Rodrigo Vergara

Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study

BACKGROUND Effective glycoconjugate vaccines against Neisseria meningitidis serogroups A, C, W-135, and Y have been developed, but serogroup B remains a major cause of severe invasive disease in infants and adolescents worldwide. We assessed immunogenicity and tolerability of a four-component vaccine (4CMenB) in adolescents. METHODS We did a randomised, observer-blind, placebo-controlled, study at 12 sites in Santiago and Valparaíso, Chile. Adolescents aged 11-17 years received one, two, or three doses of 4CMenB at 1 month, 2 month, or 6 month intervals. Immunogenicity was assessed as serum bactericidal activity using human complement (hSBA) against three reference strains for individual vaccine antigens, and assessed by ELISA against the fourth strain. Local and systemic reactions were recorded 7 days after each vaccination, and adverse events were monitored throughout the study. Participants were initially randomised to five groups (3:3:3:3:1) during the primary phase to receive either one dose, two doses 1 or 2 months apart, or three doses of 4CMenB, or three doses of placebo, with an additional three groups generated for the booster phase. All subjects received at least one dose of 4CMenB. Geometric mean titres, proportions of participants with serum bactericidal antibody titres of 4 or more, and Clopper-Pearson 95% CIs were calculated. The study is registered with ClinicalTrials.gov, number NCT00661713. FINDINGS Overall, 1631 adolescents (mean age 13·8 [SD 1·9] years) received at least one dose of 4CMenB. After two or three doses, 99-100% of recipients had hSBA titres of 4 or more against test strains, compared with 92-97% after one dose (p<0·0145) and 29-50% after placebo. At 6 months 91-100% of participants still had titres of 4 or more for each strain after two or three doses, but only 73-76% after one dose; seroresponse rates reached 99-100% for each strain after second or third doses at 6 months. Local and systemic reaction rates were similar after each 4CMenB injection and did not increase with subsequent doses, but remained higher than placebo. No vaccine-related serious adverse events were reported and no significant safety signals were identified. INTERPRETATION On the basis of immunogenicity responses this study provides evidence for an adolescent 4CMenB vaccine schedule of two doses, 1-6 months apart, to provide protection against meningococcal B infection. The extent of this protection against meningococcus B variants circulating worldwide will be determined by national surveys. FUNDING Novartis Vaccines and Diagnostics.

Persistence of antibodies in adolescents 18−24 months after immunization with one, two, or three doses of 4CMenB meningococcal serogroup B vaccine

We previously demonstrated the immunogenicity and tolerability of the serogroup B meningococcal vaccine, 4CMenB (Bexsero®), in 11−17 y-olds randomized to receive 1, 2, or 3 doses at 1, 2, or 6 mo intervals. Participants in this extension study provided an additional blood sample 18−24 mo after last vaccine dose, to assess persistence of serum bactericidal activity with human complement (hSBA), and to compare with age-matched 4CMenB-naïve controls. In the original study, one month after one 4CMenB dose, 93% of subjects had seroprotective hSBA titers (≥4) against indicator serogroup B strains for individual vaccine antigens (fHbp, NadA and NZOMV), increasing to ~100% after two or three doses. After 18−24 mo, 62−73% of subjects given one dose had titers ≥4 against the three antigens, significantly lower rates than after two (77−94%) or three (86−97%) doses. Only proportions with titers ≥ 4 against NZOMV were significantly different between the two (77%) and three (90%, p < 0.0001) dose groups. These results confirm that two doses of 4CMenB, administered 1 to 6 mo apart, provide good levels of bactericidal activity against serogroup B meningococci, which were sustained at least 18−24 mo in over 64% of adolescents for all three tested vaccine-related antigens.

Prospective characterization of norovirus compared with rotavirus acute diarrhea episodes in chilean children.

Background: Rotavirus and more recently noroviruses are recognized as main causes of moderate to severe acute diarrhea episodes (ADE) in children ≤5 years of age. Comparing epidemiologic and clinical features of norovirus to rotavirus ADE will aid in the decision-making process required to develop norovirus vaccines. Methods: Surveillance for ADE occurring in children ≤5 years of age was implemented in the emergency department (ED) and ward of a large hospital in Santiago and Valparaiso, and in 4 outpatient clinics in Santiago. A stool sample was obtained within 48 hours of consultation for rotavirus detection by enzyme-linked immunosorbent assay and noroviruses by enzyme-linked immunosorbent assay or reverse transcription polymerase chain reaction. For ED and hospital rotavirus and norovirus ADE parents were instructed to monitor clinical findings associated with severity until the end of the episode. The 20-point Vesikari score was used to determine disease severity. Results: Between July 2006 and October 2008 rotavirus and noroviruses were detected in 331 (26%) and 224 (18%) of 1913 ADE evaluated. The proportion of rotavirus-positive samples in hospital ward, ED, and outpatient clinic was 40%, 26% to 30%, and 13% compared with 18%, 17% to 19%, and 14% for noroviruses. Mean age and 25%–75% interquartile interval of children with rotavirus and norovirus ADE were remarkably similar, 15.6 months (9–20), and 15.5 months (9–19), respectively. Rotavirus cases displayed an autumn-winter peak followed 2 to 3 months later by the norovirus peak. The mean (interquartile) for the Vesikari score was 12.9 (11–15) and 11.9 (9–14.5) for rotavirus (N = 331) and norovirus (N = 224) ADE, respectively, P = 0.003. Compared with norovirus, rotavirus ADE were more common in the 11 to 16 severity score interval (P = 0.006), had a higher maximum stool output in a given day (P = 0.01) and more frequent fever (P < 0.0001). Duration of diarrhea, presence, duration and intensity of vomiting, and intensity of fever did not differ between viruses. Mixed rotavirus and norovirus infections were uncommon (<1%) and not clinically more severe. Clinical severity of ADE in young infants was similar for rotavirus and lower (P = 0.03) for noroviruses compared with older children. Conclusion: Noroviruses are a significant cause of moderate to severe endemic ADE in Chilean children. Although significantly less severe than rotavirus as a group, most norovirus episodes were moderate to severe clinically. An effective norovirus vaccine would be of significant additional benefit to the current rotavirus vaccine in decreasing disease burden associated with ADE.

Genotipos de rotavirus aislados de niños chilenos con gastroenteritis atendidos en dos hospitales públicos: variantes virales circulantes en un país con uso limitado de vacunas anti-rotavirus

BACKGROUND Rotavirus is the main cause of severe gastroenteritis (GE) in children. Two vaccines currently available have proven efficacy against the predominant genotypes. Rotavirus genotypes vary both geographically and/or temporally. Genotype surveillance is important to monitor trends associated or not with vaccine use. AIM To update information on rotavirus genotypes circulating in two main cities of Chile. METHODOLOGY Between May 2009-March 2010, children < 5y of age receiving medical care for GE in two large hospitals were recruited; none of these children had received rotavirus vaccine previously. Epidemiological information was recorded in an ad-hoc form and stool samples were collected for rotavirus detection by a commercial ELISA. Genotyping was performed by semi-nested RT-PCR. RESULTS A total of 296/967 samples (31%) were positive for rotavirus, with a peak in November/ December mostly in children 7-24 months old (67%). G9P[8] was the predominant genotype (76%), followed for G1P[8] (6%) and G2P[4] (6%) in both cities. CONCLUSIONS Rotavirus caused one third of GE requiring emergency room care and/or hospitalization, mostly in children within an age range susceptible to benefit from rotavirus vaccines. G9P[8], a genotype against which rotavirus vaccines have demonstrated high efficacy, was by far the most frequent rotavirus variant. Continued surveillance in Chile is crucial for providing background information on disease burden and strain diversity before the introduction of rotavirus vaccines.

Evaluación de la efectividad, seguridad y costos del tratamiento antimicrobiano intravenoso ambulatorio (TAIA) vs hospitalizado en infección urinaria en pediatría

BACKGROUND Childrens hospitalization for intravenous antibiotic treatment has been replaced in developed countries and in some Chilean centers to outpatient intravenous therapy (OPAT). AIM To compare the effectiveness, safety and cost of OPAT versus inpatient care. PATIENTS AND METHODS Prospective cohort study in children (2 months-5 years) with febrile urinary tract infection (UTI) attended at two public Chilean hospitals: outpatient cohort and inpatient cohort. Between November of 2009-2010, 111 children were enrolled in OPAT and between January 2010-June 2011, 81 children were hospitalized. Demographic data, costs and parental care, response to treatment, adverse events and complications were registered. RESULTS There was no difference in the effectiveness of both treatments (100% in OPAT and 98.6% in inpatient cohort, p: 0.41). Adherence to OPAT was 100%. Prevalence of adverse events was higher in inpatient cohort (76.3% versus 16.2%, p < 0.01). The average direct cost was four times higher in inpatients, mainly due to bed-day cost. Indirect cost was similar in both groups. There were more days of absence from work and care centers in inpatients (p: 0.017, p: 0.045 respectively). CONCLUSION OPAT for febrile UTI was equally effective, safer and significantly less expensive than inpatient care. OPAT represents a recommended intervention for pediatric services of Chilean public hospitals.

Modification of pertussis vaccination schedule in Chile, immunization of special groups and control strategies: Commentary from the Consultive Committee of Immunizations of The Chilean Society of Infectious Diseases

In Chile, an increased number of notifications of cases of whooping cough was detected at the beginning of October 2010, and maintained through 2012. Accumulated cases during 2011 were 2,581 (15.0 per 100,000), which is greater than the number of cases registered during the period 2008-2010 (2,460 cases). On the other hand, the local sanitary authority introduced a modification of pertussis vaccination schedule (starting 2012), which consists in the replacement of the second booster of pertussis vaccine (DTwP, administered to 4-year-old children) as well as diphtheria-tetanus toxoid (dT, administered to second grade scholars) for an acellular pertussis vaccine with reduced antigenic content (dTpa), which will be administrated to first grade scholars. The Consultive Committee of Immunizations considers that the modification is adequate, since it extends the age of protection, reducing at least in theory the infection in older scholars and adolescents -who are significant sources of transmission of Bordetella pertussis to infants- using an adequate vaccine formulation (acellular pertussis vaccine). The available evidence regarding vaccination in special groups (adolescents and adults, health-care workers and pregnant women) and cocooning strategy are commented.