SARS-CoV-2 breakthrough infections elicit potent, broad, and durable neutralizing antibody responses

Alexandra C Walls,Kaitlin R Sprouse,John E Bowen,Anshu Joshi,Nicholas Franko,Mary Jane Navarro,Cameron Stewart,Elisabetta Cameroni,Matthew Mccallum,Erin A Goecker,Emily J Degli-Angeli,Jenni Logue,Alex Greninger,Davide Corti,Helen Y Chu,David Veesler

doi:10.1016/j.cell.2022.01.011

Alexandra C Walls, Kaitlin R Sprouse + Show 14 more

Open Access

https://doi.org/10.1016/j.cell.2022.01.011

Copy DOI

Abstract

Although infections among vaccinated individuals lead to milder COVID-19 symptoms relative to those in unvaccinated subjects, the specificity and durability of antibody responses elicited by breakthrough cases remain unknown. Here, we demonstrate that breakthrough infections induce serum-binding and -neutralizing antibody responses that are markedly more potent, durable, and resilient to spike mutations observed in variants than those in subjects who received only 2 doses of vaccine. However, we show that breakthrough cases, subjects who were vaccinated after infection, and individuals vaccinated three times have serum-neutralizing activity of comparable magnitude and breadth, indicating that an increased number of exposures to SARS-CoV-2 antigen(s) enhance the quality of antibody responses. Neutralization of SARS-CoV was moderate, however, underscoring the importance of developing vaccines eliciting broad sarbecovirus immunity for pandemic preparedness.

Highlights

The SARS-CoV-2 Delta (B.1.617.2) variant of concern emerged at the end of 2020 and became dominant globally by mid2021
We show that breakthrough cases or infected/vaccinated subjects are endowed with greater potency, breadth, and durability of serum-neutralizing activity relative to individuals who received 2 doses of COVID-19 vaccine or those who were infected only by SARS-CoV-2 in 2020
Serum-neutralizing geometric mean titers (GMTs) for the breakthrough cases and infected/vaccinated subjects were greater against the Delta and Beta S variants at all time points than those of vaccinated-only individuals against G614 S pseudovirus at peak titers

Summary

Introduction

The SARS-CoV-2 Delta (B.1.617.2) variant of concern emerged at the end of 2020 and became dominant globally by mid2021. Multiple S mutations in the N-terminal domain and receptor-binding domain have been shown to promote immune evasion (McCallum et al, 2021a, 2021b; Mlcochova et al, 2021; Suryadevara et al, 2021; Ying et al, 2021) These characteristics combined with the waning of serumneutralizing antibody titers over time in vaccinated individuals have resulted in breakthrough infections that are usually associated with much milder symptoms than infections of unvaccinated individuals (Levine-Tiefenbrun et al, 2021; Mlcochova et al, 2021). To understand whether the sequence of infection and/or vaccination as well as repeated exposures alters the durability, magnitude, and breadth of antibody responses, we followed and compared serum antibodies in individuals who were vaccinated, previously infected and vaccinated, or vaccinated and infected predominantly with the SARS-CoV-2 Delta variant

Methods

Results

Conclusion