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Ghasemi M, Erturk M, Buruk K, Sonmez M. Induction of potent protection against acute and latent herpes simplex virus infection in mice vaccinated with dendritic cells. Cytotherapy 2013; 15:352-61. [PMID: 23579060 DOI: 10.1016/j.jcyt.2012.11.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Revised: 10/07/2012] [Accepted: 11/11/2012] [Indexed: 12/30/2022]
Abstract
BACKGROUND AIMS Dendritic cells (DCs) are the most potent antigen presenting cells of the immune system and have been under intense study with regard to their use in immunotherapy against cancer and infectious disease agents. In the present study, DCs were employed to assess their value in protection against live virus challenge in an experimental model using lethal and latent herpes simplex virus (HSV) infection in Balb/c mice. METHODS DCs obtained ex vivo in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4 were loaded with HSV-1 proteins (DC/HSV-1 vaccine). Groups of mice were vaccinated twice, 7 days apart, via subcutaneous, intraperitoneal or intramuscular routes with DC/HSV-1 and with mock (DC without virus protein) and positive (alum adjuvanted HSV-1 proteins [HSV-1/ALH]) control vaccines. After measuring anti-HSV-1 antibody levels in blood samples, mice were given live HSV-1 intraperitoneally or via ear pinna to assess the protection level of the vaccines with respect to lethal or latent infection challenge. RESULTS Intramuscular, but not subcutaneous or intraperitoneal, administration of DC/HSV-1 vaccine provided complete protection against lethal challenge and establishment of latent infection as assessed by death and virus recovery from the trigeminal ganglia. It was also shown that the immunity was not associated with antibody production because DC/HSV-1 vaccine, as opposed to HSV-1/ALH vaccine, produced very little, if any, HSV-1-specific antibody. CONCLUSIONS Overall, our results may have some impact on the design of vaccines against genital HSV as well as chronic viral infections such as hepatitis B virus, hepatitis C virus and human immunodeficiency virus.
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Affiliation(s)
- Mehdi Ghasemi
- Medical Microbiology Department, Medical School, Karadeniz Technical University, Trabzon, Turkey.
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2
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An adjuvanted herpes simplex virus 2 subunit vaccine elicits a T cell response in mice and is an effective therapeutic vaccine in Guinea pigs. J Virol 2013; 87:3930-42. [PMID: 23365421 DOI: 10.1128/jvi.02745-12] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Immunotherapeutic herpes simplex virus 2 (HSV-2) vaccine efficacy depends upon the promotion of antigen-specific immune responses that inhibit reactivation or reactivated virus, thus controlling both recurrent lesions and viral shedding. In the present study, a candidate subunit vaccine, GEN-003/MM-2, was evaluated for its ability to induce a broad-spectrum immune response in mice and therapeutic efficacy in HSV-2-infected guinea pigs. GEN-003 is comprised of HSV-2 glycoprotein D2 (gD2ΔTMR340-363) and a truncated form of infected cell polypeptide 4 (ICP4383-766), formulated with Matrix M-2 (MM-2) adjuvant (GEN-003/MM-2). In addition to eliciting humoral immune responses, CD4(+) and CD8(+) T cells characterized by the secretion of multiple cytokines and cytolytic antigen-specific T cell responses that were able to be recalled at least 44 days after the last immunization were induced in immunized mice. Furthermore, vaccination with either GEN-003 or GEN-003/MM-2 led to significant reductions in both the prevalence and severity of lesions in HSV-2-infected guinea pigs compared to those of phosphate-buffered saline (PBS) control-vaccinated animals. While vaccination with MM-2 adjuvant alone decreased recurrent disease symptoms compared to the PBS control group, the difference was not statistically significant. Importantly, the frequency of recurrent viral shedding was considerably reduced in GEN-003/MM-2-vaccinated animals but not in GEN-003- or MM-2-vaccinated animals. These findings suggest a possible role for immunotherapeutic GEN-003/MM-2 vaccination as a viable alternative to chronic antiviral drugs in the treatment and control of genital herpes disease.
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Abstract
Herpes simplex virus type 2 (HSV-2) is one of the most prevalent sexually transmitted infections worldwide. In addition to recurrent genital ulcers, HSV-2 causes neonatal herpes, and it is associated with a 3-fold increased risk for HIV acquisition. Although many HSV-2 vaccines have been studied in animal models, few have reached clinical trials, and those that have been tested in humans were not consistently effective. Here, we review HSV-2 pathogenesis, with a focus on novel understanding of mucosal immunobiology of HSV-2, and vaccine efforts to date, in an attempt to stimulate thinking about future directions for development of effective prophylactic and therapeutic HSV-2 vaccines.
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Affiliation(s)
- Christine Johnston
- Department of Medicine, University of Washington, Seattle, Washington, USA.
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4
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Sun HX, Xie Y, Ye YP. ISCOMs and ISCOMATRIX. Vaccine 2009; 27:4388-401. [PMID: 19450632 DOI: 10.1016/j.vaccine.2009.05.032] [Citation(s) in RCA: 170] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2008] [Revised: 02/22/2009] [Accepted: 05/09/2009] [Indexed: 10/25/2022]
Abstract
Immunostimulatory complexes (ISCOMs) are particulate antigen delivery systems composed of antigen, cholesterol, phospholipid and saponin, while ISCOMATRIX is a particulate adjuvant comprising cholesterol, phospholipid and saponin but without antigen. The combination of an antigen with ISCOMATRIX is called an ISCOMATRIX vaccine. ISCOMs and ISCOMATRIX combine the advantages of a particulate carrier system with the presence of an in-built adjuvant (Quil A) and consequently have been found to be more immunogenic, while removing its haemolytic activity of the saponin, producing less toxicity. ISCOMs and ISCOMATRIX vaccines have now been shown to induce strong antigen-specific cellular or humoral immune responses to a broad range of antigens of viral, bacterial, parasite origin or tumor in a number of animal species including non-human primates and humans. These vaccines produced by well controlled and reproducible processes have also been evaluated in human clinical trials. In this review, we summarize the recent progress of ISCOMs and ISCOMATRIX, including preparation technology as well as their application in humans and veterinary vaccine designs with particular emphasis on the current understanding of the properties and features of ISCOMs and ISCOMATRIX vaccines to induce immune responses. The mechanisms of adjuvanticity are also discussed in the light of recent findings.
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Affiliation(s)
- Hong-Xiang Sun
- Key Laboratory of Animal Epidemic Etiology & Immunological Prevention of Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Kaixuan Road 268, Hangzhou 310029, Zhejiang, China.
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Mori I, Liu B, Goshima F, Ito H, Koide N, Yoshida T, Yokochi T, Kimura Y, Nishiyama Y. HF10, an attenuated herpes simplex virus (HSV) type 1 clone, lacks neuroinvasiveness and protects mice against lethal challenge with HSV types 1 and 2. Microbes Infect 2005; 7:1492-500. [PMID: 16054416 DOI: 10.1016/j.micinf.2005.05.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2005] [Revised: 05/09/2005] [Accepted: 05/10/2005] [Indexed: 11/30/2022]
Abstract
Herpes simplex virus (HSV), a neurotropic virus, establishes life-long and, although rare, life-threatening infection in humans, and it may precipitate substantial medical and psychosocial morbidity. Here we show that HSV-1 strain HF clone 10 (HF10) exhibits impaired neuroinvasiveness in peripheral olfactory, vomeronasal and trigeminal conduits following intranasal as well as corneal inoculation. HF10 attenuation likely arises from multiple defects of HSV genes, so that HF10 will not revert to a virulent phenotype. Intranasal vaccination of mice with HF10 conferred significant protection against lethal challenge with HSV-1 and HSV-2 via the intranasal and intravaginal routes. Thus, we propose that HF10 explicitly meets the prerequisites for a candidate live attenuated HSV vaccine.
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Affiliation(s)
- Isamu Mori
- Department of Microbiology and Immunology, Aichi Medical University School of Medicine, 480-1195, Japan.
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6
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Hu WG, Wei J, Xia HC, Yang XX, Li F, Li GD, Wang Y, Zhang ZC. Identification of the immunogenic domains in HBsAg preS1 region using overlapping preS1 fragment fusion proteins. World J Gastroenterol 2005; 11:2088-94. [PMID: 15810073 PMCID: PMC4305776 DOI: 10.3748/wjg.v11.i14.2088] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: The incorporation of hepatitis B virus (HBV) preS1 region into epitope-based vaccines against HBV has been accepted widely, but the incorporate site and size of preS1 sequence is controversial. Therefore our purpose was to further investigate its immunogenic domains for the epitope-based hepatitis B vaccine design.
METHODS: Eight GST fusion proteins containing overlapping preS1 fragments in preS1 (21-119) region were expressed in E.coli. Using these purified fusion proteins, the immunogenic domains in preS1 region were identified in detail in mice and humans by Western blot analysis and ELISA.
RESULTS: The results in mice showed that the immu-nogenic domains mainly existed in preS1 (21-59) and preS1 (95-109). Similarly, these fragments had strong immunogenicity in humans; whereas the other parts except for preS1 (60-70) also had some immunogenicity. More importantly, a major immunogenic domain, preS1 (34-59), which has much stronger immunogenicity, was identified. Additionally, the antibodies against some preS1 fragments, especially preS1 (34-59), were speculated to be virus-neutralizing.
CONCLUSION: Eight GST fusion proteins containing overlapping preS1 fragments were prepared successfully. They were used for the study on the immunogenic dom-ains in preS1 (21-119) region. The preS1 (34-59) fragm-ents were the major immunogenic domains in the preS1 region, and the antibodies against these fragments were speculated to be virus-neutralizing. Therefore, the incorporation of preS1 (34-59) fragments into epitope-based HBV vaccines may be efficient for enhancement of immune response. Additionally, the results also imply that there are more complex immune responses to preS1 region and more abundant immunogenic domains in humans.
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Affiliation(s)
- Wei-Guo Hu
- Key Laboratory of Proteomics, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China
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7
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Abstract
The immunostimulating complex or 'iscom' was first described 20 years ago as an antigen delivery system with powerful immunostimulating activity. Iscoms are cage-like structures, typically 40 nm in diameter, that are comprised of antigen, cholesterol, phospholipid and saponin. ISCOM-based vaccines have been shown to promote both antibody and cellular immune responses in a variety of experimental animal models. This review focuses on the evaluation of ISCOM-based vaccines in animals over the past 10 years, as well as examining the progress that has been achieved in the development of human vaccines based on ISCOM adjuvant technology.
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Affiliation(s)
- Megan T Sanders
- Department of Microbiology and Immunology, The University of Melbourne, Australia
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Aurelian L. Herpes simplex virus type 2 vaccines: new ground for optimism? CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY 2004; 11:437-45. [PMID: 15138167 PMCID: PMC404574 DOI: 10.1128/cdli.11.3.437-445.2004] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The development of effective prophylactic and therapeutic vaccines against genital herpes has proven problematic. Difficulties are associated with the complexity of the virus life cycle (latency) and our relatively poor understanding of the mechanism of immune control of primary and recurrent disease. The types of effector cells and the mechanisms responsible for their activation and regulation are particularly important. Studies from my and other laboratories have shown that recurrent disease is prevented by virus-specific T helper 1 (Th1) cytokines (viz., gamma interferon) and activated innate immunity. Th2 cytokines (viz., interleukin-10 [IL-10]) and regulatory (suppressor) T cells downregulate this immune profile, thereby allowing unimpeded replication of reactivated virus and recurrent disease. Accordingly, an effective therapeutic vaccine must induce Th1 immunity and be defective in Th2 cytokine production, at least IL-10. These concepts are consistent with the findings of the most recent clinical trials, which indicate that (i) a herpes simplex virus type 2 (HSV-2) glycoprotein D (gD-2) vaccine formulated with a Th1-inducing adjuvant has prophylactic activity in HSV-2- and HSV-1-seronegative females, an activity attributed to the adjuvant function, and (ii) a growth-defective HSV-2 mutant (ICP10DeltaPK), which is deleted in the Th2-polarizing gene ICP10PK, induces Th1 immunity and has therapeutic activity in both genders. The ICP10DeltaPK vaccine prevents recurrent disease in 44% of treated subjects and reduces the frequency and severity of recurrences in the subjects that are not fully protected. Additional studies to evaluate these vaccines are warranted.
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Affiliation(s)
- L Aurelian
- Virology and Immunology Laboratories, Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
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Abstract
Herpes simplex viruses (HSV) cause lifelong persistent infections with numerous disease manifestations. Genital herpes infections are widespread in populations throughout the world and a vaccine to protect against or subdue established genital herpes infections has been under development for decades. Vaccine-mediated protection against persistent viral infections can be extremely difficult to achieve. The more rapidly a virus reaches its target tissue for persistence, the more vigorously a vaccine-induced immune response must defend the vaccinated individual. After exposure to HSV through sexual contact, only a few days are required for the virus to establish latent infection of its host. Despite numerous improvements, traditional vaccine approaches of whole virus or protein subunits have met with only marginal success. The many disappointments have heightened interest in determining correlates of immune protection, studies pursued both in animal models and in humans. They have also led to reassessment of the goals of vaccination. Necessity has sparked several creative new vaccine approaches involving nucleic acid or live attenuated viruses and vectors. With improved concepts of protective immune responses has come fervent discussion of the means to stimulate and maintain cell-mediated immunity. The result of this work is likely to be a more thorough understanding of antiviral immunity in the genital mucosa and the nervous system, and of HSV pathogenesis and immune evasion strategies, as additional strides are taken toward the goal of a successful vaccine with which to confront HSV.
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Affiliation(s)
- Lynda A Morrison
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Missouri 63104, USA.
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Simms JR, Jennings R, Richardson VJ, Heath AW. Large-scale comparison of experimental adjuvants with herpes simplex virus vaccine reveals a correlation of protection with IgG2a and IgG2b responses. J Med Virol 2002; 68:82-91. [PMID: 12210434 DOI: 10.1002/jmv.10173] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The potential of a large number of commercial and experimental adjuvant preparations to enhance the immunogenicity of an HSV-1 glycoprotein subunit vaccine was investigated. Evaluation was based on toxicity, HSV-specific antibody production, and protection against lethal challenge. All adjuvants tested increased the titer of antigen specific Ig levels when compared to subunit vaccine alone. However, following challenge, a broad range of protective responses were noted. Statistically significant correlations were observed between IgG antibody levels post immunization and the observed protection and these were particularly associated with antibodies of the IgG2a and IgG2b subclasses. The results emphasize the requirement of adjuvants for vaccine formulation when using subunit preparations, and demonstrate that the magnitude and efficacy of the induced immune response varies greatly with the choice of adjuvant.
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Affiliation(s)
- John R Simms
- Division of Genomic Medicine, Infection and Immunity, University of Sheffield Medical School, Sheffield, England, United Kingdom.
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Gyotoku T, Ono F, Aurelian L. Development of HSV-specific CD4+ Th1 responses and CD8+ cytotoxic T lymphocytes with antiviral activity by vaccination with the HSV-2 mutant ICP10DeltaPK. Vaccine 2002; 20:2796-807. [PMID: 12034107 DOI: 10.1016/s0264-410x(02)00199-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
A growth compromised herpes simplex virus type 2 (HSV-2) mutant which is deleted in the PK domain of the large subunit of ribonucleotide reductase (ICP10DeltaPK) protects from HSV-2 challenge in the mouse and guinea pig cutaneous and vaginal models and reduces the incidence and frequency of recurrent disease (Vaccine (17) (1999) 1951; Vaccine (19) (2001) 1879). The present studies were designed to identify the immune responses induced by ICP10DeltaPK and define the component responsible for protective activity. We found that ICP10DeltaPK elicits a predominant HSV-specific T helper type 1 (Th1) response, as evidenced by: (1) higher levels of HSV-specific IgG2a (Th1) than IgG1 (Th2) isotypes and (2) higher numbers of CD4+ IFN-gamma than IL-10 secreting T cells in popliteal lymph nodes. This Th1 response pattern was associated with a significant increase in the levels of IL-12 produced by dendritic cells from ICP10DeltaPK than HSV-2 immunized animals. Lymph node cells (LNCs) from ICP10DeltaPK immunized mice had significantly higher levels of HSV-2 specific cytolytic activity than LNCs from mice immunized with HSV-2 and it was mediated by CD8+ T cells. CD8+ CTL were not seen in LNCs from HSV-2 immunized mice. In adoptive transfer experiments, CD8+ T cells and, to a lower extent, CD4+ T cells from ICP10DeltaPK immunized mice inhibited HSV-2 replication, suggesting that they are involved in the protective immunity induced by ICP10DeltaPK vaccination.
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Affiliation(s)
- T Gyotoku
- Virology/Immunology Laboratories, Departments of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 10 S. Pine Street, Baltimore, MD 21201, USA
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12
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Guan XJ, Guan XJ, Wu YZ, Jia ZC, Shi TD, Tang Y. Construction and characterization of an experimental ISCOMS-based hepatitis B polypeptide vaccine. World J Gastroenterol 2002; 8:294-7. [PMID: 11925610 PMCID: PMC4658369 DOI: 10.3748/wjg.v8.i2.294] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To characterize the biochemical and immunological properties of an experimental ISCOMS vaccine prepared from a novel therapeutic polypeptide based on T cell epitopes of HBsAg, and a heptatis B-ISCOMS was prepared and investigated.
METHODS: An immunostimulating complexes (ISCOMS)-based vaccine containing a novel therapeutic hepatits B polypeptide was prepared by dialysis method, and its formation was visualized by electron microscopy and biochemically verified by SDS-polyacrylamide gel electrophoresis. Amount of the peptide within ISCOMS was determined by Bradford assay, and specific CTL response was detected by ELISPOT assay.
RESULTS: Typical cage-like structures of submicroparticle with a diameter of about 40 nm were observed by electron microscopy. Results from Bradford assay showed that the level of peptide incorporation was about 0.33 g•L⁻¹. At the paralleled position close to the sixth band of the molecular weight marker (3480 kDa) a clear band was shown in SDS-PAGE analysis, indicating successful incorporation of polypeptide into ISCOMS. It is suggested that ISCOMS delivery system could efficiently improve the immunogenicity of polypeptide and elicit specific immune responses in vivo by the results of ELISPOT assay, which showed that IFN-γ producing cells (specific CTL responses) were increased (spots of ISCOMS-treated group: 47 ± 5, n = 3; control group: 5 ± 2, n = 3).
CONCLUSION: ISCOMS-based hepatitis B polypeptide vaccine is successfully constructed and it induces a higher CTL response compared with short polypeptides vaccine in vivo.
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Affiliation(s)
- Xiao-Ju Guan
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200031, China
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13
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Abstract
Genital herpes is a sexually transmitted disease that has been widely investigated from both an epidemiological and a diagnostic viewpoint. Better knowledge of the disease has pointed to the important role of asymptomatic herpes simplex virus type 2 shedding as a major culprit for the spread of the virus in the world, the latest statistics showing that the incidence of genital herpes is constantly increasing. The reference compound for the treatment and prophylaxis of genital herpes is acyclovir. Recently, two drugs with better oral bioavailability, valaciclovir, the oral prodrug of acyclovir, and famciclovir, the oral prodrug of penciclovir, have been made available. Nevertheless, there is a need to develop additional approaches, to extend the therapeutic possibilities and to face the problem of emerging resistant viruses, mostly in immunocompromised patients. Therefore, efforts have been made in different directions including the exploration of new targets for antiviral chemotherapy, the use of immunomodulators and the development of specific vaccines.
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Affiliation(s)
- Robert Snoeck
- Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
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Lin WR, Jennings R, Smith TL, Wozniak MA, Itzhaki RF. Vaccination prevents latent HSV1 infection of mouse brain. Neurobiol Aging 2001; 22:699-703. [PMID: 11705626 DOI: 10.1016/s0197-4580(01)00239-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Herpes simplex encephalitis (HSE) is a rare but very serious disorder caused by herpes simplex type 1 virus (HSV-1). Treatment with acyclovir decreases mortality but many patients still suffer cognitive impairment subsequently. A vaccine against HSV1 would therefore be of great value. HSV-1 has been implicated also in Alzheimer's disease (AD): we established that HSV1 resides in the brain of about two thirds of AD patients and aged normal people, and that in carriers of the type 4 allele of the apolipoprotein E gene, it is a strong risk factor for AD. Thus a vaccine against HSV-1 might prevent development of AD in some cases. To find whether a vaccine of mixed HSV-1 glycoproteins (ISCOMs), which protects mice from latent HSV-1 infection of sensory ganglia, prevents HSV1 latency in the CNS, ISCOM-vaccinated or unvaccinated animals were infected with HSV-1. Using polymerase chain reaction (PCR) we detected HSV-1 in brain from 16 of 39 unvaccinated mice (41%), but only 3 of 41 vaccinated mice (7%) (P < 0.001). Thus, ISCOMs protect the CNS also, suggesting their possible future usage in humans.
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Affiliation(s)
- W R Lin
- University of Manchester Institute of Science & Technology, Molecular Neurobiology Laboratory, Department of Optometry & Neuroscience, M60 1QD, Manchester, UK
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Esiri MM. Potential for HSV-1 vaccination to reduce risk of HSV-1 encephalitis and/or Alzheimer's disease? Neurobiol Aging 2001; 22:711-3; discussion 717-9. [PMID: 11705628 DOI: 10.1016/s0197-4580(01)00248-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Affiliation(s)
- M M Esiri
- Department of Clinical Neurology, University of Oxford, Oxford Radcliffe NHS Trust, OX2 6HE, Oxford, UK.
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