RESUMEN

Respiratory syncytial virus (RSV) remains the most common cause of lower respiratory tract infections in children worldwide. Development of a vaccine has been hindered due the risk of enhanced respiratory disease (ERD) following natural RSV exposure and the young age (<6 months) at which children would require protection. Risk factors linked to the development of ERD include poorly neutralizing antibody, seronegative status (never been exposed to RSV), and a Th2-type immune response. Stabilization of the more antigenic prefusion F protein (PreF) has reinvigorated hope for a protective RSV vaccine that elicits potent neutralizing antibody. While anecdotal evidence suggests that children and adults previously exposed to RSV (seropositive) are not at risk for developing vaccine associated ERD, differences in host immune responses in seropositive and seronegative individuals that may protect against ERD remain unclear. It is also unclear if vaccine formulations that skew towards Th1- versus Th2-type immune responses increase pathology or provide greater protection in seropositive individuals. Therefore, the goal of this work was to compare the host immune response to a stabilized prefusion RSV antigen formulated alone or with Th1 or Th2 skewing adjuvants in seronegative and seropositive BALB/c mice. We have developed a novel BALB/c mouse model whereby mice are first infected with RSV (seropositive) and then vaccinated during pregnancy to recapitulate maternal immunization strategies. Results of these studies show that prior RSV infection mitigates vaccine-mediated skewing by Th1- and Th2-polarizing adjuvants that was observed in seronegative animals. Moreover, vaccination with PreF plus the Th1-skewing adjuvant, Advax, increased RSV F85-93-specific CD8 T cells in both seronegative and seropositive dams. These data demonstrate the importance of utilizing seropositive animals in preclinical vaccine studies to assess both the safety and efficacy of candidate RSV vaccines.

Asunto(s)

Infecciones por Virus Sincitial Respiratorio , Vacunas contra Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Ratones , Animales , Anticuerpos Antivirales , Pulmón , Anticuerpos Neutralizantes , Ratones Endogámicos BALB C , Linfocitos T CD8-positivos , Adyuvantes Inmunológicos

RESUMEN

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in children. Inactivated RSV vaccine was developed in the late 1960's, but the vaccine-enhanced disease (VED) occurred to vaccinated infants upon subsequent natural RSV infection. The excessive inflammatory immunopathology in the lungs might be involved in the VED, but the underlying mechanisms remain not fully understood. In this study, we utilized UV-inactivated RSV in the prime/boost approach followed by RSV challenge in BALB/c mice to mimic RSV VED. The dynamic virus load, cytokines, histology and transcriptome profiles in lung tissues of mice were investigated from day 1 to day 6 post-infection. Compared to PBS-treated mice, UV-RSV vaccination leads to a Th2 type inflammatory response characterized by enhanced histopathology, reduced Treg cells and increased IL4+CD4 T cells in the lung. Enhanced production of several Th2 type cytokines (IL-4, IL-5, IL-10) and TGF-ß,  reduction of IL-6 and IL-17 were observed in UV-RSV vaccinated mice. A total of 5582 differentially expressed (DE) genes between PBS-treated or vaccinated mice and naïve mice were identified by RNA-Seq. Eleven conserved high-influential modules (HMs) were recognized, majorly grouped into regulatory networks related to cell cycle and cell metabolism, signal transduction, immune and inflammatory responses. At an early time post-infection, the vaccinated mice showed obvious decreased expression patterns of DE genes in 11 HMs compared to PBS-treated mice. The extracellular matrix (HM5) and immune responses (HM8) revealed tremendous differences in expression and regulation characteristics of transcripts between PBS-treated and vaccinated mice at both early and late time points. The highly connected genes in HM5 and HM8 networks were further validated by RT-qPCR. These findings reveal the relationship between RSV VED and immune responses, which could benefit the development of novel RSV vaccines.

Asunto(s)

Infecciones por Virus Sincitial Respiratorio , Vacunas contra Virus Sincitial Respiratorio , Animales , Pulmón , Ratones , Ratones Endogámicos BALB C , Infecciones por Virus Sincitial Respiratorio/prevención & control , Vacunas contra Virus Sincitial Respiratorio/genética , Transcriptoma , Vacunación

RESUMEN

Respiratory syncytial virus (RSV) infection caused severe acute respiratory disease in children and the elderly. There is no licensed vaccine. It has been a challenging problem to avoid vaccine enhanced respiratory disease in developing a safe and effective RSV vaccine. Here, we investigated the impact of MF59-like oil-in-water emulsion adjuvant Addavax on the vaccine efficacy of inactivated split RSV (sRSV) and the roles of natural killer (NK) cells in enhanced respiratory disease in sRSV vaccinated mice after RSV infection. Addavax-adjuvanted sRSV vaccination induced higher levels of IgG1 isotype antibodies and more effective lung viral clearance upon RSV infection but promoted enhanced respiratory disease of weight loss, pulmonary inflammation, and NK and NK T (NKT) cell infiltrations in the lungs. Antibody treatment depleting NK cells prior to RSV infection resulted in preventing severe weight loss and histopathology, as well as attenuating infiltration of dendritic cell subsets and TNF-α+ T cells in the lungs. This study demonstrated the impacts of oil-in-water emulsion adjuvant on sRSV vaccination and the potential roles of NK and NKT cells in protection and respiratory disease after adjuvanted RSV vaccination and infection in a mouse model.

Asunto(s)

Infecciones por Virus Sincitial Respiratorio , Vacunas contra Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Animales , Anticuerpos Antivirales , Emulsiones , Células Asesinas Naturales , Pulmón , Ratones , Ratones Endogámicos BALB C , Infecciones por Virus Sincitial Respiratorio/prevención & control , Vacunación , Agua

RESUMEN

Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract infection in infants and young children. The vaccine-enhanced disease (VED) has greatly hindered the development of an RSV vaccine. Currently, there are no licensed vaccines for RSV. In this study, immunization of mice with hepatitis B virus core particles containing a conserved region of the G protein (HBc-tG) combined with interleukin-35 (IL-35) elicited a Th1-biased response and a high frequency of regulatory T (Treg) cells and increased the levels of IL-10, transforming growth factor ß, and IL-35 production. Importantly, immunization with HBc-tG together with IL-35 protected mice against RSV infection without vaccine-enhanced immunopathology. To explore the mechanism of how IL-35 reduces lung inflammation at the gene expression level, transcription profiles were obtained from lung tissues of immunized mice after RSV infection by the Illumina sequencing technique and further analyzed by a systems biology method. In total, 2,644 differentially expressed genes (DEGs) were identified. Twelve high-influence modules (HIMs) were selected from these DEGs on the basis of the protein-protein interaction network. A detailed analysis of HIM10, involved in the immune response network, revealed that Il10 plays a key role in regulating the host response. The selected DEGs were consistently confirmed by quantitative real-time PCR (qRT-PCR). Our results demonstrate that IL-35 inhibits vaccine-enhanced immunopathology after RSV infection and has potential for development in novel therapeutic and prophylactic strategies.IMPORTANCE In the past few decades, respiratory syncytial virus (RSV) has still been a major health concern worldwide. The vaccine-enhance disease (VED) has hindered RSV vaccine development. A truncated hepatitis B virus core protein vaccine containing the conserved region (amino acids 144 to 204) of the RSV G protein (HBc-tG) had previously been shown to induce effective immune responses and confer protection against RSV infection in mice but to also lead to VED. In this study, we investigated the effect of IL-35 on the host response and immunopathology following RSV infection in vaccinated mice. Our results indicate that HBc-tG together with IL-35 elicited a balanced immune response and protected mice against RSV infection without vaccine-enhanced immunopathology. Applying a systems biology method, we identified Il10 to be the key regulator in reducing the excessive lung inflammation. Our study provides new insight into the function of IL-35 and its regulatory mechanism of VED at the network level.

Asunto(s)

Virus de la Hepatitis B/inmunología , Interleucinas/inmunología , Infecciones por Virus Sincitial Respiratorio/prevención & control , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Línea Celular Tumoral , Chlorocebus aethiops , Femenino , Proteínas de Unión al GTP/inmunología , Proteínas de Unión al GTP/metabolismo , Células HEK293 , Virus de la Hepatitis B/metabolismo , Humanos , Inmunización , Interleucinas/metabolismo , Pulmón/virología , Ratones , Ratones Endogámicos BALB C , Infecciones por Virus Sincitial Respiratorio/virología , Vacunas contra Virus Sincitial Respiratorio/inmunología , Virus Sincitiales Respiratorios/metabolismo , Virus Sincitiales Respiratorios/patogenicidad , Linfocitos T Reguladores/inmunología , Células TH1/inmunología , Vacunación , Células Vero , Proteínas del Núcleo Viral/inmunología

RESUMEN

Although respiratory syncytial virus (RSV) infection in infants and young children is a global public health issue, development of a safe RSV vaccine has been impeded by formalin-inactivated RSV-enhanced respiratory disease (ERD). In developing a safer yet effective RSV vaccine for children, a strategy to decrease over-reactive T cells and increase neutralizing anti-RSV antibodies should be considered. We previously demonstrated that adult mice immunized with RSV recombinant G protein plus low-dose Cyclosporine A (G+ CsA) could, upon subsequent RSV challenge, produce increased levels of antigen-specific T regulatory cells in lungs that overcame the ERD. Neutralizing anti-RSV antibodies that prevented viral infection were also elicited. In this study, we investigated if such a G+ CsA vaccine could provide infant mice with the same protection from RSV infection without ERD. The results showed that the G+ CsA vaccine could prevent RSV infection with only a mild loss of body weight. Importantly, there was nearly normal morphology and no mucus appearance in lung tissues after RSV challenge. These results demonstrate that the G+ CsA vaccine strategy achieved similar benefits in the neonatal prime and infancy boost model as in the adult mouse model. The G+ CsA immunization strategy is potentially safe and effective in neonates and infants because it suppresses the devastating ERD.

Asunto(s)

Infecciones por Virus Sincitial Respiratorio , Vacunas contra Virus Sincitial Respiratorio , Animales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Inmunidad , Pulmón , Ratones , Ratones Endogámicos BALB C , Infecciones por Virus Sincitial Respiratorio/prevención & control , Virus Sincitiales Respiratorios

RESUMEN

Respiratory syncytial virus (RSV) causes severe pulmonary disease in infants, young children, and the elderly. Formalin inactivated RSV (FI-RSV) vaccine trials failed due to vaccine enhanced respiratory disease, but the underlying immune mechanisms remain not fully understood. In this study, we have used wild type C57BL/6 and CD4 knockout (CD4KO) mouse models to better understand the roles of the CD4 T cells and cellular mechanisms responsible for enhanced respiratory disease after FI-RSV vaccination and RSV infection. Less eosinophil infiltration and lower pro-inflammatory cytokine production were observed in FI-RSV vaccinated CD4KO mice after RSV infection compared to FI-RSV vaccinated C57BL/6 mice. NK cells and cytokine-producing CD8 T cells were recruited at high levels in the airways of CD4KO mice, correlating with reduced respiratory disease. Depletion studies provided evidence that virus control was primarily mediated by NK cells whereas CD8 T cells contributed to IFN-γ production and less eosinophilic lung inflammation. This study demonstrated the differential roles of effector CD4 and CD8 T cells as well as NK cells, in networking with other inflammatory infiltrates in RSV disease in immune competent and CD4-deficient condition.

RESUMEN

Formalin-inactivated respiratory syncytial virus (RSV) vaccination causes vaccine-enhanced disease (VED) after RSV infection. It is considered that vaccine platforms enabling endogenous synthesis of RSV immunogens would induce favorable immune responses than non-replicating subunit vaccines in avoiding VED. Here, we investigated the immunogenicity, protection, and disease in mice after vaccination with RSV fusion protein (F) encoding plasmid DNA (F-DNA) or virus-like particles presenting RSV F (F-VLP). F-DNA vaccination induced CD8 T cells and RSV neutralizing Abs, whereas F-VLP elicited higher levels of IgG2a isotype and neutralizing Abs, and germinal center B cells, contributing to protection by controlling lung viral loads after RSV challenge. However, mice that were immunized with F-DNA displayed weight loss and pulmonary histopathology, and induced F specific CD8 T cell responses and recruitment of monocytes and plasmacytoid dendritic cells into the lungs. These innate immune parameters, RSV disease, and pulmonary histopathology were lower in mice that were immunized with F-VLP after challenge. This study provides important insight into developing effective and safe RSV vaccines.

RESUMEN

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory disease in young children, elderly and immunocompromised adults. There is no licensed vaccine against RSV although development of an effective and safe RSV vaccine has been a high priority for several decades. Among the various vaccine platforms, the viral-vectored RSV vaccines based on licensed cold-adapted live attenuated influenza vaccine (LAIV) might offer an advantage of inducing adequate mucosal CD8 T cell immunity at the infection site of respiratory pathogens. We constructed two recombinant LAIV viruses expressing immunodominant T-cell epitopes of RSV M2-1 protein. The results in this study provide evidence that RSV CD8 T cell epitopes delivered by LAIV viral vector could confer protection against RSV infection without causing pulmonary eosinophilia and inflammatory RSV disease in mice. In addition, these chimeric LAIV-RSV vaccines retained their attenuated phenotype and ability to protect against virulent influenza virus, thus providing a unique approach to fight against two dangerous respiratory viral pathogens using a single vaccine preparation.

Asunto(s)

Alphainfluenzavirus/inmunología , Vacunas contra la Influenza/administración & dosificación , Infecciones por Orthomyxoviridae/prevención & control , Infecciones por Virus Sincitial Respiratorio/prevención & control , Vacunas contra Virus Sincitial Respiratorio/administración & dosificación , Virus Sincitial Respiratorio Humano/inmunología , Animales , Anticuerpos Antivirales/sangre , Linfocitos T CD8-positivos/inmunología , Epítopos de Linfocito T , Femenino , Vacunas contra la Influenza/genética , Vacunas contra la Influenza/inmunología , Ratones , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/inmunología , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Vacunas contra Virus Sincitial Respiratorio/genética , Vacunas contra Virus Sincitial Respiratorio/inmunología , Virus Sincitial Respiratorio Humano/genética , Vacunas Atenuadas

RESUMEN

Respiratory syncytial virus (RSV) infection is a severe threat to young children and the elderly. Despite decades of research, no vaccine has been approved. Notably, instead of affording protection, a formalin-inactivated RSV vaccine induced severe respiratory disease including deaths in vaccinated children in a 1960s clinical trial; however, recent studies indicate that other forms of experimental vaccines can also induce pulmonary pathology in pre-clinical studies. These findings suggest that multiple factors/pathways could be involved in the development of enhanced respiratory diseases. Clearly, a better understanding of the mechanisms underlying such adverse reactions is critically important for the development of safe and efficacious vaccines against RSV infection, given the exponential growth of RSV vaccine clinical trials in recent years. By employing an integrated systems biology approach in a pre-clinical cotton rat model, we unraveled a complex network of pulmonary canonical pathways leading to disease development in vaccinated animals upon subsequent RSV infections. Cytokines including IL-1, IL-6 GRO/IL-8, and IL-17 in conjunction with mobilized pulmonary inflammatory cells could play important roles in disease development, which involved a wide range of host responses including exacerbated pulmonary inflammation, oxidative stress, hyperreactivity, and homeostatic imbalance between coagulation and fibrinolysis. Moreover, the observed elevated levels of MyD88 implicate the involvement of this critical signal transduction module as the central node of the inflammatory pathways leading to exacerbated pulmonary pathology. Finally, the immunopathological consequences of inactivated vaccine immunization and subsequent RSV exposure were further substantiated by histological analyses of these key proteins along with inflammatory cytokines, while hypercoagulation was supported by increased pulmonary fibrinogen/fibrin accompanied by reduced levels of plasma D-dimers. Enhanced respiratory disease associated with inactivated RSV vaccine involves a complex network of host responses, resulting in significant pulmonary lesions and clinical manifestations such as tachypnea and airway obstruction. The mechanistic insight into the convergence of different signal pathways and identification of biomarkers could help facilitate the development of safe and effective RSV vaccine and formulation of new targeted interventions.

Asunto(s)

Pulmón/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Vacunas contra Virus Sincitial Respiratorio/efectos adversos , Virus Sincitiales Respiratorios/inmunología , Animales , Citocinas/inmunología , Pulmón/patología , Ratas , Infecciones por Virus Sincitial Respiratorio/patología , Infecciones por Virus Sincitial Respiratorio/prevención & control , Vacunas contra Virus Sincitial Respiratorio/inmunología , Vacunas contra Virus Sincitial Respiratorio/farmacología , Sigmodontinae , Vacunación , Vacunas de Productos Inactivados/efectos adversos , Vacunas de Productos Inactivados/inmunología , Vacunas de Productos Inactivados/farmacología

RESUMEN

Formalin-inactivated respiratory syncytial virus (RSV) vaccination causes vaccine-enhanced disease (VED) after RSV infection. It is considered that vaccine platforms enabling endogenous synthesis of RSV immunogens would induce favorable immune responses than non-replicating subunit vaccines in avoiding VED. Here, we investigated the immunogenicity, protection, and disease in mice after vaccination with RSV fusion protein (F) encoding plasmid DNA (F-DNA) or virus-like particles presenting RSV F (F-VLP). F-DNA vaccination induced CD8 T cells and RSV neutralizing Abs, whereas F-VLP elicited higher levels of IgG2a isotype and neutralizing Abs, and germinal center B cells, contributing to protection by controlling lung viral loads after RSV challenge. However, mice that were immunized with F-DNA displayed weight loss and pulmonary histopathology, and induced F specific CD8 T cell responses and recruitment of monocytes and plasmacytoid dendritic cells into the lungs. These innate immune parameters, RSV disease, and pulmonary histopathology were lower in mice that were immunized with F-VLP after challenge. This study provides important insight into developing effective and safe RSV vaccines.

Asunto(s)

Animales , Ratones , Linfocitos B , Células Dendríticas , ADN , Centro Germinal , Inmunoglobulina G , Pulmón , Monocitos , Plásmidos , Vacunas contra Virus Sincitial Respiratorio , Virus Sincitiales Respiratorios , Linfocitos T , Vacunación , Vacunas de Subunidad , Carga Viral , Pérdida de Peso

RESUMEN

Formalin inactivated respiratory syncytial virus (FI-RSV) vaccination caused vaccine-enhanced respiratory disease (ERD) upon exposure to RSV in children. Virus-like particles presenting RSV F fusion protein (F VLP) are known to increase T helper type-1 (Th1) immune responses and avoid ERD in animal models. We hypothesized that F VLP would prime immune responses preventing ERD upon subsequent exposure to ERD-prone FI-RSV. Here, we demonstrated that heterologous F VLP priming and FI-RSV boosting of mice prevented FI-RSV vaccine-enhanced lung inflammation and eosinophilia upon RSV challenge. F VLP priming redirected pulmonary T cells toward effector CD8 T cells producing Th1 cytokines and significantly suppressed pulmonary Th2 cytokines. This study suggests that RSV F VLP priming would modulate and shift immune responses to subsequent exposure to ERD-prone FI-RSV vaccine and RSV infection, suppressing Th2 immune-mediated pulmonary histopathology and eosinophilia.

Asunto(s)

Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Infecciones por Virus Sincitial Respiratorio/prevención & control , Vacunas contra Virus Sincitial Respiratorio/efectos adversos , Vacunas contra Virus Sincitial Respiratorio/inmunología , Virus Sincitiales Respiratorios/inmunología , Vacunas de Partículas Similares a Virus/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Citocinas/metabolismo , Ratones , Células TH1/inmunología , Vacunas de Productos Inactivados/efectos adversos , Vacunas de Productos Inactivados/inmunología

RESUMEN

Respiratory Syncycial Virus (RSV) is the most important pathogen responsible for children's severe lower respiratory tract infection. So far no RSV vaccine has yet been authorized for clinical use. The main impediment that blocked development of RSV vaccine is that inactivated RSV vaccine could cause RSV vaccine-enhanced disease (RVED). The mechanism of RVED remains unclear. Recently some researchers found that insufficient activation of innate immunity, including Toll-like receptors (TLRs), might be associated with the onset of RVED. Based on the above findings, this research was conducted to further study the mechanism of RVED. We first vaccinated mice with formalin-inactivated RSV vaccine (FIRSV) and then exposed them to RSV to establish a RVED mouse model. Consequently, we found that mice previously inoculated with FIRSV showed obvious weight loss and extensive pneumonia, as well as T helper 2 cells (Th2)-biased immunity and suppressed CD8+T cell immunity after viral exposure, suggesting that we have successfully established a RVED mouse model. Then based on this model, we further added Poly(U) (TLR7/8 agonist) and CpG (TLR9 agonist) in FIRSV to see if RVED could be ameliorated. As a result, mice inoculated with FIRSV supplemented with Poly(U) and CpG had a much relieved weight loss and pneumonia, as well as suppressed Th2-biased immunity and strengthened CD8+T cell function. Thus, the insufficient stimulation of TLR7/8 and (or) TLR9 might play a role in the development of RVED, which could provide evidence for using TLR agonists as vaccine adjuvants to confer a protective immune response against RSV.

Asunto(s)

Inmunidad/efectos de los fármacos , Oligodesoxirribonucleótidos/uso terapéutico , Neumonía/inmunología , Neumonía/virología , Vacunas contra Virus Sincitial Respiratorio/efectos adversos , Linfocitos T/inmunología , Uracilo/uso terapéutico , Animales , Peso Corporal/efectos de los fármacos , Femenino , Formaldehído , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Ratones Endogámicos BALB C , Oligodesoxirribonucleótidos/farmacología , Neumonía/patología , Virus Sincitiales Respiratorios/efectos de los fármacos , Virus Sincitiales Respiratorios/fisiología , Linfocitos T/efectos de los fármacos , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismo , Uracilo/farmacología , Vacunas de Productos Inactivados/inmunología , Carga Viral/efectos de los fármacos

RESUMEN

INTRODUCTION: Respiratory syncytial virus (RSV) infection is responsible for one-third of deaths of acute lower respiratory infection in children less than one-year-old. The formaldehyde-inactivated RSV vaccine trial conducted in the 1960s predisposed the vaccinees to more serious RSV infection instead of protection. Better understanding of the underlying mechanism is of critical importance for better designing of safe and effective RSV vaccines. Areas covered: PubMed was searched to review immunopathology induced by RSV vaccines. We intend to dissect the differences in clinical and pathological manifestations of enhanced respiratory disease (ERD) in different animal models in comparison with humans. Formaldehyde-inactivated RSV vaccine causes ERD in both humans and animals, while RSV vaccine without formaldehyde treatment could also induce similar disease in animals, suggesting multiple pathways may be involved. Expert commentary: Identification of biomarkers pertinent to clinical evaluation should be further explored for safety assessment of RSV vaccines in human trials.

Asunto(s)

Infecciones por Virus Sincitial Respiratorio/inmunología , Vacunas contra Virus Sincitial Respiratorio/efectos adversos , Virus Sincitial Respiratorio Humano/inmunología , Animales , Modelos Animales de Enfermedad , Formaldehído/química , Humanos , Infecciones por Virus Sincitial Respiratorio/etiología , Infecciones por Virus Sincitial Respiratorio/prevención & control , Vacunas contra Virus Sincitial Respiratorio/química , Vacunas contra Virus Sincitial Respiratorio/inmunología , Vacunas de Productos Inactivados/efectos adversos , Vacunas de Productos Inactivados/química , Vacunas de Productos Inactivados/inmunología

RESUMEN

The pattern of immune response to a vaccine antigen can influence both efficacy and adverse events. Th2-cell-deviated responses have been implicated in both human and murine susceptibility to enhanced disease following formalin-inactivated (FI) vaccines for measles and RSV. In this study, we used the Th2-cell-deviated murine model of FI-RSV vaccination to test the ability of a dominant negative, cell-penetrating peptide inhibitor of STAT6 (STAT6 inhibitory peptide (IP)) to modulate the vaccine-induced predisposition to exaggerated inflammation during later RSV infection. Intranasal delivery of STAT6-IP in BALB/c mice at the time of distal intramuscular FI-RSV vaccination (Early Intervention) markedly decreased vaccine-enhanced, Th2-cell-dependent pathology upon subsequent RSV challenge. Administration of the STAT6-IP at the time of RSV challenge (Late Intervention) had no effect. Following RSV challenge, the STAT6-IP-treated mice in the Early Intervention group had lower airway eosinophils, increased lung IFN-γ levels, as well as increased IFN-γ-secreting CD4(+) and CD8(+) cells in the lungs. Our findings demonstrate the feasibility of targeting intracellular signaling pathways as a new way to modulate vaccine-induced responses.

Asunto(s)

Infecciones por Virus Sincitial Respiratorio/inmunología , Infecciones por Virus Sincitial Respiratorio/prevención & control , Vacunas contra Virus Sincitial Respiratorio/farmacología , Virus Sincitiales Respiratorios/inmunología , Factor de Transcripción STAT6/antagonistas & inhibidores , Células Th2/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Línea Celular , Citocinas/inmunología , Eosinófilos/inmunología , Formaldehído , Humanos , Inmunoglobulina G/inmunología , Inflamación/inmunología , Interferón gamma/inmunología , Pulmón/inmunología , Ratones , Ratones Endogámicos BALB C , Vacunas contra Virus Sincitial Respiratorio/inmunología , Factor de Transcripción STAT6/inmunología , Transducción de Señal/inmunología , Vacunas de Productos Inactivados/inmunología , Vacunas de Productos Inactivados/farmacología

RESUMEN

Maternal immunization of mice with formalin inactivated respiratory syncytial virus (FI-RSV) resulted in the passive transfer of RSV antibodies but not cellular components to the offspring. The offspring born to FI-RSV immunized mothers showed serum RSV neutralizing activity, effectively controlled lung viral loads without vaccine-enhanced disease, did not induce pulmonary eosinophilia, and cytokine producing cells after live RSV infection. Therefore, this study provides evidence that maternal immunization provides an in vivo model in investigating the roles of antibodies independent of cellular components.

Asunto(s)

Anticuerpos Antivirales/inmunología , Inmunidad Materno-Adquirida , Infecciones por Virus Sincitial Respiratorio/prevención & control , Virus Sincitiales Respiratorios/inmunología , Vacunas de Productos Inactivados/inmunología , Vacunas Virales/inmunología , Animales , Citocinas/biosíntesis , Femenino , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Ratones , Infecciones por Virus Sincitial Respiratorio/inmunología , Infecciones por Virus Sincitial Respiratorio/patología