Verorab Mechanism of Action

Pharmacotherapeutic group: Rabies vaccines. ATC Code: J07BG01.
Pharmacology: Pharmacodynamics: Mechanism of action: Protection after vaccination is provided by the induction of anti-rabies neutralising antibodies.
Clinical studies have been conducted to assess the immunogenicity of the vaccine in post-exposure and pre-exposure prophylaxis. Rabies virus neutralising antibody levels of ≥0.5 IU/mL are considered to be protective by the WHO.
Pre-exposure prophylaxis: In clinical trials assessing a 3-dose vaccine (D0, D7, D28 (or D21) by IM route) in both adults and children, all subjects achieved an adequate immune response, with serum neutralising antibody titres ≥0.5 IU/mL by D14 after the end of the primary vaccine regimen.
A ten-year follow-up in 49 patients who received a 3-dose regimen (D0, D7 and D28) followed by a booster dose at 1 year demonstrated a persistent immune response, with neutralising antibody titres maintained for 10 years in 96.9% of vaccinated subjects.
The 1-week pre-exposure schedule by IM use (one 0.5 mL dose at D0 and one 0.5 mL dose at D7) was assessed in one study (VAJ00001) in 75 subjects (including 35 children aged 2 to 17 years).
At D21, 98.6% vaccinated subjects reached a serum antibody titre ≥0.5 IU/mL.
One year later, following a simulated post-exposure prophylaxis (PEP) with two 0.5 mL doses injected 3 days apart (at D0 and D3) by IM use, a high and rapid anamnestic response was demonstrated in all subjects from D7 (7 days after the 1st PEP dose).
In 5 other additional studies conducted with Verorab in a total of 392 subjects assessing the conventional three-dose regimen (at D0, D7, D21 or D28) by IM use, all subjects reached a serum antibody titre ≥0.5 IU/mL. After the two doses (at D0 and D7), just before the third dose at D21 or D28.
The 1-week pre-exposure schedule by intradermal use (two 0.1 mL doses at D0 and two 0.1 mL doses at D7) was assessed in one study in 75 subjects (including 36 children aged 2 to 17 years).
At D21, 97.2% subjects reached a serum antibody titre ≥0.5 IU/mL.
One year later, following a simulated PEP with two 0.1 mL doses injected 3 days apart (at D0 and D3) by ID use, a high and rapid anamnestic response was demonstrated in all subjects from D7. Except one subject who remained seronegative at every time points despite completing all study vaccinations.
In another additional study conducted in 430 subjects who received one 0.1 mL dose of Verorab at D0 and one 0.1 mL dose at D7 by ID use, 99.1% subjects reached a serum antibody titre ≥0.5 IU/mL at D21.
Post-exposure prophylaxis: In clinical trials assessing the 5-dose Essen regimen (D0, D3, D7, D14 and D28) and the 4-dose Zagreb regimen (2 doses on D0, then 1 dose on D7 and 1 dose on D21) in both children and adults. Verorab elicited neutralising antibody titres ≥0.5 IU/mL in almost all vaccinated subjects by D14 and in all subjects by D28.
PEP regimens were tested: 1 regimen in 4 sites in 1 week (4 doses on D0, 4 doses on D3 and 4 doses on D7) with or without equine rabies immunoglobulins (ERIG) on D0, and the new Thailand Red Cross regimen (2 doses on D0, 2 doses on D3, 2 doses on D7 and 2 doses on D28) with equine rabies immunoglobulins (ERIG) on D0. The Institute Pasteur of Cambodia (IPC) regimen (2 doses on D0, D3 and D7) was also included in the Thailand Red Cross regimen up to D28. Almost all vaccinated subjects (98.8%) reached rabies neutralising antibody levels ≥0.5 IU/mL by D14. Five years later and before the simulated PPE was received, the protective level of rabies neutralising antibodies was maintained in more than 84% of subjects who received a 4-site 1-week regimen with or without ERIG, and in 64.1% (95% CI: 55.1; 72.3) of subjects who received the new Thailand Red Cross regimen with ERIG. Eleven days after the simulated PPE with a 4-dose ID regimen performed in one visit, all the vaccinated subjects reached rabies neutralising antibody levels ≥0.5 IU/mL on D14 (geometric mean antibody titre [GMT] between 138 and 193 IU/mL).
The administration of human rabies immunoglobulin (HRIG) or equine rabies immunoglobulin (ERIG) concomitantly with the rabies vaccine may cause slightly lower mean neutralising antibody titres due to immune interference.
The efficacy of Verorab was assessed in 44 adult subjects bitten by animals with rabies in a phase-4 clinical trial. The subjects received the vaccine according to the 5-dose Essen regimen (D0, D3, D7, D14 and D28 by IM use) and immunoglobulins, if applicable. All subjects were alive 3 years after the post-exposure prophylaxis.
Paediatric population: There are no clinically significant differences in the immunogenicity of the vaccine in the paediatric population compared to adults.
In the study (VAJ00001) assessing the 1-week pre-exposure schedule by intradermal use (two 0.1 mL doses of Verorab at D0 and two 0.1 mL doses at D7) or by IM use (one 0.5 mL dose of Verorab at D0 and one 0.5 mL dose at D7) in 71 children aged 2 to 17 years, all children reached a serum antibody titre ≥0.5 IU/mL at D21.
One year later, following a simulated PEP with two doses injected 3 days apart (at D0 and D3) by IM or ID use, a high and rapid anamnestic response was demonstrated in all subjects from D7.
Pharmacokinetics: No pharmacokinetic studies were performed.
Toxicology: Preclinical safety data: Toxicity studies in animals (acute, subacute and chronic toxicity) do not indicate any toxic effects or target organ toxicity.