Regular and booster vaccination with inactivated vaccines enhance the neutralizing activity against Omicron variant both in the breakthrough infections and vaccinees.

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Recent articles in this Journal have reported the cross-neutralization of SARS-CoV-2 variants in individuals of vaccinees and convalescents, and compared the clinical features of Coronavirus disease 2019 (COVID-19) by SARS-CoV-2 Gamma variant based on a prospective cohort study of vaccinated and unvaccinated healthcare workers , . The emergence of SARS-CoV-2 variants with higher transmission ability and immune evasion against monoclonal antibodies, sera from natural infection and vaccine receipts, posing a serious threat to public health. On 26 November 2021, the World Health Organization named the new SARS-CoV-2 variant B.1.1.529 as Omicron, and defined it as a Variant of Concern (VOC). As the fifth VOCs currently, Omicron contains much more mutations in the Spike protein, including some mutations shown to reduce neutralizing efficiencies of COVID-19 vaccines in previous studies. As the pandemic of COVID-19 has lasted for nearly two years, there are more and more convalescents either previously infected with wild-type SARS-CoV-2 or recently emerged variants. Meanwhile, booster vaccination of SARS-CoV-2 is now rapidly rolling out in China and other countries. Accordingly, neutralizing efficiency of convalescents and vaccinees with booster vaccination against the newly emerged Omicron variant needs further elucidation. Here we evaluated the neutralizing activity of plasma from the COVID-19 convalescents with wild type SARS-CoV-2 and different VOCs, and vaccinees with both regular vaccination and homologous booster of inactivated vaccine.

A total of 92 participants were included in this study, including 24 vaccinees with homologous booster vaccination (Vaccinee group), 26 individuals previously infected with wild type (WT) SARS-CoV-2 (WT group), 16 patients infected with Alpha variant (Alpha group, 12 patients received vaccination before infection), 6 patients infected with Beta variant (Beta group), and 20 patients infected with Delta variant (Delta group, 4 patients received vaccination before infection). All the individuals with breakthrough infection received at least one-dose inactivated vaccines (CoronaVac or BBIBP-CorV before laboratory confirmation of infection, and individuals in the vaccinee group received inactivated vaccines (BBIBP-CorV) and homologous booster vaccination. The detailed information was shown in Table S1. All the plasma samples in the WT group were collected over 386 days post illness onset/laboratory confirmation (median: 431.5; range: 386–471), and most samples (40/42, 95.23%) in the Alpha, Beta, Delta groups were collected over 7 days after laboratory confirmation (median: 18; range: 1–36). Samples from the vaccinee group were collected after the two dose of vaccination with median days of 85 (range: 28–103), and 95 days after booster vaccination.

For the WT group, about 46.15% (12/26) of the samples showed inhibition rates over 50% against Omicron variant at the first dilution (1:20). The geometric mean neutralizing titers (GMTs) against wild type SARS-CoV-2 (WT) and Omicron variant were 154.07 (54.64 to 1018.82), 22.96 (10 to 145.38), respectively, and the reduction fold was 6.71 for Omicron (Fig. 1 A). This reduction is comparable with Mu variant while higher than Alpha, Beta, Gamma, Delta, Lambda variants. For the Alpha group, all the samples from breakthrough infections showed detectable 50% inhibitory dose (ID50) against Omicron variant, while 50% (2/4) were below the lower limit of quantitation in the naive infections. The overall GMTs against Alpha and Omicron variants were 7198.43 and 285 respectively, with 25.26-fold reduction for the Omicron variant (Fig. 1 B). Comparison between breakthrough and naive infection showed significantly higher ID50 against both Alpha (9.33-fold) and Omicron variants (5.61-fold) in the breakthrough infection (Fig. 1 B). Similar results were found in the Delta group, with all the samples from breakthrough infection showed detectable ID50 against Omicron variant, while 1 out of 16 was below the lower limit of quantitation in the naive infection. The overall GMTs against Delta and Omicron variants were 10,898.97 and 558.44, respectively, with 19.52-fold reduction for the Omicron variant (Fig. 1 D). Significantly higher ID50 against both Delta (3.25-fold) and Omicron variants (1.77-fold) were also found in the breakthrough infections (Fig. 1 D). For the Beta group, we only got the naive infections, and reduced neutralizing activities were also found with 18.38-fold reduction against the Omicron variant (Fig. 1 C).

Fig. 1

Neutralizing activities of plasma samples from convalescents previously infected with wild type (A), Alpha (B), Beta (C) and Delta variants (D).

In the Vaccinee group, 91.66 (22/24) showed detectable ID50 against wild type SARS-CoV-2 at 95 days post booster vaccination with GMT of 299, and 1.67-fold, 14.52-fold, 3.72-fold and 6.73-fold reduction against Alpha, Beta, Gamma and Delta variants were found, respectively (Fig. 2 A). Notably, only 25% (6/24) of the samples showed detectable ID50 against Omicron, with 16.07-fold reduction when compared with wild type SARS-CoV-2. We further compared the neutralization activity before and after booster vaccination against different VOCs. After booster vaccination, GMTs against wild type, Alpha, Beta, Gamma, Delta increased 13.47-fold, 8.63-fold, 2.06-fold, 6.75-fold and 3.96 fold, respectively (Fig. 2 B). For the Omicron variant, all samples were below the lower limit of quantitation after the first two dose vaccination, similar with previous study. However, 6 out of 24 (25%) showed detectable ID50 (GMT: 18.62; range: 10 to 454.4) after booster vaccination, with 1.86-fold increase in GMTs (Fig. 2 B).

Fig. 2

Neutralizing activities of plasma samples from vaccinees with booster vaccination. A. ID50 of samples from vaccinees with booster vaccination against wild type, Alpha, Beta, Gamma, Delta and Omicron variants. B. Comparison of the neutralizing activities before and after booster vaccination.

Although some recent studies have showed that Omicron variant could escape from the majority of existing SARS-CoV-2 neutralizing antibodies and vaccine induced immune response, our study still provide unique information as follows. Firstly, we addressed whether COVID-19 convalescents previously infected with wild type SARS-CoV-2 could provide protection against Omicron Variant even after one year. Secondly, we used paired samples with both regular vaccination and homologous booster vaccination to evaluated the efficiency of booster vaccination. Thirdly, we compared the neutralizing activities against Omicron variant between breakthrough and naive infections with different VOCs.

Similar with previous studies, significant immune evasion was found for Omicron variant both in the convalescents and vaccinees, and the reduction folds was even higher than the previously least susceptible Beta and Mu variants , , suggesting a higher risk of breakthrough infection or reinfection. It is worth noting that plasma samples collected over one year post infection showed lower reduction folds against Omicron variant when compared with other convalescents with different VOCs, which might correlate with the increase in the breadth and potency of SARS-CoV-2 specific antibodies due to the maturation of memory B cells8, 9, 10. Despite of the obvious immune evasion, our study also confirmed the importance of vaccination, both regular and booster vaccination. As shown in our study, breakthrough infections developed much higher neutralizing antibodies than the naive infection, both against the infected variant and Omicron variant. Moreover, booster vaccination could significantly increase the neutralizing responses to all the VOCs, although lower neutralizing abilities were found against some VOCs. Therefore, active vaccination still serve as one of the most effective measures to control the pandemic of COVID-19, and new vaccines with higher protective efficiency are also in urgent need.

Funding

This work was supported by grants from National Natural Science Foundation of China (32170936), National Science and Technology Major Project (2021YFC0863300, 2021YFC2301800). The authors wish to thank the biological sample bank of the Shenzhen Third People's Hospital for bio-samples and services provided.

Declaration of competing interest

The authors have declared that no conflicts of interest exist.