Human CD46-transgenic mice in studies involving replication-incompetent adenoviral type 35 vectors

Abstract

Wild-type strains of mice do not express CD46, a high-affinity receptor for human group B adenoviruses including type 35. Therefore, studies performed to date in mice using replication-incompetent Ad35 (rAd35) vaccine carriers may underestimate potency or result in altered vector distribution. Here, it is reported that CD46 transgenic mice (MYII-strain) express CD46 in all major organs and that it functions as a receptor for rAd35 vectors. Similar to monkeys and humans, MYII mice highly express CD46 in their lungs and kidneys and demonstrate low expression in muscle. Upon intravenous administration, rAd35 vector genomes as well as expression are detected in lungs of MYII mice, in contrast to wild-type littermates. Expression was predominantly detected in lung epithelial cells. Upon intramuscular administration, the initial level of luciferase expression is higher in MYII mice as compared with wild-type littermates, in spite of the fact that CD46 expression is low in muscle of MYII mice. The higher level of expression in muscle of MYII mice results in prolonged gene expression as assessed by CCD camera imaging for luciferase activity. Finally, a significant dose-sparing effect in MYII mice as compared with wild-type littermates on anti-SIVgag CD8 + T-cell induction following intramuscular vaccination with an rA35.SIVgag vaccine was observed. This dose-sparing effect was also observed when reinfusing dendritic cells derived from MYII mice after exposure to rAd35.SIVgag vaccine as compared with rAd35.SIVgag exposed dendritic cells from wild-type littermates. It was concluded that MYII mice represent an interesting preclinical model to evaluate potency and safety of rAd35 vectors.

Myeloid and Plasmacytoid Dendritic Cells Are Susceptible to Recombinant Adenovirus Vectors and Stimulate Polyfunctional Memory T Cell Responses

“…In the current study, we show that rAd35 uses CD46 to infect human primary PDCs and MDCs whereas rAd5 may enter via a CARindependent pathway. Although mice are a good animal model for testing the immunogenicity of rAd5-based vaccines, they lack expression of CD46, limiting their use in testing the immunogenicity of rAd35-based vaccines (35,40). In addition, nonhuman primates (but not humans) express CD46 on erythrocytes that may affect the distribution and access to APCs of rAd35 vectors injected into monkeys (41).…”

Intradermal Delivery of Adenoviral Type-35 Vectors Leads to High Efficiency Transduction of Mature, CD8+ T Cell-Stimulating Skin-Emigrated Dendritic Cells

“…route of administration used, which is marked by a paucity of tissue-resident DC; the skin might be a more favorable vaccination site in this respect. Interpretation of in vivo human CD46-transgenic murine and nonhuman primate data is further complicated by the presence of CD46 on erythrocytes, which, unlike in humans, might seriously affect biodistribution of the rAd35 vector (15,16). In conclusion, dissimilarities in the high-affinity CD46 receptor expression and anatomical barriers, which could result in differences in biodistribution characteristics, may render available preclinical in vivo models for rAd35 unrepresentative for the human situation.…”

Adenovirus serotype 35 vector-mediated transduction following direct administration into organs of nonhuman primates

“…Ad35 vectors transduced the muscle following intramuscular injection in wild-type mice and in CD46TG mice. 12,14 The transduction mechanism and efficiencies of Ad35 vectors in muscle fibers might differ among species, and the muscle of nonhuman primates might be more refractory to transduction than that of rodents. …”

“…8,12 However, intravenous administration of Ad35 vectors resulted in inefficient transduction in the organs of human CD46-transgenic (CD46TG) mice and cynomolgus monkeys, which express CD46 in a pattern similar to that of humans. [13][14][15] These results indicate that CD46 does not successfully serve as a receptor for intravascularly injected Ad35 vectors and that Ad35 vectors are unsuitable for intravascular transduction. However, this property of Ad35 vectors would suggest a potential advantage, in that unwanted transduction would not occur in organs other than the organs targeted following direct injection of Ad35 vectors when draining from injected sites into the bloodstream.…”