A Live Attenuated Equine H3N8 Influenza Vaccine Is Highly Immunogenic and Efficacious in Mice and Ferrets

Abstract

Equine influenza viruses (EIV) are responsible for rapidly spreading outbreaks of respiratory disease in horses. Although natural infections of humans with EIV have not been reported, experimental inoculation of humans with these viruses can lead to a productive infection and elicit a neutralizing antibody response. Moreover, EIV have crossed the species barrier to infect dogs, pigs, and camels and therefore may also pose a threat to humans. Based on serologic cross-reactivity of H3N8 EIV from different lineages and sublineages, A/equine/Georgia/1/1981 (eq/GA/81) was selected to produce a live attenuated candidate vaccine by reverse genetics with the hemagglutinin and neuraminidase genes of the eq/GA/81 wild-type (wt) virus and the six internal protein genes of the cold-adapted (ca) A/Ann Arbor/6/60 (H2N2) vaccine donor virus, which is the backbone of the licensed seasonal live attenuated influenza vaccine. In both mice and ferrets, intranasal administration of a single dose of the eq/GA/81 ca vaccine virus induced neutralizing antibodies and conferred complete protection from homologous wt virus challenge in the upper respiratory tract. One dose of the eq/GA/81 ca vaccine also induced neutralizing antibodies and conferred complete protection in mice and nearly complete protection in ferrets upon heterologous challenge with the H3N8 (eq/Newmarket/03) wt virus. These data support further evaluation of the eq/GA/81 ca vaccine in humans for use in the event of transmission of an equine H3N8 influenza virus to humans. IMPORTANCEEquine influenza viruses have crossed the species barrier to infect other mammals such as dogs, pigs, and camels and therefore may also pose a threat to humans. We believe that it is important to develop vaccines against equine influenza viruses in the event that an EIV evolves, adapts, and spreads in humans, causing disease. We generated a live attenuated H3N8 vaccine candidate and demonstrated that the vaccine was immunogenic and protected mice and ferrets against homologous and heterologous EIV. Equine influenza viruses (EIV) have been responsible for rapidly spreading outbreaks of respiratory disease in horses for centuries. Influenza A viruses contain a single-stranded, negativesense RNA genome consisting of 8 gene segments and are further classified into subtypes on the basis of the antigenicity of the two major surface glycoproteins: hemagglutinin (HA) and neuraminidase (NA) (1). Two subtypes of EIV have been isolated from horses: H7N7 and H3N8 viruses. The prototype equine H7N7 virus (A/equine/Prague/56) virus emerged in 1956 (2) but has not been isolated since the late 1970s (3), although serologic evidence suggests that this virus subtype circulated among horses in Europe and the Americas before 1956 (4, 5); its circulation in unvaccinated horses was recorded in the 1980s in India (6) and in the beginning of the 1990s in Europe and the United States (7,8). Equine H3N8 viruses were first isolated during a major epidemic in Miami in 1963 (A/eq/Miami/1/63) (9) and since then ha...

A Single Dose of an Avian H3N8 Influenza Virus Vaccine Is Highly Immunogenic and Efficacious against a Recently Emerged Seal Influenza Virus in Mice and Ferrets

“…2). We have observed similar kinetics of replication with an equine H3N8 live attenuated influenza vaccine (LAIV) candidate (23). The mean titers of the tl/TX/079/07 wt virus on days 3 and 5 were 10 4.5 and 10 4.3 PFU/g, respectively, in the lungs, while replication of the tl/TX/079/07 ca virus was not detected in the lungs, presumably because these temperature-sensitive viruses are restricted in replication at the core body temperature of ferrets.…”

“…As we recently reported with an equine H3N8 influenza vaccine candidate (23), there was a direct correlation between serum Ab response and protection against challenge in mice and ferrets that received one dose of the tl/TX/079/07 ca vaccine virus, although we cannot exclude contributions from other arms of the immune system, such as the cellular or mucosal immune response.…”

“…We have previously generated live attenuated vaccines against H1N1, H2N2, equine H3N8, H5N1, H6N1, H7N3, H7N7, H7N9, and H9N2 animal influenza viruses and found that these candidate vaccines were safe and efficacious in conferring protection against wild-type viruses in mice and ferrets (23,(27)(28)(29)(30)(31). Several of these vaccines have also been evaluated in phase 1 clinical trials (32)(33)(34)(35)(36)(37)(38).…”

Refining the Approach to Vaccines Against Influenza a Viruses with Pandemic Potential

“…Inactivated and live attenuated H5N1 vaccines were highly effective in ferrets and mice against lethal challenge with homologous and heterologous H5N1 viruses from different clades [75,76]. Similarly, live-attenuated vaccines against H2, H3, H6, H7 and H9 viruses elicited subtype-specific cross-reactive serum antibodies and reduced the replication of homologous and heterologous challenge viruses in mice or ferrets [77][78][79][80][81][82]. An inactivated monovalent H7N7 vaccine candidate conferred protection from lethal challenge of mice with H7N9 influenza virus [83].…”

Вакцины Против Гриппа Лошадей

“…Полученный рекомбинантный вирус эффективно реплицировался при пониженной температуре (33 С) и in vivo и in vitro имел фенотип, схожий с таковым в случае живой аттенуированной вакцины против гриппа лошадей Flu Avert ® . Однократное интраназальное введение рекомбинантного вируса обеспечивало защиту лошадей от контрольного заражения гомологичным вирусом дикого типа (50,51).…”