Evaluation of the safety, immunogenicity, and pharmacokinetic profile of a new, highly purified, heat-treated equine rabies immunoglobulin, administered either alone or in association with a purified, Vero-cell rabies vaccine

A clinical evaluation of a new, purified, heat-treated equine rabies immunoglobulin (PHT-Erig), F(ab')2 preparation, was carried out in Thailand and in the Philippines-two countries where rabies is endemic. An initial prospective, randomised, controlled trial (Study 1), compared the safety and pharmacokinetics (serum concentrations of rabies antibodies) after administration either of PHT-Erig or of a commercially-available, equine rabies immune globulin (Erig PMC). A second trial (Study 2) simulated post-exposure rabies prophylaxis by using a reference cell culture vaccine, the purified Vero-cell rabies vaccine (PVRV), administered in association with either Erig PMC or PHT-Erig. In Study 1, 27 healthy, Thai adults received a 40 IU kg(-1) dose of either Erig PMC (n = 12) or PHT-Erig (n = 15) via the intramuscular (i.m.) route; half of the dose was injected into the deltoid area and the other half into the buttocks. Serum for rabies antibody determination and F(ab')2 concentration was collected at hours (H) 0, 6 and 12, and on day (D) 2, 3, 4, 6, 8, 10, 12 and 15. Both products were safe, with no serious adverse events, and in particular, no anaphylactic reactions or serum sickness was reported. A statistical comparison of the pharmacokinetic parameters did not demonstrate bioequivalence of the two products. Nonetheless, the relative bioavailability of 93% and the similar absorption rates suggest the pharmacokinetic profiles of Erig and PHT-Erig are similar. The antibody level in either group were low throughout the 15-day study period. The geometric mean titer (GMT) values ranged from group 0.027-0.117 IU ml(-1) in the Erig group and from 0.029 to 0.072 IU ml(-1) in the PHT-Erig. There was no significant difference between the evolution of GMT values for the two groups. In Study 2, 71 healthy volunteers received 40 IU kg(-1) via the intramuscular route of either Erig PMC (n = 36) or PHT-Erig (n = 35) on D0, in association with five doses of PVRV on D0, D3, D7, D14 and D28. The safety evaluation was performed during the 28-day follow-up and serum samples for anti-rabies antibody titration were collected on D0 (before injection) D3, D7, D14 and D28. No serious reactions were reported in either group. In particular, no immediate (anaphylactic type) or delayed (serum sickness) allergic reactions were observed. Over the 28-day follow-up period, GMT profiles of the two groups were statistically equivalent. On D14, 100% of the subjects had protective antibody titers (anti-rabies antibodies > or = 0.5 IU ml(-1), which is the WHO-recommended level of seroconversion), and Erig PMC and PHT-Erig were indistinguishable according to the clinical definition chosen. On D28, the GMT values were 33.2 IU ml(-1) (95% CI, 23.8-46.1 IU ml(-1)) in the Erig PMC/PVRV group and 31.4 IU ml(-1) (95% confidence interval, CI, 23.4-42.2 IU ml(-1)) in the PHT-Erig/PVRV group, showing evidence of adequate vaccine-induced antibody responses in both groups. The increased purity, the heat-treatment step introduced in the manufacturing process of PHT-Erig, and the good clinical results substantiate the use of this new generation, purified equine F(ab')2 preparation in the post-exposure prophylaxis of rabies.     

Stromal keratitis induced by a unique clinical isolate of herpes simplex virus type 1

The antibody responses of 65 volunteers receiving an i.d. regimen (0.1 ml given at two sites on days 0, 3, 7 and 0.1 ml given at one site on days 30 and 90) were compared with the control group of 35 volunteers receiving the standard i.m. regimen. By day 14, seroconversion was observed in all vaccinees in both groups. Geometric Mean Titers remained higher than 0.5 IU/ml throughout the study period. At the end of the observation period on day 365, antibodies persisted in all subjects. The multisite i.d. PCEC regimen has been proved as immunogenic as the standard i.m. regimen. Both regimens were well tolerated. Thus, it would be the effective and cheapest available rabies post-exposure treatment using tissue culture vaccine.     

Failure of protection induced by a Brazilian vaccine against Brazilian wild rabies viruses

This report shows that the SMB vaccine currently used in Brazil for human immunisation provides different degrees of protection in mice, depending on the rabies virus strain used as challenge. Using the NIH and Habel potency tests to evaluate the protective activity of rabies vaccine, we observed that vaccinated mice showed a higher resistance to a challenge with a fixed rabies virus (CVS-Challenge Virus Strain). The vaccine potency using the Habel or NIH tests was respectively > 6.4 (log 10) and 1.0 (Relative Potency-RP) when the fixed rabies virus was used for challenge, and from 2.9 to 4.3 (log 10) or 0.13 to 0.8 (RP) when different wild rabies viruses were used for challenge. The presence of virus neutralising antibodies (VNA) could not explain the differences of susceptibility after vaccination, since sera of vaccinated animals had similar VNA levels against both fixed and wild strains before virus challenge (respectively, 5.6 +/- 0.24 and 5.0 +/- 0.25 IU/ml of VNA against the fixed rabies virus and the 566-M strain of wild rabies virus in sera of mice vaccinated with 0.2 units of vaccine). Only cell-mediated immunity parameters correlated with the protection induced by vaccination. The IFN gamma titers found in sera and brain tissues of animals challenged with CVS strain were higher (from 36.7 +/- 5.7 to 293.3 +/- 46.2 IU/ml) than those found in mice challenged with 566-M virus strain (from 16.7 +/- 5.8 to 36.7 +/- 5.8). The proliferation index of spleen cells obtained with CVS stimulation reached a maximal value of 15.1 +/- 0.7 while spleen cells from vaccinated mice stimulated with 566-M virus failed to proliferate. The implications of these data in human protection by vaccination are discussed.     

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.     

Perceived quality of life before and after implantation of an internal cardioverter defibrillator

One thousand three hundred and seventy-five (1375) persons, who were vaccinated against Rabies with Purified Chick Embryo Cell (PCEC) vaccine from 1984 to 1993, were included in this ten-year longitudinal study, conducted to observe the consistency, immunogenicity, inocuity, safety and efficacy of PCEC vaccine under controlled trial and field conditions. The study period was divided into three phases. Phases I and II covered the premarketing controlled trial and Phase III the post-marketing serosurveillance study of the vaccine. During Phase I, fifteen healthy volunteers were given a pre-exposure regime of vaccine on Day 0, 7 and 21, and the rest 15, simulated post-exposure regime on Day 0, 3, 7, 14, 30 and 90. All the subjects had satisfactory antirabies antibody response with mean titres, of 7.08 and 5.72 I.U./ml respectively, and minimal side reactions. In the Phase II, from 1984-85, 56 persons with proven rabid animal bites were given post-exposure vaccination and all had satisfactory antibody titres with mean titre of 4.45 I.U./ml after 6th dose of vaccine and with minimal side reactions. 19 to 36 months follow up after vaccination revealed no vaccine failures. In the Phase III post-marketing field study conducted from 1985 to 1993, 1289 persons reported to our Centre for consulation and antirabies antibody titre estimation following PCEC vaccination. One thousand two hundred and fifty-two (1252) persons took post-exposure vaccination following bites by rabid animals, contact with an hydrophobia patient and 37 high risk personnel took pre-exposure vaccination.(ABSTRACT TRUNCATED AT 250 WORDS)     

Safety and efficacy of purified Vero cell rabies vaccine given intramuscularly and intradermally. (Results of a prospective randomized trial)

OBJECTIVES: To determine adverse reactions as a result of pre- and post-exposure rabies vaccination, using the conventional intramuscular, and reduced dose intradermal regimens and purified Vero cell rabies vaccine. DESIGN: A prospective and randomized study of patients exposed to rabies and of subjects in need of pre-exposure rabies vaccination. SETTING: A metropolitan rabies control center in a canine rabies endemic country. PATIENTS: 1198 subjects were recruited between May, 1994 and March, 1996. They were divided into four groups. Patients with suspected or proven rabies exposures were given the vaccine intramuscularly using the conventional regimen, or intradermally using the World Health Organization approved Thai Red Cross schedule. Human or equine rabies immune globulin was administered where indicated. Pre-exposure and post-exposure vaccine recipients were divided randomly into two groups each and given the vaccine either by the intramuscular or intradermal schedules. MEASUREMENTS: All local and systemic adverse reactions were recorded and statistically analyzed. RESULTS: Pruritus at injection sites was the only significant local reaction. It was more common in the intradermal groups. Low-grade fever, the only significant adverse systemic event, was more common in the intramuscular groups and was noted in 8% of all subjects. Eighty-four patients bitten by proven rabid animals were found to be alive and well 3 years later. Forty-four of these had received the intramuscular and 40 the intradermal postexposure regimens with human or equine immune globulin injected into wounds on the first day of treatment. CONCLUSIONS: Purified Vero cell rabies vaccine is safe, carries a very low adverse reaction rate and is effective in preventing rabies in severely exposed subjects when used with human or equine rabies immune globulin.     

Passively acquired anti-tetanus and anti-Haemophilus antibodies and the response to Haemophilus influenzae type b-tetanus toxoid conjugate vaccine in infancy

OBJECTIVE: To study the influence of maternally inherited tetanus antitoxin (anti-TT) antibodies on the response to the Haemophilus influenzae type b (Hib) capsular polysaccharide (PS)-tetanus toxoid conjugate (PRP-T) vaccine. DESIGN: One hundred thirty healthy infants received their first dose of PRP-T in the same syringe with diphtheria-tetanus-pertussis vaccine (DTP) at 1 to 2 months, and 66 of them received a second dose at 3 to 4 months of age. RESULTS: Maternal anti-TT antibodies did not interfere with the anti-Hib PS response to the first PRP-T vaccination; the geometric mean concentration (GMC) of anti-Hib PS was 0.14 microgram/ml in those with the lowest preimmunization anti-TT (< 0.3 IU/ml, n = 15) and 0.13 microgram/ml in those with the highest anti-TT (> or = 3 IU/ml, n = 25). After the second dose of PRP-T there was a positive correlation (r = 0.37, P = 0.004) between the anti-Hib PS response and the preimmunization anti-TT; those with the lowest preimmunization anti-TT (< 0.3 IU/ml, n = 9) achieved GMC of anti-Hib PS of 1.22 micrograms/ml and those with anti-TT > or = IU/ml (n = 22) anti-Hib PS GMC of 2.67 micrograms/ml. High preimmunization anti-Hib PS antibodies did not interfere with the final antibody concentrations; the GMC of anti-Hib PS after the second dose of PRP-T was 1.60 micrograms/ml in those with a preimmunization titer > or = 1.0 microgram/ml (n = 12) and 1.57 micrograms/ml in those with a titer of < 1.0 microgram/ml (n = 53). CONCLUSION: The data suggest that infants can be safely vaccinated with PRP-T even though they have received high concentrations of anti-TT from their mother.     

Influence of high titers of maternal antibody on the serologic response of infants to diphtheria vaccination at three, five and twelve months of age

Diphtheria antitoxin was determined in serum from 44 pregnant women, of whom 26 had received one injection of diphtheria toxoid during pregnancy. Their infants were vaccinated with a combined diphtheria-tetanus vaccine at 3, 5 and 12 months of age. This vaccination schedule has been used in Sweden since 1986, replacing the old schedule of vaccination at 3, 4.5 and 6 months of age originally designed for diphtheria-tetanus-pertussis vaccine, which had not been used after cessation of general vaccination against pertussis in 1979. Serum samples from the infants were obtained at 3, 7 and 18 months of age. After 2 injections infants of mothers with high antitoxin titers, > or = 0.1 IU/ml, tended to have lower antitoxin titers than infants of mothers with low antitoxin concentrations (P = 0.067). All children had, however, antitoxin above the minimum protective level of 0.01 IU/ml. Median antitoxin titers were 1.6 IU/ml in both groups after the third booster injection. Four infants of mothers who had been vaccinated during pregnancy and who had titers of > or = 0.4 IU/ml did not reach the 0.1 IU/ml level after 2 injections: all 4 responded with high antitoxin titers after the third dose. Thus all infants were primed by 2 doses of vaccine, irrespective of maternal antibody concentration. The repressive effect of maternal antibody on titers noted after 2 doses was no longer observed after the third, booster dose.     

A regional programme to collect plasma for preparation of human immunoglobulin anti-rabies

We identified over 100 recipients of rabies vaccine (human diploid cell vaccine) and recruited them as plasma donors. Some were plasmapheresed at static centres, others by mobile teams. The operation of these teams is described in detail. No plasma was sent to the Fractionation Centre until the date of vaccination had been checked. Assay results showed that the majority of plasma collected between four and 20 weeks after the second dose of vaccine contained 6 or more IU/ml.     

High immunogenicity and good tolerability of a new hepatitis A vaccine candidate

Immunogenicity and tolerability of a new formalin-inactivated, alum-adjuvanted whole virus vaccine against hepatitis A (VAQTA, MSD, West Point, USA) were evaluated by immunizing 52 healthy, anti-HAV negative volunteers with a 1 ml dose. A booster dose was given 6 months later. In these young adult vaccinees [27 males and 25 females, 19-34 (mean 26) years of age] VAQTA proved to be well tolerated and highly immunogenic. Two weeks after administration of one vaccine dose, all but one of the recipients (98%) had anti-HAV concentrations above the presumed minimum protective level of 10 IU l-1 with a geometric mean concentration (GMC) of 165 IU l-1. After 4 weeks, a 100% seroconversion rate could be demonstrated with a fourfold increase of the GMC to 728 IU l-1. Six months after vaccination, all but one of the 50 volunteers coming back for booster (98%) showed anti-HAV levels within the protective range. The antibody concentrations had decreased in the majority of vaccinees to a GMC of 362 IU l-1. The booster dose given at that time was shown to be very effective, leading to a pronounced rise of anti-HAV levels in all recipients with a 17-fold increase of the GMC to 6040 IU l-1. Six months after the booster, all vaccinees were still seropositive with a GMC of 3444 IU l-1. Higher antibody levels were found in females, the difference being significant 4 weeks and 6 months after vaccination and 4 weeks after booster. No serious local or systemic adverse reactions were observed.     

Persistence of antibodies in children after intradermal or intramuscular administration of preexposure primary and booster immunizations with purified Vero cell rabies vaccine

BACKGROUND: The use of intradermal (i.d.) injections of purified Vero cell rabies vaccine (PVRV) for preexposure prophylaxis has not been well-established. We studied the safety and immunogenicity of i.d. and intramuscular (i.m.) PVRV injections for primary and booster preexposure immunizations. METHODS: One of two rabies preexposure PVRV regimens comprising three doses of either 0.1 ml i.d. or 0.5 ml i.m. administered during 28 days was assigned at random to 190 school children. One booster dose was given 1 year later either i.d. or i.m., according to their initial randomization group. Serologic results were available from 155 (82%) children at 1 year after primary immunization and 118 (62%) children at 2 years after booster. RESULTS: Although children vaccinated i.d. had significantly lower rabies-neutralizing antibody titers after primary immunization as well as after booster than children vaccinated i.m. (P< 0.001 for all time points), there were no significant differences in the percentages of children with adequate titers (> or =0.15 IU/ml) between the i.d. and i.m. groups after both primary and booster immunizations. Mild local reactions were more frequent after i.d. vaccination. Mild or moderate systemic reactions were infrequent and similar after i.d. and i.m. vaccinations. Fever and headache were reported by < or =6%. The reactions after booster were not different from those of post-primary immunization. CONCLUSIONS: Purified Vero cell rabies vaccine appears to be safe and immunogenic for primary and booster preexposure immunizations. An i.d. PVRV preexposure regimen should be useful especially for rabies-endemic countries with low per capita income.     

Assessment of the immunogenicity and reactogenicity of a quadrivalent diphtheria, tetanus, acellular pertussis and hepatitis B (DTPa-HBV) vaccine administered in a single injection with Haemophilus influenzae type b conjugate vaccine, to infants at 2, 4 and 6 months of age

This double-blind, randomised study was performed to assess the immunogenicity and reactogenicity of three lots of a quadrivalent diphtheria-tetanus-acellular pertussis-hepatitis B vaccine (DTPa-HBV) co-administered with three lots of Haemophilus influenzae type b conjugate (Hib) vaccine in one injection, as a primary vaccination course in healthy infants at 2, 4 and 6 months of age. 269 infants (8-11 weeks of age) were randomly allocated to three groups to receive DTPa-HBV/Hib vaccines, concomitantly with oral polio vaccine. Blood samples for antibody determinations were taken before vaccination and 1 month after the third dose in 262 subjects. Local and general symptoms were recorded by parents on diary cards. All vaccinees had post-vaccination protective anti-D and anti-T (> or = 0.1 IU ml-1) antibodies, and 98% had protective anti-HBs antibody titres (> or = 10 mIU ml-1). There were no statistically significant differences between groups in post-vaccination anti-D, anti-T, anti-HBs antibody geometric mean titres (GMT), these being 3.49 IU ml-1, 5.92 IU ml-1 and 1109 mIU ml-1, respectively. All subjects responded to three pertussis components, i.e. pertussis toxin (PT), filamentous haemagglutinin (FHA) and pertactin (PRN). Although statistically significant differences in GMTs of anti-PT, anti-FHA and anti-PRN were found between groups, these were not believed to be of any clinical relevance as the minimum GMTs were 60, 193 and 230 EL.U ml-1 for anti-PT, anti-FHA and anti-PRN, respectively. There were no statistically significant differences in anti-PRP antibody GMT (4.05 micrograms ml-1) between groups, 100% and 85% of subjects having titres > or = 0.15 and 1.0 microgram ml-1, respectively. No symptoms were reported for one third of the subjects. Fever (> 38 degrees C) was reported after 16% of doses, with < 1% having > 39.5 degrees C. Almost all local and general symptoms were mild or moderate, and lasted less than 48 h. No subject dropped out due to a severe adverse reaction. The administration of an experimental mix of DTPa-HBV and Hib vaccines in a single injection is safe, well-tolerated and immunogenic for all vaccine components.     

Hepatitis A vaccination

The safety and immunogenicity of an inactivated hepatitis A virus vaccine were assessed in 101 healthy adults. Seronegative persons with normal serum aminotransferase levels were grouped according to age: Group 1 (n = 24) and group 3 (n = 22) were between 18 and 40 years of age, and group 2 (n = 25) and group 4 (n = 30) were older than 40 years. Groups 1 and 2 received vaccine on a 0-, 1-, and 2-month schedule (schedule A), and groups 3 and 4 received the vaccine on a 0-, 1-, and 12-month schedule (schedule B). Of the 101 vaccinated subjects, 98 (97%) seroconverted with antibody titers to hepatitis A virus of > or = 20 IU per liter after the first dose, and all subjects seroconverted after the second dose. The geometric mean titers a month after the third vaccine dose were significantly greater (P < .03) on both schedules for younger subjects (schedule A, 1,743 IU per liter, and schedule B, 7,882 IU per liter) than for older subjects (schedule A, 826 IU per liter, and schedule B, 4,279 IU per liter). Also, the differences in geometric mean titers a month after the third dose were significantly greater (P < .001) for subjects in both age groups on schedule B (group 3, 7,882 IU per liter, and group 4, 4,279 IU per liter) than for those on schedule A (group 1, 1,743 IU per liter, and group 2, 826 IU per liter). The hepatitis A virus was well tolerated, with mild discomfort at the injection site being the main side effect. This vaccine is both safe and highly immunogenic.     

Pneumococcal polysaccharide vaccine in children with chronic renal disease: a prospective study of antibody response and duration

We studied the antibody response to pneumococcal serotypes 3 and 14 after pneumococcal polysaccharide vaccine was administered to 41 children with renal disease. One month after vaccination, 76% and 61% of patients achieved at least a twofold titer rise to serotypes 3 and 14, respectively; this finding was comparable to historic control values. One year after vaccination, the majority of patients retained protective antibody levels. Achieving a titer > or = 1.0 microgram/ml IgG at 1 month was highly predictive of retaining a protective antibody level > or = 0.15 microgram/ml at 1 year.     

Suppression of spermatogenesis in man induced by Nal-Glu gonadotropin releasing hormone antagonist and testosterone enanthate (TE) is maintained by TE alone

GnRH antagonists plus testosterone (T) suppress LH and FSH levels and inhibit spermatogenesis to azoospermia or severe oligozoospermia. High-dose T treatment alone has been shown to be an effective male contraceptive (contraceptive efficacy rate of 1.4 per 100 person yr). Combined GnRH antagonist and T induces azoospermia more rapidly and at a higher incidence than T alone; this combination has therefore been proposed as a prototype male contraceptive. However, because GnRH antagonists are expensive to synthesize and difficult to deliver, it would be desirable to rapidly suppress sperm counts to low levels with GnRH antagonist plus T and maintain azoospermia or severe oligozoospermia with T alone. In this study, 15 healthy men (age 21-41 yr) with normal semen analyses were treated with T enanthate (TE) 100 mg im/week plus 10 mg Nal-Glu GnRH antagonist sc daily for 12 weeks to induce azoospermia or severe oligozoospermia. At 12-16 weeks, 10 of 15 subjects had zero sperm counts, and 14 of 15 had sperm counts less than 3 x 10(6)/mL. The 14 who were suppressed on combined treatment were maintained on TE alone (100 mg/week im) for an additional 20 weeks. Thirteen of 14 subjects in the TE alone phase had sperm counts maintained at less than 3 x 10(6)/mL for 20 weeks. Ten remained persistently azoospermic or had sperm concentration of 0.1 x 10(6)/mL once during maintenance. Mean LH and FSH levels in the subjects were suppressed to 0.4+/-0.2 IU/L and 0.5+/-0.2 IU/L in the induction phase, which was maintained in the maintenance phase. The 1 subject who failed to suppress sperm counts during induction had serum LH and FSH reduced to 0.3 and 0.5 IU/L, respectively. The subject who failed to maintenance had LH and FSH suppressed to 1.0 and 0.2 IU/L, respectively, during the induction phase but these rose to 1.6 and 2.1 IU/L, respectively, during maintenance. Failure to suppress or maintain low sperm counts may be related to incomplete suppression of serum LH and FSH levels. We conclude that sperm counts suppressed with GnRH antagonist plus T can be maintained with relatively low dose TE treatment alone. This concept should be explored further in the development of effective, safe, and affordable hormonal male contraceptives.     

Daily measurements and in-vitro effects of human chorionic gonadotrophin in the early luteal phase

The purpose of the present study was to analyse daily measurements of human chorionic gonadotrophin (HCG) in in-vitro fertilization (IVF) cycles and to reproduce the effects of HCG in vitro using human granulosa-luteinized cells from the same patients. The study population consisted of nine women undergoing IVF because of tubal infertility in whom blood was drawn every 24 h from the day of the ovulatory dose of HCG (10,000 IU) until 6 days after ovum pick-up. Granulosa-luteal cells from the follicular aspirates were collected and cultured in vitro up to 6 days in the presence of increasing concentrations (0, 0.01, 0.1, 1.0 and 100.0 IU/ml) of HCG. Serum progesterone and HCG in vivo as well as progesterone accumulation in vitro on days 2, 4 and 6, were the main outcome measures. Maximum HCG concentrations (0.25 IU/ml) were reached the day before ovum pick-up, and continuously decreased until day 6 after ovum retrieval. HCG did not stimulate progesterone production in vitro at any dose tested until day 6 after ovum pick-up. Then, 0.01 IU/ml resulted significantly (P < 0.05) stimulatory compared to controls, while 1.0 IU/ml was inhibitory (P < 0.05). It is concluded that HCG supplementation in an IVF cycle is unnecessary until day 6 after ovum pick-up. On day 6, progesterone production is stimulated with very low concentrations of HCG.     

Evaluation of the safety of two attenuated oral rabies vaccines, SAG1 and SAG2, in six Arctic mammals

The safety of two attenuated oral rabies vaccines was evaluated in mink and in five species of rodents which occur in the Arctic. A 0.03 ml sample of liquid vaccine was installed directly into the mouth of voles and lemmings and 0.1 ml into the mouth of Arctic ground squirrels and mink. Animals were euthanized at 36 and 46 days postexposure; brain tissue was analyzed by FAT and serum by RFFIT. No rabies deaths occurred in 47 animals tested. Four animals representing three rodent species seroconverted, the highest titer being 0.5 IU ml-1. The absence of rabies virus in brain tissue indicates the safety of these vaccines in these species. The replacement of arginine with glutamic acid at position 333 reduces the pathogenicity of these vaccines, thereby presumably preventing the deleterious effect of viral entry into CNS neurons.     

Efficacy of an oral vaccinia-rabies glycoprotein recombinant vaccine in controlling epidemic raccoon rabies in New Jersey

A field trial to evaluate the efficacy of an oral vaccinia-rabies glycoprotein recombinant virus vaccine in controlling epidemic raccoon (Procyon lotor) rabies was conducted by distributing 180,816 doses (10(8.2)TCID50/ml) of vaccine in wax ampules within fish-meal polymer baits at a rate of 64 doses/km2/treatment throughout a 552 km2 area, forming an 18 km wide band across the northern Cape May Peninsula of New Jersey (USA). Vaccination treatments were conducted in the spring and fall between May 1992 and October 1994 from a helicopter along ecotones and from motor vehicles along roads. Vaccine-laden baits were removed by animals from tracking stations within 3 wk and 61% of the identifiable tracks were those of raccoons. Tetracycline incorporated in the baits as a biomarker was detected in 155 (73%) of the vaccination area raccoons following the fall 1993 and spring 1994 vaccinations. Eleven (61%) of the raccoons sampled in the same time period seroconverted (> or = 0.5 IU) in response to rabies virus glycoprotein. A raccoon diagnosed with rabies from the northern border of the vaccination area on 30 April 1993 provided the first evidence that the barrier was being challenged by the rabies epidemic. The prevalence of rabies in raccoons from the vaccination area for the first year (10%, n = 96) and second year (8%, n = 61) of challenge was reduced more than six-fold by vaccination compared to unvaccinated raccoons from northern adjacent surveillance areas during the corresponding first (65%, n = 189) and second years (53%, n = 43). Vaccination also effectively reduced by three-fold the rate at which the epidemic moved through the raccoon population (15 km/yr). The breach of the vaccination area resulted in a resumption of the high rate (43 km/yr) of epidemic movement and a significant nine-fold increase in rabies prevalence (77%, n = 47). The maximum linear movement (12.9 km) among five ear-tagged rabid raccoons in the study area was significantly greater than that of 19 normal radio-collared raccoons (2.58 km) in the area. These large movements of rabid raccoons, together with relocation of nuisance raccoons, spillover of raccoon rabies in skunks (Mephitis mephitis) and other species, insufficient funding and a decision to discontinue the program in 1994 (which could have resulted in insufficient population immunity among raccoons in the vaccination area) may have contributed to the eventual breach of the barrier.     

Reactivity and immunogenicity of Havrix 360 vaccine for hepatitis A

The reactogenicity and immunogenicity of a new vaccine against viral hepatitis A, under the name HAVRIX, manufactured by SmithKline Beecham Biologicals, Belgium, was studied. A single dose of 1 ml contains not less than 360 ELISA units of inactivated HAV, strain HM175, cultivated on human diploid cells. The vaccine has been applied intramuscularly to 80 second-grade primary school children under the 0, 1 and 6-month schedule. Postvaccinal reactions were followed for three days after each application of the vaccine. They were generally mild and present in less than 5% of the vaccinees (local as well as general). One month after the last vaccination the seroconversion was 100% in the anti HAV antibody test (HAVAB-ABBOT), the antibody level being over 500 IU/I, in 98% of the vaccinees. In conclusion, the tested vaccine is perfectly acceptable from both aspects, postvaccinal reactions and conferred protection. As the hepatitis A morbidity in Croatia has never been as low as in the last few years, the eventual introduction of this vaccination into the EPI is questionable.     

Manual and computer-aided space analysis: a comparative study

Separate injections of Haemophilus influenzae type b capsular polysaccharide-tetanus conjugate (PRP-T) vaccine and diphtheria-tetanus-pertussis (DTP) reconstitution of freeze-dried PRP-T vaccine with liquid DTP vaccine have been shown to be safe and immunogenic in infants. The present study was conducted to test the safety and immunogenicity of the liquid combination vaccine administered to young infants in the dual-chamber syringe. The study was a monocenter, open clinical trial of 3 month-old infants receiving PRP-T and DTP vaccines in the dual-chamber syringe reconstituted prior to injection. Healthy infants were immunized according to a 3, 4 and 5 months-of-age schedule. The vaccine was administered in a dual-chamber syringe, ready to use with two chambers. The proximal chamber contained freeze-dried PRP-T and the distal chamber contained liquid combination-vaccine DTP. The freeze-dried PRP-T vaccine was reconstituted with the liquid DTP vaccine in the same unidose dual-chamber syringe (0.5 mL) and was injected intramuscularly into the deltoid region. Blood sampling was performed prior to vaccination at 3 months of age and after the third vaccination at 6 months. The primary end-point was the serological response to PRP-T vaccine as expressed by the percentage of infants with an antibody titer greater than or equal to 1 microgram/mL. The reactogenicity was expressed as the percentage of reported local and systemic reactions. A total of 108 infants were included in the study and received the dual-chamber syringe vaccine. After the third injection, all the infants had a PRP antibody titer greater than or equal to 0.15 microgram/mL and 94.4% of infants had a PRP antibody titer greater than or equal to 1 microgram/mL; the pertussis agglutinin titers were over the threshold 40 and 80 in all infants and 98.1% were over the threshold 320. After the third injection, all the infants had diphtheria antibody titers greater than 0.1 IU/mL and 83.3% had titers greater than 1 IU/mL; all the infants had tetanus antibody titers greater than 0.1 IU/mL and 97.2% had results over 1 IU/mL. Thirty-seven infants (34.6%) had local reactions and 64.5% had systemic reactions. The dual-chamber syringe may reduce the cost of vaccine delivery, as well as the workload, and increase the vaccine acceptability and coverage rate of vaccines.