Bovine Adenoviral Vector–based H5N1 Influenza Vaccine Overcomes Exceptionally High Levels of Pre-existing Immunity Against Human Adenovirus

Abstract

Because of the high prevalence of adenovirus (Ad) infections in humans, it is believed that pre-existing Ad-neutralizing antibodies (vector immunity) may negatively impact the immune response to vaccine antigens when delivered by human Ad (HAd) vectors. In order to evaluate whether bovine Ad subtype 3 (BAd3), a non-HAd vector, can effectively elude high levels of pre-existing vector immunity, naïve and HAd serotype 5 (HAd)-primed mice were immunized with BAd-H5HA [BAd3 vector expressing the hemagglutinin (HA) gene from H5N1 influenza virus]. Even in the presence of very high levels of HAd-specific neutralizing antibody, no significant reductions in HA-specific humoral and cell-mediated immune (CMI) responses were observed in HAd-primed mice immunized with BAd-H5HA. In naïve mice immunized with HAd-H5HA (HAd5 vector expressing H5N1 HA) and boosted with BAd-H5HA, the humoral responses elicited were significantly higher (P < 0.01) than with either HAd-H5HA or BAd-H5HA alone, while the CMI responses were comparable in the groups. This finding underlines the importance of a heterologous prime-boost approach for achieving an enhanced immune response. The immunization of naïve or HAd-primed mice with BAd-H5HA bestowed full protection from morbidity and mortality following a potentially lethal challenge with A/Hong Kong/483/97. These results demonstrate the importance of BAd vectors as an alternate or supplement to HAd vectors for influenza pandemic preparedness.

A Complex Adenovirus-Vectored Vaccine against Rift Valley Fever Virus Protects Mice against Lethal Infection in the Presence of Preexisting Vector Immunity

“…To bypass anti-Ad5 immunity, (3,10) or Ad vectors of nonhuman serotypes (26,38,50). Due to antigenic differences between Ad serotypes, these alternative serotype vectors can be effective in the presence of acute immune responses against Ad5 in animal models, although their potency often does not match that of Ad5 (3,10,27).…”

A Novel Cardiotropic Murine Adenovirus Representing a Distinct Species of Mastadenoviruses

“…Nonhuman mastadenoviruses could also be exploited as animal models for the pathogenesis of human AdV infection or for development of AdV vectors for human gene therapy and vaccination approaches (26,27). The potential of MAdV-3 to be used in these fields has to be thoroughly analyzed.…”

Airway Delivery of an Adenovirus-Based Ebola Virus Vaccine Bypasses Existing Immunity to Homologous Adenovirus in Nonhuman Primates

“…Approximately 90% of sub-Saharan African and southeast Asian populations and an estimated 35% of the North America population have anti-AdHu5 antibodies capable of neutralizing AdHu5-based vaccines (21,22). It is possible to circumvent PEI to AdHu5 by either increasing the adenoviral vaccine dose (23), by using rare human serotypes, such as AdHu12, AdHu35 (24), and AdHu6 (25), or by using adenoviruses from other species, such as simian (26), bovine (27), and porcine. Alternatively, it is possible to bypass AdHu5 PEI by altering the route of vaccine delivery from the conventional intramuscular (i.m.)…”