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Clinical and Developmental Immunology
Volume 2012 (2012), Article ID 187585, 16 pages
Towards a Rational Design of an Asymptomatic Clinical Herpes Vaccine: The Old, the New, and the Unknown
1Laboratory of Cellular and Molecular Immunology, School of Medicine, University of California, Irvine, Irvine, CA 92697-4375, USA
2Department of Immunology, Pathology and Clinical Laboratory Medicine, King Fahad Medical City, Riyadh 11525, Saudi Arabia
3Institute for Immunology, School of Medicine, University of California, Irvine, Irvine, CA 92697-4120, USA
4Chao Family Comprehensive Cancer Center, University of California, Irvine Medical Center, Irvine, CA 92868-3201, USA
Received 15 November 2011; Accepted 10 January 2012
Academic Editor: Philippe Van de Perre
Copyright © 2012 Aziz Alami Chentoufi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The best hope of controlling the herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) pandemic is the development of an effective vaccine. However, in spite of several clinical trials, starting as early as 1920s, no vaccine has been proven sufficiently safe and efficient to warrant commercial development. In recent years, great strides in cellular and molecular immunology have stimulated creative efforts in controlling herpes infection and disease. However, before moving towards new vaccine strategy, it is necessary to answer two fundamental questions: (i) why past herpes vaccines have failed? (ii) Why the majority of HSV seropositive individuals (i.e., asymptomatic individuals) are naturally “protected” exhibiting few or no recurrent clinical disease, while other HSV seropositive individuals (i.e., symptomatic individuals) have frequent ocular, orofacial, and/or genital herpes clinical episodes? We recently discovered several discrete sets of HSV-1 symptomatic and asymptomatic epitopes recognized by CD4+ and CD8+ T cells from seropositive symptomatic versus asymptomatic individuals. These asymptomatic epitopes will provide a solid foundation for the development of novel herpes epitope-based vaccine strategy. Here we provide a brief overview of past clinical vaccine trials, outline current progress towards developing a new generation “asymptomatic” clinical herpes vaccines, and discuss future mucosal “asymptomatic” prime-boost vaccines that could optimize local protective immunity.
Human herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) infections cause lifelong infections, with a spectrum of clinical manifestations including cold sores, genital ulceration, corneal blindness, and encephalitis [1–10]. Despite multiple approaches of therapy and prevention, HSV-1 and HSV-2 remain among the most common infectious viral pathogens of man. Current drug therapies such as oral acyclovir, valacyclovir, or famciclovir can treat herpes disease but do not prevent future attacks. Historically, many candidate vaccines that are effective on animal models of herpes infection turned unsuccessful in clinical trials [1, 11]. Sampling of past and ongoing vaccine trials is provided in Table 1. Progress towards an effective vaccine has stalled in the face of many unknown questions related to HSV-1 and HSV-2 infection and immunity. Namely, (i) the cellular and molecular mechanisms behind the failure of past herpes vaccines remain unknown; (ii) the cellular and molecular mechanisms that lead the majority of HSV seropositive individuals to be naturally protected exhibiting few or no recurrent clinical disease (designated as asymptomatic individuals), while other HSV seropositive individuals to have frequent ocular, orofacial, and/or genital herpes clinical episodes (designated as symptomatic individuals) remain unknown. Although the majority of individuals have few or no herpetic disease symptoms, they still continue shedding HSV all times. An efficient vaccine would not only relive the patients from herpetic diseases but also prevent virus reactivation and asymptomatic shedding. In the past, many vaccine immunotherapies have tried to stimulate the immune system against herpes, including about a dozen vaccines that reached mid- and late-stage clinical trials . Every single one of these therapies had generated much excitement, but, for the most part, none of those therapies really did protect from herpes. Before devising more powerful treatments it is imperative to identify (i) the mechanisms underlying the suboptimal nonprotective immunity associated with natural infection, (ii) the major effectors of immunity that control each of the three phases of herpes infection (i.e., acute and latent), (iii) the sophisticated immune evasion strategies employed by HSV-1 and HSV-2 to dampen the immune response, (iv) the protective versus pathogenic protein (such as glycoprotein gK) Ag(s) among more than 80 immunogenic HSV proteins, and (v) a safe Ag delivery system.
Multiple review articles have adequately described and discussed the above issues [11–15]. The present paper focuses on bringing together past and recent published work that illuminates the current status of clinical herpes vaccine development. It presents an overview of our own vaccine approach to produce an “asymptomatic” herpes vaccine. First, we describe the common presentations of herpes simplex infections and diseases. Second, we portray the history of the different vaccine formulations that have led to the rationale for a herpes subunit vaccine. Third, we describe the process by which herpes protein Ags and derived “asymptomatic” epitopes suitable for inclusion in a multiepitope vaccine are being selected. Fourth, we shed new light on how an “asymptomatic” multiepitope lipopeptide vaccine can be designed to ensure optimal mucosal immunogenicity and discuss how, after prototype lipopeptide vaccines are designed, the program will move to the stage of clinical trials.
2. The Immunoepidemiology of Herpes
HSV-1 and HSV-2 are two closely related members of the Herpesviridae family and currently rank among the most prevalent infectious agents of man . Several common presentations of herpes simplex infections and diseases are recognized. Genital herpes: although, both HSV-1 and HSV-2 account for herpes genitalis, a common sexually transmitted disease (STD), HSV-2 is more severe and has become more commonly associated with genital herpes [17, 18]. Currently, over 1 billion people around the world—one-sixth of the world population—are infected with genital herpes. In the USA alone, at least 40 to 60 million individuals have been infected by HSV-2. A therapeutic vaccine would ideally cure many of the adults who often suffer frequent recurrent outbreaks of genital herpes. In addition to the pain related to herpes ulceration, genital herpes causes a substantial psychosocial morbidity [18, 19]. Herpes genitalis contributes to a 2- to 4-fold increased risk of acquiring human immunodeficiency virus (HIV) [3, 20, 21] Genital herpes in HIV-infected individuals usually needs a longer duration of antiviral therapy along with continuation of highly active antiretroviral therapy (HAART). Neonatal herpes: in some cases, herpes infections are fatal to newborns and cause neonatal encephalitis [17, 22]. Genital herpes in late pregnancy increases the risk of neonatal herpes. Annually, a minimum of 2500 cases of neonatal herpes  and 3000 cases of herpes encephalitis result in significant morbidity and mortality in spite of antiviral therapies. Ocular herpes: ocular infection with HSV-1 is the leading cause of corneal blindness worldwide. The corneal scarring induced by herpes infection often leads to blindness, making HSV-1 a major cause of virus-induced blindness [4–6, 24–26]. Ocular infection with HSV-1 can cause other eye diseases ranging from blepharitis, conjunctivitis, and dendritic keratitis to disciform stromal edema and necrotizing stromal keratitis [27–30]. In the USA alone, over 400 000 people have a history of recurrent ocular HSV episodes requiring doctor visits, medication and, in severe cases, corneal transplants [28, 29]. Nearly 50,000 new and recurring cases are diagnosed each year. Shedding of reactivated HSV is estimated to occur at rates of 3 to 28% in adults who harbor latent HSV-1 in their sensory neurons [9–12]. However, the vast majority of these individuals do not experience recurrent herpetic disease and are designated “asymptomatic patients” [11, 14, 16]. In contrast, in some individuals (symptomatic patients), reactivation of latent virus leads to induction of ineffective or “symptomatic” HSV-specific CD4+ and CD8+ T cells [11, 16, 31] (Figure 1). Recurrent disease ranges from rare episodes occurring once every 5–10 years to outbreaks occurring monthly or even more frequently among a small proportion of subjects . It is not known why ocular HSV-1 infection is asymptomatic in some individuals and symptomatic in others or why the frequency and severity of recurrences vary among symptomatic patients. The shedding rates in tears of asymptomatic individuals have been reported to be as high as 33.5% [13–16]. The immune mechanism(s) by which asymptomatic patients control herpes disease and symptomatic patients do not remains to be fully elucidated. Orofacial herpes: HSV-1-mediated recurrent facial herpes varies in severity. Symptomatic lesions usually occur on lips (cold sores), cheeks, within the nose, or on the nasal septum, which are painful and unpleasant [2, 32–34]. Dermal HSV infection can occur on any part of the body. Some oro-facial herpes are asymptomatic or appear as maculopapular lesions that may subsequently regress or develop into vesicular lesions, which then scab prior to healing. During asymptomatic or symptomatic outbreaks, HSV-1 is shed and can be transmitted to susceptible individuals.
The social and economic burden created by all types of herpes infection has set direct costs for treatment of these infections in the USA to over $400 million every year [16, 35]. Current drug therapies can treat the disease but do not prevent future viral attacks. Thus, novel strategies to treat, suppress, and prevent HSV infection are needed. An effective vaccine strategy remains the best hope for controlling the herpes pandemic. However, in spite of several clinical trials no vaccine has been proven sufficiently safe and efficient to warrant commercial development. It is imperative to know why past herpes vaccines have failed before we move towards developing a new vaccine strategy.
3. Past and Current Herpes Vaccines
Many classes of herpes vaccines and delivery systems have been attempted during the last century (Table 1). The following paragraphs review and discuss the approaches, the rationale, and the end results associated with some of the most widely studied herpes vaccines.
3.1. Inactivated and Replication-Defective Vaccines
In the early 1920s the first vaccine was introduced as an inactivated virus, which was prepared from formalin-treated tissues of HSV-infected animals [36–38]. A heat- or ultraviolet-inactivated virus, grown in embryonic eggs, was proposed later (reviewed in [37, 39]). Subsequent vaccines strategies changed from inactivated to replication-defective HSV strains such as virulent type HSV mutants (i.e., lacking ICP8, ICP10, dl5-29, or VHS), discontinuously replicating virus known as “disabled infectious single cycle” or “DISC”, and a virus with a deletion of UL22, the late gene encoding glycoprotein H (gH) . A DISC HSV-2 vaccine has entered clinical trials and has been found relatively safe with no serious adverse effects [41, 42]. Among HSV-seronegative subjects, dose-dependent induction of T-cell proliferation was noted four weeks after a single DISC HSV-2 immunization and continued for sixteen weeks after the second immunization. However, no responses were boosted in HSV-seropositive subjects. IFN-gamma (Th1) and IL-2 (Th2) production was also induced in HSV-seronegative persons in a dose-dependent fashion but not in HSV-seropositive persons. There was a lack of boosted IgG responses in both seronegative and seropositive subjects, indicating that DISC HSV-2 immunization might be shifted to Th1 responses. However, a recent immunotherapeutic phase II trial showed no clinical response in HSV-2 DISC-immunized persons .
3.2. Replication Competent Live Virus Vaccines
The replication competent live virus vaccine approach has the advantages of stimulating a broad immune response (antibody, CD4+ T cells, and CD8+ T cells) and presenting all epitopes from the entire genome to generate multiimmune responses. A case of recurrent human genital HSV-2 disease caused by a thymidine kinase-deficient, mouse-virulent strain has been reported . Mutations in thymidine kinase gene do not attenuate HSV-2 replication sufficiently when used as vaccines. A second live attenuated HSV strain developed for vaccine use is RAV 9395 . This virus was derived from HSV-2 strain G and contains deletions of both copies of the virulence factor g134.5, UL55, and UL56. Clinical results have not been reported for this mutant. The most extensive human studies are available with attenuated live HSV vaccine strain R7020, created by Branco and Fraser . This virus was originated from HSV-1 strain F and is attenuated by a deletion extending from UL54 (encoding ICP27) through the promoter region of ICP4. In a dose escalation study, local reactions and systemic side effects were noted in HSV-1-infected persons.
3.3. Recombinant Viral Vectors
A number of trials have been pursued using recombinant live attenuated adenovirus and vaccinia recombinant viruses expressing HSV glycoproteins. These vaccines elicit Ag-specific CD8+ T cells after a single immunization [47–49]. Not surprisingly, no major vaccine company, in the USA or EU, is developing inactivated live vaccine candidates. An important lesson learned from the human live vaccine trials is the true feasibility (i.e., practicability) of a herpes vaccine.
The recent emergence of new concepts and technologies in biochemistry, genetics, and immunology has opened up the way to novel approaches in vaccine development. In the following paragraphs we bring together both the challenges and some recent progress made in developing a subunit herpes vaccine.
3.4. Plasmid (Naked) DNA Vaccines
The concept of using naked DNA  as a vaccine is to introduce herpes antigenic genes into dendritic cells (DCs) for endogenous processing and presentation to CD4+ and CD8+ T cells in draining lymph nodes or into other cells (e.g., epithelial cells) for cross-presentation by DCs, without the need for a viral vector. However, the competition within viral vector epitopes for endogenous processing reduced the efficacy. In addition the prior immunity to the viral vector and the potential dangers associated with a live virus are avoided when using DNA vaccines. Constitutive, tissue-specific promoters may be used for selective expression. The results of a number of plasmid DNA vaccine experiments in animal models of ocular and genital herpes have been reported . The delivery of DNA vaccines usually requires high dosage of DNA plasmid to generate an immune response and often promotes Th2 response, which would not be expected to provide optimal protection against HSV infection and disease .
3.5. Recombinant Proteins-Based Subunit Vaccines
HSV has at least 11 enveloped glycoproteins that are expressed in infected cells. Among these, gB and gD glycoproteins are the most used immunogens since these are the dominant targets for neutralizing antibody production in HSV-infected individuals. gB and gD are attractive choices for subunit vaccines because they are the targets for both humoral (neutralizing and ADCC) and cell-mediated immunity (class I and class II restricted). gB and gD share high sequence similarity in HSV-1 and HSV-2 and may therefore provide cross-protection against both HSV-1 and HSV-2 infections.
Despite induction of high neutralizing serum antibody titers, the latest clinical vaccine trials, using recombinant protein gB and gD along with MF59 adjuvant, showed transient and partial protection [51–53]. More recently, intramuscular vaccination with a recombinant HSV-2 gD vaccine, using MPL as an adjuvant, protected ~70% of women who were HSV-1 and HSV-2 seronegative. However, there was no protection among men or among HSV-1 seropositive women [1, 53]. These results raised important questions regarding the role of gender-related factors and glycoprotein-based approach in vaccine efficacy. In this clinical trial, despite the induction of high neutralizing antibody titers that exceeded those of natural immunity, recurrent disease was not reduced suggesting that induction of a vigorous cellular immunity might be critical for therapeutic protection.
Development of a herpes subunit vaccine has been motivated by previous successes achieved with other pathogens. However, major hurdles include identification of antigens that execute the specificity of immune system on HSV-1- and HSV-2-infected cells without harming uninfected cells. So far, early clinical trials indicate the need for the identification of target Ags, other than envelope glycoproteins gB and gD. However, this task is far from complete because of the large and complex herpes genome that encodes over 80 polypeptides, each of which could be a potential target to a protective immune effector. Tegument proteins are sandwiched in between the envelope and capsid proteins of HSV and have been reported to be major targets for T-cell responses. A recent human study that utilized pools of overlapping synthetic peptides presented to CD8+ T cells through autologous dendritic cells showed that the responses to individual open reading frames (ORFs) ranged from ≤5% to a maximum of 70%. Interestingly, the highest responses detected in seropositive individuals were focused on six tegument proteins: UL39, UL25, UL27, ICP0, UL46, and UL47 in descending order. These six tegument proteins are therefore considered to be the best candidates for T-cell-based vaccines . Whether the T-cell responses of asymptomatic versus symptomatic individuals to these tegument proteins are similar or different remains to be determined.
Other current vaccine strategies, listed in Table 2, include the use of virus-like particles (VLPs), adenoviral vectors, and lipopeptide vaccines; however, very few have been approved for human use. Two promising approaches to herpes vaccination are currently being pursued in our and others laboratory based on entirely different theoretical approaches. The first approach is the subunit vaccines that use “asymptomatic” epitopes from envelop, tegument, and/or regulatory proteins with or without adjuvants [2, 32]. The second approach is the genetically engineered live attenuated vaccine without any putative neurovirulence or immuno-evasion genes [39, 55, 56]. Few vaccines with these dual modalities have attempted to provide sterilizing immunity. Nevertheless, prior attempts at HSV subunit and genetically engineered live attenuated vaccines have offered important lessons for the design of clinical and preclinical studies to evaluate vaccines of this kind.
4. T-Cell-Inducing Herpes Simplex Vaccines—What Is the Future
Shedding of reactivated HSV-1 and HSV-2 that leads to recurrent herpetic disease is estimated to occur at rates of 3 to 28% in adults who harbor latent virus in their sensory neurons [57–60]. Recurrent disease ranges from rare episodes occurring once every 5–10 years to outbreaks occurring monthly or even more frequently among a small proportion of “symptomatic patients” . For simplicity, one can categorized seropositive individuals based on the frequency of their recurrent disease into two major groups: (1) the symptomatic individuals (with a history of recurrent corneal, genital, and/or orofacial herpetic disease) and (2) the asymptomatic individuals (never had any recurrent herpes disease, ocular, genital, orofacial, or otherwise). The vast majority of seropositive individuals do not experience recurrent herpetic disease and are designated “asymptomatic” [59, 61, 62]. In contrast, in “symptomatic” individuals reactivation of latent virus leads to mild to severe herpetic disease [59, 61, 63]. It is not known why HSV-1 and HSV-2 reactivation/shedding is asymptomatic in some individuals and symptomatic in others or why the frequency and severity of recurrent disease vary among symptomatic individuals. Interestingly, for genital herpes, symptomatic and asymptomatic patients shed the virus at similar rates [59, 64]. It is likely to be the same for ocular herpes, since shedding rates in tears of asymptomatic individuals has been reported to be as high as 33.5% [61, 62, 65, 66]. The immune mechanism(s) by which asymptomatic patients control herpetic disease and symptomatic patients do not remains to be fully elucidated . Identifying these mechanisms, or at least the viral antigens (Ags) and epitopes involved, is critical to understanding how to protect against recurrent herpetic disease and for rational advances in therapeutic vaccine development. In the most recent clinical vaccine trials , despite recombinant-proteins-based HSV-2 vaccines induced neutralizing antibody titers that exceeded those produced by natural immunity, neither symptomatic infections nor symptomatic recurrences were affected by therapeutic vaccination. This suggests that induction of vigorous cellular immunity is critical for better protection [68, 69]. Thus, T cells appeared to be an important part of naturally acquired protective immune responses against herpetic disease, and inducing “asymptomatic” T cells by vaccination has dominated much of our research effort.
It is likely that Ag exposure during long-term herpes simplex infections may shape different T-cell repertoires over time, in symptomatic and asymptomatic individuals. The unique epitope-specific T-cell repertoire of each symptomatic and asymptomatic individual, known as “private specificity” [70–72], is thought to regulate whether herpes reactivation will result in viral control, asymptomatic persistence, or severe disease. Thus, in symptomatic individuals, reactivation of latent virus leads to induction of ineffective or “symptomatic” HSV-specific CD4+ and CD8+ T cells [59, 61, 63]. In contrast, in asymptomatic individuals, reactivation of latent virus leads to induction of protective or “asymptomatic” HSV-specific CD4+ and CD8+ T cells [59, 61, 63]. A good starting point for the development of an efficient therapeutic herpes vaccine would be to identify the matrices of protective or “asymptomatic” Ags and epitopes strongly recognized by T cells from asymptomatic individuals. Our recent findings support the idea that symptomatic and asymptomatic individuals have different levels of HSV-specific T-cell repertoires ([67, 73–75], Dervillez, submitted). We found that T cells from symptomatic and asymptomatic individuals, with similar HLA, have dramatically different profiles of responses to HSV epitopes. A set of human T-cell epitopes from HSV-1 glycoproteins B and D (gB&gD) are strongly recognized by T cells from HSV-1-seropositive asymptomatic individuals, but not by T cells from symptomatic individuals [67, 73–75]. In contrast, a different, nonoverlapping set of gB and gD epitopes are strongly recognized by T cells from symptomatic but not by T cells from asymptomatic individuals. However, this difference is not due to clonal T-cell deletion since there is not a complete lack of T-cell response. The “asymptomatic” T-cell precursor appears to exist in symptomatic patients and vice versa.
Our preclinical vaccine trial in “asymptomatic” HLA transgenic (HLA Tg) rabbits showed that immunization with asymptomatic human CD8+ T-cell epitopes from HSV-1 gD induced strong human epitope-specific CD8+ T cell responses and reduced HSV-1 shedding in tears and corneal disease following an ocular challenge . Rabbits support spontaneous reactivation of HSV-1 at a level similar to humans (~10%). Similarly, the rate of recurrent corneal disease in rabbits is also similar to that of humans. Unfortunately this rate is very low (<1% of eyes). However, we have been able to vaccinate HLA transgenic rabbits that developed recurrent corneal disease (i.e., a “symptomatic” HLA transgenic rabbits). One rabbit did develop a modest T-cell response against the “asymptomatic” peptides following vaccination. This suggests that symptomatic individuals will be able to respond appropriately to a therapeutic asymptomatic epitope-based vaccine and develop asymptomatic CD8+ T-cell responses specific to the asymptomatic epitopes. Despite “seeing” both “asymptomatic” and “symptomatic” epitopes (through virus exposure), the vaccinated asymptomatic individuals may not appear to revert to mixed T-cell populations but rather develop mainly the protective asymptomatic responses. The results also provide tangible preclinical evidence that immunization of “symptomatic” individuals with an “asymptomatic” epitope-based vaccine will likely boost “asymptomatic” T-cell responses in symptomatic patients (as it did in HLA Tg rabbits) and that may be sufficient to stop or reduce recurrent disease, upon encounter with the virus, through reinfection or reactivation of latent virus. In contrast, a therapeutic vaccine containing whole virus or whole viral proteins would be expected to induce symptomatic as well as asymptomatic CD8 T-cell responses, thus boosting harmful as well as protective immunity. Obviously, boosting harmful immunity should be avoided. This can be accomplished using an asymptomatic epitope-based therapeutic vaccine.
Since we have previously shown that there is significant HSV-1-specific CD8 T-cell exhaustion during latency in mice, it may be useful to complement the therapeutic asymptomatic epitope vaccine strategy with exhaustion-pathway blockage. This is likely to result in an even stronger CD8+ T cell response in latently infected “symptomatic” individuals.
5. The New Vaccines: Multivalent “Asymptomatic” Lipopeptide Vaccines
It has been demonstrated that immunizations with a single immunodominant CD8+ CTL epitope, administered in a suitably strong adjuvant, can protect MHC-haplotype-identical inbred mice against genital herpes [31, 76]. The MHC-haplotype-outbreed nature of the human population obviously complicates the development of single peptide-based vaccines. Bearing in mind the particular properties that would be required in a prospective human peptide vaccine, we conceived a strategy in which virus-specific CD4+ and CD8+ T cell responses could be generated in different haplotypes using a single or a mixture of lipopeptide vaccines [2, 34, 77, 78].
Though subunit vaccines with a combination of protective epitopes are promising, several challenges are still associated that need to be addressed. (i) Adding many epitopes together in a cocktail can lower the dose of each one, thereby reducing overall efficacy. (ii) Some balances during epitope selection must be considered in order to deal with the highly variable MHC-haplotype human population so that the immunogenicity and protection are not impaired or lost. (iii) Since both antibody and cell-mediated responses are necessary for full protection, it is important to control which epitopes stimulate which type of response. In spite of these challenges, we believe that among the current subunit vaccine types, a multiepitope peptide vaccine is best suited to provide the complex epitope combination necessary to protect a wide variety of human populations.
In other systems, induction of simultaneous responses against multiple epitopes derived from multiple Ags has already been demonstrated. The immunogenicity of multiepitope constructs appears to be strongly influenced by a number of different variables, and the immunogenicity (or antigenicity) of the same epitope expressed in the context of different vaccine constructs can vary over several orders of magnitude. This situation underscores the necessity of a systematic study of different variables in order to establish clear criteria for the optimal design of multiepitope vaccines (reviewed in [79, 80]). To address this in the context of herpes, we are designing and optimizing multiepitope vaccines comprising a panel of CD8+ and CD4+ T-cell epitopes derived from major herpes Ags as described in Figure 2. These epitopes were identified by class I and class II algorithm predictions and peptide binding/recognition strategies and recognized by recall immune responses from seropositive individuals as well as from HLA transgenic mouse models . Studies need to optimize the vaccine efficacy by (i) eliminating junctional epitopes and spaces between epitopes, (ii) the effect of flanking regions, and (iii) cellular targeting to Ag processing and presentation pathways. Recognition of individual epitopes is demonstrated by immunogenicity assays utilizing HLA transgenic mice and/or antigenicity assays using human APCs transfected in vitro with the prototype vaccine. The simplest vaccine configuration capable of effective delivery of the selected sets of epitopes will also be determined. Subsequent studies will identify the optimal vaccine delivery strategy for simultaneous induction of immune responses against multiple epitopes and the appropriate vaccine formulation. Overall, it is anticipated that these studies will define operational rules for the design and optimization of multiepitope-based vaccines.
The profile of HSV antigens presented during different phases of herpes infection implies that an ideal vaccine must be multivalent and capable of inducing multiimmune responses. Since the first demonstration of the technology, a few years ago, lipopeptide vaccines have emerged as a promising method of vaccination. In a variety of experimental systems, lipopeptide vaccines have been shown not only to induce potent immune responses but also to offer many advantages in terms of ease of construction, testing, and production (Figure 3). In the following paragraph we summarize the progress achieved in developing a lipopeptide-based vaccine that protects a progestin-induced susceptible mouse model of genital herpes from infection following intravaginal infection with either HSV-1 or HSV-2. We describe initial studies of immunogenicity and outline the strategies being employed to design the next generation of lipopeptide vaccines.
A presumed advantage of lipopeptide immunogens is the possibility of producing multivalent vaccines by a simple physical mixture and simultaneous delivery of lipopeptides bearing epitopes derived from one or more Ags, rather than chemical covalent association of T-cell epitopes in one molecule [81, 82]. Besides easy construction, such a mixture may also prove more effective than separate vaccines for each epitope. These results in mice coincide with a recent clinical trial of HIV-1 vaccine with similar strategy. The results showed that up to six T-cell lipopeptides, selected from three different HIV proteins (Gag, Nef, and Env) delivered simultaneously as a cocktail, were strongly immunogenic in humans [81, 83]. These findings are also in line with a recent report showing that immunization with a mixture of six lipopeptides derived from four malaria Ags is effective in inducing multispecific CD4+ Th1 cells, CD8+ CTLs, and IgG responses in nonselected “outbred” human populations [81, 82].
Shortcomings in developing an effective immunization strategy against genital herpes include an imperative requirement for a safe Ag delivery system . In most cases, unmodified nonvectorized peptide Ags fail to elicit virus-specific T cells, unless they are attached to a carrier protein or delivered with a strong adjuvant [84–86]. Often, the delivery of peptides in this manner is unsafe and/or promotes Th2 responses [87, 88], which would not be expected to provide optimal protection against HSV infection . Lipid tailing of peptides offers a safe formulation that generates CD4+ T cells, CD8+ T, cells and Ab responses in the absence of any adjuvant, apart from the lipid moiety itself [81, 83, 90–94].
Physicochemical safety and immunogenicity studies in animal models and in two human phase I clinical trials have established the safety and efficacy of HIV and malaria lipopeptide vaccine candidates [81, 83, 90–94]. The present paper focuses on herpes lipopeptides and demonstrates their safety and ability to induce CD4+ Th1 cell-dependent protective immunity against genital herpes when delivered in water via a parenteral route. Since HSV-1 and HSV-2 invade human mucosa, delivery of Ags through the IVAG route would induce better protection against these sexually transmitted infections [95, 96]. We previously demonstrated that intranasally administered lipopeptide epitopes induce both mucosal and systemic B- and CD4+ Th1-cell responses [2, 32–34, 97–100]. Similar results were obtained using the human cytomegalovirus pp65-derived CD8+ CTL lipopeptides in which higher levels of virus-specific CTL were obtained with lipopeptide delivered mucosally [2, 32–34, 97–101]. Assessing the immunogenicity and protective efficacy of HSV-1 and HSV-2 lipopeptides following administration through the IVAG or other mucosal routes (e.g., topical ocular, sublingual, intranasal, or intrarectal) is being pursued in our laboratory and will be addressed in future paper.
5.1. Advantages of Asymptomatic Epitope-Based Vaccines(1)exclusion of potentially harmful symptomatic epitopes,(2)focused immune response against immunodominant and protective asymptomatic epitopes,(3)molecularly defined-no immunoevasion or pathogenic molecules.
Our lipopeptide vaccine construct is molecularly defined, which makes it a particularly advantageous approach compared to other vaccine strategies (see Tables 1 and 2). Because the lipopeptide vaccine is constructed of chosen asymptomatic epitopes, we are able to exclude symptomatic epitopes that would otherwise reduce its efficacy or the harmful side effects. The “symptomatic” epitopes may direct T-cell responses away from those that are best suited to clear the viral infection with minimal pathogenic reaction (Figures 2 and 3 and ). An immunopathogenic T-cell response might occur through stimulating low-affinity oligoclonal responses that inhibit broad-based T-cell responses to other well-presented high-affinity epitopes, thus deviating protective responses to damaging responses. While protein-based vaccines contain both symptomatic and asymptomatic epitopes from the same protein, our lipopeptides exclusively contain CD4 and CD8 asymptomatic epitopes from one or many herpetic proteins . Because symptomatic epitopes can have pathological effects when used in a vaccine, our group has made it a priority to identify the asymptomatic epitopes of HSV glycoproteins, tegument proteins, and regulatory proteins [33, 67, 74, 77]. The lipopeptide vaccine has the fewest side effects compared to the majority of vaccine strategies so far used in clinical trials  (Table 2). In addition, while all the other vaccines induce a variety of specific CD4+ and CD8+ T cell responses including low-affinity ones, lipopeptides induce a focused, strong and long-lasting CD4+ and CD8+ T cell response against the selected immunodominant asymptomatic epitopes only [12, 32]. The lipopeptide vaccine strategy also excludes those HSV proteins that may enable the virus to evade the host immune system. While live attenuated virus vaccine, inactivated virus vaccine, or protein-adjuvant based vaccines contain unknown and potentially harmful molecules, lipopeptide vaccines are molecularly defined and do not contain pathologic molecules, such as ICP-47 [103–105].
5.2. Mucosal Route of Vaccination
Mucosal surfaces constitute an impressive first-line defense that is frequently exposed to HSV-1 and HSV-2 infections [106–109]. The mucosal immune system is largely separate and distinct from the systemic immune system [106–108] and is more complex [106–108]. The tissue compartments involved in mucosal immunity are mucosal inductive sites and mucosal effector sites. The inductive sites are comprised of lymphoid tissue, where the triggering of naïve immune cells and the generation of memory-effector cells take place. This is where Ags are encountered, taken up by APCs, processed, and presented to B and T cells, which may then migrate to effector sites where immune T cells function [106–108]. Mucosal tissues mostly contain DCs, which have properties to optimize Ag uptake, processing and T-cell stimulation [110–115]. Mucosal subunit vaccines are designed for needle-free application, therefore safe and cost effective compared to other vaccines. Efficacy of mucosal vaccine has been well established for the oral poliovirus vaccine, but today very few other vaccines administered by the mucosal route are available commercially. Tremendous research efforts have significantly improved the classical approach used to create these vaccines, and alternative methods of immunization based on new concepts of mucosal immunity are being developed.
6. The Unknown
Progress towards an effective vaccine has stalled in the face of many unknown questions and related to HSV-1 and HSV-2 infection and immunity. Namely, (i) the cellular and molecular mechanisms behind the failure of past herpes vaccines remain unknown, (ii) the cellular and molecular mechanisms that lead the majority of HSV seropositive individuals (i.e., asymptomatic individuals) to be naturally “protected” exhibiting few or no recurrent clinical disease while other HSV seropositive individuals (i.e., symptomatic individuals) to have frequent ocular, orofacial, and/or genital herpes clinical episodes remain unknown, (iii) HSV-specific CD8+ T cells, selectively activated and retained in latently infected trigeminal and sacral ganglia [34, 74, 116, 117], play a crucial role in suppressing full blown reactivation of HSV-1/2 latency [103, 116], apparently by interfering with virus replication and spread following the initial molecular events of reactivation. Thus, rather than completely eliminating the latent HSV-1 from trigeminal and sacral ganglia, reactivations appear to be “kept in check” by CD8+ T cells [12, 12, 74, 118]. The importance of CD8+ T cells in providing constant immunosurveillance of latently infected neurons, in which the virus starts to reactivate, is suggested by numerous mouse, guinea pig, rabbit, and human studies [34, 116, 119–122]. However, it is still unclear why and how the virus manages to sporadically escape CD8+ T cell-mediated immunosurveillance and efficiently reactivate from latency to often cause ocular, orofacial, and genital herpes diseases. Identification of the immune evasion mechanism used with HSV-1 and HSV-2 would certainly help develop stronger preemptive immunotherapeutic vaccine strategies against herpes.
In the past, dozens of vaccine immunotherapies have tried to stimulate the immune system against herpes, including about a dozen vaccines that reached mid- and late-stage clinical trials. Every single one of these therapies has generated much excitement, but, for the most part, none of those therapies really did protect against herpes. Before devising more powerful treatments it is imperative to identify (i) the mechanisms underlying the suboptimal nonprotective immunity associated with natural infection, (ii) the major effectors of immunity that control each of the three phases of herpes infection (i.e., acute and latent), (iii) the sophisticated immune evasion strategies employed by HSV-1 and HSV-2 to dampen the immune response, (iv) the protective versus pathogenic protein Ag(s) among more than 80 immunogenic HSV proteins, and (v) a safe Ag delivery system.
Our laboratory is hoping to bridge some of the gaps in our knowledge including (i) why CD4+ and CD8+ T cells from asymptomatic and symptomatic individuals tend to recognize different sets of nonoverlapping HSV Ag epitopes; (ii) Are the epitopes recognized by CD4+ and CD8+ T cells from asymptomatic individuals protective against virus replication, herpetic disease, and/or latent infection? (iii) Can the magnitude of CD4+ and CD8+ T-cell responses to “asymptomatic” human T-cell epitopes be significantly improved by epitope enhancement (increasing HLA binding affinity) or increasing their bioavailability (increase resistance to proteolysis)? (iv) Can the combination of “improved asymptomatic T-cell epitopes” broaden the ocular immune responses? (v) Can a multivalent lipopeptide vaccine, bearing combination of “improved symptomatic CD4+ and CD8+ T-cell epitopes,” delivered intranasally, topically to the eyes, or intranasally induce robust local immunity? (vi) Can local HSV-specific immunity induced at the sites of infection (i.e., the eye, the genital tract, trigeminal ganglia, and sacral ganglia) or in the draining lymph nodes prevent virus transmission/reactivation and/or limit the severity of ocular and genital herpes?
A targeted immunotherapeutic vaccine is necessary to induce robust localized immune responses (i.e., in central nervous system, spinal cord, trigeminal ganglia, and sacral ganglia), to quell virus replication, drive the pathogen into a “latent” state, and likely hinder viral reactivation. However, an immune response in the central nervous system might not be good. The release of inflammatory mediators including reactive oxygen species may cause cell death in the central nervous system (CNS). However the death from HSV-1-mediated frank sporadic encephalitis is a rare event. A good understanding of the contribution of resident and infiltrating leukocytes within the nervous system in response to herpes infection is necessary to identify candidate “asymptomatic” epitopes and immune molecules, which do not induce unwarranted inflammation coinciding with the maintenance of the antiviral state.
We believe that in the next five years research should focus on (1) identifying more “asymptomatic” versus “symptomatic” herpes epitopes, (2) qualitatively and quantitatively analyzing T cells in symptomatic versus asymptomatic patients that could break new ground in our understanding of the immune mechanisms underlying herpes pathogenesis in humans, (3) incorporating only promiscuous “asymptomatic” epitopes into vaccines, (4) using mucosal vaccine strategies, such as lipopeptides, to immunize against herpes, and (5) Using “humanized” susceptible HLA transgenic mice and rabbits to assess the immunogenicity and protective efficacy of herpes epitopes against primary and recurrent infection.
Future herpes vaccines should use a needle-free mucosal application in which the epitopes are recognized by and stimulate the mucosal immune system. We recently found that synthetic peptide epitopes extended with an agonist of Toll-like receptor 2 (TLR-2), which is abundantly expressed on dendritic and epithelial cells of the vaginal and ocular mucosa, can lead to induction of protective immunity against herpes [123, 124]. Thus mucosal (topical ocular or intravaginal) immunization with self-adjuvanting lipid-tailed peptides bearing “asymptomatic epitopes” appears to have attractive practical and immunological features.
Conflict of Interests
Dr. L. BenMohamed is the founder of Micro Antigen technologies, LLC, a Californian dedicated to herpes vaccine development. No additional conflict of interest exists. No writing assistance was utilized in the production of this paper.
Studies performed by the authors and reported herein were initiated and supported by research grants EY-014900 and EY-019896 to L. BenMohamed from the National Eye Institute, National Institutes of Health, The Discovery Eye Foundation, and Research to Prevent Blindness grants. The authors thank Dr. Gargi Dasgupta for help in editing this paper.
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domain: medical


|Area News | Home | Marketplace | Community|
|Paynesville Press - March 16, 2005|
City approves meth clean-up ordinance
The Paynesville City Council took the following actions at their meeting on Wednesday, March 9.|
*The council heard a verbal report from police chief Kent Kortlever regarding adopting the Stearns County ordinance addressing clandestine meth lab sites. The ordinance addresses cleanup procedures for meth labs as well as medical protocols for children, pregnant women, and vulnerable adults found at meth lab sites.
By adopting the Stearns County ordinance, the county will be responsible for enforcing cleanup of meth lab sites, said Kortlever, who also discussed recognizing the signs of meth labs, since small towns are a favorite place for meth producers to set up their operations. Residents should watch out for people disposing of large quantities of pseudoephedrine packages, duct tape, and other chemicals used in the production of methamphetamine. In addition, farmers and businesses that sell fertilizer need to watch for theft of anhydrous ammonia, also needed for meth production.
Kortlever also cautioned residents to be wary of buildings with strange smells and of houses or apartments with a lot of in-and-out visitors, especially if visitors only stay for a few minutes. Anyone witnessing anything suspicious should call the police department dispatcher at 320-243-3434.
*The council approved giving the Ampe Morningside Addition Plat Three a credit for a portion of a previously platted outlot that was given to the city to satisfy the city's requirement for a parkland dedication for new developments. The previously platted lot, Outlot J, was given to the city for use as a stormwater retention pond before the city requirement for parkland dedication was in place.
*After holding a public hearing, the council approved applying for a DNR grant to make improvements to the main shelter at Veteran's Memorial Park. The estimated cost of the project is $20,000, and the matching grant could pay half. The city has applied for the grant for the past two years and was turned down both times. This time, if a grant is not awarded, the city will consider paying for the project on its own.
*The council heard a verbal report from public works director Ron Mergen regarding lifeguards and a proposed fishing pier at Veteran's Memorial Park.
According to Mergen, the park committee recommended not hiring lifeguards for the beach this summer because, for the past few years, very few swimmers have been visiting the beach. Mergen also explained that the committee would like to work with DNR to place a fishing pier at the park. The pier, which would have a value of about $20,000, would come from the DNR and would be placed north of the swim area. When the pier is in place, the size of the swimming area would need to be reduced to keep anglers from casting into the swimming area, said Mergen. The city's only responsibility would be to build a handicap accessible trail from the parking area to the pier.
*The council also discussed possible park capital improvements with Mergen. The city is considering several recreational projects including: a leg of the Lake Koronis Recreational Trail, which is expected to cost the city an estimated $59,108; the Kruger Lake Nature Preserve, with an estimated city cost of $68,000; improvements to the shelter at Veteran's Memorial Park, with an estimated city cost of $10,100; and improving planters in the downtown area, with an estimated city cost of $12,000. The total cost of improvements is estimated at $149,210.
Currently, the park capital improvement fund has a balance of $145,000, with another $136,000 available in undesignated funds in the general fund. While grants, donations from the public, and bonding from the state could lower the total costs significantly, the city still needs to begin considering from where the money will come, said city administrator Steve Helget.
*The council heard a report from Mergen regarding upgrading Co. Rd. 123 to a nine-ton road. Stearns County has placed the road, which runs from Highway 23 to the Industrial Park, on its five-year improvement plan, and will likely turn it over to the city or to Paynesville Township once it is completed. The county has no use for the road, said Mergen, and has a contract with the city for maintenance.
*The council approved paying up to $10,000 for utility extensions for the proposed new SuperValu store. The layout of the proposed store on the lot, purchased from the city, has changed, which is estimated to cost about $30,000 for utility extensions.
*The council approved bids for leasing airport property for farming. Two bids were accepted from David Ampe, who will pay $39/acre on a 25-acre parcel north of the runway for three years and $37/acre for a 44 -acre parcel east of the runway for one year.
*The council approved proclaiming Friday, April 29, as Paynesville's Arbor Day.
*The council approved closing city hall on Columbus Day, Monday, Oct. 10, for the city's annual safety training day.
*The council approved paying Voss Plumbing and Heating $2,180 for water main repairs on Lake Avenue.
*The council approved a violence in the workplace policy to help protect city employees from threats and acts of violence.
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KIEV, February 16. /TASS/. Demonstrators have gathered for protests in 10 Ukrainian cities to demand resignation of Prime Minister Arseniy Yatsenyuk.
Local media reported that demonstrations are being held in Kharkiv, Lviv, Dnipropetrovsk, Odessa, Poltava, Khmelnitsky, Ivano-Frankivsk, Zhytomyr, Ternopol and Lutsk. Protesters are waving flags of "Svoboda" (Freedom) nationalist party and banners saying: "Marauder premier - to tribunal," "Marauder premier should go," "Yatsenyuk’s government — puppet of oligarchs."
More than 1,000 people have also gathered near the Verkhovna Rada building in Kiev to demand the resignation of Yatsenyuk. Among participants in the demonstration are representatives of the "Svoboda" party and "Party of Ordinary People." Activists are waving flags of Ukraine and the Right Sector extremist organization banned in Russia, as well as banners saying: "Government should resign!", "Yatsenyuk should go to prison!", "Stolen millions should be returned to budget!".
Yatsenyuk is expected to deliver a report about his government’s activities at the Verkhovna Rada today. The Petro Porosheko Bloc’s faction in the Ukrainian parliaments agreed at its yesterday’s session that the work of the Ukrainian cabinet in the past year is "unsatisfactory." The faction will vote for the cabinet’s resignation if there are enough votes in the Verkhovna Rada.
The Samopomich (Self-Assistance), Batkivshchyna (Fatherland) and Radical Party factions have already said they could vote for a complete change of government.

domain: news


text:
|Cherryville Community Forest Fuel Management Project
|Cherryville is a community of 1000 residents in the Shuswap River valley between Sugar Lake and Mabel Lake. There is no organized fire department for 340 houses, in rural residential settings. The area has a strong rural character focussing on agriculture and forestry sectors, as well as tourism and recreation opportunities. Our community is geographically diverse with a large flat bottom valley basin surrounded by steep forested hillsides. There are also significant private and crown forestlands within the community. Cherryville Community Forest is located on Cherry and Heckman ridges immediately adjacent to rural residence/forest interface neighbourhoods. This 1070 ha tenure is located in the transition zone of the ICH and IDF BEC zones within the Okanagan Shuswap Forest District. Cherry Ridge Management Committee, a non profit society registered in British Columbia, has managed the forest resource on Cherry Ridge since 1995 in cooperation with the Okanagan Shuswap Forest District. CRMC has recently received a CFA on two blocks of local forest land on Cherry and Heckman Ridges. CRMC wants to mitigate the risk of wildfires in our community by completing fuel modification projects on the Community Forest and other Cherryville Crown lands. The purpose of this project has been to define risk areas for interface fires, identify measures necessary to mitigate those risks, outline a plan of action, and implement the appropriate measures. During the past six months we have performed all these functions within the limitations of our FIA funds. As a community we are committed to the achievable goal of making our wildland interface areas fire resistant and fire smart. We have lost two houses to fire in an interface setting since we proposed this initiative. We wish to collaborate with neighbouring communities and government agencies on hazard abatement and fuel modification projects.

domain: geography


text:
Arthrosis due to lupus erythematosus is not curable. However, many patients with this condition are able to avoid amputation. The reason is unknown, but if there is ankylosis or stiffness, the joints can be relieved by non-steroidal anti-inflammatory drugs or surgical traction.
It is a condition that affects the articular surfaces of the joints, the cartilage and the underlying bone. The most common cause is osteoarthritis, which typically affects the joints of the lower limbs, such as the knees, hips and lower spine.
Injury can cause pain and swelling to occur in any joint, but certain injuries may be more likely to cause chronic pain and disability. Fractures, luxation, and instability are commonly related to pain and stiffness of joints.\n\n- Causes of Arthritis\n- Arthrotourism\n- Spinal Arthritis"
"Eriogonum mohavense\n\nEriogonum mohavense is a species of wild buckwheat known by the common name Mojave buckwheat. Along with "E. spp." var.
Surgery is used for pain when other treatments have failed or are contraindicated or if nonarthrotic problems that affect the pain are present. Arthroscopic surgery, arthrocentesis or lavage of joints, arthroplasty, or arthrodesis is typically done to decrease pain. Non surgically treated arthrosis may prove resistant to nonsurgical treatments but may have symptom improvement from medication.
A significant number of adults in the US (17% or 3.7 million) are new clients for physiotherapy each year (1.9% of all health visits to physiotherapists). An additional 6% (0.6% of new health visits to physiotherapists) are for arthrosis (other than hip/knee). Arthrosis related to knee and hip joint dysfunction is the most common type of arthrosis. Arthrosis may occur as a result of one's past, current or future activity, although, in most cases, patients report an underlying cause which causes their arthritis. The most common cause of arthrosis is arthritis caused by improper gait (e.g.
Arthrosis can be defined by radiographic findings. Arthrosis can be a chronic disease. The joint that ices is the one with chronic inflammation and ices. The most specific sign is bone resorption around the hips. Tolerable level of pain is not absolute and pain has to be assessed using the NOSE scale.
As we look toward treatments for arthrosis, activity-related therapy is gaining much attention. To date, research has concentrated on improving exercise prescription skills in individuals with knee joint disorders. In this context, a growing list of evidence-based exercise strategies has been developed in recent years. A list of relevant publications is presented and summarized below. In addition, the authors have applied a subset of these strategies in a clinical setting for the treatment of knee joint disorders and arthrosis.
The findings suggest that a physical activity behavior intervention increased physical activity among men and the women. The findings also suggest that physical activities are effective in increasing and maintaining general health conditions.
Findings suggest current practice has not yet evaluated effectiveness of a behavioral intervention, such as activity coordinators, in physical activity engagement. Identifying what is helpful and what is helpful in different settings could reduce the costs associated with conducting large randomized trials targeting physical activity behavior.
The information herein emphasizes the need for the research of new arthrosis-related treatments, and to enhance this process, one must be aware of all the research on arthrosis. It is recommended to use http://www.hindawi.com/itemped.pl?isbn=978922732557 and http://www.hindawi.com/itemped.pl?isbn=978922732564 as resources.


A Jazzy Christmas Concert at Sevenoaks
Sunday 10th December 2023
Hampstead Jazz Club in association with The Listening Room proudly present a Jazzy Christmas evening. With Jo Harrop and Paul Edis featuring a 9 piece band with Alex Garnett, Paul Booth & Gareth Lockrane.
Venue – The MAIN HALL, Wally Hall School, Hollybush Lane, Sevenoaks TN13 3UL
Show Time: 8.00pm
Featuring new arrangements of festive favourites penned by ‘brilliant young pianist’ Paul Edis and performed by some of the leading lights on the UK jazz scene including ‘velvet-voiced’ Jo Harrop.
You can expect to hear classic Christmas hits such as ‘Santa Baby’ given a big band treatment rubbing shoulders with more contemporary hits like ‘Driving Home For Christmas’ as a Brazilian samba. You don’t have to be a jazz fan to like this show, but if you are, you’ll be blown away by the standard of musicianship from some of the leading lights on the UK jazz scene.
Jo Harrop (Vocals)
Jo Harrop has a chocolate and cream croon that can melt the hardest of hearts. Described by the legendary Iggy Pop as “a very fine jazz singer”.
Paul Edis (MD)
‘A brilliant young pianist’ – The Guardian, blurring the boundaries between Bill Evans, Brad Mehldau and Claude Debussy.
Jo Harrop – Vocals
Paul Edis – MD/Piano
Alex Garnett – Alto sax/Clarinet
Sid Gould – Trumpet
Paul Booth – Tenor/Soprano
Rory Ingham – Trombone
Gareth Lockrane – Flute/Piccolo
Dominic Inham – Violin
Matt Home – Drums
Matyas Hofecker – Double Bass
£2 of every ticket will go to Sevenoaks Samaritans, who are committed to deliver the Samaritans’ vision by being there for their callers and provide the best support possible. www.samaritans.org/branches/sevenoaks/
Doors: 7:00 pm | Show: 8:00 pmBUY TICKETS


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Для получения актуальных цен по гостинице Summer, пожалуйста, укажите интересующие вас даты и выполните поиск.
The hotel is situated in Calella de la Costa, 400 m from the beach and 5 minutes from the town centre. Access to public transport is within walking distance. Barcelona is 50 km away. Girona-Costa Brava Airport is roughly 40 km from the hotel, while Barcelona Airport is approximately 70 km away.The hotel offers a family environment and a pleasant stay. It is equipped with comfortable facilities and services such as restaurant with buffet, bar with board games, WLAN Internet access in common areas, a kids' games room, a garden and a satellite TV lounge. With a total of 89 rooms on offer, the air-conditioned hotel welcomes guests in a lobby with 24-hour reception, a hotel safe, currency exchange facilities and lift access. There is also a cafA© and laundry service available.The spacious rooms are fully equipped with en suite bathrooms with shower/bathtub, an outside terrace and double bed. The renovated rooms have satellite television.The hotel has an outdoor swimming pool and a sun terrace with free sun loungers and parasols. Facilities for table tennis and pool/snooker are also provided (fees apply).Buffets are served at all meal times.
Построена в 1969 году

domain: travel


text:
June 9, 2020
“It is encouraging for the city and province to see we are in a place to advance to stage two reopenings. However, the City of Edmonton continues to review reopening plans against our current realities. This includes how we might introduce the reopenings of facilities like recreation centres, arenas, indoor pools and libraries. In order to comply with public health and safety requirements, and in consideration of operational resources, budget constraints, and public compliance it might mean that reopenings will be phased in over time or currently paused for further review.
The reopening of facilities is very complex and given the financial impacts of the pandemic, some services will not return this season. We thank Edmontonians for their patience and understanding as we work to develop, finalize and activate our relaunch plans across the many lines of business that have been impacted.
Based on the information shared today, an overview of the possible repercussions and options will be shared at the next Emergency Advisory Committee meeting on Thursday, June 11,” said David Aitken, Chair COVID-19 Task Team.


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Deak St. Kitchen, introduced in the recently opened Ritz-Carlton, Budapest, showcases the best of local ingredients, dishes and produce, alongside one of the city’s best selections of indigenous wines.
Known for its diversity, Hungarian food truly represents the history of the country. Whether that be the hearty, peasant food of the nomads, the influence of Italians and the Turkish in the 15th & 16th centuries or the later, sophisticated palate of the Austro-Hungarian empire, today’s dishes present a rich, distinct style.
Working with local suppliers, Deak St. Kitchen focuses on seasonal, national produce, ensuring guests enjoy the finest, authentic ingredients available. Continuing the farm-to-table movement, the restaurant grill serves the finest selection of meat and fish, which are offered alongside more traditional Hungarian dishes, including braised beef cheek, spätzle egg noodles, and paprika-marinated chicken.
Renowned specialist Hungarian ingredients are used throughout the menu, many of which add local flair and interest to more familiar dishes. Among these, mushrooms from the forests of the Bakony Hills, most often seen in the cooking of the Central Transdanubian region, are sautéed and served as a side dish, while Gomolya cheese, traditionally made by the shepherds in the Alfold and Transylvania, is grilled and used to finish top-grade burgers. Partly because the country is landlocked, pork has been a mainstay ingredient in Hungary for centuries and the Mangalica pig, with its 200-year-old domestic history, plays an intrinsic part of these dishes. Served as both chops and bacon in Deak St. Kitchen, the Mangalica pork is revered for its succulently marbled meat and distinct, flavorsome taste.
With over twenty wine regions, Hungary’s wine industry has increasingly diversified in recent years. Whilst many are familiar with Tokaj and its sumptuously sweet Tokaji Aszu, other regions are carving inroads into the international wine market. Deak St. Kitchen offers an unparalleled glimpse into the plentiful varieties, with almost 100 bottles of Hungarian wine available to enjoy, and a fifth of these also being served by the glass.
To delight both local and international guests alike, a sensory wine flight has been introduced in the bar of Deak St. Kitchen, giving a unique opportunity to sample seven wines, each representing one of the key regions of Hungarian wine production. Whether it’s a bright Sauvignon Blanc from Etyek with its nutrient-rich limestone, or an Olaszrizling from Hungary’s smallest wine region, Somlo, produced on a single volcanic hill of basalt rock, the hand-picked selection showcases the breadth and quality of Hungarian wines to its fullest. For those whose interest is further piqued to explore the local wine industry, The Ritz-Carlton, Budapest’s dedicated concierge team can arrange private tours and visits to some of the city’s neighbouring vineyards situated up in the cool Buda Hills, a potentially chilled respite to the summer heat.
The Ritz-Carlton, Budapest opened in April 2016, bringing contemporary luxury to Hungary as the brand’s entrée into one of Europe’s most alluring cities. Housed within an iconic historic building on Elizabeth Square in the heart of the city's cultural and shopping district, the luxury hotel features 200 elegantly appointed rooms and suites, along with an exclusive Club Level, two restaurants, and a soon-to-open Ritz-Carlton Spa.
Visit website: www.ritzcarlton.com/Budapest

domain: food