Efficacy and Safety of a Tetravalent Dengue Vaccine (TAK-003) in Children With Prior Japanese Encephalitis or Yellow Fever Vaccination.

BACKGROUND: We explored the impact of prior Yellow fever (YF) or Japanese encephalitis (JE) vaccination on the efficacy of Takeda's dengue vaccine candidate, TAK-003 (NCT02747927). METHODS: Children 4-16 years of age were randomized 2:1 to receive TAK-003 or placebo and were under active febrile surveillance. Symptomatic dengue was confirmed by serotype-specific RT-PCR. YF and JE vaccination history was recorded. RESULTS: Of the 20,071 children who received TAK-003 or placebo, 21.1% had a YF and 23.9% had a JE vaccination history at randomization. Fifty-seven months after vaccination, vaccine efficacy was 55.7% (95% CI, 39.7%-67.5%) in those with YF vaccination, 77.8% (70.8%-83.1%) for JE vaccination, and 53.5% (45.4%-60.4%) for no prior YF/JE vaccination. Regional differences in serotype distribution confound these results. The apparent higher vaccine efficacy in the JE vaccination subgroup could be largely explained by serotype-specific efficacy of TAK-003. Within 28 days of any vaccination, the proportions of participants with serious adverse events in the YF/JE prior vaccination population were comparable between the TAK-003 and placebo groups. CONCLUSIONS: The available data do not suggest a clinically relevant impact of prior JE or YF vaccination on TAK-003 performance. Overall, TAK-003 was well-tolerated and efficacious in different epidemiological settings.

Safety and Immunogenicity of a ChAd155-Vectored Respiratory Syncytial Virus Vaccine in Infants 6-7 Months of age: A Phase 1/2 Randomized Trial.

BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections in infants. This phase 1/2, observer-blind, randomized, controlled study assessed the safety and immunogenicity of an investigational chimpanzee-derived adenoviral vector RSV vaccine (ChAd155-RSV, expressing RSV F, N, and M2-1) in infants. METHODS: Healthy 6- to 7-month-olds were 1:1:1-randomized to receive 1 low ChAd155-RSV dose (1.5 × 1010 viral particles) followed by placebo (RSV_1D); 2 high ChAd155-RSV doses (5 × 1010 viral particles) (RSV_2D); or active comparator vaccines/placebo (comparator) on days 1 and 31. Follow-up lasted approximately 2 years. RESULTS: Two hundred one infants were vaccinated (RSV_1D: 65; RSV_2D: 71; comparator: 65); 159 were RSV-seronaive at baseline. Most solicited and unsolicited adverse events after ChAd155-RSV occurred at similar or lower rates than after active comparators. In infants who developed RSV infection, there was no evidence of vaccine-associated enhanced respiratory disease (VAERD). RSV-A neutralizing titers and RSV F-binding antibody concentrations were higher post-ChAd155-RSV than postcomparator at days 31, 61, and end of RSV season 1 (mean follow-up, 7 months). High-dose ChAd155-RSV induced stronger responses than low-dose, with further increases post-dose 2. CONCLUSIONS: ChAd155-RSV administered to 6- to 7-month-olds had a reactogenicity/safety profile like other childhood vaccines, showed no evidence of VAERD, and induced a humoral immune response. Clinical Trials Registration. NCT03636906.

Incidence of Respiratory Syncytial Virus-Associated Lower Respiratory Tract Illness in Infants in Low- and Middle-Income Regions During the Coronavirus Disease 2019 Pandemic.

Background: Incidence data of respiratory syncytial virus-associated lower respiratory tract illness (RSV-LRTI) are sparse in low- and middle-income countries (LMICs). We estimated RSV-LRTI incidence rates (IRs) in infants in LMICs using World Health Organization case definitions. Methods: This prospective cohort study, conducted in 10 LMICs from May 2019 to October 2021 (largely overlapping with the coronavirus disease 2019 [COVID-19] pandemic), followed infants born to women with low-risk pregnancies for 1 year from birth using active and passive surveillance to detect potential LRTIs, and quantitative reverse-transcription polymerase chain reaction on nasal swabs to detect RSV. Results: Among 2094 infants, 32 (1.5%) experienced an RSV-LRTI (8 during their first 6 months of life, 24 thereafter). Seventeen (0.8%) infants had severe RSV-LRTI and 168 (8.0%) had all-cause LRTI. IRs (95% confidence intervals [CIs]) of first RSV-LRTI episode were 1.0 (.3-2.3), 0.8 (.3-1.5), and 1.6 (1.1-2.2) per 100 person-years for infants aged 0-2, 0-5, and 0-11 months, respectively. IRs (95% CIs) of the first all-cause LRTI episode were 10.7 (8.1-14.0), 11.7 (9.6-14.0), and 8.7 (7.5-10.2) per 100 person-years, respectively. IRs varied by country (RSV-LRTI: 0.0-8.3, all-cause LRTI: 0.0-49.6 per 100 person-years for 0- to 11-month-olds). Conclusions: RSV-LRTI IRs in infants in this study were relatively low, likely due to reduced viral circulation caused by COVID-19-related nonpharmaceutical interventions. Clinical Trials Registration: NCT03614676.

Are the first 1,000 days of life a neglected vital period to prevent the impact on maternal and infant morbimortality of infectious diseases in Latin America? Proceedings of a workshop of experts from the Latin American Pediatric Infectious Diseases Society, SLIPE.

While the first 1,000 days of life are a critical period in child's development, limited information on the main determinants affecting this period in the Latin America and the Caribbean (LAC) region is available. Therefore, the Latin American Pediatric Infectious Diseases Society (SLIPE) held an ad hoc workshop in May 2022 with an expert panel designed to analyze the main factors impacting the development of childhood in the region during this period and the main causes of maternal infant morbimortality. The aim was to identify priorities, generate recommendations, and advise practical actions to improve this situation. Considerations were made about the challenges involved in bridging the gap that separates the region from more developed countries regarding an optimal early childhood and maternal care. Extensive discussion was conducted to reach consensus recommendations on general strategies intended to reduce maternal and infant mortality associated with infections and immune-preventable diseases during the first 1,000 days of life in LAC.

Risks of low vaccination coverage and strategies to prevent the resurgence of vaccine-preventable diseases in infants in the COVID-19 pandemic scenario: recommendations for Latin America and the Caribbean by the group of experts on infant immunization for Latin America.

INTRODUCTION: The WHO 2030 Immunization Agenda (IA-2030) harmonizes immunization activity plans at community, national, regional and global levels. Additionally, medical societies play an important role. The Latin American Group of Experts on Infant Immunization, established in 2018, advises on the harmonization, update, and optimization of infant vaccination programs in Latin America and the Caribbean (LAC). In September 2021, 41 such experts from 13 LAC countries met to develop recommendations for increasing regional vaccination coverage to avoid the reemergence of vaccine-preventable diseases and/or the occurrence of outbreaks. AREAS COVERED: The following items were evaluated: (i) immunization challenges before and during the COVID-19 pandemic; (ii) the status of current immunization programs, particularly infant pertussis and polio vaccination; (iii) possible solutions for overcoming vaccination challenges and achieving regional vaccination coverage targets. EXPERT OPINION/COMMENTARY: Medical societies provide valuable recommendations to guide and update vaccination schedules. In the LAC region, possible strategies to achieve target vaccination rates include the use of combination vaccines, strengthening surveillance systems, improving school attendance, advancing vaccine education and confidence, striving for vaccination equity, widening operational capacity, creating strategic alliances, and strengthening the role of medical groups. It is hoped that these recommendations will be implemented in the LAC region.

Carbapenem resistance in Enterobacterales bloodstream infections among children with cancer or post-haematopoietic stem cell transplant: a retrospective cohort study.

BACKGROUND: Risk factors for carbapenem resistance in Enterobacterales bloodstream infections among children with cancer or post-HSCT have not been thoroughly explored. METHODS: All children with cancer or post-HSCT who developed Enterobacterales bloodstream infections in two cancer referral centres in major Colombian cities between 2012 and 2021 were retrospectively examined. When the infection episode occurred, carbapenem resistance mechanisms were evaluated according to the available methods. Data were divided in a training set (80%) and a test set (20%). Three internally validated carbapenem-resistant Enterobacterales (CRE) prediction models were created: a multivariate logistic regression model, and two data mining techniques. Model performances were evaluated by calculating the average of the AUC, sensitivity, specificity and predictive values. RESULTS: A total of 285 Enterobacterales bloodstream infection episodes (229 carbapenem susceptible and 56 carbapenem resistant) occurred [median (IQR) age, 9 (3.5-14) years; 57% male]. The risk of CRE was 2.1 times higher when the infection was caused by Klebsiella spp. and 5.8 times higher when a carbapenem had been used for ≥3 days in the previous month. A model including these two predictive variables had a discriminatory performance of 77% in predicting carbapenem resistance. The model had a specificity of 97% and a negative predictive value of 81%, with low sensitivity and positive predictive value. CONCLUSIONS: Even in settings with high CRE prevalence, these two variables can help early identification of patients in whom CRE-active agents are unnecessary and highlight the importance of strengthening antibiotic stewardship strategies directed at preventing carbapenem overuse.

Adjunctive Diagnostic Studies Completed Following Detection of Candidemia in Children: Secondary Analysis of Observed Practice From a Multicenter Cohort Study Conducted by the Pediatric Fungal Network.

BACKGROUND: Adjunctive diagnostic studies (aDS) are recommended to identify occult dissemination in patients with candidemia. Patterns of evaluation with aDS across pediatric settings are unknown. METHODS: Candidemia episodes were included in a secondary analysis of a multicenter comparative effectiveness study that prospectively enrolled participants age 120 days to 17 years with invasive candidiasis (predominantly candidemia) from 2014 to 2017. Ophthalmologic examination (OE), abdominal imaging (AbdImg), echocardiogram, neuroimaging, and lumbar puncture (LP) were performed per clinician discretion. Adjunctive diagnostic studies performance and positive results were determined per episode, within 30 days from candidemia onset. Associations of aDS performance with episode characteristics were evaluated via mixed-effects logistic regression. RESULTS: In 662 pediatric candidemia episodes, 490 (74%) underwent AbdImg, 450 (68%) OE, 426 (64%) echocardiogram, 160 (24%) neuroimaging, and 76 (11%) LP; performance of each aDS per episode varied across sites up to 16-fold. Longer durations of candidemia were associated with undergoing OE, AbdImg, and echocardiogram. Immunocompromised status (58% of episodes) was associated with undergoing AbdImg (adjusted odds ratio [aOR] 2.38; 95% confidence intervals [95% CI] 1.51-3.74). Intensive care at candidemia onset (30% of episodes) was associated with undergoing echocardiogram (aOR 2.42; 95% CI 1.51-3.88). Among evaluated episodes, positive OE was reported in 15 (3%), AbdImg in 30 (6%), echocardiogram in 14 (3%), neuroimaging in 9 (6%), and LP in 3 (4%). CONCLUSIONS: Our findings show heterogeneity in practice, with some clinicians performing aDS selectively, potentially influenced by clinical factors. The low frequency of positive results suggests that targeted application of aDS is warranted.

Clinical and genomic diversity of Treponema pallidum subsp. pallidum: A global, multi-center study of early syphilis to inform vaccine research.

Background: The continuing increase in syphilis rates worldwide necessitates development of a vaccine with global efficacy. We conducted a multi-center, observational study to explore Treponema pallidum subsp. pallidum ( TPA ) molecular epidemiology essential for vaccine research by analyzing clinical data and specimens from early syphilis patients using whole-genome sequencing (WGS) and publicly available WGS data. Methods: We enrolled patients with primary (PS), secondary (SS) or early latent (ELS) syphilis from clinics in China, Colombia, Malawi and the United States between November 2019 - May 2022. Inclusion criteria included age ≥18 years, and syphilis confirmation by direct detection methods and/or serological testing. TPA detection and WGS were conducted on lesion swabs, skin biopsies/scrapings, whole blood, and/or rabbit-passaged isolates. We compared our WGS data to publicly available genomes, and analysed TPA populations to identify mutations associated with lineage and geography. Findings: We screened 2,820 patients and enrolled 233 participants - 77 (33%) with PS, 154 (66%) with SS, and two (1%) with ELS. Median age of participants was 28; 66% were cis -gender male, of which 43% reported identifying as "gay", "bisexual", or "other sexuality". Among all participants, 56 (24%) had HIV co-infection. WGS data from 113 participants demonstrated a predominance of SS14-lineage strains with geographic clustering. Phylogenomic analysis confirmed that Nichols-lineage strains are more genetically diverse than SS14-lineage strains and cluster into more distinct subclades. Differences in single nucleotide variants (SNVs) were evident by TPA lineage and geography. Mapping of highly differentiated SNVs to three-dimensional protein models demonstrated population-specific substitutions, some in outer membrane proteins (OMPs) of interest. Interpretation: Our study involving participants from four countries substantiates the global diversity of TPA strains. Additional analyses to explore TPA OMP variability within strains will be vital for vaccine development and improved understanding of syphilis pathogenesis on a population level. Funding: National Institutes of Health, Bill and Melinda Gates Foundation.

Craniofacial and dental features in children aged 3-5 years with congenital Zika syndrome.

OBJECTIVE: Zika virus infection has been associated to congenital zika syndrome (CZS) in newborns and is characterized by microcephaly, central/axial motor and sensory dysfunction, dysphagia among other previously described severe health complications. CZS is usually diagnosed postpartum by evident/apparent neural development problems. Although there are some reports of craniofacial/dentition development in CZS, several clinical oral aspects are still unknown. This study describes some structural and functional characteristics of facial and cranial growth and deciduous dentition in CZS-affected children. MATERIAL AND METHODS: Some cranial, facial and dental characteristics were determined in 14 children with CZS aged 3-5 years and compared them against 12 apparently healthy children paired by age and gender. RESULTS: Fourteen CZS cases presented microcephaly, maxillary prognathism, altered facial thirds, asymmetric pupillary line, bruxism (p = 0.006), deep and anterior open bite and distal step decidual molar relationship (p = 0.031). CZS children cannot feed by themselves and most cannot walk and have not develop coordinated and intelligible language according to their chronological age. In contrast, controls presented normal skull features, have autonomous locomotion skills, speak intelligible language, feed by themselves, presented a harmonic intermaxillary relationship and have symmetrical facial thirds. CONCLUSION: Microcephaly, dysphagia, bruxism, mandibular retrognathia, altered facial proportions and malocclusion are the main craniofacial and oral features at CZS. CLINICAL RELEVANCE: The complications of CZS including those related with the face and the oral cavity are still being identified. This study revealed some cranial, facial and oral features in children affected by CSZ. Interdisciplinary rehabilitation protocols must address these syndromic features that could improve children and parents living conditions.

Immunogenicity and tolerability of a bivalent virus-like particle norovirus vaccine candidate in children from 6 months up to 4 years of age: A phase 2 randomized, double-blind trial.

We conducted a dose-finding phase 2 study of the HilleVax bivalent virus-like particle (VLP) vaccine candidate (HIL-214) in two cohorts of children, 6-≤12 months and 1-≤4 years of age (N = 120 per cohort), in Panama and Colombia (ClinicalTrials.gov, identifier NCT02153112). On Day 1, children randomized to one of the four equal groups received intramuscular injections of four different HIL-214 formulations containing 15/15, 15/50, 50/50, or 50/150 µg of GI.1/GII.4c genotype VLPs and 0.5 mg Al(OH)3. On Day 29, half the children in each group received a second vaccination (N = 60), while the other half received saline placebo injections to maintain the blind. VLP-specific ELISA Pan-Ig and histo-blood group binding antigen-blocking antibodies (HBGA) were measured on Days 1, 29, 57 and 210. On Day 29, after one dose, there were large Pan-Ig and HBGA responses in both age cohorts with some indication of dose-dependence, and higher geometric mean titers (GMT) in the older children. A further increase in titers was observed 28 days after a second dose in the 6-≤12-month-old groups, but less so in the 1-≤4-year-old groups; GMTs at Day 57 were broadly similar across doses and in both age groups. GMTs of Pan-Ig and HBGA persisted above baseline up to Day 210. All formulations were well tolerated with mostly mild-to-moderate transient solicited adverse events reported by parents/guardians, and no vaccine-related serious adverse events occurred. Further development of HIL-214 is warranted to protect the most susceptible young children against norovirus.

Clinical Presentation and Outcomes of Kawasaki Disease in Children from Latin America: A Multicenter Observational Study from the REKAMLATINA Network.

OBJECTIVES: To describe the clinical presentation, management, and outcomes of Kawasaki disease (KD) in Latin America and to evaluate early prognostic indicators of coronary artery aneurysm (CAA). STUDY DESIGN: An observational KD registry-based study was conducted in 64 participating pediatric centers across 19 Latin American countries retrospectively between January 1, 2009, and December 31, 2013, and prospectively from June 1, 2014, to May 31, 2017. Demographic and initial clinical and laboratory data were collected. Logistic regression incorporating clinical factors and maximum coronary artery z-score at initial presentation (between 10 days before and 5 days after intravenous immunoglobulin [IVIG]) was used to develop a prognostic model for CAA during follow-up (>5 days after IVIG). RESULTS: Of 1853 patients with KD, delayed admission (>10 days after fever onset) occurred in 16%, 25% had incomplete KD, and 11% were resistant to IVIG. Among 671 subjects with reported coronary artery z-score during follow-up (median: 79 days; IQR: 36, 186), 21% had CAA, including 4% with giant aneurysms. A simple prognostic model utilizing only a maximum coronary artery z-score ≥2.5 at initial presentation was optimal to predict CAA during follow-up (area under the curve: 0.84; 95% CI: 0.80, 0.88). CONCLUSION: From our Latin American population, coronary artery z-score ≥2.5 at initial presentation was the most important prognostic factor preceding CAA during follow-up. These results highlight the importance of early echocardiography during the initial presentation of KD.

Safety and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, in children with SCD: a V114-023 (PNEU-SICKLE) study.

Sickle cell disease (SCD) is an inherited red blood cell disease that results in a multitude of medical complications, including an increased risk of invasive disease caused by encapsulated bacteria, such as Streptococcus pneumoniae. Pneumococcal vaccines have contributed to a significant reduction in pneumococcal disease (PD) in children and adults, including those with SCD. This phase 3 study evaluated the safety and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine (PCV), in children with SCD. A total of 103 children aged 5 to 17 years with SCD were randomized and received a single dose of V114 or Prevnar 13 (PCV13). Safety was evaluated as the proportion of participants with adverse events (AEs). Serotype-specific immunoglobulin G (IgG) levels and opsonophagocytic activity (OPA) were measured immediately before vaccination and 30 days after vaccination. Overall, the rates of injection-site and systemic AEs reported after vaccination were similar between the vaccination groups. Up to 6 months after vaccination, serious AEs were those expected for patients with SCD, and none were assessed to be vaccine related. IgG geometric mean concentrations (GMCs) and OPA geometric mean titers (GMTs) for the 13 shared serotypes were generally comparable between recipients of V114 and PCV13. Additionally, V114 induced immune responses to serotypes 22F and 33F, which are not included in PCV13. The safety and tolerability profiles of V114 were consistent with those reported for PCV13. Immune responses following vaccination with V114 were generally comparable to PCV13 for the shared serotypes and higher for unique serotypes 22F and 33F. These results support the use of V114 in children with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03731182.

High-throughput nanopore sequencing of Treponema pallidum tandem repeat genes arp and tp0470 reveals clade-specific patterns and recapitulates global whole genome phylogeny.

Sequencing of most Treponema pallidum genomes excludes repeat regions in tp0470 and the tp0433 gene, encoding the acidic repeat protein (arp). As a first step to understanding the evolution and function of these genes and the proteins they encode, we developed a protocol to nanopore sequence tp0470 and arp genes from 212 clinical samples collected from ten countries on six continents. Both tp0470 and arp repeat structures recapitulate the whole genome phylogeny, with subclade-specific patterns emerging. The number of tp0470 repeats is on average appears to be higher in Nichols-like clade strains than in SS14-like clade strains. Consistent with previous studies, we found that 14-repeat arp sequences predominate across both major clades, but the combination and order of repeat type varies among subclades, with many arp sequence variants limited to a single subclade. Although strains that were closely related by whole genome sequencing frequently had the same arp repeat length, this was not always the case. Structural modeling of TP0470 suggested that the eight residue repeats form an extended α-helix, predicted to be periplasmic. Modeling of the ARP revealed a C-terminal sporulation-related repeat (SPOR) domain, predicted to bind denuded peptidoglycan, with repeat regions possibly incorporated into a highly charged ß-sheet. Outside of the repeats, all TP0470 and ARP amino acid sequences were identical. Together, our data, along with functional considerations, suggests that both TP0470 and ARP proteins may be involved in T. pallidum cell envelope remodeling and homeostasis, with their highly plastic repeat regions playing as-yet-undetermined roles.

Changes in the incidence of acute bacterial meningitis caused by Streptococcus pneumoniae and the implications of serotype replacement in children in Colombia after mass vaccination with PCV10.

Introduction: Acute bacterial meningitis (ABM) is a public health problem. The disease has reemerged after the introduction of pneumococcal conjugate vaccines (PCVs) due to an increase in serotypes that are not covered. The objective was to determine the changes in the disease incidence before and after the introduction of the 10-valent vaccine (PCV10) in Colombia. Methods: This multicenter study was conducted in 17 hospitals in Colombia. Data were collected from January 2008 to December 2019 in 10 hospitals in Bogotá and from January 2017 to December 2019 in seven hospitals in Cali, Medellín and Cartagena. The data were grouped into three periods: 2008-2011, 2012-2015, and 2016-2019. Results: Of the 706 cases of invasive pneumococcal disease, 81 (11.4%) corresponded to meningitis. The relative incidence in Bogotá in the first period was 0.6 per 100,000 patients ≤ 5 years, decreased to 0.4 per 100,000 patients ≤ 5 years in the second period and increased in the third period to 0.7 per 100,000 patients ≤ 5 years. Serotypes covered by PCV10 decreased from 75 to 9.1%, with Spn19A (31.8%) and Spn34 (13.6%) emerging in the third period. Increased resistance to penicillin (13 to 37%) and to ceftriaxone (5.9 to 16%) was due to the emergence of multidrug-resistant Spn19A. The total mortality rate was 23.5% and increased from 12 to 33%. Conclusions: ABM due to pneumococcus has high morbidity and mortality rates. Reemergence of the disease has been observed due to the inclusion of polymerase chain reaction (PCR) for diagnosis and replacement of circulating serotypes after the introduction of PCV10, with an increase in Spn19A, which causes death and exhibits antimicrobial resistance. Continued surveillance is needed.

Use of polymyxins for carbapenem-resistant infections in children and adolescents.

Background: Polymyxins are still used in children in some regions due to limited availability of newer antibiotics. Objectives: To describe our experience in a cohort of children who received polymyxins for suspected or confirmed carbapenem-resistant bacterial infections (CRI), and explore potential factors associated with therapeutic success. Methods: Retrospective, observational study in children and adolescents <18 years who received IV polymyxin B or colistin therapy for suspected or culture-documented CRI and were admitted to a high complexity clinic in Cali, Colombia between 1 September 2016 and 22 June 2020. Patients' demographic, clinical and microbiological characteristics were collected and analysed; associations with therapeutic success were explored using univariate and multivariate models. Results: There were 40 episodes of polymyxin use (polymyxin B, n = 34; colistin, n = 6) in 34 patients with a median age of 10 years (IQR 7-15); 65% were male. There were 17 adverse events: 3 (17.6%) neurotoxic and 14 (82.4%) nephrotoxic. Therapeutic success was achieved in 28 episodes (70%), of which 32% (9/28) had adverse events. Therapeutic success decreased by 35% with each additional year of age (OR 0.65; 95% CI 0.49-0.80) and by 7% for every hour that elapsed between the onset of fever and the start of appropriate antibiotic therapy (OR 0.93; 95% CI 0.8-0.97) and increased with concomitant non-carbapenem treatment (OR 6.87; 95% CI 1.04-71.01) and the use of adequate empirical therapy (OR 121.36; 95% CI 2.90-1147.95). Conclusions: Several factors were associated with the therapeutic success of polymyxins, however, more than half of episodes had therapeutic failure or adverse events. Antibiotics with greater efficacy and safety are needed in regions with high rates of CRI.

Etiology and Risk Factors for Admission to the Pediatric Intensive Care Unit in Children With Encephalitis in a Developing Country.

OBJECTIVE: To describe a cohort of pediatric patients with encephalitis and their risk factors for admission to the pediatric intensive care unit (PICU). STUDY DESIGN: Children (<18 years old), with encephalitis evaluated by conventional microbiology and syndromic, multiplex test in cerebrospinal fluid (CSF) between July 2017 and July 2020, were recruited from 14 hospitals that comprise the Colombian Network of Encephalitis in Pediatrics. Multivariate analyses were used to evaluate risk factors associated with the need for PICU admission. RESULTS: Two hundred two children were included, of which 134 (66.3%) were male. The median age was 23 months (IQR 5.7-73.2). The main etiologies were bacteria (n = 55, 27%), unspecified viral encephalitis (n = 44, 22%) and enteroviruses (n = 27, 13%), with variations according to age group. Seventy-eight patients (38.6%) required management in the PICU. In multivariate analysis, factors associated with admission to the PICU were the presence of generalized seizures (OR 2.73; 95% CI: 1.82-4.11), status epilepticus (OR 3.28; 95% CI: 2.32-4.62) and low leukocyte counts in the CSF (OR 2.86; 95% CI: 1.47-5.57). Compared with enterovirus, bacterial etiology (OR 7.50; 95% CI: 1.0-56.72), herpes simplex encephalitis (OR 11.81; 95% CI: 1.44-96.64), autoimmune encephalitis (OR 22.55; 95% CI: 3.68-138.16) and other viral infections (OR 5.83; 95% CI: 1.09-31.20) increased the risk of PICU admission. CONCLUSIONS: Data from this national collaborative network of pediatric patients with encephalitis allow early identification of children at risk of needing advanced care and can guide the risk stratification of admission to the PICU.

Factors Associated With Hospitalization or Intensive Care Admission in Children With COVID-19 in Latin America.

Background: Limited data is available from low-middle and upper-middle income countries of the factors associated with hospitalization or admission to pediatric intensive care unit (PICU) for children with COVID-19. Objective: To describe the factors associated with hospitalization or PICU admission of children with COVID-19 in Latin America. Method: Multicenter, analytical, retrospective study of children reported from 10 different Latin American countries to the Latin-American Society of Pediatric Infectious Diseases (SLIPE-COVID) research network from June 1, 2020, and February 28, 2021. Outpatient or hospitalized children <18 years of age with COVID-19 confirmed by polymerase chain reaction or antigen detection from the nasopharynx were included. Children with multisystem inflammatory syndrome in children (MIS-C) were excluded. Associations were assessed using univariate and multivariable logistic regression models. Results: A total of 1063 children with COVID-19 were included; 500 (47%) hospitalized, with 419 (84%) to the pediatric wards and 81 (16%) to the ICU. In multivariable analyses, age <1 year (Odds Ratio [OR] 1.78; 95% CI 1.08-2.94), native race (OR 5.40; 95% CI 2.13-13.69) and having a co-morbid condition (OR 5.3; 95% CI 3.10-9.15), were associated with hospitalization. Children with metabolic or endocrine disorders (OR 4.22; 95% CI 1.76-10.11), immune deficiency (1.91; 95% CI 1.05-3.49), preterm birth (OR 2.52; 95% CI 1.41-4.49), anemia at presentation (OR 2.34; 95% CI 1.28-4.27), radiological peribronchial wall thickening (OR 2.59; 95% CI 1.15-5.84) and hypoxia, altered mental status, seizures, or shock were more likely to require PICU admission. The presence of pharyngitis (OR 0.34; 95% CI 0.25-0.48); myalgia (OR 0.47; 95% CI 0.28-0.79) or diarrhea (OR 0.38; 95% CI 0.21-0.67) were inversely associated with hospital admission. Conclusions: In this data analysis reported to the SLIPE research network in Latin America, infants, social inequalities, comorbidities, anemia, bronchial wall thickening and specific clinical findings on presentation were associated with higher rates of hospitalization or PICU admission. This evidence provides data for prioritization prevention and treatment strategies for children suffering from COVID-19.

Immunogenicity and safety of booster CYD-TDV dengue vaccine after alternative primary vaccination schedules in healthy individuals aged 9-50 years: a randomised, controlled, phase 2, non-inferiority study.

BACKGROUND: Dengue is endemic in many countries throughout the tropics and subtropics, and the disease causes substantial morbidity and health-care burdens in these regions. We previously compared antibody responses after one-dose, two-dose, or three-dose primary regimens with the only approved dengue vaccine CYD-TDV (Dengvaxia; Sanofi Pasteur, Lyon, France) in individuals aged 9 years and older with previous dengue exposure. In this study, we assessed the need for a CYD-TDV booster after these primary vaccination regimens. METHODS: In this randomised, controlled, phase 2, non-inferiority study, healthy individuals aged 9-50 years recruited from three sites in Colombia and three sites in the Philippines (excluding those with the usual contraindications to vaccinations) were randomly assigned 1:1:1 via a permuted block method with stratification by site and by age group using an independent voice response system to receive, at 6-month intervals, three doses of CYD-TDV (three-dose group), one dose of placebo followed by two doses of CYD-TDV (two-dose group), or two doses of placebo followed by one dose of CYD-TDV (one-dose group). Participants were also randomly assigned (1:1) to receive a CYD-TDV booster at 1 year or 2 years after the last primary dose. Each CYD-TDV dose was 0·5 mL and administered subcutaneously in the deltoid region of the upper arm. The investigators and sponsor, study staff interacting with the investigators, and participants and their parents or legally acceptable representatives were masked to group assignment. Neutralising antibodies were measured by 50% plaque reduction neutralisation testing, and geometric mean titres (GMTs) were calculated. Due to a change in study protocol, only participants who were dengue seropositive at baseline in the Colombian cohort received a booster vaccination. The primary outcome was to show non-inferiority of the booster dose administered at 1 year or 2 years after the two-dose and three-dose primary regimens; non-inferiority was shown if the lower limit of the two-sided adjusted 95% CI of the between-group (day 28 post-booster dose GMT from the three-dose or two-dose group vs day 28 GMT post-dose three of the three-dose primary regimen [three-dose group]) geometric mean ratio (GMR) was higher than 0·5 for each serotype. Non-inferiority of the 1-year or 2-year booster was shown if all four serotypes achieved non-inferiority. Safety was assessed among all participants who received the booster. This trial is registered with ClinicalTrials.gov, NCT02628444, and is closed to accrual. FINDINGS: Between May 2 and Sept 16, 2016, we recruited and enrolled 1050 individuals who received either vaccine or placebo. Of the 350, 348, and 352 individuals randomly assigned to three-dose, two-dose, and one-dose groups, respectively, 108, 115, and 115 from the Colombian cohort were dengue seropositive at baseline and received a booster; 55 and 53 in the three-dose group received a booster after 1 year and 2 years, respectively, as did 59 and 56 in the two-dose group, and 62 and 53 in the one-dose group. After the three-dose primary schedule, non-inferiority was shown for serotypes 2 (GMR 0·746; 95% CI 0·550-1·010) and 3 (1·040; 0·686-1·570) but not serotypes 1 (0·567; 0·399-0·805) and 4 (0·647; 0·434-0·963) for the 1-year booster, and again for serotypes 2 (0·871; 0·673-1·130) and 3 (1·150; 0·887-1·490) but not serotypes 1 (0·688; 0·479-0·989) and 4 (0·655; 0·471-0·911) for the 2-year booster. Similarly, after the two-dose primary schedule, non-inferiority was shown for serotypes 2 (0·809; 0·505-1·300) and 3 (1·19; 0·732-1·940) but not serotypes 1 (0·627; 0·342-1·150) and 4 (0·499; 0·331-0·754) for the 1-year booster, and for serotype 3 (0·911; 0·573-1·450) but not serotypes 1 (0·889; 0·462-1·710), 2 (0·677; 0·402-1·140), and 4 (0·702; 0·447-1·100) for the 2-year booster. Thus, non-inferiority of the 1-year or 2-year booster was not shown after the three-dose or two-dose primary vaccination regimen in dengue-seropositive participants. No safety concerns occurred with the 1-year or 2-year CYD-TDV booster. INTERPRETATION: CYD-TDV booster 1 year or 2 years after the two-dose or three-dose primary vaccination regimen does not elicit a consistent, meaningful booster effect against all dengue serotypes in participants who are seropositive for dengue at baseline. FUNDING: Sanofi Pasteur. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Efficacy of the adjuvanted subunit protein COVID-19 vaccine, SCB-2019: a phase 2 and 3 multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: A range of safe and effective vaccines against SARS CoV 2 are needed to address the COVID 19 pandemic. We aimed to assess the safety and efficacy of the COVID-19 vaccine SCB-2019. METHODS: This ongoing phase 2 and 3 double-blind, placebo-controlled trial was done in adults aged 18 years and older who were in good health or with a stable chronic health condition, at 31 sites in five countries (Belgium, Brazil, Colombia, Philippines, and South Africa). The participants were randomly assigned 1:1 using a centralised internet randomisation system to receive two 0·5 mL intramuscular doses of SCB-2019 (30 µg, adjuvanted with 1·50 mg CpG-1018 and 0·75 mg alum) or placebo (0·9% sodium chloride for injection supplied in 10 mL ampoules) 21 days apart. All study staff and participants were masked, but vaccine administrators were not. Primary endpoints were vaccine efficacy, measured by RT-PCR-confirmed COVID-19 of any severity with onset from 14 days after the second dose in baseline SARS-CoV-2 seronegative participants (the per-protocol population), and the safety and solicited local and systemic adverse events in the phase 2 subset. This study is registered on EudraCT (2020-004272-17) and ClinicalTrials.gov (NCT04672395). FINDINGS: 30 174 participants were enrolled from March 24, 2021, until the cutoff date of Aug 10, 2021, of whom 30 128 received their first assigned vaccine (n=15 064) or a placebo injection (n=15 064). The per-protocol population consisted of 12 355 baseline SARS-CoV-2-naive participants (6251 vaccinees and 6104 placebo recipients). Most exclusions (13 389 [44·4%]) were because of seropositivity at baseline. There were 207 confirmed per-protocol cases of COVID-19 at 14 days after the second dose, 52 vaccinees versus 155 placebo recipients, and an overall vaccine efficacy against any severity COVID-19 of 67·2% (95·72% CI 54·3-76·8), 83·7% (97·86% CI 55·9-95·4) against moderate-to-severe COVID-19, and 100% (97·86% CI 25·3-100·0) against severe COVID-19. All COVID-19 cases were due to virus variants; vaccine efficacy against any severity COVID-19 due to the three predominant variants was 78·7% (95% CI 57·3-90·4) for delta, 91·8% (44·9-99·8) for gamma, and 58·6% (13·3-81·5) for mu. No safety issues emerged in the follow-up period for the efficacy analysis (median of 82 days [IQR 63-103]). The vaccine elicited higher rates of mainly mild-to-moderate injection site pain than the placebo after the first (35·7% [287 of 803] vs 10·3% [81 of 786]) and second (26·9% [189 of 702] vs 7·4% [52 of 699]) doses, but the rates of other solicited local and systemic adverse events were similar between the groups. INTERPRETATION: Two doses of SCB-2019 vaccine plus CpG and alum provides notable protection against the entire severity spectrum of COVID-19 caused by circulating SAR-CoV-2 viruses, including the predominating delta variant. FUNDING: Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.

Efficacy of a Dengue Vaccine Candidate (TAK-003) in Healthy Children and Adolescents 2 Years after Vaccination.

BACKGROUND: Takeda's dengue vaccine is under evaluation in an ongoing phase 3 efficacy study; we present a 2-year update. METHODS: Children (20 099, 4-16 years old) were randomized to receive 2 doses of TAK-003 or placebo 3 months apart and are under surveillance to detect dengue by serotype-specific RT-PCR. RESULTS: Cumulative efficacy against dengue approximately 27 months since first dose was 72.7% (95% confidence interval [CI], 67.1%-77.3%), including 67.0% (95% CI, 53.6%-76.5%) in dengue-naive and 89.2% (95% CI, 82.4%-93.3%) against hospitalized dengue. In the second year, decline in efficacy was observed (56.2%; 95% CI, 42.3%-66.8%) with the largest decline in 4-5 year olds (24.5%; 95% CI, -34.2% to 57.5%); efficacy was 60.6% (95% CI, 43.8%-72.4%) in 6-11 year and 71.2% (95% CI, 41.0%-85.9%) in 12-16 year age groups. As TAK-003 efficacy varies by serotype, changes in serotype dominance partially contributed to efficacy differences in year-by-year analysis. No related serious adverse events occurred during the second year. CONCLUSIONS: TAK-003 demonstrated continued benefit independent of baseline serostatus in reducing dengue with some decline in efficacy during the second year. Three-year data will be important to see if efficacy stabilizes or declines further.Clinical Trials Registration. NCT02747927.Takeda's tetravalent dengue vaccine (TAK-003) continued to demonstrate benefit in reducing dengue independent of baseline serostatus up to 2 years after completing vaccination with some decline in efficacy during the second year in 4-16 year olds in dengue-endemic countries.