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ACS Infect Dis
. 2024 Jan 28.
doi: 10.1021/acsinfecdis.3c00483. Online ahead of print. Heterologous Sarbecovirus Receptor Binding Domains as Scaffolds for SARS-CoV-2 Receptor Binding Motif Presentation
Blake M Hauser 1 , Maya Sangesland 1 , Evan C Lam 1 , Kerri J St Denis 1 , Maegan L Sheehan 1 , Mya L Vu 1 , Agnes H Cheng 1 , Sophia Sordilla 1 , Dana Thornlow Lamson 1 2 , Ahmad W Almawi 3 , Alejandro B Balazs 1 , Daniel Lingwood 1 , Aaron G Schmidt 1 2
Affiliations
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.
Keywords: SARS-CoV-2; coronavirus; immune imprinting.
. 2024 Jan 28.
doi: 10.1021/acsinfecdis.3c00483. Online ahead of print. Heterologous Sarbecovirus Receptor Binding Domains as Scaffolds for SARS-CoV-2 Receptor Binding Motif Presentation
Blake M Hauser 1 , Maya Sangesland 1 , Evan C Lam 1 , Kerri J St Denis 1 , Maegan L Sheehan 1 , Mya L Vu 1 , Agnes H Cheng 1 , Sophia Sordilla 1 , Dana Thornlow Lamson 1 2 , Ahmad W Almawi 3 , Alejandro B Balazs 1 , Daniel Lingwood 1 , Aaron G Schmidt 1 2
Affiliations
- PMID: 38281136
- DOI: 10.1021/acsinfecdis.3c00483
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.
Keywords: SARS-CoV-2; coronavirus; immune imprinting.