Single-dose replicating poxvirus vector-based RBD vaccine drives robust humoral and T cell immune response against SARS-CoV-2 infection

Abstract

The coronavirus disease 2019 (COVID-19) pandemic requires the continued development of safe, long-lasting, and efficacious vaccines for preventive responses to major outbreaks around the world, and especially in isolated and developing countries. To combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we characterize a temperature-stable vaccine candidate (TOH-Vac1) that uses a replication-competent, attenuated vaccinia virus as a vector to express a membrane-tethered spike receptor binding domain (RBD) antigen. We evaluate the effects of dose escalation and administration routes on vaccine safety, efficacy, and immunogenicity in animal models. Our vaccine induces high levels of SARS-CoV-2 neutralizing antibodies and favorable T cell responses, while maintaining an optimal safety profile in mice and cynomolgus macaques. We demonstrate robust immune responses and protective immunity against SARS-CoV-2 variants after only a single dose. Together, these findings support further development of our novel and versatile vaccine platform as an alternative or complementary approach to current vaccines.

Oncolytic virus driven T-cell-based combination immunotherapy platform for colorectal cancer

“…[A] replication within the TME -using mouse models and patient-derived tumour explants, we have shown that VV has an inherent ability to attack aspects of the TME including the tumour neo-vasculature (34) and certain CAF populations (35); [B] the capacity to encode large and multiple therapeutic transgenes (5); [C] extensive clinical knowledge of the viral vector safety due to its use as a vaccine to eradicate smallpox (5) and treat other diseases (36,37), and [D] oncolytic VV can be selectively delivered to CRC tumours by IV administration (38) and clinical trials have demonstrated safety in CRC patients (38,39). Systemic delivery of therapeutics is of particularly importance for CRC treatment as many patients present with locally advanced or metastatic disease.…”

“…We selected a modified oncolytic Copenhagen strain of vaccinia virus (VV; ClinicalTrials.gov: NCT04301011 and patent publication 20220056480) as a therapeutic vector based on its ability to infect and kill human and murine CRC cell lines as spheroid models more efficiently than other oncolytic viruses. VV also has many desirable features which include, but are not limited to: [A] replication within the TME - using mouse models and patient-derived tumour explants, we have shown that VV has an inherent ability to attack aspects of the TME including the tumour neo-vasculature ( 34 ) and certain CAF populations ( 35 ); [B] the capacity to encode large and multiple therapeutic transgenes ( 5 ); [C] extensive clinical knowledge of the viral vector safety due to its use as a vaccine to eradicate smallpox ( 5 ) and treat other diseases ( 36 , 37 ), and [D] oncolytic VV can be selectively delivered to CRC tumours by IV administration ( 38 ) and clinical trials have demonstrated safety in CRC patients ( 38 , 39 ). Systemic delivery of therapeutics is of particularly importance for CRC treatment as many patients present with locally advanced or metastatic disease.…”

Single Immunization with Recombinant ACAM2000 Vaccinia Viruses Expressing the Spike and the Nucleocapsid Proteins Protects Hamsters against SARS-CoV-2-Caused Clinical Disease

“…Thus, there is a need to develop alternative VACV vectors to improve their immunogenicity. Two replication-competent recombinant VACV-based COVID-19 vaccine candidates have been reported to protect hamsters against SARS-CoV-2 challenge after single-dose immunization ( 15 , 46 ). One of the replication-competent VACV/COVID-19 vaccine candidates was based on the VACV NYCBH strain (the parental strain of ACAM2000 used in this study), in which the SARS-CoV-2 spike gene was inserted into the TK gene locus ( 15 ).…”

“…One of the replication-competent VACV/COVID-19 vaccine candidates was based on the VACV NYCBH strain (the parental strain of ACAM2000 used in this study), in which the SARS-CoV-2 spike gene was inserted into the TK gene locus ( 15 ). Another one was based on the VACV TianTan (TT) strain, in which the RBD of the spike protein was expressed from the B14 locus ( 46 ). The latter study also demonstrated that the replication-competent VACV TT-based vaccine candidate was significantly more immunogenic than the MVA-based counterpart in inducing both antibody and T-cell responses ( 46 ).…”

“…Another one was based on the VACV TianTan (TT) strain, in which the RBD of the spike protein was expressed from the B14 locus ( 46 ). The latter study also demonstrated that the replication-competent VACV TT-based vaccine candidate was significantly more immunogenic than the MVA-based counterpart in inducing both antibody and T-cell responses ( 46 ).…”