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Human CD46-transgenic mice in studies involving replication-incompetent adenoviral type 35 vectors
Sandra Verhaagh1, Esmeralda de Jong1, Jaap Goudsmit1
1Crucell Holland BV, Archimedesweg 4, 2333 CN Leiden, The Netherlands.
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.
Insights
CD46 transgenic mice (MYII-strain) serve as a valuable preclinical model for studying human group B adenoviruses (Ad35). These mice exhibit improved gene expression and immune responses, aiding in the evaluation of Ad35 vaccine potency and safety.
Area of Science:
- * Virology and Immunology
- * Preclinical Research Models
- * Gene Therapy Vectors
Background:
- * Wild-type mice lack CD46, a key receptor for human group B adenoviruses (Ad35), potentially limiting their use in preclinical studies of Ad35-based vaccines.
- * Replication-incompetent Ad35 (rAd35) vaccine carriers may have underestimated potency or altered distribution in wild-type mice due to the absence of CD46.
Purpose of the Study:
- * To characterize CD46 transgenic mice (MYII-strain) as a preclinical model for rAd35 vectors.
- * To evaluate the utility of MYII mice for assessing Ad35 vector potency, distribution, and immunogenicity.
Main Methods:
- * Generation and characterization of CD46 transgenic mice (MYII-strain).
- * Intravenous and intramuscular administration of rAd35 vectors in MYII and wild-type mice.
- * Assessment of vector genome distribution, gene expression (luciferase), and T-cell induction (anti-SIVgag CD8+).
- * Evaluation of dendritic cell function after exposure to rAd35 vectors.
Main Results:
- * MYII mice express functional CD46 in major organs, including lungs and kidneys, acting as an rAd35 receptor.
- * Intravenous rAd35 administration led to detectable vector genomes and gene expression in MYII mouse lungs, unlike wild-type mice.
- * Intramuscular vaccination in MYII mice showed higher initial luciferase expression and prolonged gene expression, along with a significant dose-sparing effect for anti-SIVgag CD8+ T-cell induction.
- * Dendritic cells from MYII mice exposed to rAd35.SIVgag vaccine also demonstrated a dose-sparing effect.
Conclusions:
- * MYII mice expressing CD46 represent a relevant preclinical model for evaluating rAd35 vectors.
- * This model allows for a more accurate assessment of Ad35 vector potency, biodistribution, and immunogenicity.
- * The MYII mouse model can aid in the development and optimization of Ad35-based vaccines and gene therapy strategies.
