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The Biodistribution of Replication-Defective Simian Adenovirus 1 Vector in a Mouse Model.
Juan Chen1,2, Xiaojuan Guo1, Xiaohui Zou1
1NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 100052, China.
Viruses
|April 27, 2024
Summary
The administration route significantly impacts gene transfer vector efficacy. Intranasal or intramuscular delivery of the simian adenovirus 1 vector showed promising results for vaccine development, with potential for repeated administration.
Area of Science:
- Gene Therapy
- Virology
- Immunology
Background:
- Administration route critically influences gene transfer vector biodistribution and transgene expression.
- Simian adenovirus 1 (SAdV-1) vectors are being explored for gene delivery applications.
Purpose of the Study:
- To investigate the biodistribution and expression of a novel SAdV-1 vector carrying reporter genes (luciferase and GFP) in a mouse model.
- To evaluate the impact of different administration routes (intravenous, intragastric, intranasal, intramuscular) on vector performance and immunogenicity.
- To assess the feasibility of repeated vector administration and sequential use of different adenovirus serotypes.
Main Methods:
- Construction of an SAdV-1 vector (SAdV1-GFluc) encoding firefly luciferase and GFP.
- Biodistribution analysis using bioluminescence imaging and real-time PCR for virus DNA tracking.
- Flow cytometry to identify target cells.
- Assessment of neutralizing antibody (NAb) titers.
- Immunohistochemistry to determine transduced cells in the respiratory tract.
Main Results:
- Intravenous administration resulted in liver and spleen biodistribution, targeting macrophages and hepatocytes.
- Repeated intravenous inoculations were ineffective due to induced NAbs.
- Intragastric administration showed transient expression, allowing for repeated dosing.
- Intranasal administration led to moderate, sustained respiratory tract expression, with minimal NAb increase upon repeat dosing.
- Intramuscular administration resulted in localized, sustained expression, but repeated injections compromised efficacy.
- Sequential administration of SAdV-1 and human adenovirus 5 (HAdV-5) vectors restored luciferase activity.
Conclusions:
- Intranasal and intramuscular routes are preferred for SAdV-1 vector delivery in vaccine development.
- The immune response, particularly NAbs, limits repeated administration of the same vector serotype.
- Sequential administration of different adenovirus serotypes offers a strategy to overcome immune limitations.
