Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease

Petro, Christopher D.; González, Pablo A.; Cheshenko, Natalia; Jandl, Thomas; Khajoueinejad, Nazanin; Bènard, Angéle; Sengupta, Mayami; Herold, Betsy C.; Jacobs, William R.

doi:10.7554/elife.06054

Cited by 100 publications

(133 citation statements)

References 58 publications

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“…The ability of prophylactic live-attenuated HSV vaccines to be avirulent yet drive a protective humoral immune response has been highlighted recently by several groups (25,65,(74)(75)(76). Consistent with these reports, the concept that a live-attenuated HSV vaccine is a tenable option for prophylactic protection is evident.…”

Section: Discussionsupporting

confidence: 65%

Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice

Royer

Carr

Chucair-Elliott

et al. 2017

J Virol

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Viral fitness dictates virulence and capacity to evade host immune defenses. Understanding the biological underpinnings of such features is essential for rational vaccine development. We have previously shown that the live-attenuated herpes simplex virus 1 (HSV-1) mutant lacking the nuclear localization signal (NLS) on the ICP0 gene (0ΔNLS) is sensitive to inhibition by interferon beta (IFN-␤) in vitro and functions as a highly efficacious experimental vaccine. Here, we characterize the host immune response and in vivo pathogenesis of HSV-1 0ΔNLS relative to its fully virulent parental strain in C57BL/6 mice. Additionally, we explore the role of type 1 interferon (IFN-␣/␤) signaling on virulence and immunogenicity of HSV-1 0ΔNLS and uncover a probable sex bias in the induction of IFN-␣/␤ in the cornea during HSV-1 infection. Our data show that HSV-1 0ΔNLS lacks neurovirulence even in highly immunocompromised mice lacking the IFN-␣/␤ receptor. These studies support the translational viability of the HSV-1 0ΔNLS vaccine strain by demonstrating that, while it is comparable to a virulent parental strain in terms of immunogenicity, HSV-1 0ΔNLS does not induce significant tissue pathology.IMPORTANCE HSV-1 is a common human pathogen associated with a variety of clinical presentations ranging in severity from periodic "cold sores" to lethal encephalitis. Despite the consistent failures of HSV subunit vaccines in clinical trials spanning the past 28 years, opposition to live-attenuated HSV vaccines predicated on unfounded safety concerns currently limits their widespread acceptance. Here, we demonstrate that a live-attenuated HSV-1 vaccine has great translational potential.KEYWORDS HSV-1, T cells, antibody, cornea, mouse, neovascularization S trategies for vaccine development have transitioned largely from empirical to so-called "next-generation" or rational approaches during the past 2 decades, a shift largely driven by technological advances and a better understanding of how innate immunity influences the generation of adaptive protection (1, 2). Despite these breakthroughs, the average person still acquires multiple herpesvirus infections during childhood (3). A licensed vaccine, however, exists only for varicella-zoster virus (VZV) (4). The live-attenuated Oka vaccine for VZV is generally well tolerated and has significantly reduced the incidence of VZV infection, morbidity, and mortality in the United States (5, 6). Furthermore, epidemiologic studies indicate that acquisition of herpes simplex virus 1 (HSV-1) has shifted toward early to late adolescence in recent decades within the United States, potentially creating an opportunity to introduce an effective prophylactic HSV-1 vaccine into the childhood vaccine regimen (7). HSV vaccines have been tested in multiple clinical trials, but these studies have focused on protein subunit vaccines

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Section: Discussionsupporting

confidence: 65%

Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice

Royer

Carr

Chucair-Elliott

et al. 2017

J Virol

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show abstract

“…Therefore, genetic evidence for a role for iNKT cells is strongest when the results obtained using CD1d À/À and Jα18 À/À mice are in agreement. This is the case for vaginal infection with HSV-2, in which CD1d À/À and Jα18 À/À mice were both 10-fold more susceptible to the virus (Petro et al, 2015).…”

Section: Herpesvirus Familymentioning

confidence: 96%

Activation and Function of iNKT and MAIT Cells

Chandra

Kronenberg

2015

Advances in Immunology

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“…More recently, vaccination of mice with a replication-defective HSV-2 gD deletion mutant protected animals from i.vag. challenge; while the vaccine induced very low titers of serum neutralizing antibody, it induced antibody with ADCC activity (15). In addition, live attenuated or replication-defective vaccines may induce protective immunity due to CD4 ϩ or CD8 ϩ T cells.…”

Section: Discussionmentioning

confidence: 99%

“…gD2t in alum and monophosphoryl lipid A (MPL) initially showed promising results in preventing HSV-2 infection in women who were seronegative for both HSV-1 and HSV-2 (11); however, in a phase 3 study involving over 8,000 women who were seronegative for HSV-1 and HSV-2, the vaccine showed no efficacy for preventing HSV-2 genital herpes (12). The ineffectiveness of this vaccine has increased interest in other approaches for HSV-2 vaccines, including replication-defective (13)(14)(15) and live attenuated (16)(17)(18)(19) vaccines.…”

mentioning

confidence: 99%

A Herpes Simplex Virus 2 (HSV-2) gD Mutant Impaired for Neural Tropism Is Superior to an HSV-2 gD Subunit Vaccine To Protect Animals from Challenge with HSV-2

Wang

Goodman

et al. 2016

J Virol

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G enital herpes simplex is one of the most prevalent sexually transmitted diseases. In 2012, more than 417 million persons worldwide were reported to be infected with herpes simplex virus 2 (HSV-2), with more than 19.2 million new persons infected in that year alone (1). While HSV-2 disease is mild in most cases, infection can be severe and life threatening in immunocompromised patients and neonates. In addition, genital herpes increases the risk of acquisition of HIV infection 3-fold (2). While HSV-2 traditionally has been the principal cause of genital herpes, more recent studies have shown that HSV-1 may be replacing HSV-2 as the most frequent cause of genital herpes in the United States (3, 4). While both HSV-1 and HSV-2 cause primary and recurrent genital herpes, genital recurrences are much more frequent with HSV-2 than with HSV-1 (5).HSV-2 infects epithelial cells in the vaginal mucosa, replicates in the cells, and enters the nerve endings innervating the mucosa. Viral capsids travel retrograde in axons to the cell body in sensory ganglia, where HSV establishes a latent infection in the nuclei of neurons. Latent HSV can be reactivated by multiple stimuli, such as stress, fever, and exposure to UV light. Viral capsids travel anterograde from the ganglion down the axons to the mucosa, where the virus replicates and is shed in the presence or absence of symptomatic genital lesions. This allows the virus to spread to unin- Citation Wang K, Goodman KN, Li DY, Raffeld M, Chavez M, Cohen JI. 2016. A herpes simplex virus 2 (HSV-2) gD mutant impaired for neural tropism is superior to an HSV-2 gD subunit vaccine to protect animals from challenge with HSV-2.

show abstract

Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease

Cited by 100 publications

References 58 publications

Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice

Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice

Activation and Function of iNKT and MAIT Cells

A Herpes Simplex Virus 2 (HSV-2) gD Mutant Impaired for Neural Tropism Is Superior to an HSV-2 gD Subunit Vaccine To Protect Animals from Challenge with HSV-2

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