Combination of a Sindbis-SARS-CoV-2 spike vaccine and αOX40 antibody elicits protective immunity against SARS-CoV-2 induced disease and potentiates long-term SARS-CoV-2-specific humoral and T-cell immunity

Abstract

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 is a major global public threat. Currently, a worldwide effort has been mounted to generate billions of effective SARS-CoV-2 vaccine doses to immunize the world population at record speeds. However, there is still demand for alternative effective vaccines that rapidly confer long-term protection and rely upon cost-effective, easily scaled-up manufacturing. Here, we present a Sindbis alphavirus vector (SV), transiently expressing the SARS-CoV-2 spike protein (SV.Spike), combined with the OX40 immunostimulatory antibody (OX40) as a novel, highly effective vaccine approach. We show that SV.Spike plus αOX40 elicits long-lasting neutralizing antibodies and a vigorous T cell response in mice. Protein binding, immunohistochemical and cellular infection assays all show that vaccinated mice sera inhibits spike functions. Immunophenotyping, RNA Seq transcriptome profiles and metabolic analysis indicate a reprogramming of T cells in vaccinated mice. Activated T cells were found to mobilize to lung tissue. Most importantly, SV.Spike plus αOX40 provided robust immune protection against infection with authentic coronavirus in transgenic mice expressing the human ACE2 receptor (hACE2-Tg). Finally, our immunization strategy induced strong effector memory response, potentiating protective immunity against re-exposure to SARS-CoV-2 spike protein. Our results show the potential of a new Sindbis virus-based vaccine platform to counteract waning immune response that can be used as a new candidate to combat SARS-CoV-2. Given the strong T cell responses elicited, our vaccine is likely to be effective against variants that are proving challenging, as well as, serve as a platform to develop a broader spectrum pancoronavirus vaccine. Similarly, the vaccine approach is likely to be applicable to other pathogens.

Strategy construction to minimize the limitation of respiratory viral vaccine development

“…pulmonary growth of Cryptococcus neoformans, treatment with a stimulatory OX40L.Ig fusion protein promoted fungal clearance, in case of killing the Leishmania donovani through Immunotherapy with OX40L. Ig in combination with anti-CTLA4 enhanced CD4 T cell responses and very importantly notified during vaccination where several vector based vaccines (e.g-Recombinant Rabies vaccine, vaccination with the attenuated malaria parasite, poxvirus/ vaccinia/sindbis vector-based RV vaccine) used with costimulatory OX40 alone or with another TNFR family member to expressing a nominal antigen strongly enhanced memory T cell responses to that antigen [34][35][36] showed on their animal model studies that overexpression of OX40L and increase the immunogenicity because of costimulatory activity with a vaccine against Rabies virus is occurred. Therefore, they recommended improving the vaccine potentiality that OX40L can be used as an adjuvant.…”

Self-Replicating RNA Viruses for Vaccine Development against Infectious Diseases and Cancer

“…A single immunization elicited strong neutralizing antibody responses and both 2 µg and 10 µg doses protected humanized ACE2 transgenic mice from mortality and measurable infection after challenges with wildtype SARS-CoV-2. Recently, SIN particles expressing the SARS-CoV-2 S protein were combined with the OX40 immunostimulatory antibody (αOX40) for intraperitoneal immunization of C57BL/6J mice [87]. A prime-boost vaccination strategy with 14 days between the two doses elicited long-lasting neutralizing antibodies and robust T-cell responses and sera from vaccinated mice inhibited the function of the SARS-CoV-2 S protein.…”

Self-Replicating RNA Viruses for Vaccine Development Against Infectious Diseases and Cancer

“…A single immunization elicited strong neutralizing antibody responses and both 2 μg and 10 μg doses protected humanized ACE2 transgenic mice from mortality and measurable infection after challenges with wildtype SARS-CoV-2. Recently, SIN particles expressing the SARS-CoV-2 S protein were combined with the OX40 immunostimulatory antibody (αOX40) for intraperitoneal immunization of C57BL/6J mice [94]. A prime-boost vaccination strategy with 14 days between the two doses elicited long-lasting neutralizing antibodies and robust T-cell responses and sera from vaccinated mice inhibited the function of the SARS-CoV-2 S protein.…”