BackgroundNewborns and young infants are at higher risk for infections than adults, and manifest suboptimal vaccine responses, motivating a search for novel immunomodulators and/or vaccine adjuvants effective in early life. In contrast to most TLR agonists (TLRA), TLR8 agonists such as imidazoquinolines (IMQs) induce adult-level Th1-polarizing cytokine production from human neonatal cord blood monocytes and are candidate early life adjuvants. We assessed whether TLR8-activating IMQ congeners may differ in potency and efficacy in inducing neonatal cytokine production in vitro, comparing the novel TLR7/8-activating IMQ analogues Hybrid-2, Meta-amine, and Para-amine to the benchmark IMQ resiquimod (R848).MethodsTLRA-induced NF-κB activation was measured in TLR-transfected HEK cells. Cytokine production in human newborn cord and adult peripheral blood and in monocyte-derived dendritic cell cultures were measured by ELISA and multiplex assays. X-ray crystallography characterized the interaction of human TLR8 with Hybrid-2.ResultsHybrid-2 selectively activated both TLR7 and 8 and was more potent than R848 in inducing adult-like levels of TNF-α, and IL-1β. Consistent with its relatively high in vitro activity, crystallographic studies suggest that absence in Hybrid-2 of an ether oxygen of the C2-ethoxymethyl substituent, which can engage in unfavorable electrostatic and/or dipolar interactions with the carbonyl oxygen of Gly572 in human TLR8, may confer greater efficacy and potency compared to R848.ConclusionsHybrid-2 is a selective and potent TLR7/8 agonist that is a candidate adjuvant for early life immunization.

Most infections occur in early life, prompting development of novel adjuvanted vaccines to protect newborns and infants. Several Toll-like receptor (TLR) agonists (TLRAs) are components of licensed vaccine formulations or are in development as candidate adjuvants. However, the type and magnitude of immune responses to TLRAs may vary with the TLR activated as well as age and geographic location. Most notably, in newborns, as compared to adults, the immune response to TLRAs is polarized with lower Th1 cytokine production and robust Th2 and anti-inflammatory cytokine production. The ontogeny of TLR-mediated cytokine responses in international cohorts has been reported, but no study has compared cytokine responses to TLRAs between U.S. neonates and infants at the age of 6 months. Both are critical age groups for the currently pediatric vaccine schedule. In this study, we report quantitative differences in the production of a panel of 14 cytokines and chemokines after in vitro stimulation of newborn cord blood and infant and adult peripheral blood with agonists of TLR4, including monophosphoryl lipid A (MPLA) and glucopyranosyl lipid Adjuvant aqueous formulation (GLA-AF), as well as agonists of TLR7/8 (R848) and TLR9 (CpG). Both TLR4 agonists, MPLA and GLA-AF, induced greater concentrations of Th1 cytokines CXCL10, TNF and Interleukin (IL)-12p70 in infant and adult blood compared to newborn blood. All the tested TLRAs induced greater infant IFN-α2 production compared to newborn and adult blood. In contrast, CpG induced greater IFN-γ, IL-1β, IL-4, IL-12p40, IL-10 and CXCL8 in newborn than infant and adult blood. Overall, to the extent that these in vitro studies mirror responses in vivo, our study demonstrates distinct age-specific effects of TLRAs that may inform their development as candidate adjuvants for early life vaccines.

BackgroundInvestments in faculty exchanges to build physician workforce capacity are increasing. Little attention has been paid to the expectations of host institution faculty and trainees. This prospective qualitative research study explored faculty and resident perspectives about guest faculty in paediatric departments in East Africa, asking (1) What are the benefits and challenges of hosting guest faculty, (2) What factors influence the effectiveness of faculty visits and (3) How do host institutions prepare for faculty visits?MethodsWe recruited 36 faculty members and residents from among four paediatric departments in East Africa to participate in semistructured interviews which were audio recorded and transcribed. Data were qualitatively analysed using principles of open coding and thematic analysis. We achieved saturation of themes.ResultsBenefits of faculty visits varied based on the size and needs of host institutions. Emergent themes included the importance of guest faculty time commitment, and mutual preparation to ensure that visit goals and scheduling met host needs. We documented conflicts that developed around guest emotional responses and ethical approaches to clinical resource limitations, which some hosts tried to prepare for and mitigate. Imbalance in resources led to power differentials; some hosts sought partnerships to re-establish control over the process of having guests.ConclusionsWe identified that guest faculty can assist paediatric institutions in building capacity; however, effective visits require: (1) mutually agreed on goals with appropriate scheduling, visit length and commitment to ensure that the visits meet the host's needs, (2) careful selection and preparation of guest faculty to meet the host's goals, (3) emotional preparation by prospective guests along with host orientation to clinical work in the host's setting and (4) attention to funding sources for the visit and mitigation of resulting power differentials.

Background: Adenoviruses contribute to morbidity and mortality among immunocompromised pediatric patients including stem cell and solid organ transplant recipients. Cidofovir (CDV), an antiviral compound approved by the FDA in 1996, is used for treatment of adenoviral (ADV) infections in immunocompromised patients despite concern of potential nephrotoxicity.   Methods: We conducted a retrospective 5-year review at Boston Children’s Hospital of 16 patients (mean age = 6.5 years) receiving 19 courses of CDV. During therapy all pertinent data elements were reviewed to characterize potential response to therapy and incidence of renal dysfunction.   Results: Of the 19 CDV courses prescribed, 16 courses (84%) were in patients who had a positive blood ADV Polymerase chain reaction (PCR) alone or in combination with positive ADV PCR/ Direct Immunofluorescence Assay (DFA) at another site. Respiratory symptoms with or without pneumonia were the most common presentation (10/19, 53%). In the majority of blood positive courses (10/16, 63%), viral clearance was also accompanied by clinical response. This was not the case in four courses where patients expired despite viral clearance, including one in which death was directly attributable to adenovirus. There was reversible renal dysfunction observed during the use of CDV. Conclusions:  CDV appeared safe and reasonably tolerated for treatment of ADV in this pediatric population and was associated with viral response and clinical improvement in the majority of patients but reversible renal dysfunction was a side effect. Further studies of the efficacy of CDV for immunocompromised children with ADV infection are warranted.

Introduction There are limited data on young people who inject drugs ( PWID ) from low‐ and middle‐income countries where injection drug use remains a key driver of new HIV infections. India has a diverse injection drug use epidemic and estimates suggest that at least half of PWID are ≤30 years of age. We compared injection and sexual risk behaviours and HIV incidence between younger and older PWID and characterized uptake of HIV testing and harm reduction services to inform targeted HIV prevention efforts. Methods We analysed cross‐sectional data from 14,381 PWID recruited from cities in the Northeast and North/Central regions of India in 2013 using respondent driven sampling ( RDS ). We compared “emerging‐adult” (18 to 24 years, 26% of sample) and “young‐adult” PWID (25 to 30 years, 30% of sample) to older PWID (>30 years, 44% of sample) using logistic regression to evaluate factors associated with three recent risk behaviours: needle‐sharing, multiple sexual partners and unprotected sex. We estimated age‐stratified cross‐sectional HIV incidence using a validated multi‐assay algorithm. Results Compared to older adults, emerging‐adults in the Northeastern states were significantly more likely to share needles (males adjusted odds ratio [ aOR ] 1.82; females aOR 2.29, p < 0.01), have multiple sexual partners (males aOR 1.56; females aOR 3.75, p < 0.01), and engage in unprotected sex (males aOR 2.29, p < 0.01). In the North/Central states, young‐adult males were significantly more likely to needle‐share ( aOR 1.23, p < 0.05) while emerging‐adult males were significantly more likely to have multiple sexual partners ( aOR 1.74, p < 0.05). In both regions, emerging‐adults had the lowest HIV testing. Participation in harm reduction services was low across all age groups. Annual HIV incidence was higher in emerging‐ and young‐adult PWID in the North/Central region: emerging‐adults: 4.3% (95% confidence interval [ CI ] 3.0, 5.6); young‐adults: 4.9% (95% CI 3.7, 6.2); older adults: 2.1% (95% CI 1.4, 2.8). Conclusions Higher HIV incidence an...

Abstract. To characterize clinical correlates of typhoid fever-associated encephalopathy, we performed a retrospective chart review of patients with Salmonella enterica serotype Typhi bacteremia who were hospitalized at the International Centre for Diarrhoeal Disease Research, Bangladesh, from February of 2009 to June of 2011. Of 207 patients bacteremic with Salmonella Typhi who were 5 years of age, we identified 43 (21%) patients with encephalopathy. Univariate analysis revealed that patients with encephalopathy more often presented at ages of 10-24 years and had severe dehydration, low oxygen saturation, high respiratory rate, low leukocyte count, low platelet count, and Widal flagellar H agglutinin (TH) titer 1:640 compared with typhoid patients without encephalopathy. Multivariate analysis using logistic regression showed that age, dehydration, leukocyte count, and Widal TH titer were independently associated with encephalopathy. Our findings suggest that age, severity of disease, and immune responses are associated with encephalopathy during Salmonella Typhi bacteremia, perhaps reflecting the impact of prominent inflammatory responses.

India experienced a massive surge in SARS-CoV-2 infections and deaths during April to June 2021 despite having controlled the epidemic relatively well during 2020. Using counterfactual predictions from epidemiological disease transmission models, we produce evidence in support of how strengthening public health interventions early would have helped control transmission in the country and significantly reduced mortality during the second wave, even without harsh lockdowns. We argue that enhanced surveillance at district, state, and national levels and constant assessment of risk associated with increased transmission are critical for future pandemic responsiveness. Building on our retrospective analysis, we provide a tiered data-driven framework for timely escalation of future interventions as a tool for policy-makers.

End‐organ disease caused by CMV is a significant cause of morbidity and mortality in pediatric SOT recipients. Pediatric transplant centers have adopted various approaches for CMV disease prevention in this patient population. We observed significant practice variation in CMV testing, prophylaxis, and surveillance across SOT groups in our center. To address this, we implemented evidence‐based standardized protocols and measured outcomes pre‐ and post‐implementation of these protocols. We performed retrospective chart review for SOT recipients from 2009 to 2014 at Boston Children's Hospital. Using descriptive statistics, we measured practice improvement in provision of appropriate prophylaxis, occurrence of neutropenia and associated complications, and occurrence of CMV DNAemia and CMV disease pre‐ and post‐intervention. The pre‐ and post‐intervention periods included 141 and 109 patients, respectively. With the exception of kidney transplant recipients, provision of appropriate valganciclovir prophylaxis improved across SOT groups post‐intervention (P < .01). Occurrence of >1 episode of neutropenia was greater in the preintervention period (30% vs 10%, P < .001). In both periods, neutropenia was associated with few episodes of invasive infections. The occurrence of CMV disease did not differ and was overall low. However, due to routine surveillance a significantly greater number of asymptomatic CMV DNAemia episodes were identified and treated in the post‐intervention period. Implementation of standardized prevention protocols helped to improve the provision of appropriate prophylaxis to patients at risk for CMV acquisition, increased the diagnosis and treatment of asymptomatic CMV DNAemia, and decreased episodes of recurrent neutropenia in patients receiving prophylaxis.