Clinical Immunogenicity Assessment of HIV/AIDS Vaccines: Current Progress and Future Perspectives

Developing a safe and effective HIV-1 vaccine remains the cornerstone of global efforts to terminate the AIDS pandemic. However, the virus's immense genetic diversity and the persistent absence of a universal Correlate of Protection (CoP) present formidable barriers. Concomitant with the iterative evolution of vaccine design-spanning from protein subunits to mRNA and germline-targeting platforms-immunogenicity evaluation frameworks have undergone a critical paradigm shift. The field has transitioned from relying on conventional serological assays to embracing comprehensive, high-dimensional immune profiling. This review delineates the trajectory of milestone clinical trials, including RV144, the HVTN series, and the AMP studies, to systematically summarize advancements in assessing both humoral and cellular immunity. We comprehensively examine core methodologies, such as Binding Antibody Multiplex Assays (BAMA), pseudovirus neutralization, Enzyme-Linked Immunospot (ELISpot), and Intracellular Cytokine Staining (ICS). Furthermore, we highlight a pivotal transition in evaluative logic: moving beyond a singular focus on neutralizing antibody titers to integrate Fc-mediated effector functions (e.g., Antibody-Dependent Cellular Cytotoxicity (ADCC) and Phagocytosis (ADCP)) and the synergistic roles of polyfunctional T-cells. We also explore the transformative potential of burgeoning frontiers, including systems serology, single-cell B-cell receptor (BCR) sequencing, and mucosal immunity evaluation. Ultimately, we recommend that future evaluation frameworks combine single-cell multi-omics technologies with artificial intelligence algorithms and integrate multi-dimensional data for analysis, thereby providing a solid theoretical and technical foundation for the design of next-generation HIV vaccines.Trial registration: ClinicalTrials.gov identifier: NCT05854381..