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. 2022 Jul 12;55(7):1316-1326.e4.
doi: 10.1016/j.immuni.2022.05.018. Epub 2022 May 27.

The magnitude and timing of recalled immunity after breakthrough infection is shaped by SARS-CoV-2 variants

Marios Koutsakos  1 , Wen Shi Lee  1 , Arnold Reynaldi  2 , Hyon-Xhi Tan  1 , Grace Gare  1 , Paul Kinsella  3 , Kwee Chin Liew  3 , George Taiaroa  3 , Deborah A Williamson  4 , Helen E Kent  1 , Eva Stadler  2 , Deborah Cromer  2 , David S Khoury  2 , Adam K Wheatley  5 , Jennifer A Juno  6 , Miles P Davenport  7 , Stephen J Kent  8
Affiliations

The magnitude and timing of recalled immunity after breakthrough infection is shaped by SARS-CoV-2 variants

Marios Koutsakos et al. Immunity. .

Abstract

Vaccination against SARS-CoV-2 protects from infection and improves clinical outcomes in breakthrough infections, likely reflecting residual vaccine-elicited immunity and recall of immunological memory. Here, we define the early kinetics of spike-specific humoral and cellular immunity after vaccination of seropositive individuals and after Delta or Omicron breakthrough infection in vaccinated individuals. Early longitudinal sampling revealed the timing and magnitude of recall, with the phenotypic activation of B cells preceding an increase in neutralizing antibody titers. While vaccination of seropositive individuals resulted in robust recall of humoral and T cell immunity, recall of vaccine-elicited responses was delayed and variable in magnitude during breakthrough infections and depended on the infecting variant of concern. While the delayed kinetics of immune recall provides a potential mechanism for the lack of early control of viral replication, the recall of antibodies coincided with viral clearance and likely underpins the protective effects of vaccination against severe COVID-19.

Keywords: B cell immunity; CD4 T cell immunity; CD8 T cell immunity; COVID-19 vaccines; Delta; Omicron; SARS-CoV-2; breakthrough infection; neutralizing antibodies; vaccination.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
Spike-specific humoral immunity is rapidly recalled following vaccination of seropositive individuals (A–C) Serological analysis of samples following one dose of BNT162b2 or ChAdOx1 nCoV-19. Kinetics of S-specific IgG (A) and RBD-specific IgG (B) antibodies measured by ELISA and neutralizing antibodies measured by a live virus neutralization assay (C) in SARS-CoV-2 naive or seropositive individuals (seropositive N = 19, naive N = 8). (D and E) Representative flow cytometry plots (D) and frequency (E) of antibody-secreting cells (ASCs, CD20loCD71+ B cells) in SARS-CoV-2 seropositive individuals. (F and G) Representative flow cytometry plots (F) and frequency (G) of S-specific class-switched B cells (IgD−CD19+) in vaccinated seropositive individuals. (H and I) Representative flow cytometry plots (H) and frequency (I) of activation markers (CD21, CD71) within S-specific class-switched B cells (IgD−CD19+) in vaccinated seropositive individuals. (D–I) N = 21. See also Figure S1.
Figure 2
Figure 2
Spike-specific T cell immunity is rapidly recalled following vaccination of seropositive individuals Analysis of S-specific T cells by AIM assay following one dose of BNT162b2 or ChAdOx1 nCoV-19 in SARS-CoV-2 naive or seropositive individuals. (A–G) Representative staining and frequency of AIM markers (CD25, OX-40) on CD4+ Tmem cells (CD3+CD4+CD8−CD45RA−CXCR5−) (A and B) and CD4+ cTFH cells (CD3+CD4+CD8−CD45RA−CXCR5+) (C and D), tetramer staining (E and F) or AIM markers (CD69, CD137) on CD8+ Tmem cells (CD3+CD8+CD4−non-naive) (G and H) after stimulation with 5 μg/mL of SARS-CoV-2 S protein on different timepoints after vaccination. See also Figures S1 and S2.
Figure 3
Figure 3
The recall of spike-specific humoral immunity is variable following breakthrough infection with Delta or Omicron (A and B) (A) Kinetics of S- and RBD-specific IgG antibodies measured by ELISA and (B) of neutralizing antibodies measured by a live virus microneutralization assay. (A and B) N = 8 participants for Delta (purple), N = 8 for Omicron (green), N = 15 for indeterminate (blue). (C and D) (C) Frequencies of S-specific class-switched B cells (IgD−CD19+) and (D) antibody-secreting cells (ASCs, CD20loCD71+ B cells) determined by flow cytometry. (E–G) (E) Frequencies of AIM+ (CD25, OX-40) S-specific CD4+ Tmem cells (CD3+CD4+CD8−CD45RA−CXCR5−), (F) AIM+ CD4+ cTFH cells (CD3+CD4+CD8−CD45RA−CXCR5+) and (G) AIM+ (CD69, CD137) S-specific CD8+ Tmem cells (CD3+CD8+CD4−non-naive) after stimulation with 5 μg/mL of SARS-CoV-2 S protein. (C–G) N = 8 participants for Delta (purple), N = 6 for Omicron (green). See also Figure S3.
Figure 4
Figure 4
Immune recall following breakthrough infections is delayed compared with vaccination and preceded by peak viral load (A) Comparative kinetics of immune recall following vaccination of seropositive individuals (black) and breakthrough infection of vaccinated individuals (Delta in purple, Omicron in green). (B) Ct values for SARS-CoV-2 N gene in serial nasopharyngeal swabs. N = 4 participants for Delta, N = 7 for Omicron. (C and D) Correlations between Ct value and titers of neutralizing antibodies (C) or spike IgG antibodies (D). Spearman correlation coefficients (rs) and p values are indicated on the figure, n = 24 paired samples from 4 subjects for Delta and n = 18 paired samples from 7 subjects for Omicron. (E and F) Overlayed kinetics of antibody recall (fold change over baseline) and viral load (fold change relative to peak) for neutralizing antibody titers and spike IgG antibodies for Delta (E) and Omicron (F) breakthrough infections. (A, E, and F) The lines indicate the mean estimate for each group from the piecewise linear regression model using the estimated parameters. See also Figure S4.
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References

    1. Backer J.A., Eggink D., Andeweg S.P., Veldhuijzen I.K., van Maarseveen N., Vermaas K., Vlaemynck B., Schepers R., van den Hof S., Reusken C.B., Wallinga J. Shorter serial intervals in SARS-CoV-2 cases with Omicron BA.1 variant compared with Delta variant, the Netherlands, 13 to 26 December 2021. Euro Surveill. 2022;27:2200042. doi: 10.2807/1560-7917.ES.2022.27.6.2200042. - DOI - 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. 2022;602:664–670. doi: 10.1038/s41586-021-04386-2. - DOI - PMC - PubMed
    1. Carreño J.M., Alshammary H., Tcheou J., Singh G., Raskin A.J., Kawabata H., Sominsky L.A., Clark J.J., Adelsberg D.C., Bielak D.A., et al. Activity of convalescent and vaccine serum against SARS-CoV-2 Omicron. Nature. 2022;602:682–688. doi: 10.1038/s41586-022-04399-5. - DOI - PubMed
    1. Chan J.F., Yip C.C., To K.K., Tang T.H., Wong S.C., Leung K.H., Fung A.Y., Ng A.C., Zou Z., Tsoi H.W., et al. Improved molecular diagnosis of COVID-19 by the novel, highly sensitive and specific COVID-19-RdRp/Hel real-time reverse transcription-PCR assay validated in vitro and with clinical specimens. J. Clin. Microbiol. 2020;58:e00310–e00320. doi: 10.1128/JCM.00310-20. - DOI - PMC - PubMed
    1. Chen P., Nirula A., Heller B., Gottlieb R.L., Boscia J., Morris J., Huhn G., Cardona J., Mocherla B., Stosor V., et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N. Engl. J. Med. 2021;384:229–237. doi: 10.1056/NEJMoa2029849. - DOI - PMC - PubMed

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