Anamnestic humoral correlates of immunity across SARS-CoV-2 variants of concern
ABSTRACT While immune correlates against SARS-CoV-2 are typically defined at peak immunogenicity following vaccination, immunologic responses that expand selectively during the anamnestic response following infection can provide mechanistic and detailed insights into the immune mechanisms of protect...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2023-08-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00902-23 |
| _version_ | 1797730241495433216 |
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| author | Ryan P. McNamara Jenny S. Maron Julie Boucau Vicky Roy Nicholas E. Webb Harry L. Bertera Amy K. Barczak The Positives Study Staff Nicholas Franko Jennifer K. Logue Megan Kemp Jonathan Z. Li Ling Zhou Ching-Lin Hsieh Jason S. McLellan Mark J. Siedner Michael S. Seaman Jacob E. Lemieux Helen Y. Chu Galit Alter |
| author_facet | Ryan P. McNamara Jenny S. Maron Julie Boucau Vicky Roy Nicholas E. Webb Harry L. Bertera Amy K. Barczak The Positives Study Staff Nicholas Franko Jennifer K. Logue Megan Kemp Jonathan Z. Li Ling Zhou Ching-Lin Hsieh Jason S. McLellan Mark J. Siedner Michael S. Seaman Jacob E. Lemieux Helen Y. Chu Galit Alter |
| author_sort | Ryan P. McNamara |
| collection | DOAJ |
| description | ABSTRACT While immune correlates against SARS-CoV-2 are typically defined at peak immunogenicity following vaccination, immunologic responses that expand selectively during the anamnestic response following infection can provide mechanistic and detailed insights into the immune mechanisms of protection. Moreover, whether anamnestic correlates are conserved across variants of concern (VOC), including the Delta and more distant Omicron VOC, remains unclear. To define the anamnestic correlates of immunity, across VOCs, we deeply profiled the humoral immune response in individuals infected with sequence-confirmed Delta or Omicron VOC after completing the vaccination series. While limited acute N-terminal domain and receptor-binding domain (RBD)-specific immune expansion was observed following breakthrough infection, a significant immunodominant expansion of opsonophagocytic Spike-specific antibody responses focused largely on the conserved S2-domain of SARS-CoV-2 was observed. This S2-specific functional humoral response continued to evolve over 2–3 weeks following Delta or Omicron breakthrough, targeting multiple VOCs and common coronaviruses. Strong responses were observed on the fusion peptide (FP) region and the heptad repeat 1 (HR1) region adjacent to the RBD. Notably, the FP is highly conserved across SARS-related coronaviruses and even non-SARS-related betacoronavirus. Taken together, our results point to a critical role of highly conserved, functional S2-specific responses in the anamnestic antibody response to SARS-CoV-2 infection across VOCs. These humoral responses linked to virus clearance can guide next-generation vaccine-boosting approaches to confer broad protection against future SARS-related coronaviruses. IMPORTANCE The Spike protein of SARS-CoV-2 is the primary target of antibody-based recognition. Selective pressures, be it the adaption to human-to-human transmission or evasion of previously acquired immunity, have spurred the emergence of variants of the virus such as the Delta and Omicron lineages. Therefore, understanding how antibody responses are expanded in breakthrough cases of previously vaccinated individuals can provide insights into key correlates of protection against current and future variants. Here, we show that vaccinated individuals who had documented COVID-19 breakthrough showed anamnestic antibody expansions targeting the conserved S2 subdomain of Spike, particularly within the fusion peptide region. These S2-directed antibodies were highly leveraged for non-neutralizing, phagocytic functions and were similarly expanded independent of the variant. We propose that through deep profiling of anamnestic antibody responses in breakthrough cases, we can identify antigen targets susceptible to novel monoclonal antibody therapy or vaccination-boosting strategies. |
| first_indexed | 2024-03-12T11:41:25Z |
| format | Article |
| id | doaj.art-3965379e79f746fcbfe4f35aa08c453f |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-03-12T11:41:25Z |
| publishDate | 2023-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-3965379e79f746fcbfe4f35aa08c453f2023-08-31T15:04:20ZengAmerican Society for MicrobiologymBio2150-75112023-08-0114410.1128/mbio.00902-23Anamnestic humoral correlates of immunity across SARS-CoV-2 variants of concernRyan P. McNamara0Jenny S. Maron1Julie Boucau2Vicky Roy3Nicholas E. Webb4Harry L. Bertera5Amy K. Barczak6The Positives Study Staff7Nicholas Franko8Jennifer K. Logue9Megan Kemp10Jonathan Z. Li11Ling Zhou12Ching-Lin Hsieh13Jason S. McLellan14Mark J. Siedner15Michael S. Seaman16Jacob E. Lemieux17Helen Y. Chu18Galit Alter19Ragon Institute of MGH, MIT, and Harvard , Cambridge, Massachusetts, USARagon Institute of MGH, MIT, and Harvard , Cambridge, Massachusetts, USARagon Institute of MGH, MIT, and Harvard , Cambridge, Massachusetts, USARagon Institute of MGH, MIT, and Harvard , Cambridge, Massachusetts, USARagon Institute of MGH, MIT, and Harvard , Cambridge, Massachusetts, USARagon Institute of MGH, MIT, and Harvard , Cambridge, Massachusetts, USARagon Institute of MGH, MIT, and Harvard , Cambridge, Massachusetts, USADepartment of Medicine, Massachusetts General Hospital , Boston, Massachusetts, USADivision of Allergy and Infectious Diseases, University of Washington , Seattle, Washington, USADivision of Allergy and Infectious Diseases, University of Washington , Seattle, Washington, USADivision of Allergy and Infectious Diseases, University of Washington , Seattle, Washington, USAHarvard Medical School , Boston, Massachusetts, USADepartment of Molecular Biosciences, University of Texas at Austin , Austin, Texas, USADepartment of Molecular Biosciences, University of Texas at Austin , Austin, Texas, USADepartment of Molecular Biosciences, University of Texas at Austin , Austin, Texas, USADepartment of Medicine, Massachusetts General Hospital , Boston, Massachusetts, USAHarvard Medical School , Boston, Massachusetts, USADepartment of Medicine, Massachusetts General Hospital , Boston, Massachusetts, USADivision of Allergy and Infectious Diseases, University of Washington , Seattle, Washington, USARagon Institute of MGH, MIT, and Harvard , Cambridge, Massachusetts, USAABSTRACT While immune correlates against SARS-CoV-2 are typically defined at peak immunogenicity following vaccination, immunologic responses that expand selectively during the anamnestic response following infection can provide mechanistic and detailed insights into the immune mechanisms of protection. Moreover, whether anamnestic correlates are conserved across variants of concern (VOC), including the Delta and more distant Omicron VOC, remains unclear. To define the anamnestic correlates of immunity, across VOCs, we deeply profiled the humoral immune response in individuals infected with sequence-confirmed Delta or Omicron VOC after completing the vaccination series. While limited acute N-terminal domain and receptor-binding domain (RBD)-specific immune expansion was observed following breakthrough infection, a significant immunodominant expansion of opsonophagocytic Spike-specific antibody responses focused largely on the conserved S2-domain of SARS-CoV-2 was observed. This S2-specific functional humoral response continued to evolve over 2–3 weeks following Delta or Omicron breakthrough, targeting multiple VOCs and common coronaviruses. Strong responses were observed on the fusion peptide (FP) region and the heptad repeat 1 (HR1) region adjacent to the RBD. Notably, the FP is highly conserved across SARS-related coronaviruses and even non-SARS-related betacoronavirus. Taken together, our results point to a critical role of highly conserved, functional S2-specific responses in the anamnestic antibody response to SARS-CoV-2 infection across VOCs. These humoral responses linked to virus clearance can guide next-generation vaccine-boosting approaches to confer broad protection against future SARS-related coronaviruses. IMPORTANCE The Spike protein of SARS-CoV-2 is the primary target of antibody-based recognition. Selective pressures, be it the adaption to human-to-human transmission or evasion of previously acquired immunity, have spurred the emergence of variants of the virus such as the Delta and Omicron lineages. Therefore, understanding how antibody responses are expanded in breakthrough cases of previously vaccinated individuals can provide insights into key correlates of protection against current and future variants. Here, we show that vaccinated individuals who had documented COVID-19 breakthrough showed anamnestic antibody expansions targeting the conserved S2 subdomain of Spike, particularly within the fusion peptide region. These S2-directed antibodies were highly leveraged for non-neutralizing, phagocytic functions and were similarly expanded independent of the variant. We propose that through deep profiling of anamnestic antibody responses in breakthrough cases, we can identify antigen targets susceptible to novel monoclonal antibody therapy or vaccination-boosting strategies.https://journals.asm.org/doi/10.1128/mbio.00902-23vaccinesCOVID-19breakthroughSARS-CoV-2omicrondelta |
| spellingShingle | Ryan P. McNamara Jenny S. Maron Julie Boucau Vicky Roy Nicholas E. Webb Harry L. Bertera Amy K. Barczak The Positives Study Staff Nicholas Franko Jennifer K. Logue Megan Kemp Jonathan Z. Li Ling Zhou Ching-Lin Hsieh Jason S. McLellan Mark J. Siedner Michael S. Seaman Jacob E. Lemieux Helen Y. Chu Galit Alter Anamnestic humoral correlates of immunity across SARS-CoV-2 variants of concern mBio vaccines COVID-19 breakthrough SARS-CoV-2 omicron delta |
| title | Anamnestic humoral correlates of immunity across SARS-CoV-2 variants of concern |
| title_full | Anamnestic humoral correlates of immunity across SARS-CoV-2 variants of concern |
| title_fullStr | Anamnestic humoral correlates of immunity across SARS-CoV-2 variants of concern |
| title_full_unstemmed | Anamnestic humoral correlates of immunity across SARS-CoV-2 variants of concern |
| title_short | Anamnestic humoral correlates of immunity across SARS-CoV-2 variants of concern |
| title_sort | anamnestic humoral correlates of immunity across sars cov 2 variants of concern |
| topic | vaccines COVID-19 breakthrough SARS-CoV-2 omicron delta |
| url | https://journals.asm.org/doi/10.1128/mbio.00902-23 |
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