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.

Japanese encephalitis vaccine (inactivated, BIKEN) in U.S. soldiers: immunogenicity and safety of vaccine administered in two dosing regimens.

The safety and immunogenicity of Japanese encephalitis (JE) vaccine (Nakayama strain, monovalent / BIKEN) was studied in 538 U.S. soldiers in 1990. Three doses of vaccine from three consecutively manufactured lots were given on days 0, 7, and either 14 or 30. Serum for antibody determination was drawn at months 0, 2, and 6. Japanese encephalitis plaque reduction neutralization tests were performed by three laboratories on each specimen. Five hundred twenty-eight (98%) participants completed the immunization series. All recipients without antibody before immunization developed neutralizing antibody against JE virus. There were no differences in geometric mean titer among the three test lots at months 2 and 6. Soldiers who received the third dose on day 30 had higher titers at both time points. Antibody to yellow fever had no significant effect on immune response to vaccine. Conclusions drawn from analysis of serologic data from the three labs were nearly identical. Symptoms were generally limited to mild local effects and were reduced in frequency with each subsequent does in the series (21% to 11%; P < 0.0001). Generalized symptoms were rare (e.g., fever = 5%) with no reported cases of anaphylaxis.

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.

Vaccine antigen interactions after a combination diphtheria-tetanus toxoid-acellular pertussis/purified capsular polysaccharide of Haemophilus influenzae type b-tetanus toxoid vaccine in two-, four- and six-month-old infants.

OBJECTIVE: The safety and immunogenicity of a diphtheria-tetanus toxoid-acellular pertussis vaccine (DTaP; Trepedia)/Haemophilus influenzae b polysaccharide (PRP-T; ActHib) combined vaccine (TriHibir; Pasteur Mérieux Connaught) was compared with DTaP and PRP-T given at the same visit but at separate sites in a prospective multicenter, open label trial. METHODS: Infants were randomized to four groups (three consistency lots of DTaP/PRP-T vs. one of the consistency lots given as separate vaccines); injections were administered at 2, 4 and 6 months of age. Pre-Dose 1 and post-Dose 3 sera were assayed for antibody titers against all antigens. Reactions to the vaccinations were assessed by parent questionnaire for 30 days after each injection visit. RESULTS: Four hundred eighty-five infants were enrolled; 296 evaluable infants were included in the DTaP/PRP-T group compared with 70 infants in the DTaP and PRP-T vaccine group. Infants who received the combined vaccine had higher post-Dose 3 geometric mean antibody titers to diphtheria antitoxin (P < 0.01) and pertussis filamentous hemagglutinin (P < 0.05) and lower geometric mean antibody titers to tetanus antitoxin (P < 0.05) and Haemophilus influenzae b (Hib) polysaccharide (PRP) (P < 0.05). The geometric mean anti-PRP antibody titer in the DTaP/PRP-T group was 4.3 micrograms/ml compared with 7.0 micrograms/ml in the separate vaccine group (P < 0.05), and the percentage of infants with antibody titers > or = 0.15 and 1 microgram/ml were, respectively, 95 and 86%, whereas they were 100% for both titers in the separate vaccines group. DTaP/ PRP-T vaccine given concomitantly or 1 month apart from hepatitis B vaccine and oral poliomyelitis vaccine caused no significant differences in immunogenicity or safety. The safety assessments for the DTaP/PRP-T vaccine showed no consistent differences in systemic or local injection site reactions compared with DTaP and PRP-T administered separately. CONCLUSION: Although the antibody responses to tetanus and Hib polysaccharide in the evaluated DTaP/PRP-T combined vaccine were significantly lower than those seen after separate DTaP and PRP-T administration, the combined vaccine elicited an immune response against diphtheria, tetanus, pertussis and Haemophilus influenzae b likely to confer protection.

Inactivated poliovirus vaccine alone or sequential inactivated and oral poliovirus vaccine in two-, four- and six-month-old infants with combination Haemophilus influenzae type b/hepatitis B vaccine.

BACKGROUND: Advisory committees have recommended the increased use of inactivated poliovirus vaccine (IPV) for children. OBJECTIVES: The purpose of this study was to assess the safety and immunogenicity of three schedules using IPV administered with diphtheria and tetanus toxoids and whole cell pertussis vaccines in a dual-chambered syringe. Children also received a combination of Haemophilus influenzae type b (Hib) and hepatitis B vaccines (COMVAX). METHODS: All infants (n = 295) received IPV and COMVAX at 2 and 4 months of age and IPV, oral poliovirus vaccine (OPV) or both vaccines at 6 months and OPV at 15 months of age. RESULTS: After two doses of IPV 96 to 100% of infants had antibodies to poliomyelitis viruses types 1, 2 and 3, and after a third dose of vaccine (IPV or OPV) all but one child had antibodies to all three poliovirus types. After two doses of COMVAX 89 and 96% of children had protective levels of antibody to Hib and hepatitis B, respectively. CONCLUSIONS: IPV is highly immunogenic in a two-dose schedule. Administration of a third dose of IPV or a dose of OPV at 6 months of age is highly effective. Simultaneous administration of a combination H. influenzae type b/hepatitis B vaccine did not interfere with the response to IPV.

Humoral and mucosal immunity in infants induced by three sequential inactivated poliovirus vaccine-live attenuated oral poliovirus vaccine immunization schedules. Baltimore Area Polio Vaccine Study Group.

The relative immunity induced by sequential administration of inactivated poliovirus vaccine (IPV) produced in human diploid cells and live attenuated oral poliovirus vaccine (OPV) was evaluated by randomization of 510 infants to receive IPV and OPV sequentially according to one of three experimental schedules, IPV only, or OPV only. The antibody response to two IPV doses was lower than expected. However, for each of the IPV-OPV sequential schedules, the first OPV dose significantly enhanced seroconversion rates and geometric mean microneutralization antibody titers. Three months after the final dose, 96%-99%, 99%-100%, and 81%-100% of infants had antibodies to poliovirus types 1, 2, and 3, respectively, and subjects with two or more prior OPV doses were significantly less likely than those with none or one prior OPV dose to excrete virus in feces after an OPV challenge. Sequential IPV-OPV immunization is now recommended for routine use in the United States. The optimal schedule consists of two IPV doses followed by two OPV doses.

Comparison of diphtheria-tetanus-two component acellular pertussis vaccines in United States and Japanese infants at 2, 4, and 6 months of age.

OBJECTIVE: We compared the diphtheria and tetanus toxoids and bicomponent acellular pertussis vaccine (DTaP) responses in Japanese and United States infants. DESIGN: This was a double-blind, comparative study. SETTING: Private pediatric practices in Japan and the U.S. participated. SUBJECTS: One hundred eighty-nine healthy 2-month old infants were tested. INTERVENTIONS: Infants were immunized at 2, 4, and 6 months of age. The Japanese formulation (DTaP-J) contained 20 micrograms of pertussis toxin (PT) and 20 micrograms of filamentous hemagglutinin (FHA); the U.S. formulation (DTaP-US) contained 23.4 micrograms of each antigen. Parents used a standard form to record average adverse experiences. Serum was obtained before the first immunization, 2 months after the second immunization, and 1 month after the third immunization. MEASUREMENTS: Differences in DTaP-J and DTaP-US were evaluated in Japanese infants immunized subcutaneously (s.c.). Differences due to ethnicity and to route of administration were compared in U.S. infants immunized with DTaP-US s.c. or intramuscularly (i.m.). An indirect enzyme-linked immunosorbent assay was used to determine immunoglobulin G antibody responses to PT, FHA, and tetanus toxoid. Neutralizing antibody to PT was measured by a Chinese hamster ovary call assay. Diphtheria antitoxin was assayed by serum neutralization on VERO cells. RESULTS: Statistical differences (P < .05) in adverse events included less fatigue after immunization with DTaP-US compared with DTaP-J. Erythema of more than 2.5 cm was more frequent, but erythema less than 2.5 cm was less frequent in Japanese infants compared with U.S. infants. Fewer Japanese infants were febrile ( > 38 degrees C), tired, or irritable. Subcutaneous immunization resulted in a greater frequency of erythema and induration. The DTaP-US resulted in an equivalent response to PT and a greater response to FHA. More Japanese infants demonstrated at least a fourfold response over preimmunization antibody values to FHA. In U.S. infants, antibody responses to the contained pertussis antigens were equivalent after i.m. and s.c. administration. Compared with Japanese infants receiving DTaP-J s.c., U.S. infants receiving DTaP-US i.m. had equivalent responses to PT and a greater response to FHA. CONCLUSIONS: United States infants receiving an i.m. injection of a U.S. -produced bicomponent DTaP vaccine produced antibody responses to the contained pertussis antigens at least equal to those of Japanese infants receiving a similar bicomponent DTaP vaccine shown to be effective in older Japanese children.

Safety and immunogenicity of PRP-T combined with DTP: excretion of capsular polysaccharide and antibody response in the immediate post-vaccination period.

OBJECTIVE: To evaluate whether combining Haemophilus influenzae type b capsular polysaccharide covalently linked to tetanus toxoid (PRP-T) and diphtheria-tetanus-pertussis (DTP) in one syringe produced a vaccine that was safe and immunogenic. DESIGN: Randomized clinical trial. SETTING: Suburban New Orleans pediatric population. PARTICIPANTS: Convenience sample of 150 healthy infants. METHODS: Enrollees were randomized to receive DTP and PRP-T in one injection (Group 1), DTP and PRP-T separately (Group 2), or DTP and H influenzae type b capsular saccharide coupled to a nontoxic variant of diphtheria toxin, CRM197 (HbOC) separately (Group 3) at 2, 4, and 6 months of age. All infants received oral polio vaccine at 2 and 4 months of age. Parents were instructed to record side effects on a standardized form after each vaccine administration. Blood was drawn before each immunization and at 7 months of age; an additional blood and a urine specimen was obtained 2 to 3 days after one of the vaccination visits. Serum was assayed for H influenzae anticapsular antibody (anti-PRP), anti-pertussis toxoid, anti-fimbrial hemagglutinins, anti-diphtheria and anti-tetanus toxoid antibodies, and antibody to polio viruses. Urine was assayed for H influenzae type b capsular polysaccharide. RESULTS: The rate of occurrence of fever did not differ significantly between groups. Local swelling and erythema occurred more often at the administration site in Group 1 infants than at the DTP administration sites of infants in Groups 2 and 3 after the first and second vaccinations. The mean concentration of all antibodies we assayed did not differ significantly when Group 1 and 2 infants were compared. HbOC recipients (Group 3) had lower mean anti-H influenzae anticapsular antibody and higher mean anti-diphtheria and anti-tetanus antibody concentrations after two and three doses compared with Group 1 and Group 2 infants. No group had a significant change in mean anti-PRP antibody concentration 2 to 3 days after vaccination with any dose. After vaccination, antigenuria occurred less frequently in Group 1 infants (54%, 78%, and 72% in Groups 1, 2, and 3, respectively, P < .01). CONCLUSIONS: Combining PRP-T and DTP produced a combination vaccine associated with a slight increase in the rate of erythema and swelling but with similar immunogenicity of the vaccine components and oral polio vaccine.

Haemophilus influenzae type b polysaccharide-tetanus protein conjugate vaccine does not depress serologic responses to diphtheria, tetanus or pertussis antigens when coadministered in the same syringe with diphtheria-tetanus-pertussis vaccine at two, four and six months of age.

The safety and immunogenicity of a vaccine against Haemophilus influenzae type b consisting of purified polyribosylribitol phosphate conjugated to tetanus toxoid (PRP-T) were evaluated in 277 Chilean infants who were randomly assigned to one of three treatment groups: Group A, PRP-T mixed with diphtheria-tetanus-pertussis (DTP) vaccine in a single syringe and given as a single inoculation in one arm and placebo in the other arm; Group B, PRP-T given in one arm and DTP in the other arm; Group C, DTP given in one arm and placebo in the other. Infants were immunized at 2, 4 and 6 months of age and examined daily for 4 days after each immunization. Serum PRP antibodies; tetanus, diphtheria and pertussis antitoxin; pertussis agglutinins; and antibodies to Bordetella pertussis filamentous hemagglutinin were measured at baseline and 2 months after each dose. PRP-T was well-tolerated. After three doses of PRP-T vaccine 100% of infants attained PRP antibody concentrations > or = 0.15 micrograms/ml and 96 to 99% achieved high anti-PRP concentrations (> or = 1.0 micrograms/ml). The post-third dose anti-PRP geometric mean titer was high (6.94 micrograms/ml) in infants who were given PRP-T combined with DTP, although it was somewhat lower than the geometric mean titer of the group who received PRP-T in a separate arm (9.93 micrograms/ml) (P not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Safety and immunogenicity of an acellular pertussis vaccine booster in 15- to 20-month-old children previously immunized with acellular or whole-cell pertussis vaccine as infants.

The objective of this study was to evaluate reactogenicity and immunogenicity of the recently US-licensed Connaught/BIKEN (C/B) acellular DTP (ADTP) vaccine as a booster for children aged 15 to 20 months after they had received either the C/B ADTP or the US-licensed Connaught whole-cell DTP (WDTP) vaccine as infants. After infants had received either three doses of C/B ADTP (n = 109) or three doses of WDTP vaccine (n = 30) at 2, 4, and 6 months of age according to a 3:1, randomized, prospective design, they all received booster doses at 15 to 20 months of age with C/B ADTP. Fever > 101 degrees F (38.3 degrees C), irritability, injection site redness > or = 1 inch, injection site swelling, and injection site pain, among other reactions, were monitored for 14 days after vaccination. IgG antibody to pertussis toxin (PT) and filamentous hemagglutinin were analyzed by enzyme-linked immunosorbent assay and neutralizing antibody to PT was measured by Chinese hamster ovary (CHO) cell assay. No significant differences were observed between the WDTP- and ADTP-primed infants following their ADTP booster for any of the monitored reactions within 72 hours of vaccine administration or in the 4 to 14 days after vaccination. Prior to the ADTP booster, antibody levels were higher in children who had received ADTP compared with those who had received WDTP vaccine as infants for PT antibody as measured by enzyme-linked immunosorbent assay and CHO cell assay. Higher levels of IgG antibody following the ADTP booster were observed to filamentous hemagglutinin and to PT in ADTP-primed compared with WDTP-primed children.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary immunization series for infants: comparison of two-component acellular and standard whole-cell pertussis vaccines combined with diphtheria-tetanus toxoids.

At 2 months of age, 145 infants were randomized to receive either a two-component acellular pertussis vaccine [lymphocytosis-promoting factor (LPF)/filamentous hemagglutinin (FHA)] or standard whole-cell pertussis vaccine, each combined with diphtheria-tetanus toxoids, as their primary immunization series. Of the 132 subjects (91%) who completed the study, those receiving the acellular vaccine had significantly fewer adverse reactions: 5% vs 30% (local) and 17% vs 30% (systemic, including fever). During the first 24 hours acetaminophen usage, a general measure of adverse reactions, was lower in the test group. Overall, 35% of the acellular vaccine doses were reaction free vs 12% of the whole-cell doses. No serious reactions occurred in either group. Antibody responses to LPF and to FHA were significantly increased after the second and third immunizations with the test vaccine and were consistently higher than levels achieved with the standard vaccine. Thus the two-component acellular pertussis vaccine was associated with fewer adverse reactions and improved serologic responses to LPF and FHA as compared with the currently recommended whole-cell vaccine.

Safety and immunogenicity of acellular diphtheria-tetanus-pertussis and Haemophilus conjugate vaccines given in combination or at separate injection sites.

This prospective, double-blind, randomized trial compared the immunogenicity and reactogenicity of acellular diphtheria-tetanus-pertussis vaccine and Haemophilus influenzae type b conjugate vaccine-diphtheria toxoid conjugate, given at separate injection sites or at a single site, in 79 children 18 months of age who had received three prior immunizing doses of whole-cell diphtheria-tetanus-pertussis vaccine. No significant differences were observed.

Comparison of 1 or 3 MU of interferon alfa-2b and placebo in patients with chronic non-A, non-B hepatitis.

Ninety patients with histologically documented chronic non-A, non-B hepatitis were randomly allocated to receive SC injections of placebo or of 1 or 3 MU of recombinant interferon alfa-2b three times weekly for 24 weeks. Complete normalization of alanine aminotransferase levels occurred posttreatment in 43.3% of patients receiving 3 MU, in 20% of those receiving 1 MU, and in 6.7% of untreated patients (P less than 0.0005 vs. those treated with 3 MU). Alanine aminotransferase normalization was sustained for 6 months after therapy in 13.3% of the patients treated with 3 MU and in 3.3% of those given 1 MU or placebo. The decline of alanine aminotransferase levels following interferon therapy showed independent, positive correlations with female sex (P less than 0.03) and younger age (P less than 0.05). The Knodell's fibrosis score was strongly positively correlated with age (P less than 0.0001). It is concluded that 3 MU of interferon is a more effective dose than 1 MU for controlling disease activity in non-A, non-B chronic hepatitis patients. Women and younger and noncirrhotic patients are more likely to respond.

A randomized controlled trial of a 12-month course of recombinant human interferon-alpha in chronic delta (type D) hepatitis: a multicenter Italian study.

To determine whether long-term therapy with recombinant interferon-alpha can improve the course of chronic delta hepatitis, 61 Italian patients with this disease were randomly assigned to receive either interferon-alpha-2b three times a week (5 MU/m2 for 4 mo and then 3 MU/m2 for another 8 mo) or no treatment. At the end of the 12-mo study, all patients were followed-up for 12 additional months. Normalization or decrease of more than 50% from baseline of serum ALT levels occurred in 42% of treated patients the fourth month of therapy, 26% the twelfth month and 3% the twenty-fourth month vs. 7%, 7% and 0%, respectively, in the control group. However, relapses occurred in 7 of 8 (87.5%) responders 1 to 10 mo (mean = 3.5 mo) after cessation of therapy. Liver biopsies were carried out at baseline and during the twelfth month of treatment. Histological improvement, mostly caused by decrease of portal inflammation, was observed in 57% of treated and 36% of untreated patients. Measures of antiviral activity (serum hepatitis delta virus RNA and intrahepatic hepatitis delta antigen) showed similar levels in treated and control patients. In treated patients the percentage of patients who were negative for HDV RNA never exceeded that of baseline. Although interferon-alpha in the dosage given in this study had no antiviral effect on patients with chronic hepatitis D, it reduced hepatic inflammation as measured by ALT levels. Whether a longer duration or reinstitution of interferon-alpha therapy would achieve long-term control of ALT levels and prevent chronic liver damage is not known.

A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional Therapy Group.

BACKGROUND AND METHODS: Chronic hepatitis B is a common and often progressive liver disorder for which there is no accepted therapy. To assess the efficacy of treatment with interferon, we randomly assigned patients with chronic hepatitis B to one of the following regimens: prednisone for 6 weeks followed by 5 million units of recombinant interferon alfa-2b daily for 16 weeks; placebo followed by 5 million units of interferon daily for 16 weeks; placebo followed by 1 million units of interferon daily for 16 weeks; or observation with no treatment. RESULTS: Hepatitis B e antigen and hepatitis B viral DNA disappeared from serum significantly more often in the patients given prednisone plus interferon (16 of 44 patients, or 36 percent) or 5 million units of interferon alone (15 of 41; 37 percent) than in the untreated controls (3 of 43; 7 percent; P less than 0.001); the difference between those given 1 million units of interferon (7 of 41; 17 percent) and the controls was not significant. The strongest independent predictor of a response to treatment was the amount of hepatitis B viral DNA in serum at entry (P less than 0.0001). Of the 38 patients who responded to interferon, 33 (87 percent) had normal serum aminotransferase levels after therapy; 11 patients who responded (29 percent), but no controls, lost the hepatitis B surface antigen. Blinded histologic assessment revealed a significant improvement in periportal necrosis in the treated patients (P = 0.03). CONCLUSIONS: In chronic hepatitis B, treatment with interferon alfa-2b (5 million units per day for 16 weeks) was effective in inducing a sustained loss of viral replication and achieving remission, assessed biochemically and histologically, in over a third of patients. Moreover, in about 10 percent of the patients treated with interferon, hepatitis B surface antigen disappeared from serum.