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Highlights: [•] Ty21a is immunogenic in 2–5 years young children. [•] There are no effects of deworming in concerns to the immunogenicity over Ty21a vaccination. [•] The content of Ty21a capsule can be used to prepare liquid formulation of vaccine. [•] Plasma and ALS responses can be measured with a very small volume of blood. [Copyright &y& Elsevier]

Abstract: Intranasal exposure to Streptococcus pneumoniae as well as mucosal or parenteral immunization with a recently developed killed pneumococcal whole cell vaccine, confer Th17-mediated protection against subsequent S. pneumoniae colonization in mice. Given our interest in the function of Th17 cells and the ongoing efforts to develop this vaccine for use in infants and children in developing countries, we analyzed Th17 responses to the whole cell antigen (WCA) and individual pneumococcal antigens in healthy individuals and patients with pneumococcal disease and compared responses in children and adults from Sweden and Bangladesh. Peripheral blood mononuclear cells (PBMCs) isolated from Swedish adults produced IL-17A after stimulation with WCA, with the pneumolysoid PdT and with the protein required for cell separation in group B streptococci (PcsB). IL-22 and IFN-γ responses were also detected, but these cytokines originated from separate CD4+ T cell subsets. PBMCs from Swedish children produced lower levels of IL-17A in response to WCA compared to adults, whereas no such difference was noted from the samples from Bangladesh, where responses by children and adults were both significantly higher than those in Sweden. High IL-17A responses to stimulation with WCA were also observed in children with proven or probable pneumococcal pneumonia. Our results thus demonstrate the presence of Th17-type T cells that are specific for pneumococcus in both children and adults. The different levels of Th17 responses to pneumococci in children and adults in developing and developed countries, which may at least partly be due to differences in exposure to pneumococci, are important factors to consider in the evaluation of candidate pneumococcal protein-based vaccines in human trials. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

• The killed oral ETEC vaccine ETVAX ± dmLT adjuvant was safe in Bangladeshi adults. • All vaccinees responded to all 5 primary vaccine antigens in ALS specimens. • A majority of vaccinees responded to ≥4 antigens in plasma specimens. • A sensitive electrochemiluminescence assay was established for small sample volumes. • ALS responses measured by electrochemiluminescence and ELISA assays correlated well. 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 LCTB A, 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 (n = 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 (r = 0.85 to 0.98 for the five primary antigens, P < 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. [ABSTRACT FROM AUTHOR]

Immune responses to oral enteric vaccines in children and infants may be influenced by factors such as age, previous priming with related microorganisms and breast feeding. In this study, we aimed to determine optimal time points to assess immune responses to oral enteric vaccines in different clinical specimens. This was done by investigating antibody secreting cell (ASC) and fecal antibody responses on different days after vaccination using the licensed oral cholera vaccine Dukoral, containing cholera toxin B-subunit (rCTB) and inactivated Vibrio cholerae bacteria, as a model vaccine. Two vaccine doses were given 2 weeks apart to infants (6–11 months), young children (12–18 months), toddlers (19 months–5 years) and adults in a cholera endemic country (Bangladesh). IgA ASC responses, as determined by the antibodies in lymphocyte supernatant (ALS) assay, plasma IgA and IgG responses and secretory IgA (SIgA) responses in extracts of fecal samples were evaluated 4/5 and 7 days after each vaccination. After the first vaccine dose, anti-CTB ALS IgA responses in adults and toddlers were high and comparable on day 5 and 7, while responses were low and infrequent in young children. After the second dose, highest ALS responses were detected on day 5 among the time points studied in all age groups and the responses declined until day 7. In contrast, plasma IgA and IgG anti-CTB responses were high both on day 5 and 7 after the second dose. Fecal SIgA responses in young children and infants were highest on day 7 after the second dose. Our results suggest that ASC/ALS responses to two doses of the oral cholera vaccine Dukoral and related oral vaccines should be analyzed earlier than previously recommended (day 7) at all ages. Fecal antibody responses should preferably be analyzed later than ASC/ALS responses to detect the highest antibody responses. [ABSTRACT FROM AUTHOR]

There is a need to develop cholera vaccines that are protective in young children under 5 years of age, which induce long-term immunity, and which can be incorporated into the Expanded Programme of Immunization (EPI) in cholera-endemic countries. The degree of protection afforded by currently available oral cholera vaccines (OCV) to young children is significantly lower than that induced by vaccination of older vaccine recipients. Immune responses that protect against cholera target the O-specific polysaccharide (OSP) of Vibrio cholerae , and young children have poor immunological responses to bacterial polysaccharides, which are T cell independent antigens. To overcome this, we have developed a cholera conjugate vaccine (CCV) containing the OSP of V. cholerae O1, the main cause of endemic and epidemic cholera. Here, we describe production of CCV through a scalable manufacturing process and preclinical evaluation of immunogenicity in the presence and absence of aluminum phosphate (alum) as an adjuvant. The vaccine displays V. cholerae O1 Inaba OSP in sun-burst display via single point attachment of core oligosaccharide to a recombinant tetanus toxoid heavy chain fragment (rTTHc). Two different pilot-scale production batches of non-GMP CCV were manufactured and characterized in terms of physico-chemical properties and immunogenicity. In preclinical testing, the vaccine induced OSP- and lipopolysaccharide (LPS)-specific IgG and IgM responses, vibriocidal responses, memory B cell responses, and protection in a V. cholerae O1 challenge model. The addition of alum to the administered vaccine increased OSP-specific immune responses. These results support evaluation of CCV in humans. [ABSTRACT FROM AUTHOR]

Background: A single-dose regimen of inactivated whole-cell oral cholera vaccine (OCV) is attractive because it reduces logistical challenges for vaccination and could enable more people to be vaccinated. Previously, we reported the efficacy of a single dose of an OCV vaccine during the 6 months following dosing. Herein, we report the results of 2 years of follow-up.Methods: In this placebo-controlled, double-blind trial done in Dhaka, Bangladesh, individuals aged 1 year or older with no history of receipt of OCV were randomly assigned to receive a single dose of inactivated OCV or oral placebo. The primary endpoint was a confirmed episode of non-bloody diarrhoea for which the onset was at least 7 days after dosing and a faecal culture was positive for Vibrio cholerae O1 or O139. Passive surveillance for diarrhoea was done in 13 hospitals or major clinics located in or near the study area for 2 years after the last administered dose. We assessed the protective efficacy of the OCV against culture-confirmed cholera occurring 7-730 days after dosing with both crude and multivariable per-protocol analyses. This trial is registered at ClinicalTrials.gov, number NCT02027207.Findings: Between Jan 10, 2014, and Feb 4, 2014, 205 513 people were randomly assigned to receive either vaccine or placebo, of whom 204 700 (102 552 vaccine recipients and 102 148 placebo recipients) were included in the per-protocol analysis. 287 first episodes of cholera (109 among vaccine recipients and 178 among placebo recipients) were detected during the 2-year follow-up; 138 of these episodes (46 in vaccine recipients and 92 in placebo recipients) were associated with severe dehydration. The overall incidence rates of initial cholera episodes were 0·22 (95% CI 0·18 to 0·27) per 100 000 person-days in vaccine recipients versus 0·36 (0·31 to 0·42) per 100 000 person-days in placebo recipients (adjusted protective efficacy 39%, 95% CI 23 to 52). The overall incidence of severe cholera was 0·09 (0·07 to 0·12) per 100 000 person-days versus 0·19 (0·15 to 0·23; adjusted protective efficacy 50%, 29 to 65). Vaccine protective efficacy was 52% (8 to 75) against all cholera episodes and 71% (27 to 88) against severe cholera episodes in participants aged 5 years to younger than 15 years. For participants aged 15 years or older, vaccine protective efficacy was 59% (42 to 71) against all cholera episodes and 59% (35 to 74) against severe cholera. The protection in the older age groups was sustained throughout the 2-year follow-up. In participants younger than 5 years, the vaccine did not show protection against either all cholera episodes (protective efficacy -13%, -68 to 25) or severe cholera episodes (-44%, -220 to 35).Interpretation: A single dose of the inactivated whole-cell OCV offered protection to older children and adults that was sustained for at least 2 years. The absence of protection of young children might reflect a lesser degree of pre-existing natural immunity in this age group.Funding: Bill & Melinda Gates Foundation to the International Vaccine Institute. [ABSTRACT FROM AUTHOR]