Potent Antibody Response Elicited by a Third Booster Dose of Inactivated COVID-19 Vaccine in Healthy Subjects

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine has been used worldwide on a large scale because of its potent ability to contain the coronavirus disease 2019 (COVID-19) pandemic, and the antibody response induced by the vaccine needs to be elucidated. Thus, we conducted a prospective trial in healthy subjects to observe the antibody response after three doses of inactivated vaccines. Our results showed that neutralizing antibody (NAb) levels were significantly higher after the booster vaccination compared to the second, a 4.9-fold increase, with the peak occurring at 28 days. The NAb level could be maintained for a longer period after the third vaccination, with higher levels still observed after 3 months. We did not observe significantly higher levels of SARS-CoV-2 spike-specific immunoglobulin G (S-IgG) and immunoglobulin M (IgM) after the third vaccination compared with the second vaccination; this was especially true for SARS-CoV-2 spike-specific immunoglobulin M (S-IgM), which was barely expressed. Notably, those who did not undergo NAb seroconversion after two doses of the vaccine produced high and long-lasting NAb after the third vaccination, confirming that they were not completely unresponsive to the vaccine. The NAb titer in younger subjects (aged 20–40 years) rose 3.4-fold compared with older subjects (aged 40–60 years) after the second vaccination, but the difference was narrowed after the third vaccination (2.8-fold increase). In addition, the levels of antibodies in older men were 3.4-fold lower than those in the older women after the third vaccination. Overall, this study elucidates the dynamic change in antibodies after three doses of vaccination, which provides a reference for the improvement of vaccination strategies.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which has infected over 480 million people and killed over 6.19 million people as of March 28, 2022 (Data from WHO). The SARS-CoV-2 vaccine is the most important weapon for epidemic prevention and control. Ten vaccines, including inactivated vaccines, have been approved by the WHO for emergency use (Al Kaabi et al., 2021; Ella et al., 2021), with over 11 billion doses used worldwide (data from WHO). Assessing immunogenicity and effectiveness after vaccination is critical (Manenti et al., 2022). Multiple studies have shown that serum antibody levels can reflect vaccine immunogenicity, especially the neutralizing antibody (NAb) level, which is considered a key immune indicator for the protection or treatment of viral diseases (Addetia et al., 2020; Guo et al., 2021).

In our previous study, we found that two doses of inactivated vaccine induced potent NAb responses (Zhang et al., 2021b). However, a significant reduction in NAb levels was observed 6 months after two doses of the inactivated vaccine (Xie et al., 2022). Although studies have shown the persistence of immune memory (Liao et al., 2021), the ability of booster vaccination to induce antibody responses is incompletely understood. Therefore, we sought to investigate recipients that had received two doses of inactivated vaccine for half a year and had voluntarily vaccinated with a booster dose to determine the changes in antibody kinetics after vaccination and provide a reference for subsequent vaccination.

Materials and Methods

Subjects

To observe the activation of the antibodies by the COVID-19 inactivated vaccine, 51 healthy people who were not infected with SARS-CoV-2 and voluntarily received the COVID-19 vaccine were prospectively recruited in this study. All subjects received three doses of the inactivated COVID-19 vaccine, Sinopharm COVID-19 Vaccine (BBIBP-CorV), produced by the Beijing Institute of Biological Products Co. Ltd. According to regulations, the interval between the first and second injections is 28 days, and the third injection should be more than half a year away from the first injection. Each injection contained 4 μg/0.5 mL, which was injected into the deltoid muscle by intramuscular injection. The study protocol was reviewed and approved by the Medical Ethics Committee of Shunde Hospital of Guangzhou University of Chinese Medicine (Approval No. KY2020128). Informed consent was obtained from all participants before the experiment.

Sample collection and processing

Follow-up work was performed on all subjects, and peripheral blood was collected from all subjects at 10 time points: before the first dose (1st-0); 14 days (1st-14) and 28 days (1st-28) after the first dose; 14 days (2nd-14), 28 days (2nd-28), 2 months (2nd-60), and 6 months (3rd-pre, before the third injection) after the second dose; and 14 days (3rd-14), 28 days (3rd-28), and 3 months (3rd-90) after the third dose (Fig. 1A). The EDTA-anticoagulated whole blood was mixed, and a peripheral blood count was completed within 2 h. The nonanticoagulated blood samples were collected and coagulated at room temperature for 30 min and centrifuged at 1,000 g for 15 min to separate the serum. The clinical information of the subjects, including sex, age, medical history, and adverse reactions to vaccination, was collected by questionnaire.

FIG. 1.

Longitudinal dynamics of antibody responses elicited by three doses of inactivated SARS-CoV-2 vaccine. (A) The immunization and blood collection protocol for the prospective cohort. (B) Antibody seroconversion rates of all recipients after three doses of vaccine (n = 39). (C) The dynamics of NAb in recipients who were nonseroconversion after two vaccinations but seroconversion after the third. No. 1, 42-year-old female recipient; No. 2, 45-year-old female recipient; No. 3, 31-year-old male recipient; No. 4, 28-year-old female recipient; No. 5, 51-year-old female recipient (without 3rd_14 and 3rd_28 timepoints); No. 6, 41-year-old male recipient (without 3rd_14 timepoint). (D–F) Overall distribution of NAb titers (D), S-IgG levels (E) and S-IgM levels (F). NAb, anti-SARS-CoV-2 neutralizing antibody. **p < 0.01; ***p < 0.001. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; NAb, neutralizing antibody; ns, not significant.

Microneutralization test

NAb detection was carried out by the Centers for Disease Control and Prevention of Guangdong (CDC) using a microneutralization test. First, VERO-E6 cells (2.0 × 10⁵ cells/well) were seeded in 96-well plates and grown in a monolayer. Serum samples were inactivated for 30 min at 56°C before being serially diluted fourfold (1:4 to 1:1,024). A total of 125 μL of diluted serum was mixed with 50 μL of SARS-CoV-2 prototype strain suspension containing 100 TCID₅₀ and preincubated for 120 min at 37°C in a 5% CO₂ incubator.

Then, 100 μL/well of the virus-serum mixture was added to the monolayer of Vero-E6 cells and incubated at 37°C in a 5% CO₂ incubator for 4–7 days. The cytopathic effect (CPE) in each well was recorded by two independent observers microscopically. The highest dilution that protected more than half of the cells from CPE was considered the NAb titer. NAb titers equal to or higher than 1:4 were considered positive (Marklund et al., 2020).

Laboratory index detection

S-IgG and S-IgM were detected by the Autolumo A2000 PLUS instrument and matching reagents. According to the kit instructions, the results were considered positive when S/CO was greater than or equal to 1 and negative when S/CO was less than 1. Routine blood parameters were detected by the Sysmex XN5000 hematology analyzer and its matching reagents.

Statistical analysis

Statistical analysis was performed using R (v 4.0.2) software. Continuous variables with a nonnormal distribution are expressed as medians and interquartile ranges (IQRs). Categorical variables were described as percentages. Differences between the two groups were compared using independent-sample t-tests. If the data did not meet the normal distribution and homogeneity of variance, then Mann–Whitney U tests were used. For comparison of differences between multiple groups, if the data conformed to a normal distribution and homogeneous variance, a one-way analysis of variance was used; otherwise, the Kruskal–Wallis test was used. “P < 0.05” was considered statistically significant.

Results

Study subjects

Fifty-one healthy people with an age range of 20–60 years were prospectively recruited for this study. All subjects received the booster vaccination after receiving two doses of inactivated COVID-19 vaccines for half a year. During the 10-month follow-up of the research subjects, 12 participants were excluded from the follow-up analysis due to dropout at one or more timepoints. Therefore, 39 subjects with complete time points were statistically analyzed (Fig. 1A, and Table 1), including 20 males and 19 females, with a median age of 34 years (IQR: 28–48).

Table 1.

Clinical Characteristics of the Study Subjects

Characteristics	Vaccine recipients (n = 39)
Age	M, IQR
Age 20–40	21 (53.8%)
Age 41–60	18 (46.2%)
Male	20 (51.3%)
Female	19 (48.7%)

Antibody responses after vaccination

Almost all subjects seroconverted after the third booster vaccination, with a rate of 84.6% on day 14, which was higher than that on day 14 after the second dose (82.1%). The rate then continued to increase, reaching 97.4% at 28 days after the third injection; it decreased slightly after 3 months but remained at 87.2% (Fig. 1B, and Table 2). There were 6 of 51 recipients without NAb seroconversion after 2 doses of vaccination, but surprisingly, seroconversion occurred in all 6 subjects after booster vaccination (Fig. 1C).

Table 2.

Antibody Seroconversion Rates of All Recipients After Three Doses of Vaccine (n = 39, %)

Time point	NAb	S-IgG	S-IgM
1st_0	0 (0.0%)	0 (0.0%)	0 (0.0%)
1st_14	3 (7.7%)	8 (20.5%)	3 (7.7%)
1st_28	2 (5.1%)	19 (48.7%)	4 (10.3%)
2nd_14	32 (82.1%)	39 (100.0%)	28 (71.8%)
2nd_28	31 (79.5%)	39 (100.0%)	20 (51.3%)
2nd_60	9 (23.1%)	38 (97.4%)	8 (20.5%)
3rd_pre	1 (2.6%)	25 (64.1%)	0 (0.0%)
3rd_14	33 (84.6%)	39 (100.0%)	6 (15.4%)
3rd_28	38 (97.4%)	39 (100.0%)	3 (7.7%)
3rd_90	34 (87.2%)	37 (94.9%)	0 (0.0%)

NAb, neutralizing antibody; S-IgG, SARS-CoV-2 spike-specific immunoglobulin G; S-IgM, SARS-CoV-2 spike-specific immunoglobulin M.

After the booster dose, the positive rate of S-IgG showed a similar trend to that after the second dose, reaching 100% after 14 days with a slight decrease to 94.9% at 3 months (Fig. 1B, and Table 2). In addition, we found that the positivity rate of S-IgM after the third immunization was much lower than that after the second immunization, and most subjects did not undergo S-IgM seroconversion (Fig. 1B, and Table 2).

To account for the intensity and persistence of antibody responses after vaccination, we compared the NAb, S-IgG, and S-IgM levels of subjects at each time point. The results showed that the first vaccination barely produced detectable NAb. After the second vaccination, the NAb level increased rapidly and peaked on day 14 (geometric mean titers [GMT]: 12.3) with a maximum titer of up to 1:128 and decreased without a significant difference after 2 weeks (GMT: 5.6). As expected, the NAb level increased rapidly after the third booster vaccination.

Interestingly, we observed a sustainable increase in NAb levels after the third vaccination, with a peak at day 28 (GMT: 59.6) and the highest titer of 1:512, which was much higher than that of the third injection at 14 days (GMT: 13.6, p < 0.01) and the second injection at 14 days (GMT: 12.3, p < 0.01). Although a significant decrease in NAb levels was observed 3 months after the booster vaccination (p < 0.001), the antibody levels remained comparable to those at 14 days after the second or third dose with no significant difference (Fig. 1D). This shows that the level of NAb was not only higher but also more durable after booster vaccination.

In addition, we found that the S-IgG level was also significantly increased after the third booster injection, reaching a peak at 14 days, which was not significantly different from 14 days after the second vaccination. Then, the S-IgG level dropped mildly at 2 weeks and showed a significant decrease after 3 months (Fig. 1E). S-IgM could be induced by two doses of vaccine, but the booster injection stimulated weaker S-IgM, which was mostly not expressed or at low levels (Fig. 1F). In addition, we also found that platelets were significantly elevated for 14 days after the third injection and then decreased. Although this significant difference was observed, platelet counts were in the normal range during our follow-up period (Supplementary Fig. S1).

Age and gender differences in antibody response

Age is an important determinant of vaccine response. At 14 days after the second injection, the NAb level of the younger recipients (age 20–40) was significantly higher than that of the older recipients (age 40–60) (3.36-fold, GMT, p < 0.01). Although this significant difference persisted at 14 days (3.11-fold, GMT, p < 0.05), 28 days (2.75-fold, GMT, p < 0.05), and 90 days (2.86-fold, GMT, p < 0.05) after the third injection, we were pleasantly surprised to find that the difference between the two groups narrowed. The S-IgG level also reflected this age difference, which was significantly higher in younger recipients than in older recipients at 14 days after the second injection (p < 0.05), and this difference diminished to no statistical significance after the third injection (Fig. 2A, C). Boosting immunity is important for older individuals.

FIG. 2.

Age and gender differences in antibody responses induced by inactivated SARS-CoV-2 vaccine. (A) Comparison of NAb titers between Age_1 group (aged 20–40, n = 21) and Age_2 group (aged 40–60, n = 18). (B) Comparison of NAb titers between female (n = 19) and male (n = 20). (C) NAb titers in the Female_Age_1 (n = 9), Female_Age_2 (n = 10), Male_Age_1 (n = 12), and Male_Age_2 (n = 8) groups were compared. (D) Comparison of S-IgG levels between Age_1 group (aged 20–40, n = 21) and Age_2 group (aged 40–60, n = 18). (E) Comparison of S-IgG levels between female (n = 19) and male (n = 20). (F) S-IgG level in the in the Female_Age_1 (n = 9), Female_Age_2 (n = 10), Male_Age_1 (n = 12), and Male_Age_2 (n = 8) groups were compared. *p < 0.05, **p < 0.01, ***p < 0.001.

Differences in NAb and S-IgG levels between males and females were not found in our preliminary analysis of sex (Fig. 2B, E). By further categorizing males and females by age, the following groups were formed: Female_Age_1 (n = 9, females aged 20–40 years); Female_Age_2 (n = 10, females aged 40–60 years); Male_Age_1 (n = 12, males aged 20–40 years); and Male_Age_2 (n = 8, males aged 40–60 years). The NAb and S-IgG levels were analyzed and compared among the groups. Interestingly, no significant differences were reflected between the four groups after two injections, while after the booster vaccination, we found that the NAb level was significantly higher in females aged 40–60 years than in males of the same age group at 14 days (4.1-fold, GMT) and 28 days (3.4-fold, GMT), and the S-IgG level showed a similar trend, reflecting an age-based gender difference.

Discussion

Vaccination is the most powerful and promising public health strategy to reduce infection and mortality and control the COVID-19 pandemic. In this study, participants who received three doses of the inactivated COVID-19 vaccine were followed for up to 10 months. We found that two doses of vaccine could induce the production of NAb, which decreased over the subsequent period. Such a decline in NAb was observed after either SARS-CoV-2 infection or vaccination (Dan et al., 2021; Liu et al., 2022). Despite this, studies have confirmed the persistence of immunologic memory and the ability to generate a rapid and effective immune response to viral or vaccine stimuli (Sherina et al., 2021; Zhang et al., 2021a). In this study, we observed that the booster immunization resulted in the rapid production of NAb compared to the second dose, which confirmed the body's powerful immune memory to resist virus invasion.

Moreover, booster immunization induced a long-lasting antibody response, which remained high until the end of follow-up. Interestingly, we found that the peak of NAb induced by booster immunization occurred on day 28, which was different from the peak of the second dose on day 14, indicating a more durable response of the body's memory immunity to the stimulation of the boost vaccination. In addition, the third vaccination induced a similar S-IgG response to the second vaccination but did not elicit a strong S-IgM response. This suggests that the S-IgG response plays a more important role in the antibody response induced by booster vaccines compared to S-IgM response.

Another interesting finding was that people without NAb seroconversion after receiving two doses of vaccines produced a high and long-lasting NAb after booster vaccines, which confirmed that they were not completely unresponsive to the COVID-19 vaccine. Although two immunizations of the SARS-CoV-2 vaccine could not induce detectable levels of NAb, immune memory had been successfully established in vivo, which can respond to booster vaccines or virus stimulation. Similarly, studies of the hepatitis B vaccine found that most nonresponders were not absolutely unresponsive, and they could develop protective antibodies after four or more injections (Clemens et al., 1997; Zannolli and Morgese, 1997). The causes of such a phenomenon have not been clearly defined and may be related to host factors such as age, disease, and genetics (Das et al., 2003). What is clear is that this group of people probably needs booster vaccines more urgently.

Age is an important determinant of vaccine response. Previous studies, including those on influenza (Gross et al., 1988; Keren et al., 1988) and tetanus (Burns et al., 1993) vaccination, have shown that elderly individuals induce a weaker immune response to vaccination. The main explanation can be attributed to the different cellular and humoral immune functions at different ages. Factors such as the age-related decrease in lymphocyte number and proliferation activity, cell defects, and dysfunction may change the immune response of elderly individuals (Rink et al., 1998). In this study, the antibody response of the older recipients was significantly lower than that of the younger recipients during the primary and booster immunization with the COVID-19 vaccine. Nevertheless, it is reassuring that the age-related difference in antibody response narrowed with the third dose, suggesting that booster immunization is beneficial to older adults.

We did not observe gender differences in antibody expression levels after routine two-dose vaccination, consistent with other studies on inactivated COVID-19 vaccines (Liu et al., 2022; Yue et al., 2022), which seems to suggest that the production of antibodies after vaccination is not affected by gender. However, to our surprise, further analysis of sex-based antibody responses found that the level of the NAb titer and S-IgG were significantly higher in females aged 40–60 years (Age_2 group) than in males of the same age after the third dose, suggesting that gender differences in antibody responses were induced by the COVID-19 vaccine among older adults. Such an age-related gender difference has been found in other vaccine studies.

Studies of influenza vaccination in elderly adults have revealed that the hemagglutination inhibition titer was higher in females than in males of the same age for both high and low doses (Falsey et al., 2009) and intramuscular and subcutaneous injection (Cook et al., 2006). The immunological mechanisms of sex-based differences have yet to be elucidated, and hormone levels are thought to be the main factors (Furman et al., 2014; Klein et al., 2010). However, age-related sex differences seem to be related not only to hormones but also to genetic and epigenetic regulation (Klein et al., 2015; Klein et al., 2010), microbiota structure (Klein et al., 2015), and other factors that may affect the immune response to vaccination in elderly individuals.

In conclusion, this study revealed that three doses of inactivated vaccine can induce a stronger and long-lasting antibody response in people aged 18 to 60 years, which is of great significance for resisting virus invasion and reducing the severity of infection. Despite these promising findings, our study has limitations due to the small number of subjects and the single strain used. Therefore, further studies are needed to clarify the antibody response against others mutated strain.

Footnotes

Authors' Contributions

J.X. and D.W. conceived and designed the experiments. C.K., W.L., H.Q., X.Z., and S.L. coordinated the projects. R.J., J.Z., D.L., Y.W., and A.P. collected samples and performed the experiments. J.Z., R.J., and J.X. performed the data analysis. J.Z. and R.J. wrote the article. All authors contributed to the article and approved the submitted version.

Data Availability

Data will be made available on request.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This work was supported by the Science and Technology Innovation Project of Foshan Municipality (2020001000431); the National Key Research and Development Program (2021YFC0863300); and the Emergency Key Program of Guangzhou Laboratory (EKPG21–27).

Supplementary Material

Supplementary Figure S1

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Supplementary Material

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