Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Mar 3;185(5):872-880.e3.
doi: 10.1016/j.cell.2022.01.011. Epub 2022 Jan 20.

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

Alexandra C Walls  1 , Kaitlin R Sprouse  2 , John E Bowen  2 , Anshu Joshi  2 , Nicholas Franko  3 , Mary Jane Navarro  2 , Cameron Stewart  2 , Elisabetta Cameroni  4 , Matthew McCallum  2 , Erin A Goecker  5 , Emily J Degli-Angeli  5 , Jenni Logue  3 , Alex Greninger  5 , Davide Corti  4 , Helen Y Chu  3 , David Veesler  6
Affiliations

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

Alexandra C Walls et al. Cell. .

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.

Keywords: COVID-19; Delta variant; SARS-CoV-2; antibodies; breakthrough infection; neutralization; vaccine.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The Veesler laboratory has received an unrelated sponsored research agreement from Vir Biotechnology. A.C.W. and D.V. are named as inventors on patent applications filed by the University of Washington for SARS-CoV-2 and sarbecovirus receptor-binding domain nanoparticle vaccines. E.C. and D.C. are employees of Vir Biotechnology and may hold shares in Vir Biotechnology. H.Y.C. is a consultant for Merck, Pfizer, Ellume, and the Bill and Melinda Gates Foundation and has received support from Cepheid and Sanofi-Pasteur. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

None
Graphical abstract
Figure 1
Figure 1
Repeated exposures to SARS-CoV-2 antigens through vaccination or infection enhance S-specific serum-IgG- and IgA-binding titers (A) Serum-IgG-binding titers at 30 or 60 days post infection or 10, 112, or 180 days post second or third vaccine dose were evaluated for longitudinal samples by ELISA using prefusion-stabilized SARS-CoV-2 S Hexapro as the antigen. Serum samples were obtained from individuals who had a breakthrough infection (n = 15, magenta triangle), were previously infected in 2020 and then vaccinated (n = 15, teal diamond), had only been vaccinated (n = 15, orange circle), were infected in 2020 in Washington state (n = 15, gray square), or were SARS-CoV-2 naive (samples taken prior to vaccination, n = 15, open hexagon). Demographics of each individual are shown in Table S1. Statistical significance was determined by Kruskal-Wallis and Dunn’s multiple comparisons test and is shown in Table S2. (B) Serum-IgA-binding titers at 30 days post infection or 10 days post second vaccine dose were evaluated by ELISA using prefusion-stabilized SARS-CoV-2 S Hexapro as the antigen. (C) Serum-IgM-binding titers at 30 days post infection or 10 days post second vaccine dose were evaluated by ELISA using prefusion-stabilized SARS-CoV-2 S Hexapro as the antigen. (D–F) Serum-IgG-binding titers were evaluated by ELISA at 30 days post infection, 10 days post second or third vaccine dose or prior to SARS-CoV-2 exposure (SARS-CoV-2 naive) using prefusion-stabilized (D) SARS-CoV 2P S as the antigen, OC43 S (E) or HKU1 2P S (F) as the antigen. # of exposures: number of SARS-CoV-2 S exposures (infection or vaccination). Shown are representative GMTs from at least two independent experiments. Statistical significance was determined by Kruskal-Wallis and Dunn’s multiple comparisons test and is shown only when significant. ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001; and ∗∗∗∗p < 0.0001. LOD is shown as a gray horizontal dotted line when above the x axis. Raw fits are shown in Data S1.
Figure 2
Figure 2
Breakthrough, infected/vaccinated, and triple vaccinated individuals have exceptionally high serum-neutralizing activity Serum samples were obtained from individuals who had a breakthrough infection (n = 15, magenta triangle), who were previously infected in 2020 and then vaccinated (n = 15, teal diamond, infected/vaccinated), who had been vaccinated only (n = 15, orange circle), or who were infected only in 2020 in Washington state (n = 15, gray square, HCP). All neutralization assays were performed using VeroE6-TMPRSS2 as target cells at least in duplicate. Shown are representative GMTs from at least two independent experiments. Demographics of each individuals are shown in Table S1. Statistical significance was determined by the Kruskal-Wallis and Dunn’s multiple comparison test and are shown in Table S2. ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001; and ∗∗∗∗p < 0.0001. Normalized curves and fits are shown in Data S1. (A) SARS-CoV-2 G614 S VSV pseudotype neutralization. (B) SARS-CoV-2 Delta S VSV pseudotype neutralization. (C) SARS-CoV-2 Beta S VSV pseudotype neutralization. (D) SARS-CoV-2 Omicron S VSV pseudotype neutralization. (E) SARS-CoV S VSV pseudotype neutralization. # of exposures: number of SARS-CoV-2 S exposures (infection or vaccination). (F) Fold change of 614G:Delta/Beta/Omicron/SARS-CoV colored green (small fold change) to red (large fold change). A greater sign is used when the GMTs at the limit of detection may cause aberrant results.
See this image and copyright information in PMC

Update of

References

    1. Arunachalam P.S., Walls A.C., Golden N., Atyeo C., Fischinger S., Li C., Aye P., Navarro M.J., Lai L., Edara V.V., et al. Adjuvanting a subunit COVID-19 vaccine to induce protective immunity. Nature. 2021;594:253–258. - PubMed
    1. Baden L.R., El Sahly H.M., Essink B., Kotloff K., Frey S., Novak R., Diemert D., Spector S.A., Rouphael N., Creech C.B., et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 2021;384:403–416. - PMC - PubMed
    1. Bedford T., Greninger A.L., Roychoudhury P., Starita L.M., Famulare M., Huang M.L., Nalla A., Pepper G., Reinhardt A., Xie H., et al. Cryptic transmission of SARS-CoV-2 in Washington state. Science. 2020;370:571–575. - PMC - PubMed
    1. Bowen J.E., Walls A.C., Joshi A., Sprouse K.R., Stewart C., Tortorici M.A., Franko N.M., Logue J.K., Mazzitelli I.G., Tiles S.W., et al. SARS-CoV-2 spike conformation determines plasma neutralizing activity. bioRxiv. 2021 bioRxiv:10.1101/2021.12.19.473391. - PMC - PubMed
    1. Cameroni E., Bowen J.E., Rosen L.E., Saliba C., Zepeda S.K., Culap K., Pinto D., VanBlargan L.A., De Marco A., di Iulio J., et al. Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift. Nature. 2021 doi: 10.1038/s41586-021-04386-2. - DOI - PMC - PubMed

LinkOut - more resources