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”.

Background: Rabies is an almost universally fatal disease for which post-exposure prophylaxis (PEP), including passive immunization (PI) with rabies immunoglobulin or monoclonal antibodies, remains the only effective intervention. Despite established clinical guidelines, real-world PI utilization remains suboptimal. This study aimed to investigate the prevalence and determinants of PI hesitancy among previously unvaccinated patients with Category III rabies exposure in China. Methods: This multicenter cross-sectional questionnaire study was conducted at 12 rabies PEP clinics or emergency departments in 12 provinces of mainland China. The analysis included 585 previously unvaccinated adults with Category III rabies exposure who initially hesitated to receive or declined PI. The questionnaire collected sociodemographic characteristics, exposure profiles, awareness of the early protection gap, reasons for initial PI hesitancy or refusal, the decision to receive PI during the same clinical encounter, and PI product selection. Multivariable logistic regression identified factors associated with PI treatment decisions, with results reported as adjusted odds ratios (aORs); reason-specific models used the Benjamini–Hochberg false discovery rate correction. All inferential analyses were restricted to adults. Results: Among 5068 eligible previously unvaccinated patients with Category III rabies exposure, 2866 (57%) initially hesitated to receive or declined recommended PI. Of 617 questionnaire respondents, 32 minors were excluded, leaving 585 adults for all inferential analyses. The leading reasons for initial hesitancy were lack of understanding of the immediate protective role of PI (199/585, 34%), belief that vaccination alone was sufficient (194/585, 33%), and high cost (178/585, 30%). During the same clinical encounter, 320/585 adults (55%) chose to receive PI. Awareness of the early protection gap (aOR 2.63, 95% CI 1.75–3.98, p < 0.001) and bachelor’s degree or higher (aOR 1.61, 95% CI 1.07–2.43, p = 0.023) were positively associated with the decision to receive PI, whereas head/face wounds were negatively associated (aOR 0.53, 95% CI 0.30–0.92, p = 0.026). In reason-specific models, lack of knowledge about immediate protection was associated with higher odds of choosing PI (aOR 2.43, 95% CI 1.62–3.68, BH-FDR p < 0.001), whereas high cost was associated with lower odds (aOR 0.41, 95% CI 0.27–0.62, BH-FDR p < 0.001). Conclusion: Hesitancy toward and refusal of PI were observed among previously unvaccinated adults with Category III rabies exposure, yet initial hesitation or refusal is not irreversible. Early protection gap awareness was positively associated with PI choice, whereas cost-related concern was negatively associated. Clear explanation of protection timing and attention to cost-related barriers may support informed PI treatment decisions.