The Severe Acute Respiratory Syndrome (SARS) causes significant mortality and no effective vaccine is available. Viruses closely related to SARS coronavirus (SARS-CoV) have been found in bats in several parts of the world, making re-emergence of SARS a distinct possibility. We propose to develop a safe inactivated and second-generation vaccine to prevent SARS. We showed that virus deleted in the small envelope (E) protein (rSARS-CoV-Delta E), or in this E protein plus six additional genes (6, 7a, 7b, 8a, 8b, and 9b) accessory for replication were attenuated in hamsters and mice. Among the deleted genes, E gene was the main one responsible for virus attenuation in the animal models tested. Thus, virus with either deleted or mutated E protein serves as a useful platform for the production of a chemically inactivated vaccine, and for the engineering of a live attenuated anti-SARS vaccine. We have shown that SARS-CoV E protein regulates host stress and unfolded protein responses and, consequent immune responses to the virus. We propose the identification and construction of rSARS-CoV including E protein mutants that elicit strong immune responses and are still attenuated.
The specific aims of this project are: (i) The construction of rSARS-CoV viruses with modified E protein mutants eliciting higher immune responses to the virus by maintaining E protein's role in morphogenesis. We hypothesize that preventing the interaction of E protein with host cell proteins involved in stress response signaling will lead to an enhanced immune response. E protein mutant construction will be based on the generation of an rSARS-CoV with a mutator phenotype. (ii) To test rSARSCoV-E* as vaccine candidates in mice using a mouse adapted prototype. We will analyze the immune responses to selected vaccine candidates, and the influence of non-essential group specific genes and of age. (iii) To increase the safety and titer of selected rSARS-CoV-E* vaccine candidates by modification of replicase genes, and to increase vaccine candidate titers using a virus with mutator phenotype.

Public Health Relevance

This proposal describes the development of a novel attenuated vaccine that will protect against SARS as no vaccine is available. The possibility of recurrence exists, since SARS-like CoV are present in bats. Thus, it is important to develop a vaccine that will be safe and immunogenic in order to protect human populations in future outbreaks of this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI060699-07
Application #
8379132
Study Section
Special Emphasis Panel (ZAI1-EC-M)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$289,724
Indirect Cost
$67,471
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Channappanavar, Rudragouda; Fett, Craig; Mack, Matthias et al. (2017) Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection. J Immunol 198:4046-4053
Fehr, Anthony R; Channappanavar, Rudragouda; Perlman, Stanley (2017) Middle East Respiratory Syndrome: Emergence of a Pathogenic Human Coronavirus. Annu Rev Med 68:387-399
Park, Jung-Eun; Gallagher, Tom (2017) Lipidation increases antiviral activities of coronavirus fusion-inhibiting peptides. Virology 511:9-18
Zhao, Jingxian; Alshukairi, Abeer N; Baharoon, Salim A et al. (2017) Recovery from the Middle East respiratory syndrome is associated with antibody and T-cell responses. Sci Immunol 2:
Chi, Hang; Zheng, Xuexing; Wang, Xiwen et al. (2017) DNA vaccine encoding Middle East respiratory syndrome coronavirus S1 protein induces protective immune responses in mice. Vaccine 35:2069-2075
Morales, Lucía; Oliveros, Juan Carlos; Fernandez-Delgado, Raúl et al. (2017) SARS-CoV-Encoded Small RNAs Contribute to Infection-Associated Lung Pathology. Cell Host Microbe 21:344-355
Li, Kun; Wohlford-Lenane, Christine L; Channappanavar, Rudragouda et al. (2017) Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice. Proc Natl Acad Sci U S A 114:E3119-E3128
Fehr, Anthony R; Jankevicius, Gytis; Ahel, Ivan et al. (2017) Viral Macrodomains: Unique Mediators of Viral Replication and Pathogenesis. Trends Microbiol :
Tai, Wanbo; Wang, Yufei; Fett, Craig A et al. (2017) Recombinant Receptor-Binding Domains of Multiple Middle East Respiratory Syndrome Coronaviruses (MERS-CoVs) Induce Cross-Neutralizing Antibodies against Divergent Human and Camel MERS-CoVs and Antibody Escape Mutants. J Virol 91:
Zheng, Jian; Perlman, Stanley (2017) Immune responses in influenza A virus and human coronavirus infections: an ongoing battle between the virus and host. Curr Opin Virol 28:43-52

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