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The recent SARS-CoV-2 (COVID-19) pandemic exemplifies how newly emerging and reemerging viruses can quickly overwhelm and cripple global infrastructures. Coupled with synergistic factors such as increasing population densities, the constant and massive mobility of people across geographical areas and substantial changes to ecosystems worldwide, these pathogens pose serious health concerns on a global scale. Vaccines form an indispensable defense, serving to control and mitigate the impact of devastating outbreaks and pandemics. Towards these efforts, we developed a tunable vaccine platform that can be engineered to simultaneously display multiple viral antigens. Here, we describe a second-generation version wherein chimeric proteins derived from SARS-CoV-2 and bacteriophage lambda are engineered and used to decorate phage-like particles with defined surface densities and retention of antigenicity. This streamlines the engineering of particle decoration, thus improving the overall manufacturing potential of the system. In a prime-boost regimen, mice immunized with particles containing as little as 42 copies of the chimeric protein on their surface develop potent neutralizing antibody responses, and immunization protects mice against virulent SARS-CoV-2 challenge. The platform is highly versatile, making it a promising strategy to rapidly develop vaccines against a potentially broad range of infectious diseases. 

Abstract The response by vaccine developers to the COVID-19 pandemic has been extraordinary with effective vaccines authorized for emergency use in the United States within 1 year of the appearance of the first COVID-19 cases. However, the emergence of SARS-CoV-2 variants and obstacles with the global rollout of new vaccines highlight the need for platforms that are amenable to rapid tuning and stable formulation to facilitate the logistics of vaccine delivery worldwide. We developed a “designer nanoparticle” platform using phage-like particles (PLPs) derived from bacteriophage lambda for a multivalent display of antigens in rigorously defined ratios. Here, we engineered PLPs that display the receptor-binding domain (RBD) protein from SARS-CoV-2 and MERS-CoV, alone (RBD_SARS-PLPs and RBD_MERS-PLPs) and in combination (hCoV-RBD PLPs). Functionalized particles possess physiochemical properties compatible with pharmaceutical standards and retain antigenicity. Following primary immunization, BALB/c mice immunized with RBD_SARS- or RBD_MERS-PLPs display serum RBD-specific IgG endpoint and live virus neutralization titers that, in the case of SARS-CoV-2, were comparable to those detected in convalescent plasma from infected patients. Further, these antibody levels remain elevated up to 6 months post-prime. In dose-response studies, immunization with as little as one microgram of RBD_SARS-PLPs elicited robust neutralizing antibody responses. Finally, animals immunized with RBD_SARS-PLPs, RBD_MERS-PLPs, and hCoV-RBD PLPs were protected against SARS-CoV-2 and/or MERS-CoV lung infection and disease. Collectively, these data suggest that the designer PLP system provides a platform for facile and rapid generation of single and multi-target vaccines. 

The response by vaccine developers to the COVID-19 pandemic has been extraordinary with effective vaccines authorized for emergency use in the United States within 1 year of the appearance of the first COVID-19 cases. However, the emergence of SARS-CoV-2 variants and obstacles with the global rollout of new vaccines highlight the need for platforms that are amenable to rapid tuning and stable formulation to facilitate the logistics of vaccine delivery worldwide. We developed a “designer nanoparticle” platform using phage-like particles (PLPs) derived from bacteriophage lambda for a multivalent display of antigens in rigorously defined ratios. Here, we engineered PLPs that display the receptor-binding domain (RBD) protein from SARS-CoV-2 and MERS-CoV, alone (RBDSARS-PLPs and RBDMERS-PLPs) and in combination (hCoV-RBD PLPs). Functionalized particles possess physiochemical properties compatible with pharmaceutical standards and retain antigenicity. Following primary immunization, BALB/c mice immunized with RBDSARS- or RBDMERS-PLPs display serum RBD-specific IgG endpoint and live virus neutralization titers that, in the case of SARS-CoV-2, were comparable to those detected in convalescent plasma from infected patients. Further, these antibody levels remain elevated up to 6 months post-prime. In dose-response studies, immunization with as little as one microgram of RBDSARS-PLPs elicited robust neutralizing antibody responses. Finally, animals immunized with RBDSARS-PLPs, RBDMERS-PLPs, and hCoV-RBD PLPs were protected against SARS-CoV-2 and/or MERS-CoV lung infection and disease. Collectively, these data suggest that the designer PLP system provides a platform for facile and rapid generation of single and multi-target vaccines. 

ABSTRACT The response by vaccine developers to the COVID-19 pandemic has been extraordinary with effective vaccines authorized for emergency use in the U.S. within one year of the appearance of the first COVID-19 cases. However, the emergence of SARS-CoV-2 variants and obstacles with the global rollout of new vaccines highlight the need for platforms that are amenable to rapid tuning and stable formulation to facilitate the logistics of vaccine delivery worldwide. We developed a “designer nanoparticle” platform using phage-like particles (PLPs) derived from bacteriophage lambda for multivalent display of antigens in rigorously defined ratios. Here, we engineered PLPs that display the receptor binding domain (RBD) protein from SARS-CoV-2 and MERS-CoV, alone (RBD_SARS-PLPs, RBD_MERS-PLPs) and in combination (hCoV-RBD PLPs). Functionalized particles possess physiochemical properties compatible with pharmaceutical standards and retain antigenicity. Following primary immunization, BALB/c mice immunized with RBD_SARS- or RBD_MERS-PLPs display serum RBD-specific IgG endpoint and live virus neutralization titers that, in the case of SARS-CoV-2, were comparable to those detected in convalescent plasma from infected patients. Further, these antibody levels remain elevated up to 6 months post-prime. In dose response studies, immunization with as little as one microgram of RBD_SARS-PLPs elicited robust neutralizing antibody responses. Finally, animals immunized with RBD_SARS-PLPs, RBD_MERS-PLPs, and hCoV-RBD PLPs were protected against SARS-CoV-2 and/or MERS-CoV lung infection and disease. Collectively, these data suggest that the designer PLP system provides a platform for facile and rapid generation of single and multi-target vaccines.