Fast Track Proposals will be accepted. Direct-to-Phase II will not be accepted. Number of anticipated awards: 1-3 Budget (total costs): Phase I: $ 300,000 for up to 1 year; Phase II: $ 2 million for up to 3 years. Background HIV/AIDS continues to be a major health problem throughout the world, with the greatest impact on vulnerable and underserved populations. A safe and effective HIV vaccine has been pursued for several decades. Ongoing efficacy trials with the latest HIV vaccine candidates can change this scenario and may lead the way to approval of a licensed vaccine in the near future. Several years of clinical trials have revealed that some HIV vaccines can elicit long-lasting (>15 years) serological immune responses that can be confused with HIV infection in common diagnostic tests. This phenomenon, known as vaccineinduced sero-reactivity or sero-positivity (VISR/VISP), can severely impact several life aspects of clinical trial participants: immigration, marriage, military service, blood/organ donation and employment, among others. VISR/VISP seems to be more prevalent with vaccines that incorporate (completely or partially) the gp41 region of the HIV envelope. Although a VISP result can be differentiated, most of the time, from a true HIV infection by nucleic acid tests (NAT) (e.g. RT-PCR), these are more expensive and technically challenging tests, and not always readily available. Furthermore, deployment of NATs might not be the single solution to VISP. In fact, the use of highly active antiretroviral therapy (HAART) or pre-exposure prophylaxis (PrEP) therapies can cause false-negative NAT results due to undetectable viral load. Previous attempts to develop a serological test agnostic to responses elicited by HIV vaccine candidates failed to reach the high sensitivity and specificity demanded by the regulatory agency (>99% sensitivity and specificity). The parallel detection and/or quantification of IgM and IgG antibodies against antigens absent in HIV vaccines, such as peptides of gp41, and systemically circulating HIV antigens, such as p24, are promising approaches. In order to prepare for the deployment of an HIV vaccine, after FDA registration and approval, companion diagnostic tests must be in place to avoid the problems associated with VISR/VISP in vaccine recipients. Project Goal The overarching goal of this project is to support the development of new serological and nucleic acid assays that can identify HIV infection while avoiding false-positive results due to VISP, with high sensitivity and specificity. These nextgeneration assays should be developed to address one or all applications/indications of HIV tests, namely: (1) laboratorybased tests; (2) point-of-care and clinical practices; and (3) self-testing. Ideally, these assays should be scalable and adaptable for manual performance (point-of-care, medical practices and selftesting) as well as fully or partially automated for high throughput (medical laboratories). They can be developed for performance in already existing, commercially available platforms and automated equipment or for performance using new devices. The newly developed assays should accept different biological samples, such as serum/plasma, whole blood, and saliva, although the specific application/indication might dictate the best sample collection method to reach the highest assay performance. During the development and qualification of the new assays, the proper algorithm for each application/indication should be defined. Since test(s) will also be deployed in low-to-middle-income countries and remote areas, dependency on refrigeration and electricity must be kept to a minimum and shelf life should be maximized. Special attention must be given to how results are obtained or communicated in order to protect confidentiality and privacy. Finally, production and operating costs should be Page 107 as low as possible to make it affordable to individuals and institutions, and practical for repeated testing by the end-user. Phase I activities may include, but are not limited to: • Development of Target Product Profile to address applications and assay performance indicators; • Development of assay concept/methodology and assessment of feasibility; • Generation/procurement of critical reagents and controls; • Pilot studies with prototype methodologies and antigens and/or nucleic-acid targets/sequences to determine feasibility; • Development of SOPs for the assay(s); • Primary assessment of sensitivity, specificity, low limit of detection, and linearity; and • Small scale screening of biological samples. Phase II activities may include, but are not limited to: • Market assessment and cost analysis; • Development of testing workflow for a specific product application/indication; • Adaptation of methodologies to equipment (different degrees of automation); • Large scale testing of biological samples and assessment of equivalence; • Assay validation (establishment of sensitivity, specificity, low limit of detection, and linearity and precision); and • Submission for FDA approval. This SBIR contract topic will NOT support: • The design and operation of clinical trials (see http://www.niaid.nih.gov/researchfunding/glossary/pages/c.aspx#clintrial for the NIH definition of a clinical trial); and • Testing non-HIV immunogens or studies unrelated to HIV vaccine development efforts.