Immunomodulation as a means to enhance vaccine efficacy in elderly

Aseem Kumar Pandey, Purdue University

Abstract

The ability to resist infection and respond to vaccination is severly compromised in the elderly owing to various innate and adaptive immune dysfunctions. Several strategies are currently under evaluation to address the issue of low vaccine efficacy in the elderly such as increased vaccine dose, immunostimulatory patches and adjuvants. We have evaluated the effect of murine β-defensin 2 (MBD2) on immune responses to a HAd vector-based H5N1 influenza vaccine in an aged mouse model. HAd-MBD2 activated dendritic cells (DC) in vivo and also led to better humoral and cellular immune responses to a HAd vectored influenza vaccine in an aged mouse model. This strategy may help in designing effective vaccines and immunotherapeutics for the elderly. Because of the impending threat of an influenza pandemic due to highly pathogenic avian influenza (HPAI) many egg-independent influenza vaccine strategies are being pursued with the anticipation that the conventional egg-based influenza vaccine manufacturing technologies alone, may not meet the huge global pandemic vaccine demand. We and others have demonstrated the viability of HAd vectored H5N1 influenza vaccine in animal models. However, most people have preexisting neutralizing antibodies against human adenoviruses owing to the natural exposure to these viruses since childhood. Furthermore, the high immunogenic nature of HAd vectors, triggers strong humoral and cellular immunity (vector immunity) against the vector backbone which limits their subsequent use. We evaluated the role of HAd5- specific vector immunity on the immune responses and protective efficacy of a HAd5 vector-based H5N1 influenza vaccine in a mouse model. We primed mice with various doses of wild type HAd5 (HAd-WT) to generate varied levels of vector immunity in mice prior to immunization with the vaccine. Our results suggest that low levels of vector immunity induced by priming mice with 107 p.f.u. of HAd-WT did not impact the protective efficacy of the vaccine. Higher levels of vector immunity induced by priming mice with larger doses (108 or 109 p.f.u.) of HAd-WT was partially overcome by increasing the vaccine dose or by using alternate routes of inoculation for priming and vaccination. The findings of the present study will help in designing better vaccine strategies for HAd vectored vaccines.

Degree

Ph.D.

Advisors

Mittal, Purdue University.

Subject Area

Aging|Pharmacy sciences|Virology|Immunology

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