The Omicron (B.1.1.529) variant quickly became the dominant circulating SARS-CoV-2 variant worldwide because of its enhanced transmissibility and capability of immune evasion since it was first identified in South Africa on 24 November 2021 (1–3). As of 24 May 2023, the newly reported COVID-19 Omicron cases and deaths reached 342,773 and 3,574 in the past week in the world, respectively (4). Since January 2020, China has implemented the strategy of eliminating COVID-19 by adopting prevention measures of strict physical distance, restrictions on border entry, isolation of COVID-19 cases, separation of close contacts, and application of personal protective equipment. Therefore, COVID-19 epidemics have been largely controlled in China although local outbreaks occurred occasionally. However, a major community epidemic of Omicron BA.2 sub-lineage infection began in early January 2022 in Hong Kong, China (5), followed by outbreaks of Omicron infection in Shenzhen and Shanghai in mainland China between middle and late February 2022 and between March and April 2022, respectively (6). Notably, an unexpected nationwide epidemic of SARS-CoV-2 Omicron variant infection swept across mainland China when the above restriction measures were lifted in November 2022 (7).

COVID-19 vaccination is still considered an indispensable part of the long-term management of the SARS-CoV-2 pandemic (8, 9). According to the World Health Organization (WHO), as of 24 May 2023, 65.53% and 31.40% of individuals have received full vaccination or a booster dose of COVID-19 vaccines worldwide, respectively (4). Since early 2021, four inactivated COVID-19 vaccines including CoronaVac (Sinovac), WIV04 (Sinopharm), HB02 (Sinopharm), and BICV (Biokangtai) have been distributed and administered while HB02 and CoronaVac were most frequently used in mainland China (10, 11). Although full vaccination with the two doses of COVID-19 vaccine provided effective protection against symptomatic COVID-19, especially severe COVID-19 (12), the vaccine effectiveness (VE) was rapidly waning over time (13). Therefore, in November 2021, the National Health Commission of China launched a campaign of booster vaccination with a third dose of COVID-19 vaccines for adults aged ≥ 18 years old and at least six months after full vaccination of COVID-19 vaccine in mainland China by using either homologous or heterologous vaccines.

We previously reported the effectiveness of inactivated COVID-19 vaccines against Delta variant infection of SARS-CoV-2 in real-world settings in Guangdong, China (12). However, the real-world evidence about the role of booster vaccination of inactivated COVID-19 vaccines against infection of the Omicron BA.2 variant remains limited. Although several studies have assessed the effectiveness of the booster dose of inactivated COVID-19 vaccines made in China (5, 6, 14–17), these studies only analyzed the absolute VE of the booster dose but did not compare with full vaccination (6, 14–17) except for two studies that reported the relative VE of booster vaccination by comparing with full vaccination (5, 17). One study in Hong Kong assessed the effectiveness of the CoronaVac vaccine against Omicron BA.2 sub-lineage infection and showed extra protection against severe COVID-19 over full vaccination (5). Another study in Guangzhou, China indicated that booster vaccination with inactivated vaccines did not provide any protection against Omicron BA.2 infection when compared with full vaccination (17). As SARS-CoV-2 Omicron variants keep emerging and show resistance to the neutralizing anti-SAR-CoV-2 antibodies, accelerated expansion and administration of booster vaccination of COVID-19 vaccines are ongoing (18–23). In this study, we conducted a retrospective cohort study to analyze the epidemiological characteristics and risk of Omicron BA.2 infection in the close contacts of subjects infected with the Omicron variant, and to assess the effectiveness of booster vaccination with inactivated COVID-19 vaccines when the stringent restriction measures to prevent SARS-CoV-2 infection were still active and all the close contacts were carefully traced and monitored in Guangdong, China from 1 February to 31 July 2022. Therefore, we could precisely assess the real-world effectiveness of booster vaccination with inactivated COVID-19 vaccines based on different outcomes of Omicron BA.2 variant infection (12).

A retrospective close contacts cohort study was conducted to analyze the epidemiological characteristics and Omicron infection risk, and to evaluate the effectiveness of booster vaccination with inactivated COVID-19 vaccines against SARS-CoV-2 infection, symptomatic COVID-19, and COVID-19 pneumonia during the epidemic caused by Omicron sub-lineage BA.2 from 1 February to 31 July 2022 in Guangdong, China according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 STROBE Checklist).

We conducted a real-world retrospective cohort study to analyze the epidemiological characteristics of SARS-CoV-2 Omicron BA.2 infection and the risk factors among 46,547 close contacts of COVID-19 patients, and to evaluate the effectiveness of booster vaccination with inactivated COVID-19 vaccines against infection or COVID-19 pneumonia caused by Omicron BA.2 sub-lineage by comparing with full vaccination group in Guangdong, China.

The stringent prevention strategy and measures worked well and significantly inhibited the transmission and expansion of SARS-CoV-2 infection in China, which in turn may explain the overall low cumulative incidence (6.2%) of Omicron variant infection among the close contacts of SARS-CoV-2 infected subjects in our study. A similar study conducted in 2021 when the SARS-CoV-2 Delta variant epidemic occurred in Guangdong province, China, indicated a very low incidence of 1.3% of Delta infection among 10,805 close contacts (12) partly because the early diagnosis of SARS-CoV-2-infected index cases and prompt identification, tracing, and isolation of their close contacts limited its further transmission in this population. Furthermore, in the current study, the percentage of symptomatic COVID-19, mild COVID-19, and COVID-19 pneumonia was 70.2%, 64.9%, and 5.3% among the Omicron-infected cases, respectively, which was significantly lower than the corresponding rates (97.8%, 88.2%, and 14.0%, respectively) among the Delta-infected cases (12). The two studies in the same population showed a higher incidence of Omicron infection, but a lower percentage of COVID-19 pneumonia caused by the Omicron variant compared to the Delta variant, which supported the greater transmissibility but lower virulence of the Omicron variant compared to the Delta variant (29–32). Indeed, previous studies have confirmed lower severity in the cases of Omicron infection when compared with various waves of SARS-CoV-2 infections (33–38).

In this study, several risk factors were associated with infection with the Omicron variant, i.e. occupation, gender, and vaccination status. Specifically, those unemployed or subjects who worked at home and females showed higher infection risk probably because they had more opportunities for household contact with SARS-CoV-2-infected subjects since previous studies identified household contact as the main route of SARS-CoV-2 transmission due to more frequent and longer unprotected exposure to SARS-CoV-2 (39, 40). Interestingly, we found that COVID-19 vaccination, even partial vaccination, resulted in a relatively lower incidence of Omicron infection when compared with the un-vaccinated subjects. However, it may not mean that COVID-19 vaccines can prevent Omicron infection since the effectiveness of COVID-19 vaccines was lower than 50%, which is the lower limit of the vaccine effectiveness set by WHO (41). In this study, we did not adjust the infection risk by considering all the confounding factors. Therefore, the relatively lower incidence of Omicron infection in the vaccinated group may be affected by other unmeasured factors, and further evaluation is needed.

An important goal of the current study was to evaluate the role of booster vaccination with inactivated COVID-19 vaccines to prevent infection caused by the Omicron variant in real-world settings. Our results confirmed that booster vaccination could only provide a low level of protection against Omicron infection and symptomatic COVID-19 in adults 18-59 years, but a high level of protection against COVID-19 pneumonia in adults ≥ 60 years old when compared with full vaccination. To the best of our knowledge, there were only two published studies that reported the relative effectiveness of booster vaccination with inactivated COVID-19 vaccines against infection caused by the Omicron variant (5, 17). In a test-negative case-control study in Guangzhou, China, the booster dose of inactivated COVID-19 vaccines did not provide any protection against Omicron infection when compared with full vaccination (17). A study in Hong Kong showed that the effectiveness of booster vaccination against mild or moderate COVID-19 caused by the Omicron BA.2 variant was 35·7% and 46.9% among the subjects aged 20-59 and ≥ 60 years old, respectively (5). However, booster vaccination is critical for preventing severe or fatal COVID-19 disease caused by Omicron BA.2 with an effectiveness of 80% for those aged more than 20 years old (5). Our results were consistent with the findings about the role of booster vaccination with other types of COVID-19 vaccines against Omicron BA.2 infection or COVID-19 (5, 42–44). All these studies confirmed the importance of booster vaccination with COVID-19 vaccines to mitigate the severity of COVID-19, especially in old adults, which is consistent with the WHO recommendation about the administration of COVID-19 vaccines for this group (45).

In the current study, the benefit of booster vaccination in old adults was further confirmed by the bigger reduction of attributable risk rate and smaller number needed to vaccinate (NNV). We found that booster vaccination reduced the incidence of COVID-19 pneumonia by 0.96%, and the NNV to prevent one COVID-19 pneumonia case was 104 in adults ≥ 60 years old. However, in adults 18-59 years old, the ARR was only 0.18%, and the NNV was as many as 556. There are five-fold differences in the ARR and NNV between adults over 60 years old and 18-59 years old. In other words, booster vaccination with inactivated COVID-19 vaccines may decrease the incidence of COVID-19 pneumonia and save the medical cost by about five-fold over the full vaccination group. Considering the fact that COVID-19 vaccines are more effective in reducing the occurrence of severe COVID-19 and COVID-19-related mortality in old adults, booster vaccination with COVID-19 vaccines is presumably more cost-effective in mitigating severe COVID-19 in old people. This remains to be elucidated through comprehensive cost-effectiveness analysis.

Our study had several limitations. First, our study was conducted before the stringent prevention measures were lifted at the end of 2022 in China. All the close contacts of SARS-CoV-2 positive cases were immediately identified and quarantined. Therefore, the results cannot be expanded directly to situations where no specific prevention measures exist and people can move and communicate freely. However, the effectiveness of the booster vaccination we observed is still useful for policy making and the administration of COVID-19 vaccines. Second, unmeasured confounders might compromise the validity of our results although we had tried to control the known covariates. Third, we did not use hospitalization as an outcome to evaluate vaccine effectiveness because all SARS-CoV-2- positive people must be isolated and hospitalized in China regardless of the severity of COVID-19. Instead, we utilized symptomatic COVID-19 or COVID-19 pneumonia as the major outcome of SARS-CoV-2 infection to evaluate the overall effectiveness of the COVID-19 vaccines, especially in mitigating disease severity of COVID-19 because Omicron BA. 2 infection is usually less severe than Delta variant (38, 46). Fourth, the possible differences between inactivated COVID-19 vaccines from different vendors and the duration after full or booster vaccination were not analyzed in our study due to the short period of observation. Fifth, we confirmed that senior adults over 60 years old as the best target population to receive a booster vaccination. However, they accounted for 4.3% of the close contacts analyzed in our study. The relatively small sample size may affect the reliability of our results. Finally, we did not detect anti-SARS-CoV-2 antibodies or evaluate the role of hybrid immunity. Therefore, the underlying mechanism of booster vaccination to mitigate the severity of COVID-19 was not clear.

In summary, our findings indicate that booster vaccination with inactivated COVID-19 vaccines is necessary and useful in mitigating the severity of COVID-19 caused by the SARS-CoV-2 Omicron variant. The target population should be adults over 60 years old. Further investigation is definitely needed about the durability of booster vaccination and the effectiveness of COVID-19 vaccines in preventing the emerging Omicron variants with enhanced capability for immune evasion.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the China CDC Ethical Review Committee (approval number 202210). Written informed consent was waived because the data in the study were collected from administrative requirements of disease control and surveillance by Guangdong Provincial Center for Disease Control and Prevention as required by the National Health Commission. Analytical data sets were de-linked and anonymized in this study.

XH: Conceptualization, Project administration, Writing – original draft, Writing – review & editing, Data curation, Formal Analysis, Methodology, Validation. BZ: Conceptualization, Data curation, Project administration, Writing – original draft, Writing – review & editing, Investigation. YW: Data curation, Investigation, Writing – review & editing. YP: Data curation, Investigation, Writing – review & editing. MZ: Investigation, Writing – review & editing. TH: Investigation, Writing – review & editing. YL: Writing – review & editing, Formal Analysis. MK: Writing – review & editing, Conceptualization, Project administration, Supervision, Writing – original draft. ST: Conceptualization, Project administration, Supervision, Writing – original draft, Writing – review & editing.