Durable reprogramming of neutralizing antibody responses following Omicron breakthrough infection

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection of vaccinated individuals is increasingly common with the circulation of highly immune evasive and transmissible Omicron variants. Here, we report the dynamics and durability of recalled spike-specific humoral immunity following Omicron BA.1 or BA.2 breakthrough infection, with longitudinal sampling up to 8 months after infection. Both BA.1 and BA.2 infections robustly boosted neutralization activity against the infecting strain while expanding breadth against BA.4, although neutralization activity was substantially reduced for the more recent XBB and BQ.1.1 strains. Cross-reactive memory B cells against both ancestral and Omicron spike were predominantly expanded by infection, with limited recruitment of de novo Omicron-specific B cells or antibodies. Modeling of neutralization titers predicts that protection from symptomatic reinfection against antigenically similar strains will be durable but is undermined by new emerging strains with further neutralization escape.

Preexisting immunity restricts mucosal antibody recognition of SARS-CoV-2 and Fc profiles during breakthrough infections

“…Given that prior COVID-19 infection could influence both systemic and, more importantly, mucosal humoral responses following vaccination, we next wanted to explore how prior vaccination impacted systemic and mucosal humoral responses during COVID-19 breakthrough infections. To address this, we expanded our studies to breakthrough COVID-19 cohorts and collected serial saliva and plasma samples from vaccinated individuals with acute COVID-19 from 2 VoC waves (Delta, Omicron BA.2) in Victoria, Australia ( Figure 5A , cohort information described in Supplemental Figure 8A and Supplemental Table 2 ) ( 8 , 21 , 22 ).…”

“…We also recruited previously vaccinated individuals with a nasal PCR-confirmed breakthrough COVID-19 infection ( 8 , 21 , 22 ) during the Delta and Omicron BA.2 waves in Victoria to provide serial blood and saliva samples ( Supplemental Figure 8A and Supplemental Table 2 ).…”

Vaccination impairs de novo immune response to omicron breakthrough infection, a precondition for the original antigenic sin

“…Currently-circulating omicron SARS-CoV-2 variant and its derivatives led to soaring rates of breakthrough infections due to the high density of mutations in the spike protein facilitating immune escape 15 – 17 . We and others have previously shown that vaccinated individuals with omicron SARS-CoV-2 breakthrough infection show superior plasma neutralization capacity against the omicron variant 18 – 21 . It is however unclear whether this is merely due to the boosting of vaccine-induced broadly-specific neutralizing antibodies or also due to the naïve B cell priming and production of antibodies targeting mutated neutralizing epitopes.…”

Dynamic Profiling and Prediction of Antibody Response to Booster Inactivated Vaccines by Microsample-driven Biosensor and Machine Learning

“…Although numerous clinical studies have employed ML to predict antibody response following vaccination, most have centered on predicting the probability of seroconversion at a single timepoint instead of predicting precise levels of antibody levels and their temporal dynamics in individuals [10, 11, 21−24]. Additional studies investigated the prediction of neutralization titers to multiple Omicron variants after breakthrough infection [25]. In this work, we bridged this gap by developing a model that can accurately predict the changes in antibody response at multiple timepoints based on previous measurements.…”