RESUMO
Many bacterial polysaccharide vaccines, including the typhoid Vi polysaccharide (ViPS) and tetravalent meningococcal polysaccharide conjugate (MCV4) vaccines, do not incorporate adjuvants and are not highly immunogenic, particularly in infants. I found that endotoxin, a TLR4 ligand in ViPS, contributes to the immunogenicity of typhoid vaccines. Because endotoxin is pyrogenic, and its levels are highly variable in vaccines, I developed monophosphoryl lipid A, a nontoxic TLR4 ligand-based adjuvant named Turbo. Admixing Turbo with ViPS and MCV4 vaccines improved their immunogenicity across all ages and eliminated booster requirement. To understand the characteristics of this adjuvanticity, I compared Turbo with alum. Unlike alum, which polarizes the response toward the IgG1 isotype, Turbo promoted Ab class switching to all IgG isotypes with affinity maturation; the magnitude of this IgG response is durable and accompanied by the presence of long-lived plasma cells in the mouse bone marrow. In striking contrast with the pathways employed by alum, Turbo adjuvanticity is independent of NLPR3, pyroptotic cell death effector Gasdermin D, and canonical and noncanonical inflammasome activation mediated by Caspase-1 and Caspase-11, respectively. Turbo adjuvanticity is primarily dependent on the MyD88 axis and is lost in mice deficient in costimulatory molecules CD86 and CD40, indicating that Turbo adjuvanticity includes activation of these pathways. Because Turbo formulations containing either monophosphoryl lipid A or TLR2 ligands, Pam2CysSerLys4, and Pam3CysSerLys4 help generate Ab response of all IgG isotypes, as an adjuvant Turbo can improve the immunogenicity of glycoconjugate vaccines against a wide range of bacterial pathogens whose elimination requires appropriate IgG isotypes.
Assuntos
Adjuvantes Imunológicos , Lipídeo A , Animais , Camundongos , Adjuvantes Imunológicos/administração & dosagem , Lipídeo A/análogos & derivados , Lipídeo A/imunologia , Polissacarídeos Bacterianos/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Camundongos Endogâmicos C57BL , Adjuvantes de Vacinas , Vacinas Meningocócicas/imunologia , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/imunologia , Vacinas Tíficas-Paratíficas/imunologia , Vacinas Tíficas-Paratíficas/administração & dosagem , Anticorpos Antibacterianos/imunologia , Anticorpos Antibacterianos/sangue , Feminino , Ligantes , Glicoconjugados/imunologia , Humanos , Vacinas Conjugadas/imunologia , Compostos de Alúmen/administração & dosagem , Camundongos KnockoutRESUMO
Enteric fever is caused by three Salmonella enterica serovars: Typhi, Paratyphi A, and Paratyphi B sensu stricto Although vaccines against two of these serovars are licensed (Typhi) or in clinical development (Paratyphi A), as yet there are no candidates for S. Paratyphi B. To gain genomic insight into these serovars, we sequenced 38 enteric fever-associated strains from Chile and compared these with reference genomes. Each of the serovars was separated genomically based on the core genome. Genomic comparisons identified loci that were aberrant between serovars Paratyphi B sensu stricto and Paratyphi B Java, which is typically associated with gastroenteritis; however, the majority of these were annotated as hypothetical or phage related and thus were not ideal vaccine candidates. With the genomic information in hand, we engineered a live attenuated S. Paratyphi B sensu stricto vaccine strain, CVD 2005, which was capable of protecting mice from both homologous challenge and heterologous challenge with S. Paratyphi B Java. These findings extend our understanding of S. Paratyphi B and provide a viable vaccine option for inclusion in a trivalent live attenuated enteric fever vaccine formulation.IMPORTANCE We developed a live attenuated Salmonella enterica serovar Paratyphi B vaccine that conferred protection in mice against challenge with S Paratyphi B sensu stricto and S Paratyphi B Java, which are the causes of enteric fever and gastroenteritis, respectively. Currently, the incidence of invasive S. Paratyphi B sensu stricto infections is low; however, the development of new conjugate vaccines against other enteric fever serovars could lead to the emergence of S. Paratyphi B to fill the niche left by these other pathogens. As such, an effective S. Paratyphi B vaccine would be a useful tool in the armamentarium against Salmonella infections. Comparative genomics confirmed the serovar-specific groupings of these isolates and revealed that there are a limited number of genetic differences between the sensu stricto and Java strains, which are mostly hypothetical and phage-encoded proteins. The observed level of genomic similarity likely explains why we observe some cross-protection.
Assuntos
Febre Paratifoide/prevenção & controle , Salmonella paratyphi B/imunologia , Vacinas Tíficas-Paratíficas/imunologia , Animais , Chile , Modelos Animais de Doenças , Camundongos , Salmonella paratyphi B/genética , Salmonella paratyphi B/patogenicidade , Análise de Sobrevida , Resultado do Tratamento , Vacinas Tíficas-Paratíficas/administração & dosagem , Vacinas Tíficas-Paratíficas/genética , Vacinas Tíficas-Paratíficas/isolamento & purificação , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/isolamento & purificação , Sequenciamento Completo do GenomaRESUMO
Past research has focused on typhoid fever surveillance with little attention to implementation methods or effectiveness of control interventions. This study purposefully sampled key informants working in public health in Chile, India, Pakistan, Bangladesh, Thailand, Vietnam, South Africa, and Nigeria to 1) scope typhoid-relevant interventions implemented between 1990 and 2015 and 2) explore contextual factors perceived to be associated with their implementation, based on the Consolidated Framework for Implementation Research (CFIR). We used a mixed methods design and collected quantitative data (CFIR questionnaire) and qualitative data (interviews with 34 public health experts). Interview data were analyzed using a deductive qualitative content analysis and summary descriptive statistics are provided for the CFIR data. Despite relatively few typhoid-specific interventions reportedly implemented in these countries, interventions for diarrheal disease control and regulations for food safety and food handlers were common. Most countries implemented agricultural and sewage treatment practices, yet few addressed the control of antibiotic medication. Several contextual factors were perceived to have influenced the implementation of typhoid interventions, either as enablers (e.g., economic development) or barriers (e.g., limited resources and habitual behaviors). Consolidated Framework for Implementation Research factors rated as important in the implementation of typhoid interventions were remarkably consistent across countries. The findings provide a snapshot of typhoid-relevant interventions implemented over 25 years and highlight factors associated with implementation success from the perspective of a sample of key informants. These findings can inform systematic investigations of the implementation of typhoid control interventions and contribute to a better understanding of the direct effects of implementation efforts.
Assuntos
Administração em Saúde Pública/economia , Febre Tifoide/economia , Febre Tifoide/prevenção & controle , Antibacterianos/administração & dosagem , Ásia/epidemiologia , Butanonas , Chile/epidemiologia , Feminino , Indústria Alimentícia/legislação & jurisprudência , Microbiologia de Alimentos , Humanos , Masculino , Modelos Biológicos , Nigéria/epidemiologia , Fenóis , Saneamento , Esgotos , África do Sul/epidemiologia , Febre Tifoide/epidemiologia , Vacinas Tíficas-Paratíficas/administração & dosagem , Vacinas Tíficas-Paratíficas/imunologiaRESUMO
Typhoid vaccination is an important component of typhoid fever prevention and control, and is recommended for public health programmatic use in both endemic and outbreak settings. We reviewed experiences with various vaccination strategies using the currently available typhoid vaccines (injectable Vi polysaccharide vaccine [ViPS], oral Ty21a vaccine, and injectable typhoid conjugate vaccine [TCV]). We assessed the rationale, acceptability, effectiveness, impact and implementation lessons of these strategies to inform effective typhoid vaccination strategies for the future. Vaccination strategies were categorized by vaccine disease control strategy (preemptive use for endemic disease or to prevent an outbreak, and reactive use for outbreak control) and vaccine delivery strategy (community-based routine, community-based campaign and school-based). Almost all public health typhoid vaccination programs used ViPS vaccine and have been in countries of Asia, with one example in the Pacific and one experience using the Ty21a vaccine in South America. All vaccination strategies were found to be acceptable, feasible and effective in the settings evaluated; evidence of impact, where available, was strongest in endemic settings and in the short- to medium-term. Vaccination was cost-effective in high-incidence but not low-incidence settings. Experience in disaster and outbreak settings remains limited. TCVs have recently become available and none are WHO-prequalified yet; no program experience with TCVs was found in published literature. Despite the demonstrated success of several typhoid vaccination strategies, typhoid vaccines remain underused. Implementation lessons should be applied to design optimal vaccination strategies using TCVs which have several anticipated advantages, such as potential for use in infant immunization programs and longer duration of protection, over the ViPS and Ty21a vaccines for typhoid prevention and control.
Assuntos
Programas de Imunização , Febre Tifoide/prevenção & controle , Vacinas Tíficas-Paratíficas/administração & dosagem , Ásia/epidemiologia , Criança , Pré-Escolar , Análise Custo-Benefício , Surtos de Doenças/economia , Surtos de Doenças/prevenção & controle , Humanos , Lactente , Polissacarídeos Bacterianos/administração & dosagem , América do Sul/epidemiologia , Febre Tifoide/imunologia , Vacinas Tíficas-Paratíficas/imunologia , Vacinação/economiaRESUMO
The proteoliposome derived from Vibrio cholerae O1 (PLc) is a nanoscaled structure obtained by a detergent extraction process. Intranasal (i.n) administration of PLc was immunogenic at mucosal and systemic level vs. V. cholerae; however the adjuvant potential of this structure for non-cholera antigens has not been proven yet. The aim of this work was to evaluate the effect of coadministering PLc with the Vi polysaccharide antigen (Poli Vi) of S. Typhi by the i.n route. The results showed that Poli Vi coadministered with PLc (PLc+Poli Vi) induce a higher IgA response in saliva (p<0.01) and faeces (p<0.01) than Poli Vi administered alone. Likewise, the IgG response in sera was higher in animals immunised with PLc+Poli Vi (p<0.01). Furthermore, IgG induced in sera of mice immunised with PLc+Poli Vi was similar (p>0.05) to that induced in a group of mice immunised by the parenteral route with the Cuban anti-typhoid vaccine vax-TyVi, although this vaccine did not induce a mucosal response. In conclusion, this work demonstrates that PLc can be used as a mucosal adjuvant to potentiate the immune response against a polysaccharide antigen like Poli Vi.
Assuntos
Adjuvantes Imunológicos , Polissacarídeos Bacterianos/imunologia , Proteolipídeos/imunologia , Salmonella typhi/imunologia , Febre Tifoide/imunologia , Vacinas Tíficas-Paratíficas/imunologia , Vibrio cholerae O1/imunologia , Adjuvantes Imunológicos/administração & dosagem , Administração Intranasal , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Fezes , Feminino , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Polissacarídeos Bacterianos/administração & dosagem , Proteolipídeos/administração & dosagem , Saliva/imunologia , Febre Tifoide/prevenção & controle , Vacinas Tíficas-Paratíficas/administração & dosagemRESUMO
In this study, we assessed the effectiveness of a live, attenuated Salmonella enterica serovar Typhi (S. Typhi) vaccine strain as a cancer immunotherapy in a mouse model of metastatic T-cell lymphoma. EL4 tumor-bearing C57BL/6J mice immunized with S. Typhi strain CVD 915, by injection into the tumor and the draining lymph node areas, displayed a significant decrease in tumor growth, a reduction in the mitotic index (MI) of tumors, a delayed development of palpable lymph node metastases and most importantly improved survival, compared to untreated mice. Besides, complete tumor regression was achieved in a small number of bacteria-treated mice. A successful therapeutic response associated with a significant reduction of tumor mass was evident as early as 5 days after treatment. The administration of Salmonella to tumor-bearing mice promoted early cellular infiltration (mainly neutrophils) within the tumor, and was accompanied by a decreased intratumoral interleukin 10 production as well as by leukocyte expansion in tumor draining lymph nodes. A tumor-specific memory immune response was induced in most of cured animals, as evidenced by the lack of tumor growth after a rechallenge with the same tumor. EL4 cells cultured with live Salmonella failed to proliferate and underwent apoptosis in a dose-dependent, time-dependent, and contact-dependent manner. To our knowledge, these results demonstrate for the first time the efficacy of a S. Typhi vaccine strain as an oncolytic and immunotherapeutic agent against a highly malignant tumor and support the use of S. Typhi-based vaccine strains in cancer therapy.
Assuntos
Imunoterapia/métodos , Linfoma de Células T/terapia , Salmonella typhi/imunologia , Vacinas Tíficas-Paratíficas/uso terapêutico , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Interleucina-10/biossíntese , Linfonodos/imunologia , Metástase Linfática/prevenção & controle , Linfoma de Células T/imunologia , Linfoma de Células T/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Índice Mitótico , Vacinas Tíficas-Paratíficas/imunologia , Vacinas Atenuadas/uso terapêuticoRESUMO
In randomized, controlled field trials in Area Norte and Area Occidente of Santiago, Chile, 2 (Norte) or 3 (Occidente) doses of live oral typhoid vaccine Ty21a in enteric-coated capsules conferred protection against confirmed Salmonella enterica serovar Typhi disease (53% efficacy in Norte; 67% efficacy in Occidente) during 3 years of follow-up. There was also a trend in each trial showing protection against S. enterica serovar Paratyphi B disease (56% efficacy in Norte; 42% efficacy in Occidente). To enhance statistical power, an analysis was performed using pooled data from the 2 trials; this pooling of data was justified by the following facts: epidemiologic surveillance and microbiological methods were identical, the trials overlapped during 22 of the 36 months of follow-up in each trial, the estimates of efficacy against paratyphoid B fever in the 2 trials were roughly similar, and the ratio of follow-up of vaccine recipients to control subjects in both trials was ~1 : 1. In the pooled analysis, Ty21a conferred significant protection against paratyphoid B fever (efficacy, 49%; 95% confidence interval, 8%-73%; P=.019).
Assuntos
Febre Paratifoide/prevenção & controle , Polissacarídeos Bacterianos/uso terapêutico , Salmonella paratyphi B/imunologia , Vacinas Tíficas-Paratíficas/uso terapêutico , Administração Oral , Adolescente , Adulto , Criança , Pré-Escolar , Chile/epidemiologia , Relação Dose-Resposta Imunológica , Humanos , Esquemas de Imunização , Incidência , Vacinação em Massa , Febre Paratifoide/imunologia , Polissacarídeos Bacterianos/imunologia , Salmonella paratyphi A/imunologia , Resultado do Tratamento , Vacinas Tíficas-Paratíficas/imunologia , Vacinas Atenuadas/uso terapêuticoRESUMO
A randomized, controlled, double blind study was carried out in Cuban children and teenagers aged 9-13 years to evaluate the immunogenicity of vax-TyVi-Salmonella Typhi Vi polysaccharide vaccine-with respect control vaccines. Serum samples were taken before and 21 days after the immunization, and ELISA was used for the determination of antibodies to Vi polysaccharide. Subjects who received vax-TyVi and TYPHIM Vi (Pasteur-Mérieux) showed seroconversion rates of 85.61 and 78.36%, respectively. The geometric mean titer (GMT) values for Vi antibodies induced after vaccination were 6.27 microg/ml (5.40-7.38 microg/ml) and 5.97 microg/ml (5.01-7.10 microg/ml), respectively. In contrast, subjects receiving the tetanus toxoid vaccine showed 0% seroconversion.