Related Experiment Video
Updated: Oct 1, 2026
Utilizing the Antigen Capsid-Incorporation Strategy for the Development of Adenovirus Serotype 5-Vectored Vaccine Approaches
Published on: May 6, 2015
Preexisting immunity to adenovirus in rhesus monkeys fails to prevent vector-induced toxicity
Andrei N Varnavski1, Yi Zhang, Michael Schnell
1Institute for Human Gene Therapy and Department of Molecular and Cellular Engineering, University of Pennsylvania and The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Abstract:
In an earlier study we evaluated innate immune responses to a first-generation adenoviral vector infused into the portal vein of rhesus monkeys who had never been exposed to adenovirus previously. In these animals, the systemic administration of E1/E3-deleted adenoviral vectors resulted in immediate activation of innate immunity and serious toxicity caused by targeting of vector to antigen-presenting cells and systemic inflammation. We analyze here how these responses are affected by vector-specific preexisting immunity that was induced by intramuscular immunization 6 months prior to evaluation. Our results show that preexposure to the vector substantially diminishes the transgene expression in most tissues but has little effect on gene transfer. Significantly, preimmunization does not eliminate systemic vector-induced toxicity. These conclusions are based on the presence of clinical features of coagulopathy and elevated levels of proinflammatory cytokine interleukin-6 in the serum of animals treated with vector after intramuscular immunization. Furthermore, preexisting immunity appears to induce a vector-specific inhibitory effect on erythroid progenitor development in the bone marrow that is not found when naive animals are challenged with vector.
Insights
Preexisting immunity to adenoviral vectors reduces transgene expression but does not prevent toxicity or inflammation. Pre-exposure also impairs erythroid progenitor development, highlighting safety concerns for gene therapy.
Area of Science:
- Immunology
- Gene Therapy
- Virology
Background:
- Adenoviral vectors can trigger innate immune responses and toxicity in naive subjects.
- Previous studies showed systemic toxicity upon first exposure to adenoviral vectors.
Purpose of the Study:
- To investigate the impact of preexisting immunity on adenoviral vector immunogenicity and toxicity.
- To assess how prior intramuscular immunization affects immune responses and gene transfer.
Main Methods:
- Rhesus monkeys were intramuscularly immunized with an adenoviral vector.
- Six months later, animals received a portal vein infusion of the same vector.
- Immune responses, transgene expression, toxicity, and erythroid progenitor development were analyzed.
Main Results:
- Preexposure significantly reduced transgene expression in most tissues.
- Gene transfer efficiency was minimally affected by prior immunization.
- Systemic toxicity, including coagulopathy and elevated interleukin-6, persisted despite preimmunization.
- A novel inhibitory effect on erythroid progenitor development was observed in preimmunized animals.
Conclusions:
- Preexisting immunity to adenoviral vectors does not mitigate toxicity or inflammation.
- Prior immunization can lead to reduced therapeutic efficacy due to diminished transgene expression.
- Adenoviral vector pre-exposure may pose risks to hematopoiesis, specifically erythroid development.
