Adenovirus vector vaccines

Recently, importance of vaccines for treatment and prevention of emerging and re-emerging infectious diseases has been re-recognized. A replication-incompetent adenovirus（Ad） vector vaccine expressing virus antigen proteins is one of the most advanced platforms as a novel vaccine because an Ad vector vaccine can be rapidly applicable to pandemic. In this review, we describe the basic properties of an Ad vector for vaccine, in addition to the summary of the development of an Ad vector vaccine for emerging and re-emerging infectious diseases, including Coronavirus disease 2019（COVID-19）, worldwide.Alternate :抄録非増殖型アデノウイルスベクターは、in vivoへの直接投与において優れた遺伝子導入活性を示すことから、病原体由来の抗原タンパク質を発現させることにより、新興・再興感染症に対するワクチンベクターとして積極的な開発が進められてきた。最近では、新型コロナウイルス感染症（COVID-19）に対するワクチンとして、欧米中露において迅速な実用化がなされた。本稿では、アデノウイルスベクターの特性、COVID-19に対するアデノウイルスベクターワクチンの特徴、およびアデノウイルスベクターワクチンの可能性について解説する。

Upregulation of Robo4 expression by SMAD signaling suppresses vascular permeability and mortality in endotoxemia and COVID-19 models.

There is an urgent need to develop novel drugs to reduce the mortality from severe infectious diseases with the emergence of new pathogens, including Coronavirus disease 2019 (COVID-19). Although current drugs effectively suppress the proliferation of pathogens, immune cell activation, and inflammatory cytokine functions, they cannot completely reduce mortality from severe infections and sepsis. In this study, we focused on the endothelial cell-specific protein, Roundabout 4 (Robo4), which suppresses vascular permeability by stabilizing endothelial cells, and investigated whether enhanced Robo4 expression could be a novel therapeutic strategy against severe infectious diseases. Endothelial-specific overexpression of Robo4 suppresses vascular permeability and reduces mortality in lipopolysaccharide (LPS)-treated mice. Screening of small molecules that regulate Robo4 expression and subsequent analysis revealed that two competitive small mothers against decapentaplegic (SMAD) signaling pathways, activin receptor-like kinase 5 (ALK5)-SMAD2/3 and ALK1-SMAD1/5, positively and negatively regulate Robo4 expression, respectively. An ALK1 inhibitor was found to increase Robo4 expression in mouse lungs, suppress vascular permeability, prevent extravasation of melanoma cells, and decrease mortality in LPS-treated mice. The inhibitor suppressed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced endothelial barrier disruption and decreased mortality in mice infected with SARS-CoV-2. These results indicate that enhancing Robo4 expression is an efficient strategy to suppress vascular permeability and mortality in severe infectious diseases, including COVID-19, and that small molecules that upregulate Robo4 can be potential therapeutic agents against these diseases.

Adenovirus vector-based vaccine for infectious diseases.

Replication-incompetent adenovirus (Ad) vectors have been widely used as gene delivery vehicles in both gene therapy studies and basic studies for gene function analysis due to their highly advantageous properties, which include high transduction efficiencies, relatively large capacities for transgenes, and high titer production. In addition, Ad vectors induce moderate levels of innate immunity and have relatively high thermostability, making them very attractive as potential vaccine vectors. Accordingly, it is anticipated that Ad vectors will be used in vaccines for the prevention of infectious diseases, including Ebola virus disease and acquired immune deficiency syndrome (AIDS). Much attention is currently focused on the potential use of an Ad vector vaccine for coronavirus disease 2019 (COVID-19). In this review, we describe the basic properties of an Ad vector, Ad vector-induced innate immunity and immune responses to Ad vector-produced transgene products. Development of novel Ad vectors which can overcome the drawbacks of conventional Ad vector vaccines and clinical application of Ad vector vaccines to several infectious diseases are also discussed.