Duck Embryo Vaccine Research Articles

Immunogenicity, safety and tolerance of a purified duck embryo vaccine (PDEV, VAXIRAB) for rabies post-exposure prophylaxis: Results of a multicentric study in India

Rabies continues to be a major public health problem in India. Nearly 17 million people are getting exposed to this disease every year. Therefore the need for effective post-exposure prophylaxis with safe and potent modern rabies vaccines continues to exist. Purified Duck Embryo Vaccine (PDEV) was introduced in this country to meet the ever increasing need for modern rabies vaccines. In this study we have assessed the safety, imunogenicity and tolerance of an indigenously manufactured PDEV in people exposed to dog and other animal bites. One hundred and fifty people (5-59 years) who were having WHO category II or III animal bites were vaccinated with PDEV using the Essen Intramuscular regimen and rabies immunoglobluin (RIG) was administered to category III exposures.. Their blood samples were analyzed for rabies virus neutralizing antibody response (RVNA) by Rapid Fluorescent Focus Inhibition Test (RFFIT) on day 0, 14, 30, 90, 180 and 365. Adverse effects to vaccines were monitored during the course of vaccination. There was 100% sero- conversion from day 14 onwards with adequate RVNA titers ( >= 0.5 IU/mL) up to day 365. The incidence of side effects was minimal and self limiting. Hence it can be concluded that indigenously manufactured PDEV (Vaxirab) is a safe and immunogenic vaccine and can safely be used for post-exposure prophylaxis.

A comparative study on the immunogenicity, safety and tolerance of purified duck embryo vaccine (PDEV) manufactured in India (Vaxirab) and Switzerland (Lyssavac-N): A randomized simulated post-exposure study in healthy volunteers

Purified duck embryo vaccine (PDEV, Vaxirab) for rabies prophylaxis is now indigenously manufactured in India under technology transfer from Berna Biotech who made the original PDEV (Lyssavac). In the present study we have compared the two vaccines in terms of safety, immunogenicity and tolerance. The study was conducted in 220 adult healthy volunteers. It was observed that both vaccines produced neutralizing antibody titers (as determined by rapid fluorescent focus inhibition test, RFFIT) more than 0.5 IU/mL (minimum level for seroconversion) on all days tested but the titers on days 90 and 180 were significantly higher with Lyssavac. The adverse reactions produced were slightly more with Lysssavac but both vaccines were well tolerated. In conclusion, the indigenously produced PDEV (Vaxirab) was found to be equally safe and immunogenic as the original PDEV (Lyssavac) manufactured at Switzerland.

Rabies

Rabies

Preexposure Rabies Vaccination.

Preexposure rabies vaccination consists of the provision of protective antibodies to individuals who are potentially at risk of being infected with rabies.' This is done by giving three primary injections of a tissue culture rabies vaccine one each on day 0,7, and 28 (a few days variation in timing is acceptable). The vaccine is administered either as a full dose (usually 1 mL) intramuscularly or 0.1 mL intradermally. Intramuscular injections are given into the deltoid region (or lateral thigh muscle in small children).' Human diploid cell rabies vaccine (HDCV) and rhesus monkey diploid fetal lung cell vaccines (Michigan State Laboratory) are currently the products available in North America. Other tissue culture vaccines of proven quality are marketed abroad, and several are now being considered for approval in America. They are Purified Vero Cell Rabies Vaccine (PVRV) made by the Merieux Co in France, Purified Duck Embryo Vaccine (PDEV) made by the Swiss Serum and Vaccine Institute (not t o be confused with the poorly immunogenic old Duck Embryo Vaccines), and Purified Chick Embryo Rabies Vaccine (PCEC) made by Behring in Germany and the Chemo-Sero Institute in Japan. East European and Chinese firms manufacture tissue culture vaccines grown in baby hamster cells, but there is little independent literature in peer review journals attesting to their consistent quality control and immunogenicity. Many countries still manufacture and use central nervous tissue-derived rabies vaccines such as Semple and suckling mouse brain products. Most of these are of uncertain immunogenicity and carry a risk of severe adverse neurologic reaction^.^,^ Brain tissue-derived rabies vaccines are not to be used for preexposure vaccination due to an unacceptably poor risubenefit ratio.',

Confirmed rabies exposure during pregnancy: Treatment with human rabies immune globulin and human diploid cell vaccine

A review of the literature shows 24 cases of pregnant human exposure to rabies virus through confirmed rabid animal bites. Historically, these patients received passive immunization with equine rabies immunoglobulin and/or purified vero cell vaccine or duck embryo vaccine. With the recent development of human-derived rabies vaccines, we report an additional case of human gestational rabies exposure, which was treated with human rabies immune globulin and human diploid cell vaccine.

Intradermal immunization with human diploid cell rabies vaccine. Serological and clinical responses of persons with and without prior vaccination with duck embryo vaccine

Intradermal immunization with human diploid cell rabies vaccine. Serological and clinical responses of persons with and without prior vaccination with duck embryo vaccine

A comprehensive rabies control program in Alaska.

In 1975 the State of Alaska initiated a comprehensive Rabies Control Program. Lay vaccinators trained and certified by the state provided animal vaccination in rural areas. From 1975 through 1980, 182 persons received post-exposure rabies prophylaxis with Human Rabies Immune Globulin (HRIG) plus Duck Embryo Vaccine (DEV), or Human Diploid Cell Vaccine (HDCV), while 2,569 persons initially thought to have been exposed were not treated after consultation, at a cost saving of approximately $3,220,241.

Human Diploid Cell Rabies Vaccine: More Protection for Less Risk?

It is estimated that animal bites come to medical attention at an annual rate of 1/200 persons. 1 This encounter results in rabies vaccination for 30,000 persons per year. As an infectious diseases consultant, I can certify that the complications and concerns surrounding rabies vaccination are the most frequent problems that are brought to us—as they are to the local, state, or federal epidemiologist. The concern is well based. In 1957, duck embryo vaccine (DEV) was substituted for nerve-tissue—Origin vaccine (Semple type), because the same protection could be gained for a significant decrease in reactions—from neuroparalytic reaction of about 1/2,000 vaccinates to 1/24,400 (twenty-one among 512,000 recipients of DEV 1958-1975). 2 Although this was a 12-fold reduction, the price of rabies protection remained high. The 21 reactions included five cases of transverse myelitis, seven cases of cranial or peripheral neuropathy, and nine cases of encephalopathy. Virtually all recipients of DEV

Clinical Experience With a Human Diploid Cell Rabies Vaccine

Between January 1975 and December 1977 the Center for Disease Control treated 255 persons with the human diploid cell strain rabies vaccine who did not have development of an antibody titer to duck embryo vaccine (DEV) or who were at risk for having a serious reaction to DEV. Two hundred eighteen persons were treated postexposure, and 37 persons were treated preexposure. The antibody response to the vaccine was excellent, and the reaction rates were low. No person treated has had development of rabies. This study corroborates other studies that suggest that the human diploid cell strain rabies vaccines are safe and induce excellent antibody titers to rabies.

Responses to human diploid cell rabies vaccine: neutralizing antibody responses of vaccinees receiving booster doses of human diploid cell rabies vaccine.

Rabies neutralizing antibody levels were determined before and after administration of a booster-dose of Wyeth rabies vaccine (WRV) in persons immunized earlier with either duck embryo vaccine (DEV) or with WRV. Virtually all those receiving an initial 3-dose regimen of WRV (0, 7 and 21--28 days) still had neutralizing antibody one year later, but there was a decline in titer from 10--50 IU per ml at 35 days to about 1--3 IU. Only one-half of those receiving DEV as the primary vaccine had even detectable antibody one year later. All volunteers responded anamnestically to a single WRV booster given 8--12 months after either primary vaccine. Those given WRV initially had much higher antibody levels than those given DEV, but after the WRV booster antibody levels in all vaccinees remained high, even one year later.

A COMPARISON OF A WI-38 VACCINE AND DUCK EMBRYO VACCINE FOR PREEXPOSURE RABIES PROPHYLAXIS

Two types of rabies vaccine, WI-38 vaccine (WRV) and Duck Embryo Vaccine (DEV) were compared in rabies preexposure prophylaxis. Once group of veterinary students received four doses of DEV, a second group received four doses of WRV, and a third group received two doses of WRV. Adverse reactions were found to be similar for all three gorups. The antibody responses, however, differed markedly: the mean neutralizing titer after four doses of DEV was 1:75, after four doses of WRV was 1:1517, but was only 1:164 after two doses of WRV. All students who received three or four doses of WRV developed high titers of rabies antibody, making this vaccine very desirable for preexposure prophylaxis.

Evaluation of tests for rabies antibody and analysis of serum responses after administration of three different types of rabies vaccines

Humoral antibody response to three types of rabies vaccines were assayed by the neutralization (NT), the mixed hemadsorption (MH), and the indirect immunofluorescence (IF) tests. The NT and MH tests were used to detect antibodies combining with antigens at the surface of virions and infected cells, whereas the indirect IF test measured antibodies mainly to the rabies nucleocapsid antigen. After immunization with a human diploid cell vaccine, antibodies were detected by both the NT and the MH test in the 14th- and 30th-day serum samples from each of eight vaccinated persons. There was a good correlation between titers obtained with the two tests in this group of vaccinees. Antibodies elicited by duck embryo and nervous tissue vaccines occurred less frequently and in lower titers. In these groups of vaccinees, 5 of 14 and 5 of 10, respectively, had antibodies detectable by the NT test in the 14th- and 30th-day sera but were negative by the MH test. It is suggested that this was due to the high levels of immunoglobulin M antibodies, which are known to be elicited by daily injections of vaccine. Since antibodies of the immunoglobulin M class are considered to be less important for protection against rabies, the MH test is recommended for immunity determinations. Compared with the NT test, this test also offers the advantage of being technically more convenient because of its capacity for testing numerous sera in a single run. Antibody titers obtained by the indirect IF test in the human diploid cell vaccine group were relatively low. Titers in the duck embryo and nervous tissue vaccine groups were higher but did not correlate with the results of the NT test.

Serum neutralizing antibody after rabies postexposure prophylaxis.

One hundred seventy-seven persons submitted specimens for serum neutralizing antibody titer detreminations 30 to 90 days after starting postexposure rabies prophylaxis. Ninety-two percent of those who received duck embryo vaccine alone developed adequate antibody titers. However, 23% of those who received equine antirabies serum plus duck embryo vaccine failed to develop an adequate antibody titer; one of these inadequate responders subsequently died of rabies. Factors that increased the risk of a poor antibody response included the receipt of steroids during the course of postexposure prophylaxis, and the use of more than 55 lu/kg of equine antirabies serum. Many persons receiving postexposure rabies prophylaxis fail to develop adequate humoral immunity and may have an increased risk of developing rabies. We suggest that persons receiving postexposure rabies prophylaxis should have serum neutralizing antibody determinations 30 to 40 days after starting treatment.

NEW HUMAN TISSUE CULTURE VACCINE AGAINST RABIES

Nerve tissue rabies vaccines may produce neurologic sequelae, whereas duck embryo rabies vaccine has relatively poor antigenicity. To eliminate reactions while at the same time improving antibody responses, a vaccine has been prepared by concentration of rabies virus virions from supernatant fluids of WI-38 cell cultures, followed by inactivation with Beta-propiolactone or tributyl phosphate. Trials in animals showed protection against challenge. in man 1 dose given intramuscularly elicited antibodies in most subjects, and 3 doses produced responses in 100%. Vaccination with duck embryo vaccine on the same schedule resulted in titers ten to twentyfold lower. Excellent booster responses were observed in previously vaccinated individuals, possible schedules for postexposure immunization have been worked out, based on adnninistration of only 4 doses of vaccine, preexposure vaccination will also be feasible with minimal reactions, since the vaccine contains no animal protein. (we thank the Wyeth Laboratories and the institut Merieux for preparing the vaccine).

Antibody Response to a Human Diploid Cell Rabies Vaccine

An experimentally killed rabies virus vaccine prepared in a human diploid cell strain (WI-38)-Wyeth rabies vaccine (WRV)-was used by various injection schedules in two separate studies to define more closely in human volunteer subjects an effective vaccination schedule for pre- or postexposure immunization, particularly for donors of rabies-hyperimmune plasma. To permit valid comparisons between our results and those of other workers, antibody levels achieved were expressed in terms of international units (IU) per milliliter of serum. Antibody response of previously nonvaccinated persons were only modest after a single dose of WRV, never reaching a level higher than 0.80 IU/ml over a 56-day testing period. Moreover, antibody was not detected at 0.16 IU/ml before the 14th day, either after a single dose or after two doses given 3 days apart. The best response followed four doses of WRV given within 4 weeks. This schedule resulted in the highest rate of seroconversion to the >/=6 IU/ml antibody level required of potential rabies-immune plasma donors. Giving the first vaccine dose in aluminum hydroxide diluent did not enhance the antibody response. There was a definite suggestion in the various injection schedules that higher and more sustained antibody levels were reached when the interval between the first and second vaccine doses was longest. The greater immunogenicity of WRV as compared with duck embryo vaccine was best demonstrated by the fact that a single booster dose of duck embryo vaccine to previously vaccinated individuals resulted in only a sevenfold antibody rise during the following 56 days, whereas a booster dose of WRV elicited a 69-fold rise. Al(OH)(3) in the first dose of WRV had no effect, but the enhancing effect of a longer interval between vaccine doses was noted once again; 20 of 20 subjects who received three doses of WRV with 4 weeks between doses developed good levels of rabies antibody, and 19 exceeded 6 IU/ml.

Myelopathy After Duck Embryo Rabies Vaccine

Since the introduction of the rabies duck embryo vaccine, largely replacing the rabies nerve tissue vaccine formerly used, neurological complications of rabies vaccination have become very infrequent. We report the results of studies on a patient who developed myelopathy following vaccination with duck embryo vaccine, to our knowledge, only the third report of myelopathy since the introduction of this vaccine in 1958. Immunologic studies revealed that the patient had cellular immunity to both the rabies vaccine and to central nervous system protein as evidenced by marked stimulation of the patient's lymphocytes by rabies vaccine, a lower degree of stimulation by brain protein, and production of macrophage migration inhibiting factor and lymphotoxin by her lymphocytes in response to both antigens. There was a normal antibody response to rabies virus, but no evidence of serum antibody against human myelin.

Rabies neutralizing antibody: inadequate response to equine antiserum and duck-embryo vaccine.

After exposure to a patient with rabies, 15 hospital staff members received equine antiserum to rabies and duck-embryo rabies vaccine (DEV). Three persons (20%) had a low (<1:5) or absent serum neutralizing-antibody (SN) response 15 days after treatment began. Sixty-six days after treatment began, six of 13 (46%) had absent or only a low SN response. Forty percent of patients who received both recommended boosters had SN titers at day 66 as low as those who received neither booster. These data indicate that DEV is a poor antigen when combined with horse serum even when prescribed DEV boosters are given. The antibody response of patients given equine antiserum to rabies and DEV should be determined since additional DEV boosters may be required.

Immune response in primates vaccinated with duck embryo cell culture rabies vaccine.

Adult rhesus monkeys (Macaca mulata) were vaccinated with four inactivated rabies vaccines, including two cell culture vaccines, one zonal purified cell culture vaccine, and a 10% extracted duck embryo vaccine. The vaccines were potency tested by both National Institutes of Health (NIH) and Habel methods and passed one or both tests. However, a vaccine having acceptable potency by one method frequently failed or was marginal by the other procedure. Groups of three monkeys were inoculated with each vaccine by one of two schedules. The first consisted of four weekly 1-ml doses followed by a 1-ml booster dose at 6 months, and the second consisted of seven daily 1-ml doses of vaccine with no booster. Both zonal purified and extracted duck embryo vaccines induced detectable neutralizing antibody by day 7 with either schedule, and antibody titers elicited by the cell culture vaccine remained high through 210 days. However, antibody titers produced by the 10% duck embryo vaccine dropped sharply after their 28-day peak. Duck embryo cell culture vaccines with low or marginal potency as measured by Habel or NIH tests still produced rapid, high levels of serum-neutralizing antibody in primates. LD(50) or NIH and Habel tests as measured in mice were not necessarily good indices of antibody response in the primate host. The need for a cell culture potency test that will yield a more predictable correlation with the definitive host's antibody response is discussed.

"Leg Syndrome" Following Rubella Vaccine

To the Editor.— At least five published studies which Weibel et al did not cite have indicated that joint reactions to rubella vaccination do occur in children under 12 years of age. Although these were all retrospective studies, there is little doubt that these reactions do occur in young school children. Frequency and severity are greater for dog kidney vaccines as opposed to other types, yet 4% to 5% incidence in school children who received duck embryo vaccine has been demonstrated. Although these joint reactions are usually mild, a virtual absence of these complications should not be expected. To the Editor.— Drs. Kolansky and Moore (222:35, 1972) are to be commended for their careful clinical studies of the toxic effects of long-term cannabis use. One would hope that this type of clinical assessment of adverse effects would receive at least as much public attention as uninformed laymen's enthusiastic endorsements. The

Immune Response in Primates Vaccinated with Duck Embryo Cell Culture Rabies Vaccine

Adult rhesus monkeys (Macaca mulata) were vaccinated with four inactivated rabies vaccines, including two cell culture vaccines, one zonal purified cell culture vaccine, and a 10% extracted duck embryo vaccine. The vaccines were potency tested by both National Institutes of Health (NIH) and Habel methods and passed one or both tests. However, a vaccine having acceptable potency by one method frequently failed or was marginal by the other procedure. Groups of three monkeys were inoculated with each vaccine by one of two schedules. The first consisted of four weekly 1-ml doses followed by a 1-ml booster dose at 6 months, and the second consisted of seven daily 1-ml doses of vaccine with no booster. Both zonal purified and extracted duck embryo vaccines induced detectable neutralizing antibody by day 7 with either schedule, and antibody titers elicited by the cell culture vaccine remained high through 210 days. However, antibody titers produced by the 10% duck embryo vaccine dropped sharply after their 28-day peak. Duck embryo cell culture vaccines with low or marginal potency as measured by Habel or NIH tests still produced rapid, high levels of serum-neutralizing antibody in primates. LD(50) or NIH and Habel tests as measured in mice were not necessarily good indices of antibody response in the primate host. The need for a cell culture potency test that will yield a more predictable correlation with the definitive host's antibody response is discussed.