Immunoassay-based rapid diagnostic tests (RDTs) currently represent the leading means for point-of-care diagnosis of infectious diseases in developing contexts. These assays typically employ surface-immobilized IgG antibodies as affinity agents for the capture of disease-relevant biomarkers from patient samples. However, antibodies are prone to thermal denaturation and nonspecific binding events that can render test results unreliable, and their development is costly and time-intensive, which can increase costs to the end user. These characteristics limit the potential utility of antibody-based diagnostics in resource-constrained contexts, where cold chain storage may not be feasible and financial resources are limited. In order to better address these technological gaps, we are developing robust, minimalist, immuno-orthogonal affinity agents based on thermostable protein scaffolds, using yeast surface display and flow cytometric analysis. By incorporating these robust affinity agents into low-cost, multiplexed assay formats, we aim to enable the sensitive, specific, and timely diagnosis of high-priority infectious diseases at the point-of-care.