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      Hepatitis A Virus Genotype Distribution during a Decade of Universal Vaccination of Preadolescents

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          Abstract

          A universal vaccination program among preadolescents was implemented in Catalonia, Spain, during the period of 1999–2013 and its effectiveness has been clearly demonstrated by an overall significant attack rate reduction. However, reductions were not constant over time, and increases were again observed in 2002–2009 due to the occurrence of huge outbreaks. In the following years, in the absence of large outbreaks, the attack rate decreased again to very low levels. However, an increase of symptomatic cases in the <5 age group has recently been observed. This is an unexpected observation since children younger than 6 are mostly asymptomatic. Such a long vaccination campaign offers the opportunity to analyze not only the effectiveness of vaccination, but also the influence of the circulating genotypes on the incidence of hepatitis A among the different age groups. This study has revealed the emergence of genotype IC during a foodborne outbreak, the short-lived circulation of vaccine-escape variants isolated during an outbreak among the men-having-sex-with-men group, and the association of genotype IIIA with the increase of symptomatic cases among the very young. From a public health perspective, two conclusions may be drawn: vaccination is better at an early age, and the vaccination schedule must be complete and include all recommended vaccine doses.

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          Most cited references31

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          Genetic relatedness of hepatitis A virus strains recovered from different geographical regions.

          A pairwise comparison of the nucleic acid sequence of 168 bases from 152 wild-type or unique cell culture-adapted strains of hepatitis A virus (HAV) revealed that HAV strains can be differentiated genetically into seven unique genotypes (I to VII). In general, the nucleotide sequence of viruses in different genotypes differs at 15 to 25% of positions within this segment of the genome. Viruses from four of the genotypes (I, II, III and VII) were recovered from cases of hepatitis A in humans, whereas viruses from the other three genotypes (IV, V and VI) were isolated only from simian species developing a hepatitis A-like illness during captivity. Among non-epidemiologically related human HAV strains, 81 were characterized as genotype I, and 19 as genotype III. Within each of these major genotypes, there were two distinct groups (subgenotypes), which differed in sequence at approximately 7.5% of base positions. Each genotype and subgenotype has a characteristic amino acid sequence in this region of the polyprotein, with the most divergent genotypes differing at 10 of 56 residues. Strains recovered from some geographical regions belonged to a common (endemic) genotype, whereas strains from other regions belonged to several, probably imported, genotypes. Thus, HAV strains recovered in North America were for the most part closely related at the nucleotide sequence level, whereas in other regions, such as Japan and Western Europe, HAV strains were derived from multiple genotypes or sub-genotypes. These data indicate that patterns of endemic transmission can be differentiated from situations in which infections are imported due to travel.
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            Risk assessment in shellfish-borne outbreaks of hepatitis A.

            In the present work, we aimed at determining the relationship between the hepatitis A virus (HAV) numbers in imported frozen coquina clams involved in two hepatitis outbreaks, as well as the risk for human health. Due to HAV unculturability, a standardized TaqMan real-time reverse transcription-PCR controlling the virus/nucleic acid extraction and enzyme efficiencies was employed to figure the exposure dose for clams responsible for hepatitis cases. HAV numbers were then employed to figure the risk of infection based on a dose-response model for echovirus 12. The estimated risk of infection after consumption of lightly cooked clams matched actual attack rates. Our data show that prospective monitoring of bivalve samples may fail to prevent the occurrence of outbreaks, since HAV was detected in 44% of samples directly associated with cases but was undetectable in samples that were randomly collected from the importers and belonged to the same batches. A correlation was nevertheless observed between the prevalence of hepatitis A cases in the harvesting areas and positive HAV isolation in clams, which points to the need to identify and prevent hazards rather than relying on random sampling of finished products to ensure safety. However, when evidence shows that a critical limit of viral contamination has been exceeded in the potential sources of contamination discharging into the shellfish-growing beds, quantitative virological analysis addressing quality assurance and quality control requirements should be performed with the bivalves. This work provides the first evidence of accurate HAV levels in shellfish involved in outbreaks that could be of use for risk assessment purposes.
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              Incidence of hepatitis A in the United States in the era of vaccination.

              In the United States, hepatitis A is a frequently reported vaccine-preventable disease. Vaccination has been recommended for persons at increased risk since 1996. In 1999, it was recommended that children living in 11 states with the highest incidence of hepatitis A be routinely vaccinated, and that children living in 6 additional states, with incidence above the national average, be considered for routine vaccination. To assess impact of the current vaccination strategy by evaluating trends in reported cases of hepatitis A since implementation. DESIGN, SETTING, AND CASES: A longitudinal analysis of characteristics of cases of hepatitis A reported in the United States since 1990 to the National Notifiable Diseases Surveillance System. Incidence rates of reported cases of hepatitis A. Incidence rates in 2003 were compared with those for the prevaccination baseline period (1990-1997) overall and in the 17 states in which children should be routinely vaccinated or considered for routine vaccination (vaccinating states). Incidence rates in vaccinating states were also compared with those in the remaining states where there is no recommendation for statewide vaccination of children (nonvaccinating states). Between the baseline period (1990-1997) and 2003, overall hepatitis A rates declined 76% to 2.6 per 100,000, significantly lower than previous nadirs in 1983 (9.2/100,000) and 1992 (9.1/ 100,000). The rate in vaccinating states declined 88% to 2.5 per 100,000 compared with 53% elsewhere (to 2.7/100 000). In 2003, cases from vaccinating states accounted for 33% of the national total vs 65% during the baseline period. Declines were greater among children aged 2 to 18 years (87%) than among persons older than age 18 years (69%); the proportion of cases in children dropped from 35% to 19%. Since 2001, rates in adults have been higher than among children, with the highest rates now among men aged 25 through 39 years. Following implementation of routine hepatitis A vaccination of children, hepatitis A rates have declined to historic lows, accompanied by substantial changes in the epidemiologic profile. Greater decreases in the age groups and regions where routine vaccination of children is recommended likely reflect the results of implementation of this novel vaccination strategy. Continued monitoring is needed to verify that implementation continues to proceed and that low rates are sustained.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                25 March 2015
                April 2015
                : 16
                : 4
                : 6842-6854
                Affiliations
                [1 ]Enteric Virus Laboratory, Department of Microbiology and Institute of Nutrition and Food Safety, University of Barcelona, Diagonal 643, 08028 Barcelona, Spain; E-Mails: luciadandrea@ 123456ub.edu (L.D.); fjperez@ 123456ub.edu (F.J.P.-R.); mdecastellarnau@ 123456ub.edu (M.C.); susanaguix@ 123456ub.edu (S.G.); abosch@ 123456ub.edu (A.B.)
                [2 ]Public Health Agency of Barcelona, Plaça Lesseps 1, 08023 Barcelona, Spain; E-Mail: smanzana@ 123456aspb.cat
                [3 ]Microbiology Unit, CatLab, 08232 Viladecavalls, Spain; E-Mail: jlite@ 123456catlab.cat
                Author notes
                [†]

                These authors contributed equally to this work.

                [* ] Author to whom correspondence should be addressed; E-Mail: rpinto@ 123456ub.edu ; Tel.: +34-93-4034-621; Fax: +34-93-4034-629.
                Article
                ijms-16-06842
                10.3390/ijms16046842
                4424991
                25815599
                cf1d72e5-9d2a-462d-9b61-73ee3a98883d
                © 2015 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 02 February 2015
                : 23 March 2015
                Categories
                Article

                Molecular biology
                hepatitis a,hav genotypes,age-group,children,msm,vaccine-escape variants,vaccination
                Molecular biology
                hepatitis a, hav genotypes, age-group, children, msm, vaccine-escape variants, vaccination

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