Pre-exposure rabies immunization with human diploid cell vaccine: decreased antibody responses in persons immunized in developing countries.

In November 1982, a U.S. Peace Corps volunteer in Kenya completed pre-exposure rabies prophylaxis with a standard 3 dose intradermal (ID) series of human diploid cell rabies vaccine (HDCV). In May 1983, she was bitten by a dog and died of rabies 3 months later. An initial investigation revealed that the patient, as well as 9 of 11 others immunized at the same time, had no rabies antibody titers (less than 1:5). We therefore instituted investigations into the immunogenicity of pre-exposure HDCV both in the United States and in developing countries. A serosurvey revealed unexpectedly low rabies titers in both Peace Corps volunteers and others immunized in developing countries. Antibody titers measured 2-3 weeks after ID immunization were compared in 9 groups totaling 271 persons in the United States and Kenya. There was no statistically significant difference in antibody titers in the 6 U.S. groups immunized from 1980-1984 (P greater than 0.15); however, groups immunized in the United States had significantly higher titers than a group of Kenyan nationals (P less than or equal to 0.0001), and the Kenyans had significantly higher titers than 2 Peace Corps groups immunized in Kenya (P less than or equal to 0.0001). No single hypothesis proposed (laboratory error, vaccine potency, vaccination technique, or specific immune suppression) accounted for the observed differences. Although we cannot fully explain the poor response to HDCV, it is probably due to multiple factors. We conclude that persons immunized with ID pre-exposure HDCV in developing countries should have rabies antibody titers determined to ensure their seroconversion; for persons immunized in the United States, such titers need not be routinely determined.

The early kinetics of the neutralizing antibody response after booster immunizations with human diploid cell rabies vaccine.

Persons immunized in developing countries were recently shown to have low titers after pre-exposure immunization with human diploid cell rabies vaccine (HDCV). An investigation into the response to HDCV boosters was conducted to determine if immunologic sensitization had occurred and if there was a response difference in persons immunized in and outside of the United States. Intramuscular (im) booster doses of vaccine were administered to 113 persons previously immunized outside the United States and 47 persons immunized in the United States. The post-exposure booster regimen of a single 1.0-ml im booster, as recommended by the World Health Organization for all but the most severe bites, produced a one-dilution (5-fold) rise in antibody titer in 14 (11%) of 123 persons tested 5 days after booster and in 56 (89%) of 63 persons studied 7 days after booster. Persons immunized in the United States and those immunized outside the United States had similar responses. Persons with low pre-booster titers were more likely to exhibit a 5-fold rise in antibody titer 5 days after booster (P = 0.03) than persons with higher pre-booster titers. The post-exposure booster regimen of 2 1.0-ml im doses (one each on days 0 and 3), recommended in the United States, produced a more rapid response than the single booster regimen in only some persons; a 5-fold response occurred in 6 (50%) of 12 persons 5 days after booster.(ABSTRACT TRUNCATED AT 250 WORDS)

Dual role of the immune response in street rabiesvirus infection of mice.

The cellular and humoral immune responses of mice to footpad injection of salivary gland suspensions of street rabiesvirus were investigated. Suppression of these responses with cyclophosphamide both increased the overall mortality rate from (50 to 100%) and delayed onset of disease signs and death for 1 to 2 weeks. Despite the absence of disease signs in these immunosuppressed animals, virus was present in the central nervous system, as shown by fluorescent-antibody staining of corneal epithelium. The onset of paralysis after limited immunosuppression was temporally related to a return to immune responsiveness, and passive transfer of homologous immune serum to infected immunosuppressed animals brought about their early paralysis and death. These findings indicate the importance of the immune response in the pathogenesis of street rabiesvirus infection.

Increased immunofluorescent staining of rabies-infected, formalin-fixed brain tissue after pepsin and trypsin digestion.

This study was undertaken to evaluate the sensitivity of the direct immunofluorescence test on Formalin-fixed, trypsin-digested, rabies-infected brain tissue. Our results suggest that the optimal unmasking of rabies antigenic sites is obtained by using a double enzyme digestion with pepsin and trypsin in lieu of only trypsin.

Pre-exposure rabies prophylaxis: efficacy of a new packaging and delivery system for intradermal administration of human diploid cell vaccine.

The efficacy of a newly designed syringe prepacked with human diploid cell vaccine in a sufficient quantity to deliver individual 0.1 ml doses intradermally was tested by injecting 40 veterinary students with a single dose on each of days 0, 7 and 28. A second group of 20 students received the ordinary series of three 1.0 ml intramuscular vaccine doses by needle and syringe. All participants in both groups developed neutralizing antibodies to rabies above the suggested minimum of 0.5 international units per ml by day 49. The geometric mean titres were somewhat lower in the group receiving the 0.1 ml doses compared to the group given 1.0 ml doses; however, this was considered of no clinical significance since everyone achieved a titre above the suggested minimum. There was little difficulty in reconstituting the vaccine prepacked in the lumen of the syringe and the syringe was easy to manipulate.

Stability of immunofluorescence reactions produced by polyclonal and monoclonal antibody conjugates for rabies virus.

We investigated two consumer complaints that described fading of immunofluorescence reactions associated with the use of a commercial antirabies, fluorescein-labeled, monoclonal antibody conjugate. We compared the performance of this product with that of two polyclonal antibody antirabies conjugates and observed significant diminution of fluorescence with the monoclonal antibody conjugate only. Furthermore, the fading occurred only on tissue impressions that had been mounted but not exposed to UV light excitation, thereby essentially eliminating the photobleaching associated with fluorescence microscopy as a causative factor. Our observations suggest that mounting medium pH and the holding temperature of stained slides may be critical factors in maintaining optimal immunofluorescence reactions with this monoclonal antibody conjugate. We discuss some probable mechanisms that could produce the type of fading observed and also suggest certain precautionary measures for use with this monoclonal antibody conjugate.

Preexposure immunization with intradermal human diploid cell rabies vaccine. Risks and benefits of primary and booster vaccination.

Intradermal human diploid cell rabies vaccine (ID HDCV) was licensed for preexposure use in the United States on May 30, 1986. We studied the safety and efficacy of this newly approved route and dose of administration. Serologic results were available from 112 (90%) of the 124 persons who participated in an HDCV low-dose preexposure study in which five different ID, intramuscular (IM), and subcutaneous primary immunization regimens were administered. Three 1.0-mL IM doses of vaccine resulted in titers similar to those from three 0.1-mL ID doses when compared 49 days, one year, and two years after primary immunization. Uniformly high postbooster titers occurred in all five groups when ID boosters were administered at one year or two years. Adverse reactions were similar following both ID and IM vaccination. Although ID HDCV can be a cost-effective substitute for IM vaccine, excessive use of unnecessary preexposure booster doses by any route may be inadvisable because of systemic allergic reactions. In addition, poor immune responses to HDCV have been documented in persons vaccinated in some developing countries. This may limit the use of low-dose regimens in some places.