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1.
J Glob Health ; 10(1): 010404, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32257152

RESUMO

Background: Epstein-Barr virus (EBV) is an important human pathogen; it infects >90% people globally and is linked to infectious mononucleosis and several types of cancer. Vaccines against EBV are in development. In this study we present the first systematic review of the literature on risk factors for EBV infection, and discuss how they differ between settings, in order to improve our understanding of EBV epidemiology and aid the design of effective vaccination strategies. Methods: MEDLINE, Embase, and Web of Science were searched on 6th March 2017 for observational studies of risk factors for EBV infection. Studies were excluded if they were published before 2008 to ensure relevance to the modern day, given the importance of influencing future vaccination policies. There were no language restrictions. After title, abstract and full text screening, followed by checking the reference lists of included studies to identify further studies, data were extracted into standardised spreadsheets and quality assessed. A narrative synthesis was undertaken. Results: Seventy-seven papers met our inclusion criteria, including data from 31 countries. There was consistent evidence that EBV seroprevalence was associated with age, increasing throughout childhood and adolescence and remaining constant thereafter. EBV was generally acquired at younger ages in Asia than Europe/North America. There was also compelling evidence for an association between cytomegalovirus infection and EBV. Additional factors associated with EBV seroprevalence, albeit with less consistent evidence, included ethnicity, socioeconomic status, other chronic viral infections, and genetic variants of HLA and immune response genes. Conclusions: Our study is the first systematic review to draw together the global literature on the risk factors for EBV infection and includes an evaluation of the quality of the published evidence. Across the literature, the factors examined are diverse. In Asia, early vaccination of infants would be required to prevent EBV infection. In contrast, in Western countries a vaccine could be deployed later, particularly if it has only a short duration of protection and the intention was to protect against infectious mononucleosis. There is a lack of high-quality data on the prevalence and age of EBV infection outside of Europe, North America and South-East Asia, which are essential for informing effective vaccination policies in these settings.


Assuntos
Infecções por Vírus Epstein-Barr/prevenção & controle , Herpesvirus Humano 4/imunologia , Vacinas contra Herpesvirus/imunologia , Mononucleose Infecciosa/prevenção & controle , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/genética , Vacinas contra Herpesvirus/administração & dosagem , Vacinas contra Herpesvirus/genética , Humanos , Mononucleose Infecciosa/imunologia , Mononucleose Infecciosa/virologia , Políticas , Fatores de Risco , Vacinas
2.
PLoS One ; 15(3): e0229082, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32119681

RESUMO

Gallid alphaherpesvirus 1 causes infectious laryngotracheitis (ILT) in farmed poultry worldwide. Intertypic recombination between vaccine strains of this virus has generated novel and virulent isolates in field conditions. In this study, in vitro and in ovo systems were co-infected and superinfected under different conditions with two genomically distinct and commonly used ILTV vaccines. The progeny virus populations were examined for the frequency and pattern of recombination events using multi-locus high-resolution melting curve analysis of polymerase chain reaction products. A varied level of recombination (0 to 58.9%) was detected, depending on the infection system (in ovo or in vitro), viral load, the composition of the inoculum mixture, and the timing and order of infection. Full genome analysis of selected recombinants with different in vitro phenotypes identified alterations in coding and non-coding regions. The ability of ILTV vaccines to maintain their capacity to recombine under such varied conditions highlights the significance of recombination in the evolution of this virus and demonstrates the capacity of ILTV vaccines to play a role in the emergence of recombinant viruses.


Assuntos
Infecções por Herpesviridae/veterinária , Infecções por Herpesviridae/virologia , Herpesvirus Galináceo 1/genética , Vacinas contra Herpesvirus/genética , Doenças das Aves Domésticas/virologia , Recombinação Genética , Animais , Embrião de Galinha , Vacinas Atenuadas/genética , Replicação Viral
3.
Fish Shellfish Immunol ; 93: 531-541, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31369858

RESUMO

Aquaculture is one of the world's most important and fastest growing food production sectors, with an average annual growth of 5.8% during the period 2001-2016. Common carp (Cyprinus carpio) is one of the main aquatic species produced for human consumption and is the world's third most produced finfish. Koi carp, on the other hand, are grown as a popular ornamental fish. In the late 1990s, both of these sectors were threatened by the emergence of a deadly disease caused by cyprinid herpesvirus 3 (CyHV-3; initially called koi herpesvirus or KHV). Since then, several research groups have focused their work on developing methods to fight this disease. Despite increasing knowledge about the pathobiology of this virus, there are currently no efficient and cost-effective therapeutic methods available to fight this disease. Facing the lack of efficient treatments, safe and efficacious prophylactic methods such as the use of vaccines represent the most promising approach to the control of this virus. The common carp production sector is not a heavily industrialized production sector and the fish produced have low individual value. Therefore, development of vaccine methods adapted to mass vaccination are more suitable. Multiple vaccine candidates against CyHV-3 have been developed and studied, including DNA, bacterial vector, inactivated, conventional attenuated and recombinant attenuated vaccines. However, there is currently only one vaccine commercially available in limited regions. The present review aims to summarize and evaluate the knowledge acquired from the study of these vaccines against CyHV-3 and provide discussion on future prospects.


Assuntos
Carpas/imunologia , Doenças dos Peixes/prevenção & controle , Herpesviridae/imunologia , Vacinas contra Herpesvirus/imunologia , Animais , Doenças dos Peixes/imunologia , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/prevenção & controle , Infecções por Herpesviridae/veterinária
4.
Avian Dis ; 63(2): 351-358, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31251537

RESUMO

Infectious laryngotracheitis (ILT) is a highly contagious respiratory disease of chickens that produces significant economic losses to the poultry industry. The disease is caused by Gallid alpha herpesvirus-1 (GaHV-1), commonly known as the infectious laryngotracheitis virus (ILTV). Vaccination remains necessary for the control of the disease. Due to the inherent virulence of live attenuated vaccines, in particular that of the chicken embryo origin (CEO) vaccines, the use of ILT viral vector recombinant vaccines has significantly expanded worldwide as a safer vaccination strategy. However, the protective efficacy of recombinant ILT vaccines can be compromised by the use of fractional doses and improper handling and administration of the vaccine. The objective of this study was twofold: 1) to evaluate the protection efficacy induced by a commercial recombinant HVT-LT (rHVT-LT) vaccine when administered in ovo to broilers at three standardized doses (6000 plaque-forming units [PFU], 3000 PFU, and 1000 PFU), and 2) to assess the potential of rHVT-LT-vaccinated chickens to spread virus to contact chickens after challenge. Independently of the vaccine dose, vaccinated chickens showed reduction in clinical signs, maintained body weight gain after challenge, and lessened the challenge virus replication in the trachea at a rate of 52%-65%. However, in spite of this reduction, transmission of challenge virus from rHVT-LT-vaccinated (6000/Ch, 3000/Ch) to contact-naive chickens was evident. This study is the first to support that rHVT-LT vaccination did not prevent spread of challenge virus to contact birds.


Assuntos
Galinhas , Infecções por Herpesviridae/veterinária , Herpesvirus Galináceo 1/imunologia , Vacinas contra Herpesvirus/farmacologia , Doenças das Aves Domésticas/prevenção & controle , Animais , Relação Dose-Resposta Imunológica , Infecções por Herpesviridae/prevenção & controle , Óvulo/imunologia , Vacinas Sintéticas/farmacologia
5.
Fish Shellfish Immunol ; 92: 101-110, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31163296

RESUMO

Cyprinid herpesvirus II (CyHV-2) is highly contagious and pathogenic to Carassius auratus gibelio (gibel carp), causing enormous economic losses in aquaculture in Yancheng city, Jiangsu province, China; however, to date, there is no effective way to protect C. auratus gibelio from CyHV-2 infection. In this study, a recombinant baculovirus vector vaccine, BacCarassius-D4ORFs, containing a fused codon-optimized sequence D4ORFs comprising the ORF72 (region 1-186 nt), ORF66 (region 993-1197 nt), ORF81 (region 603-783 nt) and ORF82 (region 85-186 nt) genes of CyHV-2, driven by a Megalobrama amblycephala ß-actin promoter, was constructed. Then, qPCR, Western blotting and immunofluorescence assays showed that the fused gene D4ORFs was successfully delivered and expressed in fish cells or tissues by transduction with BacCarassius-D4ORFs. The fused gene D4ORFs could not be detected by PCR in the C. auratus gibelio injected with BacCarassius-D4ORFs after 7 weeks. Specific antibody against ORF72 could be detected in the serum of vaccinated C. auratus gibelio by injection with BacCarassius-D4ORFs. Furthermore, when C. auratus gibelio were vaccinated with BacCarassius-D4ORFs via the oral or injection route, followed by challenge with CyHV-2, the relative survival rate of immunized C. auratus gibelio reached 59.3% and 80.01%, respectively. These results suggested that BacCarassius-D4ORFs has the potential to be used as a vector-based vaccine for the prevention and treatment of disease caused by CyHV-2 infection.


Assuntos
Doenças dos Peixes/prevenção & controle , Carpa Dourada/imunologia , Herpesviridae/imunologia , Vacinas contra Herpesvirus/imunologia , Animais , Genes Virais , Infecções por Herpesviridae/prevenção & controle , Infecções por Herpesviridae/veterinária , Fases de Leitura Aberta , Vacinas Atenuadas/imunologia
6.
Virology ; 531: 219-232, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30928700

RESUMO

Equid herpesvirus-1 (EHV-1) outbreaks continue despite widely used vaccination. We demonstrated previously that an ORF1/ORF71 gene deletion mutant of the EHV-1 strain Ab4 (Ab4ΔORF1/71) is less virulent than its parent Ab4 virus. Here, we describe the Ab4 challenge infection evaluating protection induced by the Ab4ΔORF1/71 vaccine candidate. Susceptible control horses developed respiratory disease, fever, nasal shedding, and viremia. Full protection after challenge infection was observed in 5/5 previously Ab4 infected horses and 3/5 Ab4ΔORF1/71 horses. Two Ab4ΔORF1/71 horses developed short-lasting viremia and/or virus shedding. Protective immunity in the respiratory tract was characterized by pre-existing EHV-1-specific IgG4/7 antibodies, the absence of IFN-α secretion and rapidly increasing IgG4/7 upon challenge infection. Pre-existing systemic EHV-1-specific IgG4/7 highly correlated with protection. T-cell immunity was overall low. In conclusion, protective immunity against EHV-1 infection including prevention of viremia was associated with robust systemic and intranasal IgG4/7 antibodies suggesting immediate virus neutralization at the local site.


Assuntos
Anticorpos Antivirais/imunologia , Infecções por Herpesviridae/veterinária , Herpesvirus Equídeo 1/imunologia , Vacinas contra Herpesvirus/administração & dosagem , Doenças dos Cavalos/prevenção & controle , Imunoglobulina G/imunologia , Viremia/veterinária , Administração Intranasal , Animais , Feminino , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/prevenção & controle , Infecções por Herpesviridae/virologia , Herpesvirus Equídeo 1/efeitos dos fármacos , Herpesvirus Equídeo 1/genética , Herpesvirus Equídeo 1/fisiologia , Vacinas contra Herpesvirus/imunologia , Doenças dos Cavalos/imunologia , Doenças dos Cavalos/virologia , Cavalos , Masculino , Mucosa Nasal/imunologia , Mucosa Nasal/virologia , Vacinação , Viremia/imunologia , Viremia/prevenção & controle , Viremia/virologia , Eliminação de Partículas Virais
7.
J Virol ; 93(9)2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30787156

RESUMO

Reactivation of herpes simplex virus 2 (HSV-2) from latency causes viral shedding that develops into recurrent genital lesions. The immune mechanisms of protection against recurrent genital herpes remain to be fully elucidated. In this preclinical study, we investigated the protective therapeutic efficacy, in the guinea pig model of recurrent genital herpes, of subunit vaccine candidates that were based on eight recombinantly expressed HSV-2 envelope and tegument proteins. These viral protein antigens (Ags) were rationally selected for their ability to recall strong CD4+ and CD8+ T-cell responses from naturally "protected" asymptomatic individuals, who, despite being infected, never develop any recurrent herpetic disease. Out of the eight HSV-2 proteins, the envelope glycoprotein D (gD), the tegument protein VP22 (encoded by the UL49 gene), and ribonucleotide reductase subunit 2 protein (RR2; encoded by the UL40 gene) produced significant protection against recurrent genital herpes. The RR2 protein, delivered either intramuscularly or intravaginally with CpG and alum adjuvants, (i) boosted the highest neutralizing antibodies, which appear to cross-react with both gB and gD, and (ii) enhanced the numbers of functional gamma interferon (IFN-γ)-producing CRTAM+ CFSE+ CD4+ and CRTAM+ CFSE+ CD8+ TRM cells, which express low levels of PD-1 and TIM-3 exhaustion markers and were localized to healed sites of the vaginal mucocutaneous (VM) tissues. The strong B- and T-cell immunogenicity of the RR2 protein was associated with a significant decrease in virus shedding and a reduction in both the severity and frequency of recurrent genital herpes lesions. In vivo depletion of either CD4+ or CD8+ T cells significantly abrogated the protection. Taken together, these preclinical results provide new insights into the immune mechanisms of protection against recurrent genital herpes and promote the tegument RR2 protein as a viable candidate Ag to be incorporated in future genital herpes therapeutic mucosal vaccines.IMPORTANCE Recurrent genital herpes is one of the most common sexually transmitted diseases, with a global prevalence of HSV-2 infection predicted to be over 536 million worldwide. Despite the availability of many intervention strategies, such as sexual behavior education, barrier methods, and the costly antiviral drug treatments, eliminating or at least reducing recurrent genital herpes remains a challenge. Currently, no FDA-approved therapeutic vaccines are available. In this preclinical study, we investigated the immunogenicity and protective efficacy, in the guinea pig model of recurrent genital herpes, of subunit vaccine candidates that were based on eight recombinantly expressed herpes envelope and tegument proteins. We discovered that similar to the dl5-29 vaccine, based on a replication-defective HSV-2 mutant virus, which has been recently tested in clinical trials, the RR2 protein-based subunit vaccine elicited a significant reduction in virus shedding and a decrease in both the severity and frequency of recurrent genital herpes sores. This protection correlated with an increase in numbers of functional tissue-resident IFN-γ+ CRTAM+ CFSE+ CD4+ and IFN-γ+ CRTAM+ CFSE+ CD8+ TRM cells that infiltrate healed sites of the vaginal tissues. Our study sheds new light on the role of TRM cells in protection against recurrent genital herpes and promotes the RR2-based subunit therapeutic vaccine to be tested in the clinic.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Herpes Genital/prevenção & controle , Herpesvirus Humano 2/imunologia , Vacinas contra Herpesvirus/farmacologia , Imunização Secundária , Ribonucleotídeo Redutases/farmacologia , Adulto , Idoso , Animais , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Feminino , Cobaias , Herpes Genital/imunologia , Herpes Genital/patologia , Vacinas contra Herpesvirus/imunologia , Humanos , Imunidade nas Mucosas/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Ribonucleotídeo Redutases/imunologia
8.
Nanomedicine ; 16: 138-148, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30594660

RESUMO

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.


Assuntos
Anticorpos Monoclonais/química , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/química , Anticorpos Antivirais/uso terapêutico , Fosfatos de Cálcio/química , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/patogenicidade , Vacinas contra Herpesvirus/imunologia , Vacinas contra Herpesvirus/uso terapêutico , Nanopartículas/química , Nanopartículas/uso terapêutico , Animais , Chlorocebus aethiops , Feminino , Vacinas contra Herpesvirus/química , Camundongos , Camundongos Endogâmicos BALB C , Células Vero
9.
PLoS Pathog ; 14(12): e1007464, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30521644

RESUMO

The ubiquitous Epstein-Barr virus (EBV) is the primary cause of infectious mononucleosis and is etiologically linked to the development of several malignancies and autoimmune diseases. EBV has a multifaceted life cycle that comprises virus lytic replication and latency programs. Considering EBV infection holistically, we rationalized that prophylactic EBV vaccines should ideally prime the immune system against lytic and latent proteins. To this end, we generated highly immunogenic particles that contain antigens from both these cycles. In addition to stimulating EBV-specific T cells that recognize lytic or latent proteins, we show that the immunogenic particles enable the ex vivo expansion of cytolytic EBV-specific T cells that efficiently control EBV-infected B cells, preventing their outgrowth. Lastly, we show that immunogenic particles containing the latent protein EBNA1 afford significant protection against wild-type EBV in a humanized mouse model. Vaccines that include antigens which predominate throughout the EBV life cycle are likely to enhance their ability to protect against EBV infection.


Assuntos
Antígenos Virais/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Vacinas contra Herpesvirus/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Camundongos , Latência Viral
11.
Vet Microbiol ; 222: 18-24, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30080668

RESUMO

Immune responses were compared after intranasal (IN) and intramuscular (IM) vaccination of horses with a modified live equine herpesvirus type-1 (EHV-1) vaccine, and the protective effect after EHV-1 challenge was evaluated. IN- and IM-vaccinated groups (n = 5 each) showed significant rises in serum virus-neutralizing titers with increased levels of IgGa and IgGb antibodies after the first vaccination (P < 0.05). In nasal secretions, the IN group had significantly increased levels of IgA antibodies after vaccination (P < 0.05), whereas the response of the IM group was dominated by IgGa and IgGb subclasses. After challenge infection, the numbers of pyretic horses from 1 to 4 days post-inoculation were 3/5 in the placebo (PBO) group (n = 5), 0/5 in the IN group, and 1/5 in the IM group. The IN and IM groups had significantly lower levels of virus shedding than the PBO group (P < 0.05). There were no significant between-group differences in the numbers of viremic horses each day. Notably, two horses in the IM group had no virus shedding or viremia, whereas all horses in the other group did. Both IN and IM vaccination induced systemic humoral immunity and mucosal immunity, suppressing virus replication in the nasal mucosa, and partially protected horses from pyrexia, especially early in infection. This study showed a mucosal antibody response was induced, not only by IN vaccination but also by IM vaccination.


Assuntos
Administração Intranasal/métodos , Infecções por Herpesviridae/veterinária , Herpesvirus Equídeo 1/imunologia , Vacinas contra Herpesvirus/imunologia , Injeções Intramusculares/métodos , Vacinação/veterinária , Animais , Anticorpos Antivirais/sangue , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/prevenção & controle , Infecções por Herpesviridae/virologia , Vacinas contra Herpesvirus/administração & dosagem , Doenças dos Cavalos/imunologia , Doenças dos Cavalos/prevenção & controle , Doenças dos Cavalos/virologia , Cavalos , Imunidade nas Mucosas , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Testes de Neutralização , Vacinação/métodos , Vacinas Atenuadas/administração & dosagem , Eliminação de Partículas Virais/imunologia
13.
J Virol ; 92(17)2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29950407

RESUMO

We previously isolated a herpes simplex virus 1 (HSV-1) mutant, KOS-NA, that carries two nonsynonymous mutations in UL39, resulting in L393P and R950H amino acid substitutions in infected cell protein 6 (ICP6). Our published data studying KOS-NA pathogenesis strongly suggest that one of these ICP6 substitutions expressed from KOS-NA, R950H, severely impaired acute viral replication in the eyes and trigeminal ganglia of mice after inoculation onto the cornea and consequently impaired establishment and reactivation from latency. Because of its significant neuroattenuation, we tested KOS-NA as a potential prophylactic vaccine against HSV-1 in a mouse model of corneal infection. KOS-NA stimulated stronger antibody and T cell responses than a replication-competent ICP0-null mutant and a replication-incompetent ICP8-null mutant optimized for immunogenicity. Immunizations with the ICP0-, ICP8-, and KOS-NA viruses all reduced replication of wild-type HSV-1 challenge virus in the corneal epithelium to similar extents. Low immunizing doses of KOS-NA and the ICP8- virus, but not the ICP0- virus, protected mice against eyelid disease (blepharitis). Notably, only KOS-NA protected almost completely against corneal disease (keratitis) and greatly reduced latent infection by challenge virus. Thus, vaccination of mice with KOS-NA prior to corneal challenge provides significant protection against HSV-1-mediated disease of the eye, even at a very low immunizing dose. These results suggest that KOS-NA may be the foundation of an effective prophylactic vaccine to prevent or limit HSV-1 ocular diseases.IMPORTANCE HSV-1 is a ubiquitous human pathogen that infects the majority of the world's population. Although most infections are asymptomatic, HSV-1 establishes lifelong latency in infected sensory neurons, from which it can reactivate to cause deadly encephalitis or potentially blinding eye disease. No clinically effective vaccine is available. In this study, we tested the protective potential of a neuroattenuated HSV-1 mutant (KOS-NA) as a vaccine in mice. We compared the effects of immunization with KOS-NA to those of two other attenuated viruses, a replication-competent (ICP0-) virus and a replication-incompetent (ICP8-) virus. Our data show that KOS-NA proved superior to the ICP0- and ICP8-null mutants in protecting mice from corneal disease and latent infection. With its significant neuroattenuation, severe impairment in establishing latency, and excellent protective effect, KOS-NA represents a significant discovery in the field of HSV-1 vaccine development.


Assuntos
Herpesvirus Humano 1/genética , Vacinas contra Herpesvirus/imunologia , Ceratite Herpética/prevenção & controle , Proteínas Virais/genética , Animais , Chlorocebus aethiops , Modelos Animais de Doenças , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 1/imunologia , Vacinas contra Herpesvirus/administração & dosagem , Vacinas contra Herpesvirus/genética , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/imunologia , Ceratite Herpética/imunologia , Ceratite Herpética/virologia , Camundongos , Mutação , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia , Células Vero , Proteínas Virais/imunologia , Latência Viral , Replicação Viral
14.
Int Immunopharmacol ; 61: 100-108, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29857239

RESUMO

Induction of robust and long-term immune responses at the portal of entry remains a big challenge for HSV-2 vaccine development. The adoption of a CD4 T cell helper peptide in the vaccine is thought to be beneficial for the enhancement of immune responses, however, its effect on HSV-2 vaccines has not yet been studied. In this study, we designed a DNA vaccine (gD-TpD) simultaneously expressing HSV-2 gD ectodomain and a universal CD4 T cell helper peptide (TpD), and tested its efficacy on a murine model. Mice were immunized 3 times with gD-TpD or control DNA formulations, and then were rested until Day 150 when they were vaginally challenged with lethal doses of HSV-2. Our data showed that gD-TpD significantly increased gD-specific IgG and IgA in both sera and vaginal washes. Furthermore, the increased antibody responses showed enhanced neutralization activity in vitro. In addition, gD-TpD induced balanced Th1/2 cellular responses and CD8+ T cell-dependent CTL activity. Although immune responses dropped over time after the final immunization, robust and rapid antibody and T cell responses were induced upon virus challenge in gD-TpD group. Moreover, gD-TpD provided full protection against lethal viral challenge in immunized mice. Together, our findings indicate that the inclusion of the CD4 T cell helper peptide TpD in HSV-2 gD subunit vaccine could induce long-term protective immunity, providing information for a rational design of vaccines against HSV-2 or even other viruses.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Herpes Genital/imunologia , Herpesvirus Humano 2/fisiologia , Vacinas contra Herpesvirus/imunologia , Células Th1/imunologia , Células Th2/imunologia , Vacinas de DNA/imunologia , Animais , Anticorpos Antivirais/metabolismo , Citotoxicidade Imunológica , Epitopos de Linfócito T/genética , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos/genética , Proteínas Virais/genética
15.
J Microbiol ; 56(6): 441-448, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29858833

RESUMO

Live attenuated vaccine strains have been developed for Varicella-Zoster virus (VZV). Compared to clinically isolated strains, the vaccine strains contain several non-synonymous mutations in open reading frames (ORFs) 0, 6, 31, 39, 55, 62, and 64. In particular, ORF62, encoding an immediate-early (IE) 62 protein that acts as a transactivator for viral gene expression, contains six non-synonymous mutations, but whether these mutations affect transactivation activity of IE62 is not understood. In this study, we investigated the role of non-synonymous vaccine-type mutations (M99T, S628G, R958G, V1197A, I1260V, and L1275S) of IE62 in Suduvax, a vaccine strain isolated in Korea, for transactivation activity. In reporter assays, Suduvax IE62 showed 2- to 4-fold lower transactivation activity toward ORF4, ORF28, ORF29, and ORF68 promoters than wild-type IE62. Introduction of individual M99T, S628G, R958G, or V1197A/I1260V/L1275S mutations into wild-type IE62 did not affect transactivation activity. However, the combination of M99T within the N-terminal Sp transcription factor binding region and V1197A/I1260V/L1275S within the C-terminal serine-enriched acidic domain (SEAD) significantly reduced the transactivation activity of IE62. The M99T/V1197A/I1260V/L1275S mutant IE62 did not show considerable alterations in intracellular distribution and Sp3 binding compared to wild-type IE62, suggesting that other alteration(s) may be responsible for the reduced transactivation activity. Collectively, our results suggest that acquisition of mutations in both Met 99 and the SEAD of IE62 is responsible for the reduced transactivation activity found in IE62 of the VZV vaccine strains and contributes to attenuation of the virus.


Assuntos
Herpesvirus Humano 3/genética , Vacinas contra Herpesvirus/genética , Vacinas contra Herpesvirus/metabolismo , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , Mutação/genética , Transativadores/genética , Transativadores/metabolismo , Ativação Transcricional , Vacinas Atenuadas/genética , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo , Sequência de Bases , Sítios de Ligação/genética , Linhagem Celular Tumoral , DNA Viral , Regulação Viral da Expressão Gênica , Genes Virais , Células HEK293 , Humanos , Fases de Leitura Aberta/genética , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética , República da Coreia , Fatores de Transcrição
16.
J Virol ; 92(16)2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29899091

RESUMO

Replication-competent controlled virus vectors were derived from the virulent herpes simplex virus 1 (HSV-1) wild-type strain 17syn+ by placing one or two replication-essential genes under the stringent control of a gene switch that is coactivated by heat and an antiprogestin. Upon activation of the gene switch, the vectors replicate in infected cells with an efficacy that approaches that of the wild-type virus from which they were derived. Essentially no replication occurs in the absence of activation. When administered to mice, localized application of a transient heat treatment in the presence of systemic antiprogestin results in efficient but limited virus replication at the site of administration. The immunogenicity of these viral vectors was tested in a mouse footpad lethal challenge model. Unactivated viral vectors-which may be regarded as equivalents of inactivated vaccines-induced detectable protection against lethality caused by wild-type virus challenge. Single activation of the viral vectors at the site of administration (rear footpads) greatly enhanced protective immune responses, and a second immunization resulted in complete protection. Once activated, vectors also induced far better neutralizing antibody and HSV-1-specific cellular immune responses than unactivated vectors. To find out whether the immunogenicity of a heterologous antigen was also enhanced in the context of efficient transient vector replication, a virus vector constitutively expressing an equine influenza virus hemagglutinin was constructed. Immunization of mice with this recombinant induced detectable antibody-mediated neutralization of equine influenza virus, as well as a hemagglutinin-specific cellular immune response. Single activation of viral replication resulted in a severalfold enhancement of these immune responses.IMPORTANCE We hypothesized that vigorous replication of a pathogen may be critical for eliciting the most potent and balanced immune response against it. Hence, attenuation/inactivation (as in conventional vaccines) should be avoided. Instead, the necessary safety should be provided by placing replication of the pathogen under stringent control and by activating time-limited replication of the pathogen strictly in an administration region in which pathology cannot develop. Immunization will then occur in the context of highly efficient pathogen replication and uncompromised safety. We found that localized activation in mice of efficient but limited replication of a replication-competent controlled herpesvirus vector resulted in a greatly enhanced immune response to the virus or an expressed heterologous antigen. This finding supports the above-mentioned hypothesis and suggests that the vectors may be promising novel agents worth exploring for the prevention/mitigation of infectious diseases for which efficient vaccination is lacking, in particular in immunocompromised patients.


Assuntos
Portadores de Fármacos , Vetores Genéticos , Herpesvirus Humano 1/genética , Vacinas contra Herpesvirus/imunologia , Temperatura Alta , Vacinas contra Influenza/imunologia , Replicação Viral , Animais , Anticorpos Antivirais/sangue , Vacinas contra Herpesvirus/administração & dosagem , Vacinas contra Herpesvirus/genética , Imunidade Celular , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/genética , Camundongos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
17.
Adv Exp Med Biol ; 1045: 123-142, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29896666

RESUMO

Varicella-zoster virus (VZV) is the first and only human herpesvirus for which a licensed live attenuated vaccine, vOka, has been developed. vOka has highly safe and effective profiles; however, worldwide herd immunity against VZV has not yet been established and it is far from eradication. Despite the successful reduction in the burden of VZV-related illness by the introduction of the vaccine, some concerns about vOka critically prevent worldwide acceptance and establishment of herd immunity, and difficulties in addressing these criticisms often relate to its ill-defined mechanism of attenuation. Advances in scientific technologies have been applied in the VZV research field and have contributed toward uncovering the mechanism of vOka attenuation as well as VZV biology at the molecular level. A subunit vaccine targeting single VZV glycoprotein, rationally designed based on the virological and immunological research, has great potential to improve the strategy for eradication of VZV infection in combination with vOka.


Assuntos
Herpesvirus Humano 3/imunologia , Vacinas contra Herpesvirus/imunologia , Infecção pelo Vírus da Varicela-Zoster/prevenção & controle , Animais , Desenho de Fármacos , Herpesvirus Humano 3/genética , Herpesvirus Humano 3/fisiologia , Vacinas contra Herpesvirus/administração & dosagem , Vacinas contra Herpesvirus/genética , Humanos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Infecção pelo Vírus da Varicela-Zoster/imunologia , Infecção pelo Vírus da Varicela-Zoster/virologia
18.
Adv Exp Med Biol ; 1045: 477-493, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29896681

RESUMO

Epstein-Barr virus (EBV) is the primary cause of infectious mononucleosis and is associated with several malignancies, including nasopharyngeal carcinoma, gastric carcinoma, Hodgkin lymphoma, Burkitt lymphoma, and lymphomas in immunocompromised persons, as well as multiple sclerosis. A vaccine is currently unavailable. While monomeric EBV gp350 was shown in a phase 2 trial to reduce the incidence of infectious mononucleosis, but not the rate of EBV infection, newer formulations of gp350 including multimeric forms, viruslike particles, and nanoparticles may be more effective. A vaccine that also includes additional viral glycoproteins, lytic proteins, or latency proteins might improve the effectiveness of an EBV gp350 vaccine. Clinical trials to determine if an EBV vaccine can reduce the rate of infectious mononucleosis or posttransplant lymphoproliferative disease should be performed. The former is important since infectious mononucleosis can be associated with debilitating fatigue as well as other complications, and EBV infectious mononucleosis is associated with increased rates of Hodgkin lymphoma and multiple sclerosis. A vaccine to reduce EBV posttransplant lymphoproliferative disease would be an important proof of principle to prevent an EBV-associated malignancy. Trials of an EBV vaccine to reduce the incidence of Hodgkin lymphoma, multiple sclerosis, or Burkitt lymphoma would be difficult but feasible.


Assuntos
Infecções por Vírus Epstein-Barr/prevenção & controle , Herpesvirus Humano 4/imunologia , Vacinas contra Herpesvirus/imunologia , Animais , Ensaios Clínicos Fase II como Assunto , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/genética , Vacinas contra Herpesvirus/administração & dosagem , Vacinas contra Herpesvirus/genética , Humanos , Mononucleose Infecciosa/imunologia , Mononucleose Infecciosa/prevenção & controle , Mononucleose Infecciosa/virologia
19.
Jpn J Infect Dis ; 71(3): 229-233, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29709968

RESUMO

A novel system was developed for generating highly attenuated vaccinia virus LC16m8 (m8, third-generation smallpox vaccine) that expresses foreign genes. The innovations in this system are its excisable selection marker, specificity of the integration site of a gene of interest, and easy identification of clones with a fluorescent signal. Using this system, recombinant m8s, which expressed herpes simplex virus 2 (HSV-2) glycoprotein B (gB)-, gD-, or both gB and gD (gB + gD), were generated, and their efficacy was evaluated. First, the induction of a specific IgG against these HSV-2 glycoproteins in mice infected with one of these recombinant m8s was confirmed by an immunofluorescent assay. Next, mice preinfected with one of the recombinant m8s were infected with HSV-2 at a lethal dose to examine the vaccine efficacy. The fatality rate among the mice preinfected with either the recombinant gB + gD- or gD-expressing m8 significantly decreased in comparison with the control. The survival rate in male and female mice preinfected with either the recombinant gB + gD- or gD-expressing m8 increased to 100% and 60%, respectively, while most of the control mice died. In summary, this new system may be applicable to creation of a novel m8-based vaccine.


Assuntos
Herpesvirus Humano 2/imunologia , Vacinas contra Herpesvirus/genética , Vírus Vaccinia/genética , Animais , Chlorocebus aethiops , Feminino , Herpes Simples/imunologia , Herpes Simples/prevenção & controle , Vacinas contra Herpesvirus/imunologia , Vacinas contra Herpesvirus/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasmídeos/genética , Vírus Vaccinia/metabolismo , Células Vero
20.
Viruses ; 10(5)2018 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-29724057

RESUMO

Herpes simplex virus type 1(HSV-1) presents a conundrum to public health worldwide because of its specific pathogenicity and clinical features. Some experimental vaccines, such as the recombinant viral glycoproteins, exhibit the viral immunogenicity of a host-specific immune response, but none of these has achieved a valid epidemiological protective efficacy in the human population. In the present study, we constructed an attenuated HSV-1 strain M3 through the partial deletion of UL7, UL41, and the latency-associated transcript (LAT) using the CRISPR/Cas9 system. The mutant strain exhibited lowered infectivity and virulence in macaques. Neutralization testing and ELISpot detection of the specific T-cell responses confirmed the specific immunity induced by M3 immunization and this immunity defended against the challenges of the wild-type strain and restricted the entry of the wild-type strain into the trigeminal ganglion. These results in rhesus macaques demonstrated the potential of the attenuated vaccine for the prevention of HSV-1 in humans.


Assuntos
Antígenos Virais/imunologia , Herpes Simples/prevenção & controle , Herpesvirus Humano 1/genética , Vacinas contra Herpesvirus/imunologia , Animais , Antígenos Virais/genética , Sistemas CRISPR-Cas , Herpes Simples/imunologia , Vacinas contra Herpesvirus/genética , Imunogenicidade da Vacina , Macaca mulatta/virologia , Mutação , Testes de Neutralização , Fenótipo , Gânglio Trigeminal/virologia , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/imunologia , Proteínas Virais/genética , Proteínas Virais/imunologia , Replicação Viral
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