Sapovirus Gastroenteritis in Finnish Children: A Minor Leaguer in the Shadow of Rotavirus and Norovirus

Acute gastroenteritis (AGE) is a common cause of child mortality globally. In developed countries with low mortality, AGE is one of the leading causes of hospitalizations in young children. Rotavirus (RV), norovirus (NoV), and sapovirus (SaV) are among the leading causes of AGE in children worldwide. In Finland, universal RV vaccinations were initiated in September 2009, and vaccine coverage has remained high, at over 90 %. This has led to an 80–90 % reduction in AGE- related hospitalizations in young children, and NoV has replaced RV as the most causative agent of viral AGE.

Long-term surveillance studies have shown that RV cannot be eradicated with current live RV vaccines. This thesis focused on studying the burden of SaV, NoV, and RV in Finnish children in the post-vaccine era. Firstly, to understand the long- term effects of universal RV vaccination on AGE in children, we examined the stool samples of 178 children with AGE seen at Tampere University Hospital between January 2017 and December 2018 for SaV, NoV, and RV using reverse transcriptase polymerase chain reaction (RT-PCR). The overall number of AGE cases had decreased by 88 % from the pre-vaccination era and by 51 % from the previous reference period (2012–2014). We noted a moderate resurgence in wild-type RVs, and RV had returned as the most detected of the pathogens seen in hospitals (32 %), while NoV was seen in 27 % of cases, and SaVs were sporadically detected in 6.3 % of cases.

Secondly, to characterize the complete burden of AGE viruses, we examined the prevalence and genotype distribution of SaV, NoV, and RV with RT-PCR from stool samples from 557 hospitalized children with respiratory tract disease and no symptoms of AGE. The results were compared to samples from 442 hospitalized children who had been diagnosed with AGE. The samples were collected in Tampere University Hospital in 2009–2011. Asymptomatic infections were seen in approximately every seventh child, especially in newborns and children under 2 years of age. NoV was the most common of the pathogens in asymptomatic children (7.2 %), followed by RV (6.1 %) and SaV (1.4 %). The genotypes of the detected viruses were similar in symptomatic and asymptomatic subjects. Almost 9 out of 10 RV cases in the asymptomatic subjects presented RV vaccine strains, while wild-type RV was detected in only a few cases.

The effects of mass vaccinations on RV and NoV epidemiology and viral genetics have been examined in Finnish children before, but the role and evolution of SaV in AGE patients are not well understood. Therefore, we used RT-PCR to examine SaV in 1612 stool samples obtained from children with AGE who were seen in the pediatric emergency room or ward in Tampere University Hospital in 2006–2008, 2009–2011, 2012–2014, and 2017–2018. There were 59 (3.7 %) sporadic cases of SaV AGE. The children seen in the hospital for SaV AGE were mostly under 2 years of age. With the initiation of RV immunization program, the proportion of SaV in all AGE increased significantly, from 1.4 % to 5.6 %, but the number of detections remained at the same level. Using Vesikari severity score, most of the cases seen in the hospital were severe, but symptoms were markedly milder than those of NoV and RV.

Shedding of RV vaccine strains is very common after immunization and may last up to several months. Prolonged shedding is most commonly associated with RV G1 VP7, which we used as our target when we examined the stool samples of 292 vaccinated children with RT-PCR. We noted that every tenth child shed a mutated vaccine strain two months after the second vaccine dose. All of these strains showed an amino acid mutation located in epitope region 7-2, and some of these mutations persisted for up to 12 weeks. Based on the nature of the mutations, we suggest that they may contribute to the idiopathic prolongation of vaccine strain shedding. The impact of mutations on escape from the immune system should be further investigated.

In summary, the number of hospital visits due to AGE has further decreased in children under 16 years of age. Currently, the role of SaV in children hospitalized for AGE is small, and the introduction of RV vaccinations has not affected the number of SaV AGE episodes. The prevalence of RV remains at a low level, but with the slight emergence of novel wild-type RV strains and the decreased number of NoV AGE, RV displaced NoV as the most common cause of viral AGE in children. This is likely the result of the persisting high efficacy of RV vaccination against RV AGE and the accumulation of immunity against circulating NoVs. SaV, NoV, and RV are commonly found in the stools of asymptomatic young children, which may function as a potential reservoir for AGE. Persistent asymptomatic infections with RV vaccine strains after immunization are common, and genetic substitutions in immunogenic regions of vaccine G1 VP7 occur frequently.