. 2025 Jun;26(6):829-836.

doi: 10.1038/s41590-025-02162-2. Epub 2025 May 27.

Intrinsic immunogenicity is a major determinant of type-specific responses in SARS-CoV-2 infections

Grace E Quirk¹, Marta V Schoenle^{2

3}, Kameron L Peyton², Jennifer L Uhrlaub², Branden Lau⁴, Chieh-Yu Liang^{5

6}, Jefferey L Burgess⁷, Katherine Ellingson⁸, Shawn Beitel⁷, James Romine⁷, Karen Lutrick⁹, Ashley Fowlkes¹⁰, Amadea Britton¹⁰, Harmony L Tyner¹¹, Alberto J Caban-Martinez¹², Allison Naleway¹³, Manjusha Gaglani¹⁴, Sarang Yoon¹⁵, Laura J Edwards¹⁶, Lauren Olsho¹⁶, Michael Dake¹⁷, Riccardo Valdez¹⁸, Aubree Gordon¹⁹, Michael S Diamond^{5

6

20}, Bonnie J LaFleur^{21

22}, Janko Ž Nikolich^{2

21

23}, Ryan Sprissler⁴, Michael Worobey^{1

21}, Deepta Bhattacharya^{24

25

26}

Affiliations

¹ Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, AZ, USA.
² Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA.
³ Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA.
⁴ University of Arizona Genomics Core and the Arizona Research Labs, University of Arizona Genetics Core, University of Arizona, Tucson, AZ, USA.
⁵ Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
⁶ Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
⁷ Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA.
⁸ Department of Epidemiology and Biostatistics, Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA.
⁹ College of Medicine-Tucson, University of Arizona, Tucson, AZ, USA.
¹⁰ National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
¹¹ St. Luke's Regional Health Care System, Duluth, MN, USA.
¹² Department of Public Health Services, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
¹³ Kaiser Permanente Northwest Center for Health Research, Portland, OR, USA.
¹⁴ Texas A&M University College of Medicine, Temple, TX, USA.
¹⁵ Rocky Mountain Center for Occupational and Environmental Health, Department of Family and Preventive Medicine, University of Utah Health, Salt Lake City, UT, USA.
¹⁶ Abt Associates, Rockville, MD, USA.
¹⁷ Office of the Senior Vice-President for Health Sciences, University of Arizona, Tucson, AZ, USA.
¹⁸ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
¹⁹ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
²⁰ Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA.
²¹ BIO5 Institute, University of Arizona, Tucson, AZ, USA.
²² R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ, USA.
²³ University of Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ, USA.
²⁴ Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA. deeptab@arizona.edu.
²⁵ BIO5 Institute, University of Arizona, Tucson, AZ, USA. deeptab@arizona.edu.
²⁶ Department of Surgery, University of Arizona College of Medicine, Tucson, AZ, USA. deeptab@arizona.edu.

PMID: 40425779
PMCID: PMC12198969
DOI: 10.1038/s41590-025-02162-2

Intrinsic immunogenicity is a major determinant of type-specific responses in SARS-CoV-2 infections

Grace E Quirk et al. Nat Immunol. 2025 Jun.

. 2025 Jun;26(6):829-836.

doi: 10.1038/s41590-025-02162-2. Epub 2025 May 27.

Authors

Affiliations

¹ Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, AZ, USA.
² Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA.
³ Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA.
⁴ University of Arizona Genomics Core and the Arizona Research Labs, University of Arizona Genetics Core, University of Arizona, Tucson, AZ, USA.
⁵ Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
⁶ Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
⁷ Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA.
⁸ Department of Epidemiology and Biostatistics, Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA.
⁹ College of Medicine-Tucson, University of Arizona, Tucson, AZ, USA.
¹⁰ National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
¹¹ St. Luke's Regional Health Care System, Duluth, MN, USA.
¹² Department of Public Health Services, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
¹³ Kaiser Permanente Northwest Center for Health Research, Portland, OR, USA.
¹⁴ Texas A&M University College of Medicine, Temple, TX, USA.
¹⁵ Rocky Mountain Center for Occupational and Environmental Health, Department of Family and Preventive Medicine, University of Utah Health, Salt Lake City, UT, USA.
¹⁶ Abt Associates, Rockville, MD, USA.
¹⁷ Office of the Senior Vice-President for Health Sciences, University of Arizona, Tucson, AZ, USA.
¹⁸ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
¹⁹ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
²⁰ Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA.
²¹ BIO5 Institute, University of Arizona, Tucson, AZ, USA.
²² R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ, USA.
²³ University of Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ, USA.
²⁴ Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA. deeptab@arizona.edu.
²⁵ BIO5 Institute, University of Arizona, Tucson, AZ, USA. deeptab@arizona.edu.
²⁶ Department of Surgery, University of Arizona College of Medicine, Tucson, AZ, USA. deeptab@arizona.edu.

PMID: 40425779
PMCID: PMC12198969
DOI: 10.1038/s41590-025-02162-2

Abstract

Few type-specific antibodies that recognize drifted epitopes are made during post-vaccination exposures to SARS-CoV-2 variants^1-12, perhaps due to suppression by previous immunity. We compared type-specific B cell responses in unvaccinated and vaccinated individuals with Delta and Omicron BA.1 SARS-CoV-2 variant infections. For both Delta, which is antigenically similar to the vaccine strain, and the more distant BA.1 variant, neutralizing antibodies were greater in post-vaccination variant infections than in primary variant infections. Delta type-specific memory B cells were reduced in post-vaccination Delta infections relative to primary variant infections. Yet some drifted epitopes in the Delta variant elicited minimal responses even in primary infections. For BA.1 infections, type-specific antibodies and memory B cells were mostly undetectable, irrespective of previous immunity. Thus, poor intrinsic antigenicity of drifted epitopes in Delta and BA.1 infections superseded the impact of previous immunity. Enhancing the immunogenicity of vaccine antigens may promote type-specific responses.

PubMed Disclaimer

Conflict of interest statement

Competing interests: Sana Biotechnology has licensed intellectual property of D.B. and Washington University in St. Louis. Jasper Therapeutics and Inograft Therapeutics have licensed intellectual property of D.B. and Stanford University. D.B. served on an advisory panel for GlaxoSmithKline on COVID-19 therapeutic antibodies. D.B. serves on the scientific advisory board for Hillevax. D.B. is a scientific cofounder of Aleutian Therapeutics. B.J.L. has a financial interest in Cofactor Genomics, Inc. and Iron Horse Dx. Geneticure Inc. has licensed intellectual property of R.S. and R.S. is a cofounder of Geneticure Inc. M.W. has received consulting fees from Gerson Lehrman Group regarding SARS-CoV-2 and the COVID-19 pandemic. M.S.D. is a consultant or advisor for Inbios, Vir Biotechnology, IntegerBio, Moderna, Merck and GlaxoSmithKline. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Emergent BioSolutions and IntegerBio. The other authors declare no competing interests.

Figures

**Extended Data Fig. 1. Post-vaccination delta and BA.1 infections report symptoms lasting for a shorter duration compared to primary delta infections.**
a. Bar plot showing percentage of individuals from each TATS cohort (primary delta infection (n = 12), post-vaccination delta infection (n = 37), and post-vaccination BA.1 infection (n=50)) that reported experiencing respiratory symptoms in study entry survey. b. Dot plot showing reported days until symptoms resolved for each TATS cohort (primary delta infection (n = 12), post-vaccination delta infection (n = 37), and post-vaccination BA.1 infection (n=50)). Each symbol represents an individual. Medians ± 95% CI are shown. Two-sided P values from t-test statistics were calculated for pairwise differences using one-way ANOVA. Post hoc Tukey’s multiple comparisons test was applied. P values greater than 0.05 are not depicted. c. Correlation of time since vaccination with PRNT₉₀ values against WuHu1 (left), antibody titers against WuHu1 RBD (middle), and the ratio of WuHu1:Delta RBD binding antibodies in vaccinated only (n = 62) cohort. Each symbol represents an individual. Medians ± 95% CI are shown. Two-sided Pearson correlation analysis was performed (left (p = 0.72), middle (p = 0.22), right (p = 0.21)).

**Extended Data Fig. 2. Flow cytometric gating strategy and quantification with Delta S1 and WuHu1 S1 tetramers.**
Flow cytometry plot showing gating strategy for B_MEM from a primary delta infection (top) and post-vaccination delta infection (bottom).

**Extended Data Fig. 3. No significant correlation is observed between antibody titers and time since infection in primary BA.1 and post-vaccination BA.1 infections.**
a. Correlation of time since infection and PRNT₉₀ values against BA.1 (left) and antibody titers against BA.1 RBD (right) in primary BA.1 infection (n = 56) cohort. Each symbol represents an individual. Two-sided Pearson correlation analysis was performed (left (p = 0.22), right (p = 0.08)). b. Correlation of time since infection and PRNT₉₀ values against BA.1 (left) and antibody titers against BA.1 RBD (right) in post-vaccination BA.1 infection (n = 50) cohort. Each symbol represents an individual. Two-sided Pearson correlation analysis was performed (left (p = 0.91), right (p = 1.0)).

**Extended Data Fig. 4. Cross-reactive and BA.1-specific B_MEM do not consistently increase over time post-infection.**
a. Flow cytometry plot showing gating strategy for B_MEM from a post-vaccination BA.1 infection. b. Plot showing quantification of WuHu1 and BA.1 RBD-specific CD19+IgD-IgM-CD27+CD38- B_MEM in primary BA.1 infection (n = 4) and post-vaccination BA.1 infection (n = 15) cohorts over time. Cells that bind both WuHu1 Spike and BA.1 RBD are quantified as cross-reactive Spike+, whereas cells that bind only BA.1 RBD are quantified as BA.1 RBD+. B_MEM are quantified as a percentage of total PBMCs. Each symbol represents an individual. Lines connect timepoints from the same individual.

**Figure 1.. Type-specific antibody responses are generated following delta infection.**
a. WA.1 and delta virus neutralization assays showing PRNT₉₀ values for vaccinated only (n = 36), primary delta infection (n = 12) and post-vaccination delta infection (n = 37) samples. Each symbol represents an individual. Medians ± 95% confidence intervals (CI) are shown. Two-sided P values were calculated for pairwise differences using two-way ANOVA with post hoc Tukey’s multiple comparisons test. P values greater than 0.05 not depicted. b. ELISA area under the curve (AUC) values for antibody binding to WuHu1-RBD and delta-RBD and the WuHu1 RBD/delta-RBD ratios in vaccinated only (n = 65), primary delta infection (n = 12) and post-vaccination delta infection (n = 37) cohorts. Each symbol represents an individual. Medians ± 95% CI are shown. Two-sided P values were calculated for pairwise differences using one-way ANOVA with post hoc Tukey’s multiple comparisons test. P values greater than 0.05 not depicted. c. ELISA of serum antibodies for delta-RBD^L452 and delta-RBD^L452/delta-RBD titer ratio in vaccinated only (n = 65), primary delta infection (n = 12) and post-vaccination delta infection (n = 37) cohorts. Each symbol represents an individual. Medians ± 95% CI are shown. Two-sided P values were calculated for pairwise differences using one-way ANOVA with post hoc Tukey’s multiple comparisons test. P values greater than 0.05 not depicted. d. ELISA of antibodies for WuHu1-S1^delta-NTD and WuHu1-S1/WuHu1-S1^delta-NTD titer ratio in vaccinated only (n = 65), primary delta infection (n = 12) and post-vaccination delta infection (n = 37). Dotted line, WuHu1-S1/WuHu1-S1^delta-NTD antibody ratio of 1. Each symbol represents an individual. Medians ± 95% CI are shown. Two-sided P values were calculated for pairwise differences using one-way ANOVA with post hoc Tukey’s multiple comparisons test. P values greater than 0.05 not depicted. e. ELISA of antibodies against WuHu1-S1, delta-S1 and WuHu1-S1/delta S1 binding ratios in vaccinated only (n = 65), primary delta infection (n = 12) and post-vaccination delta infection (n = 37). Each symbol represents an individual. Medians ± 95% CI are shown. Two-sided P values were calculated for pairwise differences using one-way ANOVA with post hoc Tukey’s multiple comparisons test. P values greater than 0.05 not depicted.

**Figure 2.. Delta infection induces type-specific and cross-reactive B_MEM cells in primary and post-vaccination infections.**
a. Representative flow cytometry plots (top) and quantification (bottom) of WuHu1 and delta S1-specific CD19⁺IgD⁻IgM⁻CD27⁺CD38⁻ B_MEM cells in naïve (n= 13), primary delta infection (n = 12), vaccinated only^TATS (n = 62) and post-vaccination delta infection (n = 37) cohorts. Cells that bound both WuHu1 S1 and delta S1 were quantified as S1 cross-reactive B_MEM cells, whereas cells that bind only WuHu1 S1 or delta S1 are quantified as WuHu1 S1-specific or delta S1-specific B_MEM cells, respectively. B_MEM cells were quantified as percentage of total PBMCs. Each symbol represents an individual. Medians ± 95% CI are shown. Two-sided P values were calculated for pairwise differences using one-way ANOVA with post hoc Tukey’s multiple comparisons test. P values greater than 0.05 are not depicted. b. Correlation of S1 cross-reactive B_MEM cells as in a, plotted against the frequency of delta S1-specific B_MEM cells as in a, in vaccinated only^TATS (n = 62) (top) and post-vaccination delta infection (n = 37) (bottom) cohorts. Each symbol represents an individual. Medians ± 95% CI are shown. Two-sided Pearson correlation analysis was performed (Vaccinated only (p = 0.45) and post-vaccination delta infection (p = 0.0028).

**Figure 3.. Type-specific antibodies are minimally elicited by BA.1 infection.**
a. Virus neutralization assays performed with WA-1 and BA.1 isolates of SARS-CoV-2 showing PRNT₉₀ values in vaccinated only^TATS (n = 62), primary BA.1 infection (n = 56) and post-vaccination BA.1 infection (n = 50) cohorts. Each symbol represents an individual. Medians ± 95% CI are shown. Two-sided P values were calculated for pairwise differences using two-way ANOVA with post hoc Tukey’s multiple comparisons test. P values greater than 0.05 are not depicted. b. ELISA showing area under the curve (AUC) values for antibody binding to WuHu1 RBD and BA.1 RBD (left and middle) and the WuHu1/BA.1 antibody binding ratios calculated by dividing WuHu1 AUC by the BA.1 AUC titer (right) in vaccinated only^TATS (n = 62), primary BA.1 (n = 56), post-vaccination BA.1 (n = 62) cohorts. Each symbol represents an individual. Medians ± 95% CI are shown. Two-sided P values from t-test statistics were calculated for pairwise differences using one-way ANOVA with post hoc Tukey’s multiple comparisons test. P values greater than 0.05 are not depicted. c. ELISA showing endpoint titer for antibody binding to WuHu1 Spike (left) and BA.1 Spike (right) in WuHu1 Spike-depleted serum from primary WuHu1 infection^IASO (n = 15) and primary BA.1 infection^IASO (n = 10) cohorts. Each symbol represents an individual and the solid line connects a sample before and after depletion. Dotted lines indicate the lower limit of detection.

**Figure 4.. BA.1-specific RBD and Spike B_MEM cells are not detected above background levels in primary and post-vaccination infections.**
a. Representative flow cytometry plots (top) and quantification (bottom) of WuHu1 and BA.1 RBD-specific CD19⁺IgD⁻IgM⁻CD27⁺CD38⁻ B_MEM cells in naïve (n= 10), vaccinated only^TATS (n = 62), primary BA.1 infection (n = 56) and post-vaccination BA.1 infection (n = 50) cohorts. Cells that bound both WuHu1 RBD and BA.1 RBD were quantified as RBD-cross-reactive B_MEM cells, whereas cells that bound only WuHu1 RBD or BA.1 RBD were designated as WuHu1 RBD-specific B_MEM cells or BA.1 RBD-specific B_MEM cells, respectively. B_MEM cells were quantified as a percentage of total PBMCs. Each symbol represents an individual. Medians ± 95% CI are shown. Two-sided P values from t-test statistics were calculated for pairwise differences using one-way ANOVA. Post hoc Tukey’s multiple comparisons test was applied. P values greater than 0.05 are not depicted. b. Representative flow cytometry plots (top) and quantification (bottom) of WuHu1 and BA.1 Spike-specific CD19⁺IgD⁻IgM⁻CD27⁺CD38⁻ B_MEM cells in naïve (n= 10), vaccinated only (n = 62), primary BA.1 infection (n = 56) and post-vaccination BA.1 infection (n = 50) cohorts. Cells that bound both WuHu1 Spike and BA.1 Spike were quantified as Spike-cross-reactive B_MEM cells, whereas cells that bound only WuHu1 Spike or BA.1 Spike were quantified as WuHu1 Spike-specific B_MEM cells or BA.1 Spike-specific B_MEM cells, respectively. B_MEM cells were quantified as a percentage of total PBMCs. Each symbol represents an individual. Medians ± 95% CI are shown. Two-sided P values from t-test statistics were calculated for pairwise differences using one-way ANOVA. Post hoc Tukey’s multiple comparisons test was applied. P values greater than 0.05 are not depicted.

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Update of

Determinants of de novo B cell responses to drifted epitopes in post-vaccination SARS-CoV-2 infections.
Quirk GE, Schoenle MV, Peyton KL, Uhrlaub JL, Lau B, Burgess JL, Ellingson K, Beitel S, Romine J, Lutrick K, Fowlkes A, Britton A, Tyner HL, Caban-Martinez AJ, Naleway A, Gaglani M, Yoon S, Edwards L, Olsho L, Dake M, LaFleur BJ, Nikolich JŽ, Sprissler R, Worobey M, Bhattacharya D. Quirk GE, et al. medRxiv [Preprint]. 2023 Sep 14:2023.09.12.23295384. doi: 10.1101/2023.09.12.23295384. medRxiv. 2023. Update in: Nat Immunol. 2025 Jun;26(6):829-836. doi: 10.1038/s41590-025-02162-2. PMID: 37745498 Free PMC article. Updated. Preprint.

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Intrinsic immunogenicity is a major determinant of type-specific responses in SARS-CoV-2 infections

Affiliations

Intrinsic immunogenicity is a major determinant of type-specific responses in SARS-CoV-2 infections

Authors

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Abstract

Conflict of interest statement

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Update of

References

Methods-only references:

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