Swei-Ju Chang

Bordetella Pertussis Infections in Vaccinated and Unvaccinated Adolescents and Adults, as Assessed in a National Prospective Randomized Acellular Pertussis Vaccine Trial (APERT)

BACKGROUND Acellular pertussis (aP) booster immunizations have been recommended for adolescents and older persons to enhance long-term protection and to possibly reduce community transmission of infections. METHODS This was a multicenter, randomized, double-blind vaccine trial in which one-half of the subjects received aP vaccine and one-half received hepatitis A vaccine (control subjects). All subjects were observed for almost 2 years for cough illnesses, and all underwent microbiologic and serologic studies for detection of pertussis infection. Immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies to pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae 2/3 were measured by enzyme-linked immunosorbent assay in serum samples obtained 1 and 12 months after immunization. Infection rates were determined with a variety of serologic criteria for control and vaccinated subjects. The incidence of prolonged cough illness was ascertained for subjects with and subjects without serologic evidence of infection. RESULTS Infection rates among control subjects are particularly representative of those in nonimmunized adults. Among control subjects, 0.4%-2.7% had increases in pertussis antibody of various types and degrees over 1 year, and 20%-46% had prolonged cough illnesses during this interval. Pertussis toxin antibody had the greatest specificity for detecting increases in antibody levels. Asymptomatic infections were approximately 5 times more common than clinical illnesses that met a strict clinical and microbiologic case definition. Relative to control subjects, aP-immunized subjects may have fewer increases in the antibody level (i.e., infections), especially for antibodies to fimbriae 2/3 (an antigen not in the vaccine). CONCLUSIONS Pertussis infections in older persons are largely asymptomatic. aP boosters confer protection for adolescents and adults against symptomatic pertussis and likely confer protection against mild and asymptomatic infections, and use of boosters may reduce transmission to others, especially infants.

Prospective, randomized, placebo-controlled evaluation of the safety and immunogenicity of three lots of intranasal trivalent influenza vaccine among young children.

BACKGROUND Trivalent formulations of an experimental, cold-adapted, intranasal influenza (CAIV) vaccine have been shown to be safe, immunogenic and efficacious in young children. METHODS We evaluated the safety and immunogenicity of three consistency lots of CAIV in children 12 to 36 months of age randomized to one of five groups: Groups 1, 2 and 3 received separate lots containing A/Shenzhen/227/95 (H1N1), A/Wuhan/359/95(H3N2) and B/Harbin/7/94-like viral strains. Group 4 received an earlier efficacy trial lot which included a different H1N1 strain (A/Texas/36/91-like); and Group 5 received placebo. We performed strain-specific serum hemagglutination inhibition antibody levels against type A (H3N2 or H1N1) or type B as appropriate. RESULTS Overall 474 children received 2 doses, 2 months apart. Each lot was well-tolerated, and there were no significant group differences between consistency lots in the proportion of children with fever and local or systemic reactions after vaccination. The 3 consistency lots were not statistically different with regard to immunogenicity as measured by seroconversion or absolute geometric mean titer. Immune responses were more robust among initially seronegative children and for H3N2 and B strains than for H1N1 strains. After 2 doses of vaccine 97, 84 and 62% had hemagglutination inhibition titers > or = 1/32 against A/H3N2, B and H1N1 strains, respectively. For A/H3N2 only, immune responses after 1 dose of vaccine are similar to those seen after 2 doses. CONCLUSIONS Each consistency lot of CAIV is as or more immunogenic than a lot used in a large efficacy trial.

Enhanced antibody responses in infants given different sequences of heterogeneous Haemophilus influenzae type b conjugate vaccines

To evaluate the safety and immunogenicity of differing sequences of heterogeneous Haemophilus influenzae type b (Hib) conjugate vaccines, we randomly assigned 300 infants to one of six vaccination schedules. At 2, 4, and 6 months of age, subjects were given single or heterogeneous vaccines: Hib polysaccharide (PRP) conjugated to mutant diphtheria toxin (HbOC), PRP conjugated to outer-membrane protein of Neisseria meningitidis (PRP-OMP), or PRP conjugated to tetanus toxoid (PRP-T). No serious reactions were attributable to immunization with heterogeneous vaccines, and there were few significant differences in the rates of minor adverse reactions among groups. PRP-OMP was the only vaccine that induced an antibody response after the first dose, but significant booster responses were not seen after the second and third doses. Subjects given PRP-T vaccine responded well after two doses, but three doses of HbOC vaccine were needed for an equivalent antibody response. All the Hib vaccine schedules evaluated were immunogenic, and schedules initiated by PRP-OMP vaccine at 2 months of age, followed by two doses of either HbOC or PRP-T vaccine at 4 and 6 months of age, induced the highest antibody levels after each dose. Such schedules may be the best for protecting infants and children who are at greatest risk of having invasive Hib disease, such as American Indian children.

Incidence of bacterial meningitis in Asia using enhanced CSF testing: polymerase chain reaction, latex agglutination and culture

To enhance the detection of bacterial meningitis in an East Asian surveillance study, we employed cerebrospinal fluid (CSF) bacterial culture, latex agglutination (LA) and polymerase chain reaction-enzyme immunoassay (PCR-EIA) testing for Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae (Sp). The sensitivity and specificity of CSF PCR-EIA testing was compared to LA and culture. A meningitis case was defined by one positive result for any of the three tests. The sensitivity of H. influenzae CSF PCR-EIA, LA, and culture was 100%, 40% and 57.5% respectively; and for Sp CSF PCR-EIA, LA and culture, the sensitivity was 100%, 58.3% and 66.7%, respectively. Hib and Sp specificity was 100% by each method. CSF PCR-EIA was more sensitive than culture or LA for the detection of Hib and Sp meningitis cases increasing their incidence by 74% and 50% compared to culture respectively. CSF PCR-EIA should be included for the detection of bacterial meningitis in surveillance studies.

Kinetics of maternal hepatitis a antibody decay in infants: implications for vaccine use.

We conducted a seroepidemiologic study to evaluate the kinetics of maternal hepatitis A antibody decay in infants. Serum samples obtained from 200 infants at 2 and 4 months of age were tested for hepatitis A antibody. Seventy-six infants (38%) were hepatitis A antibody-positive with a geometric mean antibody titer of 2634 mIU/ml. Samples collected at 4, 6 and/or 12 months of age showed seropositivity rates of 100, 95 and 39%, respectively. These data indicate that maternal antibody levels remained high through the first 6 months of life but decayed significantly by 12 months of age.

Safety and immunogenicity of a heptavalent pneumococcal conjugate vaccine in infants.

OBJECTIVE To evaluate the safety and immunogenicity of two lots of a heptavalent Streptococcus pneumoniae conjugate vaccine (PCV) containing seven capsular polysaccharide serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) conjugated to the outer membrane complex of Neisseria meningitidis serogroup B (OMPC) and administered to infants at 2, 4, 6, and 12 months of age. METHODS One hundred twenty infants were randomly assigned to concurrently receive PCV-OMPC and one of two Haemophilus influenzae type b (Hib) conjugate-DTwP combination vaccines: (1) Hib with a heterologous protein carrier (CRM(197), TETRAMUNE, Group 1) or (2) an experimental Hib-hepatitis b combination vaccine with the homologous carrier (OMPC, Group 2). All infants in Groups 1 and 2 received PCV-OMPC (lot 1) at 12 months of age. Another separate group of 120 infants (Group 3) received a different lot of PCV-OMPC concurrently with Hib-CRM(197) (TETRAMUNE) at 2, 4, and 6 months of age and then were randomized to receive either PCV-OMPC or a 23-valent polysaccharide (PS) pneumococcal vaccine at 12 months of age. RESULTS Each PCV-OMPC lot was generally well tolerated and no vaccine-related serious adverse events were reported. Following the primary series, serotype-specific anti-pneumococcal geometric mean concentrations (GMC) were highest for serotypes 14, 19F, and 4 and lowest for serotypes 6B and 23F. GMC and seroconversion rates in Group 3 (lot 2) were lower than in Group 1 (lot 1) for serotypes 6B, 14, 18C, and 23F. Antibody responses to serotypes 6B, 14, and 18C were significantly lower in Group 2 compared to Group 1. Following a booster dose of PCV-OMPC at 12 months of age, each lot was immunogenic with at least a 5-10-fold increase in antibody levels, and responses were significantly higher among those who received the PS vaccine. CONCLUSIONS PCV-OMPC is generally safe in infants, displays variable immune response by serotype, and concomitant receipt of Hib vaccine with homologous carrier may impact on its immunogenicity.

Pneumococcal and influenza immunization and human immunodeficiency virus load in children

Objective. HIV‐infected children receiving influenza vaccine, pneumococcal vaccine and both vaccines concurrently were studied to examine the effect of immunization on plasma HIV viral load. Methods. Thirteen children received immunizations: pneumococcal vaccine, 5; pneumococcal and influenza vaccines, 7; and influenza vaccine, 1. Most patients (12 of 13) were receiving combination reverse transcriptase inhibitor antiretroviral therapy without protease inhibitors at the time of immunization. Baseline plasma HIV RNA was determined 1 month prior (11 of 13), 2 weeks prior (12 of 13) and on the day of immunization (12 of 13). Plasma HIV RNA was assayed at 2 weeks (11 of 13), 4 weeks (12 of 13) and 3 months (5 of 13) after immunization. T cell activation markers (HLA‐DR+, CD38+ and CD45RO+, CD28+) were examined for both CD4+ and CD8+ lymphocytes on the day of immunization and 2 weeks after immunization for 11 children. Results. Only one child developed a >0.5‐log increase in viral load at any time after immunization. There was no correlation between an increase in viral load and antibody response to pneumococcal vaccine. At least one activation marker increased (>10%) for two children receiving pneumococcal vaccine and two children receiving pneumococcal and influenza vaccines. One of these children experienced an increase in viral load. Conclusion. Immunization with pneumococcal and influenza vaccines, alone or in combination, is rarely associated with a significant increase in HIV plasma RNA in children receiving combination antiretroviral therapy.

Immunogenicity of a Haemophilus influenzae type b-tetanus toxoid conjugate vaccine when mixed with a diphtheria-tetanus-acellular pertussis-hepatitis B combination vaccine.

BACKGROUND Combination vaccines are urgently needed to reduce the number of injections given to young children. The aim of the study was to evaluate the safety and immunogenicity of a combination vaccine that contains diphtheria and tetanus toxoids and acellular pertussis antigens (DTaP), recombinant hepatitis B surface antigen (HepB) and Haemophilus influenzae type b (Hib) polysaccharide conjugated to tetanus toxoid (PRP-T). METHODS Four hundred five infants were randomized equally to three groups and immunized at 2, 4 and 6 months of age with: (1) DTaP/HepB vaccine used to reconstitute lyophilized PRP-T vaccine and administered as a single injection; (2) DTaP/HepB vaccine and PRP-T vaccine administered as two separate injections; or (3) DTaP, HepB and PRP-T vaccines administered as three separate injections. Safety was closely monitored, and blood specimens were obtained to assess antibody responses to each vaccine antigen. RESULTS All study vaccines were well-tolerated, and the rates of systemic and injection site reactions were similar between groups. After the third dose the geometric mean antibody concentrations to Hib were significantly lower in subjects in Group 1 (1.63 microg/ml) compared with subjects in Groups 2 and 3 (6.26 and 6.15 microg/ml, respectively; P < 0.0001). Subjects with antibody concentrations <1.0 microg/ml after the third dose responded well to a booster dose of Hib conjugate vaccine given at 11 to 15 months of age (41 of 44 with anti-PRP > or = 1.0 microg/ml). Differences between groups for antibody responses to the other vaccine components were not clinically significant. CONCLUSIONS Infants given a combined DTaP/ HepB/PRP-T vaccine experienced a significantly lower antibody response to the PRP-T component than infants given PRP-T vaccine as a separate injection. However, the immune response to a booster dose of Hib conjugate vaccine indicated the presence of immunologic memory.

Cellular immunity in adolescents and adults following acellular pertussis vaccine administration.

ABSTRACT Cell-mediated immune (CMI) responses to an acellular pertussis vaccine administered to 49 subjects, a subset of participants in the National Institutes of Health-funded adult acellular pertussis vaccine efficacy trial, were evaluated and compared with antibody responses to vaccine antigens. Levels of proliferation of and cytokine secretion from lymphocytes cultured in the presence of pertussis toxin, filamentous hemagglutinin, or pertactin were measured before vaccination and 1 month and 1 year after vaccination. Statistically significant increases in lymphocyte stimulation indices and cytokine secretion were noted at both 1 month and 1 year after vaccination. Brisk pertussis antigen-specific immunoglobulin G responses were also noted at 1 month after vaccination, but these responses had declined by nearly 50% at 1 year after vaccination. These studies clearly demonstrate that both cellular and humoral immune responses occur after the administration of acellular pertussis vaccines to adolescents and adults but that the CMI responses are of greater magnitude and longer duration. CMI responses may be a better correlate of long-term protection.

Prevalence of Antibody to Bordetella pertussis Antigens in Serum Specimens Obtained from 1793 Adolescents and Adults

Serum specimens were obtained from all subjects in the adolescent and adult acellular pertussis (aP) vaccine efficacy trial before and after immunization to study the prevalence of IgG and IgA antibody and geometric mean titers to 4 Bordetella pertussis antigens. Of 1793 adolescents and adult subjects who received aP vaccine, only 20%, 68%, 59%, and 39% had concentrations of IgG antibodies to pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae types 2 and 3, respectively, that were greater than or equal to the limit of quantitation of the enzyme-linked immunosorbent assay used in the analysis. There was minimal variation in antibody prevalence with respect to geographic area, age, sex, or race.