Response of human immunodeficiency virus-infected adults to measles-rubella vaccination.

Measles-mumps-rubella vaccine (MMR) is recommended for human immunodeficiency virus-infected (HIV+) adults. Data concerning MMR vaccination of HIV+ patients are limited to children. We evaluated 39 HIV+ (97% with > 200 CD4+ lymphocytes) and 17 non-HIV+ control adults receiving measles-rubella vaccine (MR). Clinical adverse events did not differ between groups. Prevaccination, three HIV+ and two control vaccinees were measles seronegative; no HIV+ and one control vaccinee seroconverted. No initially measles-seropositive vaccinee had a significant antibody elevation. Four HIV+ and three control vaccinees were rubella seronegative prevaccination; three HIV+ and two control vaccinees seroconverted. Among those initially rubella seropositive, two HIV+ and one control vaccinee had significant antibody elevations. There were no significant percentage CD4+ or CD8+ lymphocyte changes between groups. Three HIV+ vaccinees were p24 antigen positive pre- and postvaccination. Although MR vaccination appears safe in HIV+ adults, questions remain about the response of measles and rubella antibody-negative HIV+ adults and those with < 200 CD4+ lymphocytes.

Longitudinal study of adverse reactions following diphtheria-tetanus-pertussis vaccine in infancy.

A prospective study of immunogenicity and adverse effects of 1553 doses of diphtheria and tetanus toxoids and whole cell pertussis vaccine (DTP) was performed in 538 children observed longitudinally from 2 months to 20 months of age. Subjects were randomized to the standard four-dose immunization schedule or to a three-dose schedule (with a saline injection substituted for DTP at 6 months of age). The three-dose schedule could not be recommended on the basis of serologic data. Compliance for completing a clinical observation form in the 48 hours following injections was greater than 99%. Fever, local reactions, or adverse behavioral effects were described in association with 96% of DTP doses and 36% of placebo injections. Contraindications to DTP immunization developed in 3% of study children. No convulsion, hypotonic hyporesponsive episode, encephalopathy, or temperature greater than 40.5 degrees C occurred. Behavioral and local inflammatory effects occurred maximally in the first 6 hours following vaccine but fever peaked later. There was no interrelationship between occurrence of local reaction and fever. Data suggest that age has more effect on the type and rate of adverse clinical events than does vaccine dose number. Existing antibody levels to vaccine components, lot of vaccine, breast-feeding, or gestational age did not affect rate or type of clinical reactions. Neither occurrence of reactions nor the use of acetaminophen affected antibody response to vaccine.

Relationships between functional assays and enzyme immunoassays as measurements of responses to acellular and whole-cell pertussis vaccines.

OBJECTIVE: To examine the relationships between functional assays and antigen-specific enzyme immunoassays in sera from a multicenter trial of 13 different experimental acellular pertussis vaccines and 2 licensed whole-cell vaccines, and to determine whether correlations previously observed among assays of specimens from pertussis patients and whole-cell vaccinees would apply to specimens from infants immunized with purified components in acellular vaccines. METHODS: Postimmunization sera were assayed for immunoglobulin G antibodies to pertussis toxin (PT), filamentous hemagglutinin, pertactin (PRN), and a mixture of types 2 and 3 fimbriae (FIM) by enzyme-linked immunosorbent assay, for whole-cell agglutinins (AGGs) and for PT-neutralizing antibodies by the Chinese hamster ovary (CHO) cell assay. Assay results were compared for individual sera, as well as for geometric mean antibody concentrations or titers (GMTs) calculated by vaccine or overall. RESULTS: For the 15 vaccines, the PT GMTs were highly correlated with the CHO assay GMTs (r = .92), and the FIM GMTs were highly correlated with the AGG GMTs (r = .96). For individual postvaccination sera, there was a significant correlation between the CHO titers and levels of antibody to PT whether the 15 vaccines were considered separately (.59 < or = r < or = .85) or combined (r = .81). For individual sera from infants immunized with the two whole-cell vaccines or any of the four acellular vaccines containing FIM, a strong correlation between AGG titer and FIM antibody was observed whether the vaccines were considered separately (.83 < or = r < or = .91) or together (r = .86). One vaccine without detectable FIM produced a measurable AGG response; for this vaccine, a moderate but significant correlation (R = .58) between PRN antibody and AGG titer was observed. CONCLUSION: These data indicate that appropriate antigen-specific enzyme-linked immunosorbent assays will furnish results similar to those provided by the CHO and AGG assays in the evaluation of the immunogenicity of component vaccines. Antibodies to FIM seem to include the most important AGGs; however, there is evidence that agglutination by PRN antibody may be detected in the absence of antibody to FIM.

Simultaneous administration of measles-mumps-rubella vaccine with booster doses of diphtheria-tetanus-pertussis and poliovirus vaccines.

The safety and efficacy of simultaneous administration of measles-mumps-rubella (MMR), diphtheria-tetanus-pertussis (DTP), and trivalent oral poliovirus (OPV) vaccines in a test group of 405 children were compared with the safety and efficacy of sequential administration of the same vaccines in a control group of 410 children given MMR followed by booster doses of DTP and OPV 2 months later. The study was double blind and placebo controlled with respect to DTP and OPV. Seroconversion rates to measles, mumps, and rubella exceeded 96% in both groups. Geometric mean titers to measles (P = .05) and rubella (P = .004) were higher in the test group, and titers of antibodies to the other seven antigens were similar in both groups. Clinical reaction data were analyzed in 248 of 405 test children and 249 of 410 control children. The rates of serious vaccine-associated reactions were low and similar in the two groups. Some minor side effects were reported more frequently in the test group, but these differences were judged to be related to study design rather than to differences in the safety of the two vaccine schedules. The results indicate that the safety and serologic efficacy of administering MMR simultaneously with reinforcing doses of DTP and OPV in the second year of life is equivalent to the safety and efficacy observed after administering these antigens separately.

Description and evaluation of serologic assays used in a multicenter trial of acellular pertussis vaccines.

OBJECTIVE: To describe and evaluate the assays used to measure the antibody responses in infants to 13 experimental acellular pertussis vaccines and 2 licensed whole-cell pertussis vaccines. METHODS: During a 53-week period, preimmunization and postimmunization sera were assayed for immunoglobulin G antibodies to pertussis toxin, filamentous hemagglutinin, pertactin, and a mixture of type 2 and type 3 fimbriae by enzyme-linked immunosorbent assay (ELISA), for whole-cell agglutinins (AGG), and for pertussis toxin-neutralizing antibodies by the Chinese hamster ovary cell assay. All ELISA reagents were characterized to assure antigen and isotype specificity of the assays. Intralaboratory reproducibility and temporal stability were evaluated by analysis of results of control sera and by assessment of the response to the control whole-cell vaccine. Interlaboratory reproducibility was assessed by repeating the assays on preimmunization and postimmunization sera for 10% of the infants in a second laboratory. RESULTS: For control sera having antibody concentrations at least four times the minimum level of detection, the coefficients of variation within and between the ELISAs consistently were less than 20%. Trend analysis indicated that none of the assays drifted by more than 20% during the study period, and no significant drift was seen in the response to the control whole-cell vaccine. Results from the two laboratories correlated well; correlation coefficients were .93 or greater for the four ELISAs, .79 for the Chinese hamster ovary cell assay, and .82 for the AGG assay. For four of the six assays, there was either no difference or a modest (< 15%) difference in the geometric mean values for sera tested in both laboratories. Larger quantitative differences were observed for the AGG (45% difference) and pertactin (61% difference) assays. CONCLUSION: Assay reproducibility and stability indicate that the standardized methods can be transferred between laboratories, and that the results accrued during a 1-year period for the 15 vaccines can be compared.

Simultaneous administration of Haemophilus influenzae type b vaccine with acellular or whole-cell pertussis vaccine: effects on reactogenicity and immune responses to pertussis vaccines.

OBJECTIVE: To evaluate the effect of simultaneous Haemophilus influenzae type b conjugate (Hib) vaccination on the safety and immunogenicity of selected acellular (DTaP) and whole-cell (DTP) pertussis vaccines with diphtheria and tetanus toxoids combined. METHODS: Enrollment of infants into a large multicenter study of the safety and immunogenicity of 13 DTaP and 2 DTP vaccines was partially completed when the first Hib vaccine, HbOC (Haemophilus b oligosaccharide conjugate vaccine), was licensed for use in infants. Thereafter, at each immunization most infants received HbOC simultaneously with DTaP (or DTP), administered in opposite thighs. Postvaccination geometric mean titers or concentrations (GMTs) of pertussis antibodies as measured by six different assays were compared pairwise among groups of infants receiving 0, 1, 2, or 3 simultaneous HbOC immunizations. The incidence of reactions was compared between infants who received only DTaP or DTP and those who received HbOC simultaneously. RESULTS: Comparison of postvaccination GMTs was possible among groups of infants receiving different numbers of simultaneous immunizations for 10 of the 13 DTaP and both DTP vaccines. Increased HbOC exposure had no consistent dose-response effect on antibody titers for DTaP or DTP vaccines in any assay. Significant differences between groups in postvaccination GMTs were observed with 4 DTaP vaccines in 1 to 2 assays each; the GMTs were higher with increasing HbOC exposure for 2 DTaP vaccines and lower for 2 others. There was no significant increase in reactions with simultaneous HbOC and DTaP immunization. CONCLUSIONS: Based on these retrospective analyses, there did not seem to be an interference in pertussis immunogenicity or alteration in reactogenicity associated with the simultaneous administration of HbOC and DTaP. These findings are encouraging with respect to the development of DTaP-Hib combination vaccines.

The effect of maternal antibody on the serologic response and the incidence of adverse reactions after primary immunization with acellular and whole-cell pertussis vaccines combined with diphtheria and tetanus toxoids.

OBJECTIVE: To evaluate the effect of maternally derived antibody on the immunogenicity and reactogenicity of acellular (DTaP) or whole-cell (DTP) pertussis vaccine with diphtheria and tetanus toxoids combined. METHODS: A total of 2342 infants were randomized to receive one of 13 DTaP or 2 DTP vaccines at 2, 4, and 6 months of age. The correlation between preimmunization and postimmunization antibody after three doses of vaccine and the relation between preimmunization antibody and adverse reactions after the first immunization were modeled by linear regression. RESULTS: After DTP but not DTaP, higher levels of preexisting antibody were associated with substantial (28% to 56%) reductions in the subsequent antibody response to pertussis toxin (PT). For other pertussis antibodies, modest inverse correlations were seen between preexisting antibody concentrations and most postimmunization antibody responses (resulting in 8% to 18% reductions in postimmunization antibody) for both DTP and DTaP. There was no consistent association in any DTP or DTaP group between adverse reactions and preimmunization antibody levels. CONCLUSION: The PT antibody response to DTaP, unlike DTP, is not adversely affected by preexisting antibody to PT. Inhibitory effects with respect to other antibodies, seen with both DTP and DTaP, were relatively modest. Our data suggest that the use of acellular pertussis vaccines in adults, which could confer higher levels of antibody in women before pregnancy, would be unlikely to adversely affect pertussis antibody responses after DTaP among infants born to mothers with high antibody levels.

Serologic evidence of subclinical pertussis in immunized children.

Incidental to a vaccine study involving 783 immunized children conducted at two study sites, inner city children had significantly higher geometric mean pertussis agglutinin titers compared with suburban children just before the fourth dose of diphtheria-tetanus-whole cell pertussis vaccine (47 vs. 25; P less than 0.001). Higher titers in the inner city were correlated with residence in census tracts where cases of pertussis were reported. Three hundred thirty-two children in a placebo arm of the study who were clinically observed and had paired serum samples taken during a 2- to 4-month period were analyzed for evidence of natural Bordetella infection. Twelve (11%) inner city children and three (1.3%) suburban children had spontaneous 4-fold or greater rises in at least two different pertussis antibodies measured (agglutinin, antitoxin or enzyme-linked immunosorbent assay for IgG to pertussis toxin, IgG and IgA to filamentous hemagglutinin). Eighty percent of these children had IgA to filamentous hemagglutinin. Nine of 12 inner city children with serologic evidence of pertussis lived within 6 blocks of a case of pertussis reported within 1 month of the observed antibody rise in study subjects; none had a household member with pertussis and none had symptomatic disease.

Measles control in Kinshasa, Zaire improved with high coverage and use of medium titre Edmonston Zagreb vaccine at age 6 months.

BACKGROUND: To improve measles control in Kinshasa, Zaire, a project to increase vaccine coverage was begun in 1988, and in 1989, the city vaccination programme changed measles vaccination policy from Schwartz vaccine at age 9 months to medium titre Edmonston Zagreb (EZ) vaccine at age 6 months. We report the impact of the programme on measles incidence and mortality. METHODS: Data on vaccine coverage were obtained from cluster sample surveys conducted every 1-2 years and from routine reports of vaccine doses administered. Data on measles incidence and mortality were obtained from sentinel surveillance sites. The serological response to EZ measles vaccine was evaluated at a health centre in 1989 and in a community survey in 1990. RESULTS: Measles vaccine coverage estimated in cluster surveys increased from 50% of the 1984 birth cohort to 89% of the 1989 birth cohort, accepting either a home-based record or a verbal history of vaccination. Reported measles incidence per 10,000 [corrected] population decreased by over 90%, from 37.5 in 1980 (early vaccination years) to 1.6 in 1991. There was a relative decrease in the proportion of cases aged < 9 months (32% of cases in 1986-1987 and 23% of cases in 1990-1991) and an increase in the proportion aged > 23 months (29% of cases in 1986-1987 and 43% in 1990-1991). According to ELISA assays, 74-76% of children seroresponded to EZ vaccine administered at age 6-7 months under routine programme conditions. CONCLUSIONS: Measles can be controlled in urban areas, although it is difficult to determine how great a contribution vaccination at age 6 months makes over and above the achievement of high coverage.

Immunity to diphtheria in a sample of the Canadian adult population.

OBJECTIVE: To assess immunity to diphtheria in a sample of Canadian adults. DESIGN: A seroprevalence study of a group of plasmapheresis donors was performed over a four-month period in 1996. A convenience sample of 1619 sera was collected to obtain a good distribution by age groups and centres. The determination of diphtheria antitoxin concentrations was performed by neutralization of diphtheria toxin in cell culture. SUBJECTS: A total of 1619 plasmapheresis donors from Halifax, Quebec City, London, Calgary and Edmonton were studied. RESULTS: Of the 1619 sera, 20.3% tested showed susceptibility to diphtheria (antitoxin concentration less than 0.01 IU/mL). The proportion of susceptibles increased from 9.5% in subjects 30 to 39 years of age to 36.3% in those 60 years of age or more. The age group 20 to 29 years demonstrated a higher proportion of susceptibles (18.3%) than the next age group (30 to 39 years) in four of the five centres. Significant differences in antibody levels were also observed among the centres. There was no statistically significant difference between sexes. CONCLUSIONS: Overall, detectable antibody and presumably immunity to diphtheria in the present sample of Canadian adults is relatively good. However, reason(s) for the relatively high proportion of susceptibles in those aged 20 to 29 years of age in certain centres, as well as why Canada has not experienced any diphtheria outbreaks in the past 20 years given these susceptibility levels, should be investigated further.

Immunization response varies with intensity of acute lymphoblastic leukemia therapy.

Twenty-four children receiving maintenance chemotherapy for acute lymphoblastic leukemia were given booster doses of tetanus-diphtheria combined toxoids. One month later, 19 of the 24 children were given Haemophilus influenzae B oligosaccharide-cross-reacting material conjugate vaccine. Following immunization, all patients had protective antibody titers against tetanus, 92% had protective antidiphtheria titers, and 84% had protective titers against H influenzae. Preimmunization titers, postimmunization titers, and response to immunization varied according to the intensity of therapy. There was no correlation with duration of therapy or quantitative hematologic values in the peripheral blood. These observations support the recommendation that children treated for acute lymphoblastic leukemia should be immunized against H influenzae B.

Evaluation of a single dose of diphtheria toxoid among adults in the Republic of Georgia, 1995: immunogenicity and adverse reactions.

To determine the immunogenicity and safety of a single dose of diphtheria toxoid among adults, blood samples for detecting serum antitoxin levels were obtained from 18- to 59-year-old subjects (n=248) before and 30 days after immunization with Td (tetanus-diphtheria toxoids; manufactured by Serum Institute of India). By day 30, the seroprevalence of antitoxin levels >/=0.1 IU/mL increased from 22.6% to 81.5%; median antitoxin levels increased from 0.01 to 4.0 IU/mL. These parameters were lowest among subjects who were 40-59 years old, especially among those 40-49 years old. Adverse reactions (local redness, swelling, induration, fever>39 degrees C) were reported by 5.3% of participants. Our findings suggest that, in general, one dose of the Indian-produced Td vaccine is efficacious and safe in inducing an adequate immune response against diphtheria in adults; however, in Georgia, persons 40-59 years old, especially those 40-49 years old, will require additional doses of toxoid to achieve protective levels of antitoxin.

Response to measles-mumps-rubella vaccine in children on dialysis.

Ten children receiving maintenance dialysis were immunized with the standard dose of measles-mumps-rubella vaccine between 15 and 33 months of age. Immune responses to vaccination were determined using commercially available enzyme-linked immunosorbent assays for measles, mumps, and rubella viruses. Eight children responded to measles vaccine, 5 to mumps vaccine, 8 to rubella vaccine, and only 3 children to all three vaccines, compared with a seroconversion rate of over 90% to all three vaccines in healthy children (P less than 0.0001). We contend that the relatively poor immunocompetence of our dialysis patients explains their less than optimal vaccine response and suggest that children vaccinated while undergoing dialysis be tested to confirm serological evidence of immunity.

Isotype and antigen specificity of pertussis agglutinins following whole-cell pertussis vaccination and infection with Bordetella pertussis.

Elevated agglutinin titers have been shown to correlate with protection from disease following whole-cell pertussis vaccination, but the isotype and antigen specificity of human agglutinating antibodies is unknown. In 13 immunoassays, immunoglobulin G antifimbria antibodies had the strongest correlation with agglutinin titers following culture-proven infection with Bordetella pertussis (R' = 0.79; P < 0.0001) and following whole-cell pertussis vaccination (R' = 0.87, P < 0.0001).

Impact of treatment guidelines on use of ribavirin.

During the 1987 through 1988 seasonal peak of respiratory syncytial virus (RSV), 177 courses of ribavirin were administered at St Christopher's Hospital for Children, a tertiary care medical center in Philadelphia, Pa. Charts were reviewed on 100 treated patients with proved or suspected RSV disease to determine adherence to American Academy of Pediatrics treatment guidelines. Ninety-four percent fulfilled criteria for the risk of significant morbidity: cardiac, pulmonary, or immunodeficiency conditions (38%); an age of 6 weeks or younger (35%); or severe illness (21%). Severe illness was defined as hypoxemia, hypercapnia, or marked tachypnea. Of those treated because of underlying conditions, 71% had RSV documented, as did 71% of patients aged 6 weeks or younger and 81% of patients with severe disease. A study of 80 consecutive patients who were hospitalized with illness compatible with RSV infection revealed that 56% of patients were treated with ribavirin. Adherence to guidelines led to ribavirin use in half of the hospitalized patients with suspected RSV infection. The majority of these patients received therapy because of underlying conditions or very young age.

Chronic pulmonary complications of early influenza virus infection in children.

In 3 male patients, chronic pulmonary sequelae followed influenza virus infection at 5, 24, and 42 months of age. Varying degrees of interstitial fibrosis, bronchial and bronchiolar erosions and metaplasia, obliterative bronchiolitis, and interstitial chronic inflammatory infiltrates were found on lung biopsy. Influenza A/Hong Kong/68 (H3N2) virus was isolated from the lung tissue of one patient 8 weeks after the onset of illness. This is the longest persistence of infectious virus in lung tissue yet reported. Persistent radiographic abnormalities included peribronchial thickening, interstitial densities, bronchiectasis, obliterative bronchiolitis, and segmental atelectasis. Pulmonary function tests showed an obstructive restrictive pattern, with mild improvement after bronchodilation and with deterioration after exercise. These observations suggest that influenza virus infection may be more serious in infants and young children than has been previously recognized and may contribute to the pathogenesis of unexplained interstitial pneumonitis, pulmonary fibrosis, obliterative bronchiolitis, and bronchiectasis.

Dose-response to acellular pertussis vaccine and comparison with whole cell pertussis vaccine at 15-24 months and 4-6 years of age. Acellular Pertussis Vaccine Study Team.

In a randomized double-blind trial 55 children of 15-24 months and 56 children of 4-6 years of age previously immunized with whole-cell DTP (WC-DTP) received acellular pertussis DTP vaccines containing 12.5 micrograms (AC-12.5) or 25 micrograms (AC-25) each of pertussis toxoid (PT) and filamentous haemagglutinin (FHA) per dose of WC-DTP. No differences in antibody responses or adverse events were noted for children who received AC-25 as compared with AC-12.5. All three groups had significant increases in pertussis agglutinins, but the geometric mean titre (GMT) for 4-6-year-old children who received WC-DTP was higher than the GMT for children who received acellular vaccine. No significant differences were noted in the GMT of antibodies to FHA or PT between children who received WC-DTP and recipients of acellular vaccine. The rates of several adverse reactions were significantly (p less than or equal to 0.05) higher for recipients of WC-DTP, and children given WC-DTP were significantly (p less than or equal to 0.00001) more likely to have received acetaminophen. These acellular vaccines are safe and as immunogenic for FHA and PT as WC-DTP when administered as the fourth or fifth dose to children who received three doses of WC-DTP in infancy. The lower (12.5 micrograms) dose of acellular vaccine was as effective as the higher (25 micrograms) dose in inducing antibodies to FHA and PT in children 15-24 months and 4-6 years of age.