Safety and immunogenicity of a 4-component GMMA-based Shigella vaccine in healthy European adults: Stage 1 of a randomized, controlled phase I/II clinical trial.

BACKGROUND: We report data from Stage 1 of an ongoing two-staged, phase I/II randomized clinical trial (NCT05073003) with a 4-component Generalized Modules for Membrane Antigens-based vaccine against Shigella sonnei and S. flexneri 1b, 2a and 3a (altSonflex1-2-3, GSK). METHODS: 18-50-year-old Europeans (N=102) were randomized (2:1) to receive two injections of altSonflex1-2-3 or placebo at 3- or 6-month interval. Safety and immunogenicity were assessed at pre-specified timepoints. RESULTS: The most common solicited administration-site event (until 7 days post-each injection) and unsolicited adverse event (until 28 days post-each injection) were pain (altSonflex1-2-3: 97.1%; Placebo: 58.8%) and headache (32.4%; 23.5%), respectively. All serotype-specific functional IgG antibodies peaked 14-28 days post-injection 1 and remained substantially higher than pre-vaccination at 3 or 6 months post-vaccination; the second injection did not boost but restored the initial immune response. The highest seroresponse rates (≥4-fold increase in titers over baseline) were obtained against S. flexneri 2a (ELISA: post-injection 1: 91.0%; post-injection 2 [Day {D}113; D197]: 100%; 97.0%; serum bactericidal activity (SBA): post-injection 1: 94.4%; post-injection 2: 85.7%; 88.9%) followed by S. sonnei (ELISA: post-injection 1: 77.6%; post-injection 2: 84.6%; 78.8%; SBA: post-injection 1: 83.3%; post-injection 2: 71.4%; 88.9%). Immune responses against S. flexneri 1b and S. flexneri 3a, as measured by both ELISA and SBA, were numerically lower compared to those against S. sonnei and S. flexneri 2a. CONCLUSIONS: No safety signals or concerns were identified. altSonflex1-2-3 induced functional serotype-specific immune responses, allowing further clinical development in the target population.

What is the context? Shigella bacteria cause severe and often bloody diarrhea, called shigellosis, that affects mostly young children and can be life-threatening. Shigellosis is particularly common in low- and middle-income countries due to inadequate sanitation and limited access to healthcare. Since the immune response to Shigella is serotype-specific, an ideal vaccine should include multiple Shigella serotypes to ensure broad protection. What is new? We developed a novel vaccine against Shigella that includes Shigella sonnei and three prevalent Shigella flexneri serotypes. In Stage 1 (phase I) of the study, healthy European adults received two vaccine injections given 3 or 6 months apart. We found that: The vaccine was well tolerated, and no safety signals or concerns were identified.Regardless of the interval between injections, specific antibodies were elicited against all four Shigella serotypes, with highest levels against Shigella flexneri 2a and Shigella sonnei.Functional antibody levels peaked after the first injection, remaining higher than the baseline up to 6 months. A second injection did not boost responses but restored functional antibody levels to those after the first injection. What is the impact? The vaccine can now be tested in Stage 2 (phase II) of the study in Africa, a region highly affected by shigellosis.

Effect of Intrapartum Azithromycin vs Placebo on Neonatal Sepsis and Death: A Randomized Clinical Trial.

Importance: Neonatal sepsis is a leading cause of neonatal mortality. New interventions are needed to decrease neonatal sepsis and mortality in regions with highest burden. Objective: To evaluate the efficacy of intrapartum azithromycin to reduce neonatal sepsis or mortality, as well as neonatal and maternal infections. Design, Setting, and Participants: This double-blind, placebo-controlled, randomized clinical trial enrolled and followed up birthing parents and their infants at 10 health facilities in The Gambia and Burkina Faso, West Africa, between October 2017 and May 2021. Interventions: Participants were assigned at random to receive oral azithromycin (2 g) or placebo (ratio 1:1) during labor. Main Outcomes and Measures: The primary outcome was a composite of neonatal sepsis or mortality, with the former defined based on microbiologic or clinical criteria. Secondary outcomes were neonatal infections (skin, umbilical, eye and ear infections), malaria, and fever; postpartum infections (puerperal sepsis, mastitis), fever, and malaria; and use of antibiotics during 4-week follow-up. Results: The trial randomized 11 983 persons in labor (median age, 29.9 years). Overall, 225 newborns (1.9% of 11 783 live births) met the primary end point. The incidence of neonatal mortality or sepsis was similar in the azithromycin and placebo groups (2.0% [115/5889] vs 1.9% [110/5894]; risk difference [RD], 0.09 [95% CI, -0.39 to 0.57]), as was the incidence of neonatal mortality (0.8% vs 0.8%; RD, 0.04 [95% CI, -0.27 to 0.35]) and neonatal sepsis (1.3% vs 1.3%; RD, 0.02 [95% CI, -0.38 to 0.43]). Newborns in the azithromycin group compared with the placebo group had lower incidence of skin infections (0.8% vs 1.7%; RD, -0.90 [95% CI, -1.30 to -0.49]) and need for antibiotics (6.2% vs 7.8%; RD, -1.58 [95% CI, -2.49 to -0.67]). Postpartum parents in the azithromycin group had lower incidence of mastitis (0.3% vs 0.5%; RD, -0.24 [95% CI, -0.47 to -0.01]) and puerperal fever (0.1% vs 0.3%; RD, -0.19 [95% CI, -0.36 to -0.01]). Conclusions and Relevance: Azithromycin administered orally during labor did not reduce neonatal sepsis or mortality. These results do not support routine introduction of oral intrapartum azithromycin for this purpose. Trial Registration: ClinicalTrials.gov Identifier: NCT03199547.

Knowledge and Compliance with Malaria National Treatment Guidelines among Primary Health Care Workers in a Rural Area in Northern Nigeria.

BACKGROUND: Knowledge and compliance with malaria treatment guidelines are among the major issues affecting treatment outcome for malaria in Nigeria. Primary health care (PHC) facilities are the first point of contact with the national health system for patients with malaria and other diseases. OBJECTIVE: This study assessed the knowledge and compliance with malaria National Treatment Guidelines (NTG) among PHC workers in Lere local government area of Kaduna State, North western Nigeria. METHODS: This was a descriptive cross-sectional study conducted among 42 community health workers. The total population of all eligible participants was used for subject selection. Data were analysed with SPSS IBM version 25.0 and STATA/SE 12. The level of statistical significance p-value was set at p<0.05. RESULTS: The mean age of the respondents was 38.02±9.23 years. Majority of the respondents were males (25; 59.5%) and community health extension workers (CHEWs) (24; 57.1%). Almost one-third (28.6%) of the PHC workers had poor knowledge of the recommendations of the NTG for malaria, while 14.3% had poor compliance with the NTG. Bivariate analysis showed a significant relationship between older age and good knowledge of the NTG ( χ2 =0.03, p=0.04). Multivariate analysis further revealed that the odds for poor knowledge of NTG was 40% higher among CHEWs compared to other health workers (AOR=1.40, 95% CI=0.25-7.93). The odds for good knowledge was lower by 55% among those who had practiced for <10 years compared to >10 years (OR=0.45, 95% CI=0.06-3.32). CONCLUSION: Poor knowledge and compliance to malaria NTG were commoner among lower cadre (CHEWs) staff with relatively fewer years in PHC practice. There is a need for training, retraining and equitable distribution of the NTG to ensure access and also improve knowledge and utilisation of the NTG for malaria by rural PHC workers.

CONTEXTE: La connaissance et le respect des directives de traitement du paludisme sont parmi les principaux problèmes qui affectent les résultats du traitement du paludisme au Nigéria. Les établissements de soins de santé primaires (SSP) sont le premier point de contact avec le système national de santé pour les patients atteints de paludisme et d'autres maladies. OBJECTIF DE L'ÉTUDE: Cette étude a évalué les connaissances et le respect des directives nationales de traitement du paludisme (NTG) parmi les travailleurs des SSP dans la zone de gouvernement local de Lere de l'État de Kaduna, dans le nord-ouest du Nigeria. MÉTHODES: Il s'agit d'une étude descriptive transversale menée auprès de 42 agents de santé communautaires. La population totale de tous les participants éligibles a été utilisée pour la sélection des sujets. Les données ont été analysées avec SPSS IBM version 25.0 et STATA/SE 12. Le niveau de signification statistique a été fixé à p<0,05. RÉSULTATS: L'âge moyen des personnes interrogées était de 38,02±9,23 ans. La majorité des personnes interrogées étaient des hommes (25 ; 59,5%) et des agents de vulgarisation en santé communautaire (24 ; 57,1%). Près d'un tiers (28,6 %) des agents de santé publique connaissaient mal les recommandations de la NTG pour le paludisme, tandis que 14,3 % ne respectaient pas la NTG. L'analyse bivariée a montré une relation significative entre l'âge avancé et la bonne connaissance du NTG ( χ2=0,03, p=0,04). L'analyse multivariée a également révélé que la probabilité d'une mauvaise connaissance de la NTG était 40% plus élevée chez les CHEW que chez les autres agents de santé (AOR=1,40, 95% CI=0,25-7,93). La probabilité d'une bonne connaissance était inférieure de 55% chez ceux qui avaient pratiqué pendant <10 ans par rapport à >10 ans (OR=0,45, 95% CI=0,06-3,32). CONCLUSION: Le manque de connaissances et d'observance des NTG sur le paludisme était plus fréquent parmi le personnel des cadres inférieurs (CHEWs) ayant relativement moins d'années de pratique dans les soins de santé primaires. Il est nécessaire de former, de recycler et de distribuer équitablement les NTG pour garantir l'accès et améliorer la connaissance et l'utilisation des NTG pour le paludisme par les travailleurs des SSP en milieu rural. Mots clés: Connaissance, Observance, Personnel de soins de santé primaires, Directives, Paludisme.

The ABC of reproductive intentions: a mixed-methods study exploring the spectrum of attitudes towards family building.

STUDY QUESTION: What are the intentions of men and women of reproductive age in the UK regarding reproduction and family building? SUMMARY ANSWER: We identified six main categories of people; Avoiders, Betweeners, Completers, Desirers, Expectants and Flexers, for whom reproduction education strategies should be tailored differently to suit intentions. WHAT IS KNOWN ALREADY: Several studies have highlighted poor fertility awareness across men and women of reproductive age. As the average age of first-time parents continues to rise, there has been a concerted effort from educators, healthcare professionals, charities, reproductive health groups and government policymakers, to improve fertility awareness. In order to ensure that these messages are effective and to deploy the best strategies, it is important to understand people's reproductive health needs. This study therefore aimed to explore different reproductive intentions to aid tailoring of information to help individuals and couples achieve their family building desires. STUDY DESIGN, SIZE, DURATION: We conducted a mixed-method study via a UK-wide cross-sectional survey with 1082 participants and semi-structured interviews of 20 women and 15 men who agreed to follow-up interviews. Interviews lasted an hour on average. Ethics approval from UCL Research Ethics Committee. PARTICIPANTS/MATERIALS, SETTING, METHODS: Survey participants were recruited nationwide via online newspaper and social media adverts. Interviewees were purposely sampled to include men and women from the reproductive age range (18-45 years), varying ethnicity and education background. Survey data were analysed using the Minitab statistical software package. Interview data were transcribed and analysed using the framework method. MAIN RESULTS AND THE ROLE OF CHANCE: From the survey and interviews, we identified six key categories of people, grouped alphabetically, in a user-friendly manner to highlight a spectrum of reproductive intentions: Avoiders describes respondents who have no children and do not want to have children in the future; Betweeners describes those who already have child(ren) and want more in the future but are not actively trying to conceive; Completers describes those who have child(ren) but do not want more; Desirers describes those who are actively trying to conceive or plan to have child(ren) in the future; Expectants describes those who were pregnant at the time of the study; and Flexers describes those who may or may not already have and are unsure but or open to having child(ren) in the future. Analysis of survey data identified the following proportions in our study: Avoiders, 4.7%; Betweeners, 11.3%; Completers, 13.6%; Desirers, 36.9%; Expectants, 4.1%; and Flexers 28.4% and 2.4% preferring not to answer. There was one 'other' group from qualitative analysis, who would like to have children in the future but were unsure whether they could or had changing views. We recommend classifying as 'Desirers' or 'Flexers' for the purposes of fertility education. A majority of the survey population were trying to get pregnant; were pregnant; or planning to have a child in the future-whether actively, passively or simply open to the idea, with interviews providing deep insights into their family building decision-making. LIMITATIONS, REASONS FOR CAUTION: Due to the online recruitment method, there may be a bias towards more educated respondents. WIDER IMPLICATIONS OF THE FINDINGS: We developed a user-friendly, alphabetical categorization of reproductive intentions, which may be used by individuals, healthcare professionals, educators, special interest groups, charities and policymakers to support and enable individuals and couples in making informed choices to achieve their desired intentions, if and when they choose to start a family. STUDY FUNDING/COMPETING INTEREST(S): There was no external funding for this study. The authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Staphylococcus aureus Bacteremia in Children of Rural Areas of The Gambia, 2008-2015.

Staphylococcus aureus bacteremia is a substantial cause of childhood disease and death, but few studies have described its epidemiology in developing countries. Using a population-based surveillance system for pneumonia, sepsis, and meningitis, we estimated S. aureus bacteremia incidence and the case-fatality ratio in children <5 years of age in 2 regions in the eastern part of The Gambia during 2008-2015. Among 33,060 children with suspected pneumonia, sepsis, or meningitis, we performed blood culture for 27,851; of 1,130 patients with bacteremia, 198 (17.5%) were positive for S. aureus. S. aureus bacteremia incidence was 78 (95% CI 67-91) cases/100,000 person-years in children <5 years of age and 2,080 (95% CI 1,621-2,627) cases/100,000 person-years in neonates. Incidence did not change after introduction of the pneumococcal conjugate vaccine. The case-fatality ratio was 14.1% (95% CI 9.6%-19.8%). Interventions are needed to reduce the S. aureus bacteremia burden in The Gambia, particularly among neonates.

Enablers of adherence to clinic appointments for children attending an antiretroviral clinic in Northern Nigeria: Perspectives of caregivers and care providers.

BACKGROUND: Nigeria has the highest burden of paediatric HIV infection, and the success of control efforts in the country is crucial to the global control of the HIV epidemic. However, defaults from schedules of care pose a threat to paediatric HIV control in Nigeria. This study was conducted in a pioneer facility for the implementation of the National HIV Prevention and Treatment Programmes. OBJECTIVE: The objective of this study was to explore factors that facilitate adherence to clinic appointments from perspectives of child caregivers and service providers. METHODS: This is a qualitative study using in-depth, face-to-face interviews conducted in 2016. Thirty-five participants were purposely sampled to comprise types of caregivers of HIV-exposed/infected children receiving care and from categories of service providers. The interviews were audio recorded, transcribed, thematically analysed and presented using a socioecological model. RESULTS: The themes that emerged from participants' narratives included advanced education, affluence and residing close to the clinic at the intrapersonal level. Stable family dynamics and support, HIV status disclosure and being a biologic parent or grandparent as caregiver emerged at the interpersonal level. At the community level, disclosure and support were identified, while at the health facility level, positive staff attitude, quality of healthcare and peer support group influence were factors identified to facilitate regular clinic attendance. CONCLUSION: The factors that enable retention of children in care are multidimensional and intricately connected. Programme improvement initiatives should include regular assessment of clients' perspectives to inform implementation of strategies that could reinforce caregiver confidence in the health system.

Quantitative and Qualitative Characterization of Phagocytic Activity of Macrophages of Bone Marrow and Fetal Origin.

We compared phagocytic activity of macrophages of monocyte origin and Kupffer cells under the influence of M1 and M2 inducers and without activation. Cultures of monocyte-derived macrophages and Kupffer cells were characterized by intensive expression of CD68 that was not affected by activation factors. At the same time, these cultures demonstrated different dynamics of phagocytic activity. Monocyte-derived macrophages initially had more pronounced absorption capacity that gradually increased during the experiment. Kupffer cells were characterized by abrupt fluctuations of phagocytic activity: sharp growth and rapid saturation. Despite these differences, the endosomes produced by monocyte-derived macrophages and Kupffer cells had similar degrees of maturity.

Dynamics of Expression of Cytokine Genes and Macrophage Content in the Lungs and Kidneys after Subtotal Hepatectomy in Rats.

The role of the lungs and kidneys in liver regeneration after subtotal hepatectomy was studied on a rat model. It was found that production of hepatocyte growth factor (HGF) in the lungs and kidneys and expression of cytokine genes Il1b, Il6, Il10, and tnfa significantly increased. Analysis of the dynamics of lung macrophage population showed that accumulation of HGF and the increase in the expression of cytokine genes in the lungs were accompanied by simultaneous increase in the number of CD68+ cells, which attested to the leading role of macrophages in activation of HGF synthesis in the lungs. Macrophage content in the kidneys after subtotal hepatectomy did not increase.

Population structure, epidemiology and antibiotic resistance patterns of Streptococcus pneumoniae serotype 5: prior to PCV-13 vaccine introduction in Eastern Gambia.

BACKGROUND: Streptococcus pneumoniae serotype 5 is among the most common serotypes causing invasive pneumococcal disease (IPD) in The Gambia. We anticipate that introduction of the 13-valent pneumococcal conjugate vaccine (PCV-13) into routine vaccination in The Gambia will reduce serotype 5 IPD. However, the emergence of new clones that have altered their genetic repertoire through capsular switching or genetic recombination after vaccination with PCV-13 poses a threat to this public health effort. In order to monitor for potential genetic changes post-PCV-13 vaccination, we established the baseline population structure, epidemiology, and antibiotic resistance patterns of serotype 5 before the introduction of PCV-13. METHODS: Fifty-five invasive S. pneumoniae serotype 5 isolates were recovered from January 2009 to August 2011 in a population-based study in the Upper River Region of The Gambia. Serotyping was done by latex agglutination and confirmed by serotype-specific Polymerase Chain Reaction (PCR). Genotyping was undertaken using Multilocus Sequence Typing (MLST). Antimicrobial sensitivity was done using disc diffusion. Contingency table analyses were conducted using Pearson's Chi(2) and Fisher's exact test. Clustering was performed using Bionumerics version 6.5. RESULTS: MLST resolved S. pneumoniae serotype 5 isolates into 3 sequence types (ST), namely ST 289(6/55), ST 3339(19/55) and ST 3404(30/55). ST 289 was identified as the major clonal complex. ST 3339, the prevalent genotype in 2009 [84.6% (11/13)], was replaced by ST 3404 [70.4% (19/27)] in 2010 as the dominant ST. Interestingly, ST 3404 showed lower resistance to tetracycline and oxacillin (P < 0.001), an empirical surrogate to penicillin in The Gambia. CONCLUSIONS: There has been an emergence of ST 3404 in The Gambia prior to the introduction of PCV-13. Our findings provide important background data for future assessment of the impact of PCV-13 into routine immunization in developing countries, such as The Gambia.

Expression of Cytokine Genes and Growth Factors in Rat Lungs and Kidneys after Subtotal Hepatectomy.

Expression of il1b, il6, il10, tnfa, hgf, tgfb, vegf, and fgf2 genes in the lungs and kidneys was examined on rat model of liver regeneration after subtotal hepatectomy. Enhanced expression of il6, il10, tnfa, hgf, and fgf2 genes was detected at the early terms after 80% liver resection.

Role of Progenitor Cells in Liver Regeneration after Subtotal Resection.

In the liver of rats subjected to subtotal liver resection (80% organ weight), the expression of sox9 gene and SOX9 protein content increased and cells with hepatocyte morphology expressing SOX9 appeared; the proportion of cells expressing cytokeratin-19 also increased. Based on these data, we cannot completely exclude the involvement of resident progenitor cells and hepatocyte reprogramming in liver regeneration after subtotal resection, however, the contribution of these processes seems to be insignificant. The leading mechanism of liver mass recovery after subtotal resection is proliferation of hepatocytes.

Effect of Endothelial Cells on Angiogenic Properties of Multipotent Stromal Cells from the Umbilical Cord during Angiogenesis Modeling in the Basement Membrane Matrix.

Short-term cell culturing on basement membrane matrix is a common and very convenient in vitro model of angiogenesis. We studied the possibility of interaction of multipotent stromal cells from the umbilical cord and Ea.hy926 endothelial cells on this model at the early and late periods of the experiment. Multipotent stromal cells alone and in combination with endothelial cells formed an unstable tubular network. Clusters formed after its disassembling later became the sprouting centers in co-culture of the two cell types, but not in pure culture of multipotent stromal cells. Multipotent stromal cells with CD31+ phenotype constitute the structural basis of newly formed stable 3D capillary-like network. Prolongation of the time of culturing and combination of the two in vitro models of angiogenesis (tubulogenesis and sprouting) allowed more complete assessment of the angiogenic potential of multipotent stromal cells.

Salmonella Infections in The Gambia, 2005-2015.

BACKGROUND: There are large data gaps in the epidemiology of diseases caused by Salmonella enterica in West Africa. Regional surveillance of Salmonella infections is necessary, especially with the emergence and spread of multidrug-resistant clones. METHODS: Data on Salmonella isolated from various clinical specimens from patients from across The Gambia were collected and analyzed retrospectively from 2005 to April 2015. Antibiotic sensitivity testing of Salmonella isolates was performed by disk diffusion method. Serotyping and serogrouping of Salmonella isolates was performed using standard microbiology techniques. RESULTS: Two hundred three Salmonella isolates were isolated from 190 patients: 52% (106/203) from blood and 39% (79/203) from stool specimens. Salmonella was also isolated from urine, aspirates, cerebrospinal fluid, wounds, and abscesses. The prevalence of Salmonella in blood cultures was 0.8% (106/13,905). Of the serotyped salmonellae, 14% (21/152) were Salmonella enterica serovar Typhi, whereas 86% (131/152) were serovars other than Typhi (nontyphoidal Salmonella). Of the 102 typed NTS isolates, 40% (41) were Salmonella enterica serovar Typhimurium, 10% (10) were Salmonella enterica serovar Enteritidis, and 3% (3) were Salmonella enterica serovar Arizonae. Overall, 70% (142/203) of the salmonellae were pansusceptible. Multidrug resistance was found in 4% (9/203) of the isolates, 3 of which were Salmonella Enteritidis. CONCLUSIONS: Salmonellae are associated with a wide spectrum of invasive and noninvasive infections across all ages in The Gambia. There is evidence of multidrug resistance in salmonellae that warrants vigilant monitoring and surveillance.

Microbiota that affect risk for shigellosis in children in low-income countries.

Pathogens in the gastrointestinal tract exist within a vast population of microbes. We examined associations between pathogens and composition of gut microbiota as they relate to Shigella spp./enteroinvasive Escherichia coli infection. We analyzed 3,035 stool specimens (1,735 nondiarrheal and 1,300 moderate-to-severe diarrheal) from the Global Enteric Multicenter Study for 9 enteropathogens. Diarrheal specimens had a higher number of enteropathogens (diarrheal mean 1.4, nondiarrheal mean 0.95; p<0.0001). Rotavirus showed a negative association with Shigella spp. in cases of diarrhea (odds ratio 0.31, 95% CI 0.17-0.55) and had a large combined effect on moderate-to-severe diarrhea (odds ratio 29, 95% CI 3.8-220). In 4 Lactobacillus taxa identified by 16S rRNA gene sequencing, the association between pathogen and disease was decreased, which is consistent with the possibility that Lactobacillus spp. are protective against Shigella spp.-induced diarrhea. Bacterial diversity of gut microbiota was associated with diarrhea status, not high levels of the Shigella spp. ipaH gene.

Effect of multipotent stromal cells on the function of cell mitochondria in regenerating liver.

Intrasplenic allogeneic transplantation of multipotent stromal cells from the umbilical cord stimulates hepatocyte proliferation and promotes recovery of liver weight in rats after subtotal resection (80% organ weight). It can be hypothesized that this effect of multipotent stromal cells is due to more rapid recovery of the number of mitochondria and normalization of mitochondrial function of liver hepatocytes.

The Enterics for Global Health (EFGH) Shigella Surveillance Study in The Gambia.

Background: The Gambia, located in West Africa, is one of 7 country sites conducting the Enterics for Global Health (EFGH) Shigella Surveillance Study to establish incidence and consequence of Shigella-associated medically attended diarrhea among children 6-35 months old. Methods: Here we describe the study site and research experience, sociodemographic characteristics of the study catchment area, facilities of recruitment for diarrhea case surveillance, and known care-seeking behavior for diarrheal illness. We also describe The Gambia's healthcare system and financing, current vaccine schedule and Shigella vaccine adaptation, local diarrhea management guidelines and challenges, and antibiotic resistance patterns in the region. Conclusions: The EFGH study in The Gambia will contribute to the multisite network of Shigella surveillance study and prepare the site for future vaccine trials. In addition, the data produced will inform policy makers about prevention strategies and upcoming Shigella vaccine studies among children in this setting.

Putative correlates of protection against shigellosis assessing immunomarkers across responses to S. sonnei investigational vaccine.

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 α4ß7+ 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.

Microbiological Methods Used in the Enterics for Global Health Shigella Surveillance Study.

Background: Shigella is a major cause of diarrhea in young children worldwide. Multiple vaccines targeting Shigella are in development, and phase 3 clinical trials are imminent to determine efficacy against shigellosis. Methods: The Enterics for Global Health (EFGH) Shigella 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 Shigella. We developed a standardized laboratory protocol for isolation and identification of Shigella 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 Shigella, compare isolation of Shigella from rectal swabs versus whole stool, and compare isolation of Shigella 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.

Evaluation of Fecal Inflammatory Biomarkers to Identify Bacterial Diarrhea Episodes: Systematic Review and Protocol for the Enterics for Global Health Shigella Surveillance Study.

Background: The measurement of fecal inflammatory biomarkers among individuals presenting to care with diarrhea could improve the identification of bacterial diarrheal episodes that would benefit from antibiotic therapy. We reviewed prior literature in this area and describe our proposed methods to evaluate 4 biomarkers in the Enterics for Global Health (EFGH) Shigella surveillance study. Methods: We systematically reviewed studies since 1970 from PubMed and Embase that assessed the diagnostic characteristics of inflammatory biomarkers to identify bacterial diarrhea episodes. We extracted sensitivity and specificity and summarized the evidence by biomarker and diarrhea etiology. In EFGH, we propose using commercial enzyme-linked immunosorbent assays to test for myeloperoxidase, calprotectin, lipocalin-2, and hemoglobin in stored whole stool samples collected within 24 hours of enrollment from participants in the Bangladesh, Kenya, Malawi, Pakistan, Peru, and The Gambia sites. We will develop clinical prediction scores that incorporate the inflammatory biomarkers and evaluate their ability to identify Shigella and other bacterial etiologies of diarrhea as determined by quantitative polymerase chain reaction (qPCR). Results: Forty-nine studies that assessed fecal leukocytes (n = 39), red blood cells (n = 26), lactoferrin (n = 13), calprotectin (n = 8), and myeloperoxidase (n = 1) were included in the systematic review. Sensitivities were high for identifying Shigella, moderate for identifying any bacteria, and comparable across biomarkers. Specificities varied depending on the outcomes assessed. Prior studies were generally small, identified red and white blood cells by microscopy, and used insensitive gold standard diagnostics, such as conventional bacteriological culture for pathogen detection. Conclusions: Our evaluation of inflammatory biomarkers to distinguish diarrhea etiologies as determined by qPCR will provide an important addition to the prior literature, which was likely biased by the limited sensitivity of the gold standard diagnostics used. We will determine whether point-of-care biomarker tests could be a viable strategy to inform treatment decision making and increase appropriate targeting of antibiotic treatment to bacterial diarrhea episodes.

Serogroup W135 meningococcal disease, The Gambia, 2012.

In 2012, an outbreak of Neisseria meningitidis serogroup W135 occurred in The Gambia. The attack rate was highest among young children. The associated risk factors were male sex, contact with meningitis patients, and difficult breathing. Enhanced surveillance facilitates early epidemic detection, and multiserogroup conjugate vaccine could reduce meningococcal epidemics in The Gambia.