Epidemiology of Rotavirus Gastroenteritis and Rotavirus-Associated Benign Convulsions with Mild Gastroenteritis after the Introduction of Rotavirus Vaccines in South Korea: Nationwide Data from the Health Insurance Review and Assessment Service.

Using nationwide data from the Health Insurance Review and Assessment service, we assessed the impact of rotavirus vaccines, introduced in South Korea, in 2007, on changes in the prevalence of factors (age, sex, and geographic location) associated with rotavirus gastroenteritis (RVGE) and rotavirus-associated benign convulsions with mild gastroenteritis (RaCwG). We analyzed health records of children younger than 3 years who visited clinical facilities and were diagnosed with RVGE or RaCwG between 2007 and 2019. The annual mid-year population (MYP) was obtained from the Korean Statistical Information Service. The annual prevalence of RVGE, RaCwG and associated factors were statistically analyzed. Overall, 219,686, and 4032, children were confirmed to have RVGE and RaCwG, respectively. Although the annual prevalence of RVGE decreased significantly, that of RaCwG did not. The annual ratio of RaCwG to RVGE was significantly high. Compared to the prevalence of RVGE, the prevalence of RaCwG was significantly lower in rural areas. The age of RaCwG patients was significantly lower than that of the MYP and that of RVGE patients. The decrease in the number of RaCwG patients after rotavirus vaccination was not as pronounced as the decrease in the number of RVGE patients.

Phylogenetic and immunoinformatic analysis of VP4, VP7, and NSP4 genes of rotavirus strains circulating in children with acute gastroenteritis in Indonesia.

Rotavirus is a major cause of diarrhea in Indonesian children. However, rotavirus vaccines have not been introduced in the national immunization program of Indonesia. Understanding the genetic diversity and conserved antigenic regions of circulating strains are therefore essential to assess the potential efficacy of rotavirus vaccines. We collected fecal samples from hospitalized children less than 5 years of age with acute diarrhea. Rotavirus genotyping was performed by reverse transcriptase polymerase chain reaction, followed by sequencing of the VP4, VP7, and NSP4 genes of representative strains. Phylogenetic analysis was performed to investigate their relationship with globally circulating strains. Conservational analysis, immunoinformatics, and epitope mapping in comparison to vaccine strains were also performed. The sequence analyses showed that differences of multiple amino acid residues existed between the VP4, VP7, and NSP4 antigenic regions of the vaccine strains and the Indonesian isolates. However, many predicted conserved epitopes with higher antigenicity were observed in the vaccine and Indonesian strains, conferring the importance of these epitopes. The identified epitopes showed a higher potential of rotavirus vaccine to be employed in Indonesia. It could also be helpful to inform the design of a peptide vaccine based on the conserved regions and epitopes in the viral proteins.

Effect of propensity of seeking medical care on the bias of the estimated effectiveness of rotavirus vaccines from studies using a test-negative case-control design.

BACKGROUND: Rotavirus is the leading cause of severe diarrhea among children worldwide, and vaccines can reduce morbidity and mortality by 50-98%. The test-negative control (TNC) study design is increasingly used for evaluating the effectiveness of vaccines against rotavirus and other vaccine-preventable diseases. In this study design, symptomatic patients who seek medical care are tested for the pathogen of interest. Those who test positive (negative) are classified as cases (controls). METHODS: We use a probability model to evaluate the bias of estimates of rotavirus vaccine effectiveness (VE) against rotavirus diarrhea resulting in hospitalization in the presence of possible confounding and selection biases due to differences in the propensity of seeking medical care (PSMC) between vaccinated and unvaccinated children. RESULTS: The TNC-based VE estimate corrects for confounding bias when the confounder's effects on the probabilities of rotavirus and non-rotavirus related hospitalizations are equal. If this condition is not met, then the estimated VE may be substantially biased. The bias is more severe in low-income countries, where VE is known to be lower. Under our model, differences in PSMC between vaccinated and unvaccinated children do not result in selection bias when the TNC study design is used. CONCLUSIONS: In practice, one can expect the association of PSMC (or other potential confounders) with the probabilities of rotavirus and non-rotavirus related hospitalization to be similar, in which case the confounding effects will only result in small bias in the VE estimate from TNC studies. The results of this work, along with those of our previous paper, confirm the TNC design can be expected to provide reliable estimates of rotavirus VE in both high- and low-income countries.

Immunogenicity and lot-to-lot consistency of a ready to use liquid bovine-human reassortant pentavalent rotavirus vaccine (ROTASIIL - Liquid) in Indian infants.

BACKGROUND: A lyophilized bovine-human rotavirus reassortant pentavalent vaccine (BRV-PV, Rotasiil®) was licensed in 2016. A liquid formulation of this vaccine (LBRV-PV, Rotasiil - Liquid) was subsequently developed and was tested for non-inferiority to Rotasiil® and for lot-to-lot consistency. METHODS: This Phase II/III, open label, randomized study was conducted at seven sites across India from November 2017 to June 2018. Participants were randomized into four arms; Lots A, B, and C of LBRV-PV and Rotasiil® in 1:1:1:1 ratio. Three doses of study vaccines were given at 6, 10, and 14 weeks of age. Blood samples were collected four weeks after the third dose to assess rotavirus IgA antibody levels. Non-inferiority of LBRV-PV to Rotasiil was proven if the lower limit two-sided 95% confidence interval (CI) of geometric mean concentration (GMC) ratio was at least 0.5. Lot-to-lot consistency was proven if 95% CI of the GMC ratios of three lots were between 0.5 and 2. Solicited reactions were collected by using diary cards. RESULTS: Of the 1500 randomized infants, 1436 infants completed the study. The IgA GMC ratio of LBRV-PV to Rotasiil® was 1.19 (95% CI 0.96, 1.48). The corresponding IgA seropositivity rates were 60.41% (57.41, 63.35) and 52.75% (47.48, 57.97). The IgA GMC ratios among the three LBRV-PV lots were: Lot A versus Lot B: 1.34 (1.03, 1.75); Lot A versus Lot C: 1.22 (0.93, 1.60); and Lot B versus Lot C: 0.91 (0.69, 1.19). The 95% CIs for the GMC ratios were between 0.69 and 1.75. The incidence of solicited reactions was comparable across the four arms. Only one serious adverse event of gastroenteritis event in the Rotasiil® group was causally related. CONCLUSION: The immunological non-inferiority of LBRV-PV against Rotasiil® as well as lot-to-lot consistency of LBRV-PV was demonstrated. LBRV-PV had safety profile similar to Rotasiil®. TRIAL REGISTRATION NUMBER: Clinical Trials.Gov [NCT03474055] and Clinical Trial Registry of India [CTRI/2017/10/010104].

Rotavirus vaccine will have an impact in Asia.

Carl Kirkwood and Duncan Steele discuss the evidence supporting rotavirus vaccine deployment in Asian countries.

[Distribution of Rotavirus G Genotypes during 10 years in children with acute diarrhea of the city of La Rioja, Argentina. Implications for vaccination] / Genotipos G de rotavirus durante 10 años en niños con diarrea aguda de la ciudad de La Rioja, Argentina. Implicancias en la vacunación.

Vaccination against rotavirus in Argentina is obligatory from January 2015. From 418 stools in children with acute diarrhea were collected from 2000 to 2010 in city of La Rioja, Argentina, Rotavirus was detected. The 90 rotavirus positive stools samples (21.53%) were amplified by RT-PCR and genotyped by PCR-Mix for G1, G2, G3, G4, G9 and G8. The results show that during 2000-2003, the most frequent genotype was G1 and but since 2008, the G2, G3 and G9 genotypes in single and mixed infections were detected. In La Rioja, the vaccines could prevent dehydration in older children the year but children under one year could be vulnerable to the emergence of strains with genic aberrations due to the implementation of vaccination in our region.

La vacunación para rotavirus es obligatoria en Argentina desde enero del 2015. Los genotipos G de rotavirus circulantes previo a la vacunación no fueron estudiados en la Provincia de La Rioja. El objetivo del presente trabajo fue determinar los genotipos G de rotavirus que circulan en La Rioja en niños con diarrea desde 2000 a 2010. Se determinó la presencia de rotavirus del Grupo A por Inmunocromatografía (Biomerieux) en 418 muestras de materias fecales obtenidas en niños con diarrea aguda, hospitalizados y ambulatorios, en ciudad de La Rioja, Argentina. El 40 % de los niños estudiados provenía del interior de la provincia. Las 90 muestras positivas (21,53%) fueron amplificadas por RT-PCR y genotipificadas por Multiplex-PCR para genotipos G1, G2, G3, G4, G9 y G8. Los resultados muestran que el genotipo más frecuente de2000 a2003 fue G1 pero que desde el 2008 se detectaron los genotipos G2, G3 y G9 en infecciones simples y mixtas. Los genotipos G9 y las infecciones mixta, cuádruple y quíntuple, se presentaron en niños menores de un año de vida. Este es el primer reporte de los genotipos G de rotavirus en La Rioja. Los resultados indican que los genotipos G circulantes de rotavirus son compatibles con los que se dispone en la vacuna aunque la presencia de infecciones mixtas y Genotipo G9 en niños menores de un año sugieren una mayor vulnerabilidad de este grupo para la aparición de cepas con derivas génicas durante la implementación de la vacunación en esta Provincia

A Systematic Review of Economic Evaluation Methodologies Between Resource-Limited and Resource-Rich Countries: A Case of Rotavirus Vaccines.

BACKGROUND: For more than three decades, the number and influence of economic evaluations of healthcare interventions have been increasing and gaining attention from a policy level. However, concerns about the credibility of these studies exist, particularly in studies from low- and middle- income countries (LMICs). This analysis was performed to explore economic evaluations conducted in LMICs in terms of methodological variations, quality of reporting and evidence used for the analyses. These results were compared with those studies conducted in high-income countries (HICs). METHODS: Rotavirus vaccine was selected as a case study, as it is one of the interventions that many studies in both settings have explored. The search to identify individual studies on rotavirus vaccines was performed in March 2014 using MEDLINE and the National Health Service Economic Evaluation Database. Only full economic evaluations, comparing cost and outcomes of at least two alternatives, were included for review. Selected criteria were applied to assess methodological variation, quality of reporting and quality of evidence used. RESULTS: Eighty-five studies were included, consisting of 45 studies in HICs and 40 studies in LMICs. Seventy-five percent of the studies in LMICs were published by researchers from HICs. Compared with studies in HICs, the LMIC studies showed less methodological variety. In terms of the quality of reporting, LMICs had a high adherence to technical criteria, but HICs ultimately proved to be better. The same trend applied for the quality of evidence used. CONCLUSION: Although the quality of economic evaluations in LMICs was not as high as those from HICs, it is of an acceptable level given several limitations that exist in these settings. However, the results of this study may not reflect the fact that LMICs have developed a better research capacity in the domain of health economics, given that most of the studies were in theory led by researchers from HICs. Putting more effort into fostering the development of both research infrastructure and capacity building as well as encouraging local engagement in LMICs is thus necessary.

Leveraging the National Rotavirus Surveillance Network for Monitoring Intussusception.

OBJECTIVE: To assess feasibility of monitoring intussusception by hospitals participating in the National Rotavirus Surveillance Network. METHODS: Questionnaire-based survey in 28 hospitals. One hospital with electronic records selected for detailed data analysis. RESULTS: There was 75% response to the questionnaire. Few network hospitals were suitable for monitoring intussusception in addition to ongoing activities, but there was at least one potential sentinel hospital in each region. The hospital selected for detailed data analysis of cases of intussusception reported an incidence rate of 112 per 100,000 child years in infants. Over 90% of intussusceptions were managed without surgery. CONCLUSIONS: Selection of sentinel hospitals for intussusception surveillance is feasible and necessary, but will require training, increased awareness and referral.

Effectiveness of the live attenuated rotavirus vaccine produced by a domestic manufacturer in China studied using a population-based case-control design.

A universal rotavirus (RV) immunization program is a potentially cost-effective measure for preventing RV infection in China. However, the efficacy of the only licensed RV vaccine (Lanzhou lamb rotavirus vaccine, LLR), which is made by a domestic manufacturer, has not been proven by a properly designed clinical trial. In October 2011 to March 2012, to measure the potential protection provided by LLR, a case-control study nested in a population-based active diarrhea surveillance study of children <5 years of age was conducted in rural Zhengding county. During the study period, 308 episodes of diarrhea were identified as being caused by RV infection, resulting in an incidence rate of 48.0/1000 people/year. The predominant RV serotype was G3 (61.5%), followed by G1 (15.2%), and G9 (6.5%). Overall, a protection of 35.0% (95% confidence interval (CI), 13.0%-52.0%) was identified, and higher protection was found among moderate RV gastroenteritis cases caused by the serotype G3 (52.0% 95% CI: 2.0%-76.1%). A concurrently conducted case-control study comparing non-RV viral diarrheal cases with non-diarrheal controls in the same population found that the RV vaccine offered no protection against non-RV diarrhea. Even under a less ideal immunization schedule, the oral LLR conferred a certain level of protection against RV gastroenteritis. However, further studies are needed to understand the full characteristics of the LLR, including its efficacy when administered following the optimal regimen, the potential risk of inducing intussusception, and the direct and indirect protective effects of LLR.

A proposed framework for evaluating and comparing efficacy estimates in clinical trials of new rotavirus vaccines.

Oral rotavirus vaccines have yielded different point estimates of efficacy when tested in different populations. While population and environmental factors may account for these differences, study design characteristics should also be considered. We review the study design elements of rotavirus vaccine trials that may affect point estimates of efficacy, and propose a framework for evaluating new rotavirus vaccines.

Investigation of a regulatory agency enquiry into potential porcine circovirus type 1 contamination of the human rotavirus vaccine, Rotarix: approach and outcome.

In January 2010, porcine circovirus type 1 (PCV1) DNA was unexpectedly detected in the oral live-attenuated human rotavirus vaccine, Rotarix (GlaxoSmithKline [GSK] Vaccines) by an academic research team investigating a novel, highly sensitive analysis not routinely used for adventitious agent screening. GSK rapidly initiated an investigation to confirm the source, nature and amount of PCV1 in the vaccine manufacturing process and to assess potential clinical implications of this finding. The investigation also considered the manufacturer's inactivated poliovirus (IPV)-containing vaccines, since poliovirus vaccine strains are propagated using the same cell line as the rotavirus vaccine strain. Results confirmed the presence of PCV1 DNA and low levels of PCV1 viral particles at all stages of the Rotarix manufacturing process. PCV type 2 DNA was not detected at any stage. When tested in human cell lines, productive PCV1 infection was not observed. There was no immunological or clinical evidence of PCV1 infection in infants who had received Rotarix in clinical trials. PCV1 DNA was not detected in the IPV-containing vaccine manufacturing process beyond the purification stage. Retrospective testing confirmed the presence of PCV1 DNA in Rotarix since the initial stages of its development and in vaccine lots used in clinical studies conducted pre- and post-licensure. The acceptable safety profile observed in clinical trials of Rotarix therefore reflects exposure to PCV1 DNA. The investigation into the presence of PCV1 in Rotarix could serve as a model for risk assessment in the event of new technologies identifying adventitious agents in the manufacturing of other vaccines and biological products.

Medical records-based postmarketing safety evaluation of rare events with uncertain status.

We develop a simple statistic for comparing rates of rare adverse events between treatment groups in postmarketing safety studies where the events have uncertain status. In this setting, the statistic is asymptotically equivalent to the logrank statistic, but the limiting distribution has Poisson and binomial components instead of being Gaussian. We develop two new procedures for computing critical values: a Gaussian approximation and a parametric bootstrap. Both numerical and asymptotic properties of the procedures are studied. The test procedures are demonstrated on a postmarketing safety study of the RotaTeq vaccine. This vaccine was developed to reduce the incidence of severe diarrhea in infants.

Background paper to the recommendation for routine rotavirus vaccination of infants in Germany.

Two rotavirus (RV) vaccines were introduced to the European market in 2006. To support the decision-making process of the German Standing Committee on Vaccination ("Ständige Impfkommission", STIKO) regarding adoption of routine RV vaccination into the national vaccination schedule in Germany relevant scientific background was reviewed. According to STIKO's Standard Operating Procedures for the development of evidence-based vaccination recommendations, a set of key questions was addressed and systematic reviews were performed with a focus on the efficacy, effectiveness, impact and safety of RV vaccines. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was applied to assess the quality of available evidence. Data from 5 randomized controlled trials demonstrated a high efficacy of RV vaccines in preventing severe RV-associated gastroenteritis (91%) and hospitalization (92%) in settings comparable to Germany. Post-marketing observational studies confirmed these findings. In several countries, impact studies suggest that age groups not eligible for vaccination might also benefit from herd effects and demonstrated a decrease in the number of nosocomial RV infections after RV vaccine introduction. The vaccines were considered safe, except for a slightly increased risk of intussusception shortly after the first dose, corresponding to 1-2 additional cases per 100,000 infants vaccinated (relative risk =1.21, 95% confidence interval [CI] 0.68-2.14). RV case-fatality is extremely low in Germany. However, RV incidence among children aged <5 years is high (reported 8-14 cases per 1000 children annually), and of these almost half require hositalization. In view of the available evidence and expected benefits, STIKO recommends routine rotavirus vaccination of children under the age of 6 months with the main goal of preventing RV-associated hospitalizations in Germany, especially among infants and young children.

Adoption of rotavirus vaccine by U.S. physicians: progress and challenges.

BACKGROUND: Pentavalent rotavirus vaccine (RV5) was recommended for routine use in 2006 followed by monovalent rotavirus vaccine (RV1) in 2008. PURPOSE: To describe, among a U.S. sample of pediatricians (n=289 respondents) and family medicine physicians (n=243 respondents), (1) current practices regarding rotavirus vaccine (RV) and barriers to use with comparison to a 2007 survey and (2) knowledge of recent safety concerns regarding RV1 and their impact on its use. METHODS: A mail and Internet survey was conducted with the physicians, from November 2010 to January 2011; analyses were conducted March-September 2011. RESULTS: Response rates were 70% (289/410) for pediatricians and 61% (243/401) for family medicine physicians; routine administration of RV was reported by 95% of pediatricians and 65% of family medicine physicians (2007: 85% and 45%). Almost all barriers to use of RV had decreased compared to 2007. For pediatricians and family medicine physicians, respectively, 94% and 70% were aware of the temporary suspension of RV1 due to presence of porcine circovirus; 49% and 45%, respectively, were aware of the addition to RV1 labeling regarding a possible increased risk of intussusception. Among physicians aware of the safety issues, <5% reported stopping giving RV as a result. After reading information about porcine circovirus, 35% of pediatricians and 59% of family medicine physicians reported it had increased their own concerns about the safety of RV; and 31% and 60%, respectively, reported this regarding intussusception. CONCLUSIONS: The acceptance of RV has increased, and barriers to use have decreased. Among physicians, recent safety questions about RV1 have not affected use of RV, although they have raised safety concerns.

Vaccine discontinuation and switching following regulatory interventions in response to rotavirus vaccine contamination with porcine circovirus DNA fragments.

PURPOSE: The Food and Drug Administration temporarily suspended monovalent rotavirus vaccine (RV1) use following discovery of contamination with porcine circovirus fragments and subsequently announced similar contamination of the pentavalent rotavirus vaccine (RV5) but recommended continued use of the product. We assessed the utilization of these vaccines in relation to the announcements. METHODS: Using claims submitted to a commercial health insurer for administration of RV1 and RV5, we estimated the number of administrations of the vaccines and the extent of switching between RV1 and RV5. Procedure codes on submitted claims identified vaccine administrations among infants ≤ 1 year old through 16 June 2010. Among infants who received a first dose of vaccine before the corresponding announcement, and whose second dose was anticipated following the announcement, we estimated the number who received no second dose of rotavirus vaccine. RESULTS: There were 31 178 RV1 initiators and 514 357 RV5 initiators. We observed a 93% reduction in RV1 doses in the month following the recommended suspension of use, coupled with extensive switching to RV5 (90% of subsequent doses) and a reduction in second RV1 doses (from 35.5% incomplete to 40.9%). There was a 15% increase in number of RV5 administrations following announcement of its contamination, with little switching to RV1 but with a possible decrease in completion. CONCLUSIONS: Recommended suspension of RV1 use led to a substantial decrease in use and extensive switching to RV5. The announcement that RV5 was similarly contaminated, but without a corresponding recommendation to suspend use, had little effect on use.

Improving the performance of enteric vaccines in the developing world.

Vaccines against important enteric pathogens such as rotavirus and poliovirus have shown lower efficacy in some populations. The application of new technologies and diverse scientific disciplines are needed to realize the promise of truly universal and effective solutions to combat those and other enteric diseases.