LID scientists are collaborating with scientists from MedImmune under a CRADA to generate candidate vaccines against avian influenza viruses of each subtype, including H5N1 viruses that have caused human infections since 2003. The vaccines were generated using plasmid based reverse genetics and each contains the hemagglutinin and neuraminidase genes from an avian influenza virus and six internal gene segments from the AA ca virus. Highly pathogenic avian influenza is a disease of poultry that is caused by H5 or H7 avian influenza viruses and is associated with up to 100% mortality. HPAI viruses of the H5 and H7 subtypes typically possess multiple basic amino acids around the cleavage site (MBS) of their hemagglutinin (HA) protein, a recognized virulence motif in poultry. To determine the importance of the H5 HA MBS as a virulence factor in mammals, recombinant wild-type HPAI A/Vietnam/1203/2004 (H5N1) viruses that possessed (H5N1) or lacked (ΔH5N1) the H5 HA MBS were generated and evaluated for their virulence in BALB/c mice, ferrets, and African green monkeys (Chlorocebus aethiops). The presence of the H5 HA MBS was associated with lethality, significantly higher virus titers in the respiratory tract, virus dissemination to extrapulmonary organs, lymphopenia, significantly elevated levels of pro-inflammatory cytokines and chemokines and inflammation in the lungs of mice and ferrets. In African green monkeys, neither H5N1 nor ΔH5N1 virus was lethal and neither caused clinical symptoms. The H5 HA MBS was associated with mild enhancement of replication and delayed virus clearance. Thus, the contribution of H5 HA MBS to the virulence of the HPAI H5N1 virus varies among mammalian hosts and is most significant in mice and ferrets and less remarkable in nonhuman primates.

Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2012
Total Cost
$659,222
Indirect Cost
City
State
Country
Zip Code
Paules, Catharine I; Lakdawala, Seema; McAuliffe, Josephine M et al. (2017) The Hemagglutinin A Stem Antibody MEDI8852 Prevents and Controls Disease and Limits Transmission of Pandemic Influenza Viruses. J Infect Dis 216:356-365
Boonnak, Kobporn; Matsuoka, Yumiko; Wang, Weijia et al. (2017) Development of Clade-Specific and Broadly Reactive Live Attenuated Influenza Virus Vaccines against Rapidly Evolving H5 Subtype Viruses. J Virol 91:
Kuah, Li-Fang; Tang, Lay-Hoon; Sutton, Troy et al. (2017) Induction of protective immunity against influenza A/Jiangxi-Donghu/346/2013 (H10N8) in mice. J Gen Virol 98:155-165
Sutton, Troy C; Lamirande, Elaine W; Czako, Rita et al. (2017) Evaluation of the biological properties and cross-reactive antibody response to H10 influenza viruses in ferrets. J Virol :
Broadbent, Andrew J; Santos, Celia P; Paskel, Myeisha et al. (2015) Replication of live attenuated cold-adapted H2N2 influenza virus vaccine candidates in non human primates. Vaccine 33:193-200
Baz, Mariana; Boonnak, Kobporn; Paskel, Myeisha et al. (2015) Nonreplicating influenza A virus vaccines confer broad protection against lethal challenge. MBio 6:e01487-15
Xiong, Xiaoli; Corti, Davide; Liu, Junfeng et al. (2015) Structures of complexes formed by H5 influenza hemagglutinin with a potent broadly neutralizing human monoclonal antibody. Proc Natl Acad Sci U S A 112:9430-5
Baz, Mariana; Paskel, Myeisha; Matsuoka, Yumiko et al. (2015) A live attenuated equine H3N8 influenza vaccine is highly immunogenic and efficacious in mice and ferrets. J Virol 89:1652-9
Czako, Rita; Subbarao, Kanta (2015) Refining the approach to vaccines against influenza A viruses with pandemic potential. Future Virol 10:1033-1047
Baz, Mariana; Paskel, Myeisha; Matsuoka, Yumiko et al. (2015) 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. J Virol 89:6907-17

Showing the most recent 10 out of 48 publications