Worldwide, rotavirus is the leading pathogen causing severe diarrhea in children and a major cause of under 5 years mortality. In 1998, the first rotavirus vaccine, RotaShield, was licensed in the United States but a rare adverse event, intussusception, led to its withdrawal. Seven years passed before the next generation of vaccines became available, Rotarix (GSK) and Rotateq (Merck), and 11 years later, 2 additional vaccines from India, Rotavac (Bharat) and Rotasiil (Serum Institute), were recommended by World Health Organization for all children. Today, these vaccines are used in more than 100 countries and have contributed to marked decreases in hospitalizations and deaths from diarrhea. However, these live oral vaccines are less effective in low-income countries with high under 5 years mortality for reasons that are not understood. Efforts to develop new vaccines that avoid the oral route are in progress and will likely be needed to ultimately control rotavirus disease.

Poliovirus and rotavirus share notable similarities. Although rotavirus is not amenable to eradication because of animal reservoirs, live, attenuated oral vaccines have been the bedrock of both prevention and control programs, providing intestinal and humoral immunity. Both programs have also encountered safety concerns and suboptimal immune responses to oral vaccines in low-income settings that have been challenges, prompting the search for alternative solutions. In this paper, we review the progress made by polio prevention and eradication efforts over the past six decades. Specifically, we discuss the roles of the oral polio vaccine (OPV) and the inactivated polio vaccine (IPV) in achieving polio eradication, and explore potential application of these lessons to rotavirus. Recent scientific evidence has confirmed that a combined schedule of IPV and OPV adds synergistic value that may give the polio eradication effort the tools to end all poliovirus circulation worldwide. For rotavirus, oral vaccine is the only currently licensed and recommended vaccine for use in all children worldwide, providing heterologous protection against a broad range of strains. However, parenteral rotavirus vaccines are in the pre-clinical and clinical trial stage and insight from polio provides strong justification for accelerating the development of these vaccines. While challenges for parenteral rotavirus vaccines will need to be addressed, such as achieving protection against a broad range of strains, the principle of combined use of oral and parenteral rotavirus vaccines may provide the necessary humoral and intestinal immunity necessary to close the efficacy gaps between developing and developed countries, therefore controlling rotavirus worldwide. This strategy may also potentially reduce risk of intussusception.

A parenteral inactivated rotavirus vaccine (IRV) in development could address three problems with current live oral rotavirus vaccines (ORV): their lower efficacy in low and middle-income countries (LMICs), lingering concerns about their association with intussusception, and their requirement for a separate supply chain with large volume cold storage. Adding a new parenteral IRV to the current schedule of childhood immunizations would be more acceptable if it could be combined with another injectable vaccine such as inactivated polio vaccine (IPV). Current plans for polio eradication call for phasing out oral polio vaccine (OPV) and transitioning to IPV, initially in LMICs as a single dose booster after two doses of OPV and ultimately as a two dose schedule. Today in many LMICs, IPV is administered as a standalone vaccine, which involves a separate cold chain and is relatively costly. We therefore tested in two animal models formulations of IPV with IRV to determine whether co-administration might interfere with the immune response to each product and spare antigen dose for both vaccines. Our results demonstrate that IRV when adjuvanted with alum and administered alone or in combination with IPV did not impair the immune responses to either rotavirus or poliovirus serotypes 1, 2 and 3. Similarly, IPV when formulated and administered alone or together with IRV induced comparable levels of neutralizing antibody to poliovirus type 1, 2 and 3. Furthermore, comparable antibody titers were observed in animals vaccinated with low, middle or high dose of IPV or IRV in combination. This dose sparing and the lack of interference between IPV and IRV administered together represent another step to support the further development of this novel combination vaccine for children.

Live oral rotavirus (RV) vaccines used worldwide are most effective in reducing diarrheal hospitalizations from RV in high income countries and least effective in low income countries where RV remains a prime cause of death in children. Research has failed to fully explain the reason for this difference of efficacy for RV vaccines, an observation made with other live oral vaccines for polio, cholera and typhoid fever. Use of parenteral vaccines have been successful in overcoming this problem for both polio and typhoid and parenteral RV vaccines are now in development. This approach should be pursued for rotavirus vaccine as well because in low income countries where oral RV vaccines have been introduced and are only partially effective, RV remains the most common cause of diarrhea in children under 5years. The ultimate control of RV diarrheal will likely require both oral and parenteral vaccines.

Noroviruses are now recognized as the leading cause of acute gastroenteritis across the age spectrum. New global estimates of the norovirus disease burden highlight the specific populations most affected and potential targets for prevention strategies. As traditional infection control and food hygiene measures may be inadequate to fully control norovirus disease, vaccines are an appealing option. Initial trials of candidate vaccines have demonstrated only modest efficacy, but show promise that norovirus prevention through vaccination is possible. Key issues that require further study include duration of immunity, degree of cross-protection, and efficacy in target populations. While initial introduction of norovirus vaccines is likely to occur in developed countries, the greatest public health burden and thus potential impact of such vaccines is in developing countries. | Recognition of the public health impact of noroviruses has increased dramatically in the past two decades through the application of molecular-based diagnostics. In many developed countries, noroviruses are now recognized to be the leading cause of acute gastroenteritis across the age spectrum and the leading cause of foodborne disease, including outbreaks [1]. In the United States, for example, noroviruses are responsible for approximately 20 million episodes of acute gastroenteritis annually, with about 70,000 hospitalizations and up to 800 deaths, mostly in the elderly [2]. Furthermore, following the decline in rotavirus disease after vaccine introduction in 2006, noroviruses have replaced rotavirus as the leading cause of severe gastroenteritis in US children aged <5 years [3]. However, from a global perspective, the greatest public health burden from noroviruses is undoubtedly exacted upon developing countries, where diarrheal diseases remain among the leading causes of death [4]. A recent systematic review concluded that norovirus was associated with 18% of all acute gastroenteritis worldwide [5]. Of 175 studies included in the review, 147 (84%) were published since 2008, among which 94 (64%) were conducted in developing countries. While data specifically on norovirus incidence and disease burden from these countries are more limited and some studies have suggested that detection of noroviruses may not be causally associated with illness in all cases [6,7], this review demonstrates the increased effort in recent years to better understand the public health impact of noroviruses globally so that we may better address it.

Rotavirus is the leading cause of severe diarrhea among children<5 years worldwide. Currently licensed rotavirus vaccines have been efficacious and effective, with many countries reporting substantial declines in diarrheal and rotavirus-specific morbidity and mortality. However, the full public health impact of these vaccines has not been realized. Most countries, including those with the highest disease burden, have not yet introduced rotavirus vaccines into their national immunization programs. Research activities that may help inform vaccine introduction decisions include (1) establishing effectiveness, impact, and safety for rotavirus vaccines in low-income settings; (2) identifying potential strategies to improve performance of oral rotavirus vaccines in developing countries, such as zinc supplementation; and (3) pursuing alternate approaches to oral vaccines, such as parenteral immunization. Policy- and program-level barriers, such as financial implications of new vaccine introductions, should be addressed to ensure that countries are able to make informed decisions regarding rotavirus vaccine introduction.

In January 2006, the Journal published two landmark articles reporting the safety and efficacy of two different vaccines - RotaTeq (Merck), a pentavalent vaccine (RV5) and Rotarix (GlaxoSmithKline), a monovalent vaccine (RV1) - to prevent rotavirus, the most common cause of severe childhood diarrhea worldwide and of deaths from diarrhea in low-income countries. Each trial enrolled more than 60,000 infants to determine whether these live oral vaccines caused intussusception, the rare complication that in 1999 forced the withdrawal of the first licensed rotavirus vaccine, RotaShield (Wyeth Lederle), less than a year after it was recommended for routine immunization of U.S. children.

Since 2006, the availability of two new rotavirus vaccines has raised enthusiasm to consider the eventual control and elimination of severe rotavirus diarrhea through the global use of vaccines. Rotavirus remains the most severe cause of acute diarrhea in children worldwide responsible for several hundred thousands of deaths in low income countries and up to half of hospital admissions for diarrhea around the world. The new vaccines have been recommended by WHO for all infants and in more than 47 countries, their introduction into routine childhood immunization programs has led to a remarkable decline in hospital admissions and even deaths within 3 years of introduction. Challenges remain with issues of vaccine finance globally and the problem that these live oral vaccines perform less well in low income settings where they are needed most. Ongoing research that will accompany vaccine introduction might help address these issues of efficacy and new vaccines and novel financing schemes may both help make these vaccines universally available and affordable in the decade.

There is substantial evidence for broad cross-reactive immunity and heterotypic protection among human rotavirus strains in children with natural infection or with monovalent Rotarix vaccination. In this commentary, we addressed this same question by testing sera of guinea pigs and gnotobiotic piglets that were intramuscularly immunized with an inactivated human rotavirus vaccine and also demonstrated a broad cross-protective immunity among human rotavirus strains. Our findings from a single human strain in animal studies bode well for a low cost and efficacious inactivated vaccine to protect children against rotavirus disease throughout the world.

BACKGROUND: Live oral rotavirus vaccines have been less immunogenic and efficacious for children of developing countries than for those in middle income and industrialized countries and the basis for these differences is not fully understood. Recently, we demonstrated that breastmilk from mothers in India had significantly higher IgA and neutralizing activity against rotavirus that could reduce the effective titer of rotavirus vaccines reaching the gut when compared to that from mothers in the US. We extended our study to understand the specific contribution of those non-antibody components in breastmilk to the neutralizing activity against rotavirus vaccine we observed. METHODS: Breastmilk samples were collected from mothers of breast-feeding infants aged between 4 to 29 weeks (i.e., vaccine eligible age) in India (N=40), South Africa (N=50) and the United States (N=51). We examined breastmilk for lactoferrin, lactadherin, rotavirus-specific IgA, and neutralizing activity against three rotavirus vaccine strains: Rotarix; RotaTeq G1; and 116E using enzyme immunoassays; a plaque reduction assay; or a microneutralization assay. FINDINGS: We observed higher levels of lactoferrin, lactadherin, IgA, and neutralizing activity in breastmilk specimens from Indian and South African women than those from American women. We demonstrated positive associations between levels of lactoferrin or IgA and neutralizing activity in Indian and South African specimens, but not in American specimens. We demonstrated that the inhibitory effect of lactoferrin was dose- or species-dependent, as evidenced by greater reduction in titer of Rotarix and 116E by human lactoferrin. Lactadherin also exhibited inhibitory activity to rotavirus vaccines but appeared to be less effective. INTERPRETATION: The lower immunogenicity and efficacy of rotavirus vaccines in developing countries could be explained, in part, by synergistic inhibitory effect of high levels of antibody and non-antibody components in breastmilk consumed by infants at the time of immunization. Therefore, there is a need for alternative rotavirus vaccine strategies in breastfeeding populations.

BACKGROUND: Diarrhea is a leading cause of illness and death among children aged <5 years in developing countries. This paper describes the clinical and epidemiological methods used to conduct the Global Enteric Multicenter Study (GEMS), a 3-year, prospective, age-stratified, case/control study to estimate the population-based burden, microbiologic etiology, and adverse clinical consequences of acute moderate-to-severe diarrhea (MSD) among a censused population of children aged 0-59 months seeking care at health centers in sub-Saharan Africa and South Asia. METHODS: GEMS was conducted at 7 field sites, each serving a population whose demography and healthcare utilization practices for childhood diarrhea were documented. We aimed to enroll 220 MSD cases per year from selected health centers serving each site in each of 3 age strata (0-11, 12-23, and 24-59 months), along with 1-3 matched community controls. Cases and controls supplied clinical, epidemiologic, and anthropometric data at enrollment and again approximately 60 days later, and provided enrollment stool specimens for identification and characterization of potential diarrheal pathogens. Verbal autopsy was performed if a child died. Analytic strategies will calculate the fraction of MSD attributable to each pathogen and the incidence, financial costs, nutritional consequences, and case fatality overall and by pathogen. CONCLUSIONS: When completed, GEMS will provide estimates of the incidence, etiology, and outcomes of MSD among infants and young children in sub-Saharan Africa and South Asia. This information can guide development and implementation of public health interventions to diminish morbidity and mortality from diarrheal diseases.

To understand the etiology of moderate-to-severe diarrhea among children in high mortality areas of sub-Saharan Africa and South Asia, we performed a comprehensive case/control study of children aged <5 years at 7 sites. Each site employed an identical case/control study design and each utilized a uniform comprehensive set of microbiological assays to identify the likely bacterial, viral and protozoal etiologies. The selected assays effected a balanced consideration of cost, robustness and performance, and all assays were performed at the study sites. Identification of bacterial pathogens employed streamlined conventional bacteriologic biochemical and serological algorithms. Diarrheagenic Escherichia coli were identified by application of a multiplex polymerase chain reaction assay for enterotoxigenic, enteroaggregative, and enteropathogenic E. coli. Rotavirus, adenovirus, Entamoeba histolytica, Giardia enterica, and Cryptosporidium species were detected by commercially available enzyme immunoassays on stool samples. Samples positive for adenovirus were further evaluated for adenovirus serotypes 40 and 41. We developed a novel multiplex assay to detect norovirus (types 1 and 2), astrovirus, and sapovirus. The portfolio of diagnostic assays used in the GEMS study can be broadly applied in developing countries seeking robust cost-effective methods for enteric pathogen detection.

OBJECTIVE: To estimate the number of rotavirus-associated deaths among Indian children younger than five years. METHODS: We surveyed more than 23,000 child deaths from a nationally representative survey of 1.1 million Indian households during 2001-2003. Diarrhoeal deaths were characterized by region, age and sex and were combined with the proportion of deaths attributable to rotavirus, as determined by hospital microbiologic data collected by the Indian Rotavirus Strain Surveillance Network from December 2005 to November 2007. Rotavirus vaccine efficacy data from clinical trials in developing countries were used to estimate the number of deaths preventable by a national vaccination programme. Data were analysed using Stata SE version 10. FINDINGS: Rotavirus caused an estimated 113 000 deaths (99% confidence interval, CI: 86,000-155,000); 50% (54 700) and 75% (85 400) occurred before one and two years of age, respectively. One child in 242 died from rotavirus infection before five years of age. Rotavirus-associated mortality rates overall, among girls and among boys were 4.14 (99% CI: 3.14-5.68), 4.89 (99% CI: 3.75-6.79) and 3.45 (99% CI: 2.58-4.66) deaths per 1000 live births, respectively. Rates were highest in Bihar, Uttar Pradesh and Madhya Pradesh, which together accounted for > 50% of deaths (64,400) nationally. Rotavirus vaccine could prevent 41,000-48,000 deaths among children aged 3-59 months. CONCLUSION: The burden of rotavirus-associated mortality is high among Indian children, highlighting the potential benefits of rotavirus vaccination.

BACKGROUND: Acute gastroenteritis (AGE) remains a common cause of clinic visits and hospitalizations in the United States, but the etiology is rarely determined. METHODS: We performed a prospective, multicenter emergency department-based study of adults with AGE. Subjects were interviewed on presentation and 3-4 weeks later. Serum samples, rectal swab specimens, and/or whole stool specimens were collected at presentation, and serum was collected 3-4 weeks later. Fecal specimens were tested for a comprehensive panel of viral, bacterial, and parasitic pathogens; serum was tested for calicivirus antibodies. RESULTS: Pathogens were detected in 25% of 364 subjects, including 49% who provided a whole stool specimen. The most commonly detected pathogens were norovirus (26%), rotavirus (18%), and Salmonella species (5.3%). Pathogens were detected significantly more often from whole stool samples versus a rectal swab specimen alone. Nine percent of subjects who provided whole stool samples had >1 pathogen identified. CONCLUSIONS: Viruses, especially noroviruses, play a major role as agents of severe diarrhea in adults. Further studies to confirm the unexpectedly high prevalence of rotaviruses and to explore the causes of illness among patients from whom a pathogen cannot be determined are needed. Studies of enteric pathogens should require the collection of whole stool samples.

Every winter, children, parents, and clinicians in the United States have to deal with the annual seasonal outbreak of rotavirus, the most common cause of severe diarrhea in children worldwide. Before the implementation of routine vaccination against rotavirus in 2006, most US children had experienced an episode of rotavirus diarrhea by the age of 5 years, an estimated 400 000, or 1 child in 6, required outpatient treatment and about 55 000 to 70 000 children, or 1 in 50, were hospitalized.1 The health consequences of this annual event in the United States were unsettling and were estimated to cost more than $1 billion per year.1 | When the first new rotavirus vaccine was licensed in 2006,1 uncertainty existed about whether parents would agree to have their infants immunized and whether clinicians would actively promote its use. Rotavirus vaccines had been severely stigmatized in 1999 when an earlier vaccine, tetravalent rhesus-human reassortant vaccine (RotaShield, Wyeth Laboratories) was abruptly removed from the market because of its link with intussusception, an uncommon form of intestinal obstruction. To assess whether the next generation of rotavirus vaccines harbored the same complication, the US Food and Drug Administration (FDA) required manufacturers to enroll and follow up more than 60 000 infants in clinical trials. Merck and GlaxoSmithKline set off cautiously to conduct multicenter trials of the pentavalent human-bovine WC3 reassortant rotavirus vaccine (RotaTeq, Merck & Co) and the RIX4144 strain human rotavirus vaccine (Rotarix, GlaxoSmithKline Biologicals), ultimately recruiting more than 70 000 infants each, some of the largest and most costly licensure trials ever conducted.1 Neither vaccine was associated with intussusception in these trials.

We report the first detection of a G6P[14] rotavirus strain in Egypt from the stool of a child participating in a hospital-based diarrhea surveillance study conducted throughout the year 2004. Rotavirus infection was initially detected using a rotavirus group A VP6 enzyme immunoassay; the P (VP4) and G (VP7) genotypes of the strain were identified by RT-PCR. We sequenced the VP7 gene and the VP8* portion of the VP4 gene and the strain displayed the strongest identity to the VP7 [>94% nucleotides (nt), >97% amino acids (aa)] and VP4 (>93% nt, >98% aa) sequences of PA169, a novel G6P[14] strain first isolated from a child in Italy during the winter of 1987. Additional sequencing and analysis of the other remaining structural (VP1-VP3, VP6) and non-structural (NSP1-NSP5) proteins support this animal-to-human reassortment theory. According to the full genome classification system, the G6P[14] strain (EGY3399) was assigned to G6-P[14]-I2-R2-C2-M2-A11-N2-T6-E2-H3 genotypes. The greatest similarity of EGY3399 NSP4 and NSP5 gene sequences were to those of ovine and simian origin, respectively. Coupled with other observations, our results suggest G6P[14] isolates rarely cause severe diarrhea in Egyptian children, and support other studies that indicate animal rotavirus contribute to the genetic diversity of rotavirus detected from humans through interspecies transmission and single or multiple segments reassortment.

OBJECTIVES: Deaths due to diarrhea among US children declined substantially from the 1960s through the 1980s, but have not been recently assessed. We examined diarrhea-associated mortality among young US children from 1992 to 2006 to establish baseline estimates through which the effect of rotavirus vaccines, introduced in 2006, can be assessed. METHODS: National Center for Health Statistics multiple cause-of-death mortality data were used to examine diarrhea-associated deaths and death rates among US children 1 to 59 months of age during 1992-2006. The winter residual method was used to indirectly estimate the annual number of diarrhea-associated deaths attributable to rotavirus. RESULTS: An average of 369 diarrhea-associated deaths/year (3320 total deaths) occurred among US children 1 to 59 months of age during 1992-1998 and 2005-2006. The diarrhea-associated death rate increased 40% between the first 3 and last 2 years of the study period, from an average of 1.6 deaths per 100,000 to 2.3 deaths per 100,000. Black children died at almost 4 times the rate of white children. Diarrhea-associated deaths showed a winter seasonal pattern similar to that of rotavirus, particularly among children 4 to 23 months of age. Using indirect methods, we estimated 25 yearly rotavirus-associated deaths during the study period. Rotavirus vaccination could potentially prevent 21 of these deaths annually. CONCLUSIONS: Diarrhea-associated mortality among US children stabilized but appears to be increasing in recent years. Rotavirus was associated with a small but significant number of preventable deaths. The national multiple cause-of-death data should prove useful for assessing mortality impact of rotavirus vaccination in the United States.

OBJECTIVES: The role of noroviruses in both foodborne and person-to-person outbreaks of acute gastroenteritis (AGE) has been difficult to determine in the U.S. because of lack of routine norovirus testing and of national reporting of person-to-person outbreaks. We conducted a prospective study in one state in which enhanced testing for noroviruses was performed to better understand the relative contribution of all gastroenteric pathogens. METHODS: During the two-year period, 2000-2001, we took all fecal specimens from AGE outbreaks reported in Georgia that were negative for bacteria and tested these for norovirus. RESULTS: We investigated 78 AGE outbreaks, from which suitable fecal samples were collected from 57 of them. Norovirus was identified in 25 (44%) outbreaks, bacteria in 20 (35%) outbreaks, and parasites in one (2%) outbreak. Forty-three (75%) of the outbreaks tested were foodborne, of which 17 (40%) were attributable to norovirus and 18 (42%) were attributable to bacteria. Adjusting for incomplete testing, we estimated that 53% of all AGE outbreaks were attributable to norovirus. A total of 2,674 people were reported ill in the 57 outbreaks, and norovirus infections accounted for 1,735 (65%) of these cases. Norovirus outbreaks tended to be larger than bacterial outbreaks, with a median number of 30 vs. 16 cases per outbreak, respectively (p = 0.057). CONCLUSIONS: This study provides further evidence that noroviruses are, overall, the most common cause of AGE outbreaks in the U.S. Improved specimen collection, reporting person-to-person outbreaks, and access to molecular assays are needed to further understand the role of these viruses and methods for their prevention.

Worldwide, diarrhea is the second most common cause of fatal childhood disease, estimated to cause approximately 1.34 million deaths among children aged <5 years.1 Rotavirus is the leading cause of severe diarrhea in young children and is responsible for approximately one-third of all diarrheal deaths.2 Two effective rotavirus vaccines, a single-strain attenuated human rotavirus vaccine (Rotarix, GlaxoSmithKline Biologicals) and a multistrain bovine-human reassortant vaccine (RotaTeq, Merck and Company), are now available and recommended for routine immunization of all infants by the World Health Organization (WHO).3 Efficacy of these vaccines has ranged from 80% to 98% in industrialized countries,4–7 including Latin America, and 39% to 77% in developing countries, such as Africa and Asia.8–10 On the basis of efficacy data from Europe and America, the WHO initially approved use of the vaccines in these regions in 2006 and within 2 years several countries added rotavirus vaccination into their routine immunization programs. Subsequently, after proof of efficacy in Asia and Africa, the WHO recommendation was expanded to all infants worldwide in 2009.3

BACKGROUND: A live, attenuated rotavirus vaccine, RotaTeq(R), was approved in 2006 for immunization of infants in the United States. To monitor the distribution of rotavirus genotypes before and after vaccine introduction, the Centers for Disease Control and Prevention conducted strain surveillance with the National Rotavirus Strain Surveillance System. METHODS: Over 3 rotavirus seasons, 2005-2006, 2006-2007, and 2007-2008, National Rotavirus Strain Surveillance System laboratories collected rotavirus-positive stool specimens and submitted them to the Centers for Disease Control and Prevention. Rotavirus strains were G- and P-genotyped by multiplex reverse transcription-polymerase chain reaction or nucleotide sequencing. RESULTS: During 2005-2006 and 2006-2007 seasons, G1 was the dominant G-type but in the 2007-2008 season, G3 replaced G1 as the most frequently detected strain. Four genotypes, G1P[8], G2P[4], G3P[8], and G9P[8] were detected in every season. Uncommon strains observed during the study period were G2P[8], G1P[6], G2P[6], G4P[6], G1P[4], G3P[9], G12P [6], and G12P[8]. The mean age of rotavirus cases in the 2007-2008 season increased significantly in patients less than 3 years old compared with the 2 previous seasons. CONCLUSIONS: The increased overall prevalence of G3P [8] strains in 2007-2008, the first rotavirus season with reasonable rotavirus vaccine coverage, was consistent with Australian reports of G3 dominance following RotaTeq introduction. However, these strain changes in both countries have occurred in the context of large declines in severe rotavirus disease and we cannot rule out that they are simply the result of naturally occurring changes in rotavirus strain prevalence. These findings underscore the need for careful monitoring of strains to assess possible vaccine pressure-induced changes and vaccine effectiveness against various rotavirus genotypes.

OBJECTIVE: Rotavirus is the leading cause of severe diarrhea among children worldwide, killing approximately 600,000 children annually, including 64,800 in the Eastern Mediterranean Region. Safe, effective rotavirus vaccines will be available soon, and accurate disease burden data will be needed to assess the burden of rotavirus and the value of new vaccines and monitor vaccine program impact. METHODS: To identify epidemiologic studies in which rotavirus diagnostics were applied to children with acute gastroenteritis, we performed a systematic literature review. We selected studies that met 4 criteria and extracted rotavirus data on prevalence estimates, strain identification, age distribution of patients, and seasonal trends. RESULTS: Of the 63 published studies with some rotavirus detection data, 29 met inclusion criteria. Among patients with diarrhea, rotavirus was detected in 40% of inpatients and 23% of outpatients. By 3 years of age, 75% of children experienced a documented rotavirus infection. Circulation of rotavirus occurred year-round, and no clear relationship between the timing of the rotavirus peak with either season or latitude was observed. Comparison of country-specific rotavirus detection rates indicated that the proportion of hospitalizations for rotavirus infection increased with income. CONCLUSION: This systematic review of studies of rotavirus diarrhea among children in the countries of the Eastern Mediterranean Region documents that rotavirus is one of the most significant causes of childhood diarrhea in the region. The findings of this review will be used to establish sentinel hospital surveillance in these countries, estimate disease burden, and characterize its epidemiology using common protocols and diagnostics.

Live oral rotavirus vaccines that are effective in middle and high income countries have been much less immunogenic and effective among infants in resource-limited settings. Several hypotheses might explain this difference, including neutralization of the vaccine by high levels of maternal antibody in serum and breast milk, severe malnutrition, and interference by other flora and viruses in the gut. We have pursued development of an alternative parenteral rotavirus vaccine with the goal of inducing comparable levels of immunogenicity and efficacy in populations throughout the world regardless of their income levels. In the present study, we assessed the immunogenicity and protection of a candidate inactivated rotavirus vaccine (IRV), the human strain CDC-9 (G1P[8]) formulated with aluminum phosphate, against rotavirus infection in gnotobiotic piglets. Three doses of IRV induced high titers of rotavirus-specific IgG and neutralizing activity in the sera of gnotobiotic piglets and protection against shedding of rotavirus antigen following oral challenge with a homologous virulent human strain Wa (G1P[8]). Our findings demonstrate the proof of concept for an IRV in a large animal model and provide evidence and justification for further clinical development as an alternative candidate vaccine.

Detection and characterization of group A rotavirus in Buenos Aires, Argentina, was conducted on 710 fecal samples from children 0-15 years old collected between 2004 and 2007. Rotavirus was detected in 140 (19.7%) samples with G9P[8] (30.0%) and G2P[4] (21.4%) as the most common genotypes. Mixed (G and/or P) infections accounted for 17.9% of the samples and the emerging G12 strain was detected during 2004 (3.5%) and 2007 (2.5%). Genotype G2 was the most prevalent during 2004 (43.9%) and 2007 (57.5%) and G9 during 2005 (58.0%) and 2006 (61.5%). Analysis of genotype prevalences from studies performed since 1996 in the same area showed striking natural fluctuations in G and P genotype frequencies. In particular, G2P[4] strains disappeared after 1999 and reemerged in 2004 to become the predominant strain by 2007 with a concomitant major decrease in G1P[8] prevalence. The VP7 genes from Argentinian G9 and G2 strains were sequenced and phylogenetic analysis was conducted in order to compare with sequences from strains isolated in regional countries reported previously. Several changes in the deduced amino acid sequence in antigenic regions of the VP7 protein from Argentinian and Brazilian strains were identified compared to vaccine strains. Overall, this study revealed relationships in the circulation of rotavirus strains in South American countries and major replacements in dominant genotypes, including the virtual disappearance of G1P[8] strains in a non-vaccinated population. High numbers of mixed infections speeding up evolution, circulation of rare serotypes, and antigenic drift could, eventually,become challenges for new vaccines. copyright 2010 Wiley-Liss, Inc.

BACKGROUND: Live oral rotavirus vaccines have been less immunogenic and efficacious among children in poor developing countries compared with middle income and industrialized countries for reasons that are not yet completely understood. We assessed whether the neutralizing activity of breast milk could lower the titer of vaccine virus and explain this difference in vitro. METHODS: Breast milk samples were collected from mothers who were breast-feeding infants 4 to 29 weeks of age (ie, vaccine eligible age) in India (N = 40), Vietnam (N = 77), South Korea (N = 34), and the United States (N = 51). We examined breast milk for rotavirus-specific IgA and neutralizing activity against 3 rotavirus vaccine strains-RV1, RV5 G1, and 116E using enzyme immunoassays. The inhibitory effect of breast milk on RV1 was further examined by a plaque reduction assay. FINDINGS: Breast milk from Indian women had the highest IgA and neutralizing titers against all 3 vaccine strains, while lower but comparable median IgA and neutralizing titers were detected in breast milk from Korean and Vietnamese women, and the lowest titers were seen in American women. Neutralizing activity was greatest against the 2 vaccine strains of human origin, RV1 and 116E. This neutralizing activity in one half of the breast milk specimens from Indian women could reduce the effective titer of RV1 by approximately 2 logs, of 116E by 1.5 logs, and RV5 G1 strain by approximately 1 log more than that of breast milk from American women. INTERPRETATION: The lower immunogenicity and efficacy of rotavirus vaccines in poor developing countries could be explained, in part, by higher titers of IgA and neutralizing activity in breast milk consumed by their infants at the time of immunization that could effectively reduce the potency of the vaccine. Strategies to overcome this negative effect, such as delaying breast-feeding at the time of immunization, should be evaluated.

The WHO has recently recommended the inclusion of rotavirus vaccine in the national immunization programs of all countries. In countries in the Americas, Europe and Australia that have adopted routine childhood immunization against rotavirus, significant reductions in the burden of severe childhood diarrhea have been observed. Besides protecting vaccinated children, disease rates also appear to be reduced in unvaccinated children, suggesting indirect benefits from vaccination (i.e., herd protection). Early clinical trial data from Africa and Asia are promising, and further efforts are needed to optimize the benefits of vaccination in developing countries where vaccines are likely to have their greatest impact.

BACKGROUND: Current, nationally representative data on rotavirus disease burden and rotavirus strains in India are needed to understand the potential health benefits of rotavirus vaccination. METHODS: The Indian Rotavirus Strain Surveillance Network was established with 4 laboratories and 10 hospitals in 7 different regions of India. At each hospital, children aged <5 years who presented with acute gastroenteritis and required hospitalization with rehydration for at least 6 h were enrolled. A fecal specimen was obtained and was tested for rotavirus with use of a commercial enzyme immunoassay, and strains were characterized using reverse-transcription polymerase chain reaction. RESULTS: From December 2005 through November 2007, rotavirus was found in approximately 39% of 4243 enrolled patients. Rotavirus was markedly seasonal in northern temperate locations but was less seasonal in southern locations with a tropical climate. Rotavirus detection rates were greatest among children aged 6-23 months, and 13.3% of rotavirus infections involved children aged <6 months. The most common types of strains were G2P[4] (25.7% of strains), G1P[8] (22.1%), and G9P[8] (8.5%); G12 strains were seen in combination with types P[4], P[6], and P[8] and together comprised 6.5% of strains. CONCLUSIONS: These data highlight the need for development and implementation of effective prophylactic measures, such as vaccines, to prevent the large burden of rotavirus disease among Indian children.

During a 2-year period in 2005-2007, we conducted surveillance of group A rotaviruses and other enteric agents among patients hospitalized with acute gastroenteritis in 8 different cities of the Russian Federation. Fecal specimens were gathered from 3208 children (including 2848 children aged <5 years) and 1354 adults who were admitted to hospitals in Moscow, St. Petersburg, Chelyabinsk, Nizhnii Novgorod, Tyumen, Khabarovsk, Makhachkala, and Yakutsk. Polymerase chain reaction was performed to detect rotaviruses of groups A and C, noroviruses of genogroups I and II, astrovirus, sapovirus, and enteric adenoviruses (group F). Group A rotavirus was the most common viral pathogen detected among children aged <5 years (43.6%), followed by norovirus (12.5%), whereas norovirus was the pathogen most commonly detected in adults (11.9%). P and G genotypes were determined for 515 rotavirus specimens, and the most prevalent genotypes were G1P[8] (44.9%), G4P[8] (40.0%), G2P[4] (8.5%), and G3P[8] (6.6%). This study is the first multicenter study of rotaviruses in the Russian Federation and documents the important burden of disease caused by this pathogen, which soon may be preventable by vaccination.

In Vietnam, rotavirus infection accounts for more than one-half of all hospitalizations for diarrhoea among children less than 5 years of age. While new vaccines to prevent rotavirus diarrhoea have been developed and introduced into some countries by multinational manufacturers, the ability for developing countries such as Vietnam to introduce several new and important vaccines into the routine infant immunization schedule may be challenging. In order to be partially self-sufficient in vaccine production, Vietnam has pursued the development of several rotavirus strains as candidate vaccines using isolates obtained from Vietnamese children with diarrhoea. This paper describes the origin, isolation and characterization of 3 human rotavirus strains being considered for further vaccine development in Vietnam. The goal is to prepare a monovalent G1P [8] rotavirus vaccine using one of these strains obtained in Vietnam and naturally attenuated by multiple passages in cell culture. While this is an ambitious project that will require several years' work, we are using the lessons learned to improve the overall quality of vaccine production including the use of Vero cell techniques for the manufacture of other vaccines in Vietnam.

To estimate the rotavirus-associated burden in Kyrgyzstan, we conducted hospital surveillance among children <5 years old with diarrhoea during 2005-2007. Of 3756 children hospitalized with diarrhoea, 26% had rotavirus detected in stool samples by an enzyme immunoassay. The virus genotype G1P[8] was identified in 60% of 190 characterized samples from 2005 to 2006. The estimated risk for rotavirus hospitalization by age 5 years was 1 in 28 children. One quarter of all gastroenteritis hospitalizations in children <5 years old in Kyrgyzstan may be attributable to rotavirus. Rotavirus vaccination could be an important health intervention to reduce the burden of rotavirus gastroenteritis.

This study estimates rotavirus disease burden in children under age 3 years presenting with acute gastroenteritis to hospitals in Purworejo district and Yogyakarta city from August 2001 to April 2004. Among a total of 8929 hospitalized children, 1397 (16%) presented with acute gastroenteritis and of the 1321 stool samples tested, 705 (53%) were positive for rotavirus. Rotavirus infections were most common among children aged 7-23 months and rotavirus was more common during the dry season (June through August). Logistic regression analysis showed no differences in socioeconomic indicators between the rotavirus positive and negative admissions. Rotavirus vaccination may prevent a large proportion of all hospitalizations of young children under 3 years of age presenting with acute gastroenteritis.