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Insights into the Novel Therapeutics and Vaccines against Herpes Simplex Virus

Shiza malik.

1 Bridging Health Foundation, Rawalpindi 46000, Pakistan

2 Department of Microbiology, Institute of Medicine, Tribhuvan University Teaching Hospital, Kathmandu 44600, Nepal

3 Department of Microbiology, Dr. D. Y. Patil Medical College, Hospital and Research Center, Dr. D. Y. Patil Vidyapeeth, Pune 411018, Maharashtra, India

4 Department of Medicine, School of Health Sciences, Foundation University Islamabad, DHA Phase I, Islamabad 44000, Pakistan

Khalid Muhammad

5 Department of Biology, College of Science, UAE University, Al Ain 15551, United Arab Emirates

Yasir Waheed

6 Office of Research, Innovation, and Commercialization (ORIC), Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad 44000, Pakistan

7 Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos 1401, Lebanon

Associated Data

Not applicable.

Herpes simplex virus (HSV) is a great concern of the global health community due to its linked infection of inconspicuous nature and resultant serious medical consequences. Seropositive patients may develop ocular disease or genital herpes as characteristic infectious outcomes. Moreover, the infectious nature of HSV is so complex that the available therapeutic options have been modified in certain ways to cure it. However, no permanent and highly effective cure has been discovered. This review generates insights into the available prophylactic and therapeutic interventions against HSV. A methodological research approach is used for study design and data complication. Only the latest data from publications are acquired to shed light on updated therapeutic approaches. These studies indicate that the current antiviral therapeutics can suppress the symptoms and control viral transmission up to a certain level, but cannot eradicate the natural HSV infection and latency outcomes. Most trials that have entered the clinical phase are made part of this review to understand what is new within the field. Some vaccination approaches are also discussed. Moreover, some novel therapeutic options that are currently in research annals are given due consideration for future development. The data can enable the scientific community to direct their efforts to fill the gaps that remain unfilled in terms of therapies for HSV. The need is to integrate scientific efforts to produce a proper cure against HSV to control the virus spread, resistance, and mutation in future disease management.

1. Introduction

Herpes simplex virus (HSV) belongs to the family of Alphaherpesvirinae with a characteristic double-stranded DNA structural composition [ 1 ]. Its two main serotypes, HSV-1 and HSV-2, are mainly known for their links with infectious diseases [ 2 ]. According to estimates by WHO, approximately 70–90% of the population worldwide is seropositive for HSV-2, which makes it a great concern for the healthcare community regarding the possibility of developing infections (James & Kimberlin, 2015b) [ 3 ]. HSV-1 is considered the main causative agent of ocular infection that may occur in patients already having diseases such as genital lesions, keratitis or retinal necrosis, encephalitis, iridocyclitis, or conjunctivitis [ 4 , 5 , 6 ]. Some studies have also established links between longstanding HSV-1 serology with psychological complications, including Alzheimer’s disease [ 7 ]. On the other hand, HSV-2 is predominantly linked with characteristic genital herpes disease of the herpes virus. These infections are worldwide, irrespective of the developing or industrialized national standing [ 8 ].

HSV-2 virus is a sexually transmitted infectious agent that is prevalent in approximately 536 million people worldwide, standing at an annual incidence rate of about 23.6 million cases, as per the updates by the CDC [ 9 , 10 ]. The genital area is the prime target of viral infection; however, it may also cause infections similar to HSV-1, including necrotizing stromal keratitis in the eyes, meningitis, encephalitis, and neurological complications [ 11 ]. However, not all HSV-2-positive cases develop genital herpes or ulcerative and vesicular lesions because the virus mostly remains in a latency phase that makes it possible to transmit to other members of the populace without getting noticed and without exhibiting any infectious outcomes [ 12 ]. In simple words, the sexual transmission may not be coupled with a clinical history or symptomatology of genital herpes. The symptomology makes the viral presence rarely fatal, but the same is not the case for babies from infected mothers and pregnant ladies, due to their immunocompromised system and susceptibility to easily acquire infection [ 12 , 13 , 14 ].

The most prevalent feature that makes HSV infection complications is its ability to enter a nonreplicating latency period, which enables it to survive long periods of inactivation within the host and gives it the ability to reactivate and infect the host under different external and internal stimuli [ 12 , 13 ]. The latency period is mostly asymptomatic; thus, viral transmission during this period remains unrecognized. This aspect is considered the major reason for the large-scale seroprevalence of HSV [ 13 ]. Additionally, it can infect almost every type of cell for the characteristic receptor recognition strategies, making it pertinent to large-scale population spread [ 10 ]. This property is associated with the presence of hundreds of diverse glycoproteins in HSV lipid bilayers that alter its receptor recognition and viral entry into host cells [ 8 , 15 , 16 , 17 , 18 , 19 ]. Furthermore, it uses multiple strategies for viral fusion, endocytosis, and transmission among cells, all of which cause further complications its treatment procedures [ 20 , 21 ]. Thus, most of the therapeutic studies are limited in terms of their effectiveness and inability to eradicate infections.

The complex nature of the virus, in terms of symptomatic infections and asymptomatic presence and recurrence, makes its cure difficult; for this reason, no vaccination or therapeutic cure has been devised that could completely eradicate HSV infection [ 21 , 22 ]. Moreover, the lifelong presence of HSV-2 infection further complicates the treatment procedures because it may require prolonged administration of standard proposed treatments, which is in line with its resistive nature [ 12 , 23 ]. In this review, we discuss the primary nature of HSV that makes it complicated for the design of therapeutics. This understanding can set the pace for further insight into the therapeutic interventions designed to date [ 24 ]. We discuss how the antiviral strategies are designed knowing the complexities associated with viral entry, infection, and persistence. The focus is on therapeutic developments that may hold hope for future control over HSV infections.

2. Materials and Methods

A systematic approach was used to gather the latest data regarding the different dimensions of H. simplex virus infection and the accumulated therapeutic and vaccination strategies. We searched electronic sources such as Google Scholar, Pub Med, NIH (National Library of Medicine), Scopus (Elsevier), and Web of Science. Moreover, the official websites of WHO, CDC, UNAID, and FDA were also used to obtain the statistical results and latest updates regarding HSV epidemiology, as well as ongoing treatment efforts. As the studies mainly incorporated the data regarding therapeutics against HSV viruses, the major research terms were “Herpes simplex virus”, “HSV infection”, “therapeutics against HSV”, “antiviral agents”, “vaccines against HSV”, “therapies against HSV”, “novel therapeutic approaches”, and some other linked search terms. After a thorough analysis of the dates, abstracts, titles, and journals of research publications, they were made part of this review. The process of information gathering was not limited to a few studies but rather collected from research compilations in the form of original research articles, reviews, short commentaries, case reports, and letters to the editors. Lastly, the search strategy was limited to incorporating data from 2010 to 2022 to add only the most recent advances related to HSV disease management.

3. Results and Discussion

3.1. the pathological biology of hsv and associated infection.

As explained earlier, HSV belongs to the family of neurotropic alpha herpesviruses, which are well known for latency features [ 4 , 12 ]. The virus particle consists of an internal dense electron core that contains the reproductive material in the form of double-stranded DNA [ 25 ]. All age groups of people are prone to developing HSV infection. Some other pathogenic species of viruses belonging to the same DNA herpes family of viruses include varicella-zoster virus (VZV), Epstein–Barr virus (EBV), cytomegalovirus, and human herpes types 6, 7, and 8 [ 26 ]. The two subtypes of HSV-1 and HSV-2 share close genomic relevance with >80% of the amino-acid identity profile. Moreover, both share the common infectious nature of causing oral and genital ulcerations [ 26 , 27 ].

HSV DNA has been well studied and formulated to encode 70+ genes. The genomic portion is enveloped by a viral capsid of icosahedral shape that in turn displays >162 known protein units (capsomers) [ 28 , 29 ]. The virus capsid is further surrounded by a lipid bilayer envelope consisting of tegument proteins and several dozen glycoproteins on the surface. Of this GP, five glycoproteins with known functions are gB, gC, gD, gH, and gl [ 30 ]. These proteins facilitate host viral coordination in terms of attachment, binding, and host cell penetration and entry [ 31 , 32 ]. The complex mechanism of HSV host interaction and its latency period present scientists with a great challenge [ 33 ]. The host virus entry mechanisms, cellular interaction, and infectious cycles are, thus, the prime focus of understanding for scientists developing therapeutics. This is discussed in relevance to HSV therapeutics in a later section of this article to describe to the readers the procedures, limitations, and progress achieved in this domain [ 27 , 34 ].

The virus Infection mainly begins with the epithelial cells of the skin or mucosal surfaces. The virus particle then trickles down to nerve endings and nerve axons, where the virus undergoes persistent infection within the trigeminal or lumbosacral ganglia region [ 12 , 35 ]. After establishing virus progeny in this area, it returns to the mucosal and skin surfaces to produce oral or genital ulcers. At other times, it remains asymptomatic, associated with viral shedding and silent transmission to other hosts [ 36 , 37 ]. This asymptomatic and silent transmission nature makes HSV spread quite extensively unnoticed in the population, as most cases remain subclinical and, thus, hidden from diagnosis [ 1 , 21 ]. The clinical manifestations of HSV-1 and HSV-2 vary depending on the age group, entry route, host immune response, and initial or recurrent nature of the infection [ 1 ].

HSV-1 is linked with episodes of genital and neonatal herpes, in addition to mainly causing oral and facial infections [ 38 ]. The disease incidences are higher in HICs, though the disease occurrence rates in neonates are lower compared to the incidence in children in LICs, where ≥90% people acquire HSV-1 infection by adolescence, which makes it a great healthcare burden for the world [ 10 ]. The major disease outcomes of HSV-1 infection include herpes labialis, gingivostomatitis, HSV-linked infectious encephalitis, keratitis, and pharyngitis [ 39 ]

HSV-2, on the other hand, is mainly dependent on sexual transmission and is associated with genital ulceration (genital ulcer disease (GUD)). Apart from the risk of neonatal herpes and possibly being associated with the development of neurological disorders such as Alzheimer’s at a later age, an increased risk of developing HIV infection is linked to HSV-2 infection [ 1 , 12 , 14 ]. The disease incidence is continuously rising on an annual basis due to the silent nature among sexual partners with high HSV-2 seroprevalence [ 3 , 13 ]. Additionally, the incidence rates are mostly outlined for high-income countries where R&D is progressively outlined in databases, while, in the case of low-income countries, the incidence rates are still unknown [ 10 ]. Neonatal herpes infections are often the major causes of increased morbidity and mortality rates. Most importantly, HSV-2 infection and transmission are linked with up to threefold increased incidence of HIV epidemics, with incidence rates up to 23–50% being the major concern regarding healthcare management. Moreover, the clinical complications in terms of life-threatening incidences may be accounted for in immunocompromised individuals [ 40 ].

The major diagnostic tests performed for HSV detection mainly include polymerase chain reaction, type-specific serological essays, viral culture, and antigen detection assays, which differentiate between the two subtypes of HSV [ 21 , 41 ]. The main treatment strategies against genital herpes mainly include antiviral treatments, such as acyclovir, valacyclovir, or famciclovir among other antiviral agents mentioned by WHO guidelines [ 3 , 9 , 22 ]. Most of these treatment regimens require continuous application to reduce the symptoms without permanently dealing with the virus prevalence. In the upcoming sections, we discuss the various therapeutic strategies and vaccination efforts against HSV carried out recently, as well as outline the futuristic perspective for HSV treatment.

3.2. Current Vaccination Efforts against HSV

Currently, no vaccine has been specified against HSV infection; however, several vaccination candidates are in research annals for vaccine development. Most of the clinical efforts are directed toward HSV-2 for its greater infectious outcomes, but HSV-2 vaccines will have benefits against both subtypes of viruses because of their sequence homology [ 42 , 43 , 44 ]. Several lines of research show that HSV vaccination is feasible. Successful vaccination strategies against varicella-zoster virus by using replated herpes virus biology, bovine herpesvirus-1, and herpesvirus-1 (pseudorabies virus) indicate that effective vaccine efforts against HSV can be successful [ 44 ]. Similarly, work on vaccines along with antiviral adjuvants has also presented preventive abilities against herpes zoster infection, with proven 97% efficacy in phase III trials [ 43 , 44 , 45 ].

Studies on human papillomavirus vaccination protocols are also helping with the understanding of immunomodulatory regulation which can be effectively induced with vaccination against HSV [ 43 , 46 ]. Some other research groups tested herpes vaccine trials with truncated glycoprotein D2 (Gd2T) vaccines tested on thousands of HSV-positive cases and demonstrated vaccine efficacy of up to 58% against HSV-1 with little or no effect against HSV-2. These studies indicated that immunomodulation against HSV-1 can be achieved with antibody titers, but the same cannot yet be shown for HSV-2 [ 21 , 30 ]. Additionally, the viral sequencing, widescale data availability, and genetic profiling for both HSV-1 and HSV-2 predict that better vaccination protocols could be implemented with the identification of potential targets for therapeutic development. With proper and coordinated efforts among bioinformaticians and clinicians, these efforts could be successful [ 46 , 47 ].

The rigorous efforts put forward for vaccination development come in two major forms, preventive and therapeutic vaccination protocols [ 48 ]. The former provides pre-exposure immune-protective responses against HSV-2 infection development tested over the long term up to phase III trials [ 43 ]. These trials have mostly been limited to HIC. It is hypothesized that the same preventive vaccination practices in LMIC could produce better results in terms of disease mitigation and adaptive management. For this cause, the geographic strain diversity must be accounted for during vaccination development to ensure the nonrestrictive geographic nature of HSV vaccination. Scientists propose that, if any candidate vaccine was found to be effective for both HSV subtypes, it could be shifted from adolescents to infants for the possible prevention option [ 14 , 49 ].

Therapeutic vaccines, in contrast, are being tested to reduce the disease symptoms and viral transmission across the hosts, for the larger benefit of public health management. For this route, the targeted populace is mostly HSV-2-infected persons. Some therapeutic candidates have been checked up to phase I and II trials with proven antiviral effects, as well as decreased viral shedding and lesion formation in infected subjects [ 30 , 48 ]. Similar to the first line of preventive vaccinations, this route has also been tested mostly in HIC without solid testing in LMICs [ 20 ]; a limitation to these preclinical trials on animals is that they cannot be assumed to be effective in humans since the host viral interaction could be different in people. Thus, certain limitations are attached to phase I and II trials. Therefore, some effort should be put into clinical experimentation for rapid disease management in the future [ 47 ].

3.3. Outlining the Current Vaccines against HSV

Various vaccine candidates are in research annals for preclinical and clinical evaluation. Currently, there is no specific FDA-approved vaccine against HSV infection [ 9 ]. The ongoing clinical and preclinical trials are based on the rational understanding of HSV biology and immunopathogenesis in host cells. Some of the latest vaccine designs, their working mechanism, and ongoing trials are outlined briefly in the Table 1 .

An update on current vaccine candidates against HSV.

3.3.1. Subunit Vaccines against HSV

Subunit vaccines are composed of viral components, such as glycoproteins and protein subunits, which undergo protective immune responses to the host [ 50 ]. They have proven safer, stable, and effective for HPV vaccination design and immunization design, but still lack clinical experimental success against HSV [ 51 ]. They mostly use viral glycoproteins and antigenic mediators such as Gb/Gd/gE in their antiviral design. This type of vaccine varies in function and procures the inhibition of viral entry, viral shedding, transmission across cells, and immune-evasive responses [ 42 , 50 , 51 ]. Novel experiments are ongoing that link multiple herpes antigens and peptide epitopes in one vaccination protocol. Approximately 80–300 open readings frames (ORFs) identified by multi-omics technologies are under consideration for antigenic breadth generation and efficiency in subunit vaccines against HSV [ 42 , 52 , 53 ].

This method of vaccination provides a gateway to present complex antigenic composition to the immune system that may include T- and B-cell epitopes [ 22 , 72 ]. For testing the efficacy of these vaccines, several recombinant protein formats have been tested that are conceptually similar and undergo the introduction of HSV ORFs (complete or near complete), into bacterial or other vector systems [ 54 , 73 ]. Moreover, these vaccine combinations with certain adjuvants and vaccine formats have opened a new route to explore options for HSV vaccination in the future.

3.3.2. Vectored/DNA/RNA Vaccines against HSV

DNA- and mRNA-based vaccines have been in research annals for a long time now. The same approach has been successfully used in COVID vaccination design and is now being successfully utilized against HSV [ 74 , 75 ]. Experiments have been conducted on animal models to check the efficacy of nucleoside-modified mRNA-based vaccines against HSV-2 infection [ 75 ]. The results indicated a therapeutic reduction in symptoms within animal models in a dose-dependent manner. Moreover, these vaccines stimulate immune responses in the form of neutralizing antibodies [ 76 ]. Studies have shown that DNA is a better candidate for its stability, synthesis characteristics, and purification protocol and can be better managed compared to mRNA [ 29 , 62 ].

DNA-based vector vaccines have shown efficacy even better than subunit vaccines but not as effective as live-attenuated vaccines [ 29 , 62 ]. Moreover, some clinical concerns in the form of side-effects remain linked to the application of vehicle vector carriers [ 77 ]. Thus, adenovirus vector-based vaccines exhibit a better stability profile than mRNA vaccines. Recent studies showed the use of Vaccinia and MVA vectors for the deployment of transgenetic expression and virulence in tested subjects against different viral diseases caused by HIV, influenza, measles, flavivirus, and malaria vectors [ 11 , 45 ]. Thus, these insights into vaccination approaches compel scientists to drain effective vaccination efforts against HSV [ 78 ].

3.3.3. Live-Attenuated Vaccines against HSV

The live-attenuated vaccination method has been the most used and effective method against viral infections through history, such as smallpox vaccination, poliomyelitis, measles, mumps, rubella virus, rotavirus, and many other infections [ 63 ]. The mechanism of inactivation often includes chemical or radiation-based inactivation of virus particles. One of the antiviral vaccine candidates derived for chicken pox virus/HSV-3 (varicella-zoster virus (VZV)) is also based on a live-attenuated virus vaccination protocol [ 62 ]. It is safe and well tolerated with a highly effective profile that controls viral reactivation. This and several other examples guide a more effective vaccination protocol to be designed on the basis of this mechanism [ 43 , 62 , 63 , 64 ].

Live-attenuated vaccination has also contributed to the development of FDA-approved oncolytic virotherapy against herpes simplex virus known as (TVEC or Imlygic), which limits virus replication and regulates human immunity, and which is used for treating human melanoma [ 63 ]. Following this approach, novel vaccination drives are being tailored in medical science to reduce the side-effects and induce long-term immunity against HSV infection, with the aim of achieving prophylactic and therapeutic goals to reduce viral infection and reduce the disease symptomology [ 43 , 62 ]. Moreover, efforts are being directed to reducing the neurotropism and latency associated with HSV while designing the live-attenuated vaccination regimens. Thus, by introducing certain insertions and/or or deletions in the viral progeny, the vaccination attempts show disrupting neuronal retrograde transport and the respective inability of HSV to affect neuronal cells [ 32 , 38 , 65 ]. Some important clinical ongoing trials in this regard are provided in Table 1 .

3.3.4. Peptide Vaccines against HSV

Peptide vaccines are developed on the principle that a single molecular entity or peptide epitope could generate massive immune responses to protect against a particular disease. In this regard, immunization with immuno-dominant T-cell epitopes or neutralizing epitopes has been tested and found to be protective [ 58 ]. This system of vaccination has shown better outcomes upon the combined application of certain adjuvants such as heat-shock proteins that may be expressed in recombinant viruses or bacterial expression systems [ 37 ]. However, the complications and limitations associated with the widespread human population and differential immune responses that may entail immunodominant responses by a certain peptide hinder the development of peptide-based vaccines [ 25 , 31 ]. However, efforts are still in research annals to develop better vaccination options for both serotypes of HSV.

3.3.5. Killed-Virus Vaccines against HSV

Similar to the live-attenuated mechanism, this mechanism involves variations in terms of killed virus vaccination to avoid the risk of reactivation of viruses in subjects. Traditionally, phenol chemicals and UV light treatments have been used for this purpose, but other methods of viral inactivation have also been used more recently [ 79 , 80 ]. This approach is used as immunotherapy but remains underrated as it only provides little help to regress the viral infection, which is a property of natural infection. Recent advances have been made, and some newer studies are in progress that use sonication, chemicals, radiation, UV light, formaldehyde treatment, or their combination to cause viral death [ 80 , 81 , 82 ]. Moreover, experiments are performed by regulating the dosage amount, time, route, and number of administrations and combination with adjuvants to check the efficacy. However, further work is necessary to deduce the efficiency of this vaccination method [ 80 , 83 ].

3.3.6. Fractionated-Virus Vaccines against HSV

In these protocols, HSV vaccines are prepared by subjecting the infected cultured cells to various procedures, which inactivate the virus particles while partially purifying some viral protein subsets [ 82 , 84 ]. Trials are ongoing on such vaccination methods. In simple terms, viral characteristic proteins such as those used in peptide vaccines (e.g., gPs) are mixed with inactive virus particles and with some adjuvants to produce a binding effect of the vaccine. Previous studies have shown little or no effect on immune responses; thus, this approach requires further work to induce productive clinical outcomes [ 30 , 31 ].

3.3.7. Discontinuously Replicating Virus Vaccines against HSVs

In this method, some important genes required for viral replication or transmission are either deleted or replaced with other genes. The method is mainly used to study the functionalities of different proteins; however, the same approach is often used for designing vaccines [ 22 , 73 ]. These viruses may undergo replication but are unable to further infect the cell because they are transmission noncompetent. Because of this effect, they are termed as discontinuously replicating viruses. They exhibit the property of inability to restimulate periodically to have a recurrent, peripheral lytic replication cycle [ 47 , 64 ]. They have been checked in animal subjects for creating strong immune responses, with some candidates entering clinical trials, as indicated in Table 1 . However, further work is required for effective clinical improvement in vaccination implications.

3.3.8. Replication-Competent Live-Virus Vaccines against HSV

As the name indicates, these vaccines exhibit the replication property of viruses but undergo certain insertions and or deletion of encoded genes for application. They generate broad-scale immunostimulatory effects, including reactions from T and B cells and neutralizing antibodies. [ 85 ] They undergo the presentation of a complex mixture of epitopes with only a few missing genes. In the case of latency and reactivation from virus progeny, an endogenous re-boosting effect is created [ 12 ]. However, the limitation is that the possibility of mutation and reactivity with the wildtype strain of HSV in an immunocompromised individual may alter the vaccine mechanism. Moreover, complications may also be faced in terms of viral strain production and serological testing of HSV infection [ 12 , 13 ]. Several genetic studies have been conducted to understand which genes can be deleted for the preparation of replication-competent vaccines. This method is similar or identical to the method used in live-attenuated vaccination [ 61 , 63 ].

3.4. Therapeutics and Antiviral Strategies against HSV

When HSV infection was initially identified as a health concern, several therapeutic trials were put into research trials for evaluating different drugs against it. So much research was conducted around the time of the discovery of acyclovir back in the 1980s [ 21 ]. The search has not stopped even now, and new therapeutics are being developed that focus on different mechanisms of antiviral action [ 86 , 87 , 88 ]. This may include various approaches such as virus entry inhibitors, fusion, or virus-release inhibitors. Among these trials, N-docosanol (an entry inhibitor) is the only FDA-approved drug that is used to counter herpes labialis but not recurrent genital herpes or ocular infection [ 48 ]. More effective therapies are required to contain the global burden associated with HSV infections. Some of the major drugs with varying mechanisms of action are briefly described in the next section and a summary has been presented in form of Table 2 at the end of this section.

3.4.1. Receptor Targeting Therapeutics against HSV

These therapeutics work by preventing the receptor virus binding phenomena by targeting HSV entry molecules/receptors or glycoproteins on the host cell surface. They demonstrate both prophylactic and therapeutic efficiencies against HSV [ 38 , 47 , 89 ].

Anti-Heparan Sulfate Peptides

Two important receptor peptides, G1 and G2, have a role in binding to the cell surface receptors of HS (present in almost all cell types) and targeting them to block HSV-1 infection [ 55 ]. This phenomenon has been dose-dependently checked in cell line-based experiments. These results indicate the potential benefit of the inhibition of viral replication and cell-to-cell viral spread [ 56 ]. Similarly, experiments on animal models exhibited their prophylactic properties against ocular and genital infections. The overall number of genital lesions was reduced in tested subjects. However, a limitation of these drugs is the presence of HS receptors on all cells; thus, the drugs may produce side-effects in healthy cells, while there is a need to prevent the associated cytotoxicity [ 11 , 55 , 56 ].

Apolipoprotein E

Apolipoprotein E (apoE) is a glycoprotein that helps in viral attachment and entry by binding directly to heparin sulfate proteoglycans in the extracellular matrix of the host cell membrane [ 90 ]. Specifically, the tandem repeat dimer peptide, apoEdp, exhibits antiviral activity against both HSV 1 and HSV 2, as well as HIV. The effective results of these drugs have been shown to induce corneal infection along with immunomodulation in terms of downregulated proinflammatory and angiogenic cytokines [ 40 , 90 ]. Moreover, the drugs exhibited low or no systematic toxicity in mouse models. Their effect has been comparatively evaluated to be the same as that of the currently in-use drug trifluoro thymidine (TFT) against HSV-1. The therapeutic effects have largely been shown to reduce infection symptomology in animal models [ 40 , 90 ].

AC-8-Potential Cationic Peptide

AC-8 is an igG FAB fragment that exhibits antiviral properties by binding to the glycoprotein D receptor [ 57 ]. This drug has shown efficacy in terms of reducing corneal vascularization and keratitis in mouse models. This property is produced due to the essential role of Gd in the herpes virus entry mechanism, which AC-8 successfully targets to prevent a subsequent infection. It also reduces cytotoxicity and inflammation even after repeated usage [ 25 , 37 , 56 ].

3.4.2. Nucleic Acid-Based Molecules

Aptamers are compounds that can bind with targeted molecules with a high affinity. They have characteristic features similar to antibodies; they fold in a different sequence-specific conformation determined by the target agents [ 91 ]. Several aptamer compounds have been proposed as antiviral agents in different infectious diseases, including HIV, cytomegalovirus, and recently against glycoproteins of HSV viruses [ 61 ]. RNA aptamers are major candidates under study that exhibit the antiviral potential to neutralize HSV species. Their highly specific nature allows scientists to define and manufacture specifically targeted aptamers that do not show a reaction against other viruses [ 61 , 91 , 92 ].

Dermaseptins

These form a family of associated poly cationic peptides derived from frog species. They exhibit antiviral properties against HSV species [ 93 ]. They interfere with the virus–host interaction owing to the positively charged amino acids that bind with the opposing negative charged heparin sulfate molecules of host cells [ 36 , 55 , 56 , 93 ]. Experiments showed they were effective against acyclovir-resistant HSV-1 species and had a reduced cytotoxic profile. They work well at low pH levels, which may allow them to remain active in the genital tract [ 55 , 56 ]. Some important cation ion peptides belonging to dermaseptins are indicated in Table 2 .

3.4.3. Viral Glycoprotein Targeting Therapeutics

As explained earlier, virus surface glycoproteins play an important function in fusion and viral entry into the host cell. They are positively charged molecules; hence, polyanionic compounds with negative charges could be designed and used to inhibit HSV fusion and replication in vitro by targeting the glycoprotein/sulfate compound complex [ 27 , 30 , 31 , 32 ]. Some important polyanionic compounds that have been used in research experiments are described briefly below.

Nanoparticles with Affinity to Bind GPs

Recent advances in nanotechnology-based therapeutics have presented newer methods for tackling viral infections. Hence, various experiments have been designed that may inculcate the properties of metallic nanostructure-based compounds with high affinity to bind viral glycoproteins [ 94 , 95 ]. As the virus binds to the HS with its surface gPs, a strategy could be devised simply by targeting the gPs. Some important nanoparticle species such as gold nanoparticles (AuNPs), tin oxide (SnO), zinc oxide (ZnO), mercaptoethane sulfonate (Au-MES), and some other important species are under research [ 94 , 95 , 96 , 97 ]. Moreover, the latest studies have demonstrated dual effectivity in terms of viral fusion inhibition and immune stimulation to protect against viral diseases. The overall effect is reduced virus entry, replication, transmission, mutation, and highly induced immune response against these virus infections. Moreover, the conjugation with other drugs and adjuvants may also provide added value to antiviral therapeutics [ 94 , 96 ].

K-5 and SP-510-50 Compounds

Since the presence of HSV-2 infection increases the likelihood of catching HIV-1 infection, therapeutics are being designed for a combined and simultaneous effect against both. In this regard, polyanionic K-5 compounds present a major therapeutic option to address this issue [ 30 , 31 ]. They work by inhibiting free virion infection by interfering with GPs and subsequently preventing cellular cross-transmission in vitro. With more advanced clinical experimentation, these compounds could be used against the sexual transmission of HSV and HIV diseases [ 48 ]. Similarly, SP-510-50 works as an antibody toward the gD of virus particles and, thus, provides antiviral infectivity in HSV patients. Their effect is bound to their dosage applicability for infection prevention [ 85 , 89 ]. They exhibited twofold better results compared to the commercial trifluoridine (TFT) using a lower dose. Moreover, the overall disease symptomology was reduced by their application [ 38 ].

Dendrimers are composed of an amino-acid or carbohydrate conformation that is arranged in macromolecular compositions. Like nanoparticles, they exhibit good antiviral activities for their size [ 58 ]. Moreover, their characteristics, such as ease of preparation, ability to display a wide variety of surface molecules, easier functionalization, and targeted effect against viral gPs and the host cell surface make them an important therapeutic candidate for HSV treatment [ 31 ]. The surface characteristics make them eligible to bind multiple drug regimens, with a high and multidrug payload. Their successful application against HSV is in research annals. The purpose of these trials is to properly establish the safety, tolerability, toxicity, and systematic pharmacokinetic properties of these agents [ 31 , 58 ]. Some important ongoing trials are shown in Table 2 .

3.4.4. Targeting the Downstream Signaling Cascades

Targeting various downstream molecules that conduct cell signaling to induce viral infection is an important strategy that has been the focus of cell biology and bioinformatics recently. These studies allow the exploration of wide-spectrum molecular entities that could be used to design targeted therapies [ 98 ]. For example, studies have demonstrated the mechanism of different viruses that use actin and myosin-dependent pathways for the internalization of viruses in the cell [ 99 ]. The same property is exhibited by HSV which is involved in phagocytic uptake by corneal fibroblasts and retinal epithelial cells [ 98 , 100 ]. The underlying mechanisms are controlled by various kinases such as cyclic AMP-dependent protein kinase A, Akt/PKB, and ribosomal kinases p70 and p85, which play important roles in establishing cellular fusion [ 98 , 99 , 101 ]. Thus, inhibitor therapies are being designed against PI3K kinases to regulate the cellular surfing, entry, and viral infection in targeted cells. Successful results have been acquired in vitro, while next-level studies are still ongoing.

3.5. Antimicrobial Peptides against HSV

Antimicrobial peptides (AMPs) are positively charged short oligopeptides found in virtually all organisms which exhibit diversity in structure and function. They are synthesized and processed to play a vital role in initial immune responses against injury and infections. Some examples of such AMPs in humans include defensins, transferrins, hepcidin, cathelicidins, human antimicrobial proteins, histones, AMP-derived chemokines, and antimicrobial neuropeptides. AMPs have widely been studied for their potential antiviral properties. Defensins have been shown to play a protective role against HSV by blocking virus entry and other stages of the virus life cycle [ 102 , 103 ]. Several studies have shown a vital role of AMPs against various viral infections; therefore, AMPs can be effectively used as excellent therapeutic agents against HSV [ 104 ].

3.6. Some of the Latest Therapeutic Options

3.6.1. compounds derived from marine resources (algal species).

The widespread HSV positivity in the human population has compelled the scientific community to continuously remain engaged in proposing different therapeutic regimens against HSV infections [ 21 , 46 , 48 ]. The traditionally used drugs such as acyclovir, ganciclovir, valaciclovir, and foscarnet are good options for HSV treatment; however, the development of drug resistance in patients and the ability for viruses to develop a mutation in strains has compelled scientists to look for other options [ 105 ]. Marine-based products, such as those derived from algal populations, bacterial species, fungal biomass, sponges, tunicates, echinoderms, and mollusk seaweeds, are important organisms from which these drug candidates are being derived [ 105 ]. Caulerpin is one of such candidate drugs that has its origin in marine algae and works well as an antioxidant, antifungal, antibacterial agent, and acetylcholinesterase (AChE) inhibitor [ 106 ]. It functions to inhibit the stages of the replication cycle [ 107 ]. Moreover, its application as an alternative to traditional acyclovir is under consideration. In addition to caulerpin, various other algal species (~40) are in research and development for exhibiting anti-HSV properties in resistant infections. They exhibit antiviral activity ranging from 50% to 80% for both species of HSV [ 21 , 46 , 48 , 105 , 106 ]. Different algae with antiviral properties are shown in Table 2 . These studies allow the scientific community to delve deeper into marine-based and plant-based products to find a cure for HSV.

3.6.2. Mucus Penetrating Particles

Since mucus formation is an unfortunate characteristic of the common summer cold, concurrent HSV and common cold infections could present a hurdle in drug delivery and penetration of the targeted cells [ 95 ]. Owing to the mucoadhesive characteristics exhibited by common drugs, some studies have been conducted to design mucous penetrating particles mainly based on nanoparticles. These neoformations easily penetrate the tissues of the sinuses and vagina and, thus, establish successful delivery of drugs to tissues of interest [ 95 , 96 ]. Moreover, they provide the opportunity to surface coat the particles with multiple antiviral drugs and enable better absorption of the nanosized particles for a more profound effect. Overall, MPPs improved drug binding, distribution, retention, and dosages, as well as reduced toxicity, in HSV model experiments [ 95 , 96 , 108 ].

3.6.3. Plant-Derived Therapeutic Options

Similar to algal-derived drug candidates, some recent studies have indicated the therapeutic potential of some plant-based products ( Table 2 ). Like other drug regimens, they inhibit the virus entry and replication cycle by acting as potent inhibitors of various glycoproteins specific to different antiviral plant agents [ 109 ]. Antiviral agents such as neem bark extract (NBE) derived from Azardirachta indica and cyanovirin-n (CV-N) derived from Nostoc ellipsosporum, as well as peri-acylated gossylic nitriles derived from gossypol, are some of the important drug candidates exhibiting efficient anti-HSV profiles [ 42 , 47 , 48 , 109 , 110 ]. However, the potent anti-HSV profiling, toxicity studies, pharmacokinetic profiling, and antidrug comparative studies remain to be conducted in detail to provide the benefits associated with plant-based herbal therapies [ 109 ].

3.6.4. Combined Therapies

Knowing the scope of HSV disease implications, scientists are now gathering their research focus toward combined therapies since a certain specific drug or vaccine has not yet been shown to eradicate HSV infection [ 21 , 30 , 48 , 61 ]. Therefore, more integrated and coordinated efforts are being put forth in the form of combined therapies, where several drug combinations are checked for their effect against HSV. Most of the individual drug regimens have already gone through scientific examination to establish their antiviral character. Hence, the purpose of combined therapies is to only evaluate multiplex combined antiviral effects against HSV infection [ 46 , 48 ]. Various experiments in research annals have been carried out in vitro, in animal models, and in clinical trials. Similarly, more specific studies are in the research phase against proven anti-HSV drugs such as acyclovir and acycloguanosine in terms of evaluating their cytotoxic and pharmacokinetic profiles and upgrading them by nano-scaling or conjugating with nanoparticle formulations for effective low dosage implications [ 59 , 94 , 95 , 96 , 97 ]. These latest studies have provided a doorway to the resistance that develops over time in patients. The new formulation offers lower dosage, more targeted delivery, and enhanced efficacy in tested subjects. Therefore, the field of combined therapy against HSV is a major player in the future drug and vaccination designs against HSV. A brief overview of these therapeutic strategies against HSV have been covered in a summarized version in Table 2 below.

Ongoing trials for HSV drugs.

4. Conclusions

Several vaccines and drug trials are in progress against HSV. They provide a promising therapeutic potential in individual studies. However, no profound and specific therapy has been established until now that could tackle the problem of HSV infection worldwide. The need is to establish more coordinated and integrated studies with the cooperation of scientists, doctors, and pharmacies to take drug testing one step ahead in clinical practice. This is important because the expected viral mutations present the threat of the development of another mutant HSV that could then become another complication for HSV treatment and prevention. Therefore, the most effective approach for future therapeutic development will be to develop modern drug-design approaches such as those based on plant products and nanotechnology, and to carry out more combined therapies for large-scale and broad-spectrum antiviral and immunostimulatory effects so that HSV complications can be successfully addressed in the coming years.

Abbreviations

Funding statement.

This research received no external funding.

Author Contributions

Conceptualization, S.M. and Y.W.; methodology, S.M., R.S., K.M. and Y.W.; validation, S.M., O.A., R.S. and K.M.; formal analysis, S.M., O.A., R.S., K.M. and Y.W.; resources K.M. and Y.W.; data curation, S.M., O.A., R.S., K.M. and Y.W.; writing—original draft preparation, S.M.; writing—review and editing, S.M., K.M. and Y.W.; supervision, Y.W.; project administration, Y.W. funding acquisition, Y.W. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Informed consent statement, data availability statement, conflicts of interest.

The authors declare no conflict of interest.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

With a herpes vaccine on the horizon, will the stigma persist?

When I was 9 years old, I came down with a terrifying bout of pneumonia and ended up in the hospital for a week. I remember having a panic attack when I couldn’t catch my breath and my mother, scared, called a doctor for help. He arrived quickly and calmed me down with his gentle bedside manner. He helped me take deep, slow breaths through an oxygen mask, to the tune of his voice as he counted down from 10. I egged myself on, knowing I had to relax or I’d get transferred to the local children’s hospital.

A few days later, I arrived back at school. I was in fourth grade. I had recovered but still had trouble breathing. Whenever my immune system runs low, I’m at greater risk for a herpes outbreak , and that’s exactly what happened. My face had erupted in giant, oozing cold sores. During recess, I sat on a bench alone listening to Coldplay’s “Yellow” on my Walkman. A group of older, prettier and more popular girls approached me. I pulled one of my earbuds out to hear what they were saying, only to find they were taunting me. “AIDS Face.” “Pimple Mouth.” “Zit Lips.” 

I’ve had herpes for as long as I can remember, likely contracting the virus as a grabbing toddler reaching for my mother’s face.

As these cruel names were hurled at me, I trembled, cried and hugged my legs to my chest. When treating cold sores, time is of the essence. The second you feel a tingle, you need to treat the afflicted area. This helps mitigate the severity of the breakout . However, for a period of my childhood, I chose inaction, too traumatized by the stigma to do anything about it anymore. Instead, I leaned into being the weird kid and a social pariah, allowing my face to be riddled with herpes. While being infected with the virus is common and technically not a big deal, I was astronomically ashamed and isolated. In pop culture, the word herpes is near synonymous with dirty and that’s how I felt — dirty.

I’ve had herpes for as long as I can remember, likely contracting the virus as a grabbing toddler reaching for my mother’s face. Over the decades, I have spent a considerable amount of time agonizing over how to skip work, school and social events. When hiding from the world, I have tried every home remedy, topical cream and ointment and antiviral drug available. Sadly, there is no cure for herpes, only options to limit or prevent outbreaks . But a new vaccine on the horizon could prove to be a game changer.

Moderna is developing a vaccine using mRNA technology to treat the herpes simplex virus (HSV). There are two HSV virus types — HSV-1, the one I have, that affects the mouth, face and genitals, and HSV-2, which predominantly affects the genitals. However, both viruses can spread to other parts of the body. In the United States, of people aged 14 to 49, 47.8 percent have HSV-1 and 11.9 percent have HSV-2 , according to the Centers for Disease Control and Prevention. Many people living with herpes don’t know they have it, which means these figures may be far greater. HSV remains latent in the body , staying alive through the lifelong infection of a given person. When reactivated, HSV results in visible outbreaks. The vaccine will protect against HSV-2 and provide cross-protection for HSV-1 as a suppressive antiviral treatment.

The CDC recommends against widespread testing for herpes as, alongside the risk of false positives, “the risk of shaming and stigmatizing people outweighs the potential benefits.” Throughout my life, the social stigma surrounding herpes has proven more disastrous for my mental health than the virus itself. For so long, I assumed I wasn’t likable, let alone loveable. I believed I would be consigned to a life without sex and intimacy, having internalized harmful myths about a generally harmless infection. When I’ve had an outbreak, I’ve often chosen abstinence over disclosure, too fearful of rejection to open up. Interestingly, many people don’t even realize that having had chickenpox or shingles means they’ve been infected by a member of the herpes family . (Moderna is also developing a vaccine that would reduce the rate of the varicella-zoster virus that causes shingles.) But it’s the sexual component of HSV-1 and 2 that remains socially lethal.

The CDC recommends against widespread testing for herpes as, alongside the risk of false positives, “the risk of shaming and stigmatizing people outweighs the potential benefits.”

Much of the hysteria affecting the social status of herpes has been generated by the media and pharmaceutical companies. A 1982 TIME magazine cover labeled genital herpes “Today’s Scarlet Letter.” Authors of the cover story , John Leo and Maureen Dowd, posited that it could cause the sexual revolution to grind to a shrieking halt. Even more dramatic, the story argued that herpes was “altering sexual rites in America, changing courtship patterns, sending thousands of sufferers spinning into months of depression and self-exile and delivering a numbing blow to the one-night stand.”

Given the stigma around HIV at the time, perhaps the increased awareness about herpes did make some people change their sexual behaviors, but we also know that any activity that was deemed sexually deviant was used as a scapegoat to make sex seem shameful. A 2016 Vice exposé found that, starting in the 1970s, there is evidence that “big pharma” likely conjured up and perpetuated stigma to increase sales of a new drug, one that couldn’t be used to treat all members of the herpes family. To advertise the drug, herpes had to be pushed as a disease worthy of attention, the answer to which was a sex panic.

In the age of medical misinformation, vaccines themselves are misunderstood. For example, in general, they have been said to cause autism, despite no scientific evidence. The misinformation seems to increase when it comes to newly available ones; look no further than conspiracy theories swirling around Covid-19 vaccines , which were rumored to contain infertility agents or spread HIV — another notoriously stigmatized STI. The mRNA technology used to create these life-saving Covid-19 vaccines opened up the door for those Moderna is currently developing to treat herpes. In the near future, it’s possible that people will be prevented from ever getting herpes and that those with it won’t have to suffer through outbreaks anymore. I’ve wondered if the social stigma will persist and if kids like myself will be spared the pain I have experienced since childhood.

Deidre Olsen is an award-nominated writer based in Berlin. She is writing a memoir about self-destruction, healing and resilience.

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To Patients, Herpes Can Be Devastating. To Many Doctors, It’s Not a Priority.

Billions of people live with the infection, but there has been scant progress for treatments and tests.

By Dani Blum

When Lauren went to her doctors with stinging clusters of sores on her genitals, she assumed the pain was from a urinary tract infection. But at the OB-GYN, her doctor swabbed the bumps and told her that the rash was herpes. “No,” she remembered responding. “It’s not.”

At the time, Lauren, who asked that her last name be withheld in order to talk about personal health issues, was a 19-year-old college student. She was in a two-year monogamous relationship with her second-ever sexual partner — a guy who occasionally dealt with an errant blister on his lip.

They hadn’t known that oral herpes could induce cold sores, and that HSV-1, the virus that causes oral herpes, could be transferred to the genitals. Lauren’s boyfriend was convinced that she had cheated on him, and he broke up with her, she said.

Lauren became withdrawn and almost failed out of college. “You think, Why does anything even matter anymore?” she said. “I’m never going to date. I’m never going to have a boyfriend.”

That was in 2013. Over the last decade, Lauren has had only a few additional outbreaks, none as painful as her first. The mental strain — the depression she fell into after the diagnosis, the fear that future partners wouldn’t accept her — has been, by far, the hardest part of managing the disease. “It attacks your self-worth,” she said.

Herpes is extremely common: The World Health Organization estimates that 3.7 billion people live with HSV-1, some oral and some genital. And cases like Lauren’s, where HSV-1 spreads to the genitals during oral sex, have sharply increased over the past two decades, said Dr. Jonathan Zenilman, a professor of medicine at Johns Hopkins University School of Medicine who specializes in sexually transmitted infections.

But herpes isn’t a top priority for researchers, said Dr. Larry Corey, a professor and virologist at Fred Hutch Cancer Center in Seattle who has studied the virus. It isn’t even the top priority among those who study sexually transmitted infections, he added. “The disease has been sort of ignored by both the pharmaceutical industry as well as the medical research establishment,” he said.

There are several potential reasons for this, experts theorize, including the relatively mild physical symptoms for most patients, clinicians’ reluctance to discuss sexual health and how hard it is to develop a vaccine for herpes.

“The fact that a lot of the toll is psychological makes physicians not that interested in it,” said Dr. Anna Wald, a clinical virologist and a professor of medicine at the University of Washington School of Medicine.

There has been little progress on more accurate tests, vaccines or additional treatments over the last few decades, Dr. Wald said. Part of the challenge is that the herpes virus can hide inside neurons that are shielded from the immune system, making the body’s immune response insufficient at eradicating the virus, she said — that’s why herpes remains in a person’s body for life. Vaccine attempts, so far, have not stimulated an immune response that can control the virus or prevent infection, she said.

If a patient does not have symptoms, doctors typically diagnose herpes with an antibody test that is frequently inaccurate. Up to half of positive commercial test results could be false, according to past research . There is another antibody test, called the herpes Western blot, that scientists consider the gold standard in diagnosing herpes — but the test is only available through the University of Washington, which can be cumbersome and expensive for patients to obtain. Testing is typically reliable when a patient has symptoms; doctors can swab a lesion and run a highly sensitive molecular test.

The U.S. Preventive Services Task Force doesn’t recommend routine genital herpes screenings for people without symptoms, in part because false positive rates are so high. On Tuesday, the task force reaffirmed its recommendation . In a related paper , a group of doctors wrote that the recommendation was, in part, based on “psychosocial harms” associated with false positives on herpes tests.

And so the virus continues to spread essentially unchecked — exacerbated by just how ineffective the most widely available tests for herpes are, said Terri Warren, a nurse practitioner who has researched herpes.

As cases circulate, patients are left grappling with a diagnosis that can be psychologically devastating, Dr. Zenilman said.

“You can control the symptoms,” he added. “But lots of people feel stigmatized, dirty.”

How herpes got sidelined

Herpes can be severe in certain cases: Babies can contract neonatal herpes from their mothers, putting them at risk for severe complications and even death . For people who are immunocompromised , outbreaks can be more prolonged and painful. In the vast majority of cases, though, people will have very mild symptoms, and many will have none. That’s part of the reason the infection is so pervasive: People pass it onto partners without knowing they have herpes.

Those who contract HSV-1 may develop blisters on or around their mouths or, in some cases, on their genitals. HSV-2, the other predominant strain, is usually characterized by one or more lesions around the genitals or the rectum. In the United States, around one in six people between the ages of 14 and 49 has genital herpes, and over half of adults have oral herpes.

Antiviral medications help reduce the amount of the virus a person sheds, lowering the chance that someone with herpes will pass it on to a sexual partner. Some patients take antivirals daily; others only take medication when they have an outbreak. But the risk of spreading herpes is never zero. The disease lingers in the body, putting the onus on patients to disclose their diagnosis to anyone with whom they have intimate contact.

When Lauren started dating after her diagnosis, she found herself staying in relationships for longer than she might otherwise, scared nobody else would want to be with her. “I thought I was going to die alone,” she said.

Brittany, 29, who asked that her last name be withheld in order to discuss her personal health, only thinks about her HSV-2 when she scrolls through a dating app. In the two years since she was diagnosed, she’s only had one outbreak. Still, when she looks at each profile, she wonders how the man would respond to learning about her diagnosis. “I just worry so much that people are going to judge me,” she said. “That no matter how I present it to them, I’ll still face rejection. That weighs heavily on me.”

Some men have told her, flat-out, that they would never date someone with herpes, but what bothers her, too, are the ones who say, “I’m so sorry this happened to you.”

“I don’t want people to feel sorry for me,” she said. “I wake up every day and I’m fine.”

Scientists have worked on herpes vaccines in fits and starts since the 1970s, said Dr. Harvey Friedman, a professor of medicine at the University of Pennsylvania Perelman School of Medicine who has studied the disease for over 40 years. But past attempts have failed, for reasons researchers are still trying to uncover.

Because herpes has been around for so long, the viruses have evolved alongside us, making them more difficult to eradicate, said Christine Johnston, an associate professor at the University of Washington School of Medicine who has studied herpes.

There are new vaccines under development . Dr. Friedman is working with BioNTech on an HSV-2 vaccine candidate that was given to the first human subject in December . But none are in late-stage clinical trials, said Dr. Ina Park, a professor of family and community medicine at the University of California, San Francisco, and author of “Strange Bedfellows: Adventures in the Science, History, and Surprising Secrets of S.T.D.s.” “There’s nothing anywhere close to prime time,” she said.

‘One of the biggest secret societies’

When Ella Dawson, 30, contracted genital HSV-1 in college, she started to post openly about her diagnosis on social media. To her surprise, people came out of the woodwork to share their stories — friends, relatives, even a cashier who worked at the grocery store on campus. Many told her that they had never disclosed their diagnosis to anyone other than a sexual partner.

“It’s one of the biggest secret societies in the world,” said Ms. Dawson, a novelist and writer who often speaks publicly about her experience with herpes.

Courtney Brame, 34, started the herpes education advocacy organization and podcast Something Positive for Positive People after his own HSV-2 diagnosis. He’s seen how the disease “completely shatters a person’s identity,” he said, partly because of how central sexuality can be to someone’s self-worth. “They don’t feel like they have anything to contribute to a relationship now, just because they have herpes,” he said. “It’s like, ‘Who’s going to want me now that I have this?’”

Mr. Brame has seen this in his own life. He was once messaging a woman on Tinder who brought up her struggle with chronic asthma; when he disclosed his own chronic condition, she stopped responding. But more often than facing rejection, when he shares his diagnosis, he said, he gets a different response: Women share that they, too, have herpes.

Herpes stigma stems in part from the idea that people with the infection have done something “wrong,” Dr. Park said. But you can exercise every precaution and still get it, she added — condoms do not entirely prevent transmission, and you don’t even need to have penetrative sex to contract the virus.

Though condoms can reduce the risk of transmission, not everyone with herpes will use a barrier method in long-term, monogamous relationships. In 2021, Something Positive for Positive People conducted a survey of over 1,000 people diagnosed with herpes; around 66 percent said a partner had consented to sex without a condom or other barrier method. And there is little research on how the virus spreads between women who have sex with women, Dr. Park said.

Medical providers, in general, often don’t receive extensive education on talking to patients about sexual health, Dr. Johnston said. When it comes to herpes in particular, “health care providers can be really insensitive about it and minimize it,” she said. “This is thought of more as a nuisance than a serious infection.”

“Clinicians don’t want to deal with this,” Ms. Warren said. “It involves people talking about sex. They’re crying, they’re going to have to talk about various specifics like is oral sex OK, is anal sex OK — I don’t think they want to go there,” she said.

Without support from doctors, or medical innovations to cure the infection, people with herpes are left “dealing with two viruses at the same time,” as Ms. Dawson put it. “You’re dealing with the physical symptoms of the virus,” she said, “and you’re dealing with the mental strain.”

Dani Blum is a reporter for Well. More about Dani Blum

Clinical Trials

Vaccine info, herpes vaccine candidates, herpes vaccine candidates, clinical trials 2024.

Developing protective herpes simplex virus ( HSV ) vaccines has been an ongoing challenge for decades. Various herpes vaccine candidates are based on DNA, modified mRNA, protein subunits, killed virus, and attenuated live virus vaccine technologies . The World Health Organization ( WHO ) published its preferred product characteristics for Alpha (α)-herpesviruses  vaccines and updated its pipeline review . As of April 2024, the U.S. Food and Drug Administration ( FDA ), Brazil ,  Canada , China ,  Europe , India , Japan , and the U.K.  had not authorized preventive or therapeutic herpes vaccines. 

Herpes Notice of Special Interest 2024

On March 27, 2024, the U.S. National Institute of Allergy and Infectious Diseases ( NIAID ) issued a Notice of Special Interest (NOSI): Research to Stimulate Development of Diagnostics, Therapeutics, and Vaccines for HSV. This NOSI NOT-AI-24-028  calls for developing novel HSV treatments and vaccines and applies to due dates on or after June 5, 2024, and subsequent receipt dates through April 5, 2027. On February 6, 2024, the U.S. Department of Health and Human Services ( HHS ) invited stakeholders to provide written public comments on the draft  HSV Addendum  to the  STI National Strategic Plan . In September 2023, the NIH released the NIH Strategic Plan for HSV Research 2023-2028 .

When developing herpes vaccines, candidates conduct clinical trials  called phase 1, phase 2, phase 3, and phase 4. Each development phase is essential. The  WHO , the U.S. National Instuties of Health ( NIH ), and global partners launched  STI Watch , a portal containing updated information on vaccine development status. Both preventive and therapeutic  HSV  vaccines are being explored. This HerpesFolds table gives interactive access to all AlphaFold structures of HSV-1 strain 17 (Uniprot proteome UP000009294 ), HCMV strain Merlin ( UP000000938 ), EBV strain B95-8 ( UP000153037 ), as well as KSHV strain GK18 ( UP000000942 ), visualized by 3Dmol.js. The AlphaFold includes two additional Herpesviruses: PrV ( UP000154030 ) and MHV68 ( UP000099649 ).

As of April 2024, herpes vaccine candidates conducting clinical trials include:

Herpes Simplex Virus-targeted immunotherapy ( HSVTI ) is conducting a phase 1/2 clinical study  of targeted immunotherapy ( GSK3943104A ) against HSV in healthy participants aged 18-40 years or in participants aged 18-60 years with recurrent genital herpes.

mRNA-1608 is an mRNA vaccine candidate against HSV-2 disease. The mRNA-1608-P101 phase 1 study launched on September 6, 2023, and is forecasted to be completed on June 4, 2025. With mRNA-1608, Moderna Inc.  aims to induce a strong antibody response with neutralizing and effector functionality combined with cell-mediated immunity. Independent Study : An mRNA vaccine to prevent genital herpes. Moderna stated on September 13, 2023, that the latent and other vaccine market is estimated at approximately $10 billion to $25 billion.

BNT163 is an mRNA-based HSV vaccine candidate that encodes three HSV-2 glycoproteins to help prevent HSV cellular entry and spread and counteract HSV immunosuppressive properties of HSVs.  Prof. Dr. Harvey M. Friedman , Professor of Infectious Diseases at the University of Pennsylvania Perelman School of Medicine ,   conducted preclinical and scientific research on HSV. In the  phase 1 clinical trial, the first subject was dosed in December 2022, and the safety, tolerability, and immunogenicity of BNT163 were evaluated. The last study update was posted on January 5, 2023.

Rational Vaccines's  VC2 vaccine candidate is a live-attenuated  vaccine targeting facial, ocular, and genital herpes caused by HSV-1 and potentially protects against genital herpes caused by HSV-2. On October 13, 2023 , Rational Vaccines was awarded $2.8 million by the U.S. National Institute of Health, and in a  2018 study  conducted at Louisiana State University, Brent Stanfield and colleagues examined the immune response generated by intramuscular injection of the VC2 vaccine in the guinea pig.

Delta gD-2  (∆gD-2) is a vaccine candidate based on an HSV-2 virus genetically deleting  glycoprotein D (gD-2) . 

HSV529  (HSV15) is a vaccine candidate classified as a replication-defective virus, meaning the virus possesses all the wild-type HSV virus components except two proteins, UL5 and UL29, involved in viral DNA replication.  This phase 1/2 study was last updated on January 13, 2021, by  Sanofi Pasteur and the National Institute of Allergy and Infectious Diseases.

EXD-12 is a vaccine candidate currently in preclinical testing for safety and efficacy as a prophylactic and therapeutic vaccine for herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2). 

NanoVax is an adjuvant platform to develop a vaccine candidate to protect against the two viruses that can cause genital herpes.

RVx201  is a live-attenuated HSV-2 vaccine candidate conducting an observational clinical study  RVx-001-PSS in England. It is designed to have a specific degree of attenuation through specifically designed mutations in the ICP0 protein.

Shanghai BD Gene is conducting a  phase 1/2 clinical study  in humans. It is the only gene-editing technology for Cas9 mRNA delivery by lentivirus .

Assembly Biosciences, Inc.  announced data from development candidate ABI-5366 , a long-acting HSV helicase inhibitor targeting high-recurrence genital herpes.

Repurposed BCG Vaccination Targeting Herpes

The Bacillus Calmette-Guérin ( BCG ) vaccine is an approved attenuated vaccine for tuberculosis prevention. Research published by The Lancet in 2023 suggests that BCG vaccination induces three non-specific immune responses: trained immunity, heterologous immunity, and anti-inflammatory effects. These immune responses have been used to prevent and treat various diseases, including HSV-1. In the journal eClinicalMedicine , Laure F Pittet and colleagues published their phase 3 clinical trial results conducted across multiple countries to assess the impact of BCG vaccination on recurrent herpes labialis. The BRACE trial ( NCT04327206 ) concluded that BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences. Still, it may increase the risk of a first cold sore.

A  systematic review of Medline, EMBASE, and PubMed was published in September 2020 that concluded BCG vaccination has a potential, safe, affordable, and readily available candidate intervention to decrease the high burden of disease associated with HSV infection and recurrences but adequately controlled randomized trials are required.

Herpes Vaccine Preclinical Development

Redbiotec is currently developing an HSV-2 therapeutic vaccine (immunotherapy). Their vaccine program is T-cell-mediated protection and aims to outperform antivirals and allow patients to stay symptom-free for >12 months with two injections.

Eurocine vaccine candidates against HSV-2—In a non-human study, mRNA vaccination stimulated potent T cell responses that significantly outcompeted those generated by the protein vaccine in performance in several specific areas. Dr. Karl Ljungberg, Director of Preclinical Development at Eurocine Vaccines, stated in December 2022, "The T cell responses that we report here align with those that can be detected after recovery from an infection and are focused on the part of the HSV-2 virus that we believe is important to target to obtain immunologic control of the virus."

Researchers designed and constructed an HSV-1 synthetic platform based on H129 -G4. This platform could facilitate further manipulation of the HSV-1 genome for developing neuronal circuit tracers, oncolytic viruses, and vaccines.

The journal MDPI published an article on July 18, 2023, that concluded B7 costimulation molecules expressed from a replication-defective vaccine can enhance vaccine efficacy, even in an immunocompetent host.

Herpes Vaccine Clinical Trials

Sponsored clinical trials recruit  prospective participants in various studies.  Herpes Cure Advocacy launched Herpes Cure Pipeline 2.0 ( March 2022 ), which tracks preclinical and clinical study timelines and strategies globally.

Herpes Testing

The JAMA Network published on February 14, 2023, that the U.S. Preventive Services Task Force recommends against routine serologic screening for genital HSV infection in asymptomatic adolescents and adults, including pregnant women, as neonatal herpes infection is uncommon. (D recommendation).

Herpes Treatments

Herpes treatments are available in 2024. However, these products do not cure herpes.

HSV-2 Preventive Gel Clinical Development

Researchers announced  in September 2022 that they had developed a gel-based lubricant that can potentially prevent individuals from being exposed to HSV-2. Cow mucus provides the basis for a synthetic prophylactic gel developed at the KTH Royal Institute of Technology to protect against herpes transmission. Advanced Science published this Research Article on September 14, 2022. The researchers  synthesized BSM gels that liquefied under large strain and self-healed rapidly and repeatedly after the strain was removed. They showed that these properties were essential for mucin lubrication, as evidenced by significantly improved lubrication by the mucin gels (5%, wt/v) compared to mucin solutions (5%, wt/v). They also showed that the gels inhibited the infection of HSV-2 in epithelial cells and immune cells by about 80%.

Hongji Yan, a biomaterials researcher at KTH, commented in a media statement the promising results raise hope that when it becomes available as a product, the gel could help reverse troubling trends in the spread of sexually transmitted infections. 

Genital Herpes Serologic Screening

The U.S. Preventive Services Task Force (USPSTF)  recommends against routine serologic screening for genital herpes simplex virus infection in asymptomatic adolescents and adults, including pregnant women. As of August 16, 2022, recommendations made by the USPSTF are independent of the U.S. government. 

Because of the poor performance , a high rate of false-positive test results of commercially available U.S. FDA-approved HSV tests , and the limited availability of confirmatory testing, prevention efforts for herpes transmission have been insufficient. The CDC's  Office of Science  issued a Broad Agency Announcement  in December 2022 for the competitive selection of research proposals, including an RFP for serologic tests for HSV, reported  Herpes Cure Advocacy ,

Sexually Transmitted Disease Vaccines

As of 2024, Sexually Transmitted Disease vaccine news is posted at Precision Vaccinations .

Herpes Vaccine News

February 12, 2024 - Researchers at Dartmouth's Geisel School of Medicine and Thayer School of Engineering published a new study in Cell Reports Medicine, offering insights into how antibodies function in combating HSV infections. 

December 14, 2023 —Harvard News—The findings of a new  study (Oct. 26, 2023) could inform the design of treatments for various viruses that replicate in the cell nucleus.

November 1, 2023 - The University of Pittsburg School of Medicine received a grant of $504 thousand to conduct innovative herpes research.

October 13, 2023 - Rational Vaccines was awarded $2.8 million in U.S. National Institute of Health funding in three separate grants to further its research to diagnose, treat, and prevent the spread of HSV.

September 30, 2023 - A Systematic Review was published: The Association Between Herpes Simplex Virus and Alzheimer's Disease.

May 25, 2023 - Akiko Iwasaki, Ph.D., Sterling Professor of Immunobiology and professor of dermatology, molecular, cellular & developmental biology, and epidemiology (microbial diseases) at Yale School of Medicine, developed a therapeutic vaccine candidate that may reduce the reactivation of genital herpes in guinea pigs. However, lack of investment has hindered human clinical trials.

April 21, 2023 - The NIAID announced a Request for Information on the U.S. National Institutes of Health's vital strategic approaches to developing an HSV Strategic Plan.

April 5, 2023 - The WHO published updated Herpes Facts, including an HSV-2 infection increases the risk of acquiring HIV.

March 20, 2023 - Research Article: Construction and characterization of a synthesized herpes simplex virus H129-Syn-G2.

December 21, 2022 -  BioNTech S.E. announced that the initial subject was dosed in a first-in-human Phase 1 clinical study of BNT163, an HSV prevention vaccine candidate.

December 20, 2022 —Eurocine Vaccines announced that the mRNA vaccine generates superior T-cell responses. Dr. Karl Ljungberg, Director of Preclinical Development at Eurocine Vaccines, stated, "The T cell responses that we report here are in line with those that can be detected after recovery from an infection and are focused on the part of the HSV-2 virus that we believe is important to target to obtain immunologic control of the virus."

December 15, 2022 - A study published by the peer-reviewed journal PLOS Medicine conducted if HSV-2 has indeed contributed to the transmission of HIV, then nearly one-third of antiretroviral costs and HIV-related wage losses add to herpes-related costs. Given the magnitude of the combined losses, a vaccine against HSV-2 must be a global priority.

December 12, 2022 - The Lancet Europe published a systematic review, meta-analyses, and meta-regressions on the epidemiology of HSV-2 in Europe.

December 9, 2022 - The journal Nature published an article: Urgency and necessity of Epstein-Barr virus (EBV) prophylactic vaccine development. EBV is a γ-herpesvirus that contains a double-stranded DNA genome and is the first identified human oncogenic virus. The EBV, also known as human herpesvirus 4 , is a member of the herpes virus family, says the U.S. CDC .

October 27, 2022 - Contagion (Vol. 07, No. 5) - Revisiting Old Foes: Updates on HSV.

October 22, 2022 - The JAMA Network published an Original INvestigation - Viral Shedding 1 Year Following First-Episode Genital HSV-1 Infection - that concluded genital HSV-1 shedding declined rapidly following an initial infection and during the first year.

October 6, 2022 - Wiley Online published a case report on herpetic endotheliitis and stromal keratitis following inactivated COVID-19 vaccination. This is the first report of herpetic endotheliitis and stromal keratitis following the BBIBP vaccine. Although the temporal link between vaccination and adverse ocular events, including HSV-1 reactivation, cannot be established through these case reports, these reports add to the sparse body of evidence supporting this notion. 

September 26, 2022 —The Fred Hutchinson Cancer Center in Washington announced that researchers (Drs. Keith Jerome and Martine Aubert) found substantial reductions in oral and genital viral shedding in the treated mice, with many of those treated showing no detectable virus shed. A related non-peer-reviewed study was also published: AAV-delivered gene editing for latent genital or orofacial herpes simplex virus infection reduces ganglionic viral load and minimizes subsequent viral shedding in mice.

September 23, 2022 - Nature - Scientific Reports published: HSV-1 0∆NLS vaccine elicits a robust B lymphocyte response and preserves vision without recognizing t HSV-1 glycoprotein M or thymidine kinaon. Collectively, the results suggest (1) the live-attenuated HSV-1 mutant 0∆NLS elicits a robust B cell response that drives select B cell responses more significantly than the parental HSV-1 and (2) HSV-1 TK and gM are likely expendable components in the efficacy of a humoral response to ocular HSV-1 infection.

September 19, 2022 - Virios Therapeutics, Inc. announced topline results from its Fibromyalgia Outcome Research Trial Evaluating Synergistic Suppression of HSV-1 study of oral IMC-1 for the treatment of F.M. "We believe the interplay between different COVID-19 strains and herpes virus activation may be contributing to the differential response we observed in patients enrolled in 2021 versus 2022," stated Greg Duncan, Chairman and CEO of Virios Therapeutics.

August 19, 2022 - The journal Neurology published a RESEARCH ARTICLE: Herpes Viruses: Associations With Brain Volumes, Cognitive Performance, and Plasma Biomarkers. Discussion. These findings suggest an association of symptomatic herpes virus infection with white matter volume loss, attentional decline, and astrogliosis.

August 15, 2022 - Rational Vaccines announced the launch of an observational clinical study  of RVx201  in the U.K. on August 3, 2022, that will recruit about 200 participants. In addition to assessing the typical baseline characteristics of the population, the purpose of this study is also to determine the acceptance of clinical trial procedures and understand the interest of the target patient population to participate in a therapeutic Phase 1/2 HSV-2 vaccine study.

July 8, 2022 - Rational Vaccines announced findings from a U.S. NIH-funded pilot study of RVX20intparticipatingthat it reduced recurrent genital lesions compared to the gD2-alum/MPL vaccine or placebo in vivo. In addition, RVX201 appears to generate a robust cellular immune response equivalent to that elicited by wild-type HSV-2 on Day 7 post-infection.

June 16, 2022 - Eurosurveillance reported researchers in Austria had identified a second strain of extensively drug-resistant gonorrhea. 'We describe the second global XDR N. gonorrhoeae strain, with high-level resistance to azithromycin and resistance to ceftriaxone, cefixime, cefotaxime, ciprofloxacin, and tetracycline, which caused a possible gonorrhea treatment failure with ceftriaxone (1 g) plus azithromycin (1.5 g).

June 14, 2022 - Eurocine Vaccines AB announced that it entered into a research and collaboration agreement with Redbiotec AG that transfers the exclusive global rights to develop, manufacture, and commercialize vaccine candidates against Herpes Simplex Virus Type 2, HSV-2, based on the technologies developed by Redbiotec .

June 1, 2022 - Virios Therapeutics, Inc. announced the results of a pilot study performed at the University of Alabama, titled "Gastric Herpes Simplex Virus Type 1 Infection is Associated with Functional Gastrointestinal Disorders in the Presence and Absence of Comorbid Fibromyalgia: A Pilot Case-Control Study", were published in the journal Infection in April 2022. These results provide evidence for a potential mechanistic connection between active herpes virus infection and functional gastrointestinal Disorders ("FGID"), with or without comorbid fibromyalgia ("F.M."), as well as the potential for combination antiviral therapy to treat patients with FGIDs and F.M.

May 11, 2022 - Peer-review study: The health impact of seven herpesviruses on (pre)diabetes incidence and HbA1c: results from the KORA cohort. Conclusion: HSV2 and CMV serostatus associations with (pre)diabetes incidence indicate that these herpesviruses may contribute to impaired glucose metabolism.

April 25, 2022 - Frontiers Immunology published: Combinatorial Herpes Simplex Vaccine Strategies: From Bedside to Bench and Back. 'We discussed that a prime/pull vaccine strategy using asymptomatic epitopes, combined with immune checkpoint blockade, would be a successful herpes vaccine approach.'

January 25, 2022 - PNAS published a study that developed a parameterized model predicting how much and how rapidly a betaherpesvirus-vectored transmissible vaccine can be expected to reduce the prevalence of a target pathogen. The study concluded, 'Our models are focused on transmissible vaccines designed using herpes virus vectors and demonstrate that these vaccines—currently under development for several important human pathogens—may have the potential to control zoonotic pathogens within the reservoir hosts rapidly. However, our study results suggest that the effectiveness of MCMV-vectored transmissible vaccines may depend on the virus strain used to construct the vaccine and the target population into which the vaccine is ultimately deployed.'

November 22, 2018 - Study: The live attenuated prophylactic HSV vaccine, VC2, was effective in the guinea pig model of genital HSV-2. Its decreased ability to infect neural tissues provides advantages over live attenuated vaccines. The live attenuated prophylactic HSV vaccine, VC2, was effective in the guinea pig model of genital HSV-2. Its decreased ability to infect neural tissues provides advantages over live attenuated vaccines.

January 9, 2014  - Review: The challenge of developing herpes simplex virus 2 vaccines.

Content sources include the  WHO, US CDC, NIH, research papers, ClinicalTrials.gov, and the Precision Vaccinations news network. Healthcare providers, such as Dr. Robert Carlson, fact-check content.

No clinical trials found

Fact checked by Robert Carlson, MD

Fact checked by Danielle Reiter, RN

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September 13, 2021

Evidence of a possible link between herpes simplex and neurodegenerative diseases

by University of Illinois at Chicago

A new study by researchers at University of Illinois Chicago suggests that when the protein optineurin, or OPTN, is present in cells it restricts the spread of HSV-1, the herpes simplex virus type 1.

In a "first of its kind" study, researchers also found a potential direct connection between neurodegenerative diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), glaucoma, and the herpesvirus, said Dr. Deepak Shukla, the Marion H. Schenk Esq. Professor in Ophthalmology for Research of the Aging Eye, and vice chair for research at UIC.

The research paper , "OPTN is a host intrinsic restriction factor against neuroinvasive HSV-1 infection," led by Shukla, was published recently in the journal Nature Communications.

Researchers sought to discover why HSV-1 can become fatal for individuals who are immunocompromised but not for healthy individuals. Herpesviruses naturally infect the central nervous system and can result in degenerative brain and eye disorders, as well as encephalitis. However, in most individuals, the virus is suppressed during a primary infection before it can significantly damage the central nervous system.

The new research suggests why HSV-1 is suppressed: OPTN, a conserved autophagy receptor, selectively targets HSV-1 proteins to degradation by autophagy, explained Tejabhiram Yadavalli, a co-author of the study and visiting scholar at UIC's department of ophthalmology and visual science.

"OPTN stops the virus from growing and it stops it by autophagy—engulfing the virus particles inside tiny vesicles called autophagosomes. The autophagy that happens is very selective. That has meaning for other viruses as well," Shukla said.

The researchers believe the results from this study will apply to all eight different human herpesviruses.

For the study, mice with removed OPTN genes were infected with ocular HSV-1. The virus growth was much higher in the brains of animals without OPTN, killing local neurons and eventually leading to animal death. This shows there is a faster degeneration of neurons when OPTN is not there. Additional studies are being planned to examine naturally occurring mutations in OPTN, such as the ones reported in glaucoma and ALS patients, and how they may affect neuronal health and HSV-1 infection, Shukla explained.

"Where you have mutated OPTN plus herpes, you have the recipe to create a disaster in terms of neurodegeneration," Shukla said.

 "The study also shows there is an impairment of immune response when there is a deficiency in OPTN.  OPTN is needed to signal an influx of proper immune cells at the site of infection. When you don't have it, you have issues," said Chandrashekhar Patil, also a co-author of the study and a visiting scholar at UIC's department of ophthalmology and visual science.

Some of those issues could include neurodegenerative disorders, which researchers believe further research may show.

"We think we will have data to show other viruses, such as Epstein-Barr, Kaposi's sarcoma, varicella-zoster, are all going to share this mechanism because they share homologous proteins," Shukla said.

Because the herpesvirus sits in neurons forever, there is speculation it is connected to neurodegenerative diseases . The immune system requires inflammation to constantly fight off the virus , and neurons have some degree of damage because of this continuous immune response, according to Dr. Tibor Valyi-Nagy, professor of pathology, director of neuropathology at UIC and research collaborator on the study.

The study also showed that animals without OPTN and infected with HSV-1 after 30 days lost the ability to recognize objects. Shukla said this could be an indication that having HSV-1 along with a mutation of OPTN could accelerate neuronal damage, which would translate into cognitive impairment.

"Part of our translational research can be how can we correct the problems with OPTN so that we don't have issues with neurodegeneration," Shukla said.

Additional authors are Joshua Ames, Rahul Suryawanshi, James Hopkins, Alexander Agelidis, Chandrashekhar Patil and Brian Fredericks, all of UIC, and Henry Tseng of Duke University Medical Center.

This research was supported by the National Institutes of Health and National Eye Institute grants (K08-EY021520-02, RO1 EY029426, P30 EY001792 and RO1 EY024710) as well as the Butner Pioneer Award, Duke Health Scholars and Research to Prevent Blindness unrestricted funds.

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• Correspondence
• Published: 16 April 2024

Herpes simplex virus reactivation among hematopoietic stem cell transplant recipients: re-evaluating acyclovir dosage

• Nada Alsuhebany 1 , 2 , 3 ,
• Bashayer Alshehri 1 , 2 ,
• Atheer Aldairem 1 , 2 , 3 ,
• Muneerah M. Aleissa   ORCID: orcid.org/0000-0003-2167-5122 4 ,
• Hajar AlQahtani 1 , 2 , 5 ,
• Khalid Albarqi   ORCID: orcid.org/0000-0001-7821-6088 3 ,
• Basil Almotairi 3 ,
• Mohammed AlAmri 3 ,
• Walid Alanazi 3 ,
• Saeed Alay 3 ,
• Bader Alahmari 2 , 5 , 6 &
• Mohsen Alzahrani 2 , 5 , 6  

Bone Marrow Transplantation ( 2024 ) Cite this article

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Herpes complex virus (HSV) is a common viral infection post hematopoietic stem cell transplantation (HSCT), which affects up to 80% of seropositive recipients without prophylaxis [ 1 , 2 , 3 ]. International guidelines recommend antiviral prophylaxis for all HSV-seropositive allogeneic HSCT (allo-HSCT) recipients against HSV infection [ 4 , 5 ]. Studies show that HSV reactivation rates post-HSCT range from 0 to 20% with prophylaxis, significantly lower than the 68–75% observed with placebo, highlighting acyclovir’s role as the preferred antiviral, despite varying dosage protocols [ 2 , 3 , 6 ].

The standard approach is to begin acyclovir prophylaxis at the start of the conditioning therapy and through engraftment or resolution of mucositis (approximately day +30) [ 4 , 5 ]. The recommended prophylactic acyclovir dose ranges from 400 to 800 mg orally twice daily, but a wide spectrum of doses has been reported [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Acyclovir (ACV) 400 mg orally twice daily is the standard of care at our tertiary care hospital in the Ministry of National Guard Health Affairs (MNGHA) for HSV prevention. The rate of HSV reactivation after allo-HSCT is unknown in our population, and to date there have been no studies examining the incidence of HSV reactivation in Saudi Arabia. The study aimed to evaluate the incidence of HSV reactivation and identify risks of reactivation among patients who received ACV for HSV prevention post-HSCT.

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Baumrin E, Cheng MP, Kanjilal S, Ho VT, Issa NC, Baden LR. Severe herpes zoster requiring intravenous antiviral treatment in allogeneic hematopoietic cell transplantation recipients on standard acyclovir prophylaxis. Biol Blood Marrow Transpl. 2019;25:1642–7.

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Alzahrani M, Damlaj M, Jeffries N, Alahmari B, Singh A, Rondelli D, et al. Non-myeloablative human leukocyte antigen-matched related donor transplantation in sickle cell disease: outcomes from three independent centres. Br J Haematol. 2021;192:761–8. https://doi.org/10.1111/bjh.17311 .

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Nada Alsuhebany, Bashayer Alshehri, Atheer Aldairem & Hajar AlQahtani

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Nada Alsuhebany, Bashayer Alshehri, Atheer Aldairem, Hajar AlQahtani, Bader Alahmari & Mohsen Alzahrani

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Nada Alsuhebany, Atheer Aldairem, Khalid Albarqi, Basil Almotairi, Mohammed AlAmri, Walid Alanazi & Saeed Alay

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Muneerah M. Aleissa

King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia

Hajar AlQahtani, Bader Alahmari & Mohsen Alzahrani

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NS, BS, HQ, ME, MZ and BA were responsible for designing the review protocol, and reviewing the final manuscript. AD, and ME were responsible for data analysis, and interpreting the results writing the manuscript. KB, BM, MA, WA, and SA were responsible for data collection and writing part of the manuscript.

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Alsuhebany, N., Alshehri, B., Aldairem, A. et al. Herpes simplex virus reactivation among hematopoietic stem cell transplant recipients: re-evaluating acyclovir dosage. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02273-8

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Genital Herpes – CDC Basic Fact Sheet

Researchers find evidence of possible link between herpes simplex and neurogenerative diseases

A new study by researchers at University of Illinois Chicago suggests that when the protein optineurin, or OPTN, is present in cells it restricts the spread of HSV-1, the herpes simplex virus type 1.

In a "first of its kind" study, researchers also found a potential direct connection between neurodegenerative diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), glaucoma, and the herpesvirus, said Dr. Deepak Shukla, the Marion H. Schenk Esq. Professor in Ophthalmology for Research of the Aging Eye, and vice chair for research at UIC.

The research paper, "OPTN is a host intrinsic restriction factor against neuroinvasive HSV-1 infection," led by Shukla, was published recently in the journal Nature Communications.

Researchers sought to discover why HSV-1 can become fatal for individuals who are immunocompromised but not for healthy individuals. Herpesviruses naturally infect the central nervous system and can result in degenerative brain and eye disorders, as well as encephalitis. However, in most individuals, the virus is suppressed during a primary infection before it can significantly damage the central nervous system.

The new research suggests why HSV-1 is suppressed: OPTN, a conserved autophagy receptor, selectively targets HSV-1 proteins to degradation by autophagy, explained Tejabhiram Yadavalli, a co-author of the study and visiting scholar at UIC's department of ophthalmology and visual science.

"OPTN stops the virus from growing and it stops it by autophagy -- engulfing the virus particles inside tiny vesicles called autophagosomes. The autophagy that happens is very selective. That has meaning for other viruses as well," Shukla said.

The researchers believe the results from this study will apply to all eight different human herpesviruses.

For the study, mice with removed OPTN genes were infected with ocular HSV-1. The virus growth was much higher in the brains of animals without OPTN, killing local neurons and eventually leading to animal death. This shows there is a faster degeneration of neurons when OPTN is not there. Additional studies are being planned to examine naturally occurring mutations in OPTN, such as the ones reported in glaucoma and ALS patients, and how they may affect neuronal health and HSV-1 infection, Shukla explained.

"Where you have mutated OPTN plus herpes, you have the recipe to create a disaster in terms of neurodegeneration," Shukla said.

"The study also shows there is an impairment of immune response when there is a deficiency in OPTN. OPTN is needed to signal an influx of proper immune cells at the site of infection. When you don't have it, you have issues," said Chandrashekhar Patil, also a co-author of the study and a visiting scholar at UIC's department of ophthalmology and visual science.

Some of those issues could include neurodegenerative disorders, which researchers believe further research may show.

"We think we will have data to show other viruses, such as Epstein-Barr, Kaposi's sarcoma, varicella-zoster, are all going to share this mechanism because they share homologous proteins," Shukla said.

Because the herpesvirus sits in neurons forever, there is speculation it is connected to neurodegenerative diseases. The immune system requires inflammation to constantly fight off the virus, and neurons have some degree of damage because of this continuous immune response, according to Dr. Tibor Valyi-Nagy, professor of pathology, director of neuropathology at UIC and research collaborator on the study.

The study also showed that animals without OPTN and infected with HSV-1 after 30 days lost the ability to recognize objects. Shukla said this could be an indication that having HSV-1 along with a mutation of OPTN could accelerate neuronal damage, which would translate into cognitive impairment.

"Part of our translational research can be how can we correct the problems with OPTN so that we don't have issues with neurodegeneration," Shukla said.

Additional authors are Joshua Ames, Rahul Suryawanshi, James Hopkins, Alexander Agelidis, Chandrashekhar Patil and Brian Fredericks, all of UIC, and Henry Tseng of Duke University Medical Center.

This research was supported by the National Institutes of Health and National Eye Institute grants (K08-EY021520-02, RO1 EY029426, P30 EY001792 and RO1 EY024710) as well as the Butner Pioneer Award, Duke Health Scholars and Research to Prevent Blindness unrestricted funds.

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• Neuroscience
• Brain Injury
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• Disorders and Syndromes
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• Excitotoxicity and cell damage
• Alzheimer's disease
• Dementia with Lewy bodies
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Story Source:

Materials provided by University of Illinois at Chicago . Note: Content may be edited for style and length.

Journal Reference :

• Joshua Ames, Tejabhiram Yadavalli, Rahul Suryawanshi, James Hopkins, Alexander Agelidis, Chandrashekhar Patil, Brian Fredericks, Henry Tseng, Tibor Valyi-Nagy, Deepak Shukla. OPTN is a host intrinsic restriction factor against neuroinvasive HSV-1 infection . Nature Communications , 2021; 12 (1) DOI: 10.1038/s41467-021-25642-z

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