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Development of new TB vaccine candidates with multivalent antigens

TB, caused by M. tuberculosis, is responsible for two million deaths worldwide each year. The initial licensed BCG vaccine has a limited protective effect against infectious M. tuberculosis in adults, and thus the development of an effective vaccine is urgently needed. Accordingly, we constructed recombinant vaccinia viruses by integrating M. tuberculosis genes encoding various antigens (Ag85B, etc) into an attenuated vaccinia virus (KVAC103), a third-generation smallpox vaccine candidate developed by the Korea National Institute of Health (KNIH), and tested their immunogenicity and efficacy in an animal model. Among the vaccine candidates, recombinant viruses expressing Ag85B effectively induced not only humoral but also cell-mediated immunity in vivo. We also constructed recombinant adenoviruses by integrating the genes of multiple antigens including Ag85B into adenovirus serotype 5 (Ad5) as a model vaccine vector, which can carry many foreign genes and induce cell-mediated immune response. The immunization strategies and vaccines containing multiple antigens may induce a wider immune response for better protection against M. tuberculosis infection. To induce effective immune responses, we evaluated various immunization strategies in an animal model. As a result, heterologous immunization of vaccine candidates generated high levels of IFN-γ ELISPOT responses as well as antigen-specific polyfunctional T cells secreting multiple cytokines compared to those of homologous immunization in the spleen and lungs. Heterologous immunization with these vaccine candidates induced the strongest boosting effects in BCG-primed mice. Our results indicate that appropriate immunization could be important for generation of immune response and protection against TB.

Identification of surrogate markers to assess the immunological efficacy of TB vaccines

The development of new vaccines against TB remains hampered by the difficulty in evaluating their efficacy. To identify potential biomarkers to evaluate vaccine efficacy as well as to understand host immune response, we assessed cytokine profiles and gene expression among individuals with active TB and latent infection, as well as those in healthy controls (HCs). M. tuberculosis-specific antigen-induced and unstimulated cytokines were measured by multiplexed cytokine assays in these individuals. Among the 27 cytokines, 11 biomarkers in the HCs differed significantly from those in the M. tuberculosis-infected group. We also conducted a microarray experiment to compare the gene expression profiles in peripheral blood mononuclear cells. Bioinformatic analysis revealed that most of the differentially expressed genes were associated with immune responses, inflammation pathways, and cell cycle control. Validation in a larger sample size is necessary to confirm the reliability of the biomarkers and facilitate the development of biomarkers to evaluate vaccine efficacy.

Screening of efficient antigenic candidates against variants of mumps viruses (MuV)

Mumps caused MuV is a vaccine-preventable disease. Since the MMR vaccine was incorporated into the National Immunization program in Korea in 1985, the incidence of mumps has declined. However, mumps outbreaks still occur in vaccinated children because of waning immunity or antigenic differences between the vaccine strain and circulating wild-type viruses. To investigate this concern, we have analysed the genetic characteristics of the hemagglutinin-neuraminidase (HN) gene of MuV isolated in Korea (Figure 1). We will next generate recombinant adenoviruses expressing individual antigens of various genotypes. Our goal is to provide vaccine antigen candidates for protection against diverse MuV genotypes and evaluation of their efficacy.

Figure 1. Phylogenetic tree of mumps viruses (MuVs). The phylogenetic tree of 17 Korean MuV isolates and 24 WHO reference viruses based on the entire hemagglutinin-neuraminidase (HN) gene. The phylogenetic tree was drawn via neighbour-joining and bootstrap methods using MEGA, version 6.06.

Figure 1. Phylogenetic tree of mumps viruses (MuVs)

Development of a Zika vaccine based on a rapid vaccine development platform

Following the ZIKV epidemic in 2015–2016, ZIKV infection in pregnant women was shown to potentially result in congenital Zika syndromes such as microcephaly and severe brain malfunctions in the infant. Zika can be transmitted by mosquitos and by infected individuals through sexual contact. The difficulties of disease control and irreversible foetal defects increase the importance and urgency of vaccine development. To develop a vaccine, we applied the viral vector and DNA vaccine platform, which are appropriate for rapid vaccine development against emerging infectious diseases. Four vaccinia viral vectors and adenoviral vectors expressing Zika viral antigens such as prM/E, E, and partial E were constructed, and recombinant viruses were cultured. In addition, 16 recombinant DNA vaccine candidates expressing prM/E, E, or various combination of partial E gene were also produced. The in vitro expression efficacy of these various constructs in cell lines were tested, and candidates showing little antigen expression were excluded from further analysis. We analysed the epitopes of E protein in humanized mice to overcome the limitations of mouse experiments, and the domain III of the E protein C-terminal region showed a high level of antigenicity in ELISPOT assays. We will next analyse the levels of neutralizing antibodies and antigen-specific B/T cell immune responses in immunocompetent mice. Based on this T-cell epitope region and neutralizing antibody-inducing domain, final efficient candidates will be selected and further evaluated in animal challenge models.

Korea Vaccine Research Centre (VRC)

The VRC will conduct a comprehensive vaccine research and development program for national health improvement. The primary research focus will be the development of vaccines for pandemic infectious diseases and bioterrorism. In addition, the VRC will provide nonclinical evaluation of vaccine candidate materials as well as collection and management services for vaccine candidates. The VRC building is scheduled to be completed by 2020. We established the preliminary design of the VRC building in December 2017 (Figure 2). Currently, the enforcement design is underway with an aim to start construction in the autumn 2018.

Figure 2. Preliminary design of the Korea Vaccine Research Center.
Figure 2. Preliminary design of the Korea Vaccine Research Center

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