The major objectives of the proposed research in this application from a new investigator are to develop candidate vaccines for human metapneumovirus (HMPV), identify viral determinants of virulence and define genetic diversity of HMPV over time. HMPV is a recently discovered paramyxovirus that is a major cause of lower respiratory tract disease in infants and children worldwide, causing hospitalization and fatal infections. HMPV is also associated with asthma exacerbations requiring hospitalization and causes severe disease in persons with underlying conditions such as prematurity, cardiopulmonary disease, and cancer. This work proposes to develop live attenuated vaccines against HMPV and define viral determinants of virulence. We propose three specific aims:
Specific Aim 1. Develop cell culture-passaged strains of HMPV and determine their pathogenicity and immunogenicity in animal models.
Specific Aim 2. Define viral factors that contribute to virulence and pathogenicity.
Specific Aim 3. Determine the genetic diversity and evolution of HMPV over time. This research will provide potential vaccine candidates for HMPV and provide new knowledge about pathogenesis of this important human pathogen. The proposed experiments use a combination of animal studies, classical virology techniques, cellular immunology tools, and high-throughput sequencing to define HMPV virulence factors and identify attenuating mutations. The findings will be useful for the design of reverse- engineered HMPV vaccines. Leading vaccine candidates for the related respiratory syncytial virus use reverse genetics to incorporate attenuating mutations identified by similar methods, as well as complete gene deletions. The use of high-throughput sequencing methods will provide novel information about the genetic diversity of HMPV over time. This information is essential for designing vaccines or prophylactic prevention strategies. We hypothesize that, like other paramyxoviruses, HMPV will not exhibit substantial genetic or antigenic drift over time. However, these data are not known and it is possible that HMPV would demonstrate continued mutation similar to influenza virus, requiring a new vaccine each year. HMPV has a major impact on human health and safe, effective vaccines could decrease the burden of disease associated with this novel pathogen.
Human metapneumovirus (hMPV) is an emerging virus that was discovered in 2001. hMPV is a major cause of respiratory tract disease worldwide, and leads to many hospitalizations of infants and children. The purpose of this proposal is to develop candidate vaccines for hMPV. These studies will increase understanding of how hMPV causes disease in humans, and may help develop targets for antiviral medicines and vaccines.
|Edwards, Kathryn M; Zhu, Yuwei; Griffin, Marie R et al. (2013) Burden of human metapneumovirus infection in young children. N Engl J Med 368:633-43|
|Yang, Chin-Fen; Wang, Chiaoyin K; Tollefson, Sharon J et al. (2013) Human metapneumovirus G protein is highly conserved within but not between genetic lineages. Arch Virol 158:1245-52|
|Klemenc, Jennifer; Asad Ali, S; Johnson, Monika et al. (2012) Real-time reverse transcriptase PCR assay for improved detection of human metapneumovirus. J Clin Virol 54:371-5|
|Erickson, John J; Gilchuk, Pavlo; Hastings, Andrew K et al. (2012) Viral acute lower respiratory infections impair CD8+ T cells through PD-1. J Clin Invest 122:2967-82|
|Ali, S Asad; Gern, James E; Hartert, Tina V et al. (2011) Real-world comparison of two molecular methods for detection of respiratory viruses. Virol J 8:332|
|Piyaratna, Rohith; Tollefson, Sharon J; Williams, John V (2011) Genomic analysis of four human metapneumovirus prototypes. Virus Res 160:200-5|
|Williams, John V (2010) Déjà vu all over again: Koch's postulates and virology in the 21st century. J Infect Dis 201:1611-4|
|Ryder, Alex B; Tollefson, Sharon J; Podsiad, Amy B et al. (2010) Soluble recombinant human metapneumovirus G protein is immunogenic but not protective. Vaccine 28:4145-52|
|Tollefson, Sharon J; Cox, Reagan G; Williams, John V (2010) Studies of culture conditions and environmental stability of human metapneumovirus. Virus Res 151:54-9|
|Ali, Syed Asad; Williams, John V; Chen, Qingxia et al. (2010) Human metapneumovirus in hospitalized children in Amman, Jordan. J Med Virol 82:1012-6|
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