Alexandre da Costa Linhares

Efficacy and safety of an oral live attenuated human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in Latin American infants: a randomised, double-blind, placebo-controlled phase III study

Zambia has a population of approximately 12 million. According to estimates from the 2001-2002 Zambia Demographic and Health Survey1 between 1997 and 2001 the rate of neonatal mortality was 37/1000 births the infant mortality rate was 95/1000 births and the maternal mortality ratio was 729/100 000 live births. In order to protect mothers and their newborn babies against tetanus WHO recommends that tetanus toxoid (TT) vaccine be given to all pregnant women; Zambia follows WHOs recommendations. In 2006 79% of all pregnant women received a protective dose of TT vaccine. A total of 60% of all deliveries took place in hygienic conditions (administrative data). WHO and UNICEF estimate that in 2006 90% of births were protected against tetanus. (excerpt)BACKGROUND Peak incidence of rotavirus gastroenteritis is seen in infants between 6 and 24 months of age. We therefore aimed to assess the 2-year efficacy and safety of an oral live attenuated human rotavirus vaccine for prevention of severe gastroenteritis in infants. METHODS 15 183 healthy infants aged 6-13 weeks from ten Latin American countries randomly assigned in a 1 to 1 ratio to receive two oral doses of RIX4414 or placebo at about 2 and 4 months of age in a double-blind, placebo-controlled phase III study were followed up until about 2 years of age. Primary endpoint was vaccine efficacy from 2 weeks after dose two until 1 year of age. Treatment allocation was concealed from investigators and parents of participating infants. Efficacy follow-up for gastroenteritis episodes was undertaken from 2 weeks after dose two until about 2 years of age. Analysis was according to protocol. This study is registered with ClinicalTrials.gov, number NCT00140673 (eTrack444563-023). FINDINGS 897 infants were excluded from the according-to-protocol analysis. Fewer cases (p<0.0001) of severe rotavirus gastroenteritis were recorded for the combined 2-year period in the RIX4414 group (32 [0.4%] of 7205; 95% CI 0.3-0.6) than in the placebo group (161 [2.3%] of 7081; 1.9-2.6), resulting in a vaccine efficacy of 80.5% (71.3-87.1) to 82.1% (64.6-91.9) against wild-type G1, 77.5% (64.7-86.2) against pooled non-G1 strains, and 80.5% (67.9-88.8) against pooled non-G1 P[8] strains. Vaccine efficacy for hospital admission for rotavirus gastroenteritis was 83.0% (73.1-89.7) and for admission for diarrhoea of any cause was 39.3% (29.1-48.1). No cases of intussusception were reported during the second year of follow-up. INTERPRETATION Two doses of RIX4414 were effective against severe rotavirus gastroenteritis during the first 2 years of life in a Latin American setting. Inclusion of RIX4414 in routine paediatric immunisations should reduce the burden of rotavirus gastroenteritis worldwide.

Group A rotavirus genotypes and the ongoing Brazilian experience: a review

Brazil was the first Latin American country to introduce universal group A rotavirus (RV-A) vaccination in March 2006, resulting in a unique epidemiological scenario. Since RV-A first identification in Brazil, 2,691 RV-A-positive stool samples, collected between 1982- 2007, were typed by independent research groups throughout the country. In the pre-vaccination era, 2,492 RV-A-positive samples collected from 1982-2005 were successfully typed, while 199 samples were analyzed from 2006-2007. According to the reviewed studies, there were two important times in the pre-vaccination era: (i) the period from 1982-1995, during which the detection of G5P[8] RV-A, in addition to the classical genotypes G1-4, challenged vaccine development programs; and (ii) the period from 1996-2005, during which genotype G9P[8] emerged, following a global trend. The rate of G2P[4] RV-A detection decreased from 26% (173/653) during 1982-1995 to 2% (43/1,839) during 1996-2005. The overall detection rate of RV-A genotypes from 1982-2005 was as follows: 43% (n = 1,079) G1P[8]/G1P[not typed (NT)]; 20% (n = 488) G9P[8]/G9P[NT]; 9% (n = 216) G2P[4]/G2P[NT]; 6% (n = 151) G3P[8]/G3P[NT]; 4% (n = 103) G4P[8]/G4P[NT]; and 4% (n = 94) G5P[8]/G5P[NT]. Mixed infections accounted for 189 (7%) of the positive samples, while atypical G/P combinations or other genotypes, including G6, G8, G10 and G12, were identified in 172 (7%) samples. The initial surveillance studies carried out in several Brazilian states with RV-A-positive samples collected in 2006 and 2007 show a predominance of G2P[4] strains (148/199 or 74%). Herein, we review RV-A typing studies carried out since the 1980s in Brazil, highlighting the dynamics of RV-A strain circulation profiles before and early after universal use of RV-A vaccine in Brazil.

Electrophoretic study of the genome of human rotaviruses from Rio de Janeiro, São Paulo and Pará, Brazil.

Human rotaviruses from the states of Rio de Janeiro, São Paulo and Pará of Brazil were analysed by RNA electrophoresis. At least some bands characteristic of rotavirus double-stranded RNA were detected in 138 (86.8%) of 159 faecal samples in which the presence of rotavirus had been demonstrated by enzyme immunoassay. Of the RNA-positive samples, 18 (13.0%) were classified as subgroup 1, 94 (68.1%) as subgroup 2, and 26 (18.8%) could not be classified due to absence of visible bands 10 and 11. Subgroup 2 was more frequent in the three states. All strains of subgroup 1 detected in Rio de Janeiro were associated with a single short-lived school outbreak. All strains of subgroup 1 resembled each other in electrophoretic pattern, irrespective of geographical origin, although minor differences could be detected by co-electrophoresis. Subgroup 2, on the other hand, showed a great degree of electrophoretic heterogeneity and could be divided into several sub-categories.

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.

Burden and typing of rotavirus group A in Latin America and the Caribbean: systematic review and meta-analysis

The efficacy of licensed rotavirus vaccines has only been shown against certain rotavirus group A (RV‐A) types. It is critical to understand the burden of rotavirus gastroenteritis (RVGE) and its prevalent types to assess the potential impact of these vaccines in Latin America and the Caribbean (LA&C). We performed a systematic review and meta‐analyses of all the available evidence reported from 1990 to 2009 on the burden of rotavirus disease and strains circulating in LA&C. Eligible studies—185 country‐level reports, 174 951 faecal samples—were selected from MEDLINE, Cochrane Library, EMBASE, LILACS, regional Ministries of Health, PAHO, regional proceedings, doctoral theses, reference lists of included studies and consulting experts. Arc‐sine transformations and DerSimonian–Laird random‐effects model were used for meta‐analyses. The proportion of gastroenteritis cases due to rotavirus was 24.3% (95%CI 22.3–26.4) and the incidence of RVGE was 170 per 1000 children‐years (95%CI 130–210). We estimated a global annual mortality for 22 countries of 88.2 (95%CI 79.3–97.1) deaths per 100 000 under 5 years (47 000 deaths).The most common G type detected was G1 (34.2%), followed by G9 (14.6%), and G2 (14.4%). The most common P types detected were P[8] (56.2%), P[4] (22.1%) and P[1] 5.4%, and the most prevalent P–G type associations were P[8]G1 17.9%, P[4]G2 9.1% and P[8]G9 8.8%. In the last 10 years, G9 circulation increased remarkably and G5 almost disappeared. More recently, G12 appeared and P[4]G2 re‐emerged. To our knowledge, this is the first meta‐analysis of rotavirus infection and burden of disease in LA&C. Copyright

Impact of rotavirus vaccination on childhood deaths from diarrhea in Brazil.

OBJECTIVES Rotavirus vaccination was introduced in Brazil in March 2006, targeting an annual birth cohort of approximately 3.5 million. We analyzed trends in all-cause gastroenteritis-related deaths in children <5 years of age during the pre- and post-vaccination periods. METHODS Data from the National Immunization Program and the Mortality Information System were used to calculate vaccine coverage and mortality rates related to gastroenteritis in children <1 year and 1-4 years of age, using population estimates from the census as the denominator. Relative reductions in mortality rates were calculated for 2007 and 2008, using the 2004-2005 mean as baseline before vaccine introduction. RESULTS Coverage of two doses of human rotavirus vaccine was 39% in 2006, increasing to 72% in 2007 and 77% in 2008. During 2004-2005, the gastroenteritis mortality rate in children <1 year of age was 56.9 per 100 000, decreasing by 30% (95% confidence interval (CI) 19-41) in 2007 and by 39% (95% CI 29-49) in 2008. In children 1-4 years of age, the mortality rate was 4.5 per 100 000 during 2004-2005, decreasing by 29% (95% CI 10-49) in 2007 and by 33% (95% CI 15-52) in 2008. CONCLUSIONS The decreased rates of childhood gastroenteritis-related deaths in Brazil following rotavirus vaccine introduction, particularly among children <1 year of age, suggest the potential benefit of vaccination.

Evidence for zoonotic transmission of group C rotaviruses among children in Belém, Brazil

The prevalence and potential zoonotic transmission of group C rotavirus (RVC) were examined by testing fecal samples collected from children during a longitudinal study that was carried out in the outskirts of Belém, Brazil, from December 1982 to March 1986. The study involved a group of 30 children who were followed from birth to 3 years. Of the 77 samples tested from 29 children, 5 (6.5%) were positive for human and 3 (4%) for porcine RVC by using nested PCR assay with primers specific for VP6 gene of human or porcine RVC and by Southern hybridization using a probe specific for VP6 gene of both human and porcine RVC. In addition, a total of 59 fecal specimens from the 30th child were tested, 1 (1.7%) and 14 (23.7%) were positive for human and porcine RVC, respectively. Partial nucleotide sequences of VP6 gene demonstrated that the six human strains detected in Brazil were homologous with other human RVC, and 14 of the 17 porcine RVC strains examined showed a complete homology among themselves but differed slightly from the porcine Cowden strain, suggesting that a single porcine RVC strain was circulating in Belém. This study is the first to provide evidence for transmission of RVC from swine to human. They also indicate that both human and porcine RVC were endemic in Belém. J. Med. Virol. 80:1666–1674, 2008.

Rotavirus Serotype G9 Is Associated with More-Severe Disease in Latin America

The association between rotavirus serotypes and severity is not well established. Analysis of a clinical trial conducted in Latin America points at more-severe disease associated with serotype G9. Thus, demonstration of efficacy against G9 will be an important asset of any rotavirus vaccine to be introduced into a Latin American country or any country where G9 has been shown to be prevalent.

Trends in hospitalizations from all-cause gastroenteritis in children younger than 5 years of age in Brazil before and after human rotavirus vaccine introduction, 1998-2007.

Rotavirus vaccination was introduced in Brazil in March 2006. We describe trends in hospitalizations from all-cause gastroenteritis in children younger than 5 years during pre- and postvaccination periods using hospital discharge data from Brazil Hospital Information System (SIH-SUS). A reduction in gastroenteritis hospitalizations of 26% and 48% in 2006 and in 2007, respectively, was observed among children younger than 1 year compared with prevaccination period (1998–2005). The largest reduction rates among children younger than 1 year were noted in the South and Southeast regions, approximately 56% in 2007, where vaccine coverage was the highest.

Efficacy of the Human Rotavirus Vaccine RIX4414 in Malnourished Children

This series is produced by the Health, Nutrition, and Population (HNP) Family of the World Bank’s Human Development Network. The findings, interpretations, and conclusions expressed in this paper are entirely those of the authors and should not be attributed in any manner to the World Bank, to its affiliated organizations or to the members of its Board of Executive Directors or the countries they represent.UNLABELLED The effect of nutritional status on protective efficacy of a live attenuated human rotavirus vaccine (RIX4414) was studied. Vaccine protection was evaluated through a secondary analysis of data from an efficacy study conducted in Brazil, Mexico, and Venezuela. Vaccine efficacy against rotavirus gastroenteritis (RVGE) was similar in well-nourished and malnourished infants: 74.1% (95% confidence interval [CI], 52.2%-86.2%) and 73% (95% CI, 11.2%-92.3%) for severe RVGE and 60.9% (95% CI, 37.4%-75.4%) and 61.2% (95% CI, 10.4%-83.1%) for RVGE of any severity, respectively. RIX4414 significantly decreased the rate of RVGE regardless of nutritional status, which suggests that this patient group can also benefit from rotavirus vaccination. CLINICAL TRIALS REGISTRY e-Track 444563-006, NCT00385320 (http://www.clinicaltrials.gov).