Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MenACWY-D) in infants and children.

BACKGROUND: Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55 years of age, in 2007 for children 2-10 years of age, and in 2011 for infants/toddlers 9-23 months of age. We conducted two studies at Kaiser Permanente Northern California (KPNC), an integrated health care organization, to assess the safety of MenACWY-D in 2-10-year-olds and 9-23-month-olds receiving the vaccine during routine clinical care. METHODS: We conducted observational, retrospective studies of MenACWY-D in 2-10-year-olds (October 2007-October 2010) and in 9-23-month-olds (June 2011-June 2014). We monitored all subjects for non-elective hospitalizations, emergency department visits, and selected outpatient outcomes (specified neurological conditions, hypersensitivity reactions and new-onset autoimmune diseases) up to 6 months after vaccination, depending on the study. Using a self-control risk-interval design, we calculated incidence rate ratios (IRRs) comparing outcomes during the post-vaccination risk interval (0-30 days) with those during more remote post-vaccination comparison intervals (31-60 and 31-180 days [children] or 31-75 days [infants/toddlers]). RESULTS: There were 1421 children aged 2-10 years and 116 infants/toddlers aged 9-23 months who received MenACWY-D. Approximately 30% of the 2-10-year-olds and 67% of the 9-23-month-olds were considered at increased risk of meningococcal disease. Among 2-10-year-olds, there was 1 hospitalization on post-vaccination day 5 for fever, which was considered possibly related to vaccination. The only significantly elevated outcome among 2-10-year-olds was cellulitis/abscess (2 cases occurred during the risk interval versus 0 during comparison interval; IRR not evaluable [NE], 95% CI: 1.42, NE). After medical record review, the 2 cases were considered unrelated to vaccination. Among 9-23-month-olds, no outcomes were significantly elevated after vaccination and there were no hospitalizations. There were no deaths observed during the three-year accrual and subsequent six-month surveillance period for either study. CONCLUSIONS: Immunization of infants and young children with MenACWY-D vaccine was not associated with any new safety concerns; however, these small studies had limited power to detect rare or uncommon safety events. ClinicalTrials.gov Identifiers are NCT00728260 and NCT01689155.

Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine.

BACKGROUND: Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55years of age. The aim of this study was to assess the safety of MenACWY-D administered as part of routine clinical care to patients at Kaiser Permanente Northern California (KPNC). METHODS: This was an observational, retrospective study that included all KPNC members who received MenACWY-D during the study period. We monitored all vaccine recipients for non-elective hospitalizations, emergency department visits, and selected outcomes captured in the clinic setting (Bell's palsy, seizures, neuritis, Guillain-Barré syndrome, encephalopathy, encephalitis, epilepsy, transverse myelitis, multiple sclerosis, hypersensitivity reactions, idiopathic thrombocytopenic purpura, diabetes, arthritis, hemolytic anemia, collagen-vascular disease) through 6months after vaccination. Using vaccine recipients as their own controls, we calculated incidence rate ratios (IRRs) of outcomes during the post-vaccination risk interval and compared these with rates during a comparison interval more remote from vaccination. We also compared rates of outcomes in MenACWY-D recipients with those in matched controls who received selected vaccines in the prior year. We reviewed medical records for selected outcomes. RESULTS: From April 2005 through April 2006, 31,561 KPNC patients (>99% of whom were 11-55years of age) received MenACWY-D. Overall, there were 21 outcomes with significantly elevated IRRs and 44 outcomes with significantly reduced IRRs. Medical record review of outcomes with significantly elevated IRRs did not suggest any relationship with MenACWY-D. Two serious adverse events were considered possibly related to vaccination by the study investigator. CONCLUSIONS: This study did not detect any safety concerns following MenACWY-D and provides reassurance that MenACWY-D administered as part of routine care was not associated with unexpected safety risks. ClinicalTrials.gov Identifier is NCT00254995.

Combination vaccines.

The biotechnology revolution has stimulated vaccine development, blessing us with new, safe, and effective vaccines, but burdening our vaccination schedule. The incorporation of multiple individual vaccines into combination vaccines can simplify vaccine administration programs and permit the inclusion of new antigens in the vaccine schedule. Although the development, evaluation, and implementation of combination vaccines pose numerous challenges and raise controversies that remain unresolved, there is a reasonable prospect of United States licensure within the next few years of several new combination vaccines for infant use. Approval in the United States of combination vaccines in use elsewhere might be speeded by improved vaccination tracking systems and post marketing efficacy surveillance, which would provide confidence that material reductions in efficacy could be detected following licensure, and thereby ease concerns regarding moderate, but perhaps immaterial, declines in immunogenicity seen with some combinations.

Principles of pediatric combination vaccines and practical issues related to use in clinical practice.

BACKGROUND: During the past two decades the number of injections that are required per office visit to fulfill the recommended childhood immunization schedule has increased dramatically. METHODS: By reviewing the literature, the principles associated with pediatric combination vaccines are discussed, and practical issues related to their use in clinical practice are evaluated. RESULTS: The ideal combination vaccine is safe, effective and easy to store and use, and its antigenic components fit within the recommended immunization schedule. The ideal combination is associated with fewer adverse reactions than the separately administered antigens, with improved efficacy and higher immune responses compared with its component vaccines. An acceptable combination vaccine must provide comparable efficacy and safety to its component vaccines. Although there are a limited number of combination vaccines already available [diphtheria-tetanus-pertussis, inactivated poliovirus vaccine (IPV) and measles-mumps-rubella], effort is being focused on combining these vaccines with other routine vaccines of infancy including Haemophilus influenzae type b (Hib) and hepatitis B vaccine (HepB). Currently under review by the Food and Drug Administration are diphtheria-tetanus-acellular pertussis (DTPa)-HepB-IPV and DTPa-Hib-IPV combination vaccines, and two DTPa-HepB-IPV-Hib vaccines have been licensed in Europe. As more combination vaccines become available, issues such as interchangeability and administration of extra doses are raised; however, it is important not to miss a vaccination opportunity. CONCLUSIONS: The number of injections required to fulfill the recommended childhood immunization schedule at each visit creates problems for patients and practitioner, sometimes risking a missed opportunity for vaccination. The development of combination vaccines will circumvent this problem and increase compliance and vaccination coverage rates.

Combination vaccines.

The past decade has shown a marked increase in the number of vaccines currently licensed and recommended for use in infants and children. Although most agree that it is desirable to combine as many of these vaccines as possible into a single injection, safety and efficacy must not be sacrificed. Clearly, a resurgence in Hib meningitis or measles (for example) would not be an acceptable price for the convenience of a single injection; but it is not clear how large a reduction in immunogenicity can be incurred without paying such a price. This conundrum has slowed the licensure of useful combination vaccines, despite a consensus that parents and practitioners have reached a limit to the number of injections they will deliver to young children. We anticipate US licensure for infant use of (at least) one DTaP-IPV-Hib vaccine and one DTaP-IPV-HB vaccine within the next few years, given the apparent lack of material reduction in immunogenicity of these specific combination products. Licensure in the United States of some of the other combinations now used in Europe is also possible, given supporting national surveillance data or improvements in our understanding of the correlates of immunity. Enhanced vaccination tracking systems and postmarketing efficacy surveillance should provide confidence that material reductions in efficacy could be detected following licensure, and thereby ease the approval of combinations that result in moderate, but perhaps immaterial, declines in immunogenicity.

Acellular pertussis vaccines.

Although whole-cell pertussis vaccines have been highly effective in preventing whooping cough, their common and burdensome adverse reactions have spurred the development of safer alternatives. Seven acellular vaccines are licensed in one or more countries; four have been licensed thus far in the United States, and more may follow. Although the licensed acellular pertussis vaccines differ in their immunogenicity, adverse reactions, and efficacy, all are effective and, compared with whole-cell vaccine, are associated with markedly fewer and milder adverse reactions.

A randomized, double-blinded study of remifentanil versus fentanyl for tonsillectomy and adenoidectomy surgery in pediatric ambulatory surgical patients.

UNLABELLED: We compared, in a double-blinded manner, the anesthetic maintenance and recovery properties of remifentanil with a clinically comparable fentanyl-based anesthetic technique in pediatric ambulatory surgical patients. Anesthesia was induced with either halothane or sevoflurane and nitrous oxide and oxygen. Patients were randomized (computer generated) to receive either remifentanil or fentanyl in a blinded syringe with nitrous oxide and oxygen in one of four possibilities: halothane/remifentanil, halothane/fentanyl, sevoflurane/remifentanil or sevoflurane/fentanyl. In patients receiving remifentanil, a placebo bolus was administered, and a continuous infusion (0.25 microg. kg(-1). min(-1)) was begun. In patients receiving fentanyl, a bolus (2 microg/kg) was administered followed by a placebo continuous infusion. The time from discontinuation of the anesthetic to extubation, discharge from the postanesthesia care unit (PACU), and discharge to home, as well as pain scores, were assessed by a blinded nurse observer. Systolic blood pressure and heart rate were noted at selected times, and adverse events were recorded. Remifentanil provided faster extubation times and higher pain-discomfort scores. PACU and hospital discharge times were similar. There were no statistical differences among the groups for adverse events. There were statistically, but not clinically, significant differences in hemodynamic variables. We noted that continuous infusions of remifentanil were intraoperatively as effective as bolus fentanyl. Although patients could be tracheally extubated earlier with remifentanil, this did not translate to earlier PACU or hospital discharge times. In addition, remifentanil was associated with higher postoperative pain scores. The frequent incidence of postoperative pain observed in the postoperative recovery room suggests that better intraoperative prophylactic analgesic regimens for postoperative pain control are necessary to optimize remifentanil's use as an anesthetic for children. IMPLICATIONS: This is a study designed to examine the efficacy and safety of a short-acting opioid, remifentanil, when used in pediatric patients. The frequent incidence of postoperative pain observed in the postoperative recovery room suggests that better intraoperative prophylactic analgesic regimens for postoperative pain control are necessary to optimize remifentanil's use as an anesthetic for children.

An acellular pertussis vaccine in healthy adults: safety and immunogenicity. Pennridge Pediatric Associates.

Recent data indicate that Bordetella pertussis can be an important cause of illness in adolescents and adults. In a randomized observer- and subject-blinded study, adults (> or = 18 years of age) received an acellular pertussis (aP) vaccine containing genetically inactivated pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN), or a saline placebo, and were monitored for safety and immunogenicity. IgG antibodies to PT, FHA, and PRN were measured by enzyme-linked immunosorbent assay (ELISA) and PT neutralization by a Chinese hamster ovary (CHO) cell assay. Local reactions, more common in the aP group, were mild and transient. One month after immunization, geometric mean ELISA antibody concentrations for the aP and placebo groups, respectively, were: anti-PT, 463 and 7.6; anti-FHA, 417 and 18; and anti-PRN, 855 and 14. The anti-PT neutralization titers for the aP and placebo groups were 1:3439 and 1:58 respectively. This aP vaccine is a safe and immunogenic candidate booster vaccine against pertussis for adults.

A randomized clinical trial of acellular pertussis vaccines in healthy adults: dose-response comparisons of 5 vaccines and implications for booster immunization.

The safety and immunogenicity of 5 acellular pertussis vaccines (ACVs) were compared in a multicenter, randomized, double-blind trial. A total of 481 healthy adults were given a single intramuscular booster dose of ACV or placebo. Three different dose levels were tested for 4 ACVs: full strength (the dose level proposed for infant immunization), one-third strength, and one-tenth strength. For 1 multicomponent vaccine, only the pertussis toxoid dose level varied. Minor injection site reactions were common and similar in frequency among vaccinated groups. Late-onset injection site reactions were seen in all ACV groups. Dose-related increases in mean antibody titers against vaccine antigens were seen after immunization with all ACVs. Antibody responses against antigens not known to be present in the vaccines were detected after immunization with 4/5 ACVs. Antibody levels fell significantly during the year after immunization. These data support evaluation of ACVs for broader use among adolescents and adults.

Incidence of pertussis infection in healthcare workers.

OBJECTIVE: To determine the incidence of pertussis infection in two groups of healthcare workers. DESIGN: Retrospective cohort study. SETTING: 660-bed, urban, tertiary-care university hospital. PARTICIPANTS: 106 resident physicians and 39 emergency department employees. INTERVENTIONS: Antibodies to pertussis toxin and filamentous hemagglutinin were determined in fresh serum specimens and in stored sera collected 1 to 3 years previously. A 50% rise in both the pertussis toxin and filamentous hemagglutinin from the initial to the follow-up specimen was considered diagnostic of a pertussis infection. RESULTS: Two of 106 residents had serological evidence of a pertussis infection during 151.3 subject-observation years, for an annual incidence rate of 1.3% (95% confidence interval [CI95], 0%-3.5%). Three of 39 emergency department employees had serological evidence of a pertussis infection during 81.2 subject-observation years, for an annual incidence of 3.6% (CI95, 0%-9.6%). Of these 5 subjects, 2 had symptomatic disease. CONCLUSION: We found both symptomatic and asymptomatic pertussis infections in two cohorts of healthcare workers. Although the incidence rates were somewhat lower than found in other studies, they nonetheless were higher than for almost all other diseases for which we vaccinate healthcare workers. Our results would support the use of acellular pertussis vaccine in healthcare workers.

Haemophilus influenzae type b vaccines: history, choice and comparisons.

The conjugate Haemophilus influenzae type b (Hib) vaccines are safe and far more immunogenic among infants and young children than is the unconjugated H. influenzae type b polysaccharide. The vaccines differ in their immunogenicity when used for primary immunization of infants, and these differences appear to be predictive of efficacy, such that some vaccines might be more suitable than others in certain populations.

International variation in the management of infants hospitalized with respiratory syncytial virus. International RSV Study Group.

UNLABELLED: Respiratory syncytial virus (RSV) is a frequent cause of hospitalization among infants. To compare patient management in Europe, the United States, and Australia, we analyzed the charts of 1,563 pediatric patients hospitalized with laboratory-confirmed RSV lower respiratory infections during recent RSV seasons. Half of patients had been seen initially as outpatients. Median duration of hospitalization was 4 days in Australia, Finland, the United Kingdom, and the United States, and 8 or 9 days in Belgium, France, Germany, Italy, and the Netherlands. In a linear regression model that included clinical findings, underlying conditions, prematurity, and age, the leading variable associated with length of stay was "hospitalization in continental Europe". This geographic factor conferred a 1.8-fold longer stay (95% CI: 1.7-1.9) than hospitalization elsewhere. Utilization of nine supportive therapies for RSV varied widely among hospitals, even within the same country. The individual hospital was strongly associated with the use of every therapy studied, independent of patient characteristics and clinical status. CONCLUSION: Management of RSV patients varies markedly by country and hospital. Multicenter RSV trials that measure length of stay should standardize criteria for "readiness for discharge". It may be appropriate to limit international trials to countries with similar median stays for RSV. Variability within multicenter trials could be further controlled by standardizing the use of other therapies and the diagnosis of complications.

A safety and immunogenicity comparison of 12 acellular pertussis vaccines and one whole-cell pertussis vaccine given as a fourth dose in 15- to 20-month-old children.

OBJECTIVE: To compare the safety and immunogenicity of 12 different acellular pertussis vaccines combined with diphtheria and tetanus toxoids (DTaP) with one licensed diphtheria, tetanus, and whole-cell pertussis vaccine (DTwP) as a fourth-dose booster in children who had previously received DTaP or DTwP primary vaccinations. METHODS: Healthy 15- to 20-month-old children were enrolled at six National Institutes of Health Vaccine Treatment and Evaluation Units. All had been randomly assigned to receive three primary doses of DTaP or DTwP at 2, 4, and 6 months of age as part of an earlier National Institutes of Health multicenter trial of DTaP vaccines in the same Vaccine Treatment and Evaluation Units. Parents recorded the occurrence and magnitude of fever; irritability; and injection site redness, swelling, and pain for 3 days after vaccination. Sera obtained before and 1 month after the booster vaccination were analyzed for antibody to pertussis toxin (PT), filamentous hemagglutinin (FHA), fimbriae (FIM), and pertactin (PRN). Diphtheria and tetanus toxoid as well as PT neutralizing (Chinese hamster ovary cell) and whole-cell agglutinating antibodies were measured on a subset of sera. RESULTS: A total of 1293 children contributed fourth-dose reaction data. Reactions were less frequent after DTaP than after DTwP. For children vaccinated with a fourth dose of DTaP, which was the same DTaP as received in the primary series, fever and injection site redness, swelling, and pain increased in prevalence compared with the third dose in the primary series. For children receiving DTaP as a fourth dose, injection site redness and swelling occurred more frequently in DTaP-primed than in DTwP-primed children. Variation in the occurrence of reactions among DTaP vaccines was observed. A total of 1160 paired pre- and postvaccination sera were available for analysis. Serum antibody concentrations before boosting were lower than those obtained 1 month after the primary immunization. After the fourth dose, significant increases in antibodies directed against the included antigens were observed for all vaccines; postbooster vaccination antibody titers differed significantly among the DTaP vaccines. For children primed and boosted with the same DTaP, antibody levels were not directly related to the quantity of antigen included for PT, FHA, and FIM; for PRN, there was a closer relationship. Some DTaP vaccines given as fourth-dose boosters elicited antibody to PRN or FIM in some vaccinees, although the DTaP vaccines were not reported to contain these antigens; these responses were observed more frequently in DTwP-primed children. Agglutinin antibody rises were observed in all groups immunized with four doses of a DTaP vaccine containing FHA or PRN, regardless of whether the vaccine included FIM. Diphtheria and tetanus antibody levels exceeded the presumed protective concentration (0.1 IU/mL for diphtheria and 0.01 IU/mL for tetanus) after the fourth dose for all vaccinees. CONCLUSION: Although differences were observed in reaction rates among the DTaP vaccines given as a fourth dose, the DTaP vaccines were, in general, associated with fewer adverse events than a US-licensed DTwP. For DTaP vaccines, fever; irritability; and injection site pain, redness, and swelling occurred more frequently after the fourth dose than after the third dose of the same vaccine in the primary series. No DTaP was consistently most or least reactogenic or immunogenic. Although serologic correlates of pertussis immunity are not defined, it is clear that most DTaP vaccines can stimulate comparable or higher serum antibody responses than DTwP for those antigens contained in the vaccine.

Combination vaccines consisting of acellular pertussis vaccines.

Combination vaccines consisting of multiple vaccine antigens delivered in a single injection simplify vaccine administration. Combining multiple antigens into one injection, however, presupposes that the administration of multiple vaccines in combination will not reduce the safety and immunogenicity of the component vaccines. New generation vaccines seek to combine many more antigens from multiple, different pathogens, making them difficult to study in controlled, double blind, randomized clinical trials because of the number of study arms required for complete evaluation. Methods to simplify studies of combination vaccines include building on the framework of earlier studies to calculate sample size and reduce the number of control arms, standardizing serologic assays and assessment of adverse reactions and determining serologic correlates of protection to minimize the need for multiple efficacy studies and to facilitate evaluation of immunogenicity studies. Preliminary data indicate that immune responses to combination vaccines including diphtheria-tetanus-acellular pertussis, hepatitis B and inactivated poliovirus are comparable with those seen when the vaccines are administered separately. In contrast studies of combination vaccines that include Haemophilus influenzae type b Hib antigens show a diminished Hib antibody response, although the clinical relevance of this lowered antibody response has not yet been determined. Numerous small safety studies of combined vaccines have not found evidence of increased adverse reactions.

Prevalence of positive serology for acute Chlamydia pneumoniae infection in emergency department patients with persistent cough.

OBJECTIVE: To determine the prevalence of acute Chlamydia pneumoniae infection in ED patients presenting with a persistent cough. METHODS: This was a case series consisting of a convenience sample of 65 patients > or = 18 years of age who presented with a chief complaint of a cough lasting > or = 2 weeks. Patients were treated in the ED of an urban university hospital. Patients with immunosuppression, lung disease, pneumonia, or a cough lasting > or = 3 months were excluded. Acute and convalescent sera were assayed for antibody to C. pneumoniae. Subjects with C. pneumoniae antibody titers showing a fourfold rise in either immunoglobin M (IgM) or immunoglobin G (IgG) antibody, an IgM titer of > or = 16, or an IgG titer of > or = 512 were considered to have evidence of acute C. pneumoniae infection. RESULTS: Thirteen (20%; 95% CI, 11% to 32%) of the 65 subjects had serologic evidence of acute C. pneumoniae infection. Except for an increased rate of fever, clinical signs and symptoms and laboratory studies did not differentiate those who had C. pneumoniae from those who did not have the disease. Patients diagnosed as having Bordetella pertussis or Mycoplasma pneumoniae infection did not have serologic evidence of concurrent C. pneumoniae infection. CONCLUSIONS: C. pneumoniae infection appears to be associated with a persistent cough in ED patients. Clinicians should consider this organism when evaluating these patients. It is unclear whether antibiotic therapy is indicated for these patients. If antibiotics are used, a tetracycline or macrolide antibiotic would be most appropriate.

Comparison of serological results in the NIAID Multicenter Acellular Pertussis Trial with recent efficacy trials.

Comparison of the serological results from the NIAID-funded Multicenter Acellular Pertussis Trial (MAPT) and the efficacy trials are complicated by differences in assay methods, immunization schedules, vaccine lots and populations immunized. In spite of these differences, serological results closely approximating those obtained in the MAPT were found for most or all of the assayed antibodies in the Mainz and Erlangen studies. Serological results for some of the antigens included in the vaccines used in the Italian and Stockholm trials were similar to the MAPT results, while significant differences were noted with other antigens. Differences in immunization schedules and serological assay methods made comparisons between MAPT and the Gothenburg and Senegal trials more difficult. Our understanding of the efficacy trial results, and our ability to apply those results to the U.S. population, would be enhanced markedly by simultaneous re-analysis of stored sera from MAPT and selected efficacy trials. This goal should be given priority by the study organizers and sponsors.

The multicenter acellular pertussis trial: an overview.

A multicenter, randomized, double-blind study was undertaken in 2342 infants to evaluate the safety and immunogenicity of 13 acellular and 2 whole cell pertussis vaccines combined with diphtheria and tetanus toxoids. Vaccines were administered to infants at 2, 4, and 6 months of age. Sera were obtained before the first vaccination (age 2 months) and 1 month after the third vaccination (age 7 months). All of the acellular vaccines produced significant increases in antibody for included antigens; mean antibody levels often exceeded those obtained with the reference whole cell vaccine. The vaccines were well-tolerated. All acellular vaccines were associated with significantly fewer adverse reactions than the control whole cell vaccine.