Since 1996, there have been numerous reports of human infections with avian influenza A viruses of subtypes H5N1, H7N7 and H9N2. In 2013, a new avian influenza virus strain of H7N9 subtype emerged in China causing more than 450 infections in humans resulting in 175 deaths so far. Although human-to-human transmission has been infrequent and limited, genetic reassortment between avian and human/porcine influenza viruses or mutations in some of the genes leading to virus replication in the upper respiratory tract in humans could result in the generation of a novel pandemic influenza virus strain that not only would infect but also effectively transmit among the human population which would have little or no immunity to the new virus. Our immunogenicity and protective efficacy studies showed that adenovirus (Ad) vector-based H5N1, H7N7 and H9N2 vaccines provide excellent humoral and cell-mediated immune responses leading to complete protection against challenges with H5N1, H7N7 and H9N2 influenza viruses. To further improve the breadth of protective efficacy, inclusion of neuraminidase (NA), in addition to hemagglutinin (HA) and nucleoprotein (NP), in the Ad vector-based vaccine formulations will be explored (first generation vaccines). The other strategy to enhance the breadth of protective efficacy against avian influenza viruses will be to include relatively conserved domains of influenza proteins for multi-epitope-based vaccines (second generation vaccines). This proposal is based on the hypothesis that a combination of heterosubtypic cell-mediated immunity against NP and the cross-reactive (not necessarily cross-neutralizing) humoral immune responses against other immunogenic proteins or domains will provide broad protection against potential pandemic H5N1, H7N9 or H9N2 avian influenza viruses as well as other H5, H7 or H9 divergent viruses. The vaccine approach will be based on the bovine adenovirus vector which induces improved levels of protective immune responses even in the presence of high levels of neutralizing antibodies against human Ad. The goals of this revised competitive renewal proposal are:
Aim 1) Development and evaluation of the immunogenicity and protective efficacy of broadly protective Ad-based influenza vaccines (HA, NP & NA-based or immunogenic multi-epitope-based) against H5N1, H7N9, and H9N2 avian influenza viruses in mice;
Aim 2) Evaluation of the immunogenicity and protective efficacy of selected broadly protective Ad-based vaccines against H5N1, H7N9, and H9N2 viruses in ferrets;
and Aim 3) Determination of the longevity of protective influenza immunity and the decline of Ad vector immunity with time and its effect on repeat immunization with the same Ad vector. Our efforts will be directed towards the generation of broadly protective vaccines against H5, H7 and H9 influenza subtypes which would significantly lower morbidity, hinder transmission and prevent mortality in a pandemic situation before a strain-matched vaccine can be produced. The outcome of this research will significantly impact the development efforts for better vaccines against seasonal influenza viruses.

Public Health Relevance

Since the nature of the next pandemic influenza virus is unknown, our efforts will be directed towards the generation of universal influenza vaccines that are broadly protective against H5, H7 and H9 influenza subtypes. We propose to develop a vaccine that will protect against a variety of influenza virus subtypes, is capable to being available for use before a traditional strain-matched vaccine can be produced, will hinder human-to-human transmission and lower morbidity and mortality rates in the initial stages of a pandemic event. The outcome of this project will meaningfully advance the development of broadly protective universal vaccines against avian influenza viruses for pandemic preparedness and will also provide the knowledge to devise better broadly protective vaccines for seasonal influenza.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Gordon, Jennifer L
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Purdue University
Veterinary Sciences
Schools of Veterinary Medicine
West Lafayette
United States
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Sayedahmed, Ekramy E; Kumari, Rashmi; Shukla, Shruti et al. (2018) Longevity of adenovirus vector immunity in mice and its implications for vaccine efficacy. Vaccine 36:6744-6751
Sayedahmed, Ekramy E; Hassan, Ahmed O; Kumari, Rashmi et al. (2018) A Bovine Adenoviral Vector-Based H5N1 Influenza -Vaccine Provides Enhanced Immunogenicity and Protection at a Significantly Low Dose. Mol Ther Methods Clin Dev 10:210-222
Vemula, Sai V; Sayedahmed, Ekramy E; Sambhara, Suryaprakash et al. (2017) Vaccine approaches conferring cross-protection against influenza viruses. Expert Rev Vaccines 16:1141-1154
Hassan, Ahmed O; Amen, Omar; Sayedahmed, Ekramy E et al. (2017) Adenovirus vector-based multi-epitope vaccine provides partial protection against H5, H7, and H9 avian influenza viruses. PLoS One 12:e0186244
Hassan, Ahmed O; Vemula, Sai V; Sharma, Anurag et al. (2017) 155R is a novel structural protein of bovine adenovirus type 3, but it is not essential for virus replication. J Gen Virol 98:749-753
Cao, Weiping; Liepkalns, Justine S; Hassan, Ahmed O et al. (2016) A highly immunogenic vaccine against A/H7N9 influenza virus. Vaccine 34:744-9
Vemula, Sai V; Pandey, Aseem; Singh, Neetu et al. (2013) Adenoviral vector expressing murine ?-defensin 2 enhances immunogenicity of an adenoviral vector based H5N1 influenza vaccine in aged mice. Virus Res 177:55-61
Vemula, Sai V; Amen, Omar; Katz, Jacqueline M et al. (2013) Beta-defensin 2 enhances immunogenicity and protection of an adenovirus-based H5N1 influenza vaccine at an early time. Virus Res 178:398-403
Vemula, Sai V; Ahi, Yadvinder S; Swaim, Anne-Marie et al. (2013) Broadly protective adenovirus-based multivalent vaccines against highly pathogenic avian influenza viruses for pandemic preparedness. PLoS One 8:e62496
Pandey, Aseem; Singh, Neetu; Vemula, Sai V et al. (2012) Impact of preexisting adenovirus vector immunity on immunogenicity and protection conferred with an adenovirus-based H5N1 influenza vaccine. PLoS One 7:e33428

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