-
Open Forum Infectious Diseases Mar 2024In 2002, the Centre pour le Développement des Vaccins du Mali (CVD-Mali) was established as a partnership between the Mali Ministry of Health and the University of...
BACKGROUND
In 2002, the Centre pour le Développement des Vaccins du Mali (CVD-Mali) was established as a partnership between the Mali Ministry of Health and the University of Maryland, Baltimore. Since its creation, CVD-Mali has been dedicated to describing the epidemiology of infectious diseases, supporting the development of vaccines, and training a team of local researchers. CVD-Mali participated in the Global Enteric Multicenter Study from 2007 to 2010 and the Vaccine Impact on Diarrhea in Africa study from 2015 to 2018, where the importance of as an enteric pathogen was established.
METHODS
In the Enterics for Global Health (EFGH) surveillance study, CVD-Mali will conduct surveillance at 4 health centers serving the population currently participating in a demographic surveillance system and will measure the local incidence of diarrhea and related outcomes in 6- to 35-month-old children. Antibiotic sensitivity patterns and the costs related to these cases will also be measured.
RESULTS
We anticipate reporting the number of diarrhea episodes that are positive by stool culture, the antibiotic susceptibility of these isolates, and the management and outcomes of these cases.
CONCLUSIONS
In Mali, the EFGH study will contribute valuable information to understanding the burden of in this population. These data will inform the evaluation of vaccine candidates.
PubMed: 38532954
DOI: 10.1093/ofid/ofae003 -
Open Forum Infectious Diseases Mar 2024is a major cause of diarrhea in young children worldwide. Multiple vaccines targeting are in development, and phase 3 clinical trials are imminent to determine...
BACKGROUND
is a major cause of diarrhea in young children worldwide. Multiple vaccines targeting are in development, and phase 3 clinical trials are imminent to determine efficacy against shigellosis.
METHODS
The Enterics for Global Health (EFGH) surveillance study is designed to determine the incidence of medically attended shigellosis in 6- to 35-month-old children in 7 resource-limited settings. Here, we describe the microbiological methods used to isolate and identify . We developed a standardized laboratory protocol for isolation and identification of by culture. This protocol was implemented across all 7 sites, ensuring consistency and comparability of results. Secondary objectives of the study are to determine the antibiotic resistance profiles of , compare isolation of from rectal swabs versus whole stool, and compare isolation of following transport of rectal swabs in Cary-Blair versus a modified buffered glycerol saline transport medium.
CONCLUSIONS
Data generated from EFGH using culture methods described herein can potentially be used for microbiological endpoints in future phase 3 clinical trials to evaluate vaccines against shigellosis and for other clinical and public health studies focused on these organisms.
PubMed: 38532949
DOI: 10.1093/ofid/ofad576 -
NPJ Vaccines Mar 2024Shigella spp. are a leading bacterial cause of diarrhea. No widely licensed vaccines are available and there is no generally accepted correlate of protection. We tested...
Shigella spp. are a leading bacterial cause of diarrhea. No widely licensed vaccines are available and there is no generally accepted correlate of protection. We tested a S. sonnei Generalized Modules for Membrane Antigen (GMMA)-based vaccine (1790GAHB) in a phase 2b, placebo-controlled, randomized, controlled human infection model study (NCT03527173) enrolling healthy United States adults aged 18-50 years. We report analyses evaluating immune responses to vaccination, with the aim to identify correlates of risk for shigellosis among assessed immunomarkers. We found that 1790GAHB elicited S. sonnei lipopolysaccharide specific α4β7+ immunoglobulin (Ig) G and IgA secreting B cells which are likely homing to the gut, indicating the ability to induce a mucosal in addition to a systemic response, despite parenteral delivery. We were unable to establish or confirm threshold levels that predict vaccine efficacy facilitating the evaluation of vaccine candidates. However, serum anti-lipopolysaccharide IgG and bactericidal activity were identified as potential correlates of risk for shigellosis.
PubMed: 38459072
DOI: 10.1038/s41541-024-00822-2 -
Frontiers in Immunology 2024Shigellosis mainly affects children under 5 years of age living in low- and middle-income countries, who are the target population for vaccination. There are, however,...
BACKGROUND
Shigellosis mainly affects children under 5 years of age living in low- and middle-income countries, who are the target population for vaccination. There are, however, limited data available to define the appropriate timing for vaccine administration in this age group. Information on antibody responses following natural infection, proxy for exposure, could help guide vaccination strategies.
METHODS
We undertook a retrospective analysis of antibodies to five of the most prevalent serotypes among children aged <5 years in Kenya. Serum samples from a cross-sectional serosurvey in three Kenyan sites (Nairobi, Siaya, and Kilifi) were analyzed by standardized ELISA to measure IgG against and 1b, 2a, 3a, and 6. We identified factors associated with seropositivity to each serotype, including seropositivity to other serotypes.
RESULTS
A total of 474 samples, one for each participant, were analyzed: Nairobi ( = 169), Siaya ( = 185), and Kilifi ( = 120). The median age of the participants was 13.4 months (IQR 7.0-35.6), and the male:female ratio was 1:1. Geometric mean concentrations (GMCs) for each serotype increased with age, mostly in the second year of life. The overall seroprevalence of IgG antibodies increased with age except for 6 which was high across all age subgroups. In the second year of life, there was a statistically significant increase of antibody GMCs against all five serotypes ( = 0.01-0.0001) and a significant increase of seroprevalence for 2a ( = 0.006), 3a ( = 0.006), and ( = 0.05) compared with the second part of the first year of life. Among all possible pairwise comparisons of antibody seropositivity, there was a significant association between 1b and 2a (OR = 6.75, 95% CI 3-14, < 0.001) and between 1b and 3a (OR = 23.85, 95% CI 11-54, < 0.001).
CONCLUSION
Children living in low- and middle-income settings such as Kenya are exposed to infection starting from the first year of life and acquire serotype-specific antibodies against multiple serotypes. The data from this study suggest that vaccination should be targeted to infants, ideally at 6 or at least 9 months of age, to ensure children are protected in the second year of life when exposure significantly increases.
Topics: Infant; Child; Humans; Male; Female; Child, Preschool; Kenya; Serogroup; Immunoglobulin G; Retrospective Studies; Seroepidemiologic Studies; Cross-Sectional Studies; Shigella; Dysentery, Bacillary; Vaccination
PubMed: 38361949
DOI: 10.3389/fimmu.2024.1340425 -
International Journal of Molecular... Jan 2024Shigellosis, an acute gastroenteritis infection caused by species, remains a public health burden in developing countries. Recently, many outbreaks due to...
Shigellosis, an acute gastroenteritis infection caused by species, remains a public health burden in developing countries. Recently, many outbreaks due to multidrug-resistant strains have been reported in high-income countries, and the lack of an effective vaccine represents a major hurdle to counteract this bacterial pathogen. Vaccine candidates against are under clinical development, including a Generalized Modules for Membrane Antigens (GMMA)-based vaccine. The mechanisms by which GMMA-based vaccines interact and activate human immune cells remain elusive. Our previous study provided the first evidence that both adaptive and innate immune cells are targeted and functionally shaped by the GMMA-based vaccine. Here, flow cytometry and confocal microscopy analysis allowed us to identify monocytes as the main target population interacting with the 1790-GMMA vaccine on human peripheral blood. In addition, transcriptomic analysis of this cell population revealed a molecular signature induced by 1790-GMMA mostly correlated with the inflammatory response and cytokine-induced processes. This also impacts the expression of genes associated with macrophages' differentiation and T cell regulation, suggesting a dual function for this vaccine platform both as an antigen carrier and as a regulator of immune cell activation and differentiation.
Topics: Humans; Monocytes; Shigella sonnei; Antigens, Bacterial; Vaccines; Blood Group Antigens; Gastroenteritis; Methylmethacrylates
PubMed: 38256189
DOI: 10.3390/ijms25021116 -
PloS One 2024B memory (BM) cell responses were evaluated using peripheral blood mononuclear cells that were collected and cryopreserved during a Phase 1 trial of two live Shigella...
B memory (BM) cell responses were evaluated using peripheral blood mononuclear cells that were collected and cryopreserved during a Phase 1 trial of two live Shigella sonnei vaccine candidates WRSs2 and WRSs3. An ELISpot assay was used to measure IgG+ and IgA+ BM cell responses against S. sonnei LPS, IVP and IpaB antigens. Analysis of BM cell responses at baseline, and on days 28 and 56 post vaccination indicate that after a single oral dose of WRSs2 and WRSs3, both groups of vaccinees induced IgG+ and IgA+ BM cell responses that were variable in magnitude among subjects and reached significance to IVP and IpaB at several doses. The responses generally peaked at d28 after vaccination. The baseline as well as post-vaccination levels of IgA+ BM cells were relatively higher than IgG+ BM cells, but the maximum fold-increase at d28/d56 over baseline was greater for IgG+ than IgA+ BM cell responses. Furthermore, at the three highest vaccine doses, >60-90% of subjects were considered responders indicating a ≥2-fold higher IgG+ BM cell responses to IVP and IpaB post vaccination, while fewer subjects indicated the same level of response to LPS.
Topics: Humans; Antibodies, Bacterial; Antigens; Bacterial Proteins; Immunoglobulin A; Immunoglobulin G; Leukocytes, Mononuclear; Lipopolysaccharides; Shigella sonnei; Shigella Vaccines; Vaccination; Vaccines, Attenuated; Clinical Trials, Phase I as Topic
PubMed: 38232106
DOI: 10.1371/journal.pone.0290987 -
NPJ Vaccines Jan 2024Diarrhea caused by Shigella has been associated with high morbidity and mortality in young children worldwide. There are no licensed vaccines, and those clinically...
Diarrhea caused by Shigella has been associated with high morbidity and mortality in young children worldwide. There are no licensed vaccines, and those clinically advanced have restricted coverage as they elicit serotype-specific immunity while disease is caused by multiple circulating serotypes. Our group had previously reported a close association between serum antibodies to the Shigella virulence factor VirG (or IcsA) and clinical protection in infected individuals. VirG is highly conserved among Shigella strains and appealing as a broad-spectrum vaccine candidate. In this study, we investigated the immunogenicity and protective capacity of VirG as a subunit vaccine in mice. The surface-exposed alpha (α) domain of VirG (VirGα) was produced as a recombinant protein. This region has almost identical immune reactivity to full-length VirG. Administered intramuscularly with alum, VirGα elicited robust immune responses and high protective efficacy against S. flexneri 2a and S. sonnei. Almost complete protection was afforded by VirGα given intranasally with the E. coli double mutant heat-labile toxin (dmLT). VirGα-specific antibodies recognized VirG expressed on live Shigella, and blocked Shigella adhesion and invasion to human colonic cells. These results show for the first time that VirGα is a promising cross-protective vaccine candidate to prevent Shigella infection.
PubMed: 38167387
DOI: 10.1038/s41541-023-00797-6 -
Bulletin of the World Health... Jan 2024The gram-negative bacterium is a leading cause of diarrheal morbidity and mortality in children in low- and middle-income countries. Several promising vaccine...
The gram-negative bacterium is a leading cause of diarrheal morbidity and mortality in children in low- and middle-income countries. Several promising vaccine candidates are in late stages of clinical development against this increasingly antibiotic-resistant pathogen. However, considering the increasingly crowded and costly paediatric immunization schedule, and likely advent of other important new vaccines, it is unclear whether introduction of a vaccine would represent a high priority for international agencies or health ministries in low- and middle-income countries. To determine whether there is a compelling public health value proposition for a vaccine, we used the World Health Organization's Full Value of Vaccine Assessment analytic framework and formulated five broad scientific, policy, economic and commercial-related propositions regarding the development of a vaccine. We also explored the current regulatory, clinical, policy and commercial challenges to a -containing combination vaccine development and adoption. Through a series of literature reviews, expert consultations, social science field studies and model-based analyses, we addressed each of these propositions. As described in a series of separate publications that are synthesized here, we concluded that the economic and public health value of a vaccine may be greater than previously recognized, particularly if it is found to also be effective against less severe forms of diarrheal disease and childhood stunting. The decision by pharmaceutical companies to develop a standalone vaccine or a multipathogen combination will be a key factor in determining its relative prioritization by various stakeholders in low- and middle-income countries.
Topics: Child; Humans; Shigella Vaccines; Shigella; Diarrhea; Vaccines; Global Health
PubMed: 38164339
DOI: 10.2471/BLT.23.290163 -
MSphere Jan 2024causes bacillary dysentery and is responsible for a high burden of disease globally. Several studies have emphasized the value of functional antibody activity to...
causes bacillary dysentery and is responsible for a high burden of disease globally. Several studies have emphasized the value of functional antibody activity to understand immunity and correlates of protection. The anti-microbial function of local (mucosal) antibodies and their contribution to preventing infection remain unknown. The goal of this study was to identify the functional humoral immune effectors elicited by two live oral vaccine candidates, WRSs2 and WRSs3. Complement-dependent bactericidal [serum bactericidal antibody (SBA)/bactericidal antibody (BA)] and opsonophagocytic killing antibody (OPKA) activity were determined in sera and stool extracts as indicators of systemic and local anti-microbial immunity. High levels of SBA/BA and OPKA were detected in serum as well as in fecal extracts from volunteers who received a single dose of WRSs2 and WRSs3. Functional antibody activity peaked on days 10 and 14 post-vaccination in fecal and serum samples, respectively. Bactericidal and OPKA titers were closely associated. Peak fold rises in functional antibody titers in serum and fecal extracts were also associated. Antibody activity interrogated in IgG and IgA purified from stool fractions identified IgG as the primary driver of mucosal bactericidal and OPKA activity, with minimal functional activity of IgA alone, highlighting an underappreciated role for IgG in bacterial clearance in the mucosa. The combination of IgG and IgA in equal proportions enhanced bactericidal and OPKA titers hinting at a co-operative or synergistic action. Our findings provide insight into the functional anti-microbial capacity of vaccine-induced mucosal IgG and IgA and propose an operative local humoral effector of protective immunity.IMPORTANCEThere is an urgent need for a safe, effective, and affordable vaccine against . Understanding the immunological underpinning of infection and the make-up of protective immunity is critical to achieve the best approach to prevent illness caused by this mucosal pathogen. We measured the complement-dependent bactericidal and opsonophagocytic antibody killing in serum and stool extracts from adult volunteers vaccinated with live oral vaccine candidates WRSs2 and WRSs3. For the first time, we detected functional antibody responses in stool samples that were correlated with those in sera. Using purified stool IgA and IgG fractions, we found that functional activity was mediated by IgG, with some help from IgA. These findings provide insight into the functional anti-microbial capacity of vaccine-induced mucosal IgG and IgA and support future studies to identify potential markers of protective mucosal immunity.
Topics: Adult; Humans; Shigella sonnei; Dysentery, Bacillary; Antibodies, Bacterial; Shigella; Immunization; Vaccination; Vaccines; Mucous Membrane; Immunoglobulin G; Immunoglobulin A
PubMed: 38132716
DOI: 10.1128/msphere.00419-23 -
PloS One 2023Infectious diarrhea is a World Health Organization public health priority area due to the lack of effective vaccines and an accelerating global antimicrobial resistance...
Infectious diarrhea is a World Health Organization public health priority area due to the lack of effective vaccines and an accelerating global antimicrobial resistance crisis. New strategies are urgently needed such as immunoprophylactic for prevention of diarrheal diseases. Hyperimmune bovine colostrum (HBC) is an established and effective prophylactic for infectious diarrhea. The commercial HBC product, Travelan® (Immuron Ltd, Australia) targets multiple strains of enterotoxigenic Escherichia coli (ETEC) is highly effective in preventing diarrhea in human clinical studies. Although Travelan® targets ETEC, preliminary studies suggested cross-reactivity with other Gram-negative enteric pathogens including Shigella and Salmonella species. For this study we selected an invasive diarrheal/dysentery-causing enteric pathogen, Shigella, to evaluate the effectiveness of Travelan®, both in vitro and in vivo. Here we demonstrate broad cross-reactivity of Travelan® with all four Shigella spp. (S. flexneri, S. sonnei, S. dysenteriae and S. boydii) and important virulence factor Shigella antigens. Naïve juvenile rhesus macaques (NJRM) were randomized, 8 dosed with Travelan® and 4 with a placebo intragastrically twice daily over 6 days. All NJRM were challenged with S. flexneri 2a strain 2457T on the 4th day of treatment and monitored for diarrheal symptoms. All placebo-treated NJRM displayed acute dysentery symptoms within 24-36 hours of challenge. Two Travelan®-treated NJRM displayed dysentery symptoms and six animals remained healthy and symptom-free post challenge; resulting in 75% efficacy of prevention of shigellosis (p = 0.014). These results strongly indicate that Travelan® is functionally cross-reactive and an effective prophylactic for shigellosis. This has positive implications for the prophylactic use of Travelan® for protection against both ETEC and Shigella spp. diarrheal infections. Future refinement and expansion of pathogens recognized by HBC including Travelan® could revolutionize current management of gastrointestinal infections and outbreaks in travelers' including military, peacekeepers, humanitarian workers and in populations living in endemic regions of the world.
Topics: Female; Pregnancy; Animals; Cattle; Humans; Dysentery, Bacillary; Macaca mulatta; Colostrum; Immunologic Factors; Shigella; Diarrhea; Dysentery; Enterotoxigenic Escherichia coli
PubMed: 38091314
DOI: 10.1371/journal.pone.0294021