Therapeutic vaccines for herpesviruses.

Herpesviruses establish latent infections, and most reactivate frequently, resulting in symptoms and virus shedding in healthy individuals. In immunocompromised patients, reactivating virus can cause severe disease. Persistent EBV has been associated with several malignancies in both immunocompromised and nonimmunocompromised persons. Reactivation and shedding occur with most herpesviruses, despite potent virus-specific antibodies and T cell immunity as measured in the blood. The licensure of therapeutic vaccines to reduce zoster indicates that effective therapeutic vaccines for other herpesviruses should be feasible. However, varicella-zoster virus is different from other human herpesviruses in that it is generally only shed during varicella and zoster. Unlike prophylactic vaccines, in which the correlate of immunity is antibody function, T cell immunity is the correlate of immunity for the only effective therapeutic herpesvirus vaccine-zoster vaccine. While most studies of therapeutic vaccines have measured immunity in the blood, cellular immunity at the site of reactivation is likely critical for an effective therapeutic vaccine for certain viruses. This Review summarizes the status of therapeutic vaccines for herpes simplex virus, cytomegalovirus, and Epstein-Barr virus and proposes approaches for future development.

Efficacy of vaccination against equine herpesvirus type 1 (EHV-1) infection: Systematic review and meta-analysis of randomised controlled challenge trials.

BACKGROUND: Equid herpesvirus type 1 (EHV-1) infection can cause a range of disease syndromes of variable severity that can result in a lethal outcome and restriction of horse movements, especially in the case of outbreaks involving neurological disease. Vaccination is one of the tools used to control the infection. It is widely known that vaccination is not completely effective in ensuring protection against disease caused by this virus. In fact, the real efficacy of vaccination against EHV-1 related disease has not been measured and no systematic reviews exist on this topic. OBJECTIVES: To perform a systematic review and meta-analysis on the efficacy of commercial or candidate vaccines against EHV-1 in randomised controlled trials (RCT) all of which involved experimental challenge of the test subjects. STUDY DESIGN: Systematic review and meta-analysis. METHODS: RCTs were searched using the search algorithm (([equid herpesvirus* OR equine herpesvirus* OR EHV-1]) AND vaccin*) AND (trial OR experimental OR challenge) on PubMed, Science Citation Index Expanded, Scopus, and CAB Abstracts. Where appropriate, meta-analysis was performed using RevMan 5.4. RESULTS: Eight studies were selected and were analysed for their respective characteristics and possible shortcomings. The results of RCTs revealed that there was a general improvement in the clinical and virological outcomes of EHV-1 infection following vaccination, but that the effects were very slight. The reduced beneficial effect is probably amplified by the paucity of detailed data reported in the studies that did not allow for the comparison of parameters in many of the cases analysed. MAIN LIMITATIONS: The remarkable heterogeneity and the poor quality of reporting of the selected studies. CONCLUSIONS: Meta-analysis has shown that EHV-1 vaccination generally results in a slight improvement in clinical and virological outcomes, although not to a significant extent. The cumulative results have probably been affected by the lack of information on some parameters not systematically reported in the studies. An improvement in the standard of reporting and better standardisation of the data collected would likely have improved the quality of each study and enabled more effective comparison of the studies with each other.

Vaccination against the Epstein-Barr virus.

Epstein-Barr virus (EBV) was the first human tumor virus being discovered and remains to date the only human pathogen that can transform cells in vitro. 55 years of EBV research have now brought us to the brink of an EBV vaccine. For this purpose, recombinant viral vectors and their heterologous prime-boost vaccinations, EBV-derived virus-like particles and viral envelope glycoprotein formulations are explored and are discussed in this review. Even so, cell-mediated immune control by cytotoxic lymphocytes protects healthy virus carriers from EBV-associated malignancies, antibodies might be able to prevent symptomatic primary infection, the most likely EBV-associated pathology against which EBV vaccines will be initially tested. Thus, the variety of EBV vaccines reflects the sophisticated life cycle of this human tumor virus and only vaccination in humans will finally be able to reveal the efficacy of these candidates. Nevertheless, the recently renewed efforts to develop an EBV vaccine and the long history of safe adoptive T cell transfer to treat EBV-associated malignancies suggest that this oncogenic γ-herpesvirus can be targeted by immunotherapies. Such vaccination should ideally implement the very same immune control that protects healthy EBV carriers.

Infectious laryngotracheitis: Etiology, epidemiology, pathobiology, and advances in diagnosis and control - a comprehensive review.

Infectious laryngotracheitis (ILT) is a highly contagious upper respiratory tract disease of chicken caused by a Gallid herpesvirus 1 (GaHV-1) belonging to the genus Iltovirus, and subfamily Alphaherpesvirinae within Herpesviridae family. The disease is characterized by conjunctivitis, sinusitis, oculo-nasal discharge, respiratory distress, bloody mucus, swollen orbital sinuses, high morbidity, considerable mortality and decreased egg production. It is well established in highly dense poultry producing areas of the world due to characteristic latency and carrier status of the virus. Co-infections with other respiratory pathogens and environmental factors adversely affect the respiratory system and prolong the course of the disease. Latently infected chickens are the primary source of ILT virus (ILTV) outbreaks irrespective of vaccination. Apart from conventional diagnostic methods including isolation and identification of ILTV, serological detection, advanced biotechnological tools such as PCR, quantitative real-time PCR, next generation sequencing, and others are being used in accurate diagnosis and epidemiological studies of ILTV. Vaccination is followed with the use of conventional vaccines including modified live attenuated ILTV vaccines, and advanced recombinant vector vaccines expressing different ILTV glycoproteins, but still these candidates frequently fail to reduce challenge virus shedding. Some herbal components have proved to be beneficial in reducing the severity of the clinical disease. The present review discusses ILT with respect to its current status, virus characteristics, epidemiology, transmission, pathobiology, and advances in diagnosis, vaccination and control strategies to counter this important disease of poultry.

Mechanisms of Immune Control of Mucosal HSV Infection: A Guide to Rational Vaccine Design.

Herpes Simplex Virus (HSV) is a highly prevalent sexually transmitted infection that aside from causing cold sores and genital lesions, causes complications in the immunocompromised and has facilitated a large proportion of HIV acquisition globally. Despite decades of research, there is no prophylactic HSV vaccine ready for use in humans, leaving many questioning whether a prophylactic vaccine is an achievable goal. A previous HSV vaccine trial did have partial success in decreasing acquisition of HSV2-promising evidence that vaccines can prevent acquisition. However, there is still an incomplete understanding of the immune response pathways elicited by HSV after initial mucosal infection and how best to replicate these responses with a vaccine, such that acquisition and colonization of the dorsal root ganglia could be prevented. Another factor to consider in the rational design of an HSV vaccine is adjuvant choice. Understanding the immune responses elicited by different adjuvants and whether lasting humoral and cell-mediated responses are induced is important, especially when studies of past trial vaccines found that a sufficiently protective cell-mediated response was lacking. In this review, we discuss what is known of the immune control involved in initial herpes lesions and reactivation, including the importance of CD4 and CD8 T cells, and the interplay between innate and adaptive immunity in response to primary infection, specifically focusing on the viral relay involved. Additionally, a summary of previous and current vaccine trials, including the components used, immune responses elicited and the feasibility of prophylactic vaccines looking forward, will also be discussed.

Induction of herpes simplex virus type 1 cell-to-cell spread inhibiting antibodies by a calcium phosphate nanoparticle-based vaccine.

Herpes simplex viruses 1 and 2 are among the most ubiquitous human infections and persist lifelong in their host. Upon primary infection or reactivation from ganglia, the viruses spread by direct cell-cell contacts (cell-to-cell spread) and thus escape from the host immune response. We have developed a monoclonal antibody (mAb 2c), which inhibits the HSV cell-to-cell spread, thereby protecting from lethal genital infection and blindness in animal models. In the present study we have designed a nanoparticle-based vaccine to induce protective antibody responses exceeding the cell-to-cell spread inhibiting properties of mAb 2c. We used biodegradable calcium phosphate (CaP) nanoparticles coated with a synthetic peptide that represents the conformational epitope on HSV-1 gB recognized by mAb 2c. The CaP nanoparticles additionally contained a TLR-ligand CpGm and were formulated with adjuvants to facilitate the humoral immune response. This vaccine effectively protected mice from lethal HSV-1 infection by inducing cell-to-cell spread inhibiting antibodies.

RNA-seq comparative analysis of Peking ducks spleen gene expression 24 h post-infected with duck plague virulent or attenuated virus.

Duck plague virus (DPV), a member of alphaherpesvirus sub-family, can cause significant economic losses on duck farms in China. DPV Chinese virulent strain (CHv) is highly pathogenic and could induce massive ducks death. Attenuated DPV vaccines (CHa) have been put into service against duck plague with billions of doses in China each year. Researches on DPV have been development for many years, however, a comprehensive understanding of molecular mechanisms underlying pathogenicity of CHv strain and protection of CHa strain to ducks is still blank. In present study, we performed RNA-seq technology to analyze transcriptome profiling of duck spleens for the first time to identify differentially expressed genes (DEGs) associated with the infection of CHv and CHa at 24 h. Comparison of gene expression with mock ducks revealed 748 DEGs and 484 DEGs after CHv and CHa infection, respectively. Gene pathway analysis of DEGs highlighted valuable biological processes involved in host immune response, cell apoptosis and viral invasion. Genes expressed in those pathways were different in CHv infected duck spleens and CHa vaccinated duck spleens. The results may provide valuable information for us to explore the reasons of pathogenicity caused by CHv strain and protection activated by CHa strain.

Comparison of interferon and bovine herpesvirus-1-specific IgA levels in nasal secretions of dairy cattle administered an intranasal modified live viral vaccine prior to calving or on the day of calving.

Thirty-two Holstein cows were allocated to receive intranasal vaccination with modified live bovine herpesvirus-1 (BHV-1), bovine respiratory syncytial virus (BRSV) and parainfluenza type 3 virus (PI3V) vaccine either two weeks prior to their projected calving date, or within 24h after calving. Nasal secretions were collected twice at a 12-h interval on the day prior to vaccination (day 0) and at 2, 4, 7, 10 and 14days post vaccination to measure interferon (IFN) alpha, IFN-beta, IFN-gamma, and BHV-1-specific IgA by ELISA. Serum neutralizing antibody titers to BHV-1 and BRSV were measured on days 0, 7, and 14. There was a significant treatment effect (p<0.0004) and interaction (p<0.05) on nasal BHV-1 IgA levels, with higher IgA levels in cows vaccinated within 24h after calving. There was a significant treatment effect on nasal IFN-gamma concentration (p<0.05) and on nasal total IFN concentration (p<0.05), with higher IFN-gamma and total IFN concentrations seen in cows vaccinated within 24h after calving. There was no significant treatment or interaction effect on nasal IFN-alpha or IFN-beta concentrations, or on serum neutralizing titers to BRSV. In spite of prior viral vaccination during the previous lactation, cows vaccinated on the day of calving responded to an intranasal viral vaccination with increased concentrations of IFN-gamma and increased titers of IgA following vaccination which was significantly higher than cows vaccinated precalving. This study is the first to examine respiratory mucosal responses in immunologically mature dairy cattle vaccinated intranasally before and after calving.

Neonatal Immunization with a Single IL-4/Antigen Dose Induces Increased Antibody Responses after Challenge Infection with Equine Herpesvirus Type 1 (EHV-1) at Weanling Age.

Neonatal foals respond poorly to conventional vaccines. These vaccines typically target T-helper (Th) cell dependent B-cell activation. However, Th2-cell immunity is impaired in foals during the first three months of life. In contrast, neonatal basophils are potent interleukin-4 (IL-4) producers. The purpose of this study was to develop a novel vaccine triggering the natural capacity of neonatal basophils to secrete IL-4 and to evaluate if vaccination resulted in B-cell activation and antibody production against EHV-1 glycoprotein C (gC). Neonatal vaccination was performed by oral biotinylated IgE (IgE-bio) treatment at birth followed by intramuscular injection of a single dose of streptavidin-conjugated gC/IL-4 fusion protein (Sav-gC/IL-4) for crosslinking of receptor-bound IgE-bio (group 1). Neonates in group 2 received the intramuscular Sav-gC/IL-4 vaccine only. Group 3 remained non-vaccinated at birth. After vaccination, gC antibody production was not detectable. The ability of the vaccine to induce protection was evaluated by an EHV-1 challenge infection after weaning at 7 months of age. Groups 1 and 2 responded to EHV-1 infection with an earlier onset and overall significantly increased anti-gC serum antibody responses compared to control group 3. In addition, group 1 weanlings had a decreased initial fever peak after infection indicating partial protection from EHV-1 infection. This suggested that the neonatal vaccination induced a memory B-cell response at birth that was recalled at weanling age after EHV-1 challenge. In conclusion, early stimulation of neonatal immunity via the innate arm of the immune system can induce partial protection and increased antibody responses against EHV-1.

Epidemiology of pediatric herpes zoster after varicella infection: a population-based study.

BACKGROUND: There are limited population-based data regarding pediatric herpes zoster (HZ). METHODS: Children aged <12 years with varicella infections between 2000 and 2006 were identified from a national population-based database and followed-up for a diagnosis of HZ until December 2008. Since a routine varicella vaccination program was started in 2004, vaccinated children without medically attended varicella were identified between 2004 and 2006, and followed-up for a diagnosis of HZ until December 2008. RESULTS: Of 27 517 children with medically attended varicella, 428 developed HZ. The incidence of HZ was 262.1 per 100 000 person-years. Of 25 132 vaccinated children without medically attended varicella, 106 developed HZ. The incidence of HZ was 93.3 per 100 000 person-years. The mean duration from varicella to HZ was 4.12 years. Children diagnosed with varicella at aged <2 years had a higher incidence (P < .001) and shorter duration (P = .04) than those diagnosed aged ≧2 years. Children diagnosed with varicella aged ≥2 but <8 years had a significantly increased incidence of HZ after than before the vaccination program (relative risk = 1.85 at 3 years of follow-up, P = .03). Children with varicella infections had a significantly greater risk of HZ than vaccinated children without a history of varicella (relative risk = 2.31 at 4 years of follow-up, P < .001). CONCLUSIONS: This study demonstrates the population-based epidemiologic characteristics of pediatric HZ among those who contracted varicella. In the early postvaricella vaccination period, an increased HZ incidence was observed among children with varicella infection aged ≥2 years.

Effect of vaccination against bovine herpesvirus 1 with inactivated gE-negative marker vaccines on the health of dairy cattle herds.

The aim of this study was to estimate the effect of the bovine herpesvirus 1 (BHV-1) vaccination on herd health and production in BHV-1 infected Estonian dairy cattle herds. Seven herds vaccinated with inactivated gE-negative BHV-1 marker vaccines and seven matched non-vaccinated herds were selected. In vaccinated herds the calving interval was on average 7.01 days shorter compared to that in the non-vaccinated herds (coef=-7.01, 95% CI=-11.98, -2.03, p=0.008) during the study period (2007-2012). In non-vaccinated herds the insemination index had an increasing trend (coef(log scale)=0.03, 95% CI=-0.003, 0.06, p=0.054) and the first service conception rate decreased (coef=-2.19, 95% CI=-3.91, -0.47, p=0.015), whereas no significant changes occurred in vaccinated herds. Average yearly milk yield per cow increased (coef=145.30, 95% CI=-6.11, 296.71, p=0.065) and length of the dry period decreased in BHV-1 vaccinated herds (coef(log scale)=-0.02, 95% CI=-0.04, 0.004, p=0.056) compared to non-vaccinated herds during the study years. Youngstock and the cow culling rate due to respiratory disease was significantly lower in vaccinated herds compared to non-vaccinated herds (coef=-0.29, 95% CI=-0.47, -0.11, p=0.003 and coef=-0.15, 95% CI=-0.29, -0.007, p=0.043, respectively). These results suggest that vaccination against BHV-1 is associated with herd health and productivity.

Global estimates of prevalent and incident herpes simplex virus type 2 infections in 2012.

BACKGROUND: Herpes simplex virus type 2 (HSV-2) infection causes significant disease globally. Adolescent and adult infection may present as painful genital ulcers. Neonatal infection has high morbidity and mortality. Additionally, HSV-2 likely contributes substantially to the spread of HIV infection. The global burden of HSV-2 infection was last estimated for 2003. Here we present new global estimates for 2012 of the burden of prevalent (existing) and incident (new) HSV-2 infection among females and males aged 15-49 years, using updated methodology to adjust for test performance and estimate by World Health Organization (WHO) region. METHODS AND FINDINGS: We conducted a literature review of HSV-2 prevalence studies world-wide since 2000. We then fitted a model with constant HSV-2 incidence by age to pooled HSV-2 prevalence values by age and sex. Prevalence values were adjusted for test sensitivity and specificity. The model estimated prevalence and incidence by sex for each WHO region to obtain global burden estimates. Uncertainty bounds were computed by refitting the model to reflect the variation in the underlying prevalence data. In 2012, we estimate that there were 417 million people aged 15-49 years (range: 274-678 million) living with HSV-2 infection world-wide (11.3% global prevalence), of whom 267 million were women. We also estimate that in 2012, 19.2 million (range: 13.0-28.6 million) individuals aged 15-49 years were newly-infected (0.5% of all individuals globally). The highest burden was in Africa. However, despite lower prevalence, South-East Asia and Western Pacific regions also contributed large numbers to the global totals because of large population sizes. CONCLUSIONS: The global burden of HSV-2 infection is large, leaving over 400 million people at increased risk of genital ulcer disease, HIV acquisition, and transmission of HSV-2 to partners or neonates. These estimates highlight the critical need for development of vaccines, microbicides, and other new HSV prevention strategies.

Bovine herpesvirus type 1 marker vaccine induces cross-protection against bubaline herpesvirus type 1 in water buffalo.

Water buffalo (Bubalus bubalis) are susceptible to bovine herpesvirus type 1 (BoHV-1) and a species-specific herpesvirus, bubaline herpesvirus type 1 (BuHV-1). In this study, an attenuated marker BoHV-1 based vaccine against BuHV-1 challenge was evaluated to determine whether it induces protection from viral replication. One group of water buffalo calves was immunized with an attenuated BoHV-1 marker vaccine. A second group was not vaccinated and used as the control. During the post-vaccination period, we monitored the humoral immune response. The efficacy of the vaccine was tested after intranasal challenge of the calves with a BuHV-1 strain. The experiment showed that after vaccination, BuHV-1 replication was significantly reduced by approximately three titer points compared to the controls. The control animals showed high levels of viral shedding and mild signs associated with BuHV-1 infection. Therefore, our study provides evidence for the existence of cross-protection between BoHV-1 and BuHV-1 in buffalo calves.

Epstein-Barr virus as a paradigm in nasopharyngeal cancer: from lab to clinic.

Nasopharyngeal carcinoma (NPC) of the undifferentiated subtype remains endemic in southern China, with a peak incidence in this region approaching 30 cases per 100,000 population per year. Despite advances in chemotherapy and radiation delivery techniques in localized disease, distant metastasis is still common and NPC remains the seventh leading cause of cancer death in the region. There is great need for early diagnosis, developing novel therapies, and identifying patients with localized disease at higher risk of future recurrence or metastasis to appropriately tailor their treatment and improve outcomes. Knowledge of the integral involvement of Epstein-Barr virus (EBV) in the pathogenesis of undifferentiated NPC has been of seminal importance in developing strategies to optimize disease management. The close association with EBV is being evaluated in multiple settings including screening of at-risk populations, disease prognostication, development of targeted therapies, optimizing adjuvant treatment, and early recurrence detection. These translational studies are likely to have an enormous effect on management of undifferentiated NPC and significantly improve the landscape of the disease in years to come.