RESUMO
BACKGROUND: Case-control studies to quantify oral cholera vaccine effectiveness (VE) often rely on neighbors without diarrhea as community controls. Test-negative controls can be easily recruited and may minimize bias due to differential health-seeking behavior and recall. We compared VE estimates derived from community and test-negative controls and conducted bias-indicator analyses to assess potential bias with community controls. METHODS: From October 2012 through November 2016, patients with acute watery diarrhea were recruited from cholera treatment centers in rural Haiti. Cholera cases had a positive stool culture. Non-cholera diarrhea cases (test-negative controls and non-cholera diarrhea cases for bias-indicator analyses) had a negative culture and rapid test. Up to four community controls were matched to diarrhea cases by age group, time, and neighborhood. RESULTS: Primary analyses included 181 cholera cases, 157 non-cholera diarrhea cases, 716 VE community controls and 625 bias-indicator community controls. VE for self-reported vaccination with two doses was consistent across the two control groups, with statistically significant VE estimates ranging from 72 to 74%. Sensitivity analyses revealed similar, though somewhat attenuated estimates for self-reported two dose VE. Bias-indicator estimates were consistently less than one, with VE estimates ranging from 19 to 43%, some of which were statistically significant. CONCLUSIONS: OCV estimates from case-control analyses using community and test-negative controls were similar. While bias-indicator analyses suggested possible over-estimation of VE estimates using community controls, test-negative analyses suggested this bias, if present, was minimal. Test-negative controls can be a valid low-cost and time-efficient alternative to community controls for OCV effectiveness estimation and may be especially relevant in emergency situations.
Assuntos
Vacinas contra Cólera/imunologia , Cólera/imunologia , Cólera/prevenção & controle , Administração Oral , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Diarreia/imunologia , Diarreia/prevenção & controle , Feminino , Haiti , Humanos , Masculino , Pessoa de Meia-Idade , População Rural , Vacinação/métodos , Adulto JovemRESUMO
BACKGROUND: In mass vaccination campaigns, large volumes of data must be managed efficiently and accurately. In a reactive oral cholera vaccination (OCV) campaign in rural Haiti during an ongoing epidemic, we used a mobile health (mHealth) system to manage data on 50,000 participants in two isolated communities. METHODS: Data were collected using 7-inch tablets. Teams pre-registered and distributed vaccine cards with unique barcodes to vaccine-eligible residents during a census in February 2012. First stored on devices, data were uploaded nightly via Wi-fi to a web-hosted database. During the vaccination campaign between April and June 2012, residents presented their cards at vaccination posts and their barcodes were scanned. Vaccinee data from the census were pre-loaded on tablets to autopopulate the electronic form. Nightly analysis of the day's community coverage informed the following day's vaccination strategy. We generated case-finding reports allowing us to identify those who had not yet been vaccinated. RESULTS: During 40 days of vaccination, we collected approximately 1.9 million pieces of data. A total of 45,417 people received at least one OCV dose; of those, 90.8% were documented to have received 2 doses. Though mHealth required up-front financial investment and training, it reduced the need for paper registries and manual data entry, which would have been costly, time-consuming, and is known to increase error. Using Global Positioning System coordinates, we mapped vaccine posts, population size, and vaccine coverage to understand the reach of the campaign. The hardware and software were usable by high school-educated staff. CONCLUSION: The use of mHealth technology in an OCV campaign in rural Haiti allowed timely creation of an electronic registry with population-level census data, and a targeted vaccination strategy in a dispersed rural population receiving a two-dose vaccine regimen. The use of mHealth should be strongly considered in mass vaccination campaigns in future initiatives.
Assuntos
Vacinas contra Cólera/administração & dosagem , Cólera/epidemiologia , Cólera/prevenção & controle , Telemedicina/organização & administração , Vacinação/métodos , Vacinação/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Cólera/imunologia , Feminino , Haiti/epidemiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , População Rural , Adulto JovemRESUMO
Two cholera vaccines, sold as Shanchol and Dukoral, are currently available. This review presents a critical analysis of the protective efficacies of these vaccines. Children under 5 years of age are very vulnerable to cholera and account for the highest incidence of cholera cases and more than half of the resulting deaths. Both Shanchol and Dukoral are two-spaced-dose oral vaccines comprising large numbers of killed cholera bacteria. The former contains Vibrio cholerae O1 and O139 cells, and the latter contains V. cholerae O1 cells with the recombinant B subunit of cholera toxin. In a field trial in Kolkata (India), Shanchol, the preferred vaccine, protected 45% of the test subjects in all of the age groups and only 17% of the children under 5 years of age during the first year of surveillance. In a field trial in Peru, two spaced doses of Dukoral offered negative protection in children under 5 years of age and little protection (15%) in vaccinees over 6 years of age during the first year of surveillance. Little is known about Dukoral's long-term protective efficacy. Both of these vaccines have questionable compositions, using V. cholerae O1 strains isolated in 1947 that have been inactivated by heat and formalin treatments that may denature protein. Immunological studies revealed Dukoral's reduced and short-lived efficacy, as measured by several immunological endpoints. Various factors, such as the necessity for multiple doses, poor protection of children under 5 years of age, the requirement of a cold supply chain, production costs, and complex logistics of vaccine delivery, greatly reduce the suitability of either of these vaccines for endemic or epidemic cholera control in resource-poor settings.
Assuntos
Vacinas contra Cólera/imunologia , Cólera/prevenção & controle , Administração Oral , Cólera/imunologia , Vacinas contra Cólera/administração & dosagem , Ensaios Clínicos como Assunto , Humanos , Índia , Peru , Resultado do Tratamento , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologiaRESUMO
BACKGROUND: Studies of the immunogenicity of the killed bivalent whole cell oral cholera vaccine, Shanchol, have been performed in historically cholera-endemic areas of Asia. There is a need to assess the immunogenicity of the vaccine in Haiti and other populations without historical exposure to Vibrio cholerae. METHODOLOGY/PRINCIPAL FINDINGS: We measured immune responses after administration of Shanchol, in 25 adults, 51 older children (6-17 years), and 47 younger children (1-5 years) in Haiti, where cholera was introduced in 2010. A≥4-fold increase in vibriocidal antibody titer against V. cholerae O1 Ogawa was observed in 91% of adults, 74% of older children, and 73% of younger children after two doses of Shanchol; similar responses were observed against the Inaba serotype. A≥2-fold increase in serum O-antigen specific polysaccharide IgA antibody levels against V. cholerae O1 Ogawa was observed in 59% of adults, 45% of older children, and 61% of younger children; similar responses were observed against the Inaba serotype. We compared immune responses in Haitian individuals with age- and blood group-matched individuals from Bangladesh, a historically cholera-endemic area. The geometric mean vibriocidal titers after the first dose of vaccine were lower in Haitian than in Bangladeshi vaccinees. However, the mean vibriocidal titers did not differ between the two groups after the second dose of the vaccine. CONCLUSIONS/SIGNIFICANCE: A killed bivalent whole cell oral cholera vaccine, Shanchol, is highly immunogenic in Haitian adults and children. A two-dose regimen may be important in Haiti, and other populations lacking previous repeated exposures to V. cholerae.
Assuntos
Vacinas contra Cólera/imunologia , Cólera/prevenção & controle , Vibrio cholerae O139/imunologia , Vibrio cholerae O1/imunologia , Adolescente , Adulto , Anticorpos Antibacterianos/sangue , Carga Bacteriana/efeitos dos fármacos , Criança , Pré-Escolar , Cólera/epidemiologia , Cólera/imunologia , Vacinas contra Cólera/administração & dosagem , Epidemias , Feminino , Haiti , Humanos , Lactente , Masculino , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia , Adulto JovemRESUMO
No commercially live vaccine against cholera caused by Vibrio cholerae O139 serogroup is available and it is currently needed. Virulent O139 strain CRC266 was genetically modified by firstly deleting multiple copies of the filamentous phage CTXφ, further tagging by insertion of the endoglucanase A coding gene from Clostridium thermocellum into the hemagglutinin/protease gene and finally deleting the mshA gene, just to improve the vaccine biosafety. One of the derived strains designated as TLP01 showed full attenuation and good colonizing capacity in the infant mouse cholera model, as well as highly immunogenic properties in the adult rabbit and rat models. Since TLP01 lacks MSHA fimbriae, it is refractory to infection with another filamentous phage VGJφ and therefore protected of acquiring CTXφ from a recombinant hybrid VGJφ/CTXφ. This strategy could reduce the possibilities of stable reversion to virulence out of the human gut. Furthermore, this vaccine strain was impaired to produce biofilms under certain culture conditions, which might have implications for the strain survival in natural settings contributing to vaccine biosafety as well. The above results has encouraged us to consider TLP01 as a live attenuated vaccine strain having an adequate performance in animal models, in terms of attenuation and immunogenicity, so that it fulfills the requirements to be evaluated in human volunteers.
Assuntos
Vacinas contra Cólera/imunologia , Proteínas de Fímbrias/imunologia , Vibrio cholerae O139/imunologia , Administração Oral , Animais , Anticorpos Antibacterianos/imunologia , Derrame de Bactérias , Sequência de Bases , Biofilmes , Cólera/imunologia , Cólera/prevenção & controle , Vacinas contra Cólera/genética , Vacinas contra Cólera/farmacologia , Modelos Animais de Doenças , Fezes/microbiologia , Proteínas de Fímbrias/genética , Mucosa Intestinal/imunologia , Lectina de Ligação a Manose/genética , Lectina de Ligação a Manose/imunologia , Dados de Sequência Molecular , Coelhos , Ratos , Ratos Sprague-Dawley , Alinhamento de Sequência , Deleção de Sequência/genética , Estatísticas não Paramétricas , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/farmacologia , Vibrio cholerae O139/genéticaRESUMO
On October 20, 2010, an outbreak of cholera was confirmed in Haiti for the first time in more than a century. As of April 10, 2012, a total of 534,647 cases, 287,656 hospitalizations, and 7,091 deaths have been reported in Haiti as a result of the outbreak. The Vibrio cholerae strain that caused the Haiti epidemic has been characterized as toxigenic V. cholerae, serogroup O1, serotype Ogawa, biotype El Tor.
Assuntos
Cólera/virologia , Vibrio cholerae O1/classificação , Vibrio cholerae O1/isolamento & purificação , Cólera/epidemiologia , Cólera/imunologia , Reações Cruzadas , DNA Viral/análise , Surtos de Doenças , Eletroforese em Gel de Campo Pulsado , Haiti/epidemiologia , Humanos , Análise de Sequência de DNA , Sorotipagem , Sequências de Repetição em Tandem , Vibrio cholerae O1/patogenicidadeRESUMO
The aim of this work was to evaluate the microencapsulation by spray-drying of inactivated Vibrio cholerae, using methacrylic copolymers Eudragit® L30D-55 and FS30D. The microparticles obtained presented a particle size around 3.0 µm. The preparation temperature affected the morphology and the antigenicity of microparticles, but it did not affect the V. cholerae content. In vitro release studies showed that in acid medium less than 5% of bacteria was released, and in neutral medium, Eudragit® L30D-55 microparticles released 86% after 24 h, whereas FS30D released less than 30%. Rats inoculated with microparticles exhibited vibriocidal antibody titres. Microencapsulation by spray-drying of inactivated V. cholerae could be proposed as a method to obtain an oral vaccine which provides controlled release of the bacteria.
Assuntos
Vacinas contra Cólera/administração & dosagem , Vacinas contra Cólera/imunologia , Cólera/imunologia , Vibrio cholerae/imunologia , Administração Oral , Animais , Cólera/prevenção & controle , Dessecação , Composição de Medicamentos , Viabilidade Microbiana/imunologia , Microesferas , Ácidos Polimetacrílicos , Ratos , Vacinas de Produtos Inativados/imunologiaRESUMO
This paper presents a mathematical model for cholera epidemics which comprises seasonality, loss of host immunity, and control mechanisms acting to reduce cholera transmission. A collection of data related to cholera disease allows us to show that outbreaks in endemic areas are subject to a resonant behavior, since the intrinsic oscillation period of the disease (â¼1 year) is synchronized with the annual contact rate variation. Moreover, we argue that the short period of the host immunity may be associated to secondary peaks of incidence observed in some regions (a bimodal pattern). Finally, we explore some possible mechanisms of cholera control, and analyze their efficiency. We conclude that, besides mass vaccination--which may be impracticable--improvements in sanitation system and food/personal hygiene are the most effective ways to prevent an epidemic.
Assuntos
Cólera/epidemiologia , Cólera/imunologia , Epidemias , Cólera/prevenção & controle , Cólera/transmissão , Humanos , Conceitos Matemáticos , Modelos Biológicos , Estações do AnoRESUMO
Epidemics of severe dehydrating cholera are on the increase in resource-limited settings around the world. Adults, children and young infants are all at risk of these infections. Considerable efforts have been made for the development of safe and efficacious oral cholera vaccines over the last three decades. Whole-cell-inactivated as well as live oral cholera vaccines have been developed and tested in different field settings to determine the efficacy and/or effectiveness of such vaccines for reducing life-threatening disease. This review follows the trail of the development of CholeraGarde, a live-attenuated Vibrio cholerae O1 vaccine candidate of the El Tor biotype and Inaba serotype. CholeraGarde, also well known as Peru-15, was derived from V. cholerae O1 strain C6709, a clinical isolate from Peru. The vaccine has now been tested in over 500 individuals, adults and children and shows a good safety and immunogenicity profile. At a dose of around 10(8) CFU, it is immunogenic in adults in the USA, as well as in adults, children and infants in Bangladesh. The vaccine has been tested in infants of 9 months of age where a single 10(8) CFU dose was safe and immunogenic while a tenfold lower dose was not. Excretion of the strain was higher in adults in the USA and low in Bangladeshi participants in all age groups. Phase II studies of CholeraGarde are ongoing in cholera-endemic countries to concomitantly administer it to infants with the parenteral measles vaccine. Studies on HIV-positive individuals are also ongoing to determine safety, immunogenicity and contraindications, if any. Phase III studies are being targeted to determine the protective efficacy of CholeraGarde and for further development of a single-dose vaccine that will protect infants and also other age groups from endemic and epidemic cholera.
Assuntos
Vacinas contra Cólera , Cólera/prevenção & controle , Vacinas Atenuadas , Vibrio cholerae O1/imunologia , Administração Oral , Adulto , Anticorpos Antibacterianos/sangue , Bangladesh/epidemiologia , Criança , Cólera/epidemiologia , Cólera/imunologia , Vacinas contra Cólera/administração & dosagem , Vacinas contra Cólera/efeitos adversos , Vacinas contra Cólera/imunologia , Ensaios Clínicos como Assunto , Desenho de Fármacos , Humanos , Lactente , Resultado do Tratamento , Estados Unidos/epidemiologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologiaRESUMO
A randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the safety, reactogenicity and the immunogenicity of a 2 x 10(9)CFU dose of the 638 lyophilized live attenuated cholera vaccine for oral administration, formulated and produced at Finlay Institute, City of Havana, Cuba. Thirty-six healthy female and male adult volunteers from 18 to 40 years old were involved, clinically examined and laboratory tested after the informed consent signature. Adverse events were monitored and seroconversion rates and geometrical mean titer (GMT) of vibriocidal antibodies were tested in volunteer's sera samples. Neither serious adverse events nor other damages to the volunteers due to vaccine or placebo feeding were reported during the clinical follow-up period of this study; none of the adverse events registered within the first 72 h after inoculation were life-threatening for volunteers. Neither severe nor moderate adverse events were reported. Sixty-one percent of subjects showed mild expected adverse events in an interval lower than 24h up to the first 72 h, 75% of these in the vaccinated group and 18% in the placebo group. Fourteen days after inoculation the GMT of vibriocidal antibodies in the vaccine group significantly increased in comparison to the placebo group. All subjects in the vaccine group (24) seroconverted (100%). Results show that this vaccine is safe, well tolerated and immunogenic in healthy female and male volunteers.
Assuntos
Vacinas contra Cólera/administração & dosagem , Cólera/prevenção & controle , Administração Oral , Adolescente , Adulto , Anticorpos Antibacterianos/sangue , Cólera/imunologia , Vacinas contra Cólera/efeitos adversos , Vacinas contra Cólera/imunologia , Cuba , Método Duplo-Cego , Feminino , Humanos , Masculino , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia , Adulto JovemRESUMO
A vaccine candidate against the enteric pathogen Vibrio cholerae was developed based on a proteoliposome (PL) formulation using a wild type strain C7258, V. cholerae O1, El Tor Ogawa as part of strategy to develop a combined formulation against enteric diseases preventable by the stimulation of the mucosal immune system. A detergent extraction method was applied to obtain the PL. Scanning electron microscopy and molecular exclusion chromatography showed the presence of two PL populations. Photon correlation spectroscopy studies were then carried out to evaluate the size (169.27+/-3.85nm), polydispersity (0.410) and zeta potential (-23.28+/-1.21mV) of the PL. SDS-PAGE and Western blot analysis revealed the presence of lipopolysaccharide (LPS), mannose-sensitive haemagglutinin (MSHA) and a range of outer membrane proteins, including OmpU. BALB/c mice were immunized intranasally with two doses of PL containing 25mug of LPS each 28 days apart. The mice showed high anti-LPS IgG titres (3.36+/-0.235) and vibriocidal antibodies (3.70+/-0.23) after two weeks from last dose. These results show for the first time that PL can be obtained from V. cholerae O1 and when administer by intranasal route has the potential to protect against this pathogen.
Assuntos
Anticorpos Antibacterianos/sangue , Proteínas da Membrana Bacteriana Externa/imunologia , Vacinas contra Cólera , Cólera/prevenção & controle , Proteolipídeos/administração & dosagem , Vibrio cholerae O1/imunologia , Administração Intranasal , Animais , Cólera/imunologia , Vacinas contra Cólera/administração & dosagem , Vacinas contra Cólera/imunologia , Feminino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
BACKGROUND AND AIMS: A live attenuated vaccine candidate against human cholera has been developed from the genetically modified Vibrio cholerae O1, biotype El Tor, serotype Ogawa, 638 strain. Previous single dose toxicity and local tolerance studies have demonstrated that the product is innocuous in Sprague Dawley rats by oral route and single dose. The present paper describes a repeated dose toxicity study using a further dose compared to the proposed clinical schedule. METHODS: Sprague Dawley rats (140-180g) were treated with two doses of the vaccine candidate with a dedicated placebo formulation or were not treated at all (controls). The test products were inoculated at a 21-day interval. Animals were observed daily, body weight was determined weekly and food and water intakes were measured every other day. Three and 14 days after the last inoculation, groups of rats were humanely sacrificed, bled and macroscopically examined. Blood samples were taken for hematology, serum biochemistry and to determine the vibriocide antibody titers. A comprehensive list of tissue and organ samples was taken for microscopic studies. RESULTS: There was no mortality and no animal showed any clinical symptoms. Food and water intake, body weight, and hematological and biochemical variables did not show differences of toxicological and/or statistical relevance among the experimental groups. Macroscopic examination did not demonstrate any alterations and there were no histological findings of toxicological significance. CONCLUSIONS: The vaccine was considered potentially safe for human use as indicated by the results in Sprague Dawley rats.
Assuntos
Vacinas contra Cólera/toxicidade , Cólera/prevenção & controle , Vacinas Atenuadas/toxicidade , Animais , Cólera/imunologia , Vacinas contra Cólera/imunologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Placebos , Gravidez , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Vacinas Atenuadas/imunologiaRESUMO
The immunomodulating properties of a low cholera toxin (CT) dose over the systemic antibody response against Vibrio cholerae antigens after a comparatively extensive period of time were evaluated. Groups of 10 mice were injected intraperitoneally three times at 0, 30 and 86 days with 500 microl of buffer or 10(8) viable recombinant V. cholerae bacteria (lacking cholera toxin A subunit) with or without 100 ng of CT. Sera were obtained from inoculated mice at 0, 14, 28, 37, 58, 80, 93, 114, 236 and 356 days after the first injection. Vibriocidal activity and IgM and IgG anti-lipopolysaccharide (LPS) or outer membrane protein (OMP) antibodies levels were estimated by ELISA in sera of inoculated mice. Anti-LPS IgG subclasses were measured 2 weeks after each immunization by ELISA. Treatment of mice with CT markedly influenced the immune response to LPS but not against OMP of V. cholerae. Simultaneous intraperitoneal administration of CT with V. cholerae resulted in marked enhancement of both IgM anti-LPS and vibriocidal titers which subsisted for a relatively extensive period of time after repeated antigen administration. No differences were observed in IgM and IgG anti-OMP titers after extended periods of time between CT and control treatments. A similar pattern of IgG anti-LPS subclasses was observed in the serum samples analyzed. These results suggest that long term CT administration modulates the IgM anti-V. cholerae LPS response and the serum vibriocidal activity.
Assuntos
Anticorpos Antibacterianos/sangue , Proteínas da Membrana Bacteriana Externa/imunologia , Toxina da Cólera/administração & dosagem , Toxina da Cólera/imunologia , Cólera/imunologia , Lipopolissacarídeos/imunologia , Administração Oral , Animais , Anticorpos Antibacterianos/imunologia , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Injeções Intraperitoneais , Injeções Subcutâneas , Camundongos , Vibrio cholerae/imunologiaRESUMO
Recent work has provided new insights into the pathogenesis of the potentially life-threatening diarrheas caused by Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC): a new mechanism (post-translational degradation), which is involved in the control of cholera toxin expression, has been discovered. Recent evidence also suggests that vibrios upregulate cholera toxin expression in response to intestinal fluid components, and enterotoxin-carrying bacterial outer membrane vesicles might have a function in ETEC pathogenesis. An important role of the environment is supported by the correlation between cholera incidence and elevated sea surface temperature, which supports the notion that the zooplankton is a V. cholerae reservoir. Additionally, environmental lytic cholera phages could influence cholera seasonality by 'terminating' the seasonal epidemic. Finally, the strong herd immunity elicited by an oral cholera vaccine indicates that cholera vaccination could have a significant public health impact.
Assuntos
Vacinas Bacterianas/imunologia , Cólera/microbiologia , Cólera/prevenção & controle , Diarreia/microbiologia , Diarreia/prevenção & controle , Escherichia coli/patogenicidade , Vibrio cholerae/patogenicidade , Fatores de Virulência/metabolismo , Animais , Cólera/epidemiologia , Cólera/imunologia , Diarreia/imunologia , Diarreia/metabolismo , Escherichia coli/fisiologia , Humanos , Vibrio cholerae/fisiologia , Fatores de Virulência/genéticaRESUMO
El presente artículo muestra cómo la humanidad se enfrenta a nuevos agentes patógenos (emergentes) y a otros, ya conocidos, pero que en los últimos años han aumentado su mortalidad (reemergentes). Hasta dónde la mano del hombre es responsable de éste fenómeno?La segunda parte pretende analizar los diferentes factores, sociales, políticos, morales y económicos, que incidieron para que el S.I.D.A apareciera, no como epidemia, sino como pandemia y cómo los intereses económicos primaron sobre las políticas de salud, al precio de millones de vidas.