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Front Immunol ; 12: 710263, 2021.
Article in English | MEDLINE | ID: covidwho-1315952


The unprecedented global demand for SARS-CoV-2 vaccines has demonstrated the need for highly effective vaccine candidates that are thermostable and amenable to large-scale manufacturing. Nanoparticle immunogens presenting the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein (S) in repetitive arrays are being advanced as second-generation vaccine candidates, as they feature robust manufacturing characteristics and have shown promising immunogenicity in preclinical models. Here, we used previously reported deep mutational scanning (DMS) data to guide the design of stabilized variants of the RBD. The selected mutations fill a cavity in the RBD that has been identified as a linoleic acid binding pocket. Screening of several designs led to the selection of two lead candidates that expressed at higher yields than the wild-type RBD. These stabilized RBDs possess enhanced thermal stability and resistance to aggregation, particularly when incorporated into an icosahedral nanoparticle immunogen that maintained its integrity and antigenicity for 28 days at 35-40°C, while corresponding immunogens displaying the wild-type RBD experienced aggregation and loss of antigenicity. The stabilized immunogens preserved the potent immunogenicity of the original nanoparticle immunogen, which is currently being evaluated in a Phase I/II clinical trial. Our findings may improve the scalability and stability of RBD-based coronavirus vaccines in any format and more generally highlight the utility of comprehensive DMS data in guiding vaccine design.

COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Immunization Schedule , Immunogenicity, Vaccine , Mutation , Protein Domains/genetics , Protein Domains/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/blood , COVID-19/virology , COVID-19 Vaccines/immunology , Chlorocebus aethiops , Female , HEK293 Cells , Humans , Linoleic Acids , Mice , Mice, Inbred BALB C , Nanoparticles/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Treatment Outcome , Vero Cells
NPJ Vaccines ; 6(1): 80, 2021 Jun 02.
Article in English | MEDLINE | ID: covidwho-1251648


Mucosal tissues act as a barrier throughout the oral, nasopharyngeal, lung, and intestinal systems, offering first-line protection against potential pathogens. Conventionally, vaccines are applied parenterally to induce serotype-dependent humoral response but fail to drive adequate mucosal immune protection for viral infections such as influenza, HIV, and coronaviruses. Oral mucosa, however, provides a vast immune repertoire against specific microbial pathogens and yet is shaped by an ever-present microbiome community that has co-evolved with the host over thousands of years. Adjuvants targeting mucosal T-cells abundant in oral tissues can promote soluble-IgA (sIgA)-specific protection to confer increased vaccine efficacy. Th17 cells, for example, are at the center of cell-mediated immunity and evidence demonstrates that protection against heterologous pathogen serotypes is achieved with components from the oral microbiome. At the point of entry where pathogens are first encountered, typically the oral or nasal cavity, the mucosal surfaces are layered with bacterial cohabitants that continually shape the host immune profile. Constituents of the oral microbiome including their lipids, outer membrane vesicles, and specific proteins, have been found to modulate the Th17 response in the oral mucosa, playing important roles in vaccine and adjuvant designs. Currently, there are no approved adjuvants for the induction of Th17 protection, and it is critical that this research is included in the preparedness for the current and future pandemics. Here, we discuss the potential of oral commensals, and molecules derived thereof, to induce Th17 activity and provide safer and more predictable options in adjuvant engineering to prevent emerging infectious diseases.