Thea Kølsen Fischer

Serotype Diversity and Reassortment between Human and Animal Rotavirus Strains: Implications for Rotavirus Vaccine Programs

The development of rotavirus vaccines that are based on heterotypic or serotype-specific immunity has prompted many countries to establish programs to assess the disease burden associated with rotavirus infection and the distribution of rotavirus strains. Strain surveillance helps to determine whether the most prevalent local strains are likely to be covered by the serotype antigens found in current vaccines. After introduction of a vaccine, this surveillance could detect which strains might not be covered by the vaccine. Almost 2 decades ago, studies demonstrated that 4 globally common rotavirus serotypes (G1-G4) represent >90% of the rotavirus strains in circulation. Subsequently, these 4 serotypes were used in the development of reassortant vaccines predicated on serotype-specific immunity. More recently, the application of reverse-transcription polymerase chain reaction genotyping, nucleotide sequencing, and antigenic characterization methods has confirmed the importance of the 4 globally common types, but a much greater strain diversity has also been identified (we now recognize strains with at least 42 P-G combinations). These studies also identified globally (G9) or regionally (G5, G8, and P2A[6]) common serotype antigens not covered by the reassortant vaccines that have undergone efficacy trials. The enormous diversity and capacity of human rotaviruses for change suggest that rotavirus vaccines must provide good heterotypic protection to be optimally effective.

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.

Hospitalizations and Deaths from Diarrhea and Rotavirus among Children <5 Years of Age in the United States, 1993–2003

Recently a new rotavirus vaccine was licensed in the United States and recommended for universal immunization of American children. The impact of the vaccine on a decrease in hospitalizations will take several years to assess and will be based on the availability of good baseline data on the disease. We used the largest US hospital discharge database available, the Healthcare Cost and Utilization Project (HCUP), to study national rates, trends, and risk factors for diarrhea- and rotavirus-associated hospitalizations and deaths among children <5 years of age, to establish a baseline against which vaccine implementation can be measured. Rotavirus remained the most important cause of pediatric diarrhea throughout the study period (1993-2003). When the data were extrapolated to the US population, rotavirus was estimated to be the cause of approximately 60,000 hospitalizations and 37 deaths annually. Black infants had a significantly higher risk of being hospitalized with and dying from rotavirus disease early in life, compared with white infants (risk ratio [RR] for hospitalization by 12 months of age was 2.4, with a 95% confidence interval [CI] of 1.2-4.7; RR for death was 2.0, with a 95% CI of 1.7-2.5). Such racial differences in age and risk of rotavirus-associated hospitalization and death highlight the importance of timely and early rotavirus immunization of minority children. The HCUP database serves as a sensitive and robust data source for monitoring the impact of a rotavirus-immunization program in the United States.

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.

Health Care Costs of Diarrheal Disease and Estimates of the Cost-Effectiveness of Rotavirus Vaccination in Vietnam

BACKGROUND Rotavirus disease causes a significant health and economic burden worldwide. Several rotavirus vaccines may soon be available for use. A countrys decision to introduce these vaccines will depend on its rotavirus disease burden, on the cost of the vaccine, and on the results of an economic assessment of the cost and effectiveness of a rotavirus vaccination program. METHODS Data on medical and nonmedical direct costs and indirect costs were established in Khanh Hoa Province, Vietnam, and extrapolated to national estimates on the basis of the birth cohort in 2004. The main outcome measures were economic burden and cost-effectiveness ratio (United States dollars per disability-adjusted life-year averted and dollars per life saved) of vaccination. RESULTS The disease burden is equivalent to an economic burden of an estimated 3.1 million US dollars in medical direct costs, 685,000 US dollars in nonmedical direct costs, and 1.5 million US dollars in indirect costs. From a societal perspective, treatment of rotavirus disease costs an estimated 5.3 million US dollars per year. From the health care system perspective, universal vaccination of infants at a cost of < or = 7.26 US dollars/vaccine dose would be a cost-effective public health intervention, according to the World Bank cost-effectiveness standard for low-income countries (140 US dollars/disability-adjusted life-year). CONCLUSIONS Vaccination can effectively reduce the disease burden and health care costs of rotavirus-specific diarrhea in Vietnam.

Intussusception in Early Childhood: A Cohort Study of 1.7 Million Children

Objective. To describe incidence and temporal trends of intussusceptions in Danish children during 1980 to 2001. Methods. A population-based cohort study was conducted of 1.67 million children who were younger than 5 years during 1980 to 2001 and were followed up for 6.66 million person-years. The Danish National Patient Registry was used to identify cases of intussusception in the cohort. Age-specific incidence rates were main outcome measure. Results. A total of 1814 cases of intussusception among children who were younger than 5 years were reported from 1980 to 2001. The incidence rate remained fairly constant during 1980 to 1990 but decreased by 55% (95% confidence interval: 43%–65%) from 1990 to 2001. The reduction was most pronounced among children aged 3 to 5 months. Conclusions. The incidence of intussusception among Danish children declined significantly during the 1990s, particularly among infants 3 to 5 months of age.

Protective immunity after natural rotavirus infection: a community cohort study of newborn children in Guinea-Bissau, west Africa.

To study the natural history of rotavirus infection and to determine the protection it confers against reinfection and diarrhea, 200 newborns in Guinea-Bissau were prospectively followed for up to 2 years. Rotavirus was detected in stool specimens collected weekly. By age 2 years, the incidence of primary rotavirus infection was 74%. In the first 3 months of life, 17% of the infections were diarrhea associated, compared with 60% at 9-11 months; after age 18 months, all infections were asymptomatic. A primary infection conferred 52% (95% confidence interval [CI], 16% to 73%) and 70% (95% CI, 29% to 87%) protection against subsequent rotavirus infection and rotavirus diarrhea, respectively. The protection was 66% (95% CI, 24% to 85%) against reinfection within the same epidemic, compared with 34% (95% CI, -29% to 67%) against reinfection in any subsequent epidemic. The high level of protection against symptomatic rotavirus infection provides an important incentive for development of a rotavirus vaccine.

Cohort study of Guinean children: Incidence, pathogenicity, conferred protection, and attributable risk for enteropathogens during the first 2 years of life

ABSTRACT We recruited 200 children shortly after birth and collected stool specimens weekly, irrespective of whether the children had diarrhea, until up to 2 years of age. All children were recruited during the first year of the study and were monitored for a median of 18.4 months. To measure pathogenicity, the odds ratio for diarrhea, adjusted for age, sex, and coinfections with other enteropathogens, was determined by logistic regression. Standard estimation of the population attributable risk indicated that rotavirus, enterotoxigenic Escherichia coli that produced only the heat-stable toxin ST, Isospora spp., Cryptosporidium parvum, Shiga toxin (Stx)-producing E. coli (STEC), and Shigella spp. or enteroinvasive E. coli were the most important contributors to diarrhea in this population. Stx2- but not Stx1-producing STEC strains were pathogenic. Enteroaggregative E. coli, diffusely adherent E. coli, and attaching-and-effacing E. coli strains, which were the most commonly isolated microorganisms, were not associated with diarrhea. For most of the microorganisms, primary infections did not confer protection against reinfection with the same organism, but some conferred protection against diarrhea from reinfection.

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.

Enterotoxigenic Escherichia coli Infections and Diarrhea in a Cohort of Young Children in Guinea-Bissau

In an effort to describe the natural history of enterotoxigenic Escherichia coli (ETEC) infection and diarrhea, 200 children in Guinea-Bissau, West Africa, were followed up from birth until up to age 2 years with weekly stool specimen collection, regardless of whether the children had diarrhea. ETEC isolates were tested for the presence of the porcine and human heat-stable toxins (STp and STh), the heat-labile toxin (LT), and 18 of 21 known colonization factors (CFs). The rate of primary infections increased substantially after age 3 or 6 months (depending on the type of ETEC causing the infection). The pathogenicity of STh-containing ETEC was substantially higher than that of STp-containing ETEC, and STp and STh were associated with separate sets of CFs. Small epidemics were observed, mainly caused by STh-containing ETEC. The difference in epidemic propensity, CF association, and pathogenicity suggests that STh- and STp-containing ETEC represent 2 different groups of human ETEC. Vaccines should primarily target STh-containing ETEC.