Dynamics of SARS-CoV-2 Antibody Responses up to 9 Months Post-Vaccination in Individuals with Previous SARS-CoV-2 Infection Receiving Inactivated Vaccines

Abstract

Humoral immunity confers protection against COVID-19. The longevity of antibody responses after receiving an inactivated vaccine in individuals with previous SARS-CoV-2 infection is unclear. Plasma samples were collected from 58 individuals with previous SARS-CoV-2 infection and 25 healthy donors (HDs) who had been vaccinated with an inactivated vaccine. The neutralizing antibodies (NAbs) and S1 domain-specific antibodies against the SARS-CoV-2 wild-type and Omicron strains and nucleoside protein (NP)-specific antibodies were measured using a chemiluminescent immunoassay. Statistical analysis was performed using clinical variables and antibodies at different timepoints after SARS-CoV-2 vaccination. NAbs targeting the wild-type or Omicron strain were detected in individuals with previous SARS-CoV-2 infection at 12 months after infection (wild-type: 81%, geometric mean (GM): 20.3 AU/mL; Omicron: 44%, GM: 9.4 AU/mL), and vaccination provided further enhancement of these antibody levels (wild-type: 98%, GM: 53.3 AU/mL; Omicron: 75%, GM: 27.8 AU/mL, at 3 months after vaccination), which were significantly higher than those in HDs receiving a third dose of inactivated vaccine (wild-type: 85%, GM: 33.6 AU/mL; Omicron: 45%, GM: 11.5 AU/mL). The level of NAbs in individuals with previous infection plateaued 6 months after vaccination, but the NAb levels in HDs declined continuously. NAb levels in individuals with previous infection at 3 months post-vaccination were strongly correlated with those at 6 months post-vaccination, and weakly correlated with those before vaccination. NAb levels declined substantially in most individuals, and the rate of antibody decay was negatively correlated with the neutrophil-to-lymphocyte ratio in the blood at discharge. These results suggest that the inactivated vaccine induced robust and durable NAb responses in individuals with previous infection up to 9 months after vaccination.

Keywords: COVID-19 convalescent; Omicron variant; SARS-CoV-2; inactivated vaccine; longitudinal study; neutralizing antibodies.

Figure 1

Individuals with previous SARS-CoV-2 infection and healthy donor cohorts and study design. (A) Study design of the vaccine cohort. Red and blue triangles indicate sampling collections, the numbers above the triangles indicate the days after the vaccination, and the timepoint for sampling is below the triangles. (B) Participants received the SARS-CoV-2 inactivated vaccine and donated blood at four visits. Disease severity status in individuals with previous SARS-CoV-2 infection is color-coded: mild (light green), moderate (dark green), or severe (red). Healthy donors are shown in blue. The bottom row displays the number of samples collected for each timepoint. (C) The pie plots show the distribution of sex and age in the two cohorts.

Figure 2

Dynamic changes of virus-specific antibodies in individuals with previous SARS-CoV-2 infection and healthy donors. The left parts show dynamic changes in NAbs against wild-type strain (A), NAbs against Omicron (C), Spike S1 domain-specific antibodies against wild-type strain (E), Spike S1 domain-specific antibodies against Omicron (G), and nucleoside protein-specific IgG antibodies against wild-type strain (I) in two cohorts over the different timepoints. Individuals are shown as gray symbols with connecting lines for longitudinal samples. Geometric means are shown in thick, colored lines: individuals with previous SARS-CoV-2 infection are color-coded in red and healthy donors in blue. The right parts show the comparison of antibodies between different time points. The scatter diagrams show the comparison of NAbs against wild-type strain (B), NAbs against Omicron (D), Spike S1 domain-specific antibodies against wild-type strain (F), Spike S1 domain-specific antibodies against Omicron (H), and nucleoside protein-specific IgG antibodies against wild-type strain (J) between individuals with previous SARS-CoV-2 infection and healthy donors at 3, 6, and 9 months post-vaccination. Dotted lines indicate the cut-off value. Statistics were calculated using Wilcoxon’s signed-rank test for paired groups and Mann–Whitney U test for unpaired groups: * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001. GM, geometric mean; Res, responders; NAbs, neutralizing antibodies; WT, wild-type strain; Omic, Omicron.

Figure 3

Correlation analysis between antibody levels in individuals with previous SARS-CoV-2 infection and healthy donors after vaccination. The correlation matrixes of antibody levels were calculated using nonparametric Spearman rank correlation in individuals with previous SARS-CoV-2 infection (A) and healthy donors (B). Positive correlations are shown in red and negative correlations are shown in blue. The size and color of each dot in the triangular matrix show the correlation strength between the variables: * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001. NAbs, neutralizing antibodies; WT, wild-type strain; Omic, Omicron.

Figure 4

Association of clinical factors with wild-type neutralizing antibody duration after vaccination. (A) Dot plot shows the ranges of NAbs durability index for individuals with previous SARS-CoV-2 infection (red, n = 49) and healthy donors (blue, n = 7). (B) Wild-type NAb levels in the Sustainer group (red, n = 16), Decayer group (black, n = 33), and healthy donors (blue, n = 7) after vaccination. (C) Dot plot showing the antibody levels in the Sustainer group (red, n = 16) and Decayer group (black, n = 33) at 12 months after infection (T0) and 3 months post-vaccination (T1). (D) Spearman rank correlation was used to analyze the NAbs durability index and the neutrophil-to-lymphocyte ratio at discharge (left) and 3 months after vaccination (T1) (right). The linear fitting was performed, and gray indicates 95% confidence intervals. Statistics were calculated using Wilcoxon’s signed-rank test for paired groups and Mann–Whitney U test for unpaired groups: * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001. NAbs, neutralizing antibodies; WT, wild-type strain; Omic, Omicron; NLR, neutrophil-to-lymphocyte ratio.