Our overall goal in this research has been and continues to be to design and develop a genital herpes vaccine(s) that would be effective around the world. Although considerable human disease is caused by herpes simplex viruses, there is no approved vaccine for HSV-1 or HSV-2. We have designed a replication- defective HSV-2 mutant viral strain that is efficacious in two different animal species. In the previous grant period we conducted characterization of our genital herpes vaccine candidate, HSV-2 dl5-29, and this vaccine technology was licensed to Sanofi Pasteur and they are developing and producing it for clinical trials. This was a major step forward for the advancement of this vaccine concept. However, there is a high prevalence of genital herpes in developing countries, in particular Sub-Saharan Africa, and genital herpes is associated with a 3-fold increased risk of HIV infection. We have found that our HSV-2 dl5-29 vaccine candidate induces protection against South African viruses in a murine model, but the protection against the South African viruses is not as good as against US viruses. Furthermore, the South African viruses show increased disease and replication in the animals immunized with all of the vaccines. Therefore, we hypothesize that the South African viruses show antigenic diversity and pathogenetic diversity, which we will explore in this proposed research. Research proposed in this application is aimed at modifying and further improving this vaccine candidate to optimize protection against viruses from Sub-Saharan Africa where there is a co-epidemic of HSV-2 and HIV infection. In this application our specific aims are to: 1. Test the hypothesis that there is antigenic and pathogenetic diversity among HSV-2 strains from around the world and that specific viral genetic backgrounds will need to be used as vaccine strains for optimal efficacy in Sub-Saharan Africa by a) determining the optimal genetic background for a replication-defective HSV-2 strain for use as a vaccine to immunize against HSV-2 strains from Sub-Saharan Africa and b) determining the basis for the difference in the pathogenesis of infection by clinical strains from the US versus South Africa. 2. Test the hypothesis that genetic modifications in immune evasion genes can improve the dl5-29 herpes vaccine candidate by a) replacing the UL41-2 virion host shutoff gene with the homologous HSV-1 gene, UL41-1, containing mutations in the RNase domain and b) by introducing mutations in the US3 gene, whose product inhibits interferon and inflammatory cytokine responses. 3. Test the hypothesis that mucosal priming with an HSV-1 vector expressing HSV-2 glycoproteins B and/or D followed by boosting with HSV-2 dl5-29 will provide superior protection against HSV-2 genital challenge as compared with immunization with dl5-29 virus alone.

Public Health Relevance

Genital herpes is a serious medical problem for several reasons, including the genital disease it causes, the risk of life-threatening infection in neonates and immunocompromised individuals, and the increased risk of HIV infection. However, no vaccine for herpes has been licensed. This research will continue to improve one of the leading genital herpes vaccines so it is optimally effective, and this improved vaccine could have a major impact on public health worldwide by preventing herpes and HIV infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI057552-08S1
Application #
8710791
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Hiltke, Thomas J
Project Start
2003-12-01
Project End
2015-06-30
Budget Start
2013-08-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2013
Total Cost
$65,118
Indirect Cost
$25,544
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Colgrove, Robert C; Liu, Xueqiao; Griffiths, Anthony et al. (2016) History and genomic sequence analysis of the herpes simplex virus 1 KOS and KOS1.1 sub-strains. Virology 487:215-21
Diaz, Fernando M; Knipe, David M (2016) Protection from genital herpes disease, seroconversion and latent infection in a non-lethal murine genital infection model by immunization with an HSV-2 replication-defective mutant virus. Virology 488:61-7
Taylor, Travis J; Diaz, Fernando; Colgrove, Robert C et al. (2016) Production of immunogenic West Nile virus-like particles using a herpes simplex virus 1 recombinant vector. Virology 496:186-93
Newman, Ruchi M; Lamers, Susanna L; Weiner, Brian et al. (2015) Genome Sequencing and Analysis of Geographically Diverse Clinical Isolates of Herpes Simplex Virus 2. J Virol 89:8219-32
Thomann, Sabrina; Boscheinen, Jan B; Vogel, Karin et al. (2015) Combined cytotoxic activity of an infectious, but non-replicative herpes simplex virus type 1 and plasmacytoid dendritic cells against tumour cells. Immunology 146:327-38
Lamers, Susanna L; Newman, Ruchi M; Laeyendecker, Oliver et al. (2015) Global Diversity within and between Human Herpesvirus 1 and 2 Glycoproteins. J Virol 89:8206-18
Colgrove, Robert; Diaz, Fernando; Newman, Ruchi et al. (2014) Genomic sequences of a low passage herpes simplex virus 2 clinical isolate and its plaque-purified derivative strain. Virology 450-451:140-5
Knipe, David M; Corey, Lawrence; Cohen, Jeffrey I et al. (2014) Summary and recommendations from a National Institute of Allergy and Infectious Diseases (NIAID) workshop on "Next Generation Herpes Simplex Virus Vaccines". Vaccine 32:1561-2
Larson, Alyssa M; Oh, Hyung Suk; Knipe, David M et al. (2013) Decreasing herpes simplex viral infectivity in solution by surface-immobilized and suspended N,N-dodecyl,methyl-polyethylenimine. Pharm Res 30:25-31
Sen, Jayita; Liu, Xueqiao; Roller, Richard et al. (2013) Herpes simplex virus US3 tegument protein inhibits Toll-like receptor 2 signaling at or before TRAF6 ubiquitination. Virology 439:65-73

Showing the most recent 10 out of 20 publications