Mucosal vaccination with a multicomponent adenovirus-vectored vaccine protects against Streptococcus pneumoniae infection in the lung.
ABSTRACT Streptococcus pneumoniae is a major bacterial respiratory pathogen. Current licensed pneumococcal polysaccharide and polysaccharide-protein conjugate vaccines are administered by an intramuscular injection. In order to develop a new-generation vaccine that can be administered in a needle-free mucosal manner, we have constructed early 1 and 3 gene regions (E1/E3) deleted, replication-defective adenoviral vectors encoding pneumococcal surface antigen A (PsaA), the N-fragment of pneumococcal surface protein A (N-PspA), and the detoxified mutant pneumolysin (PdB) from S. pneumoniae strain D39. Intranasal vaccination with the three adenoviral vectors (Ad/PsaA, Ad/N-PspA, and Ad/PdB) in mice resulted in robust antigen-specific serum immunoglobulin G responses, as demonstrated by an enzyme-linked immunosorbent assay. In addition, nasal mucosal vaccination with the combination of the three adenoviral vectors conferred protection against S. pneumoniae strain D39 colonization in mouse lungs. Taken together, these data demonstrate the feasibility of developing a mucosal vaccine against S. pneumoniae using recombinant adenoviruses for antigen delivery.
Article: Protection against enterovirus 71 with neutralizing epitope incorporation within adenovirus type 3 hexon.[show abstract] [hide abstract]
ABSTRACT: Enterovirus 71 (EV71) is responsible for hand, foot and mouth disease with high mortality among children. Various neutralizing B cell epitopes of EV71 have been identified as potential vaccine candidates. Capsid-incorporation of antigens into adenovirus (Ad) has been developed for a novel vaccine approach. We constructed Ad3-based EV71 vaccine vectors by incorporating a neutralizing epitope SP70 containing 15 amino acids derived from capsid protein VP1 of EV71 within the different surface-exposed domains of the capsid protein hexon of Ad3EGFP, a recombinant adenovirus type 3 (Ad3) expressing enhanced green fluorescence protein. Thermostability and growth kinetic assays suggested that the SP70 epitope incorporation into hypervariable region (HVR1, HVR2, or HVR7) of the hexon did not affect Ad fitness. The SP70 epitopes were thought to be exposed on all hexon-modified intact virion surfaces. Repeated administration of BALB/c mice with the modified Ads resulted in boosting of the anti-SP70 humoral immune response. Importantly, the modified Ads immunization of mother mice conferred protection in vivo to neonatal mice against the lethal EV71 challenge, and the modified Ads-immunized mice serum also conferred passive protection against the lethal challenge in newborn mice. Compared with the recombinant GST-fused SP70 protein immunization, immunization with the Ads containing SP70 in HVR1 or HVR2 elicited higher SP70-specific IgG titers, higher neutralization titers, and conferred more effective protection to neonatal mice. Thus, this study provides valuable information for hexon-modified Ad3 vector development as a promising EV71 vaccine candidate and as an epitope-delivering vehicle for other pathogens.PLoS ONE 01/2012; 7(7):e41381. · 4.09 Impact Factor
Article: Pre-clinical evaluation of a replication-competent recombinant adenovirus serotype 4 vaccine expressing influenza H5 hemagglutinin.[show abstract] [hide abstract]
ABSTRACT: Influenza virus remains a significant health and social concern in part because of newly emerging strains, such as avian H5N1 virus. We have developed a prototype H5N1 vaccine using a recombinant, replication-competent Adenovirus serotype 4 (Ad4) vector, derived from the U.S. military Ad4 vaccine strain, to express the hemagglutinin (HA) gene from A/Vietnam/1194/2004 influenza virus (Ad4-H5-Vtn). Our hypothesis is that a mucosally-delivered replicating Ad4-H5-Vtn recombinant vector will be safe and induce protective immunity against H5N1 influenza virus infection and disease pathogenesis. The Ad4-H5-Vtn vaccine was designed with a partial deletion of the E3 region of Ad4 to accommodate the influenza HA gene. Replication and growth kinetics of the vaccine virus in multiple human cell lines indicated that the vaccine virus is attenuated relative to the wild type virus. Expression of the HA transgene in infected cells was documented by flow cytometry, western blot analysis and induction of HA-specific antibody and cellular immune responses in mice. Of particular note, mice immunized intranasally with the Ad4-H5-Vtn vaccine were protected against lethal H5N1 reassortant viral challenge even in the presence of pre-existing immunity to the Ad4 wild type virus. Several non-clinical attributes of this vaccine including safety, induction of HA-specific humoral and cellular immunity, and efficacy were demonstrated using an animal model to support Phase 1 clinical trial evaluation of this new vaccine.PLoS ONE 01/2012; 7(2):e31177. · 4.09 Impact Factor