Circulating neutralizing antibodies and SARS-CoV-2 variant replication following postvaccination infections

Abstract

The effect of preexisting neutralizing antibodies (NAb) on SARS-CoV-2 shedding in postvaccination infection (PVI) is not well understood. We characterized viral shedding longitudinally in nasal specimens in relation to baseline (pre/periinfection) serum NAb titers in 125 participants infected with SARS-CoV-2 variants. Among 68 vaccinated participants, we quantified the effect of baseline NAb titers on maximum viral RNA titers and infectivity duration. Baseline NAbs were higher and targeted a broader range of variants in participants with monovalent ancestral booster vaccinations compared with those with a primary vaccine series. In Delta infections, baseline NAb titers targeting Delta or Wuhan-Hu-1 correlated negatively with maximum viral RNA. Per log10 increase in Delta-targeting baseline NAb IC50, maximum viral load was reduced -2.43 (95% CI: -3.76, -1.11) log10 nucleocapsid copies, and infectious viral shedding was reduced -2.79 (95% CI: -4.99, -0.60) days. Conversely, in Omicron infections (BA.1, BA.2, BA.4, or BA.5), baseline NAb titers against Omicron lineages or Wuhan-Hu-1 did not predict viral outcomes. Our results provide robust estimates of the effect of baseline NAbs on the magnitude and duration of nasal viral replication after PVI (albeit with an unclear effect on transmission) and show how immune escape variants efficiently evade these modulating effects.

Keywords: Adaptive immunity; COVID-19; Immunology; Infectious disease.

Figure 1. The influence of vaccination history and viral variant on viral shedding dynamics.

(A) Longitudinal viral shedding dynamics in nasal specimens collected over 28 days from symptom onset in unvaccinated participants (n = 57) and participants with postvaccination infections (PVI) who received a primary vaccine series (n = 37) or monovalent booster vaccinations (n = 31). Copies of SARS-CoV-2 nucleocapsid (N) RNA of each specimen and the presence of infectious virus are shown. (B) Comparison of maximum copies of N RNA between vaccine groups. (C) Comparison of the duration in days in which infectious virus was detected between vaccine groups. (D) Comparison of maximum copies of N RNA in participants stratified by infecting variant. Vaccination history is indicated by the color shown in the legend. (E) Comparison of duration in days in which infectious virus was detected stratified by infecting variant. Vaccination history is indicated the color shown in the legend. Box plots represent the IQR (box), median (line), and IQR × 1.5 values (whiskers). All pairwise comparisons were made using a 2-sided Wilcoxon rank sum test. Only statistically significant differences are shown. *P < 0.05 and **P < 0.01. CPE, cytopathic effect.

Figure 2. The magnitude and breadth of baseline NAb titers in participants with PVI.

(A) NAb titers targeting SARS-CoV-2 variants compared with Wuhan-Hu-1 in participants with PVI who received a primary vaccine series or monovalent booster vaccination. n = 22 participants with recruitment specimens taken > 7 PSO were excluded from the analysis. (B) Comparison of baseline NAb titers targeting the infecting variant (except for BA.5 infections for which responses against BA.2 are shown) between participants with PVIs who received a primary vaccine series or monovalent booster vaccination. Box plots represent the IQR (box), median (line), and IQR × 1.5 values (whiskers). Statistical comparisons were made using a 2-sided Wilcoxon rank sum test. Comparisons with P < 0.1 are shown. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0005.

Figure 3. The relationship between baseline NAb titers and viral shedding outcomes.

(A and B) The correlation between baseline NAb titer targeting the infecting variant in vaccinated participants (n = 29) infected with Delta variants and maximum RNA viral copies (A) and infectious virus shedding (B) over the study period. (C and D) The correlation between baseline NAb titer targeting the infecting variant (except for participants with BA.5 infections for which responses were against BA.2) in vaccinated participants (n = 29) infected with Omicron variants and maximum RNA viral copies (C) and infectious virus shedding (D) over the study period. Participants (n = 9) with recruitment specimens taken on day 7 PSO or later were excluded. Pearson’s correlation coefficients and infecting variant are shown.