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Enterotoxigenic Escherichia coli (ETEC) is the most prevalent bacterial pathogen causing young children to suffer acute watery diarrhea in Low- and Middle-Income Countries (LMICs) [...].
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Enterotoxigenic Escherichia coli (ETEC) is one of the leading bacterial causes of diarrhoea, especially among children in low-resource settings, and travellers and military personnel from high-income countries. WHO's primary strategic goal for ETEC vaccine development is to develop a safe, effective, and affordable ETEC vaccine that reduces mortality and morbidity due to moderate-to-severe diarrhoeal disease in infants and children under 5 years of age in LMICs, as well as the long-term negative health impact on infant physical and cognitive development resulting from infection with this enteric pathogen. An effective ETEC vaccine will also likely reduce the need for antibiotic treatment and help limit the further emergence of antimicrobial resistance bacterial pathogens. The lead ETEC vaccine candidate, ETVAX, has shown field efficacy in travellers and has moved into field efficacy testing in LMIC infants and children. A Phase 3 efficacy study in LMIC infants is projected to start in 2024 and plans for a Phase 3 trial in travellers are under discussion with the U.S. FDA. Licensing for both travel and LMIC indications is projected to be feasible in the next 5-8 years. Given increasing recognition of its negative impact on child health and development in LMICs and predominance as the leading etiology of travellers' diarrhoea (TD), a standalone vaccine for ETEC is more cost-effective than vaccines targeting other TD pathogens, and a viable commercial market also exists. In contrast, combination of an ETEC vaccine with other vaccines for childhood pathogens in LMICs would maximize protection in a more cost-effective manner than a series of stand-alone vaccines. This 'Vaccine Value Profile' (VVP) for ETEC is intended to provide a high-level, holistic assessment of available data to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public private partnerships, and multi-lateral organizations. All contributors have extensive expertise on various elements of the ETEC VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.
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Disentería , Escherichia coli Enterotoxigénica , Infecciones por Escherichia coli , Vacunas contra Escherichia coli , Preescolar , Humanos , Diarrea , LactanteRESUMEN
Oral immunization is an effective strategy for inducing protective immunity against mucosal enteric pathogens. Although live-attenuated as well as subunit approaches have been explored for vaccination against enteric pathogens, inactivated whole bacterial cells may also be effective in introducing protective immunity. Successfully accomplishing this goal with inactivated whole bacterial cells will require that a complex antigenic repertoire be presented in controlled immunogenic amounts, in a safe and relatively simple and self-contained delivery format. The benefit from immunization with whole cell vaccines can be further enhanced through genetic engineering to over-express selected antigens and also by the use of mucosal adjuvants to direct a more robust immunologic response. These steps are being taken for the development of ETVAX, the most clinically advanced vaccine candidate against the major enteric pathogen, enterotoxigenic Escherichia coli (ETEC) with significant positive impact.
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Infecciones por Escherichia coli , Vacunas contra Escherichia coli , Humanos , Inmunización , Vacunación , Adyuvantes Inmunológicos , BacteriasRESUMEN
The timelines for developing vaccines against infectious diseases are lengthy, and often vaccines that reach the stage of large phase 3 field trials fail to provide the desired level of protective efficacy. The application of controlled human challenge models of infection and disease at the appropriate stages of development could accelerate development of candidate vaccines and, in fact, has done so successfully in some limited cases. Human challenge models could potentially be used to gather critical information on pathogenesis, inform strain selection for vaccines, explore cross-protective immunity, identify immune correlates of protection and mechanisms of protection induced by infection or evoked by candidate vaccines, guide decisions on appropriate trial endpoints, and evaluate vaccine efficacy. We prepared this report to motivate fellow scientists to exploit the potential capacity of controlled human challenge experiments to advance vaccine development. In this review, we considered available challenge models for 17 infectious diseases in the context of the public health importance of each disease, the diversity and pathogenesis of the causative organisms, the vaccine candidates under development, and each model's capacity to evaluate them and identify correlates of protective immunity. Our broad assessment indicated that human challenge models have not yet reached their full potential to support the development of vaccines against infectious diseases. On the basis of our review, however, we believe that describing an ideal challenge model is possible, as is further developing existing and future challenge models.
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Modelos Biológicos , Desarrollo de Vacunas , Ensayos Clínicos Fase III como Asunto , Control de Enfermedades Transmisibles , Humanos , VacunasRESUMEN
We tested an oral enterotoxigenic Escherichia coli (ETEC) vaccine, ETVAX, consisting of inactivated E. coli overexpressing the most prevalent ETEC colonization factors (CFs) and a toxoid (LCTBA), in Bangladeshi children for capacity to induce mucosal and plasma immune responses against O78 lipopolysaccharide (LPS) expressed on the vaccine strains. The vaccine was given ± double-mutant heat-labile toxin (dmLT) adjuvant. We evaluated the impact of dmLT on anti-O78 LPS immune responses and whether such responses can predict responses against the CFs as a marker for vaccine "take". Two fractionated doses of ETVAX ± different amounts of dmLT were administered biweekly to groups of children 24-59 (n = 125), 12-23 (n = 97) and 6-11 (n = 158) months of age. Immune responses were evaluated in antibody in lymphocyte supernatants (ALS), fecal extracts and plasma. ALS IgA responses against O78 LPS were induced in 44-49% of the children aged 12-59 months. The magnitudes of the ALS responses were significantly higher in children receiving a half-dose (5 × 1010 bacteria) of ETVAX ± dmLT than in placebo recipients. <10% of the vaccinees aged 6-11 months mounted ALS responses against O78 LPS. However, 49% of the infants developed fecal secretory IgA responses which were significantly more frequent in those receiving a quarter-dose (2.5 × 1010 bacteria) of vaccine + dmLT (62%) compared to a quarter-dose alone (36%). Plasma IgA antibody responses were induced in 80% of older children and 36% of infants. The frequencies of O78 LPS responses in plasma and feces were comparable or higher than against the vaccine CFs in infants. Our findings show that ETVAX induced mucosal and systemic immune responses against O78 LPS in all age groups and that dmLT improved intestinal immune responses among infants. These observations may have implications for more successful use of other oral vaccines based on O antigens in children.
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Escherichia coli Enterotoxigénica , Infecciones por Escherichia coli , Proteínas de Escherichia coli , Vacunas contra Escherichia coli , Adolescente , Anticuerpos Antibacterianos , Formación de Anticuerpos , Niño , Humanos , Inmunoglobulina A , Lactante , Vacunas de Productos InactivadosRESUMEN
BACKGROUND: We demonstrated in a randomized placebo-controlled trial that WRSS1, a live oral Shigella sonnei vaccine candidate, is safe in Bangladeshi adults and children, and elicits antigen-specific antibodies. Here, we describe functional antibody and innate immune responses to WRSS1. METHODS: Adults (18-39 years) and children (5-9 years) received 3 doses of 3 × 105 or 3 × 106 colony forming units (CFU) of WRSS1 or placebo, 4 weeks apart; children additionally received 3 × 104 CFU. Blood and stool were collected at baseline and 7 days after each dose. Functional antibodies were measured using serum bactericidal antibody (SBA) assay. Cytokine/chemokine concentrations were measured in lymphocyte cultures. Host defense peptides LL-37, HBD-1, and HD-5 were analyzed in plasma and stool. RESULTS: Children showed increased SBA titers over baseline after the third dose of 3 × 106 CFU (Pâ =â .048). Significant increases of Th-17 and proinflammatory cytokines (TNF-α, G-CSF, MIP-1ß), and reduction of anti-inflammatory and Th2 cytokines (IL-10, IL-13, GM-CSF) were observed in children. Plasma HBD-1 and LL-37 decreased in children after vaccination but were increased/unchanged in adults. CONCLUSIONS: Functional antibodies and Th1/Th17 cytokine responses in children may serve as important indicators of immunogenicity and protective potential of WRSS1. Clinical Trials Registration: NCT01813071.
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Anticuerpos Antibacterianos/sangre , Disentería Bacilar/prevención & control , Inmunidad Innata , Inmunidad Mucosa , Vacunas contra la Shigella/administración & dosificación , Shigella sonnei/inmunología , Adolescente , Adulto , Bangladesh , Niño , Preescolar , Citocinas/sangre , Femenino , Humanos , Masculino , Vacunas Atenuadas , Adulto JovenRESUMEN
BACKGROUND: Enterotoxigenic Escherichia coli causes diarrhoea, leading to substantial mortality and morbidity in children, but no specific vaccine exists. This trial tested an oral, inactivated, enterotoxigenic E coli vaccine (ETVAX), which has been previously shown to be safe and highly immuongenic in Swedish and Bangladeshi adults. We tested the safety and immunogenicity of ETVAX, consisting of four E coli strains overexpressing the most prevalent colonisation factors (CFA/I, CS3, CS5, and CS6) and a toxoid (LCTBA) administered with or without a double-mutant heat-labile enterotoxin (dmLT) as an adjuvant, in Bangladeshi children. METHODS: We did a randomised, double-blind, placebo-controlled, dose-escalation, age-descending, phase 1/2 trial in Dhaka, Bangladesh. Healthy children in one of three age groups (24-59 months, 12-23 months, and 6-11 months) were eligible. Children were randomly assigned with block randomisation to receive either ETVAX, with or without dmLT, or placebo. ETVAX (half [5·5 × 1010 cells], quarter [2·5 × 1010 cells], or eighth [1·25 × 1010 cells] adult dose), with or without dmLT adjuvant (2·5 µg, 5·0 µg, or 10·0 µg), or placebo were administered orally in two doses 2 weeks apart. Investigators and participants were masked to treatment allocation. The primary endpoint was safety and tolerability, assessed in all children who received at least one dose of vaccine. Antibody responses to vaccine antigens, defined as at least a two-times increase in antibody levels between baseline and post-immunisation, were assessed as secondary endpoints. This trial is registered with ClinicalTrials.gov, NCT02531802. FINDINGS: Between Dec 7, 2015, and Jan 10, 2017, we screened 1500 children across the three age groups, of whom 430 were enrolled and randomly assigned to the different treatment groups (130 aged 24-59 months, 100 aged 12-23 months, and 200 aged 6-11 months). All participants received at least one dose of vaccine. No solicited adverse events occurred that were greater than moderate in severity, and most were mild. The most common solicited event was vomiting (ten [8%] of 130 patients aged 24-59 months, 13 [13%] of 100 aged 12-23 months, and 29 [15%] of 200 aged 6-11 months; mostly of mild severity), which appeared related to dose and age. The addition of dmLT did not modify the safety profile. Three serious adverse events occurred but they were not considered related to the study drug. Mucosal IgA antibody responses in lymphocyte secretions were detected against all primary vaccine antigens (CFA/I, CS3, CS5, CS6, and the LCTBA toxoid) in most participants in the two older age groups, whereas such responses to four of the five antigens were less frequent and of lower magnitude in infants aged 6-11 months than in older children. Faecal secretory IgA immune responses were recorded against all vaccine antigens in infants aged 6-11 months. 78 (56%) of 139 infants aged 6-11 months who were vaccinated developed mucosal responses against at least three of the vaccine antigens versus 14 (29%) of 49 of the infants given placebo. Addition of the adjuvant dmLT enhanced the magnitude, breadth, and kinetics (based on number of responders after the first dose of vaccine) of immune responses in infants. INTERPRETATION: The encouraging safety and immunogenicity of ETVAX and benefit of dmLT adjuvant in young children support its further assessment for protective efficacy in children in enterotoxigenic E coli-endemic areas. FUNDING: PATH (Bill & Melinda Gates Foundation and the UK's Department for International Development), the Swedish Research Council, and The Swedish Foundation for Strategic Research.
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Formación de Anticuerpos/inmunología , Escherichia coli Enterotoxigénica/inmunología , Vacunas contra Escherichia coli/efectos adversos , Vacunas contra Escherichia coli/inmunología , Vacunas de Productos Inactivados/efectos adversos , Vacunas de Productos Inactivados/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Administración Oral , Anticuerpos Antibacterianos/inmunología , Bangladesh , Niño , Preescolar , Diarrea/inmunología , Método Doble Ciego , Enterotoxinas/inmunología , Proteínas de Escherichia coli/inmunología , Femenino , Humanos , Inmunización/métodos , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Lactante , MasculinoAsunto(s)
Disentería Bacilar/prevención & control , Infecciones por Escherichia coli/prevención & control , Vacunas contra Escherichia coli/biosíntesis , Vacunas contra la Shigella/biosíntesis , Animales , Congresos como Asunto , Disentería Bacilar/epidemiología , Disentería Bacilar/inmunología , Disentería Bacilar/microbiología , Escherichia coli Enterotoxigénica/efectos de los fármacos , Escherichia coli Enterotoxigénica/inmunología , Escherichia coli Enterotoxigénica/patogenicidad , Infecciones por Escherichia coli/epidemiología , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/microbiología , Vacunas contra Escherichia coli/administración & dosificación , Humanos , Inmunización , México , Shigella/efectos de los fármacos , Shigella/inmunología , Shigella/patogenicidad , Vacunas contra la Shigella/administración & dosificaciónRESUMEN
Shigella sonnei live vaccine candidate, WRSS1, which was previously evaluated in US, Israeli and Thai volunteers, was administered orally to Bangladeshi adults and children to assess its safety, clinical tolerability and immunogenicity. In a randomized, placebo-controlled, dose-escalation, age-descending study, 39 adults (18-39 years) and 64 children (5-9 years) were enrolled. Each adult cohort (n = 13) received one dose of 3x104, or three doses of 3 × 105 or 3 × 106 colony forming unit (CFU) of WRSS1 (n = 10) or placebo (n = 3). Each child cohort (n = 16) received one dose of 3x103, or three doses of 3x104, 3x105, or 3 × 106 CFU WRSS1 (n = 12) or placebo (n = 4). WRSS1 elicited mostly mild and transient reactogenicity events in adults and children. In the 3 × 106 dose group, 50% of the adults shed the vaccine; no shedding was seen in children. At the highest dose, 100% of adults and 40% of children responded with a ≥ 4-fold increase of S. sonnei LPS-specific IgA antibody in lymphocyte supernatant (ALS). At the same dose, 63% of adults and 70% of children seroconverted with IgA to LPS, while in placebo, 33% of adults and 18% of children seroconverted. Both the vaccinees and placebos responded with fecal IgA to LPS, indicating persistent exposure to Shigella infections. In conclusion, WRSS1 was found safe up to 106 CFU dose and immunogenic in adults and children in Bangladesh. These data indicate that live, oral Shigella vaccine candidates, including WRSS1 can potentially be evaluated in toddlers and infants (<2 years of age), who comprise the target population in an endemic environment.
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Anticuerpos Antibacterianos/sangre , Disentería Bacilar/prevención & control , Vacunas contra la Shigella/inmunología , Administración Oral , Adolescente , Adulto , Bangladesh , Niño , Preescolar , Estudios de Cohortes , Relación Dosis-Respuesta Inmunológica , Heces/microbiología , Femenino , Humanos , Esquemas de Inmunización , Inmunogenicidad Vacunal , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Masculino , Vacunas contra la Shigella/administración & dosificación , Shigella sonnei , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunología , Adulto JovenRESUMEN
The safety and immunogenicity of the second generation oral enterotoxigenic Escherichia coli (ETEC) vaccine ETVAX, consisting of inactivated recombinant E. coli strains over-expressing the colonization factors (CFs) CFA/I, CS3, CS5 and CS6 and the heat labile toxoid LCTBA, were evaluated in Bangladeshi volunteers. To enable analysis of antibody responses against multiple vaccine antigens for subsequent use in small sample volumes from children, a sensitive electrochemiluminescence (ECL) assay for analysis of intestine-derived antibody-secreting cell responses using the antibodies in lymphocyte secretions (ALS) assay was established using Meso Scale Discovery technology. Three groups of Bangladeshi adults (nâ¯=â¯15 per group) received two oral doses of ETVAX with or without double mutant LT (dmLT) adjuvant or placebo in the initial part of a randomized, double-blind, placebo-controlled, age-descending, dose-escalation trial. CF- and LTB-specific ALS and plasma IgA responses were analyzed by ECL and/or ELISA. ETVAX was safe and well tolerated in the adults. Magnitudes of IgA ALS responses determined by ECL and ELISA correlated well (râ¯=â¯0.85 to 0.98 for the five primary antigens, Pâ¯<â¯0.001) and ECL was selected as the ALS readout method. ALS IgA responses against each of the primary antigens were detected in 87-100% of vaccinees after the first and in 100% after the second vaccine dose. Plasma IgA responses against different CFs and LTB were observed in 62-93% and 100% of vaccinees, respectively. No statistically significant adjuvant effect of dmLT on antibody responses to any antigen was detected, but the overall antigenic breadth of the plasma IgA response tended to favor the adjuvanted vaccine when responses to 4 or more or 5 vaccine antigens were considered. Responses in placebo recipients were infrequent and mainly detected against single antigens. The promising results in adults supported testing ETVAX in descending age groups of children. ClinicalTrials.gov Identifier: NCT02531802.
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Escherichia coli Enterotoxigénica/inmunología , Infecciones por Escherichia coli/prevención & control , Vacunas contra Escherichia coli/inmunología , Inmunogenicidad Vacunal , Adolescente , Adulto , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Bangladesh/epidemiología , Técnicas Electroquímicas , Ensayo de Inmunoadsorción Enzimática , Vacunas contra Escherichia coli/administración & dosificación , Vacunas contra Escherichia coli/efectos adversos , Femenino , Humanos , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Mediciones Luminiscentes , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
PATH hosted the inaugural Vaccines Against Shigella and Enterotoxigenic Escherichia coli (VASE) Conference in Washington, DC in June 2016, bringing together experts from around the world for a highly collaborative forum to discuss progress in the development of new enteric vaccines. Diarrheal disease and long-term sequelae caused by infections with the bacterial pathogens Shigella and enterotoxigenic E. coli (ETEC) pose a significant public health burden in low-income communities. There are currently no licensed vaccines against these pathogens, and the global health community has recently prioritized their development. The 2016 VASE Conference aimed to accelerate communication and progress among those working in the enteric vaccine field to make Shigella and ETEC vaccines a reality as quickly as possible. Research presented in oral and poster presentations at the VASE Conference covered a range of topics, including: the global burden of disease and public health case for Shigella and ETEC vaccines; current vaccine candidates in development; immunology and host responses to the pathogens; and the rationale for and status of combined Shigella-ETEC vaccine candidates. This article reviews key points and highlighted research presented in each of the plenary conference sessions and poster presentations at the 2016 conference. Planning for the 2018 VASE Conference is underway and will likely provide an important platform for sharing the latest updates on Shigella and ETEC vaccine research efforts and maintaining the momentum for accelerating this work. It is also expected that the VASE Conference will continue to provide a unique opportunity for those in the enteric vaccine field to share ideas, make connections, and create workable plans to make Shigella and ETEC vaccines a reality. (Updates available at: www.vaseconference.org.).
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Congresos como Asunto , Disentería Bacilar/prevención & control , Infecciones por Escherichia coli/prevención & control , Vacunas contra Escherichia coli/inmunología , Vacunas contra la Shigella/inmunología , Diarrea/microbiología , Diarrea/prevención & control , Disentería Bacilar/inmunología , Disentería Bacilar/microbiología , Escherichia coli Enterotoxigénica/inmunología , Infecciones por Escherichia coli/microbiología , Vacunas contra Escherichia coli/administración & dosificación , Humanos , Shigella/inmunología , Vacunas contra la Shigella/administración & dosificación , Vacunas Combinadas/administración & dosificación , Vacunas Combinadas/inmunologíaRESUMEN
BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhea in inhabitants from low-income countries and in visitors to these countries. The impact of the human intestinal microbiota on the initiation and progression of ETEC diarrhea is not yet well understood. RESULTS: We used 16S rRNA (ribosomal RNA) gene sequencing to study changes in the fecal microbiota of 12 volunteers during a human challenge study with ETEC (H10407) and subsequent treatment with ciprofloxacin. Five subjects developed severe diarrhea and seven experienced few or no symptoms. Diarrheal symptoms were associated with high concentrations of fecal E. coli as measured by quantitative culture, quantitative PCR, and normalized number of 16S rRNA gene sequences. Large changes in other members of the microbiota varied greatly from individual to individual, whether or not diarrhea occurred. Nonetheless the variation within an individual was small compared to variation between individuals. Ciprofloxacin treatment reorganized microbiota populations; however, the original structure was largely restored at one and three month follow-up visits. CONCLUSION: Symptomatic ETEC infections, but not asymptomatic infections, were associated with high fecal concentrations of E. coli. Both infection and ciprofloxacin treatment caused variable changes in other bacteria that generally reverted to baseline levels after three months.
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Ciprofloxacina/uso terapéutico , Escherichia coli Enterotoxigénica/efectos de los fármacos , Escherichia coli Enterotoxigénica/fisiología , Infecciones por Escherichia coli/tratamiento farmacológico , Infecciones por Escherichia coli/microbiología , Microbioma Gastrointestinal/efectos de los fármacos , Adulto , Ciprofloxacina/farmacología , Diarrea/tratamiento farmacológico , Diarrea/microbiología , Heces/microbiología , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Metagenoma , Metagenómica/métodos , Persona de Mediana Edad , ARN Ribosómico 16S , Curva ROC , Resultado del Tratamiento , Adulto JovenRESUMEN
The global health community is beginning to gain an understanding of the global burden of norovirus-associated disease, which appears to have significant burden in both developed- and developing-country populations. Of particular importance is the growing recognition of norovirus as a leading cause of gastroenteritis and diarrhea in countries where rotavirus vaccine has been introduced. While not as severe as rotavirus disease, the sheer number of norovirus infections not limited to early childhood makes norovirus a formidable global health problem. This article provides a landscape review of norovirus vaccine development efforts. Multiple vaccine strategies, mostly relying on virus-like particle antigens, are under development and have demonstrated proof of efficacy in human challenge studies. Several are entering phase 2 clinical development. Norovirus vaccine development challenges include, but are not limited to: valency, induction of adequate immune responses in pediatric and elderly populations, and potential for vaccine-strain mismatch. Given current strategies and global health interest, the outlook for a norovirus vaccine is promising. Because a norovirus vaccine is expected to have a dual market in both developed and developing countries, there would likely be scale-up advantages for commercial development and global distribution. Combination with or expression by another enteric pathogen, such as rotavirus, could also enhance uptake of a norovirus vaccine.
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Infecciones por Caliciviridae/prevención & control , Gastroenteritis/prevención & control , Vacunas Virales/uso terapéutico , Animales , Anticuerpos Antivirales/sangre , Investigación Biomédica/tendencias , Ensayos Clínicos como Asunto , Diarrea/prevención & control , Diarrea/virología , Gastroenteritis/virología , Humanos , Norovirus , Vacunas de Partículas Similares a Virus/uso terapéuticoRESUMEN
Enterotoxigenic Escherichia coli (ETEC) is one of the most common bacterial causes of diarrhea-associated morbidity and mortality, particularly among infants and young children in developing countries. Still, the true impact on child and traveler health is likely underestimated. There are currently no licensed vaccines for ETEC, but studies indicate high public health impact, cost-effectiveness, and feasibility of immune protection through vaccination. ETEC vaccine development remains a World Health Organization priority. Traditionally, ETEC vaccine development efforts have focused on inducing antitoxin and anticolonization antigen immunity, as studies indicate that antibodies against both antigen types can contribute to protection and thus have potential for vaccines. Leading cellular vaccine candidates are ETVAX (a mixture of four inactivated strains) and ACE527 (a mixture of three live attenuated strains), both of which have been found to be safe and immunogenic in Phase 1/2 trials. ETVAX is the furthest along in development with descending-age studies already underway in Bangladesh. Other ETEC vaccine candidates based on protein subunits, toxoids (both LT and ST), or novel, more broadly conserved ETEC antigens are also under development. Of these, a protein adhesin-based subunit approach is the most advanced. Impact and economic models suggest favorable vaccine cost-effectiveness, which may help expand market interest in ETEC vaccines. Combination vaccine formulations may help improve the economic case for development and use, and better point-of-care diagnostics will help to raise awareness of the true health burden of ETEC and highlight the potential public health benefit of ETEC vaccine introduction. Better diagnostics and vaccine demand forecasting will also improve vaccine development financing and support accelerated uptake once a licensed vaccine becomes available.
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Escherichia coli Enterotoxigénica , Infecciones por Escherichia coli/prevención & control , Vacunas contra Escherichia coli/uso terapéutico , Investigación Biomédica/tendencias , Ensayos Clínicos como Asunto , Diarrea/microbiología , Diarrea/prevención & control , Infecciones por Escherichia coli/epidemiología , Humanos , Vacunas de Subunidad/uso terapéuticoRESUMEN
Shigella are gram-negative bacteria that cause severe diarrhea and dysentery. In 2013, Shigella infections caused an estimated 34,400 deaths in children less than five years old and, in 2010, an estimated 40,000 deaths in persons older than five years globally. New disease burden estimates from newly deployed molecular diagnostic assays with increased sensitivity suggest that Shigella-associated morbidity may be much greater than previous disease estimates from culture-based methods. Primary prevention of this disease should be based on universal provision of potable water and sanitation methods and improved personal and food hygiene. However, an efficacious and low-cost vaccine would complement and accelerate disease reduction while waiting for universal access to water, sanitation, and hygiene improvements. This review article provides a landscape of Shigella vaccine development efforts. No vaccine is yet available, but human and animal challenge-rechallenge trials with virulent Shigella as well as observational studies in Shigella-endemic areas have shown that the incidence of disease decreases following Shigella infection, pointing to biological feasibility of a vaccine. Immunity to Shigella appears to be strain-specific, so a vaccine that covers the most commonly detected strains (i.e., S. flexneri 2a, 3a, 6, and S. sonnei) or a vaccine using cross-species conserved antigens would likely be most effective. Vaccine development and testing may be accelerated by use of animal models, such as the guinea pig keratoconjunctivitis or murine pneumonia models. Because there is no correlate of protection, however, human studies will be necessary to evaluate vaccine efficacy prior to deployment. A diversity of Shigella vaccine constructs are under development, including live attenuated, formalin-killed whole-cell, glycoconjugate, subunit, and novel antigen vaccines (e.g., Type III secretion system and outer membrane proteins).
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Disentería Bacilar/prevención & control , Vacunas contra la Shigella/uso terapéutico , Animales , Investigación Biomédica/tendencias , Ensayos Clínicos como Asunto , Diarrea/microbiología , Diarrea/prevención & control , Modelos Animales de Enfermedad , Humanos , Shigella , Vacunas Conjugadas/uso terapéutico , Vacunas de Subunidad/uso terapéuticoRESUMEN
Despite improvements to water quality, sanitation, and the implementation of current prevention and treatment interventions, diarrhea remains a major cause of illness and death, especially among children less than five years of age in the developing world. Rotavirus vaccines have already begun making a real impact on diarrhea, but several more enteric vaccines will be necessary to achieve broader reductions of illness and death. Among the many causes of diarrheal disease, enterotoxigenic Escherichia coli (ETEC) and Shigella are the two most important bacterial pathogens for which there are no currently licensed vaccines. Vaccines against these two pathogens could greatly reduce the impact of disease caused by these infections. This review describes the approaches to ETEC and Shigella vaccines that are currently under development, including a range of both cellular and subunit approaches for each pathogen. In addition, the review discusses strategies for maximizing the potential benefit of these vaccines, which includes the feasibility of co-administration, consolidation, and combination of vaccine candidates, as well as issues related to effective administration of enteric vaccines to infants. Recent impact studies indicate that ETEC and Shigella vaccines could significantly benefit global public health. Either vaccine, particularly if they could be combined together or with another enteric vaccine, would be an extremely valuable tool for saving lives and promoting the health of infants and children in the developing world, as well as potentially providing protection to travelers and military personnel visiting endemic areas.
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Disentería Bacilar/prevención & control , Escherichia coli Enterotoxigénica/inmunología , Infecciones por Escherichia coli/prevención & control , Vacunas contra Escherichia coli/inmunología , Vacunas contra la Shigella/inmunología , Shigella/inmunología , Niño , Preescolar , Humanos , Lactante , Potencia de la Vacuna , Vacunas de Subunidad/inmunologíaRESUMEN
PATH hosted a workshop on October 14 and 15, 2013 in Washington, DC to solicit expert opinions on the potential merits and challenges of developing combined enterotoxigenic Escherichia coli (ETEC) and Shigella vaccine products to benefit children in developing countries. This article summarizes the key issues raised during the workshop and provides an analysis of the recommendations regarding the strategic, clinical and regulatory, and manufacturing considerations for the development of a combined enteric vaccine, which aim to guide future vaccine development efforts and donor investment strategies in this area. Notwithstanding the potential technical, legal, financial, and other constraints that would be faced in developing a combined ETEC/Shigella vaccine, it is clear that this is the preferred approach over standalone products. There are many advantages to a combined vaccine, such as the potential cost-effectiveness and easier logistics of introducing a combined vaccine instead of two standalone vaccines in low-resource, endemic countries.
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Biotecnología , Vacunas contra Escherichia coli , Vacunas contra la Shigella , HumanosRESUMEN
Shigellosis is an important disease in the developing world, where about 90 million people become infected with Shigella spp. each year. We previously demonstrated that the type three secretion apparatus (T3SA) proteins IpaB and IpaD are protective antigens in the mouse lethal pulmonary model. In order to simplify vaccine formulation and process development, we have evaluated a vaccine design that incorporates both of these previously tested Shigella antigens into a single polypeptide chain. To determine if this fusion protein (DB fusion) retains the antigenic and protective capacities of IpaB and IpaD, we immunized mice with the DB fusion and compared the immune response to that elicited by the IpaB/IpaD combination vaccine. Purification of the DB fusion required coexpression with IpgC, the IpaB chaperone, and after purification it maintained the highly α-helical characteristics of IpaB and IpaD. The DB fusion also induced comparable immune responses and retained the ability to protect mice against Shigella flexneri and S. sonnei in the lethal pulmonary challenge. It also offered limited protection against S. dysenteriae challenge. Our results show the feasibility of generating a protective Shigella vaccine comprised of the DB fusion.
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Proteínas Bacterianas/inmunología , Disentería Bacilar/inmunología , Disentería Bacilar/prevención & control , Proteínas Recombinantes de Fusión/inmunología , Vacunas contra la Shigella/inmunología , Animales , Antígenos Bacterianos/genética , Antígenos Bacterianos/inmunología , Proteínas Bacterianas/genética , Femenino , Inmunización , Ratones , Ratones Endogámicos BALB C , Proteínas Recombinantes de Fusión/genética , Shigella dysenteriae/inmunología , Shigella flexneri/inmunología , Shigella sonnei/inmunología , Vacunas Sintéticas/inmunologíaRESUMEN
Enterotoxigenic Escherichia coli (ETEC) strain H10407 (serotype O78:H11 producing heat-labile toxin [LT], heat-stable toxin [ST], and colonization factor I [CFA/I]) induces reliably high diarrheal attack rates (ARs) in a human challenge model at doses of ≥10(9) CFU. A descending-dose challenge study was conducted with changes to the standard fasting time and buffer formulation, seeking conditions that permit lower inocula while maintaining reproducibly high ARs. In cohort 1, 20 subjects were fasted overnight and randomized 1:1:1:1 to receive H10407 at doses of 10(8) CFU with bicarbonate, 10(8) CFU with CeraVacx, 10(7) CFU with bicarbonate, or 10(7) CFU with CeraVacx. Subsequent cohorts received H10407 (10(7) CFU with bicarbonate) with similar fasting conditions. Cohort 2 included 15 ETEC-naïve volunteers. Cohort 3 included 10 ETEC-naïve volunteers and 10 rechallenged volunteers. In all, 25/35 (71%) ETEC-naïve recipients of 10(7) CFU of H10407 developed moderate or severe diarrhea (average maximum stool output/24 h = 1,042 g), and most (97%) shed H10407 (maximum geometric mean titer = 7.5 × 10(7) CFU/gram of stool). Only one of 10 rechallenged volunteers developed diarrhea. These rechallenged subjects had reduced intestinal colonization, reflected by quantitative microbiology of fecal samples. Among the 35 ETEC-naïve subjects, anti-lipopolysaccharide (LPS) O78 serum antibody responses were striking, with positive IgA and IgG antibody responses in 33/35 (94%) and 25/35 (71%), respectively. Anti-heat-labile enterotoxin (LTB) serum IgA and IgG responses developed in 19/35 (54%) and 14/35 (40%) subjects, respectively. Anti-CFA/I serum IgA and IgG responses were detected in 15/35 (43%) and 8/35 (23%) subjects. After the second challenge, participants exhibited blunted anti-LPS and -LTB responses but a booster response to CFA/I. This ETEC model should prove useful in the future evaluation of ETEC vaccine candidates.
Asunto(s)
Investigación Biomédica/métodos , Escherichia coli Enterotoxigénica/inmunología , Escherichia coli Enterotoxigénica/patogenicidad , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/prevención & control , Vacunas contra Escherichia coli/inmunología , Anticuerpos Antibacterianos/sangre , Diarrea/inmunología , Diarrea/microbiología , Diarrea/prevención & control , Evaluación de Medicamentos/métodos , Infecciones por Escherichia coli/microbiología , Vacunas contra Escherichia coli/administración & dosificación , Experimentación Humana , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina G/sangreRESUMEN
A human Campylobacter jejuni infection model provided controlled exposure to assess vaccine efficacy and investigate protective immunity for this important diarrheal pathogen. A well-characterized outbreak strain, C. jejuni 81-176, was investigated using a volunteer experimental infection model to evaluate the dose range and duration of protection. Healthy Campylobacter-seronegative adults received C. jejuni strain 81-176 via oral inoculation of 10(5), 10(7), or 10(9) CFU (5 adults/dose), which was followed by clinical and immunological monitoring. Based on dose range clinical outcomes, the 10(9)-CFU dose (n = 31) was used to assess homologous protection at 28 to 49 days (short-term veterans [STV]; n = 8) or 1 year (long-term veterans [LTV]; n = 7) after primary infection. An illness dose effect was observed for naïve subjects (with lower doses, 40 to 60% of the subjects were ill; with the 10(9)-CFU dose, 92% of the subjects were ill) along with complete protection for the STV group and attenuated illness for the LTV group (57%). Partial resistance to colonization was seen in STV (25% of the subjects were not infected; 3-log-lower maximum excretion level). Systemic and mucosal immune responses were robust in naïve subjects irrespective of the dose or the severity of illness. In contrast, in STV there was a lack of circulating antibody-secreting cells (ASC), reflecting the local mucosal effector responses. LTV exhibited comparable ASC responses to primary infection, and anamnestic fecal IgA responses likely contributed to self-resolving illness prior to antibiotic treatment. Campylobacter antigen-dependent production of gamma interferon by peripheral blood mononuclear cells was strongly associated with protection from illness, supporting the hypothesis that TH1 polarization has a primary role in acquired immunity to C. jejuni. This study revealed a C. jejuni dose-related increase in campylobacteriosis rates, evidence of complete short-term protection that waned with time, and immune response patterns associated with protection.