Effectiveness of Pentavalent Rotavirus Vaccine in Shanghai, China: A Test-Negative Design Study.

OBJECTIVE: To evaluate vaccine effectiveness (VE) of a live oral pentavalent rotavirus vaccine (RotaTeq, RV5) among young children in Shanghai, China, via a test-negative design study. STUDY DESIGN: We consecutively recruited children visiting a tertiary children's hospital for acute diarrhea from November 2021 to February 2022. Information on clinical data and rotavirus vaccination was collected. Fresh fecal samples were obtained for rotavirus detection and genotyping. To evaluate VE of RV5 against rotavirus gastroenteritis among young children, unconditional logistic regression models were conducted to compare ORs for vaccination between rotavirus-positive cases and test-negative controls. RESULTS: A total of 390 eligible children with acute diarrhea were enrolled, including 45 (11.54%) rotavirus-positive cases and 345 (88.46%) test-negative controls. After excluding 4 cases (8.89%) and 55 controls (15.94%) who had received the Lanzhou lamb rotavirus vaccine, 41 cases (12.39%) and 290 controls (87.61%) were included for the evaluation of RV5 VE. After adjustment for potential confounders, the 3-dose RV5 vaccination showed 85% (95% CI, 50%-95%) VE against mild to moderate rotavirus gastroenteritis among children aged 14 weeks to ≤4 years and 97% (95% CI, 83%-100%) VE among children aged 14 weeks to ≤2 years with genotypes G8P8, G9P8, and G2P4 represented 78.95%, 18.42%, and 2.63% of circulation strains, respectively. CONCLUSIONS: A 3-dose vaccination of RV5 is highly protective against rotavirus gastroenteritis among young children in Shanghai. The G8P8 genotype prevailled in Shanghai after RV5 introduction.

Efficacy, safety and effectiveness of licensed rotavirus vaccines: a systematic review and meta-analysis for Latin America and the Caribbean.

BACKGROUND: RotaTeq™ (RV5; Merck & Co. Inc., USA) and Rotarix™ (RV1, GlaxoSmithKline, Belgium) vaccines, developed to prevent rotavirus diarrhea in children under five years old, were both introduced into national immunization programs in 2006. As many countries in Latin America and the Caribbean have included either RV5 or RV1 in their routine childhood vaccination programs, we conducted a systematic review and meta-analysis to analyze efficacy, safety and effectiveness data from the region. METHODS: We conducted a systematic search in PubMed, EMBASE, Scielo, Lilacs and the Cochrane Central Register, for controlled efficacy, safety and effectiveness studies published between January 2000 until December 2011, on RV5 and RV1 across Latin America (where both vaccines are available since 2006). The primary outcome measures were: rotavirus-related gastroenteritis of any severity; rotavirus emergency department visits and hospitalization; and severe adverse events. RESULTS: The results of the meta-analysis for efficacy show that RV1 reduced the risk of any-severity rotavirus-related gastroenteritis by 65% (relative risk (RR) 0.35, 95% confidence interval (CI) 0.25; 0.50), and of severe gastroenteritis by 82% (RR 0.18, 95%CI 0.12; 0.26) versus placebo. In trials, both vaccines significantly reduced the risk of hospitalization and emergency visits by 85% (RR 0.15, 95%CI 0.09; 0.25) for RV1 and by 90% (RR 0.099, 95%CI 0.012; 0.77) for RV5. Vaccination with RV5 or RV1 did not increase the risk of death, intussusception, or other severe adverse events which were previously associated with the first licensed rotavirus vaccine. Real-world effectiveness studies showed that both vaccines reduced rotavirus hospitalization in the region by around 45-50% for RV5 (for 1 to 3 doses, respectively), and, by around 50-80% for RV1 (for 1 to 2 doses, respectively). For RV1, effectiveness against hospitalization was highest (around 80-96%) for children vaccinated before 12 months of age, compared with 5-60% effectiveness in older children. Both vaccines were most effective in preventing more severe gastroenteritis (70% for RV5 and 80-90% for RV1) and severe gastroenteritis (50% for RV5 and 70-80% for RV1). CONCLUSION: This systematic literature review confirms rotavirus vaccination has been proven effective and well tolerated in protecting children in Latin America and the Caribbean.

Long-term Consistency in Rotavirus Vaccine Protection: RV5 and RV1 Vaccine Effectiveness in US Children, 2012-2013.

BACKGROUND: Using a multicenter, active surveillance network from 2 rotavirus seasons (2012 and 2013), we assessed the vaccine effectiveness of RV5 (RotaTeq) and RV1 (Rotarix) rotavirus vaccines in preventing rotavirus gastroenteritis hospitalizations and emergency department (ED) visits for numerous demographic and secular strata. METHODS: We enrolled children hospitalized or visiting the ED with acute gastroenteritis (AGE) for the 2012 and 2013 seasons at 7 medical institutions. Stool specimens were tested for rotavirus by enzyme immunoassay and genotyped, and rotavirus vaccination histories were compared for rotavirus-positive cases and rotavirus-negative AGE controls. We calculated the vaccine effectiveness (VE) for preventing rotavirus associated hospitalizations and ED visits for each vaccine, stratified by vaccine dose, season, clinical setting, age, predominant genotype, and ethnicity. RESULTS: RV5-specific VE analyses included 2961 subjects, 402 rotavirus cases (14%) and 2559 rotavirus-negative AGE controls. RV1-specific VE analyses included 904 subjects, 100 rotavirus cases (11%), and 804 rotavirus-negative AGE controls. Over the 2 rotavirus seasons, the VE for a complete 3-dose vaccination with RV5 was 80% (confidence interval [CI], 74%-84%), and VE for a complete 2-dose vaccination with RV1 was 80% (CI, 68%-88%).Statistically significant VE was observed for each year of life for which sufficient data allowed analysis (7 years for RV5 and 3 years for RV1). Both vaccines provided statistically significant genotype-specific protection against predominant circulating rotavirus strains. CONCLUSIONS: In this large, geographically and demographically diverse sample of US children, we observed that RV5 and RV1 rotavirus vaccines each provided a lasting and broadly heterologous protection against rotavirus gastroenteritis.

Immunogenicity of RV1 and RV5 vaccines administered in standard and interchangeable mixed schedules: a randomized, double-blind, non-inferiority clinical trial in Mexican infants.

Introduction: Rotavirus-associated diarrheal diseases significantly burden healthcare systems, particularly affecting infants under five years. Both Rotarix™ (RV1) and RotaTeq™ (RV5) vaccines have been effective but have distinct application schedules and limited interchangeability data. This study aims to provide evidence on the immunogenicity, reactogenicity, and safety of mixed RV1-RV5 schedules compared to their standard counterparts. Methods: This randomized, double-blind study evaluated the non-inferiority in terms of immunogenicity of mixed rotavirus vaccine schedules compared to standard RV1 and RV5 schedules in a cohort of 1,498 healthy infants aged 6 to 10 weeks. Participants were randomly assigned to one of seven groups receiving various combinations of RV1, and RV5. Standard RV1 and RV5 schedules served as controls of immunogenicity, reactogenicity, and safety analysis. IgA antibody levels were measured from blood samples collected before the first dose and one month after the third dose. Non-inferiority was concluded if the reduction in seroresponse rate in the mixed schemes, compared to the standard highest responding scheme, did not exceed the non-inferiority margin of -0.10. Reactogenicity traits and adverse events were monitored for 30 days after each vaccination and analyzed on the entire cohort. Results: Out of the initial cohort, 1,365 infants completed the study. Immunogenicity analysis included 1,014 infants, considering IgA antibody titers ≥20 U/mL as seropositive. Mixed vaccine schedules demonstrated non-inferiority to standard schedules, with no significant differences in immunogenic response. Safety profiles were comparable across all groups, with no increased incidence of serious adverse events or intussusception. Conclusion: The study confirms that mixed rotavirus vaccine schedules are non-inferior to standard RV1 and RV5 regimens in terms of immunogenicity and safety. This finding supports the flexibility of rotavirus vaccination strategies, particularly in contexts of vaccine shortage or logistic constraints. These results contribute to the global effort to optimize rotavirus vaccination programs for broader and more effective pediatric coverage.Clinical trial registration: ClinicalTrials.gov, NCT02193061.

Health impact of rotavirus vaccination in China.

Rotavirus (RV) vaccines have demonstrated substantial effectiveness in reducing the healthcare burden caused by gastroenteritis (RVGE) worldwide. This study aims to understand the differential impact of RV vaccination in reducing RVGE burden in children under 7 years old in China. A Markov Model was used to investigate the health impact of introducing two different RV vaccines into the Chinese population. The analysis was conducted for RV5, a live pentavalent human-bovine reassortant vaccine, and Lanzhou Lamb RV (LLR), a live-attenuated monovalent RV vaccine, separately, by comparing the strategy of each vaccine to no vaccination within a Chinese birth cohort, including 100,000 children modeled until 7 years of age. The vaccination scenario assumed a vaccination coverage of 2.5%, 2.5%, 90% and 5% for doses one, two, three and no vaccine, respectively, for both vaccines. Strategies with RV5, LLR, and no vaccination were associated with 9,895, 49,069, and 64,746 symptomatic RV infections, respectively. RV5 and LLR were associated with an 85% and 24% reduction in the total symptomatic RV infections, respectively, suggesting that the health benefits of RV5 are at least three-fold greater than those associated with the LLR. Further, strategies with RV5 and LLR resulted in an estimated 206 and 59-year increase in quality-adjusted life years (QALYs), respectively. Sensitivity and scenario analyses supported the robustness of the base-case findings. Use of RV vaccine is expected to improve RV-associated health outcomes and its adoption will help alleviate the burden of RVGE in China. RV5 use will result in significantly better health outcomes.

Evaluation of the electrocardiogram RV5 /V6 criteria in the diagnosis of left ventricular hypertrophy in marathon runners.

To assess the value of electrocardiogram (ECG) RV5/V6 criteria for diagnosing left ventricular hypertrophy (LVH) in marathons. A total of 112 marathon runners who met the requirements for "Class A1" events certified by the Chinese Athletics Association in Changzhou City were selected, and their general clinical information was collected. ECG examinations were performed using a Fukuda FX7402 Cardimax Comprehensive Electrocardiograph Automatic Analyser, whereas routine cardiac ultrasound examinations were performed using a Philips EPIQ 7C echocardiography system. Real-time 3-dimensional echocardiography (RT-3DE) was performed to acquire 3-dimensional images of the left ventricle and to calculate the left ventricular mass index (LVMI). According to the LVMI criteria of the American Society of Echocardiography for the diagnosis of LVH, the participants were divided into an LVMI normal group (n = 96) and an LVH group (n = 16). The correlation between the ECG RV5/V6 criteria and LVH in marathon runners was analysed using multiple linear regression stratified by sex and compared with the Cornell (SV3 + RaVL), modified Cornell (SD + RaVL), Sokolow-Lyon (SV1 + RV5/V6), Peguero-Lo Presti (SD + SV4), SV1, SV3, SV4, and SD criteria. In marathon runners, the ECG parameters SV3 + RaVL, SD + RaVL, SV1 + RV5/V6, SD + SV4, SV3, SD, and RV5/V6 were able to identify LVH (all p < .05). When stratified by sex, linear regression analysis revealed that a significantly higher number of ECG RV5/V6 criteria were evident in the LVH group than in the LVMI normal group (p < .05), both with no adjustment and after initial adjustment (including age and body mass index), as well as after full adjustment (including age, body mass index, interventricular septal thickness, left ventricular end-diastolic diameter, left ventricular posterior wall thickness, and history of hypertension). Additionally, curve fitting showed that the ECG RV5/V6 values increased with increasing LVMI in marathon runners, exhibiting a nearly linear positive correlation. In conclusions, the ECG RV5/V6 criteria were correlated with LVH in marathon runners.

Long-term surveillance of rotavirus vaccination after implementation of a national immunization program in Finland (2008-2018).

BACKGROUND: Rotavirus (RV) vaccination was included in the Finnish National immunization Program (NIP) in 2009. RotaTeq (RV5) has been used exclusively with a national average vaccination coverage rate (VCR) of > 90%. While previous studies have demonstrated that inpatient rotavirus gastroenteritis (RVGE) admissions declined by as much as 96% in Finnish children ≤ 5 years old following RV vaccination introduction, no study has evaluated long-term protection after vaccination in Finland. In this study, we analyze incidence of hospital outpatient visits and inpatient admissions of gastroenteritis in children up to 7 years of age. METHODS: We first describe the incidence of RVGE, viral gastroenteritis (VGE), and acute gastroenteritis (AGE) for all Finnish children born during 2008-2011. Children were stratified by the year of birth into not-eligible, partially eligible and rotavirus vaccine-eligible (born in 2008, 2009, 2010 and 2011, respectively). Hospital inpatient and outpatient data was collected from the National Care Register for all children from birth until December 31st, 2018. We also studied RVGE incidence during 2014-2017 for children<3 years of age in municipalities with VCRs of 90% and above and municipalities with VCRs below 90%. RESULTS: RVGE incidence decreased significantly soon after implementation of RV vaccination in the NIP. In vaccine-eligible cohorts, no clear peak incidence in the youngest age groups could be observed, and no RVGE cases were observed beyond 6 years after vaccination, in contrast to vaccine ineligible and partially eligible cohorts. Despite an overall high VCR in Finland, regions with high VCR had lower incidence of RVGE than regions with lower VCR. CONCLUSION: Incidence of RVGE has remained low in all age groups during the 10 years following introduction of RV vaccine in the Finnish NIP. Differences in RVGE incidence were observed in regions with high as compared with lower VCR, highlighting the importance of maintaining high vaccination coverage.

Prediction and identification of new type holin protein of Escherichia coli phage ECP26.

Bacteriophages (phages) infecting specifically target bacteria utilize a unique lysis module known as the holin-endolysin cassette to release progeny. Studies on the phage lytic proteins could contribute to the development of alternatives to antibiotics. Here, we predicted and identified the holin protein of rV5-like phage ECP26 for increasing lytic activity of the phage endolysin. In silico analysis revealed that open reading frame 151 (ORF151) of ECP26 contained two transmembrane domains. Co-expression of endolysin with ORF151 resulted in the cell lysis of Escherichia coli, suggesting that ORF151 protein functioned as the holin that disrupted the cytoplasmic membrane. The putative holin showed a high amino acid homology by more than 80% to the predicted holins of rV5-like phages. Therefore, the holin protein would be helpful for developing efficient lysis strategies with endolysin against gram-negative E. coli. Supplementary information: The online version contains supplementary material available at 10.1007/s10068-022-01089-w.

Shedding of oral pentavalent bovine-human reassortant rotavirus vaccine indicates high uptake rate of vaccine and prominence of G-type G1.

BACKGROUND: Live oral pentavalent bovine-human reassortant rotavirus (RV) vaccine, RotaTeq®, contains bovine rotaviruses reassorted with human G-types G1, G2, G3 and G4, and P-type P[8]. Shedding of RotaTeq® vaccine, as studied by RT-PCR, has been shown to be more common than initially reported, and may include formation of vaccine-derived double-reassortant G1P[8] RVs. We studied the extent and duration of RotaTeq® vaccine virus shedding, genotypes shed, and clinical symptoms associated with shedding. MATERIAL AND METHODS: We enrolled a total of 301 infants who received RotaTeq® vaccine according to Finnish schedule at 2, 3 and 5 months of age. Stool samples were collected 5-10 days after the first and 0-7 days before the third dose of the vaccine. Additional stool samples 6 and 12 weeks later were collected if the second stool sample was positive. All stools were studied with RT-PCR for RV VP7, VP4 and VP6. Parents filled a symptom diary for a week after each vaccine dose. RESULTS: We found that 93% of the vaccinees shed vaccine related viral particles in one sample taken 5-10 days after the first dose, indicating that stool shedding is very common and may be regarded as a marker of successful vaccination. Genotype G1 was the predominant genotype in shedding, often in association with P[8], and the only genotype found in long-term shedding. Also G4 was commonly detected whereas other vaccine G-types and bovine-type P[5] were not. CONCLUSIONS: Shedding of RotaTeq® vaccine-derived viruses is a sign for successful vaccination. Intense shedding of G1 with or without P[8]reflects effective multiplication and may be an important factor in the induction of protective immunity. Shedding of G1 containing vaccine viruses may be prolonged up to 8 months of age. These results suggest that the pentavalent vaccine functions largely like a monovalent G1 vaccine. Eudra-CT: 2014-004252-60.

Characterization of Endolysin LysECP26 Derived from rV5-like Phage vB_EcoM-ECP26 for Inactivation of Escherichia coli O157:H7.

With an increase in the consumption of non-heated fresh food, foodborne shiga toxin-producing Escherichia coli (STEC) has emerged as one of the most problematic pathogens worldwide. Endolysin, a bacteriophage-derived lysis protein, is able to lyse the target bacteria without any special resistance, and thus has been garnering interest as a powerful antimicrobial agent. In this study, rV5-like phage endolysin targeting E. coli O157:H7, named as LysECP26, was identified and purified. This endolysin had a lysozyme-like catalytic domain, but differed markedly from the sequence of lambda phage endolysin. LysECP26 exhibited strong activity with a broad lytic spectrum against various gram-negative strains (29/29) and was relatively stable at a broad temperature range (4°C- 55°C). The optimum temperature and pH ranges of LysECP26 were identified at 37°C-42°C and pH 7- 8, respectively. NaCl supplementation did not affect the lytic activity. Although LysECP26 was limited in that it could not pass the outer membrane, E. coli O157: H7 could be effectively controlled by adding ethylenediaminetetraacetic acid (EDTA) and citric acid (1.44 and 1.14 log CFU/ml) within 30 min. Therefore, LysECP26 may serv as an effective biocontrol agent for gram-negative pathogens, including E. coli O157:H7.

Identification and characterization of new broad host-range rV5-like coliphages C203 and P206 directed against enterobacteria.

We isolated and characterized two novel rV5-like lytic bacteriophages from independently collected food samples. Nucleotide sequence analysis revealed that these phages have linear double-stranded DNA genomes comprising 138,073 bp with 213 CDS and 5 tRNA genes. The two genomes contain completely identical nucleotide sequence, albeit there is a 10,718 bp-long shift in the sequence. The GC content of the phage genomes was 43.7% and they showed high general homology to rV5-like phages. The new phages were termed C203 and P206. The genome of both phages contains a unique ORF that encodes for a putative phage homing endonuclease. The phage produced clear plaques with a burst size of approx. 1000 viral particles and a latent period of 60 min. Morphological investigation indicated that the new phages are members of the family Myoviridae with an approximate head length of 85 nm, tail length of 75 nm, and a head width of 96 nm. C203 and P206 exhibit a broad and uniform host range, which included enterohemorrhagic Escherichia coli strains of serogroup O157, multi drug resistant (MDR) E. coli strains of various sero- and pathotypes, and both Shigella sonnei and S. dysenteriae strains. C203 and P206 both effectively reduced the number of living EHEC O157:H7 Sakai in experimentally inoculated minced meat. The same broad host range, the lack of any virulence related genes, the stability and its short latent period suggest that these newly found phages could be suitable candidates as a bio-control agents against food-borne pathogenic Enterobacteria.

Concomitant administration of diphtheria, tetanus, acellular pertussis and inactivated poliovirus vaccine derived from Sabin strains (DTaP-sIPV) with pentavalent rotavirus vaccine in Japanese infants.

Rotavirus is the leading cause of severe acute gastroenteritis in infants and young children. Most children are infected with rotavirus, and the health and economic burdens of rotavirus gastroenteritis on healthcare systems and families are considerable. In 2012 pentavalent rotavirus vaccine (RV5) and diphtheria, tetanus, acellular pertussis and inactivated poliovirus vaccine derived from Sabin strains (DTaP-sIPV) were licensed in Japan. We examined the immunogenicity and safety of DTaP-sIPV when administrated concomitantly with RV5 in Japanese infants. A total of 192 infants 6 to 11 weeks of age randomized to Group 1 (N = 96) received DTaP-sIPV and RV5 concomitantly, and Group 2 (N = 96) received DTaP-sIPV and RV5 separately. Antibody titer to diphtheria toxin, pertussis antigens (PT and FHA), tetanus toxin, and poliovirus type 1, 2, and 3 were measured at 4 to 6 weeks following 3-doses of DTaP-sIPV. Seroprotection rates for all components of DTaP-sIPV were 100% in both groups, and the geometric mean titers for DTaP-sIPV in Group 1 were comparable to Group 2. Incidence of systemic AEs (including diarrhea, vomiting, fever, and nasopharyngitis) were lower in Group 1 than in Group 2. All vaccine-related AEs were mild or moderate in intensity. There were no vaccine-related serious AEs, no deaths, and no cases of intussusception during the study. Concomitant administration of DTaP-sIPV and RV5 induced satisfactory immune responses to DTaP-sIPV and acceptable safety profile. The administration of DTaP-sIPV given concomitantly with RV5 is expected to facilitate compliance with the vaccination schedule and improve vaccine coverage in Japanese infants.

Postdose 3 G1 serum neutralizing antibody as correlate of protection for pentavalent rotavirus vaccine.

Although clinical trials of the pentavalent rotavirus vaccine (RotaTeq®, RV5) have demonstrated efficacy against RV gastroenteritis (RGE) in low and high-income settings, a clear correlate of protection or a measure of immune response that could predict efficacy has yet to be identified. This is the first time that immunogenicity data with both serum neutralized antibody (SNA) titers and anti-RV IgA titers from several clinical efficacy trials were pooled to provide a unique context for evaluating the correlation between immunogenicity and RGE risk or efficacy of RV5. The correlation between immunogenicity and RGE risk is evaluated with data at the individual subject level. The analyses show that higher Postdose 3 (PD3) G1 SNA titers are associated with lower odds of contracting any RGE. The correlation between immunogenicity and efficacy is assessed using aggregated population level data, which shows higher efficacy associated with higher PD3 G1 SNA geometric mean titer (GMT) ratio (between RV5 and placebo) and PD3 serum anti-RV IgA GMT ratio. Among high-income countries, efficacy plateaus over the range of PD3 G1 SNA GMT ratios and PD3 serum anti-RV IgA GMT ratios. From both individual- and population-level analyses, PD3 G1 SNA titers correlated most closely with the RGE risk or efficacy for RV5.

Intussusception following rotavirus vaccination in the Valencia Region, Spain.

Studies have shown high intussusception rates in Spain. We performed a hospital-based retrospective observational study of the intussusception risk following rotavirus vaccinations among infants in Valencia, a region of Spain with an annual birth cohort of approximately 48,000 children, during 2007-2011, using a self-controlled case series design. We performed medical record review of all cases using Brighton Collaboration's case definition and assessed the positive predictive value (PPV) of the intussusception diagnosis code. Among 151 hospitalized cases discharged as intussusception, we confirmed 136 as Brighton Collaboration's Levels 1 or 2, resulting in a PPV of 93% (95% CI: 87%-96%). Three confirmed cases occurred within days 1-7 following the first rotavirus vaccination. The incidence rate ratio was 9.0 (95% CI: 0.9-86.5) (crude) and 4.7 (95% CI:0.3-74.1)(age adjusted). In this first study in Europe, the intussusception risk point estimate was comparable to other studies, although results were not statistically significant, maybe due to limited power. The high PPV found will facilitate implementation of a larger study without requiring medical record review. Our finding of very few vaccinated cases despite a thorough 5-year investigation in a country that, according to previous studies, may have a large background rate of intussusception is reassuring and should contribute to deliberations about the need to include rotavirus vaccines in the official Spanish calendars.

Safety and immunogenicity of pentavalent rotavirus vaccine in a randomized, double-blind, placebo-controlled study in healthy elderly subjects.

Rotavirus may be an important causative agent of acute gastroenteritis (AGE) in the elderly, a population that is particularly vulnerable due to waning immunity. It is estimated that rotavirus may account for 2-5% of adult gastroenteritis hospitalizations in the United States. This is the first study to assess the safety and immunogenicity of the live pentavalent rotavirus vaccine (RV5) in an elderly population. In this study, healthy, independently living adults aged 65-80 years were randomized in a 2:1 ratio to receive three 2-mL oral doses of RV5 or placebo administered 28-42 days apart. All subjects were followed for safety for 42 days post any vaccination and up to 180 days after the final vaccination for clinical adverse events. Immunogenicity of RV5 was measured by serum anti-rotavirus IgA enzyme immunoassay and serum neutralizing antibody responses to human rotavirus serotypes prior to and after each dose. Results of this study demonstrated that RV5 was generally safe and well tolerated in healthy elderly adults, where 9% of placebo and 27% of RV5 recipients experienced a vaccine-related adverse event of mild or moderate intensity. Immune responses (serum anti-rotavirus immunoglobulin A [IgA] and serum neutralizing antibodies against human rotavirus serotypes in the vaccine) were augmented in this population after a single dose of RV5, despite the factors of older age and preexisting antibodies to the virus. Therefore, if vaccination in the elderly is needed, further evaluation of RV5 as a candidate vaccine in this age group may be warranted.

Analysis by rotavirus gene 6 reverse transcriptase-polymerase chain reaction assay of rotavirus-positive gastroenteritis cases observed during the vaccination phase of the Rotavirus Efficacy and Safety Trial (REST).

During the vaccination phase of the Rotavirus Efficacy and Safety Trial (REST), the period between the administration of dose 1 through 13 days after the administration of dose 3, there were more wild-type rotavirus gastroenteritis (RVGE) cases among vaccine recipients compared with placebo recipients using the protocol-specified microbiological plaque assay in the clinical-efficacy cohort, a subset of subjects where vaccine efficacy against RVGE of any severity was assessed. In this study, a rotavirus genome segment 6-based reverse transcriptase-polymerase chain reaction assay was applied post hoc to clarify the accuracy of type categorization of all these RVGE cases in vaccine recipients during the vaccination phase of REST. The assay characterized 147 (90%) of 163 re-assayed RVGE cases or rotavirus-associated health care contacts as type-determinable: either wild-type or vaccine-type rotavirus strains. In the clinical-efficacy cohort (N = 5673), 19 (18.8%) of 101 samples from RVGE cases contained wild-type rotavirus, 70 (69.3%) vaccine virus, and 12 (11.9%) were indeterminable. In the large-scale cohort (N = 68,038), 10 (34.5%) of 29 samples from RVGE-related health care contacts contained wild-type rotavirus strains, 15 (51.7%) vaccine-type rotavirus strains, and 4 (13.8%) were indeterminable. Of the 33 samples from RVGE cases in placebo recipients, all were confirmed to contain wild-type rotaviruses. Altogether, this post-hoc re-evaluation showed that the majority (75%) of type-determinable RVGE cases or health care contacts that occurred during the vaccination phase of REST in vaccine recipients were associated with vaccine-type rotavirus strains rather than wild-type rotavirus strains.

Correlates of protection for rotavirus vaccines: Possible alternative trial endpoints, opportunities, and challenges.

Rotavirus (RV) is a major vaccine-preventable killer of young children worldwide. Two RV vaccines are globally commercially available and other vaccines are in different stages of development. Due to the absence of a suitable correlate of protection (CoP), all RV vaccine efficacy trials have had clinical endpoints. These trials represent an important challenge since RV vaccines have to be introduced in many different settings, placebo-controlled studies are unethical due to the availability of licensed vaccines, and comparator assessments for new vaccines with clinical endpoints are very large, complex, and expensive to conduct. A CoP as a surrogate endpoint would allow predictions of vaccine efficacy for new RV vaccines and enable a regulatory pathway, contributing to the more rapid development of new RV vaccines. The goal of this review is to summarize experiences from RV natural infection and vaccine studies to evaluate potential CoP for use as surrogate endpoints for assessment of new RV vaccines, and to explore challenges and opportunities in the field.

Efficacy and safety of pentavalent rotavirus vaccine in Japan: a randomized, double-blind, placebo-controlled, multicenter trial.

Rotavirus is the most common cause of severe gastroenteritis in children under 5 y of age. Estimates of disease burden in Japan suggest that between 26,500 and 78,000 children in this age group need hospitalization each year, resulting in a direct medical cost of 10 to 24 billion Yen. Since being introduced in routine infant immunization schedules in the United States in 2006, the oral live pentavalent rotavirus vaccine RV5 (RotaTeq™) has contributed to dramatic reductions in the incidence of rotavirus gastroenteritis (RVGE) and in health care resource utilization. This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of a 3-dose regimen of RV5 in healthy infants, age 6 to 12 weeks, at 32 sites across Japan. The results indicate that RV5 was significantly efficacious in preventing any severity [74.5% (95% confidence interval [CI]: 39.9%, 90.6%; p<0.001)], moderate-to-severe [80.2% (95% CI: 47.4%, 94.1%)], and severe [100% (95% CI: 55.4%, 100%)] RVGE caused by viruses with serotypes contained in the vaccine. The observed cases of RVGE included rotavirus types G1 (n=19), G3 (n=9), G9 (n=5) and one unspecified G serotype with P1A[8]. No G2 or G4 RVGE cases were observed, and this study was not powered to evaluate efficacy against individual serotypes. RV5 was generally safe and well tolerated in Japanese infants. These results are comparable to those observed in clinical studies conducted in other developed countries. Introduction of the vaccine in Japan may reduce disease burden and associated health care costs.

Effectiveness of vaccination with the pentavalent rotavirus vaccine in Nicaragua as determined using the screening method.

The screening method is a surveillance tool to evaluate vaccine effectiveness (VE) using coverage data on cases and available administrative estimates of vaccine coverage in the population. The aim of this analysis was to evaluate the utility and limitations of using the screening methodology to estimate VE, particularly in a developing world country with a high coverage rate, and to compare it with the VE estimates from 2 case-control studies. Using data from 2008, the screening method employed in this study estimated that VE for 3 doses of RV5 among children<12 mo of age to prevent wild-type severe disease, resulting in hospitalization or emergency department visits, was 92% (95% confidence interval [CI]: 78-100%). Additional sensitivity analysis demonstrated that the point estimates of VE against severe disease ranged from 72% (95% CI: 62-83%) to 92% (95% CI: 78-100%); this range of VE estimates, although wide, is relatively consistent with results reported from 2 case-control studies in Nicaragua for the same time period. When the infrastructure is in place to collect reasonably robust case data, the use of the screening method to estimate VE is possible in the developing world setting. Cases of severe wild-type rotavirus gastroenteritis were obtained through an observational, hospital-based, prospective, surveillance program to assess rotavirus acute gastroenteritis. The proportion of cases vaccinated was estimated using the child's vaccination card or health record. The proportion of the population vaccinated was estimated using administrative population-based vaccination coverage estimates provided by the Nicaraguan Ministry of Health.