Rising global threat of human metapneumovirus (hMPV in 2024/2025): pathogenesis, immune dynamics, vulnerabilities in immunocompromised individuals, and lessons from past pandemics

Abstract Human metapneumovirus (hMPV), a prominent respiratory pathogen with a history of global circulation spanning over seven decades, has re-emerged as a critical public health concern. Since late 2024, there has been a significant global surge in hMPV cases, first reported in China and subsequently spreading to countries such as the USA, India, and Pakistan. Although the World Health Organization (WHO) and Chinese authorities have downplayed the severity of this increase, attributing it to expected seasonal trends, the growing prevalence of hMPV raises alarm due to its potential to cause severe respiratory illness. Particularly at risk are vulnerable populations, including children, the elderly, and immunocompromised individuals. Recent epidemiological data indicate a 17% increase in pediatric hMPV-related hospital admissions in the first quarter of 2025 compared to the same period in 2023 in both the USA and China, with similar trends observed among elderly and immunocompromised patients. These findings highlight the urgent need for enhanced surveillance and public health preparedness. This study explores the immunopathogenesis of hMPV, which is marked by its immune evasion strategies, including inhibition of interferon signaling pathways and suppression of key antiviral cytokines. These mechanisms enable persistent viral replication and contribute to severe respiratory pathologies. Moreover, dysregulated cytokine production, particularly the overexpression of pro-inflammatory cytokines, exacerbates immune responses and leads to tissue damage, further worsening clinical outcomes in vulnerable populations. This review delves into the complex immune dynamics of hMPV infection, highlighting impaired dendritic cell activation and suboptimal T-cell responses, which hinder long-lasting immunity, especially in immunocompromised individuals. The virus's high mutation rate (6.95 to 7.12 × 10−4 substitutions/site/year), along with its immune evasion mechanisms and significant cytopathic effects, further enhances its pathogenicity. The global spread of hMPV underscores its resilience and adaptability, making it a growing threat to public health. As hMPV-related immunology becomes increasingly relevant amid this new outbreak, this review emphasizes the need for robust genomic surveillance, targeted antiviral therapies, and vaccine development. Drawing on lessons from COVID-19 and Ebola, the importance of early detection systems, antiviral research, and targeted immunization strategies is paramount to mitigating the impact of this emerging viral threat. With insights from the current study, future immunological approaches should prioritize the development of novel vaccine candidates, enhancement of monoclonal antibody therapies, and improvement of host-directed immunomodulatory treatments. By integrating these strategies, global health systems can effectively respond to future hMPV outbreaks and safeguard vulnerable populations.