Abstract
The prevalence of preexisting immunity to adenoviruses in the majority of the human population might adversely impact the development of adaptive immune responses against adenovirus vector-based vaccines. To address this issue, we primed BALB/c mice either intranasally (i.n.) or intramuscularly (i.m.) with varying doses of wild type (WT) human adenovirus subtype 5 (HAd5). Following the development of immunity against HAd5, we immunized animals via the i.n. or i.m. route of inoculation with a HAd vector (HAd-HA-NP) expressing the hemagglutinin (HA) and nucleoprotein (NP) of A/Vietnam/1203/04 (H5N1) influenza virus. The immunogenicity and protection results suggest that low levels of vector immunity (<520 virus-neutralization titer) induced by priming mice with up to 107 plaque forming units (p.f.u.) of HAd-WT did not adversely impact the protective efficacy of the vaccine. Furthermore, high levels of vector immunity (approximately 1500 virus-neutralization titer) induced by priming mice with 108 p.f.u. of HAd-WT were overcome by either increasing the vaccine dose or using alternate routes of vaccination. A further increase in the priming dose to 109 p.f.u. allowed only partial protection. These results suggest possible strategies to overcome the variable levels of human immunity against adenoviruses, leading to better utilization of HAd vector-based vaccines.
Highlights
Adenoviruses (Ad) possess several attributes that make them suitable candidates for vaccine vectors [1,2]
The full coding region of HA under the control of the cytomegalovirus (CMV) immediate early promoter and bovine growth hormone (BGH) polyadenylation signal and full length coding region of NP gene of the A/Vietnam/1203/04 virus under the control of the murine CMV promoter and the simian virus 40 (SV40) polyA were inserted into early region 1 (E1) of the HAd genome using the Cre-recombinase-mediated site-specific recombination system [20]
HAd-primed groups immunized with HAd-HA-NP, a hemagglutination inhibition (HI) titer of 30 was induced, and there were no significant changes in the titers by either alternating the route of vaccine inoculation or with an increased vaccine dose. These results indicate that the levels of vector immunity induced by i.m. priming with 109 p.f.u. of human Ad serotype 5 (HAd5)-wild type (WT) negatively impact the development of a humoral immune response against a HAd vector-based vaccine
Summary
Adenoviruses (Ad) possess several attributes that make them suitable candidates for vaccine vectors [1,2]. The effectiveness of Ad vector-based vaccines against many infectious diseases, including measles, severe acute respiratory syndrome (SARS), human immunodeficiency virus (HIV), hepatitis B and Ebola has been evaluated in animal models and clinical trials in humans [5,6,7,8,9]. There is a high incidence of Ad infections in the general population due to the circulation of more than fifty Ad serotypes. Their ubiquitous nature results in the development of Ad-specific neutralizing antibodies, popularly known as ‘preexisting vector immunity’ in the majority of the individuals [13,14,15].
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