Maria Cleonice Aguiar Justino

Effectiveness of the monovalent G1P[8] human rotavirus vaccine against hospitalization for severe G2P[4] rotavirus gastroenteritis in Belém, Brazil.

Background: Brazil initiated universal immunization of infants with the G1P[8] human rotavirus (RV) vaccine in March 2006. This study evaluated vaccine effectiveness (VE) against severe rotavirus gastroenteritis (RVGE) hospitalizations. Methods: Matched case-control study conducted at 4 hospitals in Belém from May 2008 to May 2009. Cases were children hospitalized with RVGE age-eligible to have received 2 doses of the human RV vaccine (≥12 weeks of age and born after March 6, 2006). For each case, 1 neighborhood and 1 hospital control without gastroenteritis was selected, matching by birth date (±8 and ±6 weeks, respectively). Matched odds ratio of 2-dose RV vaccination in cases versus controls was used to estimate VE (1 − odds ratio × 100%). Results: Of 538 RVGE cases, 507 hospital controls and 346 neighborhood controls included, 54%, 61%, and 74% had received both RV vaccine doses. VE against RVGE hospitalization was 75.8% (95% confidence interval [CI]: 58.1–86.0) using neighborhood controls and 40.0% (95% CI: 14.2–58.1) using hospital controls. VE in children 3 to 11 months and ≥12 months of age was 95.7% (95% CI: 67.8–99.4) and 65.1% (95% CI: 37.2–80.6) using neighborhood controls, and 55.6% (95% CI: 12.3–77.5) and 32.1% (95% CI: −3.7–55.5) using hospital controls. G2P[4] accounted for 82.0% of RVGE hospitalizations. G2P[4]-specific VE was 75.4% (95% CI: 56.7–86.0) using neighborhood controls and 38.9% (95% CI: 11.1–58.0) using hospital controls. Conclusions: Although fully heterotypic G2P[4] was the predominant RV strain, good VE was demonstrated. VE was highest in children aged 3 to 11 months. However, protection in children ≥12 months of age, important for optimal public health impact, was significantly sustained based on estimates obtained using neighborhood controls.

Segurança, imunogenicidade e eficácia protetora de duas doses da vacina RIX4414 contendo rotavírus atenuado de origem humana

OBJECTIVE: To determine the safety, immunogenicity and efficacy of two doses of rotavirus vaccine in healthy Brazilian infants. METHODS: A randomized, multicenter, double-blind, placebo-controlled trial was conducted in Brazil, Mexico and Venezuela. Infants received two oral doses of vaccine or placebo at 2 and 4 months of age, concurrently with routine immunizations, except for oral poliomyelitis vaccine (OPV). This paper reports results from Belem, Brazil, where the number of subjects per group and the viral vaccine titers were: 194 (104.7 focus forming units - FFU), 196 (105.2 FFU), 194 (105.8 FFU) and 194 (placebo). Anti-rotavirus (anti-RV) antibody response was assessed in 307 subjects. Clinical severity of gastroenteritis episodes was measured using a 20-point scoring system with a score of > 11 defined as severe GE. RESULTS: The rates of solicited general symptoms were similar in vaccine and placebo recipients. At 2 months after the second dose, a serum IgA response to RV occurred in 54.7 to 74.4% of vaccinees. No interference was seen in the immunogenicity of routine vaccines. Vaccine efficacy against any rotavirus gastroenteritis (RVGE) was 63.5% (95%CI 20.8-84.4) for the highest concentration (105.8 FFU). Efficacy was 81.5% (95%CI 44.5-95.4) against severe RVGE. At its highest concentration (105.8 FFU), RIX4414 provided 79.8% (95%CI 26.4-96.3) protection against severe RVGE by G9 strain. CONCLUSIONS: RIX4414 was highly immunogenic with a low reactogenicity profile and did not interfere with seroresponse to diptheria, tetanus, pertussis, hepatitis B and Hib antigens. Two doses of RIX4414 provided significant protection against severe GE caused by RV.

Rotavirus vaccination in Brazil: effectiveness and health impact seven years post-introduction

Before vaccine introduction in Brazil, rotavirus caused approximately 650,000 outpatient visits, 92,000 hospitalizations and 850 deaths annually among children aged <5 years. Brazil was one of the first countries to introduce rotavirus vaccination into the National Immunisation Program (NIP), in 2006, but estimated coverage (87.1%) for 2011 remained lower if compared with other routine immunizations (95%). Case–control studies reached effectiveness rates as high as 85%. Observational studies showed a significant reduction in gastroenteritis-related hospitalizations and deaths among children aged <1 year, at rates as high as 48 and 54%, respectively. There was a significant increase in the relative prevalence of G2P[4] genotype after vaccine introduction, reaching 100% of strains in some settings. A small increase in intussusception incidence was seen within 1 week following the second vaccine dose, but benefits far outweigh any potential risk. This article provides an in-depth review of postlicensure studies conducted in Brazil 7-year postintroduction.

Prevalence and clinical features of respiratory syncytial virus in children hospitalized for community-acquired pneumonia in northern Brazil

BackgroundChildhood pneumonia and bronchiolitis is a leading cause of illness and death in young children worldwide with Respiratory Syncytial Virus (RSV) as the main viral cause. RSV has been associated with annual respiratory disease outbreaks and bacterial co-infection has also been reported. This study is the first RSV epidemiological study in young children hospitalized with community-acquired pneumonia (CAP) in Belém city, Pará (Northern Brazil).MethodsWith the objective of determining the prevalence of RSV infection and evaluating the patients’ clinical and epidemiological features, we conducted a prospective study across eight hospitals from November 2006 to October 2007. In this study, 1,050 nasopharyngeal aspirate samples were obtained from hospitalized children up to the age of three years with CAP, and tested for RSV antigen by direct immunofluorescence assay and by Reverse Transcription Polymerase Chain Reaction (RT-PCR) for RSV Group identification.ResultsRSV infection was detected in 243 (23.1%) children. The mean age of the RSV-positive group was lower than the RSV-negative group (12.1 months vs 15.5 months, p<0.001) whereas gender distribution was similar. The RSV-positive group showed lower means of C-reactive protein (CRP) in comparison to the RSV-negative group (15.3 vs 24.0 mg/dL, p<0.05). Radiological findings showed that 54.2% of RSV-positive group and 50.3% of RSV-negative group had interstitial infiltrate. Bacterial infection was identified predominantly in the RSV-positive group (10% vs 4.5%, p<0.05). Rhinorrhea and nasal obstruction were predominantly observed in the RSV-positive group. A co-circulation of RSV Groups A and B was identified, with a predominance of Group B (209/227). Multivariate analysis revealed that age under 1 year (p<0.015), CRP levels under 48 mg/dL (p<0.001) and bacterial co-infection (p<0.032) were independently associated with the presence of RSV and, in the analyze of symptoms, nasal obstruction were independently associated with RSV-positive group (p<0.001).ConclusionThe present study highlights the relevance of RSV infection in hospitalized cases of CAP in our region; our findings warrant the conduct of further investigations which can help design strategies for controlling the disease.

Norovirus Infection in Children Admitted to Hospital for Acute Gastroenteritis in Belem, Para ´ , Northern Brazil

Noroviruses are the leading cause of epidemic, non‐bacterial outbreaks of acute gastroenteritis, and are also a major cause of sporadic acute gastroenteritis in infants. The aim of the present study was to identify norovirus infections in children not infected by rotavirus admitted to hospital for acute gastroenteritis in Belém. A total of 348 fecal specimens were obtained from children with diarrhea aged less than 5 years, all of whom had tested negative for rotavirus, between May 2008 and April 2010. Fecal samples were screened for norovirus antigen using enzyme‐immunoassay (EIA). Specimens were subjected to reverse‐transcription polymerase chain reaction (RT‐PCR) using the primers Mon432/434–Mon431/433 for detection of the GI and GII norovirus strains, respectively. Based on both methods, the overall norovirus positivity rate was 36.5% (127/348). Of the 169 samples collected in the first year, 44.4% (n = 75) tested positive for norovirus using both methods, 35.5% (n = 60) by EIA and 40.8% (n = 69) by RT‐PCR. Using RT‐PCR as a reference standard, a sensitivity of 78.3%, specificity of 94%, and agreement of 87.6% were recorded. Genome sequencing was obtained for 22 (31.9%) of the 69 positive samples, of which 90.9% (20/22) were genotype GII.4d and 9.1% (2/22) were genotype GII.b. Norovirus infection was most frequent in children under 2 years of age (41.5%–115/277). The peak incidence (62.1%) of norovirus‐related acute gastroenteritis in these patients (not infected by rotavirus) was observed in February 2010. These findings emphasize the importance of norovirus as a cause of severe acute gastroenteritis among children in Belém, Pará, Northern Brazil. J. Med. Virol. 85:737–744, 2013.

Rotavirus strain surveillance for three years following the introduction of rotavirus vaccine into Belém, Brazil

The monovalent human rotavirus (RV) vaccine, RIX4414 (Rotarix™, GlaxoSmithKline Biologicals) was introduced into Brazils Expanded Program on Immunization in March 2006. One year after vaccine introduction, the G2P[4] strain was found to be predominant, with an apparent extinction of many non‐G2 strains. This study investigated the diversity of circulating strains in the three years following RIX4414 introduction. Between May 2008 and May 2011, stool samples were collected from children aged ≥12 weeks who were hospitalized for severe lab confirmed RV‐gastroenteritis (≥3 liquid or semi‐liquid motions over a 24‐h period for <14 days, requiring ≥1 overnight hospital stay and intravenous rehydration therapy) in Belém, Brazil. RV‐gastroenteritis was detected by ELISA and the G‐ and P‐types were determined by RT‐PCR assays. During the first year of surveillance nucleotide sequencing was used for typing those samples not previously typed by RT‐PCR. A total of 1,726 of 10,030 severe gastroentertis hospitalizations (17.2%) were due to severe RVGE. G2P[4] was detected in 57.2% of circulating strains over the whole study period, however it predominated during the first 20 months from May 2008 to January 2009. G1P[8] increased in the last part of the study period from May 2010 to May 2011 and represented 36.6% (112/306) of the circulating strains. G2P[4] was the predominant RV strain circulating during the first 20 months of the study, followed by G1P[8]. These findings probably reflect a natural fluctuation in RV strains over time, rather than a vaccine‐induced selective pressure. J. Med. Virol. 87:1303–1310, 2015.

Group A rotavirus and norovirus display sharply distinct seasonal profiles in Belem, northern Brazil.

Several viruses have been associated with acute gastroenteritis (AGE), and group A rotavirus (RVA) and norovirus (NoV) are the most prevalent. This study aimed to assess their prevalence among children hospitalised for diarrhoea during a three-year surveillance study. From May 2008-April 2011, overall positivity rates of 21.6% (628/2904) and 35.4% (171/483) were observed for RVA and NoV, respectively. The seasonality observed indicated distinct patterns when both viruses were compared. This finding may explain why hospitalisation for AGE remains constant throughout the year. Continuous AGE monitoring is needed to better assess the patterns of infection.

Oral live attenuated human rotavirus vaccine (RotarixTM) offers sustained high protection against severe G9P[8] rotavirus gastroenteritis during the first two years of life in Brazilian children

In a large Phase III trial conducted in 10 Latin American countries, the safety and efficacy of the live attenuated monovalent rotavirus vaccine RIX4414 was evaluated in 15,183 healthy infants followed up during the first two years of life. Belém was the only site in Brazil included in this multicentre trial. The study in Belém included a subset of 653 infants who were followed up until 24 months of age for protection against severe rotavirus gastroenteritis. These subjects were randomly assigned in a 1:1 ratio to receive two doses of vaccine (n = 328) or two doses of placebo (n = 325) at approximately two and four months of age. Of the 653 enrolled infants, 23 dropped out during the study period. For the combined two-year period, the efficacy of RIX4414 was 72.3% [95% confidence interval (CI) 37.5-89.1%] against severe rotavirus-related gastroenteritis, reaching a protection rate of 81.8% (95% CI 36.4-96.6%) against circulating wild-type G9 rotavirus strains. It is concluded that two doses of RIX4414 are highly efficacious against severe rotavirus gastroenteritis in Belém during the first two years of life and provide high protection against the worldwide emergence and spread of G9P[8] strains.

Characterization of novel intragenotype recombination events among norovirus pandemic GII.4 variants

Recently, there has been an increase in the number of children hospitalized due to norovirus infection in Brazil. This is due both to the occurrence of more severe norovirus-related gastroenteritis cases after the introduction of the rotavirus vaccine and an increase in the tools for the detection of the disease. This pathogen is transmitted by the fecal-oral route, and the illness is characterized by diarrhea, vomiting, nausea and abdominal cramps. The genome of the virus is organized into three open reading frames showing strong mutation rates. Additionally, homologous recombination events, which can increase the virulence of the virus and lead to genotyping mistakes in molecular epidemiological studies, frequently occur. The purpose of this study was to describe two recombination events among different GII.4 variants that infected children who were hospitalized for severe acute gastroenteritis during distinct periods of time in Belém, Brazil. The recombination among the variants US95_96/Kaiso_2003 and Den Haag_2006b/Yerseke_2006a were observed in May 2003 and February 2009, respectively. In both cases, the association between the dominant variant at that point in time and another that was circulating at a low frequency in the population of Belém was demonstrated. Interestingly, the position of the breakpoint of the recombination event in the genome was the polymerase gene and was located at the nucleotide positions 4.834 and 5.002, which is an unusual location for the occurrence of recombination as other studies have previously reported the junction region as a breakpoint. In this study, both recombinant variant strains were related to severe cases of diarrhea that lead to hospitalization, demonstrating the viral evolution of GII.4 in response to selective pressures, which ultimately lead to the emergence of novel viral types in the pediatric population. The cases discussed here reinforce the need for continuous norovirus surveillance. To our knowledge, these two GII.4 variant recombinations have not yet been previously described.

Detection and genetic characterization of the emergent GII.17_2014 norovirus genotype among children with gastroenteritis from Northern Brazil

Norovirus is the most important cause of viral gastroenteritis outbreaks worldwide. Recently, a novel GII.17 norovirus variant emerged and caused epidemics in Asian countries, replacing the GII.4 Sydney 2012 strain in hospitalized cases. In this study we describe the emergence of this novel NoV GII.17_2014 strain in Brazil.