Background/Objectives: The development of an effective HIV vaccine has faced persistent challenges, as evidenced by the recent discontinuation of the Mosaico phase 3 trial. This study aims to critically examine the obstacles encountered in HIV vaccine development, with a focus on the Mosaico trial, which tested the Ad26.Mos4.HIV vaccine among 3,900 participants across multiple countries. We also explore emerging vaccine technologies and their potential in overcoming these challenges, while reflecting on lessons from previous trials to inform future strategies. Methods: We reviewed the Mosaico trial’s approach, which involved testing the efficacy of the Ad26.Mos4.HIV vaccine. We compared the outcomes of the Mosaico trial with other major HIV vaccine trials, including HVTN 702, Imbokodo, and RV144. We explored the limitations of the immune responses elicited by the Mosaico vaccine. The review focused on the generation of broadly neutralizing antibodies (bNAbs) and the challenges related to antigenic diversity and B-cell engagement. Emerging vaccine technologies, such as virus-like particles (VLPs), nanoparticles, SOSIP trimers, and mRNA platforms, were also analysed for their scalability, immune durability, and potential to advance HIV vaccine development. Results: The Mosaico trial was discontinued due to insufficient efficacy in reducing HIV acquisition, primarily due to the inability of the vaccine to induce bNAbs, which are crucial for targeting the diverse HIV-1 strains. A major challenge was the inadequate engagement of germline B-cell precursors, compounded by the antigenic diversity of the virus. The analysis showed that emerging vaccine platforms, such as VLPs, nanoparticles, SOSIP trimers, and mRNA-based approaches, hold promise but present challenges related to scalability and the durability of immune responses. The role of T cells and adjuvants in enhancing vaccine efficacy was also highlighted as critical for integrating both humoral and cellular immunity. Conclusions: The Mosaico trial, as well as other major HIV vaccine trials, underscores the need for a multi-pronged approach that incorporates both antibody and T-cell responses to tackle the complexities of HIV-1. Future efforts in HIV vaccine development must focus on inducing bNAbs, generating robust T-cell responses, and utilizing scalable vaccine platforms. The integration of artificial intelligence (AI) into vaccine design offers new opportunities to optimize immunogenic targets, which could significantly improve the potential for durable and broad immune protection. The development of a successful HIV vaccine by 2030 is achievable but relies on leverage on advanced technologies including artificial intelligence, innovation and insights from past trial data.