Abstract
All studies using human serotype 5 Adenovirus (Ad) vectors must address two major obstacles: safety and the presence of pre-existing neutralizing antibodies. Helper-Dependent (HD) Ads have been proposed as alternative vectors for gene therapy and vaccine development because they have an improved safety profile. To evaluate the potential of HD-Ad vaccines, we compared replication-competent (RC), first-generation (FG) and HD vectors for their ability to induce immune responses in mice. We show that RC-Ad5 and HD-Ad5 vectors generate stronger immune responses than FG-Ad5 vectors. HD-Ad5 vectors gave lower side effects than RC or FG-Ad, producing lower levels of tissue damage and anti-Ad T cell responses. Also, HD vectors have the benefit of being packaged by all subgroup C serotype helper viruses. We found that HD serotypes 1, 2, 5, and 6 induce anti-HIV responses equivalently. By using these HD serotypes in heterologous succession we showed that HD vectors can be used to significantly boost anti-HIV immune responses in mice and in FG-Ad5-immune macaques. Since HD vectors have been show to have an increased safety profile, do not possess any Ad genes, can be packaged by multiple serotype helper viruses, and elicit strong anti-HIV immune responses, they warrant further investigation as alternatives to FG vectors as gene-based vaccines.
Highlights
A multitude of viral and non-viral vectors are being developed as vaccines for HIV-1
Helper-dependent Ad (HD-Ad) vectors have been shown to be less immunogenic, have improved safety, and mediate extended expression of transgene products relative to FG vectors [19,20,21,26]. This extended expression is thought to be due to the complete deletion of all Ad open reading frames (ORFs)(Fig. 1C) to reduce T cell responses against Ad antigens in transduced cells
To evaluate both vaccine potential and vector side effects, we compared HD5-Ad to replication-defective FG5-Ad and replication-competent RC5-Ad. These data demonstrate that HD-Ad and replication-competent Ad (RC-Ad) both generate stronger immune responses than firstgeneration adenovirus (FG-Ad)
Summary
A multitude of viral and non-viral vectors are being developed as vaccines for HIV-1. Most work with Ad vectors utilizes FG-Ad vectors that are replication-defective due to a deletion of the E1 gene (Fig. 1B). While they are replicationdefective, these vectors still carry most of the other Ad genes. These vectors still carry most of the other Ad genes These Ad genes can be expressed in transduced cells and be presented by MHC I and MHC II molecules to immune effector cells. Neutralizing antibodies are a significant obstacle for the use of Ad5 viral vectored vaccines. Antibodies are generated with each administration of Ad vector These neutralizing antibodies can bind, inactivate and attenuate subsequent gene delivery by these viral vectors (10)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
