Medical cure of apparent brain abscesses.

Two children with apparent brain abscesses were cured with antibiotic therapy. Review of the literature reveals clinical and experimental evidence that both cerebritis and an encapsulated abscess may appear as an enhancing ring lesion on cranial computed tomography. Patients reported to have had brain abscesses cured without surgery actually may have had cerebritis. There are only preliminary hints as to how to differentiate patients with cerebritis from those with an abscess. More experience is necessary to develop criteria to determine which patients may be appropriately treated with antibiotic therapy alone.

Comparison of immunogenicity and efficacy of rhesus rotavirus reassortant vaccines in breastfed and nonbreastfed children. US Rotavirus Vaccine Efficacy Group.

OBJECTIVE: To evaluate whether breastfeeding affected the immunogenicity and/or efficacy of candidate rhesus-human rotavirus reassortant vaccines. METHODS: A total of 989 healthy infants between 4 and 26 weeks of age were enrolled into a 23-center, prospective, randomized, double-masked, controlled study of the safety, immunogenicity, and efficacy of three doses (4 x 10(4) plaque-forming units) of monovalent rhesus-human viral protein 7, or G, serotype 1 reassortant vaccine, (RRV-S1) or tetravalent vaccine (RRV-TV) consisting of rhesus-human reassortant G serotypes 1, 2, and 4, and the parent RRV G serotype 3. Vaccine efficacy was compared in the breastfed and nonbreastfed children as well as seroconversion rates and postvaccination geometric mean titers (GMTs) of neutralizing antibodies to human serotypes 1, 2, 3, and 4, RRV, and immunoglobulin A to RRV. GMTs in the two feeding groups were compared with and without adjustment for age at initiation of vaccination, prevaccination antibody titers, and the age and prevaccination titer interaction. RESULTS: The seroconversion rates to both vaccines by one or more assays were similar for the breastfed and the nonbreastfed groups (RRV-S1, 84% and 85%, respectively; RRV-TV, 94% and 93%, respectively). There were no significant differences in postvaccination GMTs to either vaccine, measured by any serologic assay, in the two feeding groups. The efficacy of the RRV-S1 vaccine was not significantly lower among the breastfed children than the nonbreastfed children (28% and 39%, respectively). RRV-TV, which is the vaccine being further evaluated for licensure, was equally protective in breastfed and nonbreastfed infants (50% and 51%, respectively). Logistic regression analysis, taking into account differences in age at vaccination and day 1 titer, revealed no evidence of differential vaccine efficacy in the two feeding groups for either vaccine. CONCLUSIONS: These results indicate that the RRV-TV vaccine, given as three doses of 4 x 10(4) plaque-forming units, induces similar seroresponses and protection in breastfed and nonbreastfed US children.

Chlamydia trachomatis infection in infant delivered by cesarean section.

Neonatal Chlamydia trachomatis infection is thought to be acquired as a result of contact with infected cervical secretions during vaginal delivery. An infant, delivered by cesarean section, who was infected with C trachomatis has been described. At 31 days of age he had conjunctivitis and respiratory distress. Nasopharyngeal aspirate grew C trachomatis and serum IgM antibody titer was 1:32 for serotype J. The patient's mother had serum IgG antibody against C trachomatis serotype J. Her cervical culture was negative for Chlamydia; however, cultures were not taken until two months after delivery and she had received antibiotics for postpartum fever and abdominal pain. The literature has been reviewed and possible modes of transmission have been discussed.

Defining the key parameters for comparing reactions among acellular and whole-cell pertussis vaccines.

OBJECTIVE: To facilitate future vaccine reaction data collection and analysis, we sought to determine the minimum data set required to describe accurately and to compare common reactions after the administration of acellular (DTaP) or whole-cell (DTP) pertussis vaccine with diphtheria and tetanus toxoids combined. METHODS: Thirteen DTaP and 2 DTP vaccines were studied in a multicenter trial involving 2342 infants who received a primary series of vaccinations at 2, 4, and 6 months of age. Temperature, fussiness, redness, swelling and pain at the injection site, antipyretic use, drowsiness, loss of appetite, and vomiting were evaluated. Reactions were assessed at 3 hours and (if not immunized in the evening) 6 hours after immunization, at bedtime each evening for 7 evenings, and on the 14th evening after immunization. RESULTS: Two reaction assessment approaches were compared: (1) analysis of all reactions, regardless of the degree of severity; and (2) a condensation of the data to five key reactions (fever > 100 degrees F, moderate or more fussiness, any local redness, any local swelling, and moderate or more local pain). We found that the onset of reactions was infrequent beyond the second evening, and that collection and analysis of reaction data beyond that time did not further discriminate among the vaccines. Information regarding antipyretic use, loss of appetite, drowsiness, or vomiting did not assist in differentiating among these vaccines. CONCLUSION: Monitoring the occurrence of fever greater than 100 degrees F, moderate or severe fussiness, injection site redness or swelling, and moderate or severe injection site pain occurring through the second evening after immunization will provide the minimum data set needed to discriminate among DTaP and DTP vaccines with respect to the common adverse reactions.

Comparison of 13 acellular pertussis vaccines: overview and serologic response.

OBJECTIVE: To compare the immunogenicity of a licensed conventional whole-cell (WCL) and 13 diphtheria-tetanus-acellular pertussis (DTaP) vaccines that differed in source, method of manufacture, and included antigens; all vaccines included diphtheria and tetanus toxoids. METHODS: Healthy infants were enrolled through six university-based vaccine and treatment evaluation units and were randomized to receive one of the study vaccines at 2, 4, and 6 months of age. Sera were obtained before the first immunization and 1 month after the third immunization and were analyzed for antibody to pertussis toxin (PT), filamentous hemagglutinin, fimbriae, pertactin, and diphtheria and tetanus toxins. Chinese hamster ovary cell toxin neutralization assays were performed, and levels of agglutinating antibodies were determined. RESULTS: Of 2342 infants enrolled, 1942 contributed usable preimmunization and postimmunization serum specimens. Each vaccine produced significant increases in antibodies directed against the included antigens; postimmunization antibody titers differed significantly among the DTaP vaccines. For each evaluated antigen, the majority of DTaP vaccines produced antibody responses that equaled or exceeded those produced by WCL. For some antigens (eg, PT), mean antibody levels by vaccine correlated poorly with the quantity of antigen included in each vaccine; for others (eg., fimbriae), there was a close correlation. CONCLUSION: Although serologic correlates of pertussis immunity are not defined, it is clear that DTaP vaccines can stimulate immune responses that exceed those of licensed whole-cell vaccine with respect to the measured antibodies. Particularly for PT, immunogenicity seems to depend on factors in addition to antigen concentration, possibly including antigen derivation and formulation. No DTaP was most or least immunogenic with respect to all included antigens.

Comparison of 13 acellular pertussis vaccines: adverse reactions.

OBJECTIVE: To compare the reactogenicity of a licensed conventional whole-cell (WCL) and 13 acellular pertussis vaccines that differed in the source, manufacture, and quantity of included antigens; all vaccines included diphtheria and tetanus toxoids. METHODS: Healthy infants were enrolled through six university-based vaccine and treatment evaluation units and were randomized to receive one of the study vaccines at 2, 4, and 6 months of age. Parents recorded the occurrence of fever, redness, swelling, pain, fussiness, drowsiness, anorexia, and use of antipyretics for 2 weeks after each inoculation; nurses interviewed parents on the third day and at each succeeding visit; long-term follow-up information was collected from parents and medical records 1 year after the third immunization. RESULTS: Of 2200 vaccinated infants, 2189 contributed reaction data after 6375 vaccinations. For every acellular vaccine, every monitored reaction except vomiting occurred at a significantly lower frequency and severity than was seen with WCL. The groups receiving acellular pertussis vaccines differed significantly with respect to redness, swelling, pain, and vomiting, but not with respect to fussiness, antipyretic use, drowsiness, or anorexia. CONCLUSION: Although there were differences among the acellular vaccines, none was consistently the most or least reactogenic; all were associated with substantially fewer and less severe adverse reactions than a standard commercial whole-cell vaccine. Selection of acellular vaccines for further development and for introduction into efficacy trials can give priority to assessments of immunogenicity and purity, with comparative reactogenicity a secondary consideration.

A randomized comparison of reactogenicity and immunogenicity of two whole-cell pertussis vaccines.

OBJECTIVE: To compare prospectively the reactogenicity and immunogenicity of two licensed whole-cell pertussis vaccines. METHODS: We conducted a prospective, randomized, double-blinded assessment of two licensed whole-cell pertussis vaccines with diphtheria and tetanus toxoids that were included in a multicenter trial evaluating 13 acellular pertussis vaccines. Infants were immunized at 2, 4, and 6 months of age with a single lot of Lederle (309 infants) or Massachusetts Public Health Biologic Laboratories (MPHBL; 94 infants) vaccine. RESULTS: The group receiving the Lederle vaccine demonstrated significantly higher antibody titers to pertussis toxin by enzyme-linked immunosorbent assay (ELISA) and by the Chinese hamster ovary cell pertussis toxin neutralization assay, and to fimbrial antigens by ELISA, as well as higher mean agglutinin titers. In contrast, the group receiving the MPHBL vaccine demonstrated higher ELISA antibody levels to filamentous hemagglutinin and pertactin. Similar differences were observed in the proportions of vaccinees seroconverting to these antigens. Rates of systemic and local reactions were relatively low for both vaccines. Although the Lederle product had substantially lower reactogenicity in this study than previously reported for that vaccine, the MPHBL vaccine was significantly less reactogenic in nearly all clinical categories. CONCLUSION: The two whole-cell vaccines demonstrated statistically significant differences in postimmunization antibody levels to all six evaluated pertussis antigens. Whether these statistically significant differences in antibody levels have clinical relevance is not clear. Rates of nearly all local and systemic reactions were significantly lower among the MPHBL group than the Lederle group. Licensed whole-cell diphtheria-tetanus-pertussis vaccines produced by different manufacturers cannot be assumed to be similar in reactogenicity or immunogenicity.

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.

Effect of gender, race, and parental education on immunogenicity and reported reactogenicity of acellular and whole-cell pertussis vaccines.

OBJECTIVE: To determine whether gender, race (black or white), or level of parental education influenced serologic responses or reporting of clinical reactions after immunization with acellular (DTaP) or whole-cell (DTP) pertussis vaccine with diphtheria and tetanus toxoids combined. METHODS: Healthy infants were prospectively randomized to receive one of 13 DTaP, Lederle DTP, or another DTP. Parents recorded the occurrence of adverse reactions for 2 weeks after each inoculation. Sera obtained before the first immunization and 1 month after the third immunization were analyzed for antibody to pertussis toxin, filamentous hemagglutinin, fimbriae, and pertactin (PRN). Chinese hamster ovary cell pertussis toxin neutralization assays were performed, and levels of agglutinating antibodies determined. RESULTS: Prevaccination antibody levels did not differ by race, gender, or parental education. Postimmunization geometric mean titers (GMTs) were strongly and consistently associated with race. For both DTaP and DTP and for every included antigen, postimmunization GMTs were about twice as high for black as for white infants. Among DTaP recipients, these differences were significant for pertussis toxin, Chinese hamster ovary cell pertussis toxin neutralization assay, filamentous hemagglutinin, PRN, and agglutinins; among the much smaller sample of WCL recipients, the differences achieved or approached statistical significance for agglutinins, PRN, and fimbriae. These findings were confirmed by regression analyses that controlled for gender, parental education, study site, and preimmunization antibody level. Reported reactions were not correlated with parental education level and showed no material correlation with gender. Black infants were reported to have had more pain than white infants after receiving WCL and DTaP and were reported to be more fussy after receiving WCL. CONCLUSIONS: The consistently higher postimmunization GMTs among black infants seems to be a real finding for which we have no explanation; the infants did not significantly differ by race in vaccine assignment, preimmunization antibody levels, age at immunization, or interval from immunization to phlebotomy. These observations should be confirmed and further evaluated in future pertussis vaccine trials. Reported differences by race in pain and fussiness after receiving WCL might reflect chance, differences by race in the occurrence of reactions, or differences by race in the reporting of reactions.

Association of reactions after consecutive acellular or whole-cell pertussis vaccine immunizations.

OBJECTIVE: To evaluate the relative frequency of adverse reactions after initial and subsequent immunizations among infants receiving primary immunization with acellular (DTaP) or whole-cell (DTP) pertussis vaccine with diphtheria and tetanus combined. METHODS: We examined the occurrence of common reactions in 2127 infants within 48 hours after immunization at 2, 4, and 6 months with one of 13 DTaP or with Lederle DTP (WCL). Data on at least two consecutive immunizations were available for 357 WCL recipients and 1770 DTaP recipients. For these analyses, reactions evaluated included fever of 100.4 degrees F (38 degrees C) or greater, redness of 21 mm or larger, swelling of 21 mm or larger, moderate or severe pain, moderate or severe fussiness, loss of appetite, drowsiness, and vomiting. RESULTS: With one exception, reactions were approximately 1.5 to 8 times more likely to occur in WCL recipients if the same reaction had been observed at the previous immunization (the single exception was redness after the second immunization). Both initial and repeated reactions were less likely in DTaP than in WCL recipients. As with WCL recipients, risks of repeated reactions in DTaP recipients were higher than the risks of initial reactions (from 2.5 to 24 times as high). CONCLUSION: Reactions after a second or third immunization with either WCL or DTaP vaccine are more likely to occur in infants who had the same reaction after the preceding immunization. Absolute risks of repeated reactions tended to be lower after DTaP vaccine than after the WCL vaccine.

Safety and efficacy of high-dose rhesus-human reassortant rotavirus vaccines--report of the National Multicenter Trial. United States Rotavirus Vaccine Efficacy Group.

OBJECTIVE: Rotavirus is a leading cause of morbidity and mortality from dehydrating gastroenteritis in infants and young children worldwide. Virtually every child is infected by age 4 years, justifying universal childhood immunization when a safe and effective vaccine is available. We report the results of a multicenter, placebo-controlled field trial in the United States of monovalent serotype 1 and tetravalent (TV) rhesus-human reassortant rotavirus vaccines (RRVs). DESIGN: In this randomized, double-blind trial, 1278 healthy infants ages 5 to 25 weeks received three oral doses of RRV serotype 1, RRV-TV, or a placebo at approximately 2, 4, and 6 months of age. Vaccines contained 4 x 10(5) plaque-forming units of virus. Gastroenteritis episodes were monitored, and severity was graded throughout one rotavirus season. Two stool specimens per episode were tested for rotavirus. RESULTS: The incidence of reactions did not differ among treatment groups during the 5-day, postvaccination safety surveillance period for any of the three doses. Both vaccines significantly reduced the incidence of rotavirus gastroenteritis. Vaccination was most protective against serious rotavirus illness; RRV-TV prevented 49% of rotavirus episodes, 80% of very severe episodes, and 100% of dehydrating rotavirus illness. Reduction of rotavirus disease by RRV-TV resulted in significantly fewer total episodes of gastroenteritis of all causes and an 82% reduction in all cases of dehydrating diarrhea. CONCLUSION: RRV-TV is highly protective against very severe, dehydrating rotavirus gastroenteritis.

Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM197 in United States infants.

OBJECTIVE: To determine the safety and immunogenicity of heptavalent pneumococcal saccharide vaccine (serotypes 4, 6B, 9V, 14, 18C, 19F, 23F) individually conjugated to CRM197 (PNCRM7), administered at 2, 4, 6, and 12 to 15 months of age. DESIGN: Two hundred twelve healthy 2-month-old infants were equally randomized to receive four consecutive doses of PNCRM7 or an investigational meningococcal group C conjugate vaccine, which served as a control. Concomitantly administered routine vaccines were oral polio vaccine and combined diphtheria toxoid, tetanus toxoid, and whole cell pertussis vaccine/Haemophilus influenzae type b vaccine consisting of capsular oligosaccharides conjugated to CRM197 (DTP/HbOC) at 2, 4, and 6 months, and either measles-mumps-rubella vaccine or HbOC at 12 to 15 months. Active safety surveillance was conducted for 3 days after each dose. Antibody concentrations to each of the 7 pneumococcal serotypes were measured by enzyme-linked immunosorbent assay prevaccination, after doses two and three, prebooster, and postbooster. RESULTS: Significantly fewer children experienced local reactions at the PNCRM7 injection site than at the DTP/HbOC site. There was no increase in the incidence or severity of local reactions at the PNCRM7 site with increasing doses of vaccine. Mild to moderate postvaccination fever was common in both the PNCRM7 and control vaccine groups, however DTP/HbOC was administered concurrently. All 7 vaccine serotypes were immunogenic. The kinetics of the immune responses were serotype-specific. After three doses of PNCRM7, between 92% to 100% of children had >/=0.15 microg/mL of antibody, and 51% to 90% achieved a level of >/=1 microg/mL against specific serotypes. A booster dose of PNCRM7 resulted in a brisk anamnestic response to all 7 vaccine serotypes, demonstrating effective stimulation of T-cell memory by the primary series of vaccinations. CONCLUSION: Primary immunization followed by a booster dose of PNCRM7 seemed to be acceptably safe and resulted in significant rises in antibody to all 7 serotypes. Implications. Studies to assess vaccine efficacy of PNCRM7 for prevention of systemic disease, nasopharyngeal colonization, and acute otitis media are in progress. If PNCRM7 proves to be protective, there is the potential to prevent up to 85% of invasive pneumococcal disease occurring in US children.

Systemic and mucosal immune responses to rhesus rotavirus vaccine MMU 18006.

Thirty-four children 3 to 20 months of age ingested either 10(5), 10(4) or 10(3) plaque-forming units of rhesus rotavirus vaccine, MMU 18006, which possesses human rotavirus serotype 3 neutralization antigen. Immune responses were evaluated by a plaque reduction neutralization (PRN) assay to rotavirus serotypes 1, 2 and 3 and by a serum IgG, IgM and IgA and fecal IgA class-specific enzyme-linked immunosorbent assay. Homotypic PRN antibody seroconversions to serotype 3 rotavirus were detected in 31 of 34 children (91%), whereas rises in heterotypic PRN antibody to human rotavirus serotypes 1 or 2 were found in only 3 of 21 (14%) (p less than 0.00000001). Thirty of the 34 vaccinated children (88%) had at least one class of rotavirus-specific serum antibody detected by enzyme-linked immunosorbent assay. A rotavirus-specific IgA coproantibody response was seen in 11 of 16 children (69%) following vaccination. Two children who had no evidence of PRN antibody to serotype 3 after vaccination had evidence of both a fecal and a serum rotavirus-specific IgA response, suggesting that in these children the response to the vaccine was primarily mucosal. These data show that orally administered rhesus rotavirus vaccine MMU 18006 elicits local intestinal immunity but produces primarily a homotypic serum neutralization response as measured by plaque reduction neutralization assays.

Oral tetravalent rotavirus vaccine can be successfully coadministered with oral poliovirus vaccine and a combined diphtheria, tetanus, pertussis and Haemophilus influenzae type b vaccine. US Rhesus Rotavirus Vaccine Study Group.

AIM: To determine whether an oral tetravalent rotavirus vaccine (RV-TV) can be safely coadministered with a combined diphtheria-tetanus-pertussis-Haemophilus influenzae type b vaccine (DTP/Hib) and oral poliovirus vaccine (OPV) to healthy infants without interfering with the immune responses to any of the component antigens. METHODS: Two hundred sixty-seven infants ages 2 to 3 months were randomly assigned in a double blind fashion to receive three doses of either placebo or RV-TV, each containing 4 x 10(5) plaque-forming units, concurrently with DTP/ Hib (Tetramune) and OPV at approximately 2, 4 and 6 months of age. Infants were followed for 5 days after each dose for the occurrence of adverse events and subsequently until 3 to 6 weeks after the third dose of RV-TV or placebo. Immune responses were assessed by measuring the postvaccination serum antibody titers to each component of DTP/ Hib and OPV at 3 to 6 weeks after the third dose. RESULTS: The percentage of infants who attained protective antibody titers and the distribution of antibody titers against diphtheria toxoid, tetanus toxoid and H. influenzae type b were not statistically different between RV-TV and placebo recipients. The distribution of antibody titers against different antigens of Bordetella pertussis (agglutinins, pertussis toxoid, filamentous hemagglutinin, fimbriae antigens and the 69-kDa outer membrane protein) was compared and no significant differences were found. The percentage of infants with detectable neutralizing antibodies against the three serotypes of poliovirus and the distribution of antibody titers was not statistically different between RV-TV and placebo recipients. There were no clinically meaningful differences in postvaccination reactions between RV-TV and placebo recipients. CONCLUSIONS: Three doses of RV-TV can be safely coadministered with three doses of DTP/ Hib and OPV without diminishing an infant's serum antibody responses to each component of these vaccines. Therefore RV-TV can be given at the standard childhood visits at 2, 4 and 6 months of age.

Fifth vaccination with dipthteria, tetanus and acellular pertussis is beneficial in four- to six-year-olds.

OBJECTIVE: Diphtheria, tetanus and pertussis serum antibody titers were assessed before a fifth dose of diphtheria-tetanus-acellular pertussis (DTaP) or diphtheria-tetanus-whole cell pertussis (DTwP) vaccination at age 4 to 6 years. METHODS: Healthy children who had participated in a series of National Institutes of Health-sponsored trials assessing DTwP and DTaP vaccines provided prevaccination sera before a fifth dose of DTwP or DTaP. The trial design was prospective, randomized and double blind. Diphtheria, tetanus and pertussis antibody titers were measured by enzyme-linked immunosorbent assay. Pertussis results are expressed in enzyme-linked immunosorbent assay units/ml based on US Food and Drug Administration reference sera. Tetanus and diphtheria toxin concentrations are expressed in IU/ml with a WHO international reference sera as a standard. RESULTS: For diphtheria 100% of the children had antibody titers above the minimum protective level of 0.01 IU/ml and 86 to 100% (depending on prior vaccine product) had titers >0.1 IU/ml. However, only 0 to 40% of the children had antibody titers > or =1.0 IU/ml, a titer associated with more certain durable protection. For tetanus none of the children had an antibody titer below 0.01 IU/ml, and 93 to 100% had titers > or =0.1 IU/ml, a titer associated with more certain, durable protection. For pertussis the geometric mean concentrations of antibody before booster were uniformly very low, and the percentage of children exceeding the minimum detectable titer of antibody by 4-fold was also low. CONCLUSION: Before a 4- to 6-year-old booster, a large proportion of children have titers of antibody to diphtheria below the certain, durable protective level. Because serologic correlates and minimum protective titers of antibody to pertussis antigens have not been established, the relevance of the low titers determined in the current study is unknown but a potential concern.

Effect of dose and a comparison of measures of vaccine take for oral rhesus rotavirus vaccine. The Maryland Clinical Studies Group.

Ninety-six healthy infants ages 2 to 5 months received rhesus rotavirus vaccine serotype 3 (RRV) as a single dose of 10(3), 10(4) or 10(5) plaque-forming units (pfu) in this double-blinded, placebo-controlled study. Half of the infants in each dose group were also randomized to receive either 30 ml of infant formula as buffer before vaccination or were vaccinated on an empty stomach. The incidence of fever, increased stool frequency and decreased activity level was consistently higher among infants who received RRV than those who received placebo. There was no consistent increase in incidence of symptoms as the dose of RRV was increased. Possible vaccine-related side effects were increased in older vaccinees and in those with higher pre-vaccination antibody titers. The seroconversion rate and pre to postvaccination antibody rise, evaluated by enzyme-linked immunosorbent assay and by plaque reduction neutralization, correlated well. The 10(5) and 10(4) pfu RRV dose produced significantly higher rates of seroconversion and higher antibody rises than did placebo (P less than 0.001 for 10(5) and P = 0.005 for 10(4]. The 10(3) pfu dose was no more immunogenic than placebo. In the 10(4) pfu dose group 73% of infants receiving formula as a "buffer" seroconverted compared with 36% of those not receiving formula; 63% of infants partially breast-fed or formula-fed seroconverted compared with 17% of those exclusively breast-fed. These differences in seroconversion rate were largely overcome by increasing the RRV dose to 10(5) pfu. Stool (copro IgA) antibody responses were examined; of six infants showing a copro IgA response only one had seroconverted based on enzyme-linked immunosorbent assay or plaque reduction neutralization. RRV was recovered by tissue culture more frequently from the stool in those infants who received RRV 10(5) and 10(4) pfu than among those receiving 10(3) pfu or placebo (P less than 0.001).

Diminution of the anti-polyribosylribitol phosphate response to a combined diphtheria-tetanus-acellular pertussis/Haemophilus influenzae type b vaccine by concurrent inactivated poliovirus vaccination.

BACKGROUND: Prelicensure studies of Haemophilus influenzae type b vaccines (Hib) and diphtheria-tetanus-acellular pertussis vaccines (DTaP) were evaluated with concurrent oral poliovirus vaccine (OPV). However, inactivated poliovirus vaccine (IPV) is now recommended. A trial was conducted in which infants received a DTaP and Hib vaccine, separately (+) or combined (/), with either all OPV, all IPV or sequential IPV-OPV for the primary series of vaccinations. METHODS: In this protocol 567 infants were equally randomized to receive one of the following: Reference Arm A, DTaP + Hib + OPV; Treatment Arm B, DTaP/Hib + OPV; Treatment Arm C, DTaP/Hib + IPV at 2 and 4 months and OPV at 6 months; or Treatment Arm D, DTaP/Hib + IPV. antibodies against all administered antigens were measured at 7 months of age. Children with an antibody response to Hib (anti-polyribosylribitol phosphate (anti-PRP) <0.15 microg/ml had an antibody titer repeated after the toddler booster immunization. RESULTS: A significant diminution in the anti-PRP response was observed at 7 months of age in children given two or three doses of IPV concurrently with DTaP/Hib, compared with the groups given OPV. The geometric mean concentration of anti-PRP, percentage of children with > or = 0.15 microg/ml and percentage of children with > or = 1.0 microg/ ml, respectively, were: A, 4.4, 98%, 81%; B, 3.2, 94%, 78%; C, 1.3, 86%, 58% and D, 1.2, 84%, 53%. CONCLUSION: In this trial concurrent IPV appeared to interfere with the anti-PRP response to DTaP/Hib vaccine, suggesting that introduction of new vaccines may require evaluation of immune responses to all concurrently administered vaccines.

Immunogenicity and reactogenicity of lowered doses of rhesus rotavirus vaccine strain MMU 18006 in young children.

Rhesus rotavirus oral vaccine strain MMU 18006 at a dose of 10(5) plaque-forming units (PFU), a 1:10 dilution of the original undiluted vaccine, is highly immunogenic in young children. Fevers have occurred, however, on Days 3 and 4 following vaccination. This study was conducted to determine whether febrile reactions could be eliminated and immunogenicity maintained by (1) giving smaller doses of vaccine or (2) vaccinating younger infants. Thirty-one children between 3 and 11 months of age received, in a randomized, double blind manner, either 10(4) PFU of vaccine virus, 10(3) PFU of vaccine virus or placebo. All recipients of the 10(4) PFU dose had a seroresponse; however, some degree of immunogenicity was lost with the smaller dose (10(3) PFU). Fevers were observed in recipients of both of the lowered doses of vaccine but the febrile reactions were related to the age of the vaccinee. No infant younger than 5 months of age experienced a temperature elevation, whereas the majority of children older than 5 months had fevers. Our data suggest that the lack of reaction in the younger infants correlates with the presence of prevaccination neutralizing antibody, presumably transplacentally acquired. We conclude that the rhesus rotavirus oral vaccine at a dose of 10(4) PFU is immunogenic and appears to be safe in young infants.

Safety and immunogenicity of four doses of Neisseria meningitidis group C vaccine conjugated to CRM197 in United States infants.

BACKGROUND: Following widespread use of conjugate pneumococcal vaccine, Neisseria meningitidis likely will become the leading cause of bacterial sepsis and meningitis in US children. This report describes the safety and immunogenicity in US children of four consecutive doses of a meningococcal group C vaccine conjugated to CRM197 via reductive amination (MnCC). METHODS: One hundred six healthy 2-month-old infants received MnCC at 2, 4 and 6 months of age in a randomized, controlled double blind study; children in the other treatment arm were given a 7-valent conjugate pneumococcal vaccine. Parents reenrolled 64 of these children at 12 to 15 months to receive a fourth dose of MnCC. Routine childhood vaccines, including DTP, were coadministered. Temperatures and symptoms were recorded for 3 days after each immunization. Serum enzyme-linked immunosorbent assay IgG and bactericidal antibodies were measured prevaccination and before and 1 month after Doses 3 and 4. RESULTS: Moderate to severe local reactions, defined as erythema or induration > or =2.4 cm or pain that interfered with limb movement was reported after 0 to 3.2% of MnCC injections, depending on the reaction and dose. Fever occurred in 23 to 37% of children, but the contribution of MnCC to the febrile reactions is unknown. Geometric mean concentrations of IgG antibody to group C meningococcal polysaccharide were 3.72 microg/ml after Dose 3 and 8.03 microg/ml after the booster. Geometric mean functional serum bactericidal antibody titers after Doses 3 and 4 were 1:463 and 1:2341, respectively. One hundred percent of children had a serum bactericidal antibody titer of > or =1:64 after three doses and > or = 1:128 after the booster. CONCLUSIONS: The MnCC vaccine had an acceptable safety profile and generated high titers of bactericidal antibody in immunized US infants and toddlers. It appears to be an attractive candidate vaccine for the prevention of serogroup C meningococcal disease in young children.