E. Anthony S. Nelson

Systematic review of regional and temporal trends in global rotavirus strain diversity in the pre rotavirus vaccine era: insights for understanding the impact of rotavirus vaccination programs.

Recently, two rotavirus vaccines have been recommended for routine immunization of infants worldwide. These vaccines proved efficacious during clinical trials and field use in both developing and developed countries, and appear to provide good protection against a range of rotavirus genotypes, including some that are not included in the vaccines. However, since conclusive data that the vaccines will protect against a wide variety of rotavirus strains are still lacking and since vaccines may exert some selection pressure, a detailed picture of global strain prevalence from the pre-rotavirus vaccine era is important to evaluate any potential changes in circulating strains observed after widespread introduction of rotavirus vaccines. Thus, we systematically reviewed rotavirus genotyping studies spanning a 12-year period from 1996 to 2007. In total, ~110,000 strains were genotyped from 100 reporting countries. Five genotypes (G1-G4, and G9) accounted for 88% of all strains, although extensive geographic and temporal differences were observed. For example, the prevalence of G1 strains declined from 2000 onward, while G3 strains re-emerged, and G9 and G12 strains emerged during the same period. When crude strain prevalence data were weighted by region based on the regions contribution to global rotavirus mortality, the importance of genotypes G1 and G9 strains that were more prevalent in regions with low mortality was reduced and conversely the importance of G8 strains that were more prevalent in African settings with greater contribution to global rotavirus mortality was increased. This study provides the most comprehensive, up-to-date information on rotavirus strain surveillance in the pre-rotavirus vaccine era and will provide useful background to examine the impact of rotavirus vaccine introduction on future strain prevalence.

Rapid emergence and predominance of a broadly recognizing and fast-evolving norovirus GII.17 variant in late 2014.

Norovirus genogroup II genotype 4 (GII.4) has been the predominant cause of viral gastroenteritis since 1996. Here we show that during the winter of 2014–2015, an emergent variant of a previously rare norovirus GII.17 genotype, Kawasaki 2014, predominated in Hong Kong and outcompeted contemporary GII.4 Sydney 2012 in hospitalized cases. GII.17 cases were significantly older than GII.4 cases. Root-to-tip and Bayesian BEAST analyses estimate GII.17 viral protein 1 (VP1) evolves one order of magnitude faster than GII.4 VP1. Residue substitutions and insertion occur in four of five inferred antigenic epitopes, suggesting immune evasion. Sequential GII.4-GII.17 infections are noted, implicating a lack of cross-protection. Virus bound to saliva of secretor histo-blood groups A, B and O, indicating broad susceptibility. This fast-evolving, broadly recognizing and probably immune-escaped emergent GII.17 variant causes severe gastroenteritis and hospitalization across all age groups, including populations who were previously less vulnerable to GII.4 variants; therefore, the global spread of GII.17 Kawasaki 2014 needs to be monitored.

Reliability of pubertal self‐assessment in Hong Kong Chinese children

Aim:  To validate a Tanner stages self‐assessment questionnaire using gender‐specific line drawings and brief explanatory text in Chinese.

Estimates of Rotavirus Disease Burden in Hong Kong: Hospital-Based Surveillance

BACKGROUND We conducted prospective, hospital-based surveillance for rotavirus disease for a 2-year period at 4 of 12 public government (Hospital Authority [HA]) hospitals in Hong Kong. It has been estimated that HA hospitals provide 90% of inpatient care in Hong Kong. METHODS Information was collected for children <5 years old who had a primary or secondary diagnosis of diarrhea or for whom a stool sample was tested for the presence of rotavirus (by enzyme immunoassay) or bacteria (by culture). Surveillance data were compared with routine discharge information from the HAs computerized Clinical Management System (CMS). RESULTS During a 2-year period (1 April 2001 through 31 March 2003), 7391 children were admitted to the hospital with diarrhea or developed diarrhea during their hospital stay. Of these children, 5881 (80%) had a stool sample tested for the presence of rotavirus, and 30% were positive for rotavirus (representing 24% of all diarrhea-associated admissions). CMS data underreported the total percentage of diarrhea-associated admissions (15% vs. 20%) and the percentage of diarrhea-associated admissions that were the result of rotavirus infection (13% vs. 24%). Estimated rates of hospitalization for rotavirus infection (8.8 admissions/1000 children <5 years old and 18.4 admissions/1000 children <1 year old) were 4-fold higher than our previous estimates, which were determined on the basis of CMS data alone. We estimate that the cumulative risk of hospitalization with rotavirus diarrhea by age 5 years is 1 in 24. Combined active and passive (CMS) surveillance data indicate that 4.6% of all general pediatric admissions to HA hospitals in Hong Kong were associated with rotavirus infection. CONCLUSION Our study combined passive surveillance data from all Hong Kong HA hospitals with active surveillance data from 4 sentinel hospitals. The estimates of rotavirus disease burden obtained will help emphasize the effect of this important disease and create awareness of the potential for rotavirus vaccines. The surveillance model developed could also be a powerful tool for monitoring the effect of a vaccine.

Diagnosis, management, and prevention of rotavirus gastroenteritis in children

#### Summary points Rotavirus is the leading cause of severe childhood gastroenteritis. Each year, rotavirus is responsible for about 25 million clinic visits, two million hospital admissions, and 180 000-450 000 deaths in children under 5 years of age globally.1 2 3 Although rotavirus infection is prevalent worldwide, most deaths from this infection occur in developing countries (fig 1⇓). Gastroenteritis caused by rotavirus cannot be clinically distinguished from that caused by other enteric pathogens; diagnosis requires testing of fecal specimens with commercially available assays. However, rotavirus is not routinely tested for in patients with gastroenteritis because the results do not alter clinical management, which relies mainly on appropriate rehydration therapy. Orally administered live attenuated vaccines that mimic natural infection offer the best protection against rotavirus. Two licensed rotavirus vaccines have been available since 2006 and have been implemented in many countries. We review approaches to diagnosis, management, and prevention of rotavirus gastroenteritis. #### Sources and selection criteria We looked at recent conference proceedings and searched PubMed, the Cochrane Database of Systematic Reviews, and Clinical Evidence online using the terms “rotavirus”, “rotavirus gastroenteritis”, and “rotavirus vaccines”. We focused on …

Hospital-Based Study of the Economic Burden Associated with Rotavirus Diarrhea in Hong Kong

BACKGROUND Rotavirus infection is the most common cause of severe diarrhea in both developed and developing countries. METHODS To estimate the economic burden associated with rotavirus infection in Hong Kong, we combined data on the disease burden of rotavirus-associated hospital admissions with detailed cost data for a subsample of 471 children with diarrhea admitted to hospitals. RESULTS The annual total social cost and total direct medical cost for rotavirus-associated admissions were calculated as 4.3 US dollars and 4 million US dollars, respectively, by use of data collected during March 2001 to March 2003. The estimate of the direct medical costs was approximately 4-fold higher than a previous estimate; this difference largely reflects the greater disease burden identified through active disease surveillance conducted under the auspices of the Asian Rotavirus Surveillance Network. On average, families spent 120 US dollars when their childs admission was associated with rotavirus infection; this cost represents approximately 10% of the monthly salary of an unskilled or service worker. CONCLUSIONS These data emphasize the potential for a safe and effective rotavirus vaccine to reduce the economic burden associated with rotavirus disease.

Co-dominance of G1 and emerging G3 rotaviruses in Hong Kong: A three-year surveillance in three major hospitals

BACKGROUND The World Health Organization recommends rotavirus vaccines be included in all national immunization programs as part of a strategy to control diarrhoeal diseases. Sentinel surveillance is advised to monitor impact post-vaccine introduction and to document changes in genotype distribution. OBJECTIVES To determine the molecular epidemiology of circulating rotaviruses in Hong Kong prior to implementation of universal rotavirus vaccination. STUDY DESIGN From December 2004 through December 2007, 830 rotavirus-positive stool samples from subjects admitted for acute diarrhea to three major hospitals in Hong Kong were examined. The electropherotypes, and the G and P genotypes of these rotaviruses were determined. Phylogenetic analysis of the VP7 gene was performed. RESULTS G3P[8] was the dominant genotype (46.1%), followed by G1P[8] (36.5%) and G9P[8] (9.2%). A total of 35 electropherotypes were identified. The G3 and G1 strains had high sequence similarities among themselves and were clustered with strains from Asia particularly mainland China. The G9 strains were clustered with the globally spreading strains. G12 and G4 were not found. The prevalence of rotavirus infection peaked in winter season when temperature was low, atmospheric pressure was high, relative humidity was low and rainfall was negligible. CONCLUSIONS Genotype G3 and G1 were the dominant rotaviruses circulating in Hong Kong between 2004 and 2007. Strains were mainly related with those from mainland China. Ongoing surveillance of circulating genotypes should continue in anticipation of universal rotavirus vaccine introduction.

Informing decision makers: Experience and process of 15 National Immunization Technical Advisory Groups

This supplement of Vaccine contains detailed descriptions of the experiences and processes of 15 well-established National Immunization Technical Advisory Committees from all regions of the world. All of these committees provide information to national governments that is used to make evidence-based decisions regarding vaccine and immunization policy. Nevertheless, many differences between committees exist including their legal basis, size and scope of committee membership, scope of work, role of the Ministry of Health on the committee, existence of conflict of interest policies, and ultimate role in the decision-making process. Individual country authors identified numerous areas for improvement and these are summarized here.

A pilot randomized study to assess immunogenicity, reactogenicity, safety and tolerability of two human papillomavirus vaccines administered intramuscularly and intradermally to females aged 18-26 years.

Intradermal administration of human papillomavirus (HPV) vaccines could be dose-sparing and cost-saving. This pilot randomized study assessed Cervarix(®) and Gardasil(®) administered either intramuscularly or intradermally, in different doses (full-dose or reduced to 20%) by different methods (needle and syringe or PharmaJet needle-free jet injection device). Following an initial reactogenicity study of 10 male subjects, sexually naïve women aged 18-26 years were randomized to the eight study groups to receive vaccine at 0, 2 and 6 months. 42 female subjects were enrolled and complete data were available for 40 subjects. Intradermal administration of either vaccine raised no safety concerns but was more reactogenic than intramuscular administration, although still tolerable. All subjects demonstrated a seroconversion (titre≥1:320) by Day 95. Further evaluation of intradermal HPV vaccination and its potential for cost reduction in resource poor settings is warranted.

Levels of PCDDs, PCDFs, and dioxin-like PCBs in human milk among Hong Kong mothers

Dioxins are a family of persistent organic pollutants (POPs) listed under the Stockholm Convention, and include PCDDs, PCDFs, and dioxin-like PCBs. These toxic chemicals are carcinogenic, widely dispersed, and have long half-lives. They have contaminated the food web and, being fat-soluble, accumulate in adipose tissues and milk in the human body. To assess human exposure, we collected breast milk samples from 137 first-time mothers recruited from around Hong Kong. Samples were analysed by HRGC-HRMS in four pools, according to the subjects age and length of residency. Exposure was related to age, duration of stay, and possibly diet. Generally, older mothers, and mothers with a longer stay in Hong Kong, had higher levels of dioxins in their milk. This pattern was clearest for the PCBs, although deviations were observed for some of the PCDD/Fs. Mean concentrations, measured per gram of lipid weight in terms of WHO toxic equivalents (WHO-TEQs), were 7.48 pg/g for PCDD/Fs and 3.79 pg/g for PCBs, giving a total of 11.27 pg/g for PCDD/Fs and PCBs combined. Compared to an earlier Hong Kong study we conducted in 2002, the mean WHO-TEQ values in our latest findings were about 9% lower overall for PCDD/Fs and 19% lower for PCBs, with the mean total WHO-TEQ for PCDD/Fs and PCBs being around 13% lower in this study. This indicates a general declining trend in the levels of POPs in Hong Kong. However, our levels were still high when compared to those in some other Asian-Pacific countries. More stringent policies on reducing and eliminating POPs should help to lower these. Continued surveillance for POPs in human milk, as well as in common foodstuffs, will provide us with important information on human exposures that will be necessary for tracking our progress, and making future health risk assessments.