Vaccine Development for Herpes Simplex Viruses

A special issue of Vaccines (ISSN 2076-393X).

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 29629

Special Issue Editors

Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy
Interests: human viruses; delivery systems; vaccines; preclinical development; immune metabolisms
Special Issues, Collections and Topics in MDPI journals
Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy
Interests: herpes simplex virus; vaccine; virus host interactions; immune responses to viruses; molecular virology; viral gene therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As you are already aware, herpes simplex viruses type 1 and type 2 (HSV-1 and HSV-2) are highly prevalent pathogens transmitted by direct contact, including sexual and mouth-to-genital transmission, which cause both lytic infection of epithelial cells and latent infection in sensory ganglia, which reactivate periodically. Recurrent productive infections are responsible for several painful clinical illnesses, including cold sores, keratitis, blepharitis, meningitis, encephalitis, genital infections, and overt disease and severe sequelae in neonatal and immune-compromised patients. Such recurrences are usually localized but can be generalized when the host is immune-compromised. In addition, roughly 1% of all HSV infected persons experience subclinical reactivation on any given day, allowing unknown spreading of virus infection. Herpes outbreaks make people more susceptible to other sexually transmitted infections and have facilitated a large proportion of HIV acquisition globally. Moreover, repeated reactivation of latent HSV-1 in the brain is considered a major risk for AD pathogenesis.

Current drugs are efficacious only in replicating HSV without any effect on latent virus, on its reactivation nor on preventing virus spread. Thus, disease caused by HSVs represent significant public health burdens.

The only means to prevent HSV infections and virus spreading and reactivation from latency is the development of an efficacious therapeutic and/or prophylactic vaccine. However, there is still an incomplete understanding of the immune response pathways elicited by HSV after initial mucosal infection, the correlates of protections, and how to prevent colonization and invasion of the dorsal root ganglia and nervous system. While no HSV licensed vaccine is available yet, there is the will to fill these gaps by rational design of HSV prophylactic and/or therapeutic vaccines and the choice of the proper adjuvant to elicit protective response.

To achieve a more extensive understanding of recent scientific knowledge and current trends in HSV vaccine development, this Special issue is focused on the recent scientific and technical progresses made in this field. Based on your extensive knowledge and experience, we invite you to contribute with an original report, original observation or review, to highlight (i) correlates of protection, (ii) immune pathways after primary infection, (iii) mechanisms of colonization and invasion of the nervous system, and (iv) recent advances in novel prophylactic and therapeutic vaccines.

Dr. Antonella Caputo
Dr. Peggy Marconi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Vaccines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (8 papers)

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Editorial

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3 pages, 181 KiB  
Editorial
Vaccine Development for Herpes Simplex Viruses: A Commentary of Special Issue Editors
Vaccines 2021, 9(2), 158; https://doi.org/10.3390/vaccines9020158 - 16 Feb 2021
Cited by 2 | Viewed by 2090
Abstract
Herpes simplex virus type 1 and 2 (HSV1 and HSV2) are global, widespread human pathogens transmitted by direct contact that cause lifelong, recurrent asymptomatic and painful symptomatic clinical illnesses (cold sores, keratitis, blepharitis, meningitis, encephalitis, genital infections), overt disease and severe sequelae in [...] Read more.
Herpes simplex virus type 1 and 2 (HSV1 and HSV2) are global, widespread human pathogens transmitted by direct contact that cause lifelong, recurrent asymptomatic and painful symptomatic clinical illnesses (cold sores, keratitis, blepharitis, meningitis, encephalitis, genital infections), overt disease and severe sequelae in neonatal and immune-compromised patients, and increased risk of cervical cancer and other sexually transmitted infections, including HIV [...] Full article
(This article belongs to the Special Issue Vaccine Development for Herpes Simplex Viruses)

Research

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19 pages, 2674 KiB  
Article
Epidemiological Impact of Novel Preventive and Therapeutic HSV-2 Vaccination in the United States: Mathematical Modeling Analyses
Vaccines 2020, 8(3), 366; https://doi.org/10.3390/vaccines8030366 - 08 Jul 2020
Cited by 15 | Viewed by 3131
Abstract
This study aims to inform herpes simplex virus type 2 (HSV-2) vaccine development, licensure, and implementation by delineating the population-level impact of vaccination. Mathematical models were constructed to describe the transmission dynamics in presence of prophylactic or therapeutic vaccines assuming 50% efficacy, with [...] Read more.
This study aims to inform herpes simplex virus type 2 (HSV-2) vaccine development, licensure, and implementation by delineating the population-level impact of vaccination. Mathematical models were constructed to describe the transmission dynamics in presence of prophylactic or therapeutic vaccines assuming 50% efficacy, with application to the United States. Catch-up prophylactic vaccination will reduce, by 2050, annual number of new infections by 58%, incidence rate by 60%, seroprevalence by 21%, and avert yearly as much as 350,000 infections. Number of vaccinations needed to avert one infection was only 50 by 2050, 34 by prioritizing those aged 15–19 years, 4 by prioritizing the highest sexual risk group, 43 by prioritizing women, and 47 by prioritizing men. Therapeutic vaccination of infected adults with symptomatic disease will reduce, by 2050, annual number of new infections by 12%, incidence rate by 13%, seroprevalence by 4%, and avert yearly as much as 76,000 infections. Number of vaccinations needed to avert one infection was eight by 2050, two by prioritizing those aged 15–19 years, three by prioritizing the highest sexual risk group, seven by prioritizing men, and ten by prioritizing women. HSV-2 vaccination offers an impactful and cost-effective intervention to prevent genital herpes medical and psychosexual disease burden. Full article
(This article belongs to the Special Issue Vaccine Development for Herpes Simplex Viruses)
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14 pages, 3375 KiB  
Article
Vaccination Route as a Determinant of Protective Antibody Responses against Herpes Simplex Virus
Vaccines 2020, 8(2), 277; https://doi.org/10.3390/vaccines8020277 - 05 Jun 2020
Cited by 12 | Viewed by 3309
Abstract
Herpes simplex viruses (HSV) are significant global health problems associated with mucosal and neurologic disease. Prior experimental vaccines primarily elicited neutralizing antibodies targeting glycoprotein D (gD), but those that advanced to clinical efficacy trials have failed. Preclinical studies with an HSV-2 strain deleted [...] Read more.
Herpes simplex viruses (HSV) are significant global health problems associated with mucosal and neurologic disease. Prior experimental vaccines primarily elicited neutralizing antibodies targeting glycoprotein D (gD), but those that advanced to clinical efficacy trials have failed. Preclinical studies with an HSV-2 strain deleted in gD (ΔgD-2) administered subcutaneously demonstrated that it elicited a high titer, weakly neutralizing antibodies that activated Fcγ receptors to mediate antibody-dependent cellular cytotoxicity (ADCC), and completely protected mice against lethal disease and latency following vaginal or skin challenge with HSV-1 or HSV-2. Vaccine efficacy, however, may be impacted by dose and route of immunization. Thus, the current studies were designed to compare immunogenicity and efficacy following different routes of vaccination with escalating doses of ΔgD-2. We compared ΔgD-2 with two other candidates: recombinant gD protein combined with aluminum hydroxide and monophosphoryl lipid A adjuvants and a replication-defective virus deleted in two proteins involved in viral replication, dl5-29. Compared to the subcutaneous route, intramuscular and/or intradermal immunization resulted in increased total HSV antibody responses for all three vaccines and boosted the ADCC, but not the neutralizing response to ΔgD and dl5-29. The adjuvanted gD protein vaccine provided only partial protection and failed to elicit ADCC independent of route of administration. In contrast, the increased ADCC following intramuscular or intradermal administration of ΔgD-2 or dl5-29 translated into significantly increased protection. The ΔgD-2 vaccine provided 100% protection at doses as low as 5 × 104 pfu when administered intramuscularly or intradermally, but not subcutaneously. However, administration of a combination of low dose subcutaneous ΔgD-2 and adjuvanted gD protein resulted in greater protection than low dose ΔgD-2 alone indicating that gD neutralizing antibodies may contribute to protection. Taken together, these results demonstrate that ADCC provides a more predictive correlate of protection against HSV challenge in mice and support intramuscular or intradermal routes of vaccination. Full article
(This article belongs to the Special Issue Vaccine Development for Herpes Simplex Viruses)
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11 pages, 660 KiB  
Communication
The Tat Protein of HIV-1 Prevents the Loss of HSV-Specific Memory Adaptive Responses and Favors the Control of Viral Reactivation
Vaccines 2020, 8(2), 274; https://doi.org/10.3390/vaccines8020274 - 04 Jun 2020
Cited by 3 | Viewed by 2375
Abstract
The development of therapeutic strategies to control the reactivation of the Herpes Simplex Virus (HSV) is an unaddressed priority. In this study, we evaluated whether Tat, a HIV-1 protein displaying adjuvant functions, could improve previously established HSV-specific memory responses and prevent viral reactivation. [...] Read more.
The development of therapeutic strategies to control the reactivation of the Herpes Simplex Virus (HSV) is an unaddressed priority. In this study, we evaluated whether Tat, a HIV-1 protein displaying adjuvant functions, could improve previously established HSV-specific memory responses and prevent viral reactivation. To this aim, mice were infected with non-lethal doses of HSV-1 and, 44 days later, injected or not with Tat. Mice were then monitored to check their health status and measure memory HSV-specific cellular and humoral responses. The appearance of symptoms associated with HSV-reactivation was observed at significantly higher frequencies in the control group than in the Tat-treated mice. In addition, the control animals experienced a time-dependent decrease in HSV-specific Immunoglobulin G (IgG), while the Tat-treated mice maintained antibody titers over time. IgG levels were directly correlated with the number of HSV-specific CD8+ T cells, suggesting an effect of Tat on both arms of the adaptive immunity. Consistent with the maintenance of HSV-specific immune memory, Tat-treated mice showed a better control of HSV-1 re-infection. Although further studies are necessary to assess whether similar effects are observed in other models, these results indicate that Tat exerts a therapeutic effect against latent HSV-1 infection and re-infection by favoring the maintenance of adaptive immunity. Full article
(This article belongs to the Special Issue Vaccine Development for Herpes Simplex Viruses)
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10 pages, 1297 KiB  
Article
HSV-1-Specific IgG3 Titers Correlate with Brain Cortical Thinning in Individuals with Mild Cognitive Impairment and Alzheimer’s Disease
Vaccines 2020, 8(2), 255; https://doi.org/10.3390/vaccines8020255 - 29 May 2020
Cited by 10 | Viewed by 2589
Abstract
Repeated reactivations of latent herpes simplex virus type-1 (HSV-1) in the central nervous system (CNS) may contribute to neurodegeneration in Alzheimer’s disease (AD) patients. Immune response is a key element for the control of viral reactivation. HSV-1 uses a number of strategies to [...] Read more.
Repeated reactivations of latent herpes simplex virus type-1 (HSV-1) in the central nervous system (CNS) may contribute to neurodegeneration in Alzheimer’s disease (AD) patients. Immune response is a key element for the control of viral reactivation. HSV-1 uses a number of strategies to evade immune recognition, Immunoglobulin G 3 (IgG3) alone counteracts humoral immunoevasion, as it is the only IgG subclass that is not blocked by the HSV-1 Fc receptor, a protein that protects virion and infected cells from antibody-mediated effector mechanisms. We examined HSV-1-specific IgG3 titers in serum of AD (n = 70) and mild cognitive impairment (MCI) (n = 61) subjects comparing the results to those of 67 age- and sex-matched healthy controls (HC); associations between MRI-determined brain cortical health and HSV-1-specific IgG3 were analyzed in a subgroup of AD and MCI subjects. HSV-1-specific IgG3 were more frequently detected in MCI compared to AD and HC subjects. Significant inverse correlations were found between IgG3 titers and brain cortical thickness in areas typically involved in dementia and HSV-1 encephalitis in AD patients; interestingly, this negative correlation was much less important in MCI subjects. All together these results suggest that in AD an inefficient IgG3 humoral immune response, failing to block viral replication, contributes to progressive neurodegeneration. Full article
(This article belongs to the Special Issue Vaccine Development for Herpes Simplex Viruses)
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Review

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22 pages, 524 KiB  
Review
Immune Response to Herpes Simplex Virus Infection and Vaccine Development
Vaccines 2020, 8(2), 302; https://doi.org/10.3390/vaccines8020302 - 12 Jun 2020
Cited by 20 | Viewed by 6882
Abstract
Herpes simplex virus (HSV) infections are among the most common viral infections and usually last for a lifetime. The virus can potentially be controlled with vaccines since humans are the only known host. However, despite the development and trial of many vaccines, this [...] Read more.
Herpes simplex virus (HSV) infections are among the most common viral infections and usually last for a lifetime. The virus can potentially be controlled with vaccines since humans are the only known host. However, despite the development and trial of many vaccines, this has not yet been possible. This is normally attributed to the high latency potential of the virus. Numerous immune cells, particularly the natural killer cells and interferon gamma and pathways that are used by the body to fight HSV infections have been identified. On the other hand, the virus has developed different mechanisms, including using different microRNAs to inhibit apoptosis and autophagy to avoid clearance and aid latency induction. Both traditional and new methods of vaccine development, including the use of live attenuated vaccines, replication incompetent vaccines, subunit vaccines and recombinant DNA vaccines are now being employed to develop an effective vaccine against the virus. We conclude that this review has contributed to a better understanding of the interplay between the immune system and the virus, which is necessary for the development of an effective vaccine against HSV. Full article
(This article belongs to the Special Issue Vaccine Development for Herpes Simplex Viruses)
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16 pages, 881 KiB  
Review
Herpes Simplex Viruses Whose Replication Can Be Deliberately Controlled as Candidate Vaccines
Vaccines 2020, 8(2), 230; https://doi.org/10.3390/vaccines8020230 - 18 May 2020
Cited by 3 | Viewed by 2679
Abstract
Over the last few years, we have been evaluating a novel paradigm for immunization using viruses or virus-based vectors. Safety is provided not by attenuation or inactivation of vaccine viruses, but by the introduction into the viral genomes of genetic mechanisms that allow [...] Read more.
Over the last few years, we have been evaluating a novel paradigm for immunization using viruses or virus-based vectors. Safety is provided not by attenuation or inactivation of vaccine viruses, but by the introduction into the viral genomes of genetic mechanisms that allow for stringent, deliberate spatial and temporal control of virus replication. The resulting replication-competent controlled viruses (RCCVs) can be activated to undergo one or, if desired, several rounds of efficient replication at the inoculation site, but are nonreplicating in the absence of activation. Extrapolating from observations that attenuated replicating viruses are better immunogens than replication-defective or inactivated viruses, it was hypothesized that RCCVs that replicate with wild-type-like efficiency when activated will be even better immunogens. The vigorous replication of the RCCVs should also render heterologous antigens expressed from them highly immunogenic. RCCVs for administration to skin sites or mucosal membranes were constructed using a virulent wild-type HSV-1 strain as the backbone. The recombinants are activated by a localized heat treatment to the inoculation site in the presence of a small-molecule regulator (SMR). Derivatives expressing influenza virus antigens were also prepared. Immunization/challenge experiments in mouse models revealed that the activated RCCVs induced far better protective immune responses against themselves as well as against the heterologous antigens they express than unactivated RCCVs or a replication-defective HSV-1 strain. Neutralizing antibody and proliferation responses mirrored these findings. We believe that the data obtained so far warrant further research to explore the possibility of developing effective RCCV-based vaccines directed to herpetic diseases and/or diseases caused by other pathogens. Full article
(This article belongs to the Special Issue Vaccine Development for Herpes Simplex Viruses)
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Other

11 pages, 676 KiB  
Brief Report
Herpes Simplex Virus Type 2 Is More Difficult to Neutralize by Antibodies Than Herpes Simplex Virus Type 1
Vaccines 2020, 8(3), 478; https://doi.org/10.3390/vaccines8030478 - 27 Aug 2020
Cited by 6 | Viewed by 4289
Abstract
Infections with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are a global health burden. Besides painful oral or genital lesions in otherwise healthy subjects, both viruses can cause devastating morbidity and mortality in immune-compromised and immune-immature individuals. The latter are [...] Read more.
Infections with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are a global health burden. Besides painful oral or genital lesions in otherwise healthy subjects, both viruses can cause devastating morbidity and mortality in immune-compromised and immune-immature individuals. The latter are particularly susceptible to a disseminated, life-threatening disease. Neutralizing antibodies (NAb) constitute a correlate of protection from disease, and are promising candidates for the prophylactic or therapeutic treatment of severe HSV infections. However, a clinical vaccine trial suggested that HSV-2 might be more resistant to NAbs than HSV-1. In the present study, we investigated the antiviral efficacy of the well-characterized humanized monoclonal antibody (mAb) hu2c against HSV-2, in a NOD/SCID immunodeficiency mouse model. Despite the fact that hu2c recognizes a fully conserved epitope and binds HSV-1 and HSV-2 glycoprotein B with equal affinity, it was much less effective against HSV-2 in vitro and in NOD/SCID mice. Although intravenous antibody treatment prolonged the survival of HSV-2-infected mice, complete protection from death was not achieved. Our data demonstrate that HSV-2 is more resistant to NAbs than HSV-1, even if the same antibody and antigen are concerned, making the development of a vaccine or therapeutic antibodies more challenging. Full article
(This article belongs to the Special Issue Vaccine Development for Herpes Simplex Viruses)
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