Vaccination with a HSV-2 UL24 mutant induces a protective immune response in murine and guinea pig vaginal infection models

Visalli, Robert J.; Natuk, Robert J.; Kowalski, Jacek; Guo, Min; Blakeney, Susan J; Gangolli, Seema; Cooper, David A.

doi:10.1016/j.vaccine.2013.10.079

Cited by 11 publications

(5 citation statements)

References 70 publications

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“…In guinea pigs immunized with UL24-βgluc following a prime boost regimen prior to intravaginal challenge with WT HSV-2, the mean number of lesions as well as the cumulative number of recurrences was significantly reduced compared to sham-inoculated animals. Of note, HSV-2 DNA could not be detected in the DRGs of 75% of the guinea pigs vaccinated with UL24-βgluc prior to challenge with WT virus [98]. These results are promising and suggest that a Th1 skewed response may be commonly generated, recurrent disease symptoms can be ameliorated, and that establishment of latency can be interrupted following inoculation with live attenuated HSV-2 vaccine candidates.…”

Section: Discussionmentioning

confidence: 92%

“…Several live-attenuated HSV-2 vaccine candidates targeting various components of HSV-2 (e.g., ICP10, gE2, and UL24) have been developed pre-clinically and tested in animal models but none have completed human trials [93][94][95][96][97][98]. A replication-competent HSV-2 gE2 deletion mutant (gE2-del virus) deficient in epithelial cell-to-neuron spread was investigated as a therapeutic vaccine candidate in guinea pigs previously infected with HSV-2.…”

Section: Discussionmentioning

confidence: 99%

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Assessment of Two Novel Live-Attenuated Vaccine Candidates for Herpes Simplex Virus 2 (HSV-2) in Guinea Pigs

et al. 2021

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Treatment to ameliorate the symptoms of infection with herpes simplex virus 2 (HSV-2) and to suppress reactivation has been available for decades. However, a safe and effective preventative or therapeutic vaccine has eluded development. Two novel live-attenuated HSV-2 vaccine candidates (RVx201 and RVx202) have been tested preclinically for safety. Hartley guinea pigs were inoculated vaginally (n = 3) or intradermally (n = 16) with either vaccine candidate (2 × 107 PFU) and observed for disease for 28 days. All animals survived to study end without developing HSV-2-associated disease. Neither vaccine candidate established latency in dorsal root or sacral sympathetic ganglia, as determined by viral DNA quantification, LAT expression, or explant reactivation. Infectious virus was shed in vaginal secretions for three days following vaginal inoculation with RVx202, but not RVx201, although active or latent HSV-2 was not detected at study end. In contrast, guinea pigs inoculated with wild-type HSV-2 MS (2 × 105 PFU) vaginally (n = 5) or intradermally (n = 16) developed acute disease, neurological signs, shed virus in vaginal secretions, experienced periodic recurrences throughout the study period, and had latent HSV-2 in their dorsal root and sacral sympathetic ganglia at study end. Both vaccine candidates generated neutralizing antibody. Taken together, these findings suggest that these novel vaccine candidates are safe in guinea pigs and should be tested for efficacy as preventative and/or therapeutic anti-HSV-2 vaccines.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Assessment of Two Novel Live-Attenuated Vaccine Candidates for Herpes Simplex Virus 2 (HSV-2) in Guinea Pigs

et al. 2021

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“…The mice did not show clinical symptoms, and the latent infection and reactivation of the virus in the trigeminal ganglion were also greatly reduced (Jacobson et al, 1998;Rochette et al, 2015). Reduced pathogenicity was also observed in UL24 mutants of other herpesviruses, such as HSV-2 (Blakeney et al, 2005;Visalli et al, 2014). EHV-1 did not produce any neurotoxicity or lethal effects on mice after deletion of ORF37 (Kasem et al, 2010).…”

Section: Ul24 Affects Virus Pathogenicitymentioning

confidence: 99%

Mechanism of herpesvirus UL24 protein regulating viral immune escape and virulence

Ruan,

Wang,

Cheng

et al. 2023

Front. Microbiol.

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Herpesviruses have evolved a series of abilities involved in the process of host infection that are conducive to virus survival and adaptation to the host, such as immune escape, latent infection, and induction of programmed cell death for sustainable infection. The herpesvirus gene UL24 encodes a highly conserved core protein that plays an important role in effective viral infection. The UL24 protein can inhibit the innate immune response of the host by acting on multiple immune signaling pathways during virus infection, and it also plays a key role in the proliferation and pathogenicity of the virus in the later stage of infection. This article reviews the mechanism by which the UL24 protein mediates herpesvirus immune escape and its effects on viral proliferation and virulence by influencing syncytial formation, DNA damage and the cell cycle. Reviewing these studies will enhance our understanding of the pathogenesis of herpesvirus infection and provide evidence for new strategies to combat against viral infection.

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“…However, due mostly to safety concerns, only a few of these live vaccines have progressed into clinical trials ( 63 ). Live-attenuated HSV vaccines include: ( 1 ) The HSV-2 TK (-) mutant reported back in 1995 by Milligan and Bernstein and then by Kiyono in 2014 ( 72 ); ( 2 ) the RAV 9395 live attenuated recombinant virus; evaluated in guinea pigs and reported by Spaete back in 1998 ( 70 ); ( 3 ) AD472, a live attenuated recombinant HSV-2 vaccine evaluated in guinea pigs was reported back in 2005 ( 51 ); ( 4 ) The most studied HSV-1 and HSV-2 ICP0 (-) live-attenuated mutant vaccines, lacking the nuclear localization signal (NLS) on the ICP0 gene (0DeltaNLS), developed in 2010 by Halford and tested in mice and guinea pigs ( 69 , 73 – 76 ); ( 5 ) The HSV2-gD27 mutant vaccine reported by Cohen in 2012 ( 77 ); ( 6 ) The HSV-2 gE2-del mutant vaccine reported by Friedman in 2012 ( 78 ); ( 7 ) The HSV-2 UL24 mutant tested in mice and guinea pigs reported by Visalli in 2014 ( 67 ); and ( 8 ) The HSV-1 VC2 mutant reported by Kousoulas in 2014 ( 79 ).…”

Section: Hsv Vaccines: From Past To Presentmentioning

confidence: 99%

Combinatorial Herpes Simplex Vaccine Strategies: From Bedside to Bench and Back

et al. 2022

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The development of vaccines against herpes simplex virus type 1 and type 2 (HSV1 and HSV-2) is an important goal for global health. In this review we reexamined (i) the status of ocular herpes vaccines in clinical trials; and (ii) discusses the recent scientific advances in the understanding of differential immune response between HSV infected asymptomatic and symptomatic individuals that form the basis for the new combinatorial vaccine strategies targeting HSV; and (iii) shed light on our novel “asymptomatic” herpes approach based on protective immune mechanisms in seropositive asymptomatic individuals who are “naturally” protected from recurrent herpetic diseases. We previously reported that phenotypically and functionally distinct HSV-specific memory CD8+ T cell subsets in asymptomatic and symptomatic HSV-infected individuals. Moreover, a better protection induced following a prime/pull vaccine approach that consists of first priming anti-viral effector memory T cells systemically and then pulling them to the sites of virus reactivation (e.g., sensory ganglia) and replication (e.g., eyes and vaginal mucosa), following mucosal administration of vectors expressing T cell-attracting chemokines. In addition, we reported that a combination of prime/pull vaccine approach with approaches to reverse T cell exhaustion led to even better protection against herpes infection and disease. Blocking PD-1, LAG-3, TIGIT and/or TIM-3 immune checkpoint pathways helped in restoring the function of antiviral HSV-specific CD8+ T cells in latently infected ganglia and increased efficacy and longevity of the prime/pull herpes vaccine. We discussed that a prime/pull vaccine strategy that use of asymptomatic epitopes, combined with immune checkpoint blockade would prove to be a successful herpes vaccine approach.

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Vaccination with a HSV-2 UL24 mutant induces a protective immune response in murine and guinea pig vaginal infection models

Cited by 11 publications

References 70 publications

Assessment of Two Novel Live-Attenuated Vaccine Candidates for Herpes Simplex Virus 2 (HSV-2) in Guinea Pigs

Assessment of Two Novel Live-Attenuated Vaccine Candidates for Herpes Simplex Virus 2 (HSV-2) in Guinea Pigs

Mechanism of herpesvirus UL24 protein regulating viral immune escape and virulence

Combinatorial Herpes Simplex Vaccine Strategies: From Bedside to Bench and Back

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