Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 24 4 2025 06 26 403 427 Somayeh Mami Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Sajjad Shekarchian Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran Mohammad Mousavi Department of Hematology, School of Para-Medicine, Bushehr University of Medical Sciences, Bushehr, Iran AND Clinical Research Development Center, The Persian Gulf Martyrs Hospital, Bushehr University of Medical Sciences, Bushehr, Iran Mohammad Nicknam Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran AND Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran 2024 11 30 2024 12 31 Human cytomegalovirus (HCMV) poses a significant challenge to vaccine development due to its complex biology characterized by latency, immune evasion strategies, and undefined correlates of protection (CoPs). HCMV latency allows the virus to evade immune surveillance by remaining in a quiescent state in host cells, with the risk of reactivation triggered by immune damage or cell differentiation. In addition, HCMV employs an arsenal of immune evasion strategies, including modulating MHC expression, inhibiting natural killer (NK) cell activity, and subverting antibody-mediated responses, so these mechanisms further complicate vaccine design. Despite these obstacles, advances in basic research in immunology and vaccine technologies offer new opportunities. Strategies such as targeting latency-associated mechanisms, using memory inflation of CMV-specific T cells to induce long-term tissue-resident immunity, and developing immunogens that antagonize viral immunoevasins are promising approaches. New platforms, including mRNA and vector-based vaccines, show the potential to elicit robust humoral and cellular responses against key viral antigens such as glycoprotein B, pentamer complex, and pp65. In addition, adjuvants that restore impaired NK and T cell function could improve vaccine effectiveness. This review examines the molecular and immunological barriers to HCMV vaccine development and highlights innovative approaches to address these challenges. By addressing the complexities of latency, immune evasion, and CoPs, we propose a roadmap for developing a multimodal vaccine that can provide effective and durable protection against HCMV infections. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4263 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4263/2183