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1 These two authors contributed equally to this work.
Shanshan Han
Footnotes
1 These two authors contributed equally to this work.
Affiliations
School of Public Health and Health Management, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
School of Public Health and Health Management, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
Shandong Provincial Key Laboratory of Infectious Disease Control and Prevention, Shandong Center for Disease Control and Prevention, Jinan, ChinaSchool of Public Health and Health Management, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong Province, ChinaSchool of Public Health and Management, Binzhou Medical University, Yantai, Shandong Province, China
However, with the decline of vaccine efficacy and the emergence of variants of concern (VOCs), massive breakthrough infections have occurred in vaccinated populations.
Recent articles in this journal mentioned that breakthrough infections caused by VOCs can induce higher immune responses than original infections and simple vaccination.
Regular and booster vaccination with inactivated vaccines enhance the neutralizing activity against Omicron variant both in the breakthrough infections and vaccinees.
The evaluation of neutralization capacity against omicron induced by the “hybrid immunity” elicited by different vaccines and infections is crucial to the future vaccination strategy and the development of new vaccines.
In this study, we recruited 60 participants from 3 locally clustered COVID-19 outbreaks in Rizhao, Jinan, and Weihai, Shandong Province, China in October 2021, May and June 2022. They were all confirmed cases of COVID-19 with positive PCR tests, and the SARS-CoV-2 sequence of most participants has been confirmed by whole genome sequencing on Miseq. We examined neutralizing activity against the wild-type SARS-CoV-2 and omicron BA.2.3 sub-variant from convalescent individuals with AY.126, P.1.15 or BA.2 breakthrough infections through live virus neutralization assay. The indirect ELISA kit (Vazyme, China) based on spike protein were used to quantify S-binding IgG antibodies against SARS-CoV-2. The design of this study and the spike protein mutations of the VOCs involved are shown in Fig. 1A-B. See supplementary materials for detailed participant characteristics and methods.
Fig. 1(A) The details of this study design. (B) The spike protein mutations of SARS-CoV-2 in breakthrough-infected individuals and live virus neutralization assays.
Notably, the neutralization ability against BA.2.3 of all breakthrough infection patients was 3.18–8 times lower than wild-type. In breakthrough infections following two doses of vaccine, the geometric mean titre (GMT) against wild-type and BA.2.3 in the 6 individuals who breakthrough by AY.126 were 3.32-times(from 1952.12 to 587.37) and 2.62-times(from 232.59 to 88.61) higher than individuals with BA.2 breakthrough infections; 3 patients who breakthrough by P.1.15 had 1.58-times(from 930.37 to 587.37) and 3.31-times(from 293.05 to 88.61) higher GMT than individuals who breakthrough by BA.2 (Fig. 2A). After three doses of the inactivated vaccine, patients with P.1.15 breakthrough infection also had a 1.83-times(from 1254.14 to 686.06) and 1.37-times(from 156.77 to 114.07) higher titre against wild-type and BA.2.3 compared with individuals who breakthrough by BA.2 (Fig. 2B).
Fig. 2Neutralizing Antibodies against wild-type SARS-CoV-2 and omicron BA.2.3 sub-variant from breakthrough-infected individuals. Box violin plots show differences in neutralizing antibody titers against wild-type SARS-CoV-2 and Omicron BA.2.3 from AY.126, P.1.15 and BA.2 breakthrough-infected individuals after two doses of vaccine(A), P.1.15 and BA.2 breakthrough-infected individuals after three doses of vaccine(B), 13 P1.15 breakthrough-infected individuals(C), and 41 BA.2 breakthrough-infected individuals(D). The geomatic mean titers (GMTs) are shown above each column.
Among the 13 P1.15-infected patients, 10 patients received three doses of vaccine had 1.35-times(from 1254.14 to 930.37) higher titre against wild-type than patients who received two doses, but no improvement for BA.2.3 (Fig. 2C). Of the 41 BA.2-infected patients, 5 unvaccinated patients didn't develop high neutralizing antibodies by virtue of only once infection. For individuals with inactivated vaccines, the GMT against wild-type and BA.2.3 increased from 256.00, 41.93 to 686.06, 114.07, respectively, with the increase of pre-infection doses. In patients who vaccinated with three doses, the ZF2001 vaccine induced 1.45-times(from 991.79 to 686.06) and 1.64-times(from 187.04 to 114.07) higher titre against wild-type and BA.2.3 than the inactivated vaccine (Fig. 2D).
The change trend of S-binding IgG antibody level in each group was similar to that of neutralizing antibody. The correlation results between neutralizing titers against wild-type SARS-CoV-2, and BA.2.3, and S-binding IgG titer were R = 0.64 (p < 0.0001), R = 0.54 (p < 0.0001), and R = 0.54 (p < 0.0001), and showing a moderate significant positive correlation between antibodies(Figure S1–2). Similar to a recent study,
the immune evasion ability of the omicron shouldn't be underestimated. Under the same vaccination conditions, the resistance to wild-type and BA.2.3 after BA.2 breakthrough infection was weaker than that of AY.126 and P.1.15 breakthrough infection. It suggests that the heterologous “hybrid immunity” could mediate stronger humoral immunity, whereas the omicron variant is less immunogenic in comparison.
Although breakthrough infections may still occur after vaccination, vaccinated individuals could trigger stronger immune recall after infection than unvaccinated individuals.
A limitation of this study is based on a small number of individuals. But this real-world antibody results from breakthrough infections individuals suggest that implementing complete vaccinations, optimizing vaccination and developing new vaccines regimens the key to combating VOCs and reducing the incidence of COVID-19.
Funding
This work was supported by the Major Scientific and Technological Innovation Project in Shandong Province (grant numbers: 2020SFXGFY02–1), Key Research and Development plan of Shandong Province (grant numbers: 2021RZA01021) and Natural Science Foundation of Shandong Province(grant numbers: ZR202112040005).
Declaration of Competing Interest
The authors have declared that no conflicts of interest exist.
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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