Highly attenuated β-herpesvirus with potent immunomodulatory capacity as vaccine vector against SARS-CoV-2
Project title: Highly attenuated β-herpesvirus with potent immunomodulatory capacity as vaccine vector against SARS-CoV-2
Grantor: Croatian Science Foundation
Grantor’s website: www.hrzz.hr
Coordinator: Prof. Dr. Astrid Krmpotic
Asst. Prof. Dr. Irena Slavuljica
Dr. Maja Cokaric Brdovcak
Dr. Lea Hirsl
Mijo Golemac, dr. med.
Tina Jenus, mag. biotech. in med.
Marko Sustic, dr. med.
Mihaela Kordun, dipl. ing. mol.
Total funding: EUR 197.200,00
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), appeared in China at the end of 2019 and has rapidly increased into global pandemic and a major public health issue. COVID-19 symptoms can range from very mild to severe illness. An effective anti SARS-CoV-2 treatment has not been identified yet and there is an urgent need to develop an effective vaccine against this virus. Studies on other coronaviruses indicate that viral structural proteins, with many B cell and T cell epitopes, are the most immunogenic. Data published so far on immune responses against SARS-CoV-2 indicate that in addition to antibody response, T cells, especially those residing in the respiratory tract, are important for SARS-CoV-2 immune control providing long-term protection.
Human cytomegalovirus (HCMV) is β-herpesvirus that is widely present in the human population, but infection is usually asymptomatic in immunocompetent individuals. CMV infection induces a unique CD8 T cell response in a process known as "memory inflation" - CD8 T cells specific for certain viral epitopes continue to expand during viral latency and eventually stabilize at high frequencies. In addition, CMV-specific CD8 T cells are biased toward mucosal tissue distribution, which is relevant for the control of pathogens at their sites of entry. Our group has studied for years, many immunoevasion mechanisms that CMVs develop to avoid host’s immune control. Based on the data obtained on immunology of recombinant CMVs lacking immunoevasion genes, we have constructed recombinant CMV-based vaccine vectors. We have designed recombinant mouse CMV (MCMV) in which RAE-1γ, a ligand of activating immune receptor NKG2D, was inserted into the viral genome in place of its inhibitor (RAE-1γMCMV). This virus is highly attenuated but at the same time is able to generate highly protective antibody as well as T cell response. We have also generated RAE1γMCMV-based vectors expressing foreign epitopes (e.g. immunodominant CD8 T cell epitope of L. monocytogenes) and confirmed that the expression of the NKG2D ligand RAE-1γ by an MCMV vector bearing a foreign CD8 T cell epitope significantly increased the magnitude and effector functions of the CD8 T cell response.
All in all, our data provide strong evidence that CMV expressing cellular ligand for NKG2D receptor represents an excellent vaccine vector against emerging pathogens, such as SARS-CoV-2. Therefore, the major goal of the project is to generate recombinant RAE-1γMCMVs expressing S, M or N structural proteins of SARS-CoV-2 and to investigate their vaccine potential. In transgenic mice expressing human ACE2 receptor immunized with MCMV-based vectors expressing NKG2D ligand and SARS-CoV-2 structural proteins, we will analyze not only SARS-CoV-2-specific antibodies and T cell response, but also capacity of these vaccine vectors to contain SARS-CoV-2 infection in a way to limit its spread within tissue and prevent overwhelming immunopathology. The obtained results should be important in designing HCMV-based vaccine vectors against SARS-CoV-2.
In addition to the scientists from University of Rijeka Faculty of Medicine, in this research are also involved scientists from Germany, Israel and University Hospital for Infectious Diseases “Dr. Fran Mihaljević”.