Safety and efficacy results of simulated post-exposure prophylaxis with human immune globulin (HRIG; KEDRAB) co-administered with active vaccine in healthy subjects: a comparative phase 2/3 trial

Abstract

We conducted a clinical trial to assess the safety and putative efficacy of an additional human rabies immune globulin (HRIG; KEDRAB) versus an older product (Comparator, HyperRAB S/D® [Grifols]) and determine whether HRIG interferes with development of endogenous antibodies versus Comparator, when each is given with an active rabies vaccine. This was a prospective, double-blind, single-period, non-inferiority study in which subjects were randomized (1:1) to a single dose (20 IU/kg) of HRIG or Comparator on day 0 and rabies vaccine (RabAvert® [GlaxoSmithKline]; 1 mL of ≥2.5 IU/mL) on days 0, 3, 7, 14, and 28. Anti-rabies antibodies were measured by rapid fluorescent focus inhibition test on day 14, and subjects were followed until day 185. Rabies virus neutralizing antibody (RVNA) titers ≥0.5 IU/mL were considered seroconversion putatively indicative of protection. The non-inferiority criterion was the lower limit of the 90% confidence interval (CI) >-10%, for the between-group difference in the proportion of subjects achieving RVNA ≥0.5 IU/ mL. On day 14, 98.3% of 59 subjects in the HRIG group and 100% of 59 in the Comparator group had RVNA ≥0.5 IU/mL (difference between proportions -1.8%; 90% CI, -8.2, 3.1; non-inferiority criterion met). One subject in the HRIG group did not meet the seroconversion criteria for anti-rabies antibody, and one subject in the Comparator group showed an anamnestic response, with much higher than expected anti-rabies antibody levels at both baseline and on day 14. Thus, HRIG allows for prophylactic anti-rabies antibody titers and is non-inferior to Comparator, when administered with rabies vaccine.

Antibody Response to Severe Acute Respiratory Syndrome‐ Corona Virus 2, Diagnostic and Therapeutic Implications

“…( 82 ) Similar techniques for concentrating antibodies are being used for the treatment and prevention of other diseases. ( 98 ) This is similar to the concept of using hyperimmune globulin for various indications, including viral diseases in immunocompetent and immunocompromised hosts. ( 99‐101 ) A “cocktail antibody approach” for SARS‐CoV‐2 was proposed based on studies suggesting that the combination of antibodies from diverse donors may exert a synergistic neutralization effect.…”

Safety and efficacy of rabies immunoglobulin in pediatric patients with suspected exposure

“…RVNA titers denote the geometric mean of the results per participant per visit. 27 min – max, minimum to maximum; RVNA, rabies virus neutralizing antibody; SD, standard deviation. …”

“…Registrational trials for HRIG products have, to date, enrolled no pediatric subjects (HyperRAB – 12 adults, KEDRAB – 59 adults, Imogam-HT – 32 adults). 21 , 22 , 27 The present study evaluated a cohort of 30 pediatric participants based on feasibility of enrolling subjects indicated for post-exposure prophylaxis, and is comparable in size to other HRIG registrational studies supporting FDA approvals. To our knowledge, this is the first study in pediatric patients for any RIG currently available in the United States.…”

The Diagnosis, Clinical Course, Treatment, and Prevention of the Rabies Virus

“…Although the vaccines have been proven to stimulate an appropriate immune response to RABV, this immune response is often too delayed to prevent the virus from entering the nerves [42]. With this knowledge, passive immunization is recommended for all patients that have no previous history with the disease or a pre-exposure vaccination.…”

“…If the patient has multiple bites or wounds, the RIG needs to be applied at each site to be effective [44]. HRIG is to be administered at a dosage or 20 IU/kg while the recommended dosage for ERIG is 40 IU/kg [42,44]. Due to higher odds of sensitization as well as quicker elimination of the RVNA, HRIG is generally the most preferred option for passive immunization.…”