Rotavirus vaccines: current prospects and future challenges.

Rotavirus is the most common cause of severe diarrhoea in children worldwide and diarrhoeal deaths in children in developing countries. Accelerated development and introduction of rotavirus vaccines into global immunisation programmes has been a high priority for many international agencies, including WHO and the Global Alliance for Vaccines and Immunizations. Vaccines have been developed that could prevent the enormous morbidity and mortality from rotavirus and their effect should be measurable within 2-3 years. Two live oral rotavirus vaccines have been licensed in many countries; one is derived from an attenuated human strain of rotavirus and the other combines five bovine-human reassortant strains. Each vaccine has proven highly effective in preventing severe rotavirus diarrhoea in children and safe from the possible complication of intussusception. In developed countries, these vaccines could substantially reduce the number and associated costs of child hospitalisations and clinical visits for acute diarrhoea. In developing countries, they could reduce deaths from diarrhoea and improve child survival through programmes for childhood immunisations and diarrhoeal disease control. Although many scientific, programmatic, and financial challenges face the global use of rotavirus vaccines, these vaccines-and new candidates in the pipeline-hold promise to make an immediate and measurable effect to improve child health and survival from this common burden affecting all children.

Temporal and geographic trends of rotavirus activity in the United States, 1997-2004.

Rotavirus (RV) has a characteristic seasonal pattern in the 48 contiguous states of the continental United States, and climatologic factors have been implicated though not confirmed. Since 1997, three significant events occurred, including strong El Niño and La Niña climatologic phenomena, and the brief introduction of a rotavirus (RV) vaccine. We examined trends in RV activity in the continental United States between 1997 and 2004, using data from a network of over 70 laboratories that voluntarily report weekly RV detection rates within the National Respiratory and Enteric Virus Surveillance System (NREVSS). Analysis of NREVSS data indicates characteristic winter activity that begins in the Southwest in December or January, moves across the country, and ends in the Northeast in April or May. This pattern was not affected by the brief use of RV vaccine nor by periods of climate change associated with the El Niño and La Niña phenomena. The temporal and geographic pattern of RV spread in the United States has persisted since its initial description and defies easy explanation. An impact of the RV vaccine was not observed, either because of the limited uptake of the vaccine or the inherent variability of the system. NRVESS permits a gross assessment of RV geographic and temporal trends in the United States, but underscores the need for additional assessment mechanisms.

Reevaluation of epidemiological criteria for identifying outbreaks of acute gastroenteritis due to norovirus: United States, 1998-2000.

BACKGROUND: Noroviruses are believed to be the most common etiologic agent of foodborne outbreaks of gastroenteritis, yet diagnostic tests for these agents are not readily available in the United States. In the absence of assays to detect norovirus, several clinical and epidemiologic profiles--the criteria of Kaplan et al. (vomiting in >50% of patients, mean incubation period of 24-48 h, mean duration of illness of 12-60 h, and no bacterial pathogen) and the ratios of fever to vomiting and diarrhea to vomiting--have been used to distinguish foodborne outbreaks of gastroenteritis caused by noroviruses from those caused by bacteria. METHODS: To examine how well clinical and epidemiological profiles discriminate between foodborne outbreaks of gastroenteritis due to noroviruses and those due to bacteria and to estimate the proportion of reported outbreaks that might be attributable to noroviruses, we reviewed subsets of the 4050 outbreaks reported from 1998 to 2000. RESULTS: The set of criteria of Kaplan et al. is highly specific (99%) and moderately sensitive (68%) in discriminating confirmed outbreaks due to bacteria from those due to norovirus and was the most useful diagnostic aid evaluated. Each individual component of the criteria, the fever-to-vomiting ratio, and the diarrhea-to-vomiting ratio were more sensitive, yet less specific, and therefore less useful, than the criteria of Kaplan et al. We estimated that, at a minimum, 28% of all the foodborne outbreaks reported to the Centers for Disease Control and Prevention may be attributed to norovirus on the basis of these criteria. CONCLUSION: Until norovirus diagnostic tests become widely available, the criteria of Kaplan et al. remain the most useful and discriminating diagnostic aid to identify foodborne outbreaks of gastroenteritis due to noroviruses.

Rotavirus vaccines: targeting the developing world.

For the past 2 decades, rotavirus infection, the most common cause of severe diarrhea in children, has been a priority target for vaccine development. This decision to develop rotavirus vaccines is predicated on the great burden associated with fatal rotavirus disease (i.e., 440,000 deaths/year), the firm scientific basis for developing live oral vaccines, the belief that increased investment in development at this time could speed the introduction of vaccines in developing countries, and the appreciation that implementation of a vaccine program should result in a measurable decrease in the number of hospitalizations and deaths associated with rotavirus disease within 2-3 years. RotaShield (Wyeth-Ayerst), the first rotavirus vaccine licensed in the United States, was withdrawn after 9 months because of a rare association of the vaccine with the development of intussusception. In the developing world, this vaccine could still have had a measurable effect, because the benefits of preventing deaths due to rotavirus disease would have been substantially greater than the rare risk of intussusception. Two live oral vaccines being prepared by GlaxoSmithKline and Merck have completed large-scale clinical trials. The GlaxoSmithKline vaccine has been licensed in Mexico and the Dominican Republic, and the Merck vaccine could be licensed in the United States within 1 year; several other candidate vaccines are in earlier stages of testing. However, many challenges remain before any of these vaccines can be incorporated into childhood immunization programs in the developing world. First, vaccine efficacy, which has already been demonstrated in children in industrialized and middle-income countries, needs to be proven in poor developing countries in Africa and Asia. The safety of vaccines with regard to the associated risk of intussusception must be demonstrated as well. Novel financing strategies will be needed to ensure that new vaccines are affordable and available in the developing world. Decision makers and parents in developing countries need to know about this disease that has little name recognition and is rarely diagnosed. Finally, for the global effort toward the prevention of rotavirus disease to be successful, special efforts will be required in India, China, and Indonesia, because one-third of all deaths due to rotavirus disease occur in these countries, and because these countries depend almost entirely on vaccines manufactured domestically.

Rotavirus antigenemia in patients with acute gastroenteritis.

Although rotavirus infections are generally considered to be confined to the intestine, recent reports suggest that extraintestinal disease occurs. We studied whether rotavirus infection was associated with antigenemia during a major outbreak of gastroenteritis in the Kingston metropolitan area, during July-August 2003. Rotavirus antigen was identified in 30 of 70 acute-phase serum samples (including from 2 deceased individuals) but in only 1 of 53 control samples. Serum antigen levels were inversely associated with time since symptom onset and were directly associated with antigen levels in stool (P = .02). Serum antigen levels were significantly elevated during primary infections (acute-phase serum immunoglobulin G [IgG] titers, <25), compared with those in subsequent infections (acute-phase serum IgG titers, > or = 25) (P = .02). Antigenemia was common in this outbreak and might provide a mechanism to help explain rare but well-documented reports of findings of extraintestinal rotavirus. In situations in which stool samples are not readily available (i.e., patients with severe dehydration or those recently recovered or deceased), serum testing by enzyme immunoassay offers a new and practical diagnostic tool.

The epidemiology of rotavirus diarrhea in Latin America: anticipating rotavirus vaccines

OBJETIVO: Valorar la carga de enfermedad e identificar las características epidemiológicas de la diarrea causada por rotavirus en América Latina. MÉTODOS: Realizamos una revisión de la literatura que abarcaba los estudios de niños menores de 5 años que fueron hospitalizados o atendidos como pacientes ambulatorios a causa de la diarrea, y en los cuales se buscó al rotavirus como agente etiológico de la diarrea. Nuestro trabajo de revisión incluye los estudios publicados desde el año 1998 sobre pacientes ingresados y ambulatorios, que incluyeron a 100 niños o más, y que informaron sobre actividades de vigilancia que se prolongaron durante al menos 12 meses consecutivos. RESULTADOS: Un total de 18 estudios de pacientes ingresados y 10 estudios de pacientes ambulatorios satisficieron los criterios de inclusión de nuestro trabajo de revisión. Se detectó el rotavirus en el 31% (mediano) de los pacientes ingresados (intervalo del 16% al 52%) y en el 30.5% de los pacientes ambulatorios (intervalo del 4% al 42%). La tasa mediana de detección fue mayor en los estudios que emplearon un ensayo de encimoinmunoanálisis (ELISA) (pacientes ingresados: 38%, pacientes ambulatorios: 33%) frente a otros métodos de detección menos sensibles. La distribución de la enfermedad rotavírica según la edad difería entre países, aunque la proporción de niños hospitalizados durante el primer año de vida fue del 65% al 85%. En la mayoría de los países se produjeron ingresos hospitalarios por rotavirus durante todo el año, y el rotavirus normalmente mostraba un máximo estacional en el invierno tanto en las zonas de clima tropical como en aquellas de clima templado. CONCLUSIONES: La importante carga de enfermedad que se atribuye al rotavirus en América Latina sugiere que las vacunas que están siendo ensayadas en la actualidad podrían tener un impacto considerable en la prevención de las hospitalizaciones, consultas a los centros de salud, y muertes. La distribución de la enfermedad entre los pacientes más jóvenes subraya la importancia de la inmunización precoz en el éxito de los programas de vacunación. Los datos sugieren que en el futuro, los programas de vigilancia para detectar la diarrea causada por rotavirus en América Latina deberían usar un protocolo normalizado de vigilancia con ELISA para la detección del virus. Los datos provenientes de estudios de vigilancia serán de importancia fundamental para el seguimiento del impacto de la introducción de vacunas en el futuro.

Rotavirus in El Salvador: an outbreak, surveillance and estimates of disease burden, 2000-2002.

BACKGROUND: In December 2000, a large outbreak of gastroenteritis occurred in El Salvador that was associated with hospitalizations and deaths among children nationwide. Public concern was raised because the etiology was initially unknown and enteric control measures seemed ineffective. The outbreak was eventually linked to rotavirus, control measures were redirected to improving treatment with oral rehydration and surveillance was initiated to characterize the etiologic agents of gastroenteritis. METHODS: Demographic and clinical data and fecal specimens were collected from a systematic sample of children younger than 5 years old with acute gastroenteritis. Stools were tested for rotavirus, bacteria and parasites. Surveillance results were extrapolated to national data to estimate the national burden of rotavirus disease. RESULTS: Surveillance between May 2001 and April 2002 demonstrated that rotavirus has winter seasonality, was associated with vomiting and dehydration and accounted for an estimated 27% of 12,083 consultations for diarrhea. Children with rotavirus gastroenteritis were younger (median, 9 months) than those with gastroenteritis caused by other agents (median, 13 months for bacteria, 16 months for parasites). Extrapolating to national data, we estimated the risk of a child experiencing a rotavirus-related medical visit, hospitalization and death by the age of 5 years as 1:7, 1:56 and 1:531, respectively. CONCLUSIONS: The outbreak of gastroenteritis among children younger than 5 years of age between December 2000 and February 2001 represented an exaggerated rotavirus season. The surveillance activity after the outbreak suggests that rotavirus is the most common cause of diarrheal disease in El Salvador. Further surveillance could provide a sound basis for improving the response to epidemics of gastroenteritis and could provide data needed to decide whether rotavirus vaccination should be included in the national program for childhood immunizations.

The epidemiology of rotavirus diarrhea in Latin America. Anticipating rotavirus vaccines.

OBJECTIVE: To assess the disease burden and characterize the epidemiology of rotavirus diarrhea in Latin America. METHODS: We conducted a literature review of studies of children < 5 years of age who were hospitalized or seen as outpatients for diarrhea and for whom rotavirus was sought as the etiologic agent of the diarrhea. This review included inpatient and outpatient studies published since 1998 that included at least 100 children and reported surveillance activities lasting at least 12 consecutive months. RESULTS: A total of 18 inpatient and 10 outpatient studies met the criteria for inclusion in this review. Rotavirus was detected in a median of 31% of inpatients (range, 16%-52%) and 30.5% of outpatients (range, 4%-42%). The median detection rate was higher in studies that used an enzyme-linked immunosorbent assay (ELISA) (inpatients 38%, outpatients 33%) versus less sensitive methods of detection. The age distribution of rotavirus disease varied among countries, with 65%-85% of children hospitalized in the first year of life. Most countries had rotavirus admissions year round, and rotavirus generally exhibited a winter seasonal peak in both temperate and tropical climates. CONCLUSIONS: The heavy burden of disease attributable to rotavirus in Latin America suggests that vaccines currently being tested could have considerable impact in preventing hospitalizations, clinic visits, and deaths. The findings of the young age distribution of patients highlight the importance of early immunization for the success of a vaccine program. The data suggest that future surveillance for rotavirus diarrhea in Latin America should use a standardized surveillance protocol with an ELISA for detection. Data from surveillance studies will be critical to monitor the impact of the future introduction of vaccines.

Enhanced drop-in syndromic surveillance in New York City following September 11, 2001.

After the 2001 World Trade Center disaster, the New York City Department of Health was under heightened alert for bioterrorist attacks in the city. An emergency department (ED) syndromic surveillance system was implemented with the assistance of the Centers for Disease Control and Prevention to ensure early recognition of an increase or clustering of disease syndromes that might represent a disease outbreak, whether natural or intentional. The surveillance system was based on data collected 7 days a week at area EDs. Data collected were translated into syndromes, entered into an electronic database, and analyzed for aberrations in space and time within 24 hours. From September 14-27, personnel were stationed at 15 EDs on a 24-hour basis (first staffing period); from September 29-October 12, due to resource limitations, personnel were stationed at 12 EDs on an 18-hour basis (second staffing period). A standardized form was used to obtain demographic information and classify each patient visit into 12 syndrome categories. Seven of these represented early manifestations of bioterrorist agents. Data transfer and analysis for time and space clustering (alarms) by syndrome and age occurred daily. Retrospective analyses examined syndrome trends, differences in reporting between staffing periods, and the staff's experience during the project. A total of 67,536 reports were received. The system captured 83.9% of patient visits during the first staffing period, and 60.8% during the second staffing period (P < 0.01). Five syndromes each accounted for more than 1% of visits: trauma, asthma, gastrointestinal illness, upper/lower respiratory infection with fever, and anxiety. Citywide temporal alarms occurred eight times for three of the major bioterrorism-related syndromes. Spatial clustering alarms occurred 16 times by hospital location and 9 times by ZIP code for the same three syndromes. No outbreaks were detected. On-site staffing to facilitate data collection and entry, supported by daily analysis of ED visits, is a feasible short-term approach to syndromic surveillance during high-profile events. The resources required to operate such a system, however, cannot be sustained for the long term. This system was changed to an electronic-based ED syndromic system using triage log data that remains in operation.