Rabies is a major global health issue that kills approximately 40,000 to 70,000 people per year and over 10 million people receive post-exposure prophylaxis (PEP) after exposure to potentially infected animals. Cost and compliance issues have greatly hampered the effectiveness of current vaccines. To confound this issue, current vaccines are not effective at preventing disease from several newly identified rabies related viruses. In addition, live rabies virus (RV) was recently discovered in a lot of vaccine that was supposed to contain inactivated RV. Taken together, the development of novel pre- and post-exposure vaccines is necessary to combat this global health issue. Since pre-exposure vaccination is reserved only for those at-risk populations, such as laboratory workers and veterinarians, PEP is the world-wide standard for human rabies prevention. Current PEPs are comprised of one dose of passive immunization (rabies immune globulin) along with five active immunizations with rabies vaccines. The experiments in this proposal are designed to test the hypothesis that replication-deficient RVs would make excellent rabies PEPs and will require only one to two doses. A hallmark of RV infection that makes PEP feasible is the relatively long period between the time of exposure at the peripheral site and the time when RV infects the central nervous system. As such, a rapid humoral response is absolutely required for a successful PEP. Therefore, the goal of this grant application to identify the most promising vector in small animal models [mice (Aim I) and Syrian hamsters, (Aim II)]. The responses and protection will be compared with animals inoculated with a commercially available inactivated RV vaccine. In summary, the development of a treatment that relies on only one to two doses of vaccine instead of six inoculations will greatly enhance the effectiveness of human RV prevention and has the potential to save many lives and reduce costs in both developing and developed countries. In addition, this data will be useful for the development of replication-deficient RV vectors for vaccines against other infectious diseases, such as HIV-1.

Public Health Relevance

The goal of this application is to develop safe and effective alternatives to the current human rabies post- exposure prophylaxis. The development of treatment that relies on only one to two doses of vaccine instead of six inoculations will greatly enhance the effectiveness of rabies virus prevention, save lives and reduce costs in developing and developed countries.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI079211-04
Application #
8289515
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Cassetti, Cristina
Project Start
2009-07-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$378,564
Indirect Cost
$133,539
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Norton Jr, James E; Lytle, Andrew G; Shen, Shixue et al. (2014) ICAM-1-based rabies virus vaccine shows increased infection and activation of primary murine B cells in vitro and enhanced antibody titers in-vivo. PLoS One 9:e87098
McGettigan, James P; David, Frederic; Figueiredo, Monica Dias et al. (2014) Safety and serological response to a matrix gene-deleted rabies virus-based vaccine vector in dogs. Vaccine 32:1716-9
Dorfmeier, Corin L; Shen, Shixue; Tzvetkov, Evgeni P et al. (2013) Reinvestigating the role of IgM in rabies virus postexposure vaccination. J Virol 87:9217-22
Dorfmeier, Corin L; Tzvetkov, Evgeni P; Gatt, Anthony et al. (2013) Investigating the role for IL-21 in rabies virus vaccine-induced immunity. PLoS Negl Trop Dis 7:e2129
Lytle, Andrew G; Norton Jr, James E; Dorfmeier, Corin L et al. (2013) B cell infection and activation by rabies virus-based vaccines. J Virol 87:9097-110
McGettigan, James P (2010) Experimental rabies vaccines for humans. Expert Rev Vaccines 9:1177-86