Post-exposure prophylaxis (PEP) represents the critical intervention for preventing rabies and comprises three essential components: thorough wound cleansing, vaccination, and administration of rabies immunoglobulin (RIG) or monoclonal antibodies (mAbs) for category III exposures. The World Health Organization (WHO) endorses the use of mAb cocktails as an effective replacement for RIG in PEP protocols. Since 2016, four anti-rabies monoclonal antibodies (RmAbs) have received clinical approval for use in India and China. This article provides an overview of the current research status of RmAb. By reviewing clinical studies related to RmAb, it highlights the clinical advantages of RmAb over HRIG in terms of efficacy, accessibility, safety, acceptability, and clinical application in special populations. Additionally, it explores the future clinical prospects of RmAb, including their use in extremely high-risk cases, their impact on circulating antibodies, and their potential role in rabies treatment.

Since the introduction of Pasteur's rabies vaccine in 1885, rabies prophylaxis and post-exposure prophylaxis (PEP) have been widely administered globally under the recommendation of the World Health Organization (WHO). However, 124 documented cases of PEP failure had been reported worldwide between 1980 and 2023. Additionally, sporadic media reports from China had highlighted occasional PEP failures between 2017 and 2024. These incidents underscore the ongoing global challenge of ensuring the effectiveness of PEP. Rabies remains a serious public health problem in over 150 countries and regions. In this review, we summarize widely recognized PEP procedures recommended by the Advisory Committee on Immunization Practices (ACIP) and the WHO. We also analyze potential contributing factors to PEP failure, propose a concept of circulating antibodies, and discuss their roles in PEP. Furthermore, we summarize key guidelines for clinical trial design from U.S. Food and Drug Administration (FDA) and China’s Center for Drug Evaluation (CDE), and share the latest developments in monoclonal antibody (cocktail) therapies. Adherence to core PEP practices, such as wound cleansing, infiltration of wounds with immunoglobulin (mAbs), and administration of vaccines, is crucial for preventing rabies infection in most cases. For high-risk exposures or immunocompromised individuals, the provision of circulating antibodies through high-dose human rabies immune globulin (HRIG) or mAbs is of utmost importance to prevent PEP failure. Addressing rabies requires the involvement of the entire society. Only through collective efforts can we tackle this neglected disease and achieve the WHO’s goal of “zero by 30”.

Background: Since the introduction of Pasteur’s rabies vaccine in 1885, rabies prophylaxis and post-exposure prophylaxis (PEP) have been widely administered globally under the recommendation of the World Health Organization (WHO). However, 124 documented cases of PEP failure had been reported worldwide between 1980 and 2023. Additionally, sporadic media reports from China showed occasional PEP failures between 2017 and 2024. Rabies remains a serious public health problem in over 150 countries and regions. Methods: In this review, we summarize PEP procedures recommended by the Advisory Committee on Immunization Practices (ACIP) and the WHO. We also analyze potential contributing factors to PEP failure, propose a concept of circulating antibodies, and discuss their roles in PEP. Furthermore, we summarize key guidelines for clinical trial design from the U.S. Food and Drug Administration (FDA) and China’s Center for Drug Evaluation (CDE), as well as the latest developments in monoclonal antibody (cocktail) therapies. Results: Adherence to core PEP practices, such as wound cleansing, infiltration of wounds with immunoglobulin (mAbs), and administration of vaccines, and broader societal involvement are crucial for preventing rabies infection in most cases. For high-risk exposures or immunocompromised individuals, the provision of circulating antibodies through high-dose human rabies immune globulin (HRIG) or mAbs is of utmost importance for preventing PEP failure. Conclusions: Early, high-concentration circulating antibodies are important for preventing PEP failure. Addressing the global issue of rabies requires involvement of the entire society. Only through collective efforts can we tackle this neglected disease and achieve WHO’s goal of “zero by 30”.