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Article ; Online: Heterologous Sarbecovirus Receptor Binding Domains as Scaffolds for SARS-CoV-2 Receptor Binding Motif Presentation.

Hauser, Blake M / Sangesland, Maya / Lam, Evan C / St Denis, Kerri J / Sheehan, Maegan L / Vu, Mya L / Cheng, Agnes H / Sordilla, Sophia / Lamson, Dana Thornlow / Almawi, Ahmad W / Balazs, Alejandro B / Lingwood, Daniel / Schmidt, Aaron G

ACS infectious diseases

2024 Volume 10, Issue 2, Page(s) 553–561

Abstract: Structure-guided rational immunogen design can generate optimized immunogens that elicit a desired humoral response. Design strategies often center on targeting conserved sites on viral glycoproteins that will ultimately confer potent neutralization. For ...

Abstract	Structure-guided rational immunogen design can generate optimized immunogens that elicit a desired humoral response. Design strategies often center on targeting conserved sites on viral glycoproteins that will ultimately confer potent neutralization. For SARS-CoV-2 (SARS-2), the surface-exposed spike glycoprotein includes a broadly conserved portion, the receptor binding motif (RBM), that is required to engage the host cellular receptor, ACE2. Expanding humoral responses to this site may result in a more potent neutralizing antibody response against diverse sarbecoviruses. Here, we used a "resurfacing" approach and iterative design cycles to graft the SARS-2 RBM onto heterologous sarbecovirus scaffolds. The scaffolds were selected to vary the antigenic distance relative to SARS-2 to potentially focus responses to RBM. Multimerized versions of these immunogens elicited broad neutralization against sarbecoviruses in the context of preexisting SARS-2 immunity. These validated engineering approaches can help inform future immunogen design efforts for sarbecoviruses and are generally applicable to other viruses.
MeSH term(s)	Humans ; SARS-CoV-2 ; Severe acute respiratory syndrome-related coronavirus ; COVID-19 ; Antibodies, Neutralizing
Chemical Substances	Antibodies, Neutralizing
Language	English
Publishing date	2024-01-28
Publishing country	United States
Document type	Journal Article
ISSN	2373-8227
ISSN (online)	2373-8227
DOI	10.1021/acsinfecdis.3c00483
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Humoral responses to the SARS-CoV-2 spike and receptor binding domain in context of pre-existing immunity confer broad sarbecovirus neutralization.

Hauser, Blake M / Sangesland, Maya / Lam, Evan C / Feldman, Jared / Balazs, Alejandro B / Lingwood, Daniel / Schmidt, Aaron G

Frontiers in immunology

2022 Volume 13, Page(s) 902260

Abstract: Since the emergence of SARS-CoV-2 (SARS-2), multiple vaccine candidates were developed and studied both preclinically and clinically. Nearly all are based on the SARS-2 spike glycoprotein or its receptor binding domain (RBD). Studies of these vaccine ... ...

Abstract	Since the emergence of SARS-CoV-2 (SARS-2), multiple vaccine candidates were developed and studied both preclinically and clinically. Nearly all are based on the SARS-2 spike glycoprotein or its receptor binding domain (RBD). Studies of these vaccine candidates have largely been in a SARS-2 naïve context. However, pre-existing immunity to SARS-2 acquired through infection or vaccination continues to increase. Evaluating future vaccine candidates in context of this pre-existing immunity is necessary to understand how immune responses are subsequently influenced. Here, we evaluated the serum and IgG
MeSH term(s)	Antibodies, Viral ; COVID-19/prevention & control ; Epitopes ; Humans ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus
Chemical Substances	Antibodies, Viral ; Epitopes ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-08-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.902260
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Article: Ongoing evolution of SARS-CoV-2 drives escape from mRNA vaccine-induced humoral immunity.

Roederer, Alex L / Cao, Yi / Denis, Kerri St / Sheehan, Maegan L / Li, Chia Jung / Lam, Evan C / Gregory, David J / Poznansky, Mark C / Iafrate, A John / Canaday, David H / Gravenstein, Stefan / Garcia-Beltran, Wilfredo F / Balazs, Alejandro B

medRxiv : the preprint server for health sciences

2024

Abstract: Since the COVID-19 pandemic began in 2020, viral sequencing has documented 131 individual mutations in the viral spike protein across 48 named variants. To determine the ability of vaccine-mediated humoral immunity to keep pace with continued SARS-CoV-2 ... ...

Abstract	Since the COVID-19 pandemic began in 2020, viral sequencing has documented 131 individual mutations in the viral spike protein across 48 named variants. To determine the ability of vaccine-mediated humoral immunity to keep pace with continued SARS-CoV-2 evolution, we assessed the neutralization potency of sera from 76 vaccine recipients collected after 2 to 6 immunizations against a comprehensive panel of mutations observed during the pandemic. Remarkably, while many individual mutations that emerged between 2020 and 2022 exhibit escape from sera following primary vaccination, few escape boosted sera. However, progressive loss of neutralization was observed across newer variants, irrespective of vaccine doses. Importantly, an updated XBB.1.5 booster significantly increased titers against newer variants but not JN.1. These findings demonstrate that seasonal boosters improve titers against contemporaneous strains, but novel variants continue to evade updated mRNA vaccines, demonstrating the need for novel approaches to adequately control SARS-CoV-2 transmission.
Language	English
Publishing date	2024-03-07
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.05.24303815
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Enhancing antibody responses by multivalent antigen display on thymus-independent DNA origami scaffolds.

Wamhoff, Eike-Christian / Ronsard, Larance / Feldman, Jared / Knappe, Grant A / Hauser, Blake M / Romanov, Anna / Case, James Brett / Sanapala, Shilpa / Lam, Evan C / Denis, Kerri J St / Boucau, Julie / Barczak, Amy K / Balazs, Alejandro B / Diamond, Michael S / Schmidt, Aaron G / Lingwood, Daniel / Bathe, Mark

Nature communications

2024 Volume 15, Issue 1, Page(s) 795

Abstract: Protein-based virus-like particles (P-VLPs) are commonly used to spatially organize antigens and enhance humoral immunity through multivalent antigen display. However, P-VLPs are thymus-dependent antigens that are themselves immunogenic and can induce B ... ...

Abstract	Protein-based virus-like particles (P-VLPs) are commonly used to spatially organize antigens and enhance humoral immunity through multivalent antigen display. However, P-VLPs are thymus-dependent antigens that are themselves immunogenic and can induce B cell responses that may neutralize the platform. Here, we investigate thymus-independent DNA origami as an alternative material for multivalent antigen display using the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, the primary target of neutralizing antibody responses. Sequential immunization of mice with DNA-based VLPs (DNA-VLPs) elicits protective neutralizing antibodies to SARS-CoV-2 in a manner that depends on the valency of the antigen displayed and on T cell help. Importantly, the immune sera do not contain boosted, class-switched antibodies against the DNA scaffold, in contrast to P-VLPs that elicit strong B cell memory against both the target antigen and the scaffold. Thus, DNA-VLPs enhance target antigen immunogenicity without generating scaffold-directed immunity and thereby offer an important alternative material for particulate vaccine design.
MeSH term(s)	Humans ; Animals ; Mice ; Antibody Formation ; Antibodies, Blocking ; Vaccines, Virus-Like Particle/genetics ; Antibodies, Neutralizing ; DNA ; Antibodies, Viral ; Spike Glycoprotein, Coronavirus
Chemical Substances	spike protein, SARS-CoV-2 ; Antibodies, Blocking ; Vaccines, Virus-Like Particle ; Antibodies, Neutralizing ; DNA (9007-49-2) ; Antibodies, Viral ; Spike Glycoprotein, Coronavirus
Language	English
Publishing date	2024-01-30
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-44869-0
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Article: Enhancing antibody responses by multivalent antigen display on thymus-independent DNA origami scaffolds.

Wamhoff, Eike-Christian / Ronsard, Larance / Feldman, Jared / Knappe, Grant A / Hauser, Blake M / Romanov, Anna / Lam, Evan / Denis, Kerri St / Boucau, Julie / Barczak, Amy K / Balazs, Alejandro B / Schmidt, Aaron / Lingwood, Daniel / Bathe, Mark

bioRxiv : the preprint server for biology

2023

Abstract: Multivalent antigen display is a well-established principle to enhance humoral immunity. Protein-based virus-like particles (VLPs) are commonly used to spatially organize antigens. However, protein-based VLPs are limited in their ability to control ... ...

Abstract	Multivalent antigen display is a well-established principle to enhance humoral immunity. Protein-based virus-like particles (VLPs) are commonly used to spatially organize antigens. However, protein-based VLPs are limited in their ability to control valency on fixed scaffold geometries and are thymus-dependent antigens that elicit neutralizing B cell memory themselves, which can distract immune responses. Here, we investigated DNA origami as an alternative material for multivalent antigen display in vivo, applied to the receptor binding domain (RBD) of SARS-CoV2 that is the primary antigenic target of neutralizing antibody responses. Icosahedral DNA-VLPs elicited neutralizing antibodies to SARS-CoV-2 in a valency-dependent manner following sequential immunization in mice, quantified by pseudo- and live-virus neutralization assays. Further, induction of B cell memory against the RBD required T cell help, but the immune sera did not contain boosted, class-switched antibodies against the DNA scaffold. This contrasted with protein-based VLP display of the RBD that elicited B cell memory against both the target antigen and the scaffold. Thus, DNA-based VLPs enhance target antigen immunogenicity without generating off-target, scaffold-directed immune memory, thereby offering a potentially important alternative material for particulate vaccine design.
Language	English
Publishing date	2023-06-19
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.08.16.504128
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Heterologous sarbecovirus receptor binding domains as scaffolds for SARS-CoV-2 receptor binding motif presentation.

Hauser, Blake M / Sangesland, Maya / Lam, Evan C / Denis, Kerri J St / Sheehan, Maegan L / Vu, Mya L / Cheng, Agnes H / Balazs, Alejandro B / Lingwood, Daniel / Schmidt, Aaron G

bioRxiv : the preprint server for biology

2023

Abstract: Structure-guided rational immunogen design can generate optimized immunogens that elicit a desired humoral response. Design strategies often center upon targeting conserved sites on viral glycoproteins that will ultimately confer potent neutralization. ... ...

Abstract	Structure-guided rational immunogen design can generate optimized immunogens that elicit a desired humoral response. Design strategies often center upon targeting conserved sites on viral glycoproteins that will ultimately confer potent neutralization. For SARS-CoV-2 (SARS-2), the surface-exposed spike glycoprotein includes a broadly conserved portion, the receptor binding motif (RBM), that is required to engage the host cellular receptor, ACE2. Expanding humoral responses to this site may result in a more potently neutralizing antibody response against diverse sarbecoviruses. Here, we used a "resurfacing" approach and iterative design cycles to graft the SARS-2 RBM onto heterologous sarbecovirus scaffolds. The scaffolds were selected to vary the antigenic distance relative to SARS-2 to potentially focus responses to RBM. Multimerized versions of these immunogens elicited broad neutralization against sarbecoviruses in the context of preexisting SARS-2 immunity. These validated engineering approaches can help inform future immunogen design efforts for sarbecoviruses and are generally applicable to other viruses.
Language	English
Publishing date	2023-08-22
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.21.554179
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Article ; Online: Ongoing evolution of SARS-CoV-2 drives escape from mRNA vaccine-induced humoral immunity

Roederer, Alex L. / Cao, Yi / St. Denis, Kerri / Sheehan, Maegan L. / Li, Chia Jung / Lam, Evan C. / Gregory, David J. / Poznansky, Mark C. / Iafrate, A. John / Canaday, David H. / Gravenstein, Stefan / Garcia-Beltran, Wilfredo F. / Balazs, Alejandro B.

medRxiv

Abstract	Since the COVID-19 pandemic began in 2020, viral sequencing has documented 131 individual mutations in the viral spike protein across 48 named variants. To determine the ability of vaccine-mediated humoral immunity to keep pace with continued SARS-CoV-2 evolution, we assessed the neutralization potency of sera from 76 vaccine recipients collected after 2 to 6 immunizations against a comprehensive panel of mutations observed during the pandemic. Remarkably, while many individual mutations that emerged between 2020 and 2022 exhibit escape from sera following primary vaccination, few escape boosted sera. However, progressive loss of neutralization was observed across newer variants, irrespective of vaccine doses. Importantly, an updated XBB.1.5 booster significantly increased titers against newer variants but not JN.1. These findings demonstrate that seasonal boosters improve titers against contemporaneous strains, but novel variants continue to evade updated mRNA vaccines, demonstrating the need for novel approaches to adequately control SARS-CoV-2 transmission.
Keywords	covid19
Language	English
Publishing date	2024-03-07
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2024.03.05.24303815
Database	COVID19

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Article ; Online: Rationally designed immunogens enable immune focusing following SARS-CoV-2 spike imprinting.

Hauser, Blake M / Sangesland, Maya / St Denis, Kerri J / Lam, Evan C / Case, James Brett / Windsor, Ian W / Feldman, Jared / Caradonna, Timothy M / Kannegieter, Ty / Diamond, Michael S / Balazs, Alejandro B / Lingwood, Daniel / Schmidt, Aaron G

Cell reports

2022 Volume 38, Issue 12, Page(s) 110561

Abstract: Eliciting antibodies to surface-exposed viral glycoproteins can generate protective responses that control and prevent future infections. Targeting conserved sites may reduce the likelihood of viral escape and limit the spread of related viruses with ... ...

Abstract	Eliciting antibodies to surface-exposed viral glycoproteins can generate protective responses that control and prevent future infections. Targeting conserved sites may reduce the likelihood of viral escape and limit the spread of related viruses with pandemic potential. Here we leverage rational immunogen design to focus humoral responses on conserved epitopes. Using glycan engineering and epitope scaffolding in boosting immunogens, we focus murine serum antibody responses to conserved receptor binding motif (RBM) and receptor binding domain (RBD) epitopes following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike imprinting. Although all engineered immunogens elicit a robust SARS-CoV-2-neutralizing serum response, RBM-focusing immunogens exhibit increased potency against related sarbecoviruses, SARS-CoV, WIV1-CoV, RaTG13-CoV, and SHC014-CoV; structural characterization of representative antibodies defines a conserved epitope. RBM-focused sera confer protection against SARS-CoV-2 challenge. Thus, RBM focusing is a promising strategy to elicit breadth across emerging sarbecoviruses without compromising SARS-CoV-2 protection. These engineering strategies are adaptable to other viral glycoproteins for targeting conserved epitopes.
MeSH term(s)	Animals ; COVID-19 ; Mice ; Mice, Inbred BALB C ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; Viral Envelope Proteins
Chemical Substances	Spike Glycoprotein, Coronavirus ; Viral Envelope Proteins ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-03-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.110561
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Article ; Online: Neutralization breadth of SARS-CoV-2 viral variants following primary series and booster SARS-CoV-2 vaccines in patients with cancer.

Naranbhai, Vivek / St Denis, Kerri J / Lam, Evan C / Ofoman, Onosereme / Garcia-Beltran, Wilfredo F / Mairena, Cristhian B / Bhan, Atul K / Gainor, Justin F / Balazs, Alejandro B / Iafrate, A John

Cancer cell

2022 Volume 40, Issue 1, Page(s) 103–108.e2

Abstract: Patients with cancer are more likely to have impaired immune responses to SARS-CoV-2 vaccines. We study the breadth of responses against SARS-CoV-2 variants after primary vaccination in 178 patients with a variety of tumor types and after booster doses ... ...

Abstract	Patients with cancer are more likely to have impaired immune responses to SARS-CoV-2 vaccines. We study the breadth of responses against SARS-CoV-2 variants after primary vaccination in 178 patients with a variety of tumor types and after booster doses in a subset. Neutralization of alpha, beta, gamma, and delta SARS-CoV-2 variants is impaired relative to wildtype, regardless of vaccine type. Regardless of viral variant, mRNA1273 is the most immunogenic, followed by BNT162b2, and then Ad26.COV2.S. Neutralization of more variants (breadth) is associated with a greater magnitude of wildtype neutralization, and increases with time since vaccination; advancing age associates with a lower breadth. The concentrations of anti-spike protein antibody are a good surrogate for breadth (positive predictive value of =90% at >1,000 U/mL). Booster SARS-CoV-2 vaccines confer enhanced breadth. These data suggest that achieving a high antibody titer is desirable to achieve broad neutralization; a single booster dose with the current vaccines increases the breadth of responses against variants.
MeSH term(s)	Aged ; Aging/immunology ; Antibodies, Neutralizing/biosynthesis ; Antibodies, Viral/biosynthesis ; Antigens, Viral/immunology ; COVID-19/prevention & control ; COVID-19 Vaccines/immunology ; Female ; Humans ; Immunization, Secondary ; Immunocompromised Host ; Immunogenicity, Vaccine ; In Vitro Techniques ; Male ; Middle Aged ; Neoplasms/immunology ; Neoplasms/therapy ; SARS-CoV-2/immunology ; Spike Glycoprotein, Coronavirus/immunology ; Viral Load
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Antigens, Viral ; COVID-19 Vaccines ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-01-05
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2021.12.002
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Article: Rationally designed immunogens enable immune focusing to the SARS-CoV-2 receptor binding motif.

Hauser, Blake M / Sangesland, Maya / Denis, Kerri J St / Windsor, Ian W / Feldman, Jared / Lam, Evan C / Kannegieter, Ty / Balazs, Alejandro B / Lingwood, Daniel / Schmidt, Aaron G

bioRxiv : the preprint server for biology

2021

Abstract: Eliciting antibodies to surface-exposed viral glycoproteins can lead to protective responses that ultimately control and prevent future infections. Targeting functionally conserved epitopes may help reduce the likelihood of viral escape and aid in ... ...

Abstract	Eliciting antibodies to surface-exposed viral glycoproteins can lead to protective responses that ultimately control and prevent future infections. Targeting functionally conserved epitopes may help reduce the likelihood of viral escape and aid in preventing the spread of related viruses with pandemic potential. One such functionally conserved viral epitope is the site to which a receptor must bind to facilitate viral entry. Here, we leveraged rational immunogen design strategies to focus humoral responses to the receptor binding motif (RBM) on the SARS-CoV-2 spike. Using glycan engineering and epitope scaffolding, we find an improved targeting of the serum response to the RBM in context of SARS-CoV-2 spike imprinting. Furthermore, we observed a robust SARS-CoV-2-neutralizing serum response with increased potency against related sarbecoviruses, SARS-CoV, WIV1-CoV, RaTG13-CoV, and SHC014-CoV. Thus, RBM focusing is a promising strategy to elicit breadth across emerging sarbecoviruses and represents an adaptable design approach for targeting conserved epitopes on other viral glycoproteins. One sentence summary: SARS-CoV-2 immune focusing with engineered immunogens.
Language	English
Publishing date	2021-07-09
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.03.15.435440
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