Enhanced Virus Surveillance and Intervention Strategies for Health Preparedness in Uganda

The East African region, well-known for its vast biodiversity, serves as a vital sentinel area for the study of viral zoonoses. Uganda, in particular, stands out in virus discovery research and faces a disproportionate impact from emerging zoonotic infections. Over the past decade, the nation has witnessed over 50 outbreaks of viral hemorrhagic fevers (VHFs), including Ebola (EBOV), Sudan (SUDV), Marburg (MARV), Rift Valley fever (RVFV), yellow fever (YFV), and Crimean-Congo hemorrhagic fever (CCHFV) viruses. Additionally, vector-borne arboviral infections such as Zika (ZIKV), Semliki Forest (SFV), chikungunya (CHIKV), O'Nyong Nyong (ONNV), and West Nile virus (WNV) are prevalent in the region. Notably, several of these viruses were first identified in East Africa. Despite these challenges, Uganda has demonstrated remarkable resilience and capability in addressing serious health crises, as evidenced by its response to the HIV pandemic in the 1980s. However, current diagnostic limitations hinder effective management of viral diseases, particularly in the face of a changing planet. The prevailing diagnostic landscape is constrained by the availability, sensitivity, and specificity of pathogen-specific tests, leading to misdiagnoses and potential unchecked viral spread. The advent of Next-Generation Sequencing (NGS)-based diagnostic methods offers a cutting-edge solution to these challenges. Acute febrile illness (AFI), often attributed to malaria, is a common presentation in healthcare settings across sub-Saharan Africa. However, viral infections account for a significant proportion of AFI cases, a fact frequently overlooked due to traditional diagnostic method limitations. This gap in diagnosis not only impedes accurate disease management but also impacts local economic productivity. The urgent need for advanced, unbiased diagnostic approaches is clear. This fellowship application proposes the implementation of innovative NGS-based 'enhanced' diagnostic methods as a comprehensive approach to improve the detection and management of viral infections in Uganda. These methods, aimed at detecting viral nucleic acids or specific antibody responses, promise to revolutionize our understanding of and response to viral outbreaks, thereby contributing significantly to global health security. The research vision is to develop and apply innovative high-throughput NGS-based diagnostic approaches for population-based surveillance in sentinel global sites, using Uganda as a pilot setting. The research questions focus on assessing the sensitivity and specificity of Metagenomic-NGS (M-NGS) and Target-Enrichment NGS (TE-NGS) compared to standard-of-care assays, their effectiveness in increasing diagnostic yield for population-based syndromic surveillance, the utility of NGS serology (PhipSeq) in identifying risk factors in key occupational groups, and the potential of M-NGS and TE-NGS in systematically identifying circulating pathogens in wastewater. The aims are multifaceted: to evaluate the sensitivity and specificity of NGS-based diagnostic assays compared to the standard of care, to employ M-NGS and TE-NGS in identifying acute infection in sentinel clinical sites, to use NGS serology for identifying risk factors in key occupational settings, and to establish M-NGS and TE-NGS wastewater surveillance in Uganda. This comprehensive approach is expected to identify viruses circulating in the community, enhancing our capacity to respond to viral outbreaks and safeguarding global health security.