS-CoV-2 delta-variant infection in Northern Jiangsu People’s Hospital, in order to explore the protective effect of the SARS-CoV-2 vaccine against the delta-variant infection. Overall, we found that two doses of the SARS-CoV-2 vaccine offered a high level of effectiveness against symptomatic disease and reduced the immune response, while one dose did not seem to be effective. Thus, our results support administering two doses of the vaccine to populations vulnerable to the rapid spread of the delta variant. 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Analysis of clinical characteristics and laboratory findings of 95 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a retrospective analysis . Respir Res , 21 : 74 . https://doi.org/10.1186/s12931-020-01338-8 https://doi.org/10.1186/s12931-020-01338-8 Analysis of clinical characteristics and laboratory findings of 95 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a retrospective analysis Cunjin WANG, Yong LI, Yuchen PAN, and Luojing ZHOU contributed to data collection, analysis, interpretation, and writing of the manuscript. Xi ZHANG, Yan WEI, and Fang GUO contributed to figure preparation and manuscript editing. Yusheng SHU and Ju GAO contributed to the study concept and design, clinical and pathological analyses, study supervision, and critical revision of the manuscript. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data. This work was supported by the National Natural Science Foundation of China (Nos. 82171207 and 82172190), the Jiangsu Association for Science and Technology Young Scientific and Technological Talents Support Project (No. 2021-008), the Jiangsu Province “333” High-level Talents Training Project (No. 2022-3-6-146), and the Yangzhou Science and Technology Plan Project (Nos. YZ2021088 and YZ2021148). The authors thank Prof. Yang YANG (Clinical Medical College, Yangzhou University, Yangzhou, China) for her guidance on statistics. 10.1631/jzus.B2200054 1673-1581（2022）11-0899-16 This work was supported by the National Natural Science Foundation of China (Nos. 82171207 and 82172190), the Jiangsu Association for Science and Technology Young Scientific and Technological Talents Support Project (No. 2021-008), the Jiangsu Province “333” High-level Talents Training Project (No. 2022-3-6-146), and the Yangzhou Science and Technology Plan Project (Nos. YZ2021088 and YZ2021148). 2022-02-07 2022-06-12 2022-11-15 2022-12-27 2022-11-11 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2022 2022 浙江大学出版社 Cunjin WANG, Yong LI, Yuchen PAN, Luojing ZHOU, Xi ZHANG, Yan WEI, Fang GUO, Yusheng SHU, and Ju GAO declare that they have no conflict of interest. This study was approved by the Research Ethics Committees of Northern Jiangsu People's Hospital (No. 2021ky284), and was performed in compliance with World Medical Association guidelines and the Helsinki Declaration of 1975, as revised in 2008 (5). The need for written informed consent was waived because this was a chart review, and the study protocol was approved under rapid review due to the urgent need to collect and report data. The data were collected and analyzed by three authors, who ensured the accuracy and integrity of the data and ensured that the data-collection process complied with the protocol. Compliance with ethics guidelines Supplementary information 1 Figs. S1‒S5 浙江大学学报（英文版）（B辑：生物医学和生物技术） 11 23