Advancing human metapneumovirus vaccine development through fusion protein stabilization.

Human metapneumovirus (hMPV) is a major respiratory pathogen that causes a substantial global disease burden, particularly in infants, older adults, and immunocompromised individuals. Despite more than two decades of research, no licensed vaccines or antiviral therapies are available, underscoring a persistent unmet clinical need. The viral fusion (F) glycoprotein is the leading target for vaccine and immunotherapeutic development due to its essential role in viral entry and its ability to elicit neutralizing antibodies. However, hMPV-F is highly metastable and undergoes conformational transitions from a prefusion (pre-F) state on infectious virions to a more stable postfusion (post-F) conformation. Although neutralizing antibodies can target epitopes in both conformations, the pre-F state is particularly important for eliciting the most potent neutralizing responses and is therefore the preferred immunogen for vaccine and antibody-based therapeutic design. This review summarizes recent structure-guided strategies to stabilize hMPV-F in its pre-F conformation, including proline substitutions, disulfide bond engineering, cavity-filling mutations, and scaffold-based approaches. We also synthesize preclinical immunogenicity data from multiple animal models and discuss implications for rational vaccine design. Collectively, these advances, combined with emerging immunological tools and the clinical success of respiratory syncytial virus (RSV) pre-F vaccines, provide a strong foundation to accelerate the development of effective hMPV vaccines and immunotherapeutics.