Depression of anticapsular antibody after immunization with Haemophilus influenzae type b polysaccharide-diphtheria conjugate vaccine.

Invasive Haemophilus influenzae type b infections have been observed in the week after immunization with capsular polysaccharide vaccine. We sought to document depression of antibody concentrations after immunization of 18-month-old infants with H. influenzae type b capsular polysaccharide-diphtheria conjugate vaccine. All 9 infants with detectable preimmunization anticapsular antibody had depression of antibody concentrations on the second day after immunization (P = 0.002). By Day 7 all had achieved anticapsular antibody concentrations greater than 0.15 micrograms/ml, a level believed to provide protection to immediate challenge with H. influenzae type b. Of those without detectable preimmunization antibody, 7 of 21 (33%; 95% confidence interval, 11 to 56%) had not achieved concentrations of greater than 0.15 mg/ml 1 week after immunization. We conclude that there is depression of anticapsular antibody concentrations during the first week after immunization with H. influenzae type b capsular polysaccharide-diphtheria conjugate vaccine. We speculate that H. influenzae type b infections after immunization with H. influenzae type b vaccines may be the result of: (1) low antibody concentrations because of either depression of antibody concentrations or failure to develop antibody; and (2) exposure to H. influenzae type b. Depression of antibody concentrations could be explained by binding of in vivo antibody to the vaccine.

Safety evaluation of PRP-D Haemophilus influenzae type b conjugate vaccine in children immunized at 18 months of age and older: follow-up study of 30,000 children.

We evaluated the safety of the PRP-D conjugate Hib vaccine (ProHIBit, Connaught) in 29,309 children vaccinated at 18-60 months of age in the Southern California Kaiser Permanente medical clinics during the period April 1, 1988, to July 31, 1989. Surveillance for potential reactions involved postcard questionnaires, telephone surveys, reports of Kaiser staff and review of hospitalizations and covered two periods following immunization: (1) the first 48 hours and (2) days 2 through 30. Surveillance for invasive Hib disease involved the above methods in addition to systematic reviews of laboratory and hospital records through January 31, 1990. Rates of local and systemic reactions within 48 hours of vaccination with PRP-D alone were low (less than or equal to 2% for fever greater than 102 degrees F, local redness or swelling) and similar to those previously reported after vaccination with PRP. Hospitalization and seizures (0.15% and 0.09% of vaccinated children, respectively) occurring within 1 month of immunization appeared to be unrelated to vaccination. One 29-month-old child had onset of a fatal episode of Hib sepsis/meningitis within 48 hours of vaccination. Also, a 30-month-old child developed Hib meningitis 10 months after PRP-D vaccination. We conclude that PRP-D is safe when given alone or in combination with other childhood vaccines between 18 and 60 months of age.

Streptococcus pneumoniae capsular polysaccharide-diphtheria toxoid conjugate vaccine is immunogenic in early infancy and able to induce immunologic memory.

BACKGROUND: Pneumococcal polysaccharide vaccines are not protective against the most common pneumococcal infections in infancy. The importance of pneumococcal diseases and emerging antimicrobial resistance emphasize the need for prophylaxis. METHODS: Pneumococcal conjugate vaccine, containing capsular polysaccharides from serotypes 6B, 14, 19F and 23F conjugated to diphtheria toxoid (PncD), was given to 75 infants at 2, 4 and 6 months of age. Three dosages (1, 3 or 10 microg of each) were used. A placebo group of 49 infants received physiologic saline. Children were given a booster dose of either polysaccharide or conjugate vaccine at 14 months of age; the placebo group received conjugate vaccine. Antibody concentrations were determined with an enzyme immunoassay. RESULTS: The highest dose induced the strongest response after primary immunization, but booster response was greatest in the group primed with the lowest dose. Polysaccharide and conjugate vaccines induced booster responses of the same magnitude. At 24 and 36 months of age the antibody concentrations were similar in children who had received the PncD in infancy and in children immunized at 14 months of age only. CONCLUSIONS: The PncD conjugate vaccine is immunogenic and able to induce immunologic memory.

Safety and immunogenicity of Biken acellular pertussis vaccine in combination with diphtheria and tetanus toxoid as a fifth dose at four to six years of age. Munich Vaccine Study Group.

OBJECTIVES: To evaluate the safety and immunogenicity of Biken acellular pertussis vaccine in combination with diphtheria and tetanus toxoid (Biken DTaP) vaccine administered to children 4 to 6 years of age who had previously received four doses of Biken DTaP. METHODS: 580 children were enrolled to receive one dose of Biken DTaP. Local and systemic reactions were collected by parent diary for all subjects within 3 days after vaccination and in a subset for 14 days. All adverse events occurring within 30 days after vaccination were recorded. RESULTS: Any redness and swelling occurred in 59.8 and 61.4%, respectively. Redness or swelling larger than 5 cm/10 cm occurred in 31%/6.1% and 25%/6.5% of the children, respectively. Any pain was reported in 58.8%, but clinically significant pain occurred in 2.1% of the children. Fever >38.0 degrees C occurred in 3.8% of the children. Fussiness, drowsiness, anorexia and vomiting were experienced by 19.7, 15.5, 7.3 and 2.2%, respectively. Sixty-three of 247 adverse events (25%) occurring within 30 days after vaccination were assessed to possibly be vaccine-related. Fifty-eight of the 63 possibly related events (92%) were caused by local reactions as redness, swelling or itchiness. The remaining 5 events included hematoma, headache, stomachache and sleep disturbance. All local and systemic reactions and adverse events resolved without sequelae. Immunogenicity analysis showed a 4-fold antibody increase to pertussis toxin in 97% of subjects and to filamentous hemagglutinin in 82%. All subjects had postvaccination antibody titers of 0.1 IU/ml or greater against diphtheria and tetanus. Higher prevaccination antibody titers against diphtheria toxoid, pertussis toxin and filamentous hemagglutinin were associated with a higher frequency of large local reactions. CONCLUSION: In comparison with a fourth dose of Biken DTaP administered at 18 to 24 months of age in the same population, the rate of local reactions increased after the fifth dose, whereas systemic reactions remained similarly low or decreased.

Efficacy of a two-component acellular pertussis vaccine in infants.

OBJECTIVE: This case-control study investigated the protective efficacy against pertussis of three doses of a two-component acellular pertussis vaccine (manufactured by Biken in Japan) combined with diphtheria and tetanus toxoids (manufactured by Connaught Laboratories in the US) in infants. METHODS: A case-control study was performed in 63 pediatric practices in Germany. Prospective recruitment of 16,780 infants ages 6 to 17 weeks took place between February, 1993, and July, 1994. According to parental choice infants received either Biken acellular pertussis vaccine combined with diphtheria and tetanus toxoids (DTacP) (74.6%) at approximately 2, 4 and 6 months of age, or a licensed German diphtheria-tetanus toxoids-whole cell pertussis vaccine (10.9%), diphtheria-tetanus toxoids vaccine (12.5%) or no vaccine (2.0%). Prospective surveillance of pertussis cases between February, 1993, and May, 1995, was accomplished by culturing all infants < or =2 years of age presenting with cough > or = 7 days. A pertussis case was defined as any cough of 21 days or longer plus a positive Bordetella pertussis culture or household contact exposure. RESULTS: We identified 241 pertussis cases prospectively by 11,017 B. pertussis cultures and 949 controls matched for age were selected from the same pediatric practices. Medical history and demographic and vaccine status data were collected from each case and for four controls. Data were analyzed through conditional logistic regression taking into account individual matching and adjusting for potential confounding variables. DTacP combined with diphtheria and tetanus toxoids vaccine was 82% protective (95% confidence interval, 68 to 90), diphtheria-tetanus toxoids-whole cell pertussis vaccine was 96% protective (95% confidence interval, 78 to 99). Protection against typical B. pertussis infection characterized by paroxysmal cough lasting > or =21 days was 96% (95% confidence interval, 87 to 99) for DTacP and was 97% (95% confidence interval, 79 to 100) for diphtheria-tetanus toxoids-whole cell pertussis vaccine. Adjustment for potentially confounding variables did not change the results significantly. CONCLUSIONS: Three doses of the two-component acellular pertussis vaccine protected infants against pertussis disease during the period before the recommended booster vaccination. For typical pertussis disease as defined by the WHO efficacy was high and similar to that of a licensed German diphtheria-tetanus toxoids-whole cell pertussis vaccine.

Immunoglobulin deficiency and idiotype expression in children developing Haemophilus influenzae type b disease after vaccination with conjugate vaccine. The Collaborative Study Group.

OBJECTIVE: --Haemophilus influenzae type b (Hib) conjugate vaccines are effective in preventing Haemophilus disease in most children. The reasons why the vaccination fails in some children are unknown. This study investigated host factors in children who developed the disease despite conjugate vaccination. DESIGN, PATIENTS, OUTCOME MEASURES:--A convenience sample of 23 patients in whom Hib disease developed 14 days or more after conjugate vaccination was investigated for the presence of subnormal serum immunoglobulin concentrations and anticapsular antibody responses to Hib disease. We also investigated expression of the Hib idiotype 1 (Hibld-1), a serological marker of a VKII chain that comprises a major portion of the normal variable region repertoire of the antibody response to Hib polysaccharide. The results were compared with those of 149 patients in whom the unconjugated Hib polysaccharide vaccine failed and of 90 unvaccinated patients who developed the disease. RESULTS: --Compared with children in whom the unconjugated polysaccharide vaccination failed, the relative risk of a subnormal serum concentration of IgM, IgA, IgG, and/or IgG2 in the children in whom the conjugate vaccination failed was 4.9 (95% confidence interval [CI], 1.8 to 14; P less than .003) and of IgG2 was 22 (95% CI, 3.5 to 146; P less than .001). With the exception of the children with subnormal serum immunoglobulin concentrations, most of the children with conjugate vaccination failure showed normal or high anticapsular antibody responses to the disease, whereas the children with polysaccharide vaccination failure showed impaired responses. The Hibld-1 was expressed by the majority of the children in both vaccination failure groups and of the unvaccinated patients. CONCLUSIONS: --In most patients, vaccination failure is not attributable to lack of expression of the variable region gene encoding Hibld-1. However, children in whom conjugate vaccination has failed frequently have subnormal serum immunoglobulin concentrations and should be evaluated for immunodeficiency.

Diphtheria antitoxin levels among children primed with a diphtheria and tetanus toxoids and acellular pertussis vaccine lot with a subpotent diphtheria toxoid component.

One lot of a nationally distributed diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine was recalled in January 1999 because of a subpotent diphtheria toxoid component. To evaluate vaccine immunogenicity, children who had received the recalled lot for at least 2 of the 3 doses of their primary series were identified. Diphtheria antitoxin (DAT) levels were then prospectively assessed before and after dose 4 of (fully potent) DTaP vaccine. Of the 105 children evaluated, 84% had prevaccination DAT levels <0.10 IU/mL, which is the level generally accepted as protective. DAT levels rose a mean of 92-fold after dose 4; 100% of subjects had DAT levels >or=0.10 IU/mL, and 69% had DAT levels >or=1.0 IU/mL. These results indicate that diphtheria potency testing can identify vaccine that is less immunogenic when administered during the primary series. The booster response to dose 4, although reduced, was sufficient to confer adequate protection in the interval before receipt of the fifth dose of DTaP.

Evaluation of the safety and immunogenicity of a new, heat-treated human rabies immune globulin using a sham, post-exposure prophylaxis of rabies.

A double-blind, controlled, randomized trial was conducted to evaluate the safety and immunogenicity of a new human rabies immune globulin (HTRIG). This product, manufactured by Pasteur Merieux Connaught, PMC, has undergone a heat-treatment step (10 h at 60 degrees C) and removal of mercurothiolate. The corresponding unheated product available from the same manufacturer (human rabies immune globulin, HRIG, IMOGAM RABIES[spr2]) was used for comparison. These two rabies immune globulins (RIGs) were administered either alone or in association with the human diploid cell rabies vaccine (HDCV, IMOVAX[spr2] RABIES, PMC) according to a standard, post-exposure rabies prophylaxis schedule. Sixty-four healthy adults were randomly assigned to four groups of 16 to receive either HRIG/placebo, HTRIG/placebo, HRIG/HDCV or HTRIG/HDCV. RIG was administered at the recommended dose of 20 IU/kg by three intramuscular (i.m.) injections in the gluteus. HDCV or placebo was given on day (D) 0, D3, D7, D14, and D28 into the deltoid by the intramuscular (i.m.) route. Any local reaction from D0 to D3 at the immune globulin injection site, and any systemic reaction from D0 to D42, were monitored by subject diaries. Rabies-neutralizing serum antibody levels were assessed by the rapid fluorescent focus inhibition test (RFFIT) before treatment and on D3, D7, D14, D28, D35, and D42. No serious adverse reactions and, in particular, no allergic-type reactions were reported. The safety profiles of HTRIG and HRIG were similar, except that complaints of pain, or tenderness at the injection site were half as common in the HTRIG group. Most of the local reactions were mild or moderate. After the administration of HTRIG/placebo or HRIG/placebo, 60% of subjects had detectable rabies antibodies levels, but by D42 all titres were below the seroprotective level (i.e. below 0.5 IU/ml). In the groups HTRIG/HDCV and HRIG/HDCV, the antibody titres rose markedly from D7, and reached a maximum value of 19 IU/ml (95% CI, 11 to 38 IU/ml) and 31 IU/ml (95% CI, 20 to 48 IU/ml), respectively, on day 14. All subjects who received RIG and vaccine maintained a protective antibody level from D14 to D42. No significant difference in immunogenicity results between these two groups (HTRIG/HDCV and HRIG/HDCV) was observed, and no interference of immune globulin with vaccine was reported. The safety and immunogenicity profiles of PMC HTRIG appear comparable with the current reference product. The heat-treatment step will enhance the safety by further reducing the probability of virus transmission through immune globulin treatment. The low levels of rabies antibodies obtained by intramuscular administration of either PMC HTRIG or of PMC HRIG support the recommendations that call for local infiltration of wounds with RIG.

Comparison of the safety and immunogenicity of acellular (BIKEN) and whole-cell pertussis vaccines in 15- to 20-month-old children.

OBJECTIVE: To compare the immunogenicity and reactogenicity of a two-component acellular pertussis vaccine (BIKEN) with whole-cell diphtheria and tetanus toxoids and pertussis vaccine (WC-DTP) when administered to children aged 15 to 20 months. DESIGN: A randomized, double-blind study. SETTING: Children in this study were from 12 general pediatric practices (11 were private and one was university-affiliated) and one inner-city university pediatric clinic. PARTICIPANTS: Two hundred forty-six children aged 15 to 20 months who had received a three-dose primary series of standard WC-DTP vaccine during infancy. SELECTION PROCEDURES: Children were randomly assigned to receive either WC-DTP or one of three lots of acellular diphtheria and tetanus toxoids and pertussis vaccine (DT-aP) in a 1:3 ratio at the 11 private practices and in a 1:1 ratio at the university-affiliated practice and inner-city university pediatric clinic. INTERVENTIONS: The DT-aP vaccines contained 23.4 micrograms each of pertussis toxin and filamentous hemagglutinin per 0.5 mL and the same concentrations of diphtheria and tetanus toxoids as WC-DTP. Serum samples were obtained on the day of immunization and 4 to 6 weeks later. Adverse reactions at 6, 24, 48, and 72 hours were recorded by parents who were contacted by telephone at 24 and 72 hours and 14 days after immunization. MEASUREMENTS/MAIN RESULTS: An indirect enzyme-linked immunosorbent assay method was used to determine IgG antibody response to pertussis toxin and filamentous hemagglutinin and IgG, IgA, and IgM to tetanus toxoids; a Chinese hamster ovary cell assay was used to measure functional antibodies to pertussis toxin; serum neutralization on VERO cells assayed diphtheria anti-toxin. Recipients of the DT-aP vaccine had fewer local reactions in the first 6 to 48 hours and fewer systemic reactions at 24 hours than did recipients of the WC-DTP vaccine. Acetaminophen was administered to 31% of DT-aP recipients compared with 63% of WC-DTP recipients. Infants given DT-aP had higher geometric mean antibody titer levels against pertussis antigens after vaccination. CONCLUSION: The BIKEN DT-aP vaccine used in this study is less reactogenic and more immunogenic for selected pertussis antigens than the WC-DTP vaccine in children aged 15 to 20 months.

Choosing a route of administration for quadrivalent meningococcal polysaccharide vaccine: intramuscular versus subcutaneous.

A clinical trial was conducted to compare intramuscular (im) with subcutaneous (sc) routes for administration of quadrivalent meningococcal polysaccharide vaccine in 141 adults. Safety assessment showed the im route had reduced erythema (P<.01) and reduced headache on days 1 and 2 (P<.05). Serological testing for serum bactericidal antibody titers against capsular groups A and C did not detect significant differences.

Immunogenicity, safety and lot consistency in adults of a chromatographically purified Vero-cell rabies vaccine: a randomized, double-blind trial with human diploid cell rabies vaccine.

The immunogenicity and safety of a chromatographically purified rabies vaccine (CPRV) was evaluated using US veterinary medical students. In the first study, 242 healthy adults were enrolled in a randomized, modified double-blind, multicenter trial and received five doses of either CPRV or human diploid cell vaccine (HDCV) by intramuscular injection on days 0, 3, 7, 14, and 28 concurrently with human rabies immunoglobulin in a simulated post-exposure prophylaxis regimen. Post-immunization titers in the CPRV and HDCV groups reached 0.5 IU/ml (the WHO-recommended minimally acceptable titer) or greater in all subjects in both vaccine groups by day 14 and remained above that level through day 90. In the second study, 438 healthy adults were enrolled in a randomized, double-blind, multicenter trial and assigned to receive five doses from one of three lots of CPRV by intramuscular injection on days 0, 3, 7, 14, and 28 in a simulated post-exposure prophylaxis regimen to evaluate lot consistency. Post-immunization titers rapidly increased to over 0.5 IU/ml by day 14 for all subjects and remained above that level through day 42 when the study was terminated. The three lots were considered equivalent. The percentage of subjects with at least one local reaction during the five-dose regimen was slightly lower in the CPRV group than in the HDCV group (P=0.06). The most frequently reported local reaction for all doses of vaccine was pain at the injection site. Headache, myalgia, and malaise were the most frequently reported systemic events. The percentage of subjects with at least one systemic event was significantly lower for CPRV (P=0.0084). No vaccine-related serious adverse reaction was reported in these studies. The results of these studies indicate that CPRV administered intramuscularly to healthy adults is immunogenic and is associated with fewer local and systemic reactions than HDCV.