{'fraction_non_alphanumeric': 0.029479639693292637, 'fraction_numerical': 0.028511873743765355, 'mean_word_length': 5.062274368231047, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Rotarix in Japan: Expectations and Concerns

A live-attenuated, orally-administered, monovalent, human rotavirus vaccine, Rotarix® (GlaxoSmithKline Biologicals, Rixensart, Belgium), was licensed and launched in 2011 as the first rotavirus vaccine in Japan. The rotavirus causes a substantial disease burden with an estimated 790,000 outpatient visits, 27,000–78,000 hospitalizations, and approximately 10 deaths each year in Japan. Since a recent clinical trial showed that Rotarix was as efficacious in Japan as in other industrialized countries, it is expected that the annual number of rotavirus hospitalizations will be reduced to between 1000–3000, and that outpatient visits will be reduced to 200,000. The universal rotavirus immunization program with Rotarix was calculated to be at the threshold of being cost-effective, even from the healthcare perspective, and it was highly cost-effective from the societal perspective, assuming that Rotarix is co-administered with other childhood vaccines. While Rotarix contains only a single G1P[8] human rotavirus, the postlicensure studies in Brazil showed that Rotarix provided a 75%–85% protective efficacy against severe dehydrating diarrhea or hospitalizations due to fully-heterotypic G2P[4] strains. While postlicensure studies detected a small and finite risk of intussusception associated with the administration of Rotarix, the authors conclude that Rotarix is safe to administer to infants between 6-12 weeks of age for the first dose and by 24 weeks of age for the second dose. However, the authors strongly discourage the delayed administration of the first dose between 13-20 weeks of age, which is allowed without any warning. Given the high incidence of naturally-occurring intussusception in Japan (185 cases per 100,000 children/year among children less than 1 year of age), this should prevent pediatricians and parents from having ill-perceptions of Rotarix being associated with an increased number of temporally-associated intussusception, and fully appreciate the benefit of the rotavirus vaccine.

clinical trial showed that Rotarix was as efficacious in Japan as in other industrialized countries, it is expected that the annual number of rotavirus hospitalizations will be reduced to between 1000-3000, and that outpatient visits will be reduced to 200,000. The universal rotavirus immunization program with Rotarix was calculated to be at the threshold of being cost-effective, even from the healthcare perspective, and it was highly cost-effective from the societal perspective, assuming that Rotarix is co-administered with other childhood vaccines. While Rotarix contains only a single G1P [8] human rotavirus, the postlicensure studies in Brazil showed that Rotarix provided a 75%-85% protective efficacy against severe dehydrating diarrhea or hospitalizations due to fully-heterotypic G2P [4] strains. While postlicensure studies detected a small and finite risk of intussusception associated with the administration of Rotarix, the authors conclude that Rotarix is safe to administer to infants between 6-12 weeks of age for the first dose and by 24 weeks of age for the second dose. However, the authors strongly discourage the delayed administration of the first dose between 13-20 weeks of age, which is allowed without any warning. Given the high incidence of naturally-occurring intussusception in Japan

ROTAVIRUS AND ITS SEROTYPES
Rotavirus, taxonomically a species (Rotavirus A) within genus Rotavirus, family Reoviridae, is a nonenveloped RNA virus with icosahedral symmetry. 9 The outer surface of the virion consists of viral spikes (made up of the VP4 trimers) and the outercapsid proteins (made up of the VP7 trimers). 9 Both VP4 and VP7 independently serve as a neutralization antigen, and define the protease-sensitive protein (P) type and the glycoprotein (G) type, respectively. 2,9 While serotype should, by definition, be determined by serologic assays, molecular assays have replaced serologic assays in the determination of G and P types of a rotavirus in clinical specimens; hence, referred to as the genotype. 9 While there is an exact match between G serotype and G genotype, different numbering systems were adopted to designate P serotype and P genotype, with P genotype being designated within squared brackets. Thus, the P serotype of RIX4414, the vaccine strain in Rotarix, is P1A, whereas its P genotype is P [8]. There are 27 G genotypes and 35 P genotypes described to date, 10 but the G and P type combinations detected in human rotaviruses are mostly limited to G1P [8], G2P [4], G3P [8], G4P [8], and G9P [8]. 11,12 However, previously rare G12 strains appear to have emerged across the globe [13][14][15] and G8 strains, with either P [6] or P [4], account for a significant proportion of human rotavirus strains in Africa. 16,17 Such genetic diversity appears to be generated by frequent reassortment of the genome segments and interspecies transmission of rotaviruses between humans and animals. [18][19][20][21]

PROTECTIVE IMMUNITY AFTER NATURAL INFECTION AND THE GUIDING PRINCIPLE OF ROTAVIRUS VACCINES
Complete protection against moderate-to-severe rotavirus-associated diarrhea, but not against mild diarrhea or infection itself, is obtained after asymptomatic infection in the neonatal period 22 or after two infections with rotavirus, regardless of whether the infections are symptomatic or asymptomatic. 23 In a cohort study in Mexico, 23 the adjusted efficacy in protecting against subsequent rotavirus infection was 38% after one infection, 60% after two infections, and 66% after three infections. In contrast, the efficacy against rotavirus-associated diarrhea of any severity was 77% after one infection, 83% after two infections, and 92% after three infections.
Against moderate-to-severe rotavirus-associated diarrhea, protection is greater with 87% after one infection and 100% after two or three infections.
In the same study, repeated infections with the same G type were less likely to occur, suggesting the presence of homotypic immunity. It is generally believed that, while infection with one serotype provides serotype-specific (homotypic) protection, repeated infections tend to provide broader protection that exerts over different serotypes; ie, heterotypic protection. 24

THE BURDEN OF ROTAVIRUS DIARRHEA IN JAPAN
Given that the aim of the rotavirus vaccine is to reduce the burden of rotavirus-associated diarrhea in the society, the key information is the annual number of cases of rotavirus-associated diarrhea and the associated cost. The cost needs to be viewed from both the healthcare and the societal perspectives. With regard to the annual number of cases of rotavirus-associated diarrhea, the most important is the number of rotavirus hospitalization at a national level and whether the estimated reduction of the disease burden will be cost-effective. The major difference between the cost calculated from the healthcare perspective and that calculated from the societal perspective is that the latter includes the productivity loss of care-givers of sick children. This productivity loss accounts for the vast majority of the indirect cost associated with rotavirus-associated diarrhea. 27,28 The birth cohort in Japan is approximately 1 million and the information required is the number of children who will be hospitalized due to rotavirus-associated diarrhea when the cohort is followed for 5 years. Only a few studies are available in Japan, and it was estimated that there were 790,000 outpatient visits, 29 27,000-78,000 hospitalizations, 30

Product Specifications of Rotarix
Rotarix contains a live-attenuated G1P [8] human rotavirus strain, RIX4414, that contains at least 1 million median cell culture infective dose (CCID 50 ) in 1.5 mL of calcium carbonate buffer. While a ready-to-use liquid formulation is a welcome addition, a 50% increase in volume from the formulation that requires reconstitution The WHO recommends that the first dose should be administered at age 6-15 weeks. 41 In Australia, the first dose of Rotarix is scheduled to be given to infants between 6-14 weeks of age (Figure 1). 42 In the US, the Advisory Committee on Immunization Practices (ACIP) revised its recommendation in 2009 to extend the maximum age for the first dose to be 14 weeks and 6 days, 43 but it clearly stated that vaccination should not be initiated for infants after 15 weeks and 0 days (Figure 1).
In Europe, the European Medicines Agency 44 states that both doses should preferably be administered before 16 weeks of age, meaning that the first dose is to be given to infants at Figure 1. The age period during which the first and the second dose of Rotarix are to be administered according to the package insert distributed in Japan. The first dose may start at 6 weeks of age but before 20 weeks of age, and the second dose may start at 10 weeks of age and end before 24 weeks of age. In Europe, the upper limit of the first dose is 12 weeks, while in the US and Australia it is 14 weeks. As the first dose of Rotarix is allowed to be given to infants between 13-20 weeks of age in Japan (the area highlighted in green), a concern arises that there will be an increased number of Rotarix recipients who develop intussusception by chance alone in the first week after the first dose.

Failed Administration (Regurgitation)
The Rotarix package insert states that a single replacement dose may be given at the same vaccination visit in the event that the infant spits out or regurgitates most of the vaccine dose. 35 The ACIP does not recommend re-dosing after regurgitation of any amount on the basis of the absence of data on the benefits or risks with re-dosing. 43 From a practical perspective, who should pay the cost of re-dosing may also be an issue.

Concomitant Vaccine Administration
In countries where Rotarix is given as part of Age in months Percentage of intussusception cases Figure 2. Age distribution of patients with naturallyoccurring intussusception in a sentinel hospital in northern Japan. Note that there was no case of intussusception during the first 3 months of life (0-2 months of age). Adapted from the figure published in Nakagomi T, Takahashi Y, Arisawa K, Nakagomi O. A high incidence of intussusception in Japan as studied in a sentinel hospital over a 25-year period (1978-2002). Epidemiol Infect. 2006;134:57-61. 40 tuberculosis vaccine) immunization, which is administered between 3-6 months of age. The first issue is about a persisting concern derived from the fact that Rotarix is a vaccine containing only a single human G1P [8] strain, RIX4414. The guiding principle for the development of a single-strain human rotavirus vaccine was that the induction of protective immunity does not entirely depend on neutralizing antibodies specific to either G or P serotype, but more on factors that mediate heterotypic immunity. [52][53][54][55] In a large clinical trial in Latin America, and later in Europe, Rotarix was shown to be effective in preventing severe rotavirus diarrhea caused by partially heterotypic G3P [8], G4P [8], and G9P [8] strains, as well as fully-homotypic G1P [8] strains. 56,57 Since fully-heterotypic G2P [4] strains were infrequent during these clinical trials, protective efficacy appeared less convincing, with wide 95% CIs. Soon after the introduction of Rotarix into the universal immunization schedule in Brazil, Gurgel et al. 58 and Nakagomi et al. 59 noticed a high predominance of G2P [4] strains, although there was also a simultaneous marked decrease in the detection rate of rotavirus. 59 While these studies suggested a shift in the predominantly circulating strains to G2P [4] 64 and 75% (95% CI: 57-86) in Belém. 65 These data provide strong evidence for the protective efficacy of Rotarix even against rotaviruses fully heterotypic to the vaccine strain. This has important implications because Rotarix would also be expected to provide a reasonable level of protection against fully heterotypic strains other than G2P [4]; these include G12P [6], prevalent in Nepal, 14 and G8P [6], prevalent in Malawi. 16  Secondly, since RIX4414 was originally derived from a virulent human rotavirus, natural infection with wild-type rotavirus can also cause intussusceptions; a hypothesis that the authors have previously maintained. 69,70 Reviewing these emerging data and recognizing a very small, yet finite, level of risk associated with the Rotarix vaccination, the authors conclude that Rotarix is safe to administer to infants at the globallyrecommended age period, such as between 6-12 weeks of age, when naturally occurring intussusception is rare (Figures 1 and 2). On the other hand, the authors see no reason to be bold enough to recommend the Rotarix immunization beyond 13-15 weeks of age, as is allowed according to the package insert of Rotarix in Japan 35 and promotional pamphlets. 37

Contraindications
The benefits that will be gained by expanding the immunization period for the first dose to 20 weeks of age very unlikely outweighs the risk of an increased number of intussusception cases, whose causal relationship with Rotarix will never be ruled out at the individual case level.
If one were to suppose that the attributable risk is 5%, there would be no way to tell which one of 20 patients (5%) with intussusception that occurred in the first week after the first dose was