Sex- and age-related differences in rabies immunoglobulin hypersensitivity.

We retrospectively reviewed 72132 patients who had received rabies immunoglobulin between 1987 and 2005 at the Queen Saovabha Memorial Institute, Bangkok. Purified equine rabies immunoglobulin (ERIG) was given to 42965 (59.56%) patients and human rabies immunoglobulin (HRIG) to 29167 (40.44%) patients. A total of 812 patients from both groups (1.13%) reported adverse reactions; among those who had received ERIG, 43.13% were male and 56.87% were female, and among those who had received HRIG, 34.62% were male and 65.38% were female. Females were at higher risk of exhibiting ERIG or HRIG hypersensitivity than males (P<0.01). None of the reactions was life-threatening. Serum sickness-like reactions to ERIG and HRIG were rare under the age of 10 years (0.05 and 0.01% among recipients in that age group).

Survival of neutralizing antibody in previously rabies vaccinated subjects: a prospective study showing long lasting immunity.

Physicians dealing with potential rabies exposures and travel medicine are frequently asked how long previous pre- or post-exposure rabies vaccination induced immunity persists. We therefore carried out a prospective study on 118 rabies vaccine recipients who had received pre- or post-exposure regimens with tissue culture rabies vaccines by intramuscular or intradermal schedules 5-21 years previously. Rabies neutralizing antibody was detectable in the sera of all subjects on day 0. They then received one intradermal 0.1 mL booster injection on days 0 and 3. Neutralizing antibody determination was carried out on days 5, 7 and 14. All except one subject showed an accelerated antibody response following the two booster injections. Vaccination with a WHO recognized tissue culture rabies vaccine evokes long lasting immunity. This study supports current recommendations that immunity is long lasting and that boosters without immunoglobulin are sufficient even when prior vaccination was longer than 5 years previously.

Antibody response after a four-site intradermal booster vaccination with cell-culture rabies vaccine.

The current World Health Organization recommendation for booster vaccination of previously immunized individuals with potential exposure to rabies is two doses of vaccine intramuscularly or intradermally on days 0 and 3. We report responses to two types of postexposure treatment of healthy individuals who had received preexposure rabies vaccination 1 year previously. Group A individuals received four intradermal doses (one-fifth of the diluent volume of vaccine per dose) on day 0, and group B individuals received two intramuscular doses on days 0 and 3. Immunogenicity of the two booster regimens was assessed by titrating the amount of neutralizing antibody (Nab). We found that the booster doses of vaccine produced remarkable responses in all subjects. Nab titers of > or = 0.5 IU/mL (acceptable antibody level for protection against rabies) were detected in all subjects on day 14, and they were shown to be consistently high 1 year after the booster vaccination. We also found that the Nab titers for group A were significantly higher (two- to eightfold) than those for group B on days 5, 14, 150, and 360 after the initial booster vaccination (P < .05). Our study shows that the four-site intradermal booster regimen with use of one-fifth of the diluent volume of cell-culture rabies vaccine on day 0 is associated with a significantly higher antibody response than is the conventional booster regimen for subsequent postexposure rabies treatment of individuals who have received preexposure rabies vaccination with cell-culture rabies vaccine 1 year previously.

Problems with rabies postexposure management: a survey of 499 public hospitals in Thailand.

Rabies is still a major public health problem in Asia. The incidence of known annual human cases in India alone has recently been revised from 20,000 to 30,000, and over 500,000 patients are given some form of postexposure rabies treatment. Only China, Peninsular Malaysia, Singapore, and Thailand are reporting a significant decrease in the prevalence of this disease in humans. Over 150,000 courses of postexposure treatment (PET) are given in Thailand every year. To determine remaining barriers to further reduction of the number of human rabies deaths, we carried out a questionnaire study of government hospitals throughout the Kingdom.

An immunogenicity and efficacy study of purified chick embryo cell culture rabies vaccine manufactured in Japan.

Purified chick embryo cell rabies vaccine manufactured by the Chemo-Sero-Therapeutic Institute(Kaketsuken) at Kumamoto, Japan (Kaketsuken) was submitted to an immunogenicity and efficacy study. 52 severely rabies exposed patients were treated with the conventional five doses intramuscular WHO approved ('Essen') postexposure schedule. This included the administration of 40 IU kg-1 of equine rabies immune globulin on Day 0. A control group of equally severely exposed subjects were treated with human diploid cell rabies vaccine manufactured by the Swiss Serum and Vaccine Institute as well as human rabies immune globulin. There were no deaths in either group in the more than 2 years follow-up period. Subjects treated with the chick embryo vaccine showed greater suppression of the neutralizing antibody response by the equine rabies immune globulin than those given the human diploid cell vaccine and human rabies immune globulin. A group of 20 less severely rabies exposed patients who received only the chick embryo vaccine without immune globulin all had antibody titers greater than the WHO minimal acceptable level on Day 14, 30, 90 and 180. Fourteen subjects among the severely exposed vaccine and immune globulin study group were given vaccine boosters on Day 180 because of low antibody titers. It is concluded that chick embryo rabies vaccine manufactured by Kaketsuken is an immunogenic and effective rabies vaccine, but that the potency of future batches must be increased to provide a greater safety margin.

Immune response to tissue culture rabies vaccine in subjects who had previous postexposure treatment with Semple or suckling mouse brain vaccine.

Nerve tissue derived Semple and suckling mouse brain rabies vaccines are still widely used. Patients who experience a new rabies exposure and who were given such vaccines decades earlier are not uncommon in rabies endemic countries. The World Health Organization recommends that persons who have had a previous course of a potent tissue or avian culture rabies vaccine and are reexposed, be given booster infections on days 0 and 3 without rabies immune globulin. Persons who have had previous pre- or postexposure vaccination with a vaccine of unproven potency, should receive a full course of tissue or avian cell vaccine and immune globulin in the event of a new exposure. This study evaluated the immune response in 98 Thai patients who gave a history of rabies postexposure treatment with Semple or suckling mouse brain vaccines 10-50 years previously. The majority (81) had an anamnestic response and developed neutralizing antibodies that were above the recommended minimal acceptable level (0.5 IU ml-1) on day 7. This suggests that they still had immunological memory. A minority of 18% had antibody titers below this level on day 7. However, they all developed titers above 0.5 IU ml-1 on days 14 and 30. Failure to have an accelerated response to revaccination by day 7 did not appear to be related to age or time elapsed since previous nerve tissue derived vaccine administration. It was not possible to predict which subject will or will not have an acceptable level of antibody before day 14. Rabies exposed patients who give a prior history of vaccination with an unknown or nerve tissue derived vaccine should therefore be treated as if they had never been vaccinated.

What is an acceptable delay in rabies immune globulin administration when vaccine alone had been given previously?

Rabies immune globulins (RIG) are not always available. Rabies-exposed patients often present to medical centers, particularly in canine rabies infested regions, after a vaccine series has been started without immune globulin administration. It is known that rabies immune globulin can result in suppression of the neutralizing antibody response which usually yields detectable antibodies by day 7. We have shown that it can be administered with a delay of up to 5 days after the start of vaccine treatment without significant antibody suppression within the first month. This study utilized the WHO approved multisite Thai Red Cross intradermal postexposure regimen. Effective use of rabies immune globulin in severe and multiple wounds, particularly in small children, may require dilution of the RIG in normal saline to provide a volume adequate for infiltration of all wounds.

Value of skin testing for predicting reactions to equine rabies immune globulin.

The high cost of postexposure prophylaxis for rabies is one reason that treatment is inadequate in developing countries. This problem has kindled interest in the use of equine rabies immune globulin, which is a less expensive, yet effective, substitute for human rabies immune globulin. Fatal anaphylaxis is a feared complication of the administration of heterologous serum; therefore, authoritative sources recommend prior skin testing. However, recommendations for methods of administering such a skin test and for its interpretation vary greatly. We embarked on a long-term study to develop guidelines for administration and interpretation of skin test results and to eventually determine a cost-benefit ratio. The skin test is not predictive of serum sickness. Anaphylaxis is rare with modern purified and pepsin-digested equine rabies immune globulins. We consider a skin test to be positive only if a wheal of > 10 mm in diameter, with or without flare, or a wheal of 5-10 mm in diameter with a flare of > 20 mm develops. Long-term studies will be required to answer the remaining questions regarding test criteria and cost benefits.

Efficacy study of a new albumin-free human diploid cell rabies vaccine (Lyssavac-HDC, Berna) in 100 severely rabies-exposed Thai patients.

A newly developed human diploid cell rabies vaccine (Lyssavac-HDC), produced without added serum albumin and with an effort to remove the virus-inactivating beta-propriolactone prior to addition of the gelatin, L-cysteine and potassium phosphate stabilizer, was tested for safety immunogenicity, adverse reactions and efficacy in 100 severely rabies-exposed Thais. All patients also received human rabies immune globulin and vaccine was administered using the conventional 5-dose intramuscular schedule of one dose on days 0, 3, 7, 14 and 28. One hundred percent of a subgroup of 40 subjects, where blood had been collected, had neutralizing antibodies greater than 0.5 IU ml-1 on days 28 and 90 and all had detectable titers on days 7, 14, 28, 90, 180 and 360. All patients could be followed for at least 1 year and remained well. No significant side-effects from this vaccine were noted.

Postexposure rabies vaccination during pregnancy: effect on 202 women and their infants.

This prospective study of 202 pregnant Thai women who received postexposure treatment for rabies with a tissue culture-derived rabies vaccine and human or equine rabies immune globulin revealed an adverse reaction rate similar to that seen among nonpregnant Thai patients who received the same treatment. Tissue culture-derived rabies vaccines as well as immune globulins are safe to use for postexposure prophylaxis during pregnancy. Such treatment should never be withheld or delayed if the patient possibly was exposed to rabies.

Immunogenicity of purified duck embryo rabies vaccine (Lyssavac-N) with use of the WHO-approved intradermal postexposure regimen.

The World Health Organization (WHO) has recommended the following regimen for administration of intradermal postexposure rabies vaccines (tissue or avian cultures): 0.1 mL of the vaccine given intradermally at two sites on days 0, 3, and 7 and at one site on days 28 and 90. WHO did not specify which types of vaccines should be used when following this regimen. We evaluated the efficacy of purified duck embryo rabies vaccine (Lyssavac-N) under the above regimen conditions; although purified duck embryo rabies vaccine is highly immunogenic when given intramuscularly, it differs significantly from the other rabies vaccination products in that it is not a solution, but rather, a suspension with an added preservative. Lyssavac-N was found to produce lower mean neutralizing antibody titers with the WHO-recommended intradermal regimen. However, when the volume of each dose was increased from 0.1 mL to 0.2 mL and the same schedule of administration was followed, satisfactory titers were obtained. We concluded that the WHO intradermal postexposure rabies vaccine regimen should only be used with vaccines that have been subjected to immunogenicity studies with satisfactory results.

What happens if intradermal injections of rabies vaccine are partially or entirely injected subcutaneously?

Reported are the results of a study with the Thai Red Cross two-site intradermal purified Vero-cell rabies vaccine (PVRV) schedule that was deliberately injected into subcutaneous tissue. The 44 healthy nonimmune Thai adults who were enrolled in the study were randomly assigned to the following groups and given PVRV as shown: group A (two intradermal injections on days 0, 3, and 7); group B (one intradermal and one subcutaneous injection on days 0, 3, and 7); and group C (two subcutaneous injections on days 0, 3, and 7). Neutralizing antirabies antibody titres were determined on day 14 using the rapid fluorescent focus inhibition test. High rabies antibody titres were obtained for all three groups. These results suggest that the economical and safe Thai Red Cross intradermal PVRV regimen could be used in selected general health care facilities.

What happens if intradermal injections of rabies vaccine are partially or entirely injected subcutaneously?

Reported are the results of a study with the Thai Red Cross two-site intradermal purified Vero-cell rabies vaccine (PVRV) schedule that was deliverately injected into subcutaneous tissue. The 44 healthy nonimmune Thai adults who were enrolled in the study were randomly assigned to the following groups and given PVRV as shown: group A (two intradermal injections on days 0, 3, and 7); group B (one intradermal and one subcutaneous injection on days 0, 3, and 7); and group C (two subcutaneous injections on days 0, 3, and 7). Neutralizing antirabies antibody titres were determined on day 14 using the rapid fluorescent focus inhibition test. High rabies antibody titres were obtained for all three groups

These results suggest that the economical and safe Thai Red Cross intradermal PVRV regimen could be used in selected general health care facilties(AU)