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Japanese encephalitis (JE) is a significant public health concern in Asia, particularly in children, where vaccination plays a crucial role in prevention. In this study, we investigated the immunogenicity and safety of two different live-attenuated JE vaccines used as primary and booster doses. Fifty healthy participants aged 1-3 years, who were primed with the chimeric JE vaccine IMOJEV® a year earlier, received a booster dose of the SA14-14-2 JE vaccine CD.JEVAX®. To evaluate the immune response, JE-neutralizing antibody titers were assessed on day 0 (pre-booster), day 30, and annually from 1 to 5 years post-booster using the 50% plaque reduction neutralization test (JEPRNT50). The assessment revealed strong immunogenicity 30 d post-booster, with a geometric mean titer of 2092.4 [95% confidence interval (CI): 1473.9-2970.5] and a seroprotection rate of 100%, which gradually decreased to 97.5% at 5 years post-booster. No severe adverse events were observed. The most common reaction within 7 d of vaccination was fever (20%; 95% CI: 10.7-32.3). These results indicate that a booster dose of CD.JEVAX® elicits a strong immune response in children previously vaccinated with IMOJEV® while maintaining a good safety profile, thus supporting the interchangeability of these two live-attenuated JE vaccines. Registered at www.thaiclinicaltrials.org (TCTR ID: TCTR20221102003), our study suggests that CD.JEVAX® can be a viable option for booster vaccination in JE prevention programs, potentially enhancing vaccine flexibility and accessibility.

Vaccine safety and immunogenicity data in human immunodeficiency virus (HIV)-exposed uninfected (HEU) children are important for decision-making in HIV and typhoid co-endemic countries. In an open-label study, we recruited Malawian HEU and HIV unexposed uninfected (HUU) infants aged 9 - 11 months. HEU participants were randomized to receive Vi-tetanus toxoid conjugate vaccine (Vi-TT) at 9 months, Vi-TT at 15 months, or Vi-TT at 9 and 15 months. HUU participants received Vi-TT at 9 and 15 months. Safety outcomes included solicited and unsolicited adverse events (AE) and serious AEs (SAEs) within 7 days, 28 days, and 6 months of vaccination, respectively. Serum was collected before and at day 28 after each vaccination to measure anti-Vi IgG antibodies by enzyme-linked immunosorbent assay (ELISA). Cohort 1 (66 participants) enrollment began 02 December 2019, and follow-up was terminated before completion due to the COVID-19 pandemic. Cohort 2 (100 participants) enrollment began 25 March 2020. Solicited AEs were mostly mild, with no significant differences between HEU and HUU participants or one- and two-dose groups. All six SAEs were unrelated to vaccination. Anti-Vi geometric mean titers (GMT) increased significantly from 4.1 to 4.6 ELISA units (EU)/mL at baseline to 2572.0 - 4117.6 EU/mL on day 28 post-vaccination, and similarly between HEU and HUU participants for both one- and two-dose schedules. All participants seroconverted (>4-fold increase in GMT) by the final study visit. Our findings of comparable safety and immunogenicity of Vi-TT in HUU and HEU children support country introductions with single-dose Vi-TT in HIV-endemic countries.

Parasitic infections are a major global health challenge, driven in part by complex interactions between parasites, host microbiota, and immune responses. Recent advances in microbiome research highlight the critical role of microbiota in influencing disease outcomes and treatment effectiveness. This review examines how changes in the microbiota impact parasite transmission, disease progression, and responses to treatment, focusing on key parasitic diseases such as Chagas disease, leishmaniasis, and ascariasis. The microbiota can either exacerbate or mitigate disease severity, depending on its composition, providing critical insights for novel therapeutic strategies. Emerging approaches discussed include the use of targeted probiotics, prebiotics, and microbiota-modulating drugs to influence parasite dynamics and enhance conventional therapies. The review also explores the potential of integrating microbiota knowledge into vaccine design and immunotherapy, aiming to develop vaccines that elicit stronger immune responses and identify new therapeutic targets. A multidisciplinary approach is essential for translating these findings into effective clinical solutions, with future research focusing on validating microbiota-based interventions in clinical settings. In conclusion, the interaction between microbiota and parasitic infections presents a promising avenue for innovative therapies, with the potential to significantly improve global health outcomes.

Background: Quantitative molecular assays are increasingly used for detection of enteric viruses., Methods: We compared the clinical severity using the modified Vesikari score (mVS) of enteric viruses detected by conventional assays (enzyme immunoassays [EIAs] for rotavirus and adenovirus 40/41 and conventional polymerase chain reaction for astrovirus, sapovirus, and norovirus) and a quantitative molecular assay (TaqMan Array Card [TAC]) among children aged 0-59 months in the Global Enteric Multicenter Study. For rotavirus and adenovirus 40/41, we compared severity between EIA-positive and TAC-positive cases assigned etiologies using different cycle threshold (Ct) cutoffs., Results: Using conventional assays, the median mVS (interquartile range) was 10 (8-11) for rotavirus, 9 (7-11) for adenovirus 40/41, 8 (6-10) for astrovirus, sapovirus, and norovirus GII, and 7 (6-9) for norovirus GI. Compared with rotavirus EIA-positive cases, the median mVS was 2 and 3 points lower for EIA-negative/TAC-positive cases with Ct <32.6 or Ct ≥32.6 and <35, respectively (P < .001). Adenovirus 40/41 EIA-positive and EIA-negative/TAC-positive cases were similar, regardless of Ct cutoff., Conclusions: Quantitative molecular assays compared with conventional assays, such as EIA, may influence the severity of identified cases, especially for rotavirus. Cutoffs to assign etiology for quantitative assays should be considered in the design and interpretation of enteric virus studies., Competing Interests: Potential conflicts of interest. D. S. reports employment and shares with GSK Vaccines, outside the submitted work. A. K. M. Z. was involved in this work as the site principial investigator of the GEMS study at the Aga Khan University during 2008–2012; she is currently the President of Gender Equality at the Bill & Melinda Gates Foundation and has not influenced this analysis from her position there. K. L. K. received funding from the Bill & Melinda Gates Foundation for part of the submitted work and outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

The complex interactions between parasites, their hosts, and associated microbiota hold significant implications for host health and disease outcomes. Helminths like Ascaris lumbricoides and Ascaris suum can significantly alter the host's intestinal microbiota, affecting both parasite biology and host pathology. Despite extensive research on host-microbiota changes due to helminth infections, the study of helminth-associated microbiota remains limited. This study aims to characterize the microbiota associated with Ascaris larvae and surrounding host tissues at distinct developmental stages (day 4, day 8, day 14), during larval migration through the liver, lungs, and intestine, and its impact on the host's microbiota in a murine model. Twenty mice were infected with 2500 embryonated A. suum eggs via oral gavage. Five Ascaris-infected mice and age-matched naïve mice were euthanized at 4-, 8-, and 14-days post-infection (DPI). Stool, intestine, liver, and lung samples were collected. Larvae were isolated from embryonated eggs in vitro, from the liver at 4 DPI, and the lung at 8 DPI. Utilizing 16S rRNA sequencing, we analyzed bacterial diversity in samples from different Ascaris stages and host tissues. Our results revealed a total of 8040 amplicon sequence variants (ASVs) with Ascaris samples displaying the highest diversity. Notably, Ascaris-larvae associated microbiota differed significantly from that of the host, with higher diversity observed in the parasite. Differential abundance analysis identified distinct taxonomic patterns, highlighting specific genera such as Bradyrhizobium, Achromobacter, and Pseudomonas in Ascaris. Our findings suggest that Ascaris harbors a unique microbiota that potentially exchanges bacteria with the host during larval migration. These insights pave the way for further research into the ecological and functional dynamics of helminth-microbiota interactions, which may inform novel therapeutic strategies targeting these microbial relationships to mitigate helminth infections and improve host health outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Plasmodium falciparum (P. falciparum) remains a significant public health challenge globally, especially in sub-Saharan Africa (SSA), where it accounts for 99% of all malaria infections. The outcomes of P. falciparum infection vary, ranging from asymptomatic to severe, and are associated with factors such as host immunity, parasite genetic diversity, and multiplicity of infection (MOI). Using seven neutral microsatellite markers, the current study investigated P. falciparum genetic diversity and MOI in both asymptomatic and symptomatic malaria individuals in Uganda., Methods: This cross-sectional study analyzed 225 P. falciparum isolates from both asymptomatic and symptomatic malaria patients, ranging in age from 6 months to ≥ 18 years. P. falciparum genetic diversity, MOI, and multi-locus linkage disequilibrium (LD) were assessed through genotyping of seven neutral microsatellite markers: Poly-α, TA1, TA109, PfPK2, 2490, C2M34-313, and C3M69-383. Genetic data analysis was performed using appropriate genetic analysis software., Results: P. falciparum infections exhibited high genetic diversity in both asymptomatic and symptomatic individuals. The mean expected heterozygosity (He) ranged from 0.79 in symptomatic uncomplicated malaria cases to 0.81 in asymptomatic individuals. There was no significant difference (p = 0.33) in MOI between individuals with asymptomatic and symptomatic infections, with the mean MOI ranging from 1.92 in symptomatic complicated cases to 2.10 in asymptomatic individuals. Polyclonal infections were prevalent, varying from 58.5% in symptomatic complicated malaria to 63% in symptomatic uncomplicated malaria cases. A significant linkage disequilibrium (LD) was observed between asymptomatic and symptomatic uncomplicated/complicated infections (p < 0.01). Genetic differentiation was low, with F ST values ranging from 0.0034 to 0.0105 among P. falciparum parasite populations in asymptomatic and symptomatic uncomplicated/complicated infections., Conclusion: There is a high level of P. falciparum genetic diversity and MOI among both symptomatic and asymptomatic individuals in Uganda. Asymptomatic carriers harbor a diverse range of parasites, which poses challenges for malaria control and necessitates targeted interventions to develop effective strategies., Competing Interests: Declarations Ethics approval and consent to participate This study utilized secondary data without participant interaction. Study approval and a waiver of consent were provided by the Makerere University School of Medicine Institutional Review Board (# Mak-SOMREC-2021-152) and the Uganda National Council for Science and Technology (# HS2744ES). Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Intensive malaria control and elimination efforts have led to substantial reductions in malaria incidence over the past two decades. However, the reduction in Plasmodium falciparum malaria cases has led to a species shift in some geographic areas, with P. vivax predominating in many areas outside of Africa. Despite its wide geographic distribution, P. vivax vaccine development has lagged far behind that for P. falciparum, in part due to the inability to cultivate P. vivax in vitro, hindering traditional approaches for antigen identification. In a prior study, we have used a positive-unlabeled random forest (PURF) machine learning approach to identify P. falciparum antigens based on features of known antigens for consideration in vaccine development efforts. Here we integrate systems data from P. falciparum (the better-studied species) to improve PURF models to predict potential P. vivax vaccine antigen candidates. We further show that inclusion of known antigens from the other species is critical for model performance, but the inclusion of only the unlabeled proteins from the other species can result in misdirection of the model toward predictors of species classification, rather than antigen identification. Beyond malaria, incorporating antigens from a closely related species may aid in vaccine development for emerging pathogens having few or no known antigens., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The investigation of factors associated with susceptibility to severe malaria is best achieved using case-control studies. The presence of a history of severe malaria in controls could affect the quality of their phenotype and study findings and hence should be rigorously determined. Here, we assessed the performance of a qualitative questionnaire to identify a history of cerebral malaria in controls in a case-control study of severe malaria in Mali. We evaluated the archived medical records of 220 children diagnosed with severe diseases at health care centers in rural and urban settings in Mali from 2018 to 2019. Parents of enrolled children were then identified and interviewed using a structured questionnaire by an investigator blinded to the diagnosis. The diagnosis derived from the interview was then compared with the diagnosis from the medical records as the reference diagnosis. The sensitivity and specificity of the questionnaire to detect cerebral malaria in history were, respectively, 84% and 76%. The questionnaire was concordant with the medical record diagnosis in 60% (95% CI: 50-71%) of cases. For other clinical phenotypes of malaria (severe malaria anemia, uncomplicated malaria, and severe malaria anemia concurrent with cerebral malaria), sensitivity and specificity ranged from 42% to 85% and 88% to 96%, respectively. Positive and negative predictive values were, respectively, 75% and 85%. The questionnaire demonstrated suitable sensitivity and specificity to identify cerebral malaria in a participant's history. In sub-Saharan Africa, a region with suboptimal medical record archives, such a tool could be used in case-control studies of severe malaria to select controls.

This study investigated the mediators of the association between socioeconomic position (SEP) and Plasmodium falciparum (Pf) infection in Southern region of Malawi. We utilized data from the 2014 International Center of Excellence for Malaria Research (ICEMR) surveys from Malawi in which blood samples of all individuals from selected households in Blantyre, Thyolo and Chikhwawa were tested for Pf parasitemia. We assessed household SEP and potential mediators - housing quality, food security, education status of household heads, and use of long-lasting Insecticide-treated nets (LLINs) and nutritional status. We conducted causal mediation analyses to assess the proportion of SEP effect that is attributed to each mediator and combination of mediators. The mediation analysis shows that during the rainy season, improved housing and educational attainment explained 39.4% and 17.0% of the SEP effect on Pf infection, respectively, and collectively 66.4%. In the dry season, housing, educational attainment, and LLIN usage collectively mediated 33.4% of SEP's effect with individual contributions of 15.6%, 11.2%, and 3.8%, respectively. Nutrition also played a role, particularly for children, mediating 9.2% of SEP's effect in the rainy season and 3.7% in the dry season. The study concluded that multifaceted interventions targeting housing, education, LLIN usage, and nutrition are vital to reducing socioeconomic disparities in Pf infection risk in the Southern region of Malawi., (© 2024. The Author(s).)

Background: The role of meningitis in causing deaths and in children under 5 is unclear, especially since widespread use of vaccines to prevent common causes of meningitis. Child Health and Mortality Prevention Surveillance (CHAMPS) uses post-mortem minimally invasive tissue sampling (MITS) and ante-mortem data to explore death causes. We aimed to assess meningitis's contribution to mortality and identify causative pathogens in children under 5 within CHAMPS Network sites., Method: In this observational study, we analyzed deaths in live-born children <5 years of age that occurred between December 16, 2016, and December 31, 2023, in CHAMPS catchments in six sub-Saharan African countries (Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, South Africa) and Bangladesh. MITS was conducted within 24-72 h of death, including blood and cerebrospinal fluid (CSF) culture, multi-organism targeted nucleic acid amplification tests on blood, CSF and lung tissue, and histopathology of lung, liver and brain. Expert panels at each site reviewed data to attribute causes of death following ICD-10 standards., Result: Meningitis was in the causal pathway for 7.0% (270/3857) of deaths; in 4.8% (13/270) meningitis was considered the underlying condition. Neonates accounted for 65.9% (178/270) and infants or children 34.1% (92/270). Among neonatal meningitis deaths, 55.6% (99/178) occurred ≥72 h post-hospital admission; and common pathogens were Acinetobacter baumannii (49.5%, 49/99; mainly from South Africa) and Klebsiella pneumoniae (40.4%, 40/99). Forty-four percent (79/178) of neonatal meningitis deaths were community-associated, primarily due to K. pneumoniae (35.4%, 28/79) and Escherichia coli (13.9%, 11/79). Among infant and child meningitis deaths, 43.5% (40/92) occurred ≥72 h post-admission; and common pathogens were K. pneumoniae (42.5%,17/40) and A. baumannii (17.5%, 7/40). Among community-associated meningitis deaths in infants and children (56.5%, 52/92), Streptococcus pneumoniae (34.6%, 18/52) and K. pneumoniae (19.2%, 10/52) were common pathogens. Pathogen prevalence varied by region., Conclusion: Our study highlights meningitis as a significant contributor to under-5 mortality in low-middle-income countries. The prominent role of K. pneumoniae and A. baumannii, particularly in healthcare settings and specific regions, highlights the need for better infection control, targeted interventions, and more effective treatment strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Acyclovir (ACV) is a vital treatment for herpes simplex (HSV) and varicella-zoster virus (VZV) infections that inhibit viral DNA polymerase. Phosphoramidate ProTides-ACV, a promising technology, circumvents the reliance on thymidine kinase (TK) for activation. Twelve novel single isomers of phosphoramidate ProTide-ACV were synthesized. Successful isomer separation was achieved, emphasizing the importance of single isomers in medical advancements. The enzymatic hydrolysis kinetics of the synthesized compounds were investigated by using carboxypeptidase Y (CPY). The results revealed a faster conversion for the isomer R p- than for the S p-diastereomer. Hydrolysis experiments confirmed steric hindrance effects, particularly with the tert -butyl and isopropyl groups. Molecular modeling elucidated the mechanisms of hydrolysis, supporting the results of the experiments. This research sheds light on the potential of phosphoramidate ProTides-ACV, bridging the gap in understanding their biological and metabolic properties, while supporting future investigations into anti-HSV activity. Preliminary screening revealed that three of the four single isomers demonstrated superior antiviral efficacy against wild-type HSV-1 compared to acyclovir, with isomer 24a ultimately reducing the viral yield at 200 μM. These findings emphasize the importance of isolating racemic ACV-ProTides as pure single isomers for future drug development., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Objectives: After respiratory syncytial virus (RSV), human metapneumovirus (hMPV) was the second-ranked pathogen attributed to severe pneumonia in the PERCH study. We sought to characterize hMPV-positive cases in high-burden settings, which have limited data, by comparing with RSV-positive and other cases., Methods: Children aged 1-59 months hospitalized with suspected severe pneumonia and age/season-matched community controls in seven African and Asian countries had nasopharyngeal/oropharyngeal swabs tested by multiplex PCR for 32 respiratory pathogens, among other clinical and lab assessments at admission. Odds ratios adjusted for age and site (adjusted OR [aOR]) were calculated using logistic regression. Aetiologic probability was estimated using Bayesian nested partial latent class analysis. Latent class analysis identified syndromic constellations of clinical characteristics., Results: hMPV was detected more frequently among cases (267/3887, 6.9%) than controls (115/4976, 2.3%), among cases with pneumonia chest X-ray findings (8.5%) than without (5.5%), and among controls with respiratory tract illness (3.8%) than without (1.8%; all p ≤ 0.001). HMPV-positive cases were negatively associated with the detection of other viruses (aOR, 0.18), especially RSV (aOR, 0.11; all p < 0.0001), and positively associated with the detection of bacteria (aORs, 1.77; p 0.03). No single clinical syndrome distinguished hMPV-positive from other cases. Among hMPV-positive cases, 65.2% were aged <1 year and 27.5% had pneumonia danger signs; positive predictive value for hMPV aetiology was 74.5%; mortality was 3.9%, similar to RSV-positive (2.4%) and lower than that among other cases (9.6%)., Discussion: HMPV-associated severe paediatric pneumonia in high-burden settings was predominantly in young infants and clinically indistinguishable from RSV. HMPV-positives had low case fatality, similar to that in RSV-positives., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: ZR-202-CoV and ZR-202a-CoV are novel recombinant vaccines containing 25 µg of the prototype (Wuhan strain) or B.1.351 strain (Beta variant) SARS-CoV-2 S-protein expressed in CHO cells, respectively, adjuvanted with Al(OH) 3 and CpG-ODN. We assessed their safety and immunogenicity in this Phase I, randomized, observer-blind, controlled study in Mali., Design: Sixty healthy 18-55-year-old adults randomized 1:1:1 received two doses of ZR-202-CoV, ZR-202a-CoV, or Comirnaty Ⓡ 28 days apart. Primary outcome measures were solicited and unsolicited adverse events (AEs) including AESI (Adverse Events of Special Interest); secondary outcome was immunogenicity measured as SARS-CoV-2 specific neutralizing antibodies. Participants were followed up for 1 year., Results: Injection site pain and headache were the most frequent solicited local and systemic AEs, respectively. No unsolicited AEs or SAEs related to vaccination were reported during the study period. Although most participants had detectable neutralizing antibodies at baseline robust immune responses were observed in all vaccine groups after the first dose with no further increase after the second dose. Cross-neutralizing antibody responses against Beta, Delta, and Omicron BA.5 variants were similar in magnitude after ZR-202-CoV, ZR-202a-CoV and Comirnaty Ⓡ ., Conclusions: Similar reactogenicity and immunogenicity profiles of ZR-202-CoV, ZR-202a-CoV and Comirnaty Ⓡ support further clinical investigation in a wider population., Competing Interests: Declarations of competing interest The authors declare the following competing interests: Min Ji, Xi Han, and Chenliang Zhou are employees of Shanghai Zerun Biotechnology Co., Ltd. All other authors report no potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: We used machine learning to identify novel strategies to target azithromycin to the children with watery diarrhea who are most likely to benefit., Methods: Using data from a randomized trial of azithromycin for watery diarrhea, we developed personalized treatment rules given sets of diagnostic, child, and clinical characteristics, employing a robust ensemble machine learning-based procedure. For each rule, we estimated the proportion treated under the rule and the average benefits of treatment., Results: Among 6,692 children, treatment was recommended on average for approximately one third of children. The risk of diarrhea on day 3 was 10.1% lower (95% CI: 5.4, 14.9) with azithromycin compared to placebo among children recommended for treatment. For day 90 re-hospitalization and death, risk was 2.4% lower (95% CI: 0.6, 4.1) with azithromycin compared to placebo among those recommended for treatment. While pathogen diagnostics were strong determinants of azithromycin effects on diarrhea duration, host characteristics were more relevant for predicting benefits for re-hospitalization or death., Conclusion: The ability of host characteristics to predict which children benefit from azithromycin with respect to the most severe outcomes suggests appropriate targeting of antibiotic treatment among children with watery diarrhea may be possible without access to pathogen diagnostics., Competing Interests: Competing interests The authors have no competing interests as defined by Nature Research, or other interests that might be perceived to influence the interpretation of the article.

The quality of protective immunity plays a critical role in modulating vaccine efficacy, with native antigens often not able to trigger sufficiently strong immune responses for pathogen killing. This warrants creation of structure-based vaccine design, leveraging high-resolution antigen structures for mutagenesis to improve protein stability and efficient immunization strategies. Here, we investigated the mechanisms underlying structure-based vaccine design using CspZ-YA, a vaccine antigen from Borrelia burgdorferi , the bacteria causing Lyme disease (LD), the most common vector-borne disease in the Northern Hemisphere. Compared to wild-type CspZ-YA, we found CspZ-YA I183Y and CspZ-YA C187S required lower immunization frequency to protect mice from LD-associated manifestations and bacterial colonization. We observed indistinguishable human and mouse antigenicity between wild-type and mutant CspZ-YA proteins after native infection or active immunization. This supports our newly generated, high-resolution structures of CspZ-YA I183Y and CspZ-YA C187S , showing no altered surface epitopes after mutagenesis. However, CspZ-YA I183Y and CspZ-YA C187S favored the interactions between helices H and I, consistent with their elevated thermostability. Such findings are further strengthened by increasing ability of protective CspZ-YA monoclonal antibodies in binding to CspZ-YA at a physiological temperature (37°C). Overall, this study demonstrated enhanced intramolecular interactions improved long-term stability of antigens while maintaining protective epitopes, providing a mechanism for structure-based vaccine design. These findings can ultimately be extended to other vaccine antigens against newly emerging pathogens for the improvement of protective immunity.

Klebsiella pneumoniae is well recognized as a serious cause of infection in healthcare-associated settings and immunocompromised individuals; however, accumulating evidence from resource-limited nations documents an alarming rise in community-acquired K . pneumoniae infections, manifesting as bacteremia and pneumonia as well as neonatal sepsis. The emergence of hypervirulent and antibiotic-resistant K . pneumoniae strains threatens treatment options for clinicians. Effective vaccination strategies could represent a viable alternative that would both preempt the need for antibiotics to treat K . pneumoniae infections and reduce the burden of K . pneumoniae disease globally. There are currently no approved K. pneumoniae vaccines. We review the evidence for K . pneumoniae lipopolysaccharide (LPS) as a vaccine and immunotherapeutic target and discuss the role of antibodies specific for the core or O-antigen determinants within LPS in protection against Klebsiella spp. disease. We expand on the known role of the Klebsiella spp. capsule and O-antigen modifications in antibody surface accessibility to LPS as well as the in vitro and in vivo effector functions reported for LPS-specific antibodies. We summarize key hypotheses stemming from these studies, review the role of humoral immunity against K . pneumoniae O-antigen for protection, and identify areas requiring further research.

Background: This study aims to understand factors contributing to pediatric COVID-19 vaccine hesitancy among pregnant and postpartum adults., Method: The study used targeted intercept advertising on Facebook, Twitter, and Instagram to recruit a panel of 3600 pregnant and postpartum US adults. Data were collected between December 2021 and April 2022 (i.e., before the introduction of pediatric COVID-19 vaccines in the U.S.). We used logistic regression to understand factors associated with pregnant and postpartum women's hesitancy towards getting children <5 vaccinated against COVID-19. Poststratification weights were applied to analyses to promote the representativeness of the sample. We also conducted a qualitative thematic analysis to determine the reasons for pediatric vaccine hesitancy., Results: Nearly half (45.6 %) of pregnant or postpartum women were hesitant to vaccinate their child against COVID-19. Vaccine hesitancy was lower among those who had a high perceived susceptibility to COVID-19, had increased perceived severity of COVID-19, and increased perceived benefits of the COVID-19 vaccine. Perceived barriers related to long-term side effects of vaccines were positively associated with hesitancy to vaccinate children. Older women, women in urban areas, and those born outside the US were less likely to be hesitant to vaccinate children <5 against COVID-19. Compared to respondents with a high school education or less, the odds of pediatric vaccine hesitancy were higher among respondents with some college. Pregnant and postpartum women who were hesitant about getting children <5 vaccinated cited the following reasons for hesitancy: concerns about the vaccine, lack of evidence on vaccine safety, and the COVID-19 vaccine is not necessary for children., Conclusion: Our findings suggest that public health messages to promote the COVID-19 vaccine for young children should focus on the risks and consequences of the disease and share data on the effectiveness of the vaccine in preventing severe COVID-19-related outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Diarrhoeal diseases cause a heavy burden in developing countries. Although studies have described the seasonality of diarrhoeal diseases, the association of weather variables with diarrhoeal diseases has not been well characterized in resource-limited settings where the burden remains high. We examined short-term associations between ambient temperature, precipitation and hospital visits due to diarrhoea among children in seven low- and middle-income countries., Methodology: Hospital visits due to diarrhoeal diseases under 5 years old were collected from seven sites in The Gambia, Mali, Mozambique, Kenya, India, Bangladesh, and Pakistan via the Global Enteric Multicenter Study from December 2007 to March 2011. Daily weather data during the same period were downloaded from the ERA5-Land. We fitted time-series regression models to examine the relationships of daily diarrhoea cases with daily ambient temperature and precipitation. Then, we used meta-analytic tools to examine the heterogeneity between the site-specific estimates., Principal Findings: The cumulative relative risk (RR) of diarrhoea for temperature exposure (95th percentile vs. 1st percentile) ranged from 0.24 to 8.07, with Mozambique and Bangladesh showing positive associations, while Mali and Pakistan showed negative associations. The RR for precipitation (95th percentile vs. 1st percentile) ranged from 0.77 to 1.55, with Mali and India showing positive associations, while the only negative association was observed in Pakistan. Meta-analysis showed substantial heterogeneity in the association between temperature-diarrhoea and precipitation-diarrhoea across sites, with I2 of 84.2% and 67.5%, respectively., Conclusions: Child diarrhoea and weather factors have diverse and complex associations across South Asia and Sub-Saharan Africa. Diarrhoeal surveillance system settings should be conceptualized based on the observed pattern of climate change in these locations., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hossain et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Severe dehydration due to acute infectious diarrhea remains a leading cause of death among young children worldwide. Diarrhea with severe dehydration is a clinical syndrome with distinct management per the World Health Organization (WHO) Integrated Management of Childhood Illness (IMCI) and the WHO Global Task Force on Cholera Control (GTFCC) guidelines. We sought to characterize the pathogens causing severe dehydration using data from the Global Enteric Multicenter Study., Methods: We used the IMCI and GTFCC guidelines to define severe dehydration and quantitative polymerase chain reaction-based attribution models to assign the etiology of diarrhea associated with severe dehydration., Results: The IMCI or GTFCC guidelines classified 2284 of the 5304 (43%) cases with moderate-to-severe diarrhea as having severe dehydration. In one-third of the cases with severe dehydration, no pathogens were attributed. The top pathogens attributed to children with guidelines-classified severe dehydration varied by age and were similar among those requiring intravenous hydration and hospitalization. Rotavirus (30.9%), Cryptosporidium (12.0%), and heat-stable (ST) enterotoxigenic Escherichia coli (ETEC) (10.3%) were the most common pathogens for ages 0-11 months, while Shigella /enteroinvasive E coli (EIEC) (25.8%), rotavirus (19.3%), and ST-ETEC (10.9%) were the most common for ages 12-23 months. Shigella /EIEC (25.9%), Vibrio cholerae (10.4%), and rotavirus (9.2%) were the most common among ages 24-59 months., Conclusions: The findings inform prioritization of pathogens, in addition to V cholerae , that cause severe dehydration for future preventive and treatment efforts. The schema for prioritization is driven primarily by age stratifications., Competing Interests: Potential conflicts of interest. A. T. P. has served as a consultant to Sanofi, GSK, and Haleon, unrelated to the current work. All other authors report no potential conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Approximately 12% of all diarrhoeal episodes last for 7-13 days. As such, they are termed prolonged diarrhoea, and are associated with over two-thirds of all diarrhoeal deaths. Due to a lack of robust data, we aimed to evaluate a comparative background characteristics of young children with acute and prolonged diarrhoea, and their outcomes at day 90 follow-up., Methods: We performed a secondary analysis of data from the Antibiotics for Children with Diarrhea (ABCD) trial. Children aged 2-23 months were enrolled between July 2017 and July 2019 from seven Asian and sub-Saharan African countries. For this analysis, we divide diarrhoea into two categories: acute diarrhoea (duration <7 days) and prolonged diarrhoea (duration ≥7-13 days). We used logistic regression to observe baseline crude and adjusted associations and linear regression to compare post-discharge outcomes., Results: We analysed data on 8266 children, of whom 756 (9%) had prolonged diarrhoea and 7510 (91%) had acute diarrhoea. Pakistan had the highest proportion of children with prolonged diarrhoea (n/N = 178/1132, 16%), while Tanzania had the lowest (n/N = 12/1200, 1%). From an analysis that adjusted for sex, breastfeeding, nutritional status, clinical presentation, housing, water supply, sanitation, and country, we observed that presentation at a health facility with prolonged diarrhoea was associated with low age (2-12 months) (adjusted odds ratio (aOR) = 1.25; 95% confidence interval (CI) = 1.02, 1.53; P = 0.028), presence of three or more under-five children in the family (aOR = 1.54; 95% CI = 1.26, 1.87; P < 0.001), maternal illiteracy (aOR = 1.45; 95% CI = 1.21, 1.74, P < 0.001), moderate underweight (aOR = 1.25; 95% CI = 1.01, 1.55; P = 0.042) and pathogen (Campylobacter) (aOR = 1.27; 95% CI = 1.12, 1.44; P < 0.001). At day 90 follow-up, children with prolonged diarrhoea had significantly lower weight-for-age z-score compared to children with acute diarrhoea (-1.62, standard deviation (SD) = 1.11 vs -1.52, SD = 1.20; P = 0.032), as well as significantly higher frequency of hospital admission (6.1% vs 4.5%; P = 0.042)., Conclusions: Prolonged diarrhoea was more common in children of younger age, those who were moderately underweight, those with Campylobacter in stool, those with three or more under-five children in a family, and those with illiterate mothers compared to those who had acute diarrhoea. Children with prolonged diarrhoea more often required hospitalisation during the three-month follow-up period compared to their counterparts., Competing Interests: Disclosure of interests: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Gelatin methacryloyl (GelMA), typically derived from mammalian sources, has recently emerged as an ideal bio-ink for three-dimensional (3D) bioprinting. Herein, we developed a fish skin-based GelMA bio-ink for the fabrication of a 3D GelMA skin substitute with a 3D bioprinter. Several concentrations of methacrylic acid anhydride were used to fabricate GelMA, in which their physical-mechanical properties were assessed. This fish skin-based GelMA bio-ink was loaded with human adipose tissue-derived mesenchymal stromal cells (ASCs) and human platelet lysate (HPL) and then printed to obtain 3D ASCs + HPL-loaded GelMA scaffolds. Cell viability test and a preliminary investigation of its effectiveness in promoting wound closure were evaluated in a critical-sized full thickness skin defect in a rat model. The cell viability results showed that the number of ASCs increased significantly within the 3D GelMA hydrogel scaffold, indicating its biocompatibility property. In vivo results demonstrated that ASCs + HPL-loaded GelMA scaffolds could delay wound contraction, markedly enhanced collagen deposition, and promoted the formation of new blood vessels, especially at the wound edge, compared to the untreated group. Therefore, this newly fish skin-based GelMA bio-ink developed in this study has the potential to be utilized for the printing of 3D GelMA skin substitutes., (© 2024. The Author(s).)

Plasmodium parasites, the causative organism of malaria, caused over 600,000 deaths in 2022. In Mali, Plasmodium falciparum causes the majority of malaria cases and deaths and is transmitted seasonally. Anti-malarial immunity develops slowly over repeated exposures to P. falciparum and some aspects of this immunity (e.g., antibody titers) wane during the non-transmission, dry season. Here, we sequenced RNA from 33 pediatric blood samples collected during P. falciparum infections at the beginning or end of a transmission season, and characterized the host and parasite gene expression profiles for paired, consecutive infections. We found that human gene expression changes more over the course of one transmission season than between seasons, with signatures of partial development of an adaptive immune response during one transmission season and stability in gene expression during the dry season. Additionally, we found that P. falciparum gene expression did not vary with timing during the season and remained stable both across and between seasons, despite varying human immune pressures. Our results provide insights into the dynamics of anti-malarial immune response development over short time frames that could be exploited by future vaccine and prevention efforts., Importance: Our work seeks to understand how the immune response to Plasmodium falciparum malaria changes between infections that occur during low and high malaria transmission seasons, and highlights that immune gene expression changes more during the high transmission season. This provides important insight into the dynamics of the anti-malarial immune response that are important to characterize over these short time frames to better understand how to exploit this immune response with future vaccine efforts., Competing Interests: The authors declare no conflict of interest.