RESUMO
Respiratory syncytial virus (RSV) infection is a frequent cause of morbidity and mortality in children. Recently, great advances have been made in the development of new monoclonal antibodies and vaccines thanks to the recognition of the structural conformation of virus proteins. The objective of this study was to review the advances related to the prevention of RSV infection in the first 6 months of life. Advances in structural biology have shown that the RSV fusion protein (F-Protein) in its prefusion state (Pre-F) is an excellent antigen for developing monoclonal antibodies and vaccines to prevent respiratory syncytial virus (RSV) infections. A new single-dose monoclonal antibody, Nirsevimab, has greater neutralizing power than currently available Palivizumab, and prolonged protection for 5 to 6 months. Nirsevimab has demonstrated an efficacy of 76.8% (95% CI, 49.4 to 89.4) in preventing lower respiratory infection 150 days after vaccination, decreasing the risk of ICU admission by 90.1% (95% CI: 16.4-98.8). Clesrovimab is another single-dose monoclonal antibody that has also shown promising results in phase 1b-2a trials. More recently, a bivalent vaccine against RSV A and B (Bivalent Prefusion F) has also been developed by replicating the F-protein stabilized in its Pre-F state as an antigen, using genetic engineering. This antigen, when administered to pregnant women between 24-36 weeks of gestation, induces high levels of antibodies in the mother with high transplacental transfer to the fetus. This vaccine has demonstrated an efficacy of 81.8% (95% CI: 40.6-96.3) at 90 days and 69.4% (95% CI: 44.3-84.1) at 180 days to prevent severe RSV disease (primary endpoint) without safety events detected so far. Nirsevimab and the Pre-F vaccine for pregnant women confer effective protection through passive immunity against RSV that lasts for the first 5 to 6 months of life and have already been approved for use in Europe by the EMA and in Canada and the United States by the FDA.
Assuntos
Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Vírus Sincicial Respiratório Humano , Feminino , Humanos , Gravidez , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes , Anticorpos Antivirais , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Infecções por Vírus Respiratório Sincicial/genética , Vacinas contra Vírus Sincicial Respiratório/uso terapêutico , Vacinas contra Vírus Sincicial Respiratório/genética , Vírus Sincicial Respiratório Humano/genética , LactenteRESUMO
The human Respiratory Syncytial Virus (hRSV) causes lower respiratory tract infections including pneumonia and bronchiolitis. Such infections also cause a large number of hospitalizations and affects mainly newborns, young children and the elderly worldwide. Symptoms associated with hRSV infection are due to an exacerbated immune response characterized by low levels of IFN-γ, recruitment of neutrophils and eosinophils to the site of infection and lung damage. Although hRSV is a major health problem, no vaccines are currently available. Different immunization approaches have been developed to achieve a vaccine that activates the immune system, without triggering an unbalanced inflammation. These approaches include live attenuated vaccine, DNA or proteins technologies, and the use of vectors to express proteins of the virus. In this review, we discuss the host immune response to hRSV and the immunological mechanisms underlying an effective and safe BCG vectored vaccine against hRSV.
Assuntos
Vacina BCG , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Animais , Bronquiolite/prevenção & controle , Bronquiolite/virologia , Criança , Humanos , Recém-Nascido , Pulmão/imunologia , Pulmão/virologia , Camundongos , Infecções por Vírus Respiratório Sincicial/imunologia , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vacinas contra Vírus Sincicial Respiratório/genética , Vírus Sincicial Respiratório Humano/genética , Vacinação , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/genéticaRESUMO
Human respiratory syncytial virus (hRSV) is a major health burden worldwide, causing the majority of hospitalizations in children under two years old due to bronchiolitis and pneumonia. HRSV causes year-to-year outbreaks of disease, which also affects the elderly and immunocompromised adults. Furthermore, both hRSV morbidity and epidemics are explained by a consistently high rate of re-infections that take place throughout the patient life. Although significant efforts have been invested worldwide, currently there are no licensed vaccines to prevent hRSV infection. Here, we describe that a recombinant Bacillus Calmette-Guerin (BCG) vaccine expressing the nucleoprotein (N) of hRSV formulated under current good manufacture practices (cGMP rBCG-N-hRSV) confers protective immunity to the virus in mice. Our results show that a single dose of the GMP rBCG-N-hRSV vaccine retains its capacity to protect mice against a challenge with a disease-causing infection of 1×107 plaque-forming units (PFUs) of the hRSV A2 clinical strain 13018-8. Compared to unimmunized infected controls, vaccinated mice displayed reduced weight loss and less infiltration of neutrophils within the airways, as well as reduced viral loads in bronchoalveolar lavages, parameters that are characteristic of hRSV infection in mice. Also, ex vivo re-stimulation of splenic T cells at 28days post-immunization activated a repertoire of T cells secreting IFN-γ and IL-17, which further suggest that the rBCG-N-hRSV vaccine induced a mixed, CD8+ and CD4+ T cell response capable of both restraining viral spread and preventing damage of the lungs. All these features support the notion that rBCG-N-hRSV is a promising candidate vaccine to be used in humans to prevent the disease caused by hRSV in the susceptible population.
Assuntos
Vacina BCG/administração & dosagem , Linfócitos T CD8-Positivos/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Vacina BCG/genética , Vacina BCG/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Humanos , Esquemas de Imunização , Imunogenicidade da Vacina , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-17/biossíntese , Interleucina-17/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/virologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Nucleoproteínas/genética , Nucleoproteínas/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/virologia , Vacinas contra Vírus Sincicial Respiratório/genética , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Vírus Sincicial Respiratório Humano/patogenicidade , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/virologia , Células Th17/imunologia , Células Th17/virologia , Vacinas Sintéticas , Proteínas Virais/genética , Proteínas Virais/imunologiaRESUMO
Human respiratory syncytial virus (HRSV) is the major pathogen leading to respiratory disease in infants and neonates worldwide. An effective vaccine has not yet been developed against this virus, despite considerable efforts in basic and clinical research. HRSV replication is independent of the nuclear RNA processing constraints, since the virus genes are adapted to the cytoplasmic transcription, a process performed by the viral RNA-dependent RNA polymerase. This study shows that meaningful nuclear RNA polymerase II dependent expression of the HRSV nucleoprotein (N) and phosphoprotein (P) proteins can only be achieved with the optimization of their genes, and that the intracellular localization of N and P proteins changes when they are expressed out of the virus replication context. Immunization tests performed in mice resulted in the induction of humoral immunity using the optimized genes. This result was not observed for the non-optimized genes. In conclusion, optimization is a valuable tool for improving expression of HRSV genes in DNA vaccines.
Assuntos
Anticorpos Antivirais/sangue , Nucleoproteínas/imunologia , Fosfoproteínas/imunologia , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Proteínas Virais/imunologia , Animais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Nucleoproteínas/biossíntese , Nucleoproteínas/genética , Fosfoproteínas/biossíntese , Fosfoproteínas/genética , Vacinas contra Vírus Sincicial Respiratório/biossíntese , Vacinas contra Vírus Sincicial Respiratório/genética , Proteínas Virais/biossíntese , Proteínas Virais/genéticaRESUMO
Respiratory syncytial virus (RSV) is one of the leading causes of childhood hospitalization and a major health burden worldwide. Unfortunately, because of an inefficient immunological memory, RSV infection provides limited immune protection against reinfection. Furthermore, RSV can induce an inadequate Th2-type immune response that causes severe respiratory tract inflammation and obstruction. It is thought that effective RSV clearance requires the induction of balanced Th1-type immunity, involving the activation of IFN-gamma-secreting cytotoxic T cells. A recognized inducer of Th1 immunity is Mycobacterium bovis bacillus Calmette-Guérin (BCG), which has been used in newborns for decades in several countries as a tuberculosis vaccine. Here, we show that immunization with recombinant BCG strains expressing RSV antigens promotes protective Th1-type immunity against RSV in mice. Activation of RSV-specific T cells producing IFN-gamma and IL-2 was efficiently obtained after immunization with recombinant BCG. This type of T cell immunity was protective against RSV challenge and caused a significant reduction of inflammatory cell infiltration in the airways. Furthermore, mice immunized with recombinant BCG showed no weight loss and reduced lung viral loads. These data strongly support recombinant BCG as an efficient vaccine against RSV because of its capacity to promote protective Th1 immunity.
Assuntos
Antígenos Virais/imunologia , Mycobacterium bovis/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sinciciais Respiratórios/imunologia , Células Th1/imunologia , Animais , Antígenos Virais/genética , Imunidade Celular , Interferon gama/genética , Interferon gama/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Pulmão/imunologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium bovis/genética , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/genética , Vacinas contra Vírus Sincicial Respiratório/farmacologia , Vírus Sinciciais Respiratórios/genética , Carga ViralRESUMO
Respiratory syncytial virus (RSV) is an important viral pathogen that causes severe lower respiratory tract infection in infants, the elderly, and immunocompromised individuals. There are no licensed RSV vaccines to date. To prevent RSV infection, immune responses in both the upper and lower respiratory tracts are required. Previously, immunization with Venezuelan equine encephalitis virus replicon particles (VRPs) demonstrated effectiveness in inducing mucosal protection against various pathogens. In this study, we developed VRPs encoding RSV fusion (F) or attachment (G) glycoproteins and evaluated the immunogenicity and efficacy of these vaccine candidates in mice and cotton rats. VRPs, when administered intranasally, induced surface glycoprotein-specific virus neutralizing antibodies in serum and immunoglobulin A (IgA) antibodies in secretions at the respiratory mucosa. In addition, fusion protein-encoding VRPs induced gamma interferon (IFN-gamma)-secreting T cells in the lungs and spleen, as measured by reaction with an H-2K(d)-restricted CD8(+) T-cell epitope. In animals vaccinated with F protein VRPs, challenge virus replication was reduced below the level of detection in both the upper and lower respiratory tracts following intranasal RSV challenge, while in those vaccinated with G protein VRPs, challenge virus was detected in the upper but not the lower respiratory tract. Close examination of histopathology of the lungs of vaccinated animals following RSV challenge revealed no enhanced inflammation. Immunization with VRPs induced balanced Th1/Th2 immune responses, as measured by the cytokine profile in the lungs and antibody isotype of the humoral immune response. These results represent an important first step toward the use of VRPs encoding RSV proteins as a prophylactic vaccine for RSV.