Abstract
Rotavirus (RV) is one of the major causes of acute viral gastroenteritis in children. Symptoms include fever, vomiting and watery diarrhea which may lead to fatal dehydration. Before the development of RV vaccines and their introduction into National Immunization Programs, RV gastroenteritis caused more than 400,000 deaths each year globally. RV vaccines are currently used in more than 90 countries, and the number of deaths has decreased to a third, but RV still remains as one of the main causes of mortality in children under five years of age. The majority of the fatalities occur in low-to-middle income countries, whereas in developed countries, RV is the cause of a substantial medical and financial burden. After the introduction of vaccines, an increase of diversity and changes in circulating RV strains have been reported globally.
RotaTeq consists of five human-bovine reassortant RVs (G1P[5], G2P[5], G3P[5], G4P[5] and G6P[8]) on bovine G6P[5] backbone. The shedding of RotaTeq vaccine viruses was originally reported to occur at a low level but more recent studies have shown higher rates of shedding. In early studies, the duration of shedding ranged from a week, even up to hundreds of days in immunocompromised children. Nevertheless, the characteristics of RotaTeq vaccine strain shedding have not been studied thoroughly. Similarly, the formation and potential higher virulence of vaccine-derived double-reassortant G1P[8] (vdG1P[8]) is mainly unknown.
This thesis focused on studying the characteristics of RotaTeq vaccine virus shedding in children without symptoms of acute gastroenteritis. First, stool samples collected from children hospitalized due to a respiratory tract infection between 2009 and 2011 were studied. The study showed that prolonged asymptomatic shedding was more common than previously expected. The occurrence of shedding was highly associated with vaccine genotype G1 as it was detected in 93 % of the cases. Half of the children shed for more than 14 days, and the longest duration of shedding was 84 days after the third dose of the RotaTeq vaccine.
Secondly, in a prospective study, 301 children received the RotaTeq vaccine at their respective child welfare clinic according to the Finnish schedule at the ages of two, three and five months. RotaTeq vaccine strains were detected in the stools of 93 % of the children 5-10 days after the first dose of the vaccine. Of those children, 20 % continued to shed until the third dose of the vaccine, whereas only two children were detected with the vaccine strain in stools three months after the third dose. The study confirmed G1 to be highly prevalent in shedding: it was found in 82 % of the samples taken after the first dose, it was the only genotype found in long-term shedding continuing up to eight months of age. Children who became long-term shedders were found with more severe symptoms after the first dose of the vaccine, whereas similar association was not found when comparing the possible vdG1P[8] combination to other genotypes. Altogether these results suggest that the five-strain- containing RotaTeq vaccine functions in a similar manner as the single human G1P[8] strain vaccine, Rotarix.
RV was added as part of the microbe strain collection in Finland in 2013, and all laboratory confirmed RV cases from the entire country covering all age groups were collected for genotyping. This material was used to study the long-term effects of the RotaTeq vaccine on circulating RV genotypes in a high vaccine coverage setting for five consecutive RV seasons from September 2013 to August 2018. The total number of RV cases remained stable and at a low level throughout the follow-up, indicating that the RotaTeq vaccine has remained highly efficacious. In children, diversification and redistribution of circulating genotypes, similar to other RotaTeq- using countries, was detected, as G1P[8], G2P[4] and G4P[8] were replaced by G12P[8], G9P[4] and G9P[8]. Two distinct age clusters were also identified, as in addition to children, RV was detected in the elderly more frequently than expected. The genotypes of this age group differed from those of the children, as G2P[4] was predominant during most of the follow-up period. The changes in the circulating genotypes were detected in the elderly a season later, suggesting transmission of the disease from children to older age groups. Overall, this period is long enough to suggest that wild-type RVs cannot be eliminated from circulation even with a high-coverage vaccination using a highly efficacious live oral RV vaccine.
RotaTeq consists of five human-bovine reassortant RVs (G1P[5], G2P[5], G3P[5], G4P[5] and G6P[8]) on bovine G6P[5] backbone. The shedding of RotaTeq vaccine viruses was originally reported to occur at a low level but more recent studies have shown higher rates of shedding. In early studies, the duration of shedding ranged from a week, even up to hundreds of days in immunocompromised children. Nevertheless, the characteristics of RotaTeq vaccine strain shedding have not been studied thoroughly. Similarly, the formation and potential higher virulence of vaccine-derived double-reassortant G1P[8] (vdG1P[8]) is mainly unknown.
This thesis focused on studying the characteristics of RotaTeq vaccine virus shedding in children without symptoms of acute gastroenteritis. First, stool samples collected from children hospitalized due to a respiratory tract infection between 2009 and 2011 were studied. The study showed that prolonged asymptomatic shedding was more common than previously expected. The occurrence of shedding was highly associated with vaccine genotype G1 as it was detected in 93 % of the cases. Half of the children shed for more than 14 days, and the longest duration of shedding was 84 days after the third dose of the RotaTeq vaccine.
Secondly, in a prospective study, 301 children received the RotaTeq vaccine at their respective child welfare clinic according to the Finnish schedule at the ages of two, three and five months. RotaTeq vaccine strains were detected in the stools of 93 % of the children 5-10 days after the first dose of the vaccine. Of those children, 20 % continued to shed until the third dose of the vaccine, whereas only two children were detected with the vaccine strain in stools three months after the third dose. The study confirmed G1 to be highly prevalent in shedding: it was found in 82 % of the samples taken after the first dose, it was the only genotype found in long-term shedding continuing up to eight months of age. Children who became long-term shedders were found with more severe symptoms after the first dose of the vaccine, whereas similar association was not found when comparing the possible vdG1P[8] combination to other genotypes. Altogether these results suggest that the five-strain- containing RotaTeq vaccine functions in a similar manner as the single human G1P[8] strain vaccine, Rotarix.
RV was added as part of the microbe strain collection in Finland in 2013, and all laboratory confirmed RV cases from the entire country covering all age groups were collected for genotyping. This material was used to study the long-term effects of the RotaTeq vaccine on circulating RV genotypes in a high vaccine coverage setting for five consecutive RV seasons from September 2013 to August 2018. The total number of RV cases remained stable and at a low level throughout the follow-up, indicating that the RotaTeq vaccine has remained highly efficacious. In children, diversification and redistribution of circulating genotypes, similar to other RotaTeq- using countries, was detected, as G1P[8], G2P[4] and G4P[8] were replaced by G12P[8], G9P[4] and G9P[8]. Two distinct age clusters were also identified, as in addition to children, RV was detected in the elderly more frequently than expected. The genotypes of this age group differed from those of the children, as G2P[4] was predominant during most of the follow-up period. The changes in the circulating genotypes were detected in the elderly a season later, suggesting transmission of the disease from children to older age groups. Overall, this period is long enough to suggest that wild-type RVs cannot be eliminated from circulation even with a high-coverage vaccination using a highly efficacious live oral RV vaccine.
Original language | English |
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Place of Publication | Tampere |
Publisher | Tampere University |
ISBN (Electronic) | 978-952-03-1411-8 |
ISBN (Print) | 978-952-03-1410-1 |
Publication status | Published - 2020 |
Publication type | G5 Doctoral dissertation (articles) |
Publication series
Name | Tampere University Dissertations - Tampereen yliopiston väitöskirjat |
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Volume | 199 |
ISSN (Print) | 2489-9860 |
ISSN (Electronic) | 2490-0028 |