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Evaluation of the safety, immunogenicity, and pharmacokinetic profile of a new, highly purified, heat-treated equine rabies immunoglobulin, administered either alone or in association with a purified, Vero-cell rabies vaccine.

Abstract: A clinical evaluation of a new, purified, heat-treated equine rabies immunoglobulin (PHT-Erig), F(ab')2 preparation, was carried out in Thailand and in the Philippines-two countries where rabies is endemic. An initial prospective, randomised, controlled trial (Study 1), compared the safety and pharmacokinetics (serum concentrations of rabies antibodies) after administration either of PHT-Erig or of a commercially-available, equine rabies immune globulin (Erig PMC). A second trial (Study 2) simulated post-exposure rabies prophylaxis by using a reference cell culture vaccine, the purified Vero-cell rabies vaccine (PVRV), administered 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 (i.m.) route; half 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 serious adverse events, and in particular, no anaphylactic reactions or serum sickness was reported. A statistical comparison of the pharmacokinetic parameters did not demonstrate bioequivalence of the two products. Nonetheless, the relative bioavailability of 93% and the similar absorption rates suggest the pharmacokinetic profiles of Erig and PHT-Erig are similar. The antibody level in either group were low throughout the 15-day study period. The geometric mean titer (GMT) values ranged from group 0.027-0.117 IU ml(-1) in the Erig group and from 0.029 to 0.072 IU ml(-1) in the PHT-Erig. There was no significant difference between the evolution of GMT values for the two groups. In Study 2, 71 healthy volunteers received 40 IU kg(-1) via the intramuscular route of either Erig PMC (n = 36) or PHT-Erig (n = 35) on D0, 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-rabies antibody titration were collected on D0 (before injection) D3, D7, D14 and D28. No serious reactions were reported in either group. In particular, no immediate (anaphylactic type) or delayed (serum sickness) 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 antibodies > or = 0.5 IU ml(-1), which is the WHO-recommended level of seroconversion), and Erig PMC and PHT-Erig were indistinguishable according to the clinical definition chosen. On D28, the GMT values were 33.2 IU ml(-1) (95% CI, 23.8-46.1 IU ml(-1)) in the Erig PMC/PVRV group and 31.4 IU ml(-1) (95% confidence interval, CI, 23.4-42.2 IU ml(-1)) in the PHT-Erig/PVRV group, showing evidence of adequate vaccine-induced antibody responses in both groups. The increased purity, the heat-treatment step introduced in the manufacturing process of PHT-Erig, and the good clinical results substantiate the use of this new generation, purified equine F(ab')2 preparation in the post-exposure prophylaxis of rabies.
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Publication Date: PubMed ID: 9777717
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Summary

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This research study evaluates the safety, immune response, and pharmacokinetic profile of a new, highly purified, heat-treated equine rabies immunoglobulin (PHT-Erig) in Thailand and in the Philippines. This immunoglobulin was compared with a commercially-available equine rabies immune globulin (Erig PMC) and tested alongside a cell culture rabies vaccine. The findings support the safety and effectiveness of the new purified equine F(ab’)2 preparation in post-exposure prophylaxis of rabies.

Comparative Study of Two Immunoglobulins – PHT-Erig and Erig PMC

In the first study, 27 healthy Thai adults received a single dosage of either PHT-Erig or Erig PMC. This was administered via the intramuscular route, with half of the dose injected into the deltoid area and the other half into the buttocks. Key aspects of this study included:

  • The serum of these individuals was collected at numerous points over 15 days to determine concentrations of rabies antibody and F(ab’)2.
  • Both products showed a positive safety profile, with no serious adverse events, anaphylactic reactions, or cases of serum sickness reported.
  • A comparison of the pharmacokinetic parameters did not indicate bioequivalence of the two products, although their absorption rates and relative bioavailability (93%) suggested similar pharmacokinetic profiles.
  • No significant difference was observed in the geometric mean titer (GMT), an indirect measure of the concentration of antibodies, of the two groups.

Immunoglobulins in Conjunction with Purified Vero-cell Rabies Vaccine

A second study simulated post-exposure rabies prophylaxis. This study involved 71 healthy volunteers who received either PHT-Erig or Erig PMC, along with five doses of a purified Vero-cell rabies vaccine (PVRV). Other aspects of the second trial included:

  • Safety evaluation was conducted during the 28-day follow-up and no serious reactions were reported.
  • The GMT profiles of the two groups were statistically equivalent.
  • By day 14, 100% of the volunteers had developed protective antibody titers (anti-rabies antibodies ≥ 0.5 IU ml(-1)), meeting the WHO-recommended level of seroconversion.
  • On day 28, adequate vaccine-induced antibody responses were manifested in both groups, with indistinguishable results in the Erig PMC and PHT-Erig groups.

Conclusion and Implications

The findings indicate that the highly purified, heat-treated PHT-Erig showed a promising safety and immunogenicity profile, both alone and in combination with a purified Vero-cell rabies vaccine. This substantiates its use in the post-exposure prophylaxis of rabies. The PHT-Erig, with its increased purity and added heat-treatment step in the manufacturing process, could potentially serve as a new standard in rabies immunoglobulin formulations.

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(). Evaluation of the safety, immunogenicity, and pharmacokinetic profile of a new, highly purified, heat-treated equine rabies immunoglobulin, administered either alone or in association with a purified, Vero-cell rabies vaccine. .

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This article has been cited 18 times.
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