Eduardo L. López

Safety and pharmacokinetics of urtoxazumab, a humanized monoclonal antibody, against shiga-like toxin 2 in healthy adults and in pediatric patients infected with shiga-like toxin-producing Escherichia coli.

ABSTRACT Shiga-like toxin-producing Escherichia coli (STEC) infection causes diarrhea, which is often bloody and which can result in potentially life-threatening hemolytic-uremic syndrome (HUS). Urtoxazumab, a humanized monoclonal antibody directed against the Shiga-like toxin 2 (Stx2) produced by STEC, has been developed as a promising agent for the prevention of HUS. Single randomized, intravenous, double-blind, placebo-controlled doses of urtoxazumab were administered to assess its safety and pharmacokinetics in healthy adults (0.1 to 3.0 mg/kg of body weight) and STEC-infected pediatric patients (1.0 and 3.0 mg/kg). No dose-related safety trends were noted, nor were antiurtoxazumab antibodies detected. The disposition of urtoxazumab showed a biexponential decline, regardless of the dose. In healthy adults, the mean terminal elimination half-life was consistent across the dose groups and ranged from 24.6 days (3.0-mg/kg dose group) to 28.9 days (0.3-mg/kg dose group). The mean maximum serum drug concentration (Cmax) ranged from 2.6 μg/ml at 0.1 mg/kg to 71.7 μg/ml at 3.0 mg/kg. The disposition of urtoxazumab following the administration of doses of 1.0 and 3.0 mg/kg in pediatric patients showed mean Cmaxs of 19.6 and 56.1 μg/ml, respectively. Urtoxazumab was well tolerated, appears to be safe at doses of up to 3.0 mg/kg, and is a potential candidate for the prevention of HUS in pediatric patients.

Open label, multicenter study of gatifloxacin treatment of recurrent otitis media and acute otitis media treatment failure.

Background. Recurrent otitis media and treatment failures of acute infections are refractory to therapy. Newer fluoroquinolones have excellent activity against respiratory pathogens, but their use in children has been limited because of concerns about adverse effects. Methods. This was an open label, multicenter trial in which patients with recurrent otitis media or acute otitis media (AOM) treatment failure were treated with 10 mg/kg gatifloxacin oral suspension once daily for 10 days. Before treatment a tympanocentesis or a swab of middle ear fluid was obtained. Nasopharyngeal swabs were obtained at baseline and at the end of therapy. Efficacy was evaluated 3 to 10 days after cessation of treatment and at 3 to 4 weeks. Safety monitoring included special attention to any sign or symptom suggestive of joint or bone abnormality. Results. The study enrolled 254 patients 6 months to 7 years of age, with one-half (52%) of the patients having recurrent otitis media, 17% having AOM treatment failure and 28% having both. Cure was achieved posttreatment in 88% of 198 clinically evaluable patients, with similar outcomes for patients younger or older than 2 years of age. Of the 45 evaluable patients with Streptococcus pneumoniae, 38 (84%) were cured, including 25 of 28 with penicillin-nonsusceptible strains. Also cured were 89% of those with Haemophilus influenzae and those with Moraxella catarrhalis. No selection of resistance to gatifloxacin was detected among nasopharyngeal pathogens. Eighty-three percent of the children had sustained cure at the 4 weeks follow-up visit. Adverse events were primarily mild gastrointestinal, with no occurrences of arthropathy. Conclusion. Gatifloxacin is safe and effective for treatment of recurrent otitis media and AOM treatment failure in children.

Humoral and intestinal immunity induced by new schedules of bivalent oral poliovirus vaccine and one or two doses of inactivated poliovirus vaccine in Latin American infants: an open-label randomised controlled trial

BACKGROUND Replacement of the trivalent oral poliovirus vaccine (tOPV) with bivalent types 1 and 3 oral poliovirus vaccine (bOPV) and global introduction of inactivated poliovirus vaccine (IPV) are major steps in the polio endgame strategy. In this study, we assessed humoral and intestinal immunity in Latin American infants after three doses of bOPV combined with zero, one, or two doses of IPV. METHODS This open-label randomised controlled multicentre trial was part of a larger study. 6-week-old full-term infants due for their first polio vaccinations, who were healthy on physical examination, with no obvious medical conditions and no known chronic medical disorders, were enrolled from four investigational sites in Colombia, Dominican Republic, Guatemala, and Panama. The infants were randomly assigned by permuted block randomisation (through the use of a computer-generated list, block size 36) to nine groups, of which five will be discussed in this report. These five groups were randomly assigned 1:1:1:1 to four permutations of schedule: groups 1 and 2 (control groups) received bOPV at 6, 10, and 14 weeks; group 3 (also a control group, which did not count as a permutation) received tOPV at 6, 10, and 14 weeks; group 4 received bOPV plus one dose of IPV at 14 weeks; and group 5 received bOPV plus two doses of IPV at 14 and 36 weeks. Infants in all groups were challenged with monovalent type 2 vaccine (mOPV2) at 18 weeks (groups 1, 3, and 4) or 40 weeks (groups 2 and 5). The primary objective was to assess the superiority of bOPV-IPV schedules over bOPV alone, as assessed by the primary endpoints of humoral immunity (neutralising antibodies-ie, seroconversion) to all three serotypes and intestinal immunity (faecal viral shedding post-challenge) to serotype 2, analysed in the per-protocol population. Serious and medically important adverse events were monitored for up to 6 months after the study vaccination. This study is registered with ClinicalTrials.gov, number NCT01831050, and has been completed. FINDINGS Between May 20, 2013, and Aug 15, 2013, 940 eligible infants were enrolled and randomly assigned to the five treatment groups (210 to group 1, 210 to group 2, 100 to group 3, 210 to group 4, and 210 to group 5). One infant in group 1 was not vaccinated because their parents withdrew consent after enrolment and randomisation, so 939 infants actually received the vaccinations. Three doses of bOPV or tOPV elicited type 1 and 3 seroconversion rates of at least 97·7%. Type 2 seroconversion occurred in 19 of 198 infants (9·6%, 95% CI 6·2-14·5) in the bOPV-only groups, 86 of 88 (97·7%, 92·1-99·4) in the tOPV-only group (p<0·0001 vs bOPV-only), and 156 of 194 (80·4%, 74·3-85·4) infants in the bOPV-one dose of IPV group (p<0·0001 vs bOPV-only). A further 20 of 193 (10%) infants in the latter group seroconverted 1 week after mOPV2 challenge, resulting in around 98% of infants being seropositive against type 2. After a bOPV-two IPV schedule, all 193 infants (100%, 98·0-100; p<0·0001 vs bOPV-only) seroconverted to type 2. IPV induced small but significant decreases in a composite serotype 2 viral shedding index after mOPV2 challenge. 21 serious adverse events were reported in 20 patients during the study, including two that were judged to be possibly related to the vaccines. Most of the serious adverse events (18 [86%] of 21) and 24 (80%) of the 30 important medical events reported were infections and infestations. No deaths occurred during the study. INTERPRETATION bOPV provided humoral protection similar to tOPV against polio serotypes 1 and 3. After one or two IPV doses in addition to bOPV, 80% and 100% of infants seroconverted, respectively, and the vaccination induced a degree of intestinal immunity against type 2 poliovirus. FUNDING Bill & Melinda Gates Foundation.

The current situation of meningococcal disease in Latin America and updated Global Meningococcal Initiative (GMI) recommendations

The Global Meningococcal Initiative (GMI) was established in 2009 and comprises an international team of scientists, clinicians, and public health officials with expertise in meningococcal disease (MD). Its primary goal is to promote global prevention of MD through education, research, international cooperation, and developing recommendations that include decreasing the burden of severe disease. The group held its first roundtable meeting with experts from Latin American countries in 2011, and subsequently proposed several recommendations to reduce the regional burden of MD. A second roundtable meeting was convened with Latin American representatives in June 2013 to reassess MD epidemiology, vaccination strategies, and unmet needs in the region, as well as to update the earlier recommendations. Special emphasis was placed on the emergence and spread of serogroup W disease in Argentina and Chile, and the control measures put in place in Chile were a particular focus of discussions. The impact of routine meningococcal vaccination programs, notably in Brazil, was also evaluated. There have been considerable improvements in MD surveillance systems and diagnostic techniques in some countries (e.g., Brazil and Chile), but the lack of adequate infrastructure, trained personnel, and equipment/reagents remains a major barrier to progress in resource-poor countries. The Pan American Health Organizations Revolving Fund is likely to play an important role in improving access to meningococcal vaccines in Latin America. Additional innovative approaches are needed to redress the imbalance in expertise and resources between countries, and thereby improve the control of MD. In Latin America, the GMI recommends establishment of a detailed and comprehensive national/regional surveillance system, standardization of laboratory procedures, adoption of a uniform MD case definition, maintaining laboratory-based surveillance, replacement of polysaccharide vaccines with conjugate formulations (wherever possible), monitoring and evaluating implemented vaccination strategies, conducting cost-effectiveness studies, and developing specific recommendations for vaccination of high-risk groups.

The current situation of meningococcal disease in Latin America and recommendations for a new case definition from the Global Meningococcal Initiative

The Global Meningococcal Initiative (GMI) is an international group of scientists and clinicians with expertise in meningococcal disease (MD). It promotes MD prevention through education and research. Given geographic differences in disease epidemiology, prevention strategies (e.g., vaccination) should be country-specific to ensure local needs are met. However, regional policies/recommendations and standardized disease diagnostic criteria should be implemented to improve surveillance and control strategies, and allow for more robust data comparisons. Consequently, the GMI convened a meeting with Latin American representatives to discuss the burden of MD and vaccination practices/policies, and consider if the global GMI recommendations could be tailored. The group determined that as robust, uniform epidemiologic data are required to make informed health-policy decisions, it would be useful to first summarize the regional situation herein (including disease surveillance, case definitions, epidemiology, vaccination and outbreak control strategies) and then determine a consensus-based meningococcal case definition for use throughout the region.

Long-term immunity after two doses of inactivated hepatitis A vaccine, in Argentinean children.

We examined long-term anti-hepatitis A virus antibody persistence in Argentinean children 10 years after the initial study in which they received 2 doses of inactivated hepatitis A vaccine (Avaxim 80U). Of the 111 children, 48 from the initial trial were enrolled. Of 48, 47 (97.9%) participants had serum anti-hepatitis A virus antibody titers ≥20 mIU/mL, with the geometric mean concentration of 390.91 (±370.14) mIU/mL; (95% confidence interval, 282.2–499.5 mIU/mL), range, 36 to 1860.

Emergence of intratreatment resistance to oseltamivir in pandemic influenza A H1N1 2009 virus

BACKGROUND Pandemic influenza A H1N1 2009 virus presents a new challenge to health authorities and communities worldwide. In Argentina, the outbreak was at its peak by the end of June 2009, during the southern winter. A systematic analysis of samples from patients with pandemic H1N1 2009 studied in our laboratory (Virology Laboratory, Hospital de Niños R Gutiérrez, Buenos Aires, Argentina) detected two patients presenting intratreatment emergence of the H275Y neuraminidase mutation, which confers resistance to oseltamivir. METHODS Complementary DNAs, including the 275 codon, were obtained by reverse transcriptase PCR using viral RNAs extracted from nasopharyngeal or tracheal aspirates. Conventional sequencing and pyrosequencing were performed on each sample. In order to measure the virus susceptibility to oseltamivir, 50% inhibitory concentration determinations were performed by chemiluminescence. RESULTS Sequential samples of two paediatric patients under oseltamivir treatment were analysed. Pretreatment samples were composed of 100% oseltamivir-sensitive variants. In case 1, the oseltamivir-resistant variant was found 8 days after the beginning of treatment. In case 2, the viral population became resistant on the second day of treatment, with 83% of the viral population bearing the mutation and this reached 100% on the seventh day. CONCLUSIONS We describe the intratreatment emergence of oseltamivir resistance in two paediatric patients. Pyrosequencing allowed us to detect variant mixtures, showing the transition of the viral population from sensitive to resistant.

Enfermedad meningocóccica: siempre presente. Cambios en los serogrupos en el Cono Sur

Meningococcal disease (MD) caused by Neisseria meningitidis is a condition with high mortality rates in childhood. Serogroup W135 N. meningitidis (MenW135) is usually associated with 1 to 8% of MD cases worldwide, and with a low carriage rate. During March 2000, an increase in the number of cases of MenW135 in Saudi Arabia was reported that coincided with the Hajj pilgrimage (Hajj-2000 strain). Mayer et al studied MenW135 strains from outbreaks related with this pilgrimage and found that all had been caused by the same hypervirulent clone (ST-11/complex ET-37). The circulation of this strain could also be documented in Latin America. In the last years, changes in serogroup prevalence have been observed in the region, the increase of MenW135 in the Southern Cone being the most significant. N. meningitidis infections of several serogroups including MenW135 may be prevented with chemoprophylaxis with antibiotics and quadrivalent vaccines. Better knowledge of the global epidemiology through the new molecular techniques, jointly with the availability of vaccines are the most relevant tools to control hyperendemic or epidemic periods of MD.

Modeling the Long-term Persistence of Hepatitis A Antibody After a Two-Dose Vaccination Schedule in Argentinean Children.

Background: Long-term seroprotection data are essential for decision-making on the need and timing of vaccine boosters. Based on data from longitudinal serological studies, modeling can provide estimates on long-term antibody persistence and inform such decision-making. Methods: We examined long-term anti-hepatitis A virus (anti-HAV) antibody persistence in Argentinean children ⩽15 years after the initial study where they completed a 2-dose course of inactivated hepatitis A vaccine (Avaxim® 80U Pediatric, Sanofi Pasteur, Lyon, France). Blood serum samples were taken at baseline, 2 weeks (post first dose), 6 months (pre-booster), 6.5 months (post-booster), 10 years and 14–15 years after first vaccine dose. We fitted 8 statistical model types, predominantly mixed effects models, to anti-HAV persistence data, to identify the most appropriate and best fitting models for our data set and to predict individuals’ anti-HAV levels and seroprotection rates up to 30 years post vaccination. Results: Fifty-four children (mean age at enrollment 30.4 months) were enrolled up to 15 years post first vaccine dose. There were 3 distinct periods of antibody concentration: rapid rise up to peak concentration post-booster, rapid decay from post-booster to 10 years, followed by slower decay. A 3-segmented linear mixed effects model was the most appropriate for the data set. Extrapolating based on the available 14–15-year follow-up, the analysis predicted that 88% of individuals anti-HAV seronegative prior to vaccination would remain seroprotected at 30 years post vaccination and lifelong seroprotection for vaccinees seropositive prior to vaccination. Conclusions: Currently available data demonstrate that Avaxim® 80U Pediatric confers to most vaccinees a high level of seroprotection against hepatitis A infection for at least 20–30 years.

National Immunization Commission: strengthening evidence-based decision making in Argentina.

In Argentina, the National Technical Advisory Group on Immunizations is represented by the National Immunization Commission (CoNaIn), an organization created by the Ministry of Health in 2000. Recently, the Argentine government has decided to prioritize vaccination as a state policy, emphasizing this strategy as a sign of social equity so CoNaIn was restructured to increase its capacity to formulate sound and evidence-based recommendations. The commission shall consist of a group of immunization experts, representatives of scientific societies, the immunization program and the Ministry of Health. Its functions include the formulation of recommendations on the introduction of vaccines into the immunization program. The recommendations are based on technical, programmatic and social criteria. This decision-making process transparent with the support and advice of experts and scientific societies and guided by available evidence decisions help strengthen the Ministry of Health immunization policy generating greater confidence and support from the population and health professionals.