F. Raúl Velázquez

Rotavirus Infection in Infants as Protection against Subsequent Infections

BACKGROUND Rotavirus is the leading cause of severe diarrhea in infants. To provide a base line for assessing the efficacy of rotavirus vaccines, we evaluated the protection that is conferred by natural rotavirus infection. METHODS We monitored 200 Mexican infants from birth to two years of age by weekly home visits and stool collections. A physician assessed the severity of any episodes of diarrhea and collected additional stool specimens for testing by enzyme immunoassay and typing of strains. Serum collected during the first week of life and every four months thereafter was tested for antirotavirus IgA and IgG. RESULTS A total of 316 rotavirus infections were detected on the basis of the fecal excretion of virus (56 percent) or a serologic response (77 percent), of which 52 percent were first and 48 percent repeated infections. Children with one, two, or three previous infections had progressively lower risks of both subsequent rotavirus infection (adjusted relative risk, 0.62, 0.40, and 0.34, respectively) and diarrhea (adjusted relative risk, 0.23, 0.17, and 0.08) than children who had no previous infections. No child had moderate-to-severe diarrhea after two infections, whether symptomatic or asymptomatic. Subsequent infections were significantly less severe than first infections (P=0.024), and second infections were more likely to be caused by another G type (P=0.054). CONCLUSION In infants, natural rotavirus infection confers protection against subsequent infection. This protection increases with each new infection and reduces the severity of the diarrhea.

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.

Serum Antibody as a Marker of Protection against Natural Rotavirus Infection and Disease

To determine whether naturally acquired serum IgA and IgG antibodies were associated with protection against rotavirus infection and illness, a cohort of 200 Mexican infants was monitored weekly for rotavirus excretion and diarrhea from birth to age 2 years. Serum samples collected during the first week after birth and every 4 months were tested for anti-rotavirus IgA and IgG. Children with an IgA titer >1:800 had a lower risk of rotavirus infection (adjusted relative risk [aRR], 0.21; P<.001) and diarrhea (aRR, 0. 16; P=.01) and were protected completely against moderate-to-severe diarrhea. However, children with an IgG titer >1:6400 were protected against rotavirus infection (aRR, 0.51; P<.001) but not against rotavirus diarrhea. Protective antibody titers were achieved after 2 consecutive symptomatic or asymptomatic rotavirus infections. These findings indicate that serum anti-rotavirus antibody, especially IgA, was a marker of protection against rotavirus infection and moderate-to-severe diarrhea.

Single Multiplex Polymerase Chain Reaction To Detect Diverse Loci Associated with Diarrheagenic Escherichia coli

We developed and tested a single multiplex polymerase chain reaction (PCR) that detects enterotoxigenic, enteropathogenic, enteroinvasive, and Shiga-toxin–producing Escherichia coli. This PCR is specific, sensitive, and rapid in detecting target isolates in stool and food. Because of its simplicity, economy, and efficiency, this protocol warrants further evaluation in large, prospective studies of polymicrobial substances.

Postmarketing surveillance of intussusception following mass introduction of the attenuated human rotavirus vaccine in Mexico.

Background: Mexico initiated mass vaccination with the attenuated human rotavirus vaccine (Rotarix) in 2006. This postlicensure study aimed to assess any potential temporal association between vaccination and intussusception in Mexican infants. Methods: Prospective, active surveillance for intussusception among infants aged less than 1 year was conducted in 221 hospitals across Mexico from the Mexican Institute of Social Security between January 2008 and October 2010. The temporal association between vaccination and intussusception was assessed by self-controlled case-series analysis. Results: Of the 753 episodes of intussusception reported in 750 infants, 701 were in vaccinated infants (34.5% post–dose 1, 65.5% post–dose 2). The relative incidence of intussusception within 31 days of vaccination was 1.75 (95.5% confidence interval [CI]: 1.24–2.48; P = 0.001) post–dose 1 and 1.06 (95.5% CI: 0.75–1.48; P = 0.75) post–dose 2. The relative incidence of intussusception within 7 days of vaccination was 6.49 post–dose 1 (95.5% CI: 4.17–10.09; P < 0.001) and 1.29 post–dose 2 (95.5% CI: 0.80–2.11; P = 0.29). Clustering of intussusception within 7 days of vaccination was observed post–dose 1. An attributable risk of 3 to 4 additional cases of intussusception per 100,000 vaccinated infants was estimated. Conclusion: This is the largest surveillance study for intussusception after rotavirus vaccination to date. A temporal increase in the risk for intussusception was seen within 7 days of administration of the first vaccine dose. It is still uncertain whether rotavirus vaccination has any impact on the overall incidence of intussusception. This finding has to be put in perspective with the well-documented substantial benefits of rotavirus vaccination.

Rotavirus P[4]G2 in a Vaccinated Population, Brazil

We acknowledge the comments by Patel et al. (1) and by Linhares and Velazquez (2) about our article that documented the presence of a single rotavirus genotype (P[4]G2) in Aracaju, northeastern Brazil, after the introduction of a human, monovalent rotavirus vaccine (3). Both letters emphasize that the predominance of P[4]G2 may be caused by a natural genotype variation unrelated to vaccination. We agree that our observation could be explained by natural variation of circulating rotavirus genotypes in the region, but an alternative possibility is that the introduction of the G1P[8] rotavirus vaccine into the childhood immunization schedule created conditions in which P[4]G2 strains had a selective advantage over strains with which the vaccine shares G type, P type, or both. According to a systematic review of rotavirus genotypes reported in the 25 years preceding introduction of the vaccine in Brazil, the prevalence of P[4]G2 strains varied from 19% (1986–1995) to 12% (1996–2000) to 1% thereafter, thus not reaching the detection rate we observed in Aracaju (R.Q. Gurgel et al., unpub data). Furthermore, in the ensuing 8-month period, no genotype other than P[4]G2 had been detected in Aracaju, suggesting that our initial findings were not spurious (R.Q. Gurgel et al., unpub data). In addition, in a separate study we conducted in Recife, a city 500 km north of Aracaju, we observed a significant increase in the proportion of G2 strains detected from 47% (21/45) during the 3-month period immediately after vaccine introduction (March 2006–May 2006) to 100% (11/11) during the same 3-month period 1 year after the vaccine introduction (March 2007–May 2007) (4). We believe that our findings are consistent with results of field trials that indicated that the vaccine provided relatively less protection against P[4]G2 strains than against other rotavirus strain types (5). The beneficial impact of rotavirus vaccination in northeastern Brazil is reflected in the reduction of the detection rate of rotavirus among severe diarrhea cases in our study in Recife, which fell from 27% (45/166 cases) to 5.0% (11/221 cases) in the postvaccine 3-month reporting periods, respectively (4). Our data from Aracaju are indicative of heterotypic protection, although this is not statistically significant (1), against P[4]G2 strains. Further postlicensure studies in Brazil are required to document continuing effectiveness of the national vaccination program as well as to closely monitor the circulating rotavirus strain types (6).

Diarrhea morbidity and mortality in Mexican children: impact of rotavirus disease.

Aim: To analyze changes in prevalence and seasonality of diarrhea morbidity and mortality and to evaluate the impact of rotavirus disease among Mexican children younger than 5 years old. Methods: Diarrhea surveillance was performed from 1990 to 2002. Rotavirus testing was performed on stool specimens from 1996 to 2002. Data were obtained from different surveillance systems considering a nationwide representation in Mexico. Diarrhea morbidity and mortality rates were analyzed against time to determine trends or seasonal patterns. Results: Improvement of surveillance for all diarrhea episodes denoted an initial morbidity increase from 1995 to 1999, followed by a decrease by 2002, without any seasonal pattern. However, from 1990 to 1995, morbidity for severe diarrhea decreased 63%. From 1996 to 2002, 62–68% of severe diarrhea episodes occurring during the fall-winter season (FWS) were rotavirus-positive compared with 6–12% in the spring-summer season (SSS). From 1990 to 2002, diarrhea mortality decreased 84%. Higher mortality rates for children younger than 1 year old coincided precisely during the FWS, annually. Both severe diarrhea episodes and diarrhea deaths denoted a changing seasonal pattern. In 1990–1991, 2 waves of increased diarrhea activity occurred. The increase in SSS was much more pronounced than that in FWS. From 1992 to 1995 for severe diarrhea and from 1993 to 2002 for diarrhea deaths, the SSS frequencies subsequently reduced, whereas the FWS peaks remained annually. Conclusions: A significant reduction in morbidity and mortality of severe diarrhea has occurred from 1990 and 2002 in Mexican children younger than 5 years old. This is a consequence of preventive programs initiated for cholera control since 1991, which had greater impact on SSS diarrhea and limited response for FWS diarrhea, when rotavirus is mainly present. Currently rotavirus diarrhea requires new prevention strategies and specific control measures, such as a specific national vaccine program.

Protective effects of natural rotavirus infection.

Rotavirus is a ubiquitous infection that is the leading cause of severe diarrhea worldwide. Severe infections are most commonly observed in the first 2 years of life. Rotavirus-induced diarrhea is associated with substantial morbidity and mortality rates and socioeconomic costs with adverse outcomes particularly prevalent in developing countries. The natural history of rotavirus infection can provide guidance for the development and optimization of an effective vaccine. Epidemiologic studies have demonstrated that children who acquire natural rotavirus infections develop immunity to subsequent infections, with the protective effect increasing with each natural infection. Natural infections also decrease the severity of any subsequent rotavirus infections. Notably, asymptomatic infections provide protection similar to that induced by symptomatic infections. Data also suggest that the antibody response to natural infection is heterotypic, and therefore may provide protection against multiple serotypes. These data suggest that the development of a vaccine that produces asymptomatic infection at an optimal time point may provide effective immunity. An effective vaccine should mimic protection provided by natural infection and provide protection against the most common rotavirus serotypes (ie, G1, G2, G3, G4, G9) and be able to decrease disease severity, reduce hospitalizations, and decrease disease-related costs.

Economic impact of a rotavirus vaccination program in Mexico

OBJECTIVES To evaluate the cost and benefits of a national rotavirus childhood vaccination program in Mexico. METHODS A decision-analysis model was designed to take the Mexican health care systems perspective on a comparison of two alternatives: to vaccinate against rotavirus or not. Using published, national data, estimations were calculated for the rotavirus illnesses, deaths, and disability-adjusted life years (DALYs) that would be averted and the incremental cost-effectiveness ratios (US

Molecular detection of respiratory syncytial virus in postmortem lung tissue samples from Mexican children deceased with pneumonia.

/DALY) of a hypothetical annual birth cohort of 2 285 000 children, with certain assumptions made for cost, coverage, and efficacy rates. RESULTS With 93% coverage and a vaccine price of US