Disease profile and plasma neutralizing activity of post-vaccination Omicron BA.1 infection in Tianjin, China: a retrospective study

Background SARS-CoV-2 Omicron variant BA.1 first emerged on the Chinese mainland in January 2022 in Tianjin and caused a large wave of infections. During mass PCR testing, a total of 430 cases infected with Omicron were recorded between January 8 and February 7, 2022, with no new infections detected for the following 16 days. Most patients had been vaccinated with SARS-CoV-2 inactivated vaccines. The disease profile associated with BA.1 infection, especially after vaccination with inactivated vaccines, is unclear. Whether BA.1 breakthrough infection after receiving inactivated vaccine could create a strong enough humoral immunity barrier against Omicron is not yet investigated. Methods We collected the clinical information and vaccination history of the 430 COVID-19 patients infected with Omicron BA.1. Re-positive cases and inflammation markers were monitored during the patient's convalescence phase. Ordered multiclass logistic regression model was used to identify risk factors for COVID-19 disease severity. Authentic virus neutralization assays against SARS-CoV-2 wildtype, Beta and Omicron BA.1 were conducted to examine the plasma neutralizing titers induced after post-vaccination Omicron BA.1 infection, and were compared to a group of uninfected healthy individuals who were selected to have a matched vaccination profile. Findings Among the 430 patients, 316 (73.5%) were adults with a median age of 47 years, and 114 (26.5%) were under-age with a median age of 10 years. Female and male patients account for 55.6% and 44.4%, respectively. Most of the patients presented with mild (47.7%) to moderate diseases (50.2%), with only 2 severe cases (0.5%) and 7 (1.6%) asymptomatic infections. No death was recorded. 341 (79.3%) of the 430 patients received inactivated vaccines (54.3% BBIBP-CorV vs. 45.5% CoronaVac), 49 (11.4%) received adenovirus-vectored vaccines (Ad5-nCoV), 2 (0.5%) received recombinant protein subunit vaccines (ZF2001), and 38 (8.8%) received no vaccination. No vaccination is associated with a substantially higher ICU admission rate among Omicron BA.1 infected patients (2.0% for vaccinated patients vs. 23.7% for unvaccinated patients, P<0.001). Compared with adults, child patients presented with less severe illness (82.5% mild cases for children vs. 35.1% for adults, P<0.001), no ICU admission, fewer comorbidities (3.5% vs. 53.2%, P<0.001), and less chance of turning re-positive on nucleic acid tests (12.3% vs. 22.5%, P=0.019). For adult patients, compared with no prior vaccination, receiving 3 doses of inactivated vaccine was associated with significantly lower risk of severe disease (OR 0.227 [0.065-0.787], P=0.020), less ICU admission (OR 0.023 [0.002-0.214], P=0.001), lower re-positive rate on PCR (OR 0.240 [0.098-0.587], P=0.002), and shorter duration of hospitalization and recovery (OR 0.233 [0.091-0.596], P=0.002). At the beginning of the convalescence phase, patients who had received 3 doses of inactivated vaccine had substantially lower systemic immune-inflammation index (SII) and C-reactive protein than unvaccinated patients, while CD4+/CD8+ ratio, activated Treg cells and Th1/Th2 ratio were higher compared to their 2-dose counterparts, suggesting that receipt of 3 doses of inactivated vaccine could step up inflammation resolution after infection. Plasma neutralization titers against Omicron, Beta, and wildtype significantly increased after breakthrough infection with Omicron. Moderate symptoms were associated with higher plasma neutralization titers than mild symptoms. However, vaccination profiles prior to infection, whether 2 doses versus 3 doses or types of vaccines, had no significant effect on post-infection neutralization titer. Among recipients of 3 doses of CoronaVac, infection with Omicron BA.1 largely increased neutralization titers against Omicron BA.1 (8.7x), Beta (4.5x), and wildtype (2.2x), compared with uninfected healthy individuals who have a matched vaccination profile. Interpretation Receipt of 3-dose inactivated vaccines can substantially reduce the disease severity of Omicron BA.1 infection, with most vaccinated patients presenting with mild to moderate illness. Child patients present with less severe disease than adult patients after infection. Omicron BA.1 convalescents who had received inactivated vaccines showed significantly increased plasma neutralizing antibody titers against Omicron BA.1, Beta, and wildtype SARS-CoV-2 compared with vaccinated healthy individuals.

Dear Editor, SARS-CoV-2 Omicron variant BA.1 first emerged on the Chinese mainland on January 8, 2022, in Tianjin and caused a large wave of infections. 1 Four rounds of mass testing of its~14 million residents were launched on January 9, 12, 15, and 20, respectively. As of February 7, 2022, a total of 430 individuals were tested positive for Omicron BA.1, with no new infections detected for the following 16 days.
In the Chinese mainland, the most delivered vaccines are inactivated vaccines. As of January 8, 2022, up to 93.2% of Tianjin's residents had been vaccinated with at least one dose. 2 We investigated the protection conferred by vaccination against Omicron BA.1 by examining the breakthrough infections among vaccinees as compared with unvaccinated cases. Our study population comprised all 430 cases during the outbreak of Omicron BA.1 in Tianjin.
Based on data from the 341 patients who had received inactivated vaccines (3-dose, n = 157; 2-dose, n = 178; 1-dose, n = 6) and 38 patients who had no SARS-CoV-2 vaccination, we found that when all age groups were considered together, 2 doses of inactivated vaccines were associated with a larger proportion of asymptomatic to mild disease compared with 3 doses (P = 0.003), which may be because most under-age patients had received 2 doses of inactivated vaccine and presented with mild illness (Supplementary information, Table S4). In adult patients alone, 3 doses reduced disease severity compared with no vaccination (P = 0.004, Fig. 1b).
ICU admission rate was only 0.6% for patients who had received a booster dose of inactivated vaccine and 4.8% for those who only received two-dose primary series, both significantly lower than the 37.5% for unvaccinated patients (P < 0.001, Fig. 1b).
Patients who had received a booster dose of inactivated vaccine experienced a shorter period of hospitalization and recovery. For patients across all age groups, the duration of hospitalization and recovery was 2 days shorter for those who had received 3 doses of inactivated vaccine than for unvaccinated patients (P = 0.009; Supplementary information, Table S4). For adult patients specifically, the duration of hospitalization and recovery for those who had received 3 doses (27 vs 30 days, P = 0.001) or 2 doses (28 vs 30 days, P = 0.026) of inactivated vaccine was shorter than unvaccinated patients (Fig. 1b). Compared with unvaccinated patients, receipt of 3 doses (19.4% vs 50.0%, P = 0.001) or 2 doses (19.0% vs 50.0%, P = 0.002) is also associated with lower repositive rates during convalescence (Fig. 1b).
Vaccination status also correlated with immunity and inflammation-related laboratory findings (Supplementary information, Table S5). Compared with no vaccination, patients who received 3 doses of inactivated vaccines showed significantly lower levels of the systemic immune-inflammatory index (SII) and C-reactive protein during the early stage of recovery after nucleic acid tests turned negative, suggesting that receipt of inactivated vaccine can step up inflammation resolution. Due to relatively lower levels of lymphocytes, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and monocyte/lymphocyte ratio (MLR) was higher in patients inoculated with three doses of inactivated vaccine than that of patients vaccinated with two doses. It has been reported that patients with severe COVID-19 are more prone to leukopenia and lymphopenia, and overly reduced lymphocyte percentage can be used as an indicator of disease severity. 3,4 However, based on the overall immune characteristics of patients during the convalescence phase, we believe that these laboratory findings point to a lower degree of inflammation, suggesting that 3 doses of inactivated vaccine may shorten the course of illness by inducing resolution of inflammation. T-cell clustering indicated that the booster dose of inactivated vaccine led to a significant elevation of the CD4 + /CD8 + ratio, Th1/Th2 ratio, and the ratio of activated Treg cells, suggesting that vaccination and infection may activate immune responses also by inducing spike-specific Th1 responses. 5,6 This implies that even if mutations on Omicron spike protein affect T-cell epitopes, immune responses mediated by T cells or non-neutralizing antibodies can still provide protection. 7,8 Tests of liver and kidney functions suggest that the number of inactivated vaccine doses did not affect liver and kidney function (Supplementary information, Table S6).
Ordered multi-class logistic regression model was constructed based on age, gender, number of vaccine doses, and comorbidities.
To check whether BA.1 infection could induce a strong enough humoral immunity against Omicron, we obtained plasma samples from 135 Omicron convalescent patients 1 month after hospital discharge, including 60 mild cases and 75 moderate cases (Supplementary information, Table S11). We used authentic SARS-CoV-2 virus neutralization assays (CPE) to determine the plasma neutralizing antibody titers against WT, Beta, and Omicron BA.1. Overall, the geometric mean of 50% neutralizing titer (NT 50 ) against WT was still higher than that against Omicron after BA.1 infection (Fig. 1d). Interestingly, the number of vaccine doses received before breakthrough infection does not significantly affect the NT 50 after infection (Fig. 1d). Also, patients who had received the inactivated vaccine, BBIBP-CorV or CoronaVac, displayed a similar level of neutralizing antibody titers. Those who had received the adenovirus-vectored vaccine (Ad5-nCoV) showed slightly higher NT 50 against WT, Beta, and Omicron BA.1; however, no statistical significance was achieved (Fig. 1e). Among patients who had received 3 doses of inactivated vaccines, the overall plasma neutralizing titer of moderate patients was higher than that of mild patients (Fig. 1f), consistent with the previous report. 9 We compared the Omicron convalescent patients who had received 3 doses of CoronaVac (n = 42) with the healthy individuals who were also vaccinated with 3 doses of CoronaVac (n = 114) regarding the neutralizing antibody titers against WT, Beta, and Omicron BA.  Table S12). Finally, since the vaccination-infection interval was different for the 2-dose and 3-dose groups, a comparison could not be conducted between the protective efficiency against severe diseases by three doses vs two doses. Fig. 1 Protection of inactivated vaccine against Omicron BA.1. a Characteristics of Omicron-infected patients. Continuous variables were shown in median (IQR) and categorical variables were summarized as counts (percentages). COVID-19 disease severity was defined according to WHO living guidance for clinical management of COVID-19. 10 IV, inactivated vaccine; AVV, adenovirus-vectored vaccine; PSV, recombinant protein subunit vaccine. b Correlation between inactivated vaccine doses and COVID-19 disease severity and progression in adult patients. PCR re-positive during convalescence phase was defined as PCR Ct value less than 40 after two independent PCR-negative results with an interval of more than 24 h. c Multivariate analysis of risk and protective factors for COVID-19 disease severity in Omicron-infected adult individuals. Statistical significance was determined by ordered multi-class logistic regression. d Humoral immune responses against WT and variants of SARS-CoV-2 among breakthrough Omicron convalescents. The geometric mean titer (GMT), geometric standard deviation, and fold-changes of 50% neutralization titers (NT 50 ) are labeled. Dashed lines show the limit of detection. Statistical significance was determined by a two-tailed Wilcoxon test. e NT 50 from the breakthrough BA.1 convalescents who were vaccinated with BBIBP-CorV (n = 54), CoronaVac (n = 65), or Ad5-nCoV (n = 16) vaccine. The plasma titers refer to all the recipients of the same type of vaccine, including 1-dose, 2-dose, and 3-dose vaccines. f NT 50 from the breakthrough BA.1 convalescents with mild (n = 36) or moderate (n = 43) symptoms after 3 doses of inactive vaccine immunization. g NT 50 from the breakthrough BA.1 convalescents who were vaccinated with 3 doses of CoronaVac vaccine (n = 42) or from the uninfected vaccinees who had matched vaccination profiles (n = 114).