The Henry M. Jackson Foundation

Developing an effective HIV vaccine is a momentous challenge. An exceptionally wide range of candidate HIV vaccines have been tested, yet many were poorly immunogenic, and of the select few that advanced into efficacy trials, only one demonstrated any efficacy. Here we report the results of the largest-scale cross-protocol immunogenicity comparison to date: 13 HIV vaccine trials (including 36 vaccine regimens) conducted across nine countries worldwide, strengthened by standardized trial designs, validated assays in centralized laboratories, and harmonized immunogenicity endpoints - providing an objective approach to identify the HIV vaccine candidate(s) with the best immunogenicity. A polyvalent DNA prime + protein boost regimen (HVTN 124) including Env immunogens of four subtypes, matched between prime and boost, achieved the best anti-V1V2 antibody responses by a large margin and also induced high CD4+ T-cell responses - two key immune responses implicated in HIV vaccine protection. Our results provide strong support to test this promising HIV vaccine design in more advanced phase clinical trials and will also guide the future design of additional HIV vaccines.Trial registration: ClinicalTrials.gov identifier: NCT01799954..Trial registration: ClinicalTrials.gov identifier: NCT02109354..Trial registration: ClinicalTrials.gov identifier: NCT02404311..Trial registration: ClinicalTrials.gov identifier: NCT02207920..Trial registration: ClinicalTrials.gov identifier: NCT02296541..Trial registration: ClinicalTrials.gov identifier: NCT03284710..Trial registration: ClinicalTrials.gov identifier: NCT02915016..Trial registration: ClinicalTrials.gov identifier: NCT02997969..Trial registration: ClinicalTrials.gov identifier: NCT03122223..Trial registration: ClinicalTrials.gov identifier: NCT03409276..Trial registration: ClinicalTrials.gov identifier: NCT02968849..Trial registration: ClinicalTrials.gov identifier: NCT03060629..Trial registration: ClinicalTrials.gov identifier: NCT00223080..

Information, education, and communication programs to improve HIV knowledge and communication skills are critical to HIV responses. It is unclear if improved HIV knowledge translates to decreased HIV acquisition risks. We identified typologies of HIV knowledge to assess the relationship with HIV risk perceptions and prevention behaviors using data from reproductive-aged adults without previously diagnosed HIV at screening for entry into the RV393 HIV incidence cohort in Kisumu County, Kenya. Staff-administered questionnaires on sociodemographic characteristics, HIV knowledge, information sources (e.g., radio, television, community, school, etc.), and prevention/risk behaviors. HIV knowledge and information source typologies were identified using latent profile analysis (LPA). Mixture modeling was used to assess the relationship between typologies and perceived risk. Prevention/risk behaviors were compared and stratified by typology and risk perception (high or low/no risk). Of 926 participants in the analyses, 46.8% were female and 58.1% had at least a secondary education. LPA fit statistics suggested a three-class model (BIC = 7738; entropy = 0.793). Differences in latent profiles were characterized by engagement in community-sourced information. Across all classes, participants with high risk perception reported significantly greater numbers of sex partners and were more likely to exchange sex compared to those reporting low/no risk. HIV testing practices and consistent condom use were similar irrespective of typology. There was alignment between risk perception and risk/prevention behaviors, but knowledge and information typologies were not significantly associated with risk perception. Building knowledge alone may not be sufficient to improve outcomes, thus necessitating structural interventions that facilitate enabling environments for prevention services.

Noninvasive monitoring of immune responses is important for increasing the efficacy of cancer immunotherapy. Although several approaches exist, few methods directly report on T-cell activation. We aimed to develop a novel PET probe targeting C-X-C motif chemokine ligand 9 (CXCL9), a chemokine specifically induced by interferon gamma (IFN-γ), a cytokine that is produced by activated T cells and group 1 innate lymphoid cells. CXCL9 binds to glycosaminoglycans, which are expressed on cell surfaces and the extracellular matrix, to recruit or position cells in the tumor microenvironment. In cancers, expression of CXCL9 has been associated with improved survival and predicts and reflects responses to immunotherapy. The pronounced upregulation of CXCL9 by IFN-γ and CXCL9's extracellular accessibility and site-specific accumulation make it a compelling biomarker for detecting T-cell activation. Methods: We developed a PET tracer targeting CXCL9 based on a high-affinity, antihuman CXCL9 nanobody (h2A12), which was isolated from a llama-derived phage display library and labeled with ¹⁸F. The tracer was evaluated in cell culture, a subcutaneous xenograft model, and a humanized mouse model of T-cell engager therapy. Results: The h2A12 nanobody demonstrated high specificity for human CXCL9 (K _d, 4.07 ± 0.44 nM) with no cross-reactivity to related chemokines. In xenograft models, [¹⁸F]F-h2A12 showed significant uptake in CXCL9-expressing tumors (10.33 ± 1.23 %IA/g) compared with control tumors (0.25 ± 0.04 %IA/g) at 2 h after injection, with excellent tumor-to-background ratios. In the humanized model, T-cell engager therapy induced CXCL9 expression that peaked at day 7, corresponding with increased [¹⁸F]F-h2A12 uptake in treated tumors (2.61 ± 0.50 %IA/g) versus controls (0.67 ± 0.12 %IA/g). Conclusion: [¹⁸F]F-h2A12 PET imaging enables noninvasive visualization of CXCL9 expression as a biomarker of immune activation. This approach offers potential applications in monitoring immunotherapy responses and studying immune-mediated diseases.