Antigens and Reassortants for Rotaviruses Circulating in Africa (2nd project period)

Rotaviruses are distributed in humans and animals and are transmitted by direct contact or contaminated drinking water or food. Rotavirus infections are the main cause of severe gastroenteritis in young children worldwide. Life-threatening disease mainly occurs in developing countries in Africa and Asia. The use of live-attenuated vaccines led to a significant decrease of rotavirus disease worldwide. However, the vaccine efficacyClose dialogefficacyPositive Predictive ValueTo glossary is considerably lower in Africa as compared to Europe and North America. This could be because the vaccines are mainly based on rotavirus strains predominantly found in Europe and North America and do not include strains circulating in Africa. The goal of this project is to provide strategies for the generation of antigens and recombinant reassortant strains for future vaccine development based on rotavirus strains circulating in Africa. In the first project period, the actual occurrence of different rotavirus strains was assessed in Mozambique and first systems for generation of antigens using reverse genetics were developed. The developed technologies will be further optimized during the second project period in order to overcome the limitations that became obvious during the first project period. Newly determined African strains will be integrated to broaden the antigenic repertoire. In addition, antigenicity testing of the generated reassortants in animals as well as the targeted attenuation of rotaviruses will be included. Surveillance will be expanded using an extended One-Health approach including animal and environmental samples, applied to specific regions in Mozambique. The project will give further insights into the genetic and antigenic properties of rotaviruses currently circulating in Africa, and techniques for generation of antigens, which are specifically designed for vaccines for the African continent, will be further developed.

Rotaviruses are a leading cause of acute diarrhoea requiring hospitalization in children under five years of age worldwide. In the absence of symptomatic treatment, rotavirus infections can become life-threatening due to dehydration. The availability of live-attenuated rotavirus vaccines led to significant reduction of rotavirus-related hospitalizations and deaths. However, remarkably lower vaccine efficacies have been reported in low- and middle-income countries with high child mortality - especially in Sub-Sahara Africa - compared to high income countries. The lower vaccine efficacyClose dialogefficacyPositive Predictive ValueTo glossary could be because the vaccines are mainly based on rotavirus strains predominantly found in Europe and North America and do not include strains circulating in Africa, which are often more diverse and distinct from the used vaccine strains. The major aim of the project was therefore to provide antigens based on rotavirus strains circulating in Africa, which can be used for future development of vaccines for the African continent. Because isolation of human rotavirus field strains in cell culture is difficult and often not successful, recombinant technologies using state-of-the-art reverse genetics systems were used for incorporation of African strain antigens into replication-competent attenuated rotaviruses. This system enables quick change of antigens in case of emergence of novel strains. During the two project periods, several data on vaccine efficacyClose dialogefficacyPositive Predictive ValueTo glossary and the actual variability of rotavirus strains were generated, particularly for Mozambique. It was evident that vaccine efficacyClose dialogefficacyPositive Predictive ValueTo glossary in Mozambique between 2017 and 2019 was indeed very low (around 35%). At the same time, it was shown that the circulating rotavirus genotypes often differed significantly from those present in the vaccine, and that the proportion of these genotypes increased over time. Rotaviruses were also detected in various animal species such as cattle, goat and pig from Mozambique and South Africa. Using reverse genetics, the capsid proteins of selected genotypes were inserted into the laboratory strain SA11. For genotypes where this was not successful, various novel strategies were developed to solve the ossurring problems. As a result, six different replicating reassortants were generated, which contained for the first time the most important antigens of human rotavirus genotypes from Africa. Further reassortants with antigens from rotaviruses of various animal species were also successfully generated. In addition, some targeted modifications were introduced into the viruses, which may contribute to attenuation and thus enable their use in vaccines.The results show that rotavirus vaccines should be further optimized for their use in Africa and adapted to the strains that circulate there. The studies also show that rotaviruses in Africa cannot only be transmitted from person to person, but also occur in various animal species, indicating the application of the One Health concept to combat rotavirus infection. Novel strategies have been developed in the project to incorporate antigens of African strains into laboratory viruses, which can later be further developed into vaccines. Viruses with the most important rotavirus strains circulating in Africa could be generated and are now available for further development. The findings and virus strains generated in the project should be used in future to further develop rotavirus vaccines adapted to Africa, in order to prevent the serious diseases occurring there.