Early host immune responses in a human organoid-derived gallbladder monolayer to Salmonella Typhi strains from patients with acute and chronic infections: a comparative analysis.

Salmonella enterica serovar Typhi (S. Typhi), a human-restricted pathogen, invades the host through the gut to cause typhoid fever. Recent calculations of the typhoid fever burden estimated that more than 10 million new typhoid fever cases occur in low and middle-income countries, resulting in 65,400-187,700 deaths yearly. Interestingly, if not antibiotic-treated, upon the resolution of acute disease, 1%-5% of patients become asymptomatic chronic carriers. Chronically infected hosts are not only critical reservoirs of infection that transmit the disease to naive individuals but are also predisposed to developing gallbladder carcinoma. Nevertheless, the molecular mechanisms involved in the early interactions between gallbladder epithelial cells and S. Typhi remain largely unknown. Based on our previous studies showing that closely related S. Typhi strains elicit distinct innate immune responses, we hypothesized that host molecular pathways activated by S. Typhi strains derived from acutely and chronically infected patients would differ. To test this hypothesis, we used a novel human organoid-derived polarized gallbladder monolayer model, and S. Typhi strains derived from acutely and chronically infected patients. We found that S. Typhi strains derived from acutely and chronically infected patients differentially regulate host mitogen-activated protein kinase (MAPK) and S6 transcription factors. These variations might be attributed to differential cytokine signaling, predominantly via TNF-α and IL-6 production and appear to be influenced by the duration the isolate was subjected to selective pressures in the gallbladder. These findings represent a significant leap in understanding the complexities behind chronic S. Typhi infections in the gallbladder and may uncover potential intervention targets.

Detecting residual chronic Salmonella Typhi carriers on the road to typhoid elimination in Santiago, Chile, 2017-2019.

OBJECTIVES: In Santiago, Chile, where typhoid had been hyperendemic (1977-1991), we investigated whether residual chronic carriers could be detected among household contacts of non-travel-related typhoid cases occurring 2017-2019. METHODS: Culture-confirmed cases were classified as "autochthonous" (domestically-acquired) versus "travel/immigration-related". Household contacts of cases had stool cultures and serum Vi antibody measurements to detect chronic Salmonella Typhi carriers. Whole genome sequences of acute cases and their epidemiologically-linked chronic carrier isolates were compared. RESULTS: Five of 16 autochthonous typhoid cases (31.3%) were linked to four chronic carriers in case households; two cases (onsets 23 months apart) were linked to the same carrier. Carriers were women aged 69-79 years with gallbladder dysfunction and Typhi fecal excretion; three had highly elevated serum anti-Vi titers. Genomic analyses revealed close identity (≤11 core genome SNP [Single Nucleotide Polymorphism] differences) between case and epidemiologically-linked carrier isolates; all were genotypes prevalent in 1980s Santiago. A cluster of four additional autochthonous cases un-linked to a carrier was identified based on genomic identity (0-1 SNPs). Travel/immigration isolate genotypes were typical for the countries of travel/immigration. CONCLUSIONS: Although autochthonous typhoid cases in Santiago are currently rare, 5/16 such cases (31.3%) were linked to elderly chronic carriers identified among household contacts of cases.

Whole genome sequence analysis of Salmonella Typhi provides evidence of phylogenetic linkage between cases of typhoid fever in Santiago, Chile in the 1980s and 2010-2016.

Typhoid fever epidemiology was investigated rigorously in Santiago, Chile during the 1980s, when Salmonella enterica serovar Typhi (S. Typhi) caused seasonal, hyperendemic disease. Targeted interventions reduced the annual typhoid incidence rates from 128-220 cases/105 population occurring between 1977-1984 to <8 cases/105 from 1992 onwards. As such, Santiago represents a contemporary example of the epidemiologic transition of an industrialized city from amplified hyperendemic typhoid fever to a period when typhoid is no longer endemic. We used whole genome sequencing (WGS) and phylogenetic analysis to compare the genotypes of S. Typhi cultured from acute cases of typhoid fever occurring in Santiago during the hyperendemic period of the 1980s (n = 74) versus the nonendemic 2010s (n = 80) when typhoid fever was rare. The genotype distribution between "historical" (1980s) isolates and "modern" (2011-2016) isolates was similar, with genotypes 3.5 and 2 comprising the majority of isolations, and 73/80 (91.3%) of modern isolates matching a genotype detected in the 1980s. Additionally, phylogenomically 'ancient' genotypes 1.1 and 1.2.1, uncommon in the global collections, were also detected in both eras, with a notable rise amongst the modern isolates. Thus, genotypes of S. Typhi causing acute illness in the modern nonendemic era match the genotypes circulating during the hyperendemic 1980s. The persistence of historical genotypes may be explained by chronic typhoid carriers originally infected during or before the 1980s.

Detection of Salmonella Typhi in Bile by Quantitative Real-Time PCR.

In countries where the incidence of typhoid fever is high, fecal material from short-term carriers of Salmonella Typhi contaminates inadequately treated water supplies. As treated water supplies and improved sanitation become available, chronic (mainly gallbladder) carriers of S. Typhi become important. The objective of this study was to develop a method for detection of S. Typhi in bile by quantitative real-time PCR (qPCR) in patients undergoing cholecystectomy. We evaluated sensitivity and specificity of probesets that target oriC, viaB, fliC-d, STY0201, and stoD. We optimized DNA extraction from bile and compared the sensitivity of culture and our qPCR method to detect S. Typhi in bile samples containing various cephalosporins. With the use of an optimized DNA extraction technique, our limit of detection of S. Typhi in spiked human bile samples was 7.4 × 102 CFU/mL. We observed that S. Typhi could be detected by qPCR in samples containing cefazolin, cefotaxime, or ceftriaxone whereas culture could only detect Typhi in samples containing cefazolin but not cefotaxime or ceftriaxone. Our qPCR detection method for S. Typhi in bile should be preferred in areas where antibiotic usage is common. IMPORTANCE New Salmonella Typhi conjugate vaccines have been deployed, which will potentially lead to a fall in incidence rates of typhoid fever in endemic areas. Identification of chronic carriers of S. Typhi will be important as these individuals can be a potential source of transmission to susceptible persons. To address this public health concern, we have developed a novel method to detect S. Typhi in bile using real-time PCR. Our method can be used to identify carriers of S. Typhi among patients undergoing cholecystectomy (gallbladder removal surgery). The sensitivity of our molecular-based assay was superior to culture when performed in the presence of antibiotics commonly used during surgery. Our methodology will complement efforts to eliminate typhoid disease.

The burden of norovirus disease in children: a multi-country study in Chile, Brazil, Thailand and the Philippines.

BACKGROUND: Noroviruses (NoVs) cause acute gastroenteritis (AGE) worldwide, affecting children in particular. We aimed to estimate the burden of disease due to NoV among children aged <6 years in Brazil, Chile, Philippines and Thailand. METHODS: This was a prospective, hospital-based, observational study. Children were recruited over one year between 2014 and 2017. Four cohorts were analysed: community-acquired AGE outpatients and inpatients, nosocomial AGE inpatients, and asymptomatic outpatients. We collected demographic and clinical data, and a stool sample that was tested for NoV. Positive samples were tested for Rotavirus (RV) and NoV-genotyped. Disease severity was assessed by the Vesikari and modified Vesikari scores. Prevalence and incidence of NoV-AGE were estimated by cohort and country. RESULTS: 1637 participants yielded valid laboratory results. The proportion of NoV-positive cases was 23.8% (95% CI 20.8-27.2) in the outpatient cohort, 17.9% (15.0-21.3) in the hospital cohort, 21.4% (12.7-33.8) in the nosocomial cohort and 9.6% (6.9-13.2) in the asymptomatic cohort. Genotype GII.4 was predominant (58%). Less than 4% samples had RV coinfection. In general, NoV-positive subjects had more severe presentations than NoV-negative subjects. CONCLUSIONS: NoV caused AGE with substantial burden throughout the studied settings, with higher relative frequency in Brazil where RV vaccination coverage is high.

Viewpoint of a WHO Advisory Group Tasked to Consider Establishing a Closely-monitored Challenge Model of Coronavirus Disease 2019 (COVID-19) in Healthy Volunteers.

WHO convened an Advisory Group (AG) to consider the feasibility, potential value, and limitations of establishing a closely-monitored challenge model of experimental severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) in healthy adult volunteers. The AG included experts in design, establishment, and performance of challenges. This report summarizes issues that render a COVID-19 model daunting to establish (the potential of SARS-CoV-2 to cause severe/fatal illness, its high transmissibility, and lack of a "rescue treatment" to prevent progression from mild/moderate to severe clinical illness) and it proffers prudent strategies for stepwise model development, challenge virus selection, guidelines for manufacturing challenge doses, and ways to contain SARS-CoV-2 and prevent transmission to household/community contacts. A COVID-19 model could demonstrate protection against virus shedding and/or illness induced by prior SARS-CoV-2 challenge or vaccination. A limitation of the model is that vaccine efficacy in experimentally challenged healthy young adults cannot per se be extrapolated to predict efficacy in elderly/high-risk adults.

Multiple Introductions of Salmonella enterica Serovar Typhi H58 with Reduced Fluoroquinolone Susceptibility into Chile.

Salmonella enterica serovar Typhi H58, an antimicrobial-resistant lineage, is globally disseminated but has not been reported in Latin America. Genomic analysis revealed 3 independent introductions of Salmonella Typhi H58 with reduced fluoroquinolone susceptibility into Chile. Our findings highlight the utility of enhanced genomic surveillance for typhoid fever in this region.

Placebo use in vaccine trials: recommendations of a WHO expert panel.

Vaccines are among the most cost-effective interventions against infectious diseases. Many candidate vaccines targeting neglected diseases in low- and middle-income countries are now progressing to large-scale clinical testing. However, controversy surrounds the appropriate design of vaccine trials and, in particular, the use of unvaccinated controls (with or without placebo) when an efficacious vaccine already exists. This paper specifies four situations in which placebo use may be acceptable, provided that the study question cannot be answered in an active-controlled trial design; the risks of delaying or foregoing an efficacious vaccine are mitigated; the risks of using a placebo control are justified by the social and public health value of the research; and the research is responsive to local health needs. The four situations are: (1) developing a locally affordable vaccine, (2) evaluating the local safety and efficacy of an existing vaccine, (3) testing a new vaccine when an existing vaccine is considered inappropriate for local use (e.g. based on epidemiologic or demographic factors), and (4) determining the local burden of disease.

Age-dependent association among Helicobacter pylori infection, serum pepsinogen levels and immune response of children to live oral cholera vaccine CVD 103-HgR.

BACKGROUND: Through its effects on gastric secretion, we hypothesized that Helicobacter pylori infection may influence oral immunization. Accordingly, we examined the association between H. pylori infection, serum pepsinogen (PG) (measures for H. pylori gastritis) and vibriocidal antibody (a correlate of protection) seroconversion following oral immunization with CVD 103-HgR live cholera vaccine among children of different ages. METHODS: Sera from 422 Chilean children who were vaccinated with a single dose of CVD 103-HgR were tested by ELISA for serum IgG antibodies to H. pylori, PG I and PG II levels and antibodies to Shigella flexneri 2a lipopolysaccharide and hepatitis A virus (as markers of low socioeconomic status and exposure to enteric pathogens). RESULTS: The likelihood of vibriocidal antibody seroconversion following vaccination with CVD 103-HgR was significantly decreased in H. pylori-seropositive children age 6 months to 4 years with PG II>8 µg/L (adjusted OR 0.14 (95% CI 0.03-0.61; P = 0.009), and also in H. pylori seropositives with lower PG II level (adjusted OR 0.34, 95% CI 0.14-0.83; P = 0.017), compared to H. pylori-seronegatives. H. pylori-seropositive children aged 5-9 years with serum PG I>30 µg/L (indicating more severe gastritis) had higher odds of vibriocidal seroconversion than those with lower PG I levels (adjusted OR 4.41, 95%CI 1.26-15.38; P = 0.02). There was no significant association between exposures to S. flexneri 2a or hepatitis A virus and vibriocidal seroconversion. CONCLUSIONS: As H. pylori gastritis progresses with increasing pediatric age in developing country venues, changes in gastric secretion ensue that we believe explain the observed differences in age-related immune responses to immunization with live oral cholera vaccine. The effect of H. pylori and changes of gastric acid secretion on the immunogenicity of various oral vaccines should be studied in different developing, transitional and industrialized country settings.

Motavizumab treatment of infants hospitalized with respiratory syncytial virus infection does not decrease viral load or severity of illness.

BACKGROUND: This study was conducted to determine whether treatment with motavizumab, an anti-respiratory syncytial virus (RSV) monoclonal antibody, would decrease viral load and improve clinical outcomes in previously healthy term infants hospitalized with RSV lower respiratory tract infection. METHODS: Infants hospitalized with lower respiratory tract infection and a positive RSV test performed locally were randomized to receive 1 intravenous dose of motavizumab (30 or 100 mg/kg) or placebo. Nasal wash samples were tested by real-time reverse transcriptase polymerase chain reaction at a central laboratory to determine viral load. Clinical data were collected during RSV hospitalization and at 12-month follow up. RESULTS: Of 118 infants, 112 were confirmed RSV positive by real-time reverse transcriptase polymerase chain reaction. In each study group, median (range) RSV load (log10 copies/mL) decreased at a similar rate from baseline to study day 7 [motavizumab 30 mg/kg: 8.35 (2.5-9.5) to 5.03 (2.5-6.8); motavizumab 100 mg/kg: 8.22 (5.5-9.7) to 4.25 (2.5-8.0); placebo: 8.02 (6.7-9.8) to 5.17 (2.5-7.3)]. Median (range) duration of hospitalization was 3.05 (0.8-16.0), 2.99 (1.0-25.0) and 2.88 (0.8-11.7) days for the motavizumab 30 mg/kg, motavizumab 100 mg/kg and placebo groups, respectively. Six (8%) motavizumab and 0 placebo recipients were admitted to the intensive care unit and 4 required mechanical ventilation. The incidence of wheezing episodes during the 12-month follow up was comparable for all 3 groups. CONCLUSIONS: Motavizumab had no appreciable effect on RSV viral load measured in the upper respiratory tract of children hospitalized for RSV lower respiratory tract infection. No differences were observed for duration of hospitalization, severity of illness measures or wheezing episodes during 12-month follow up in children treated with motavizumab or placebo.

Rapid research response to the 2009 A(H1N1)pdm09 influenza pandemic (Revised).

BACKGROUND: When novel influenza viruses cause human infections, it is critical to characterize the illnesses, viruses, and immune responses to infection in order to develop diagnostics, treatments, and vaccines. The objective of the study was to collect samples from patients with suspected or confirmed A(H1N1)pdm09 infections that could be made available to the scientific community. Respiratory secretions, sera and peripheral blood mononuclear cells (PBMCs) were collected sequentially (when possible) from patients presenting with suspected or previously confirmed A(H1N1)pdm09 infections. Clinical manifestations and illness outcomes were assessed. Respiratory secretions were tested for the presence of A(H1N1)pdm09 virus by means of isolation in tissue culture and real time RT-PCR. Sera were tested for the presence and level of HAI and neutralizing antibodies against the A(H1N1)pdm09 virus. FINDINGS AND CONCLUSIONS: Thirty patients with confirmed A(H1N1)pdm09 infection were enrolled at Baylor College of Medicine (BCM). Clinical manifestations of illness were consistent with typical influenza. Twenty-eight of 30 had virological confirmation of illness; all recovered fully. Most patients had serum antibody responses or high levels of antibody in convalescent samples. Virus-positive samples were sent to J. Craig Venter Institute for sequencing and sequences were deposited in GenBank. Large volumes of sera collected from 2 convalescent adults were used to standardize antibody assays; aliquots of these sera are available from the repository. Aliquots of serum, PBMCs and stool collected from BCM subjects and subjects enrolled at other study sites are available for use by the scientific community, upon request.

Impact of vaccination against Haemophilus influenzae type b with and without a booster dose on meningitis in four South American countries.

To inform World Health Organization recommendations regarding use of Haemophilus influenzae type b (Hib) vaccines in national immunization programs, a multi-country evaluation of trends in Hib meningitis incidence and prevalence of nasopharyngeal Hib carriage was conducted in four South American countries using either a primary, three-dose immunization schedule without a booster dose or with a booster dose in the second year of life. Surveillance data suggest that high coverage of Hib conjugate vaccine sustained low incidence of Hib meningitis and low prevalence of Hib carriage whether or not a booster dose was used.

Safety and immunogenicity of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in Chilean children.

The safety and immunogenicity of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, Synflorix™) were assessed in 240 healthy Chilean children randomized to receive 3 doses of PHiD-CV (PHiD-CV group) or hepatitis A vaccine (HAV control group) at 2-4-6 months of age. All were offered 1 HAV dose at 12 months (outside study). The PHiD-CV group received a second HAV dose at 18-21 months and PHiD-CV booster at 20-23 months. The HAV control group received 2 PHiD-CV catch-up doses at 18-21 and 20-23 months. Adverse events were recorded and pneumococcal antibody responses and opsonophagocytic activity (OPA) were measured. Both PHiD-CV vaccination schedules were well tolerated and immunogenic against the pneumococcal vaccine serotypes and protein D. The reactogenicity of PHiD-CV primary, booster and catch-up doses was in line with previous PHiD-CV studies, although generally higher than with HAV. For each vaccine serotype, the percentage of subjects with antibody concentrations ≥0.2 µg/ml (GSK's 22F-inhibition ELISA) was at least 93.2% following 3 PHiD-CV primary doses and at least 97.4% post-booster; percentages with OPA titers ≥8 were at least 91.7% post-booster. After 2-dose catch-up, at least 94.3% of children had antibody concentrations ≥0.2 µg/ml against each serotype except 6B (84.3%); at least 95.2% had OPA titers ≥8 except against serotypes 1, 5 and 6B. In conclusion, the safety profiles of 2 PHiD-CV vaccination schedules (3-dose primary plus booster and 2-dose catch-up) were in line with previous studies and PHiD-CV was immunogenic for all 10 vaccine serotypes and protein D.

Mucosal IgA responses in healthy adult volunteers following intranasal spray delivery of a live attenuated measles vaccine.

Measles remains an important cause of morbidity and mortality among children in the developing world. The goal of this study was to examine measles virus-specific mucosal immune responses in healthy immune (n = 24; plaque reduction neutralization [PRN] titers of ≥200 mIU/ml) and nonimmune (n = 24) young adult volunteers who received the monovalent Moraten measles vaccine via intranasal (spray delivery) or subcutaneous immunization. Serum, oral fluid, and nasal wash samples were examined for measles virus-specific and total IgG and IgA on day 0 (prior to vaccination) and on days 14, 28, and 90 after vaccination. Nonimmune subjects vaccinated subcutaneously developed high levels of measles virus PRN, IgG, and IgA antibodies in serum, oral fluid, and nasal washes. Total IgG and secretory IgA (sIgA) titers were increased in nasal washes, and total IgG was increased in oral fluid specimens. There was a strong correlation between PRN and measles virus-specific IgG titers measured in serum, oral fluid, and nasal washes, whereas a weak correlation was found between PRN and measles virus-specific IgA titers. Notably, intranasal measles vaccination resulted in increased production of measles virus-specific sIgA in oral fluid and nasal washes in nonimmune individuals, without evidence of a systemic immune response. In contrast, no significant vaccine-induced responses were observed in immune subjects, regardless of the route of immunization. These results demonstrate that (i) intranasal measles immunization can elicit a mucosal response independent of the induction of serum antibodies and (ii) both mucosal and systemic antibody responses following nasal or subcutaneous immunization are blunted by preexisting measles immunity.

[Direct medical costs of invasive pneumococcal disease and radiologically-diagnosed pneumonia among Chilean children]. / Costos médicos directos de enfermedades neumocócicas invasoras y neumonías con diagnóstico radiológico en niños chilenos.

OBJECTIVES: To determine the direct medical costs of health care services for cases of invasive pneumococcal disease (IPD) and pneumonia acquired in the community and confirmed by radiology (NAC-Rx) among Chilean children. METHODS: A prospective follow-up study of the health services delivered to 594 children 0-35 months of age with IPD and 1 489 children 1-35 months with NAC-Rx, diagnosed and treated by organizations within public health network of the Región Metropolitana de Chile. The value of the health services was established according to rates supplied by the Fondo Nacional de Salud (FONASA, the National Health Fund) and prices charged by two private clinics. The national IPD and NAC-Rx rates were estimated to calculate the total national economic burden for the population covered by state health insurance. RESULTS: The mean cost of cases requiring hospitalization was US$ 1 056.20 for IPD and US$ 594.80 for NAC-Rx, while that of cases treated by out-patient services was US$ 77.70 and US$ 65.20, respectively. The cost of the same services for in-patient care at the private clinics was US$ 4 484.10 and US$ 2 962.70 at one clinic and US$ 9 967.50 and US$ 6 578.40 at the other. The estimated national annual cost of services for children under 5 years of age, according to FONASA rates, was US$ 789 045 for IPD and US$ 13 823 289 for NAC-Rx. CONCLUSIONS: The high demand for services and financial resources for NAC-Rx in children 0-3 years of age is a tremendously powerful public health reason to support the routine use of pneumococcal vaccination in Chilean children.

Characterization of the most prevalent colonization factor antigens present in Chilean clinical enterotoxigenic Escherichia coli strains using a new multiplex polymerase chain reaction.

Current methods to detect the colonization factor antigens (CFAs) associated with enterotoxigenic Escherichia coli (ETEC) strains are cumbersome, with some methods requiring antibodies that are not readily available. To achieve a gene-based method, we designed 2 multiplex polymerase chain reaction reactions to detect genes encoding the most common ETEC fimbrial colonization factors, including CFA/I and coli surface (CS) antigens CS1, CS2, CS3, CS4, CS5, and CS6. Analysis of 183 clinical ETEC strains shows that the most prevalent colonization factors were CFA/I only, CS1 and CS3, CS2 and CS3, and CS6 only. Interestingly, we identified 3 clinical isolates expressing CS1 only without its regulator rns. The method described here proved to be rapid and robust and correlates well with phenotypic expression of the CFAs, becoming a novel molecular diagnostic and research tool for future epidemiologic studies.

Costos médicos directos de enfermedades neumocócicas invasoras y neumonías con diagnóstico radiológico en niños chilenos / Direct medical costs of invasive pneumococcal disease and radiologically-diagnosed pneumonia among Chilean children

OBJETIVOS: Determinar los costos médicos directos relacionados con la atención sanitaria de los casos de enfermedades neumocócicas invasoras (ENI) y neumonías adquiridas en la comunidad confirmadas mediante radiología (NAC-Rx) en niños chilenos. MÉTODO: Estudio de seguimiento prospectivo de las prestaciones de salud entregadas a 594 niños de 0 a 35 meses con ENI y 1489 niños de 1 a 35 meses con NAC-Rx, diagnosticados y tratados en establecimientos de la red pública de salud de la Región Metropolitana de Chile. Las prestaciones se valoraron según las tarifas del Fondo Nacional de Salud (FONASA) y los precios de dos clínicas privadas. Se estimó la incidencia nacional anual de ENI y NAC-Rx para calcular la carga económica total nacional de la población afiliada al seguro de salud estatal. RESULTADOS: Los costos promedio de los casos que requirieron hospitalización fueron US$ 1056,20 para las ENI y US$ 594,80 para las NAC-Rx, mientras que para los casos tratados en forma ambulatoria fueron US$ 77,70 y US$ 65,20, respectivamente. Los precios por los mismos servicios de internación fueron US$ 4484,10 y US$ 2962,70 en una de las clínicas privadas y US$ 9967,50 y US$ 6578,40 en la otra. El costo anual nacional estimado de la atención de los niños menores de 5 años según las tarifas de FONASA fue de US$ 789045 para las ENI y US$ 13823289 para las NAC-Rx. CONCLUSIONES: La alta demanda asistencial y económica por NAC-Rx en niños de 0 a 3 años es una razón de salud pública tremendamente poderosa que apoya el uso sistemático de la vacunación antineumocócica en niños chilenos.

OBJECTIVES: To determine the direct medical costs of health care services for cases of invasive pneumococcal disease (IPD) and pneumonia acquired in the community and confirmed by radiology (NAC-Rx) among Chilean children. METHODS: A prospective follow-up study of the health services delivered to 594 children 0-35 months of age with IPD and 1 489 children 1-35 months with NAC-Rx, diagnosed and treated by organizations within public health network of the Región Metropolitana de Chile. The value of the health services was established according to rates supplied by the Fondo Nacional de Salud (FONASA, the National Health Fund) and prices charged by two private clinics. The national IPD and NAC-Rx rates were estimated to calculate the total national economic burden for the population covered by state health insurance. RESULTS: The mean cost of cases requiring hospitalization was US$ 1056.20 for IPD and US$ 594.80 for NAC-Rx, while that of cases treated by out-patient services was US$ 77.70 and US$ 65.20, respectively. The cost of the same services for in-patient care at the private clinics was US$ 4484.10 and US$ 2962.70 at one clinic and US$ 9967.50 and US$ 6578.40 at the other. The estimated national annual cost of services for children under 5 years of age, according to FONASA rates, was US$ 789045 for IPD and US$ 13823289 for NAC-Rx. CONCLUSION: The high demand for services and financial resources for NAC-Rx in children 0-3 years of age is a tremendously powerful public health reason to support the routine use of pneumococcal vaccination in Chilean children.

A multinational, randomized, placebo-controlled trial to assess the immunogenicity, safety, and tolerability of live attenuated influenza vaccine coadministered with oral poliovirus vaccine in healthy young children.

Live attenuated influenza vaccine (LAIV) provides a useful tool to rapidly immunize populations in the developing world to prevent influenza outbreaks. In this noninferiority trial conducted in Asia and South America, where oral poliovirus vaccine (OPV) is still used, 2503 children aged 6 to <36 months with three polio immunizations were randomized to receive LAIV+OPV, placebo+OPV, or LAIV only. Immune responses in children receiving concomitant LAIV+OPV were noninferior to those observed in recipients of either vaccine alone. Response rates for different poliovirus types were similar in recipients of LAIV+OPV and placebo+OPV. Response rates to all influenza strains were similar in LAIV+OPV and LAIV-only recipients. Concomitant OPV and LAIV were safely administered to young children.

Safety and antiviral activity of motavizumab, a respiratory syncytial virus (RSV)-specific humanized monoclonal antibody, when administered to RSV-infected children.

Previously healthy children hospitalized with respiratory syncytial virus (RSV) received motavizumab (3, 15, or 30 mg/kg intravenously), an RSV-specific monoclonal antibody, or placebo. Safety, tolerability, motavizumab concentrations, and immunogenicity were assessed. Cultivatable RSV in the upper respiratory tract was significantly reduced with motavizumab compared with placebo day 1 post-treatment. No adverse events were considered motavizumab-related by site investigators.

Immunology of combining CRM(197) conjugates for Streptococcus pneumoniae, Neisseria meningitis and Haemophilus influenzae in Chilean infants.

We evaluated the immunogenicity and safety of an investigational combination of 9-valent pneumococcal conjugate vaccine (PCV9) and meningococcal group C conjugate (MnCC) vaccine (PCV9-MnCC) administered concomitantly with Haemophilus influenzae type b (Hib) conjugate vaccine, and of a combination of the three vaccines mixed together as a single injection (Hib-PCV9-MnCC), and compared them to separately administered PCV9 and MnCC dispensed to Chilean infants at 2, 4, and 6 months of age. The frequency of adverse events was similar among groups. Recipients of PCV9 alone or in combination with the other vaccines mounted significant antibody responses to the nine pneumococcal serotypes in PCV9, with >88% achieving protective levels of > or =0.35microg/mL. For serotypes 6B, 9V, and 5, recipients of PCV9 alone had significantly higher geometric mean concentrations (GMCs) than those of the other vaccine groups. Similarly, the GMC of anti-PRP antibodies was significantly lower among recipients of Hib-PCV9-MnCC than among those who received Hib vaccine separately from PCV9 or MnCC. In Chilean infants, PCV9, PCV9-MnCC, and Hib-PCV9-MnCC were highly immunogenic and safe. Overall, interactions of PCV9, MnCC and Hib affected the magnitude (GMC) of the primary antibody responses to some of the antigens, but not the percentage of subjects who achieved protective antibody thresholds.