The MVA vector technology has demonstrated efficacy against HIV, influenza, parainfluenza, measles, flavivirus, and even malaria [ 30 ].
Atukorale et al. The authors also demonstrated that the transgene insertion site could dictate vector stability with a prolonged serial passage in cells, indicating that vaccinia vectors can be a viable platform for sound engineering. Live-attenuated vaccines have been the most effective vaccines to combat human and animal viral infections in medical history.
The repertoire of these successes includes the eradication of smallpox, poliomyelitis, measles, mumps, rubella, rotavirus, and others reviewed in: [ 31 ]. A live-attenuated varicella-zoster virus VZV human herpesvirus 3 HHV-3 or chickenpox virus vaccine is widely used worldwide and shown to be highly efficacious in controlling viral reactivation.
Live varicella vaccine is generally safe and well-tolerated [ 32 ]. The success of the alphaherpesvirus VZV live-attenuated vaccines provides a primary example suggesting that a similar approach may be efficacious in combating herpes simplex infections which, like VZV, establish latency in neurons.
In addition, the only FDA-approved oncolytic virotherapy on the market is a live-attenuated herpes simplex virus TVEC or Imlygic approved for the treatment of human melanoma. This virus was designed as an oncolytic and immunotherapeutic virus that augments anti-tumor immunological responses.
These deletions limit virus replication in cancer cells and eliminate the inhibition of antigen presentation by the ICP47 gene. Additionally, the virus expresses human GM-CSF, which stimulates the recruitment of antigen presenting cells providing enhanced immunogenicity [ 33 ]. The generation of a safe and effective herpes simplex vaccine must focus on preparing attenuated viruses that can generate robust immune responses.
To this end, novel live-attenuated vaccine strategies are being implemented to tame the virus in vivo. These vectors are controlled by placing one or two essential genes under the stringent control of a gene switch coactivated by heat and antiprogestin.
In the absence of these activating factors, the controlled HSV-1 vectors do not replicate. In this study, the unactivated HSV-1 vectors offer equivalent protection to chemically inactivated vaccines. However, the activation of these controlled HSV-1 vectors increases vaccine efficacy over inactivated vaccines [ 16 ].
Vaccinated mice also showed suppressed T cell activation in the draining lymph nodes following the challenge. Vaccine efficacy correlated with serum neutralizing antibody titers. Humoral immunity was identified as a significant correlate of protection against corneal neovascularization, HSV-1 shedding, and latency through passive immunization [ 35 , 36 ].
Interestingly, vaccination with the VC-2 vaccine protected mice from developing any appreciable ocular pathology, while vaccination with the attenuated parental HSV-1 F strain only offered partial protection.
Animals vaccinated with VC-2 produced higher neutralizing antibody titers than the parental HSV-1 F strain post-challenge. Neurotropism is the main hallmark of alphaherpesviruses and a major challenge in designing live-attenuated viruses that ideally should not establish latency in neurons. Recent attempts to inhibit virus entry into neuronal axons have yielded several novel live-attenuated HSV-1 vectors.
UL37 has been shown to play a conserved role in alphaherpesvirus neurotropism by facilitating retrograde virion transport upon infection of neuronal axons [ 37 ]. The mutations in the R2 live-attenuated vaccine disrupt neuronal retrograde transport rendering the virus unable to establish latent infection in the nucleus of the neuronal cell body. In the guinea pig model of genital HSV-2 disease, intradermal ID vaccination with the R2 vaccine demonstrated superior performance to intramuscular IM vaccination with the gD2 monovalent subunit vaccine.
Similarly, ID vaccination with R2 induced higher neutralizing antibody titers than IM vaccination with the gD2 subunit vaccine alone [ 20 ]. In comparison, the non-neuroinvasive HSV-1 VC2 vaccine demonstrated superior protection to the gD2 subunit vaccine while generating long-lasting efficacy up to 6 months post-vaccination in a guinea pig model of genital HSV-2 infection [ 19 , 38 ].
Glycoprotein K gK is a highly hydrophobic glycoprotein having four transmembrane domains placing both amino and carboxy termini extracellularly. Glycoprotein K gK is required for efficient virus envelopment and functions as a heterodimer with the membrane protein UL20 [ 39 , 40 ].
The majority of mutations that cause enhanced virus-induced cell fusion are found within gK mediated primarily by interactions between gK and the amino terminus of gB [ 41 , 42 , 43 , 44 ]. Together gK and UL20 are highly conserved among neurotrophic alphaherpesviruses indicating highly conserved functions within this virus family [ 45 , 46 , 47 ].
Additionally, the amino terminus of gK is required for the interaction between gB and the cellular protein Akt. Upon binding to gB, Akt is phosphorylated and induces calcium release from the cell [ 48 ]. HSV is known to enter into cells by two mechanisms: fusion between the viral envelope and the cellular plasma membrane and endocytosis.
In some cases, HSV will enter by endocytosis, resulting in a double-membraned virion in the cytoplasm. Escape from endocytic vesicles is pH-dependent; however, release from the endocytic vesicle ultimately requires fusion of the viral envelope with the membrane of the endocytic vesicle [ 54 ].
Specifically, this mechanistic switch is known to occur via interactions between gB and gK. However, entry into the axons of sensory neurons is strictly dependent on the direct fusion between the viral envelope and axonal cellular membranes [ 57 ]. Disruption of the ability of gK to induce gB-mediated membrane fusion restricts HSV-1 to replication in epithelial cells allowing for the presentation of all viral antigens.
At the same time, the virus cannot establish latency in neurons. Initially identified as a viral factor for viral replication in vitro, the ICP0-null virus demonstrated a significant growth defect, especially at low multiplicities of infection [ 59 , 60 , 61 , 62 , 63 ]. Subsequent in vivo experiments demonstrated the requirements of ICP0 for productive replication and reactivation from latent infection [ 64 , 65 , 66 , 67 ].
Recent publications have identified ICP0 as a critical mediator of host cell chromatin architecture via the targeted degradation of the cellular epigenetic machinery. Host cell recognition of cytosolic viral DNA is crucial for early antiviral defenses.
IFI16 is primarily localized to the nucleus but shuttles between the nucleus and cytoplasm via acetylation by the histone acetyltransferase p Upon infection with HSV-1, IFI16 recognizes viral DNA in the nucleus and is rapidly acetylated for distribution to the cytoplasm, where it activates interferon production to restrict viral replication [ 75 , 76 ]. IFI16 is targeted by ICP0 for ubiquitination and degradation by the cellular proteasome [ 77 , 78 , 79 ]. Also, ICP0 inhibits important components of the antigen presentation pathway in sentinel cells, which are responsible for activating the adaptive arm of the immune system.
Virus lacking ICP0 is more immunogenic, increasing the breadth of antigen recognition by antibodies from immunized animals and generating superior protection compared with the gD2 subunit vaccine in mice and guinea pig models of genital HSV-2 disease [ 83 , 84 , 85 ].
Apparently, deletion of ICP0 unlocked the immune response to HSV infection, leading to greater antigen presentation and altering the inflammatory response to HSV infection. The polyfunctionality of the ICP0 protein establishes it an ideal target for vaccine and vector attenuation. The primary endpoints of this clinical trial include: 1 Evaluation of the safety profile of different investigational vaccine regimens against HSV-2; 2 evaluation of the relative efficacy of investigational vaccine regimens concerning the frequency of HSV shedding by PCR to detect viral DNA in the genital area shedding rate following the two-dose vaccine schedule; 3 determining the proportion of participants free of HSV genital recurrence at 6 months after the two-dose vaccine schedule.
The secondary objectives of this study include: 1 Evaluating the impact of each investigational vaccine regimen in terms of the total number of days with genital lesions up to 6 months after the second vaccination, and number of recurrences 60 days after the second vaccination compared to the placebo group; 2 describing the efficacy of each investigational vaccine regimen concerning the frequency of HSV DNA detection in the genital area shedding rate 60 days following the first vaccination visit plus 60 days following the second vaccination visit compared to the placebo group; 3 describing the efficacy of the investigational vaccine regimens with respect to HSV DNA detection in the genital area shedding rate 60 days after the first vaccination visit compared to the placebo group.
Despite the historical failure to deliver an FDA-approved successful vaccine strategy by existing vaccine approaches, much knowledge has accumulated from past and ongoing studies regarding immunological features required for successfully confronting herpes simplex infections. Several novel vaccine approaches are in late-stage preclinical development, moving toward phase 1 trials in the coming years Table 2.
These approaches will likely demonstrate varied efficacy in clinical trials; although, they have demonstrated high efficacy in preclinical animal models. Therefore, an effective vaccine approach is required to protect without exacerbating the reactivation of the latent virus, suggesting that both inflammatory and immune-regulatory pathways and cellular milieus must be considered.
Forthcoming phase I and II clinical trials are needed to provide necessary human data showing that these vaccines are well-tolerated while generating effective and broadly therapeutic immune responses. Importantly, these viruses can also be efficiently used as vectors for producing vaccines against other human pathogens due to their ability to express multiple genes as insertions into their genomes without appreciably affecting their viral infectivity.
Conceptualization, B. All authors have read and agreed to the published version of the manuscript. S received consulting fees from RVx. These declared competing interests did not affect our adherence to MDPI policies. National Center for Biotechnology Information , U. Journal List Viruses v.
Published online Aug Brent A. Stanfield , 1 Konstantin G. Konstantin G. Agustin Fernandez 3 Rational Vaccines Inc. Edward Gershburg 3 Rational Vaccines Inc.
It was tested as both a prophylactic and therapeutic vaccine. Recent studies have demonstrated the production of antibodies mediating NK cell activation. Additionally, HSV-2 gD antibodies were detected in cervicovaginal fluid at around one-third of the serum level Wang et al. Nucleoside analogs, including acyclovir, valacyclovir, and famciclovir, remain standard therapies for mucocutaneous and visceral HSV infection. Idoxuridine, trifluorothymidine, vidarabine, and cidofovir are used topically for ocular HSV infections Beigel and Kottilil, IV Foscarnet and cidofovir are usually effective for acyclovir resistant viral strains Beigel and Kottilil, Continued exposure to cidofovir does not easily induce resistance.
There have been various attempts at formulating an effective vaccine for herpes simplex virus, especially given its wide prevalence and ability to cause significant morbidity and mortality. A prophylactic vaccine would be ideal. It would be effective at preventing active infection and transmission of the virus, which would avoid latent infection of the dorsal root ganglia trigeminal and sacral ganglia , reactivation and the clinical manifestations accompanying it.
This would prevent the sequelae of primary infection and viral spread within the population and severe complications involving reactivation. However, the utility of such a vaccine is in question. Most herpesvirus infections occur in adolescence James et al. While a prophylactic vaccine would be optimal for the prevention of all complications, it might be more realistic to focus on therapeutic vaccines that would reduce disease severity measured in recurrences, duration of clinical symptoms and viral shedding.
A therapeutic vaccine would potentially be able to benefit a wider proportion of the populations given the high proportion of seropositive individuals James et al.
HSV infection has a wide range of presentation that varies by the individual ranging from asymptomatic to severe complications like ocular keratitis; Bolognia et al. A therapeutic vaccine would be cost-effective and more efficiently administered compared to a prophylactic vaccine, targeting the subset of seropositive individuals with clinical symptoms. This would be a more effective strategy for the prevention of severe clinical complications compared to prophylactic vaccines.
While there are risk factors for primary infection with HSV, there are no clear risk factors for the development of severe complications which would make it difficult to target vulnerable populations only, instead of the entire population. What has emerged with the development of vaccines for herpes is some vaccines like the G vaccine with prophylactic as well as a therapeutic utility Odegard et al.
Although they are with their differences in molecular structure, the vast majority of vaccine candidates while targeted to one subtype have been shown to be effective in both HSV-1 and HSV-2 models. Furthermore, this cross-protection would be useful to prevent not only the genital reactivations of herpesvirus, but the ocular and systemic manifestations as well.
Current therapies for HSV including acyclovir and valacyclovir are effective at reducing viral shedding, symptom duration, and severity Gupta et al. However, there is a short treatment window for effective treatment. Treatment needs to be started in the prodromal phase to have optimal effects on controlling viral replication, as late treatment has limited effectiveness.
Additionally, their effectiveness is limited with only marginal reductions to symptom durations and severity Harmenberg et al. Given our knowledge of HSV pathogenesis and latency, an immune system modifying drug or therapeutic vaccination has potential to address these limitations.
Although the prevalence of acyclovir-, valacyclovir,- and cidofovir-resistant strains of HSV is low, therapeutic vaccination has an additional use as an alternative treatment for those rare cases Beigel and Kottilil, This is particularly the case with increasing resistance to acyclovir in immunocompromised patients, where IV Foscarnet, the next-line treatment, has limitations due to its side effects Harmenberg et al.
Taking into account the increased incidence of resistance in immunocompromised patients, it would be prudent to prioritize the development of subunit, nucleic acid vaccines, and replication defective vaccines over live-attenuated vaccines Birkmann and Zimmermann, Live-attenuated vaccines, while effective, are associated with increased safety concerns, especially in immunocompromised patients.
Our understanding of the complexities of herpes simplex virus pathogenesis and immune evasion is consistently evolving, along with our understanding of viral latency. Designing an effective therapeutic or prophylactic vaccine requires further understanding these processes. Trials that had been successful in the pre-clinical realm with murine model and guinea pig models have been effective, but have not translated well in the clinical realm.
To us, the HSV and G appear to be promising from early studies in the pre-clinical stage. Additionally, they are likely to have less issues with safety as they are not live-attenuated vaccines. It remains to be seen whether mRNA vaccines might have a utility for HSV; however, initial studies with the trivalent vaccine have been promising, showing increased efficacy compared to a subunit formulation Liu et al.
The advantages of an mRNA vaccine were previously discussed: It does not integrate within the host genome, translates in both proliferating and non-proliferating cells, with immediate protein production for a controllable amount of time Pardi et al.
It would additionally be prudent to utilize our increasing knowledge of the pathogenesis of herpes simplex virus and its interaction with the immune system in order to formulate novel therapies that could include therapeutic vaccination.
PS contributed to conception and outline of the article. RK wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. National Center for Biotechnology Information , U. Front Microbiol. Published online Dec 7. Rohini Krishnan and Patrick M. Author information Article notes Copyright and License information Disclaimer.
Louis, MO, United States. Stuart, ude. This article was submitted to Virology, a section of the journal Frontiers in Microbiology. Received Oct 20; Accepted Nov The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. Keywords: vaccines, herpes simplex virus type 1, herpes simplex virus type 2, mRNA vaccine, live attenuated vaccine, subunit vaccine, DNA vaccine.
Introduction Herpes simplex virus HSV is a prevalent sexually transmitted infection, a leading cause of infectious blindness in the Western world, and is the most common cause of focal, sporadic encephalitis in the United States. Open in a separate window. Figure 1. Figure 2. Clinical Herpes Simplex Infection Primary infection with herpes simplex involves grouped vesicles on an erythematous base. Primary and Secondary Immune Responses to HSV Innate Immune Response The innate immune system consists of a variety of components including neutrophils, natural killer cells, monocytes, dendritic cells, macrophages, and the complement cascade Xu et al.
Adaptive Immune Response Unlike the innate immune system, the adaptive immune system is targeted to the pathogen and more sophisticated, conferring enduring protection. Approaches to Vaccine Development Although there are no currently available vaccines for herpes simplex 1 and 2, there are various candidates in both the pre-clinical and the clinical phases currently in development.
Vaccines in Development Table 1 lists the vaccines in development in both the pre-clinical and the clinical arena. Table 1 Vaccines in development for infection with HSV Live-Attenuated Vaccines Various live-attenuated vaccines for HSV have been tested in the pre-clinical and the clinical stages.
Subunit Vaccines Subunit vaccines have become a powerful tool to mount immune responses against viral proteins. Approach To Herpes Simplex Virus Therapy Nucleoside analogs, including acyclovir, valacyclovir, and famciclovir, remain standard therapies for mucocutaneous and visceral HSV infection. Discussion There have been various attempts at formulating an effective vaccine for herpes simplex virus, especially given its wide prevalence and ability to cause significant morbidity and mortality.
Further Considerations for the Future of Herpes Simplex Virus Vaccine Development Our understanding of the complexities of herpes simplex virus pathogenesis and immune evasion is consistently evolving, along with our understanding of viral latency. Author Contributions PS contributed to conception and outline of the article.
Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References Alberts B. Molecular Biology of the Cell. New York: Garland Science. An HSV-2 trivalent vaccine is immunogenic in rhesus macaques and highly efficacious in Guinea pigs.
Using a murine model of nHSV, we demonstrated that maternal immunization with the trivalent vaccine protected offspring against nHSV-disseminated disease and mortality. In addition, offspring of immunized dams were substantially protected from behavioral pathology following HSV infection. This study supports the idea that maternal immunization is a viable strategy for the prevention of neonatal infections.
Current antiviral therapies can prevent mortality if infection is recognized early and treated promptly. Most children who survive nHSV develop lifelong neurological and behavioral deficits, despite aggressive antiviral treatment. Owing to difficulties in ensuring that the entire virus is inactivated, vaccine developers isolated HSV components from detergent extracts of inactivated virus-infected cells.
This vaccine was highly immunogenic in laboratory animals; however, it was poorly immunogenic in vaccinated subjects and there was no significant difference in reduction of clinical disease between the control and vaccine recipients. In , Mertz et al. The vaccine failed to protect HSV-2 seronegative recipients, whose partners had documented recurrent genital herpes, from developing HSV-2 genital disease. Antibody titers to HSV-2 gD and gB were very low compared with the partners with recurrent genital herpes.
Skinner et al. A multicenter, placebo-controlled trial of this vaccine in patients with frequently recurring genital herpes revealed that the vaccine did not significantly decrease the frequency of genital herpes recurrences in women at 3 and 6 months after vaccination [ 49 ]. However, the severity of recurrences was significantly decreased as defined by a reduced number of lesions and reduced symptoms per recurrence.
The vaccine induced both neutralizing antibody and cellular immunity to HSV Glycoprotein vaccines consist of one or more glycoproteins combined with adjuvants that boost their immunity. This vaccine was evaluated in two randomized, double-blind, placebo-controlled studies.
The first included HSV-2 seronegative partners of HSVinfected persons, and the second study included individuals attending a sexually transmitted diseases clinic and at high risk of HSV-2 infection Table 2 [ 50 ]. However, the vaccine was not successful in preventing infection after 1 year of follow-up and there was no effect on the rate of symptomatic HSV-2 infection, despite inducing neutralizing antibody levels exceeding those induced by natural infection.
These results suggest that neutralizing antibodies alone may not be sufficient to protect against genital HSV-2 infection. Pre-existing immunity to HSV-1 did not influence the rate of acquisition of HSV-2 but did increase the proportion of asymptomatic infections. Randomized, double-blind, placebo-controlled human trials of prophylactic recombinant subunit herpes simplex virus-2 vaccines with clinical end points. Two trials were performed and the results reported together [ 51 ].
Surprisingly, the vaccine was not effective in preventing genital herpes disease the primary endpoint or infection. R is an attenuated live HSV-1 vaccine that has a bp deletion in the thymidine kinase gene and a 14 kbp deletion into which are inserted several glycoproteins of HSV-2 [ 52 ]. In clinical studies, the vaccine was poorly immunogenic at the maximum dose tested 10 5 pfu [ 53 ].
Straus et al. The primary end point of the trials was the frequency of symptomatic outbreaks of genital herpes. In the first trial, recipients of a recombinant gD2 vaccine with alum experienced significantly fewer virologically confirmed recurrences per month [ 54 ].
However, the duration of new lesion formation, symptoms and time to healing for the first recurrence after vaccination were significantly shortened. They concluded that their studies support the concept of a therapeutic vaccine for ameliorating recurrences of HSV Randomized, double-blind, placebo-controlled human trials of therapeutic subunit or live virus herpes simplex virus-2 vaccines with clinical end points. Casonova et al.
The virus is impaired in its ability to establish latency in dorsal root ganglia and to reactivate from latency. Vaccinated patients had fewer recurrences 1. While these results are promising, recurrences were not documented virologically. The only replication-defective therapeutic vaccine evaluated in a multicenter, randomized, controlled clinical trial in persons with frequently recurrent genital herpes was the disabled infectious single cycle gH deleted vaccine [ 58 ].
The recombinant vaccine virus was propagated in complementing cells that express the HSV-2 gH gene. The virus can infect cells but only undergoes a single cycle of replication in vivo , since normal human cells do not express gH.
The vaccine had no effect on reducing the time to first recurrence of genital herpes after vaccination the primary end point , clinical disease or genital shedding. Investigators are applying novel molecular approaches to HSV-2 vaccine development. For example, Cattamanchi et al. Therefore, higher doses of vaccine or adjuvants will likely be required to generate an immune response.
Koelle et al. Heat shock proteins have previously been shown to elicit T-cell responses against peptides that they chaperone [ 61 ]. HSV immune evasion genes are important for virus manipulation of the immune system. The smallpox vaccine vaccinia virus is lacking a large number of immune evasion genes that contribute to its attenuation.
HSV-2 gC binds the C3b component of complement and inhibits complement-mediated neutralization of the virus [ 62 ]; therefore, antibodies to gC2 could block the ability of the virus to evade neutralization by complement. Immunization of mice with combined gC2 and gD2 in CpG and alum increased neutralizing antibody in the presence of complement, and reduced the amount of virus in ganglia after intravaginal challenge compared with animals that received gD2 alone; however, acute disease scores were not significantly better than for animals receiving gD2 alone [ 63 ].
Vaccination of guinea pigs with combined gC2 and gD2 in CpG and alum resulted in higher neutralizing antibody titers in the presence of complement, and fewer days of HSV-2 shedding during recurrent infection after challenge compared with animals vaccinated with gD2 alone; however, acute disease, vaginal shedding during acute disease and the frequency of recurrent genital disease after challenge was not reduced compared with animals receiving gD2 alone [ 63 ].
While inactivated HSV-2 has not been shown to be protective in humans, these vaccines were not given with newer adjuvants.
All four vaccines showed similar levels of protection against acute disease, virus shedding and recurrence rates of genital herpes in guinea pigs. The three vaccines containing inactivated HSV-2 but not the gD vaccine significantly reduced the latent virus load compared with control.
Thus, an inactivated HSV-2 in an effective adjuvant is another approach that should be considered in addition to replication-defective or live attenuated vaccines.
Vaccine HSV-2 dl is deleted for two viral genes UL5 and UL29 that are essential for virus replication and is grown in complementing cells that express these two proteins [ 65 ].
HSV-2 dl is impaired for latency in mice [ 66 ] and guinea pigs [ 67 ]. Repeated immunization of mice subcutaneously with HSV-2 dl reduced acute virus shedding, vaginal lesions and mortality. HSV-2 dl also decreased latent infection after intranasal challenge with wild-type virus HSV-2 [ 66 ].
Vaccination of guinea pigs with HSV-2 dl reduced acute, recurrent and latent infection as well as shedding after challenge with wild-type virus when compared with unvaccinated animals [ 67 ]. Prior infection with HSV-1 did not diminish the effectiveness of HSV-2 dl vaccine to reduce acute and recurrent disease after challenge with HSV-2 in guinea pigs when compared with unvaccinated animals.
The virus has a dominant negative mutation in UL9, which results in inability to replicate both its own viral DNA as well as that of wild-type virus in cells infected with the vaccine strain. Vaccination of mice with CJ9-gD reduced shedding, genital lesions, hind limb paralysis and death after intravaginal challenge with HSV-2 [ 71 ]. Vaccination of guinea pigs with CJ9-gD protected the animals from acute genital lesions and hindlimb paralysis, reduced virus shedding, prevented recurrent disease and reduced latent viral DNA after challenge with wild-type HSV-2 [ 72 ].
A third promising replication-defective HSV vaccine in development was created by deletion of UL29 and expressing the costimulation molecule, B7, in an attempt to enhance the T-cell immune response in a replication-defective vaccine [ 73 ]. The only licensed human herpes virus vaccines are the live attenuated varicella vaccine to prevent chickenpox and the zoster vaccine to prevent shingles.
Thus, a live attenuated vaccine may be more likely to be effective than a subunit vaccine; however, safety issues are paramount, especially if the vaccine virus can establish latency.
HSV-2 gE is critical for cell-to-cell spread in vitro , including from epithelial cells to axons, from neurons to epithelial cells, and for anterograde transport from neuron cell bodies to axons [ 75 ].
Two prophylactic immunizations of guinea pigs with the HSV-2 gE mutant resulted in reduced acute vaginal shedding and disease, and reduced recurrent vaginal shedding and lesions compared with control cell lysate after challenge with HSV-2 [ 76 ]. Therapeutic immunization of guinea pigs previously infected with HSV-2 reduced the incidence of recurrent genital disease. HSV-2 gD binds to several receptors, principally nectin-1, on epithelial cells and neurons, and to herpes virus entry mediator HVEM on epithelial cells and lymphocytes.
HSV-1 pseudotyped to carry gD mutations showed that amino acid substitutions at amino acids , and of gD reduced binding to nectin-1 and impaired nectinmediated entry of virus into cells; however, the mutations did not inhibit binding to HVEM or entry into cells expressing HVEM [ 80 ]. These studies suggested that HSV with gD mutants that impair entry via nectin-1 might be used as vaccine candidates in that they would replicate in epithelial cells in the periphery, but not infect neurons.
Based in part on these findings, an HSV-1 candidate vaccine was constructed with a mutation at amino acid 3 of gD; the mutant was impaired for entry into nectin-1 as well as HVEM expressing cells [ 81 ]. The mutant was attenuated, and protected mice from acute and recurrent disease and death after challenge with HSV-1 inoculated into the flank. An HSV-2 candidate vaccine with mutations at amino acids , and in gD infected human epithelial cells but was severely impaired for infecting neuronal cells [ 82 ].
When inoculated into mice, the vaccine was safe and protected against challenge with a lethal dose of wild-type HSV-2 [Wang et al , Unpublished Data]. While the ultimate goal of any vaccine is to induce sterilizing immunity, a more practical goal for an HSV-2 vaccine would be to reduce disease and genital shedding. The only licensed herpes virus vaccine that reduces disease due to primary infection is the varicella vaccine, which diminishes disease associated with varicella, but does not induce sterilizing immunity [ 83 ].
In addition, the observation that persons can be infected with more than one strain of HSV-2 implies that sterilizing immunity might not be possible [ 44 ]. An HSV-2 vaccine that protects the recipient from primary disease and reduces reactivation and shedding, even without inducing sterilizing immunity, would reduce transmission of virus and potentially alter the epidemiology of HSV-2 infection.
Such a vaccine would be a major contribution to public health. In our opinion, however, it will be more difficult to achieve success in a therapeutic vaccine trial, as the vaccine would need to induce a more effective immune response than is naturally produced in a person with frequent virus reactivation [ 84 ]. Therefore, it is possible that a failed therapeutic vaccine might be fully successful if it is tested as a prophylactic vaccine [ 58 ]. In our opinion, efforts should focus primarily on the development of prophylactic vaccines until more is understood about the biology and immunology of reactivation.
While numerous virus vaccines are approved to prevent disease associated with primary infection, only the herpes zoster vaccine is licensed to prevent reactivation of a virus infection. Importantly, varicella-zoster virus, which causes shingles, is thought to reactivate only once in most persons, while HSV-2 reactivates on nearly a daily basis [ 85 ]. Therefore, while the zoster vaccine is an important precedent for a therapeutic HSV-2 vaccine, the pathophysiology of varicella-zoster virus and HSV-2 reactivation are very different.
Glycoprotein vaccines are likely to be extremely safe and induce high levels of neutralizing antibody; however, they are unlikely to be effective as both a prophylactic and therapeutic vaccine. The observation that an HSV-2 gD vaccine induced antibodies at levels higher than those observed in healthy seropositive persons and did not protect humans from HSV-2 disease [ 27 ] suggests that gD alone may be insufficient or that more immunogenic methods are needed to deliver gD.
A vaccine that induces both potent antibody and T-cell responses will likely protect against primary disease, as well as reduce reactivation in those who eventually become infected, since cellular immunity is important for control of virus reactivation.
The only licensed vaccine that protects against primary infection with a human herpes virus is the live attenuated varicella vaccine, which induces both potent humoral and cellular immunity. This suggests that a live attenuated HSV-2 vaccine would most likely be successful, if it is sufficiently safe.
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