2009

2009. we compared the immunogenicity and efficacy of a single intranasal dose of an Ad5-vectored hemagglutinin (Ad5-HA) vaccine to those of a traditional intramuscular administration of WIV vaccine. Ad5-HA vaccination induced a mucosal IgA response toward homologous IAV and primed an antigen-specific gamma interferon (IFN-) response against both challenge viruses. The Ad5-HA vaccine provided protective immunity to homologous challenge and partial protection against heterologous challenge, unlike the WIV vaccine. Nasal shedding was significantly reduced and computer virus was cleared from the lung by day 5 postinfection following heterologous challenge of Ad5-HA-vaccinated pigs. However, the WIV-vaccinated pigs displayed vaccine-associated enhanced respiratory disease (VAERD) following heterologous challenge, characterized by enhanced macroscopic lung lesions. This study demonstrates that a single intranasal vaccination with an Ad5-HA construct can provide complete protection from homologous challenge and partial protection from heterologous challenge, as opposed to Ulipristal acetate VAERD, which can occur with adjuvanted WIV vaccines. INTRODUCTION Influenza A computer virus (IAV) contamination in swine can lead to significant economic losses through decreased weight gain and increased time to market. IAV also increases the susceptibility to secondary bacterial infection, leading to pneumonia, and in severe cases, to death (8, 16, 18). Due to the high rates of antigenic drift and antigenic shift, there are multiple antigenically diverse strains of IAV currently circulating throughout the swine populace (32, 33). Furthermore, introductions of human and avian IAV into the swine populace continue to increase the number of distinct circulating IAV strains (2, 11, 20, 33). The ever-changing diversity in circulating IAV strains is usually problematic for vaccine-mediated protection because the vaccine has to be updated repeatedly to provide sufficient protection against circulating strains. Vaccines currently used in the swine industry for the control of IAV are whole inactivated computer virus (WIV) preparations. WIV vaccines are typically multivalent mixtures prepared with an adjuvant and administered intramuscularly using a prime-boost vaccination strategy. Adjuvanted WIV vaccines can elicit sterilizing immunity against homologous computer virus (14, 30, 31). However, WIV vaccines are often ineffective at protecting against heterologous strains beyond a reduction in clinical presentation of disease (1, 6, 17, 24, 31). Moreover, recent evidence indicates that WIV vaccines may, in some circumstances, result in the development of vaccine-associated enhanced respiratory disease (VAERD) when a vaccinated pig is usually infected with an antigenically divergent computer virus (6, 14, Ulipristal acetate 31). VAERD is usually characterized by the presence of cross-reactive, nonneutralizing antibodies to heterologous computer virus and by enhanced lung pathology in WIV-vaccinated pigs following heterologous infection compared to PRPF10 that in nonvaccinated pigs (6, 14, 31). Thus, there is a need for option vaccine platforms that protect against heterologous contamination without resulting in VAERD. Aside from the possible enhancement of disease, WIV vaccines can also be plagued by relatively long production occasions (38). The large amount of time needed to license, approve, and produce a WIV vaccine for swine severely hinders its use during a novel IAV outbreak. An alternative platform to WIV that has quick production potential is usually a replication-defective human adenovirus 5 vector (Ad5) carrying IAV genes. Ad5 is usually a complete virion that was made replication defective by the removal of two segments of the Ad5 genome (10). Deletion of two Ad5 genomic sequences permits the insertion of an IAV antigen sequence for recombinant expression (reviewed in reference 29). A recent report indicates that a novel Ad5 construct can be created in less than 21 days once an antigen sequence is Ulipristal acetate usually identified (25). The Ad5 construct can be replicated rapidly using a small bioreactor system, with viral titers of 1010 to 1011 PFU per ml in as few as 3 days (see the supplemental material). Considering that traditional WIV vaccine production for humans has been reported to take 5 to 6 months and takes at least as long for fully licensed commercial veterinary vaccines, the Ad5 construct is usually considerably faster (38). In addition to fast production potential, Ad5 makes an excellent intranasal vaccine platform due to its natural predisposition for respiratory tract infection (28). The Ad5 platform allows for the delivery and presentation of IAV antigen to the site of natural contamination, and because Ad5 is an infectious particle, it initiates.