EVALUATION OF THE SAFETY, IMMUNOGENICITY, AND PHARMACOKINETIC PROFILEOF A NEW, HIGHLY PURIFIED, HEAT-TREATED EQUINE RABIES IMMUNOGLOBULIN,ADMINISTERED EITHER ALONE OR IN ASSOCIATION WITH A PURIFIED, VERO-CELL RABIES VACCINE

A clinical evaluation of a new, purified, heat-treated equine rabies i mmunoglobulin (PHT-Erig), F(ab')(2) preparation, was carried out in Th ailand and in the Philippines-two countries where rabies is endemic. A n initial prospective, randomised, controlled trial (Study 1), compare d the safety and pharmacokinetics (serum concentrations of rabies anti bodies) after administration either of PHT-Erig or of a commercially-a vailable, equine rabies immune globulin (Erig PMC). A second trial (St udy 2) simulated post-exposure rabies prophylaxis by using a reference cell culture vaccine, the purified Vero-cell rabies vaccine (PVRV), a dministered in association with either Erig PMC or PHT-Erig. In Study 1, 27 healthy, Thai adults received a 40 IU kg(-1) dose of either Erig PMC (n = 12) or PHT-Erig (n = 15) via the intramuscular (IM) route; h alf of the dose was injected into the deltoid area and the other half into the buttocks. Serum for rabies antibody determination and F(ab')( 2) concentration was collected at hours (H) 0, 6 and 12, and on day (D ) 2, 3, 4, 6, 8, 10, 12 and 15. Both products were safe, with no serio us adverse events, and in particular, no anaphylactic reactions or ser um sickness was reported. A statistical comparison of the pharmacokine tic parameters did not demonstrate bioequivalence of the two products. Nonetheless, the relative bioavaibility of 93% and the similar absorp tion rates suggest the pharmacokinetic profiles of Erig and PHT-Erig a re similar. The antibody level in either group were low throughout the 15-day study period. The geometric mean titer (GMT) values ranged fro m group 0.027-0.117 IU ml(-1) in the Erig group and from 0.029 to 0.07 2 IU ml(-1) in the PHT-Erig. There was no significant difference betwe en the evolution of GMT values for the two groups. In Study 2, 71 heal thy volunteers received 40 IU kg(-1) via the intramuscular route of ei ther Erig PMC (n = 36) or PHT-Erig (n = 35) on DO, in association with five doses of PVRV on D0, D3, D7, D14 and D28. The safety evaluation was performed during the 28-day follow-up and serum samples for anti-r abies antibody titration were collected on DO (before injection) D3, D 7, D14 and D28. No serious reactions were reported in either group. In particular, no immediate (anaphylactic type) or delayed (serum sickne ss) allergic reactions were observed. Over the 28-day follow-up period ? GMT profiles of the two groups were statistically equivalent. On D14 , 100% of the subjects had protective antibody titers (anti-rabies ant ibodies greater than or equal to 0.5 IU ml(-1), which is the WHO-recom mended level of seroconversion), and Erig PMC and PHT-Erig were indist inguishable according to the clinical definition chosen. On D28, the G MT values were 33.2 IU ml(-1) (95% CI, 23.8-46.1 IU ml(-1)) in the Eri g PMC/PVRV group and 31.4 IU ml(-1) (95% confidence interval, CI, 23.3 -42.2 IU ml(-1)) in the PHT-Erig/PVRV group, showing evidence of adequ ate vaccine-induced antibody responses in both groups. The increased p urity, the heat-treatment step introduced in the manufacturing process of PHT-Erig, and the good clinical results substantiate the use of th is new generation, purified equine F(ab')(2) preparation in the post-e xposure prophylaxis of rabies. (C) 1998 Elsevier Science B.V. All righ ts reserved.