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  1. 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Engineered receptor binding domain immunogens elicit pan-sarbecovirus neutralizing antibodies outside the receptor binding motif.

    Hauser, Blake M / Sangesland, Maya / Lam, Evan C / Denis, Kerri J St / Feldman, Jared / Yousif, Ashraf S / Caradonna, Timothy M / Kannegieter, Ty / Balazs, Alejandro B / Lingwood, Daniel / Schmidt, Aaron G

    bioRxiv : the preprint server for biology

    2021  

    Abstract: Effective countermeasures are needed against emerging coronaviruses of pandemic potential, similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Designing immunogens that elicit broadly neutralizing antibodies to conserved viral ... ...

    Abstract Effective countermeasures are needed against emerging coronaviruses of pandemic potential, similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Designing immunogens that elicit broadly neutralizing antibodies to conserved viral epitopes on the major surface glycoprotein, spike, such as the receptor binding domain (RBD) is one potential approach. Here, we report the generation of homotrimeric RBD immunogens from different sarbecoviruses using a stabilized, immune-silent trimerization tag. In mice, we find that a cocktail of these homotrimeric sarbecovirus RBDs elicits antibodies to conserved viral epitopes outside of the ACE2 receptor binding motif (RBM). Importantly, these responses neutralize all sarbecovirus components even in context of prior SARS-CoV-2 imprinting. We further show that a substantial fraction of the neutralizing antibodies elicited after vaccination in humans also engages non-RBM epitopes on the RBD. Collectively, our results suggest a strategy for eliciting broadly neutralizing responses leading to a pan-sarbecovirus vaccine.
    Author summary: Immunity to SARS-CoV-2 in the human population will be widespread due to natural infection and vaccination. However, another novel coronavirus will likely emerge in the future and may cause a subsequent pandemic. Humoral responses induced by SARS-CoV-2 infection and vaccination provide limited protection against even closely related coronaviruses. We show immunization with a cocktail of trimeric coronavirus receptor binding domains induces a neutralizing antibody response that is broadened to related coronaviruses with pandemic potential. Importantly, this broadening occurs in context of an initial imprinted SARS-CoV-2 spike immunization showing that preexisting immunity can be expanded to recognize other related coronaviruses. Our immunogens focused the serum antibody response to conserved epitopes on the receptor binding domain outside of the ACE2 receptor binding motif; this contrasts with current SARS-CoV-2 therapeutic antibodies, which predominantly target the receptor binding motif.
    Language English
    Publishing date 2021-06-29
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2020.12.07.415216
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: T cell reactivity to the SARS-CoV-2 Omicron variant is preserved in most but not all prior infected and vaccinated individuals.

    Naranbhai, Vivek / Nathan, Anusha / Kaseke, Clarety / Berrios, Cristhian / Khatri, Ashok / Choi, Shawn / Getz, Matthew A / Tano-Menka, Rhoda / Ofoman, Onosereme / Gayton, Alton / Senjobe, Fernando / Denis, Kerri J St / Lam, Evan C / Garcia-Beltran, Wilfredo F / Balazs, Alejandro B / Walker, Bruce D / Iafrate, A John / Gaiha, Gaurav D

    medRxiv : the preprint server for health sciences

    2022  

    Abstract: The SARS-CoV-2 Omicron variant (B.1.1.529) contains mutations that mediate escape from infection and vaccine-induced antibody responses, although the extent to which these substitutions in spike and non-spike proteins affect T cell recognition is unknown. ...

    Abstract The SARS-CoV-2 Omicron variant (B.1.1.529) contains mutations that mediate escape from infection and vaccine-induced antibody responses, although the extent to which these substitutions in spike and non-spike proteins affect T cell recognition is unknown. Here we show that T cell responses in individuals with prior infection, vaccination, both prior infection and vaccination, and boosted vaccination are largely preserved to Omicron spike and non-spike proteins. However, we also identify a subset of individuals (∼21%) with a >50% reduction in T cell reactivity to the Omicron spike. Evaluation of functional CD4
    Language English
    Publishing date 2022-01-05
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2022.01.04.21268586
    Database MEDical Literature Analysis and Retrieval System OnLINE

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