Circulating Antibody's Role During Post-Exposure Prophylaxis, and Beyond for Rabies: A Review

Abstract

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".

Keywords: PEP failure; circulating antibody; monoclonal antibodies; rabies.

Figure 1

Composite rabies virus neutralizing antibody induction after human post-exposure prophylaxis trials of different mAbs + vaccine vs. HRIG + vaccine. (a) SII Rmab (3.3 IU/kg) + vaccine vs. HRIG (20 IU/kg) + vaccine. (b) RabiMabs (40 IU/kg) + vaccine vs. HRIG (20 IU/kg) + vaccine. (c) Ormutivimab (20 IU/kg) + vaccine vs. HRIG (20 IU/kg) + vaccine. (d) Zamerovimab/Mazorelvimab (0.3 mg/kg) + vaccine vs. HRIG (20 IU/kg) + vaccine. (e) Composite rabies virus neutralizing antibody induction after human post-exposure prophylaxis trials of different mAbs + vaccine vs. HRIG + vaccine.

Figure 2

Percentage of responders with GMC RVNA ≥ 0.5 IU/mL after human post-exposure prophylaxis trials of different mAbs + vaccine vs. HRIG + vaccine. (a) SII Rmab (3.3 IU/kg) + vaccine vs. HRIG (20 IU/kg) + vaccine. (b) RabiMabs (40 IU/kg) + vaccine vs. HRIG (20 IU/kg) + vaccine. (c) Ormutivimab (20 IU/kg) + vaccine vs. HRIG (20 IU/kg) + vaccine. (d) Zamerovimab/Mazorelvimab (0.3 mg/kg) + vaccine vs. HRIG (20 IU/kg) + vaccine. (e) Composite percentage of responders with GMC RVNA ≥ 0.5 IU/mL after human post-exposure prophylaxis trials of different mAbs + vaccine vs. HRIG + vaccine.

Figure 3

Illustration of the rabies virus loads/circulating antibody model in PEP and beyond (a). Generally, HRIG-induced antibodies could cover almost all local rabies viruses by following PEP core practices, including cleaning wounds carefully and timely. For high loads of viruses in escape situations, high concentrations of circulating antibodies are needed, as there is insufficient time to wait for vaccine-induced active immune responses. (b) The model with two situations of low and high viral loads.