Global status of routine introduction of rotavirus vaccination. Table 4 Impact of rotavirus vaccines on diarrheal deaths if introduced at level of DTP-3, stratified by national income stratum. Table 5 Impact of rotavirus vaccines on diarrheal deaths if introduced at level of DTP-3, stratified by region a. Conclusion Rotavirus is the leading cause of diarrheal morbidity and mortality globally, with nearly every child being infected in early childhood.
Figure 5. Footnotes Disclosure The authors report no conflicts of interest in this work. References 1. The epidemiology of rotavirus diarrhea in the United States: surveillance and estimates of disease burden. J Infect Dis. Dennehy PH. Rotavirus vaccines: an overview. Clin Microbiol Rev. Global mortality associated with rotavirus disease among children in Rotavirus and severe childhood diarrhea. Emerg Infect Dis. Bernstein DI. Rotavirus overview. Pediatr Infect Dis J.
Acute, infectious diarrhea among children in developing countries. Semin Pediatr Infect Dis. Current status and future priorities for rotavirus vaccine development, evaluation and implementation in developing countries. Rotavirus infections in infants as protection against subsequent infections. N Engl J Med. Development of candidate rotavirus vaccines derived from neonatal strains in India. Zoonotic aspects of rotaviruses. Vet Microbiol. Rotaviruses: from pathogenesis to vaccination.
Santos N, Hoshino Y. Rotavirus vaccines. Philadelphia, PA: Saunders Elsevier; Rotavirus disease and vaccination: impact on genotype diversity. Future Microbiol.
Secular variation in United States rotavirus disease rates and serotypes: implications for assessing the rotavirus vaccination program. Rotavirus infection of the oropharynx and respiratory tract in young children.
J Med Virol. Risk factors for norovirus, Sapporo-like virus, and group A rotavirus gastroenteritis. Detection of rotavirus in respiratory secretions of children with pneumonia. J Pediatr. Rotaviruses and rotavirus vaccines. Br Med Bull.
Ramig RF. Pathogenesis of intestinal and systemic rotavirus infection. J Virol. Clinical presentations of rotavirus infection among hospitalized children. Epidemiology, clinical presentations and burden of rotavirus diarrhea in children under five seen at Ramathibodi Hospital, Thailand.
J Med Assoc Thai. Infectious diarrhea in developed and developing countries. J Clin Gastroenterol. Geneva, Switzerland: WHO; The management of acute diarrhea in children: oral rehydration, maintenance, and nutritional therapy.
Centers for Disease Control and Prevention. WHO estimates of the causes of death in children. Updating the DALYs for diarrhoeal disease. Trends Parasitol.
Early childhood diarrhea is associated with diminished cognitive function 4 to 7 years later in children in a northeast Brazilian shantytown. Am J Trop Med Hyg. Early childhood diarrhea predicts impaired school performance. Claeson M, Merson MH. Global progress in the control of diarrheal diseases. Reduced osmolarity oral rehydration solution for treating dehydration caused by acute diarrhoea in children. Cochrane Database Syst Rev. Chung AW, Viscorova B.
The effect of early oral feeding versus early oral starvation on the course of infantile diarrhea. Evaluation of infant feeding in acute gastroenteritis. J Pediatr Gastroenterol Nutr. Rapid versus gradual refeeding in acute gastroenteritis in childhood: energy intake and weight gain. Early feeding in childhood gastroenteritis.
Oral rehydration therapy and dietary therapy for acute childhood diarrhea. Pediatr Rev. Role of soy-based, lactose-free formula during treatment of acute diarrhea.
Meta-analysis: zinc supplementation for acute gastroenteritis in children. Aliment Pharmacol Ther. Lazzerini M, Ronfani L. Oral zinc for treating diarrhoea in children. A meta-analysis of the effects of oral zinc in the treatment of acute and persistent diarrhea. Effect of zinc supplementation started during diarrhoea on morbidity and mortality in Bangladeshi children: community randomised trial.
Effectiveness of zinc supplementation plus oral rehydration salts compared with oral rehydration salts alone as a treatment for acute diarrhea in a primary care setting: a cluster randomized trial. Meta-analysis: Lactobacillus GG for treating acute diarrhoea in children. A randomized controlled trial to evaluate the efficacy of lactobacillus GG in infantile diarrhea. Guandalini S. Probiotics for children with diarrhea: an update.
Pulling M, Surawicz CM. Loperamide use for acute infectious diarrhea in children: safe and sound? Use of racecadotril as outpatient treatment for acute gastroenteritis: a prospective, randomized, parallel study.
Effect of cholestyramine on acute diarrhoea in children receiving rapid oral rehydration and full feedings. Ann Clin Res. Management of acute diarrhea in children: lessons learned.
Alam NH, Ashraf H. Treatment of infectious diarrhea in children. Paediatr Drugs. Effect of nitazoxanide for treatment of severe rotavirus diarrhoea: randomised double-blind placebo-controlled trial. Nitazoxanide vs probiotics for the treatment of acute rotavirus diarrhea in children: a randomized, single-blind, controlled trial in Bolivian children.
Int J Infect Dis. Fecal antibody responses to symptomatic and asymptomatic rotavirus infections. Protective immunity after natural rotavirus infection: a community cohort study of newborn children in Guinea-Bissau, west Africa.
Clinical immunity after neonatal rotavirus infection. A prospective longitudinal study in young children. Protective effect of naturally acquired homotypic and heterotypic rotavirus antibodies. Diverse serologic response to rotavirus infection of infants in a single epidemic. Pediatr Infect Dis. Clinical efficacy of the RIT live attenuated bovine rotavirus vaccine in infants vaccinated before a rotavirus epidemic.
Protection of infants against rotavirus diarrhoea by RIT attenuated bovine rotavirus strain vaccine. Failure of live, attenuated oral rotavirus vaccine.
A field study of the safety and efficacy of two candidate rotavirus vaccines in a Native American population. As the number and diversity of available, licensed, and WHO-prequalified rotavirus vaccines increases [ 15 ], studies such as this provide valuable information for the planning of national immunization programs and future vaccine development.
The underlying mechanisms for this efficacy gap remain poorly understood [ 22 ], but the gap may be due to differences in rotavirus epidemiology e. A better understanding of the biological causes of reduced rotavirus vaccine efficacy in low-resource settings is needed to maximize the impact of rotavirus vaccines in the populations that are at highest risk for rotavirus morbidity and mortality, and additional studies are underway to elucidate how to improve the performance of live oral attenuated vaccines, including studies evaluating the influence of the microbiome and the effect of additional doses and improved sanitation [ 30 ].
We reported declines in vaccine efficacy beyond the first year of life, from This decline is in contrast to low-mortality countries, where vaccine efficacy was maintained into the second year of life [ 19 , 31 — 35 ], but consistent with clinical studies in high- and moderate-mortality settings, where vaccine efficacy was lower in the second year of life [ 18 , 36 — 38 ]. Several post-introduction effectiveness studies in resource-poor settings have also reported similar observations of a higher impact of the vaccine on hospitalizations in the first year of life [ 5 , 39 ].
While this study was not powered to measure vaccine efficacy in the second year of life, the lower efficacy observed in this period may be due to a number of factors, including high rotavirus incidence in this setting and waning immunity. Since exposure to natural rotavirus infection confers protection against the subsequent development of severe rotavirus disease [ 24 ], reduced efficacy in the second year of life could be partly explained by exposure of the placebo group to natural rotavirus infection, and acquired immunity, in the first year of life.
Lower incidence and lower efficacy in the second year of life may be due to natural protection among the unvaccinated children due to repeated natural infection [ 30 ]. Early immunization e. A second possible explanation for lower efficacy over the second year may be related to waning immunity. Children in high- and moderate-mortality settings had lower geometric mean titers of antirotavirus antibodies after vaccination than children in low-mortality countries [ 18 , 47 — 50 ].
Lower antibody titers after vaccination might wane sooner than higher levels, resulting in lower protection in the second year. Booster doses may be considered to counteract waning immunity. In our study, we detected a wide variety of rotavirus genotypes circulating over 4 rotavirus seasons.
Only Strain diversity has been shown to be high in Africa, where G1 and G2 strains have dominated but G8 and G9 have emerged [ 52 — 54 ]. Importantly, strain diversity can be cyclical in human populations, with dominant strains emerging every 3—4 years [ 55 , 56 ], but strains are known to have important geographical differences and to evolve over time with natural molecular evolution [ 57 , 58 ].
The second year of this study demonstrated a shift in strain predominance from G2 to G1, as well as a large increase in G9 and G3. The wide circulation of diverse rotavirus strains in the region raises the question of whether protective immunity is homotypic same G or P type or heterotypic different G or P type [ 59 ] and underscores the importance of demonstrating cross-protective efficacy of the rotavirus vaccines in preventing severe gastroenteritis.
Given the diversity of the rotavirus types in circulation and the global emergence of new strains in the human population, homotypic protection alone would be unlikely to provide complete protection against SRVGE. Here, Rotasiil efficacy was demonstrated against individual rotavirus genotypes contained and not contained in the vaccine, suggesting significant homotypic and heterotypic protection against SRVGE.
These data are consistent with other clinical trials that have demonstrated heterotypic protection of rotavirus vaccines against multiple rotavirus strains [ 17 , 60 , 61 ] and suggest that rotavirus diversity per se may not be a critical challenge for vaccine performance. The heterotypic protection afforded by Rotasiil suggests it may be effectively used throughout sub-Saharan Africa and in other regions of the world.
The potential for widespread use of rotavirus vaccines to result in evolutionary selective pressure resulting in strain replacement [ 62 , 63 ]—and subsequent impacts on vaccine performance, as was seen after the introduction of pneumococcal vaccine—can be assessed through continued monitoring to ensure that rotavirus vaccines continue overall to provide an important public health impact in reducing disease and virus transmission. Our study was designed to include a population broadly representative of those in sub-Saharan Africa, with poor socioeconomic conditions and high mortality from diarrhea.
Our study setting was notably characterized by a high incidence of rotavirus disease, high exposure to natural rotavirus infection early in infancy, and a wide diversity of circulating rotavirus strains. The delivery of rotavirus vaccines in routine childhood immunization schedules in settings where the burden of rotavirus mortality is highest will have a profound public health impact. Current guidance emphasizes the importance of complete vaccination with any rotavirus vaccine to prevent childhood mortality and morbidity [ 64 ].
National cost-effectiveness analyses can help make the case for vaccine delivery and provide compelling evidence to guide policy in resource-limited settings [ 65 ]. This study has several limitations. First, study vaccine was not consistently given concomitantly with OPV. Extrapolation to settings with concomitant administration of OPV may be limited; however, secondary analysis estimating vaccine efficacy by OPV vaccine administration status suggested that the high efficacy observed in this study is not due to lower rates of concomitant administration [ 11 ].
Second, the Vesikari score was originally designed for use in settings of high parental literacy, which may have led to underscoring of some cases, although this would not differ between groups. Third, the study had limited power to assess efficacy in the second year of life owing to the low number of observed cases. Finally, the study was unblinded following the primary analysis to allow placebo children to receive the study vaccine, and follow-up among children initially randomized to placebo was censored at the time of receipt of study vaccine to allow for comparison of vaccine efficacy.
The loss of follow-up may have contributed to further bias, but the magnitude is expected to be limited given the small number of children affected and the older age at the time of vaccine receipt compared to the early age of first infection.
We showed that Rotasiil, a heat-stable, affordable oral rotavirus vaccine, offered substantial protection against SRVGE through 2 years of life and across a wide diversity of strains—confirming that the potential public health impact of introducing rotavirus vaccines in Niger can be substantial. Vaccines that are safe, effective, and protective against multiple strains represent the best hope for preventing the severe consequences of rotavirus infection, especially in resource-limited settings, where access to care may be limited.
Delivery of this vaccine in national childhood immunization schedules can be expected to greatly reduce the burden of rotavirus disease. Abstract Background Rotavirus vaccination is recommended in all countries to reduce the burden of diarrhea-related morbidity and mortality in children.
Methods and findings From August to November , infants were randomized in a ratio to receive 3 doses of Rotasiil or placebo at approximately 6, 10, and 14 weeks of age. Conclusions Rotasiil provided protection against SRVGE in infants through an extended follow-up period of approximately 2 years.
Trial registration ClinicalTrials. Author summary Why was this study done? The World Health Organization WHO recommends rotavirus vaccine use in all countries, but several questions remain for countries that have not yet implemented rotavirus vaccination or are weighing different vaccine options. In resource-limited settings, where rotavirus vaccine delivery has important cost implications, evidence for protection beyond the first year of life and against the evolving variety of rotavirus strains is important.
What did the researchers do and find? In the present analysis, we assessed the extended and strain-specific vaccine efficacy of Rotasiil in children up to 24 months of age. Rotasiil provided protection against SRVGE in infants through an extended follow-up period and against a changing pattern of rotavirus strains during the 2-year efficacy period. What do these findings mean? Vaccines that are safe, effective, and protective against multiple strains represent the best hope for preventing the severe consequences of rotavirus infection, and can be expected to greatly reduce the burden of rotavirus disease.
Introduction Rotavirus is the leading cause of childhood diarrhea and a major cause of diarrhea-related hospitalizations and mortality in children less than 5 years of age [ 1 , 2 ].
Study design and participants Infants were randomized in a ratio to receive 3 doses of Rotasiil or placebo at approximately 6, 10, and 14 weeks of age. The trial was conducted in accordance with Good Clinical Practice guidelines.
Randomization and blinding Unique allocation numbers were prepared using a computer-generated random number list with permuted blocks of random sizes DiagnoSearch LifeSciences, Mumbai, India.
Assessment of efficacy We defined gastroenteritis as the passage of 3 or more looser-than-normal stools in a hour period with or without vomiting.
Statistical analysis The primary endpoint was vaccine efficacy of 3 doses of vaccine versus placebo against a first episode of laboratory-confirmed SRVGE from 28 days after dose 3, as previously reported [ 11 ]. Download: PPT. Table 2. Vaccine efficacy against gastroenteritis in the per-protocol population. Fig 3. Two rotavirus vaccines were authorised for prevention of rotavirus gastroenteritis in The remaining countries have not yet introduced the vaccine into their programmes for reasons related to cost effectiveness, insufficient expected epidemiological impact and competing health priorities.
Other reasons identified included risk of emergence of serotypes not covered by the vaccine, improved clinical management preferred to vaccination, and concerns regarding safety, such as intussusception a condition characterised by telescoping of the intestine onto itself.
Benefit-risk has been assessed by regulatory agencies worldwide and was found to be positive given the severity of disease and the availability of treatment of intussusception. In addition, a recent meta-analysis indicates that the risk of vaccine-related intussusception is reduced from approximately 1 in 20 to approximately 1 in 50 above the background incidence of 33 to per , in unvaccinated, if the first dose is given before the age of 12 weeks.
Vaccines represent one of the most effective and cost-saving public health intervention. Commonly asked questions about vaccines and immunisation with suggested answers that can be used to assist with conversations with patients, parents or caregivers, or made into information sheets. Although human rotavirus strains that possess a high degree of genetic homology with animal strains have been identified, animal-to-human transmission of whole virions appears to be uncommon.
Most human rotaviruses having some genetic similarity to animal rotaviruses appear formed by reassortment of one or more animal rotavirus genes into a human rotavirus during a mixed infection in vivo. In rare instances, [ 22 ] reassortment between RotaTeq vaccine component strains of genotypes P7[5]G1 and P1A[8]G6 have been observed to occur during human in vivo replication.
This vaccine-derived reassortant has been demonstrated to be transmissible, and is capable of causing symptomatic gastroenteritis. Top of Page. Three doses of this vaccine are recommended to be administered at 2, 4, and 6 months of age, concurrently with other vaccines given at this age.
RotaTeq has been tested in 2 phase III trials,[ 30,31 ] including a large-scale clinical trial of more than 70, infants enrolled primarily in the United States and Finland. This live vaccine contains the attenuated monovalent G1, P[8] human rotavirus strain and is recommended by the manufacturer to be orally administered in 2 doses to infants at 2 and 4 months of age.
In a large clinical trial of more than 63, infants from 11 Latin American countries, Rotarix was found to be safe and highly immunogenic. Rotarix provided protection against a broad range of rotavirus serotypes during the 2-year study period, including against the less common G9, P[8] strain. In a randomized, double-blind, placebo-controlled study conducted in 6 European countries, Rotarix was observed to be highly immunogenic.
For harmonization of vaccination administration scheduling, the ACIP now recommends that, for both vaccines, the maximum age for dose 1 is 14 weeks and 6 days previous recommendation: 12 weeks , and the maximum age for the last dose of rotavirus vaccine is 8 months and 0 days previous recommendation: 32 weeks.
Figure 2. Percentage of U. Rotavirus vaccination rates for either vaccine among U. By , nearly three-quarters of U. During the pre-rotavirus vaccine era, it was estimated that , physician visits; , ED visits; and 55,—70, hospitalizations were attributable to rotavirus infections in U.
Figure 3. Numerous post-licensure publications documenting rotavirus vaccine impact have demonstrated great declines in the incidence of rotavirus gastroenteritis. Since , the National Respiratory and Enteric Virus Surveillance System NREVSS , a network of 17 laboratories, has continuously provided laboratory reports of rotavirus tests performed and positive results, showing that the number of laboratory-detected rotavirus-attributable infections has plummeted since rotavirus vaccine introduction Figure 3.
These analyses were among the first to find that RotaTeq vaccine introduction was associated with a dramatic reduction in rotavirus gastroenteritis among U. Figure 4.
Declines in discharge- coded inpatient rotavirus gastroenteritis hospital visits — reported in the State Inpatient Databases.
Subsequent analyses in other databases and clinical settings have reinforced those findings. Figure 5. Declines in emergency department visits attributed to rotavirus gastroenteritis, from —, using the State Emergency Department Visit database.
Each of these analyses also revealed an interesting biennial disease trend, regardless of clinical setting. This biennial trend emerged immediately following rotavirus vaccine introduction, whereby rotavirus incidence was sharply curtailed during the winters of even-numbered years e.
Predicted in rotavirus modeling analyses,[ 42 ] this observed biennial trend in clinical and laboratory reports is believed to be due to annual fluctuations in susceptible children and the efficiency of rotavirus transmission.
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