Suppressant effect of human or equine rabies immunoglobulins on the immunogenicity of post-exposure rabies vaccination under the 2-1-1 regimen: a field trial in Indonesia. MAS054 Clinical Investigator Group.

Introduction Rabies is a lethal viral encephalitis usually transmitted by the bite or scratch of a rabid animal to humans or another animal. Two post-exposure rabies vaccination protocols are currently recommended by WHO for intramuscular (IM) administration of cell-culture rabies vaccines (1). The reference protocol advises five single doses of vaccine over a 30-day period -- on days 0 (D0), 3, 7, 14, and 30. The second protocol (described as 2-1-1) advises, over a 21-day period, two doses at two separate sites on D0, followed by single doses on days 7 and 21. The combined use of specific rabies immunoglobulin (RIG) on D0 is recommended for severe cases (exposure severity, grade III). Since human RIG (HRIG) is barely affordable and often not available in developing countries, the pepsin-digested, purified equine RIG (ERIG) is attracting increased interest (2). Compared with the reference protocol, the 2-1-1 protocol, which provides two doses of antigen at the initial step of treatment, saves one dose of vaccine and two medical visits. With simultaneous administration of RIG in the 2-1-1 protocol, however, probably owing to the early high concentration of antigen and the absence of booster injections on days 3 and 14, there was a smaller antibody response even to cell-culture, purified rabies vaccines such as PVRV (3-8). The original 1992 WHO recommendations therefore did not advocate the use of the 2-1-1 regimen for severe rabies cases when RIG was indicated (1). This paper describes a multicentre trial which compared, under field conditions, the immunogenicity of a cell-culture rabies vaccine (PVRV) when given alone, by the 2-1-1 protocol, and in combination with RIG. In addition, to study specifically the role of homologous versus heterologous RIG on the vaccine-induced antibody response, we compared the 2-1-1 schedule when combined with HRIG or ERIG. Population and method Indonesian males and females, aged 13-55 years, who had never received pre- or post-exposure rabies vaccination and who freely gave their informed consent, were enrolled between July 1993 and May 1994 into the study, which followed WHO recommendations on good clinical practice. The subjects were recruited from four centres (three in Java and one in Sumatra) and either had been exposed to rabies (and required treatment within 24 hours of exposure) or were healthy volunteers. Subjects in group A showed an exposure severity of grade I or were healthy volunteers and received the 2-1-1 PVRV treatment without rabies immunoglobulins. Subjects who were given RIG (groups B and C) had been bitten, with an exposure severity of grade II (for the purpose of this clinical trial) or grade III (by the WHO definition). All subjects in groups B and C received the same 2-1-1 vaccine treatment as group A, but also a booster vaccine injection on day 90. On day 0, group B subjects received ERIG while group C received HRIG with the vaccine injection. A commercially available, rabies cell-culture vaccine, prepared on Vero cells (Verorab[TM], Pasteur Merieux Connaught (PMC), Lyon, France) and having an antigen content greater than 2.5IU/dose (batch H0768; exact titre, 4.3IU/0.5ml) as determined by the National Institutes of Health test, was injected into the deltoid muscle. More than 10 million doses of this vaccine, first registered in 1986 and marketed in over 40 countries, have been distributed worldwide. All subjects received two 0.5-ml vaccine doses on D0 and single doses on D7 and D21. As specified in the protocol, an additional 0.5-ml dose was administered on D90 to the subjects in groups B and C. ERIG (Pasteur Rabies Serum[TM], PMC; commercial batch, H5717) at a titre of 200 IU/ml (as determined by the mouse neutralization test) was used at the WHO-recommended dose of 40 IU/kg. HRIG (Imogam[TM] Rabies, commercial batch J0106, PMC) with a titre of 150IU/ml (as determined by the rapid fluorescent focus test, RFFIT) was given at the WHO-recommended dose of 20 IU/kg. …