Research Project
10142775
7. Project Summary/Abstract Coronaviruses have been identified in several avian hosts, as well as in various mammals, including camels, bats, palm civets, mice, dogs, and cats. Among the coronaviruses that are pathogenic to humans, most are associated with mild clinical symptoms. However, In the last 18 years there have now been 3 significant coronavirus outbreaks that have greatly impacted global health. First, there was the Severe Acute Respiratory Syndrome (SARS) in 2002, then the Middle East Respiratory Syndrome (MERS) in 2012, and most recently a novel coronavirus in 2019, now officially named SARS-CoV-2 and the disease it causes in referred to as COVID-19. On March 11, 2020, as a result of the rapid global spread of the virus, the WHO declared that COVID-19 had reached pandemic levels. The emergence of the novel SARS-CoV-2 necessitates the need to develop effective medical counter measures to effectively respond to the public health threat posed by this virus. Currently, there are at least 40 SARS-CoV-2 vaccine candidates in development. These employ methods that include nucleic acid-based vaccines, viral vectored vaccines, VLP based vaccines, and recombinant subunit vaccines. Our approach to develop a SARS-CoV-2 vaccine is to use an Administrate Supplement to the current SBIR Phase IIB grant (2R44AI118017-03), ?Cross-Protective Multivalent Vaccine for Tick-Borne Flaviviruses.? The overall goal of this administrative supplement is to expand the scope of the current grant and leverage the use of the S2 cell vaccine platform to express recombinant subunits representing the SARS-CoV-2 spike protein and determine their potential as vaccine candidates. Subunits that represent the Spike (S) glycoprotein ectodomain (transmembrane region removed) and the S RBD will be expressed with and without trimerization domains. The biochemical and immunological characteristics of subunits will be determined. The evaluation of immune responses elicited by the SARS-CoV-2 recombinant subunits will include novel adjuvant formulations with different mechanisms of action in an effort to identify formulations that induce potent, protective immune responses, and support dose sparing, while avoiding Th2 biases immune responses. Formulations that provide the best immunogenic responses will be utilized to assess protective efficacy in a transgenic mouse model. In the development of coronavirus vaccines, it is important to carefully evaluate vaccine candidates in terms of safety as prior studies have identified concerns of enhanced disease as a result of skewed antibody responses that result in inflammatory alveolar damage. Our studies are designed to address these concerns through the design of subunits and the use of adjuvants that engender balanced Th1/Th2, or Th1 biased responses. The proposed recombinant subunit approach provides a means to deliver a safe, stable, and established manufacturing platform for a SARS CoV-2 vaccine.
