Pre-existing vector immunity does not prevent replication deficient adenovirus from inducing efficient CD8 T-cell...

Area of Science:

• Immunology
• Vaccinology
• Viral Vector Technology

Background:

• Adenoviral vectors are promising for vaccines, inducing strong CD8 T-cell responses.
• Pre-existing immunity, particularly to Ad5, limits adenoviral vector efficacy in many populations.
• An improved adenoviral vector system expresses transgenes linked to the MHC class II associated invariant chain (Ii).

Purpose of the Study:

• To investigate if pre-existing immunity inhibits the improved adenoviral vector system.
• To understand the mechanisms of inhibitory immunity against adenoviral vectors.
• To assess the potential for generating CD8 T-cell memory despite pre-existing immunity.

Main Methods:

• Evaluation of an improved adenoviral vector system in the context of pre-existing immunity.
• Assessment of antibody-mediated inhibition and T-cell responses in B-cell deficient mice.
• Analysis of primary and memory CD8 T-cell responses following vaccination in immune and non-immune animals.
• Investigation of homologous re-immunization for boosting transgene-specific responses.

Main Results:

• Pre-existing immunity, dominated by antibodies, inhibited the improved adenoviral vector system.
• CD8 T cells against vector epitopes correlated with repressed responses in re-vaccinated B-cell deficient mice.
• Despite initial repression, vaccination in Ad5-immune animals generated memory CD8 T cells, enabling efficient recall responses and protection.
• Transgene-specific responses were boostable by homologous re-immunization.

Conclusions:

• Adenoviral vectors can overcome inhibitory immunity to induce robust CD8 T-cell memory.
• The generation of memory T cells provides a basis for effective recall responses and protection, even in immunocompetent individuals with prior vector exposure.
• This highlights the potential of adenoviral vectors for vaccine development in diverse populations.