Humoral and Cell-Mediated Immune Responses to Alternate Booster Schedules of Anthrax Vaccine Adsorbed in Humans.

Protective antigen (PA)-specific antibody and cell-mediated immune (CMI) responses to annual and alternate booster schedules of anthrax vaccine adsorbed (AVA; BioThrax) were characterized in humans over 43 months. Study participants received 1 of 6 vaccination schedules: a 3-dose intramuscular (IM) priming series (0, 1, and 6 months) with a single booster at 42 months (4-IM); 3-dose IM priming with boosters at 18 and 42 months (5-IM); 3-dose IM priming with boosters at 12, 18, 30, and 42 months (7-IM); the 1970 licensed priming series of 6 doses (0, 0.5, 1, 6, 12, and 18 months) and two annual boosters (30 and 42 months) administered either subcutaneously (SQ) (8-SQ) or IM (8-IM); or saline placebo control at all eight time points. Antibody response profiles included serum anti-PA IgG levels, subclass distributions, avidity, and lethal toxin neutralization activity (TNA). CMI profiles included frequencies of gamma interferon (IFN-γ)- and interleukin 4 (IL-4)-secreting cells and memory B cells (MBCs), lymphocyte stimulation indices (SI), and induction of IFN-γ, IL-2, IL-4, IL-6, IL-1ß, and tumor necrosis factor alpha (TNF-α) mRNA. All active schedules elicited high-avidity PA-specific IgG, TNA, MBCs, and T cell responses with a mixed Th1-Th2 profile and Th2 dominance. Anti-PA IgG and TNA were highly correlated (e.g., month 7,r(2)= 0.86,P< 0.0001, log10 transformed) and declined in the absence of boosters. Boosters administered IM generated the highest antibody responses. Increasing time intervals between boosters generated antibody responses that were faster than and superior to those obtained with the final month 42 vaccination. CMI responses to the 3-dose IM priming remained elevated up to 43 months. (This study has been registered at ClinicalTrials.gov under registration no. NCT00119067.).

Evaluation of sex, race, body mass index and pre-vaccination serum progesterone levels and post-vaccination serum anti-anthrax protective immunoglobulin G on injection site adverse events following anthrax vaccine adsorbed (AVA) in the CDC AVA human clinical trial.

BACKGROUND: Anthrax vaccine adsorbed (AVA) administered intramuscularly (IM) results in fewer adverse events (AEs) than subcutaneous (SQ) administration. Women experience more AEs than men. Antibody response, female hormones, race, and body mass index (BMI) may contribute to increased frequency of reported injection site AEs. METHODS: We analyzed data from the CDC AVA human clinical trial. This double blind, randomized, placebo controlled trial enrolled 1563 participants and followed them through 8 injections (AVA or placebo) over a period of 42 months. For the trial's vaccinated cohort (n=1267), we used multivariable logistic regression to model the effects of study group (SQ or IM), sex, race, study site, BMI, age, and post-vaccination serum anti-PA IgG on occurrence of AEs of any severity grade. Also, in a women-only subset (n=227), we assessed effect of pre-vaccination serum progesterone level and menstrual phase on AEs. RESULTS: Participants who received SQ injections had significantly higher proportions of itching, redness, swelling, tenderness and warmth compared to the IM study group after adjusting for other risk factors. The proportions of redness, swelling, tenderness and warmth were all significantly lower in blacks vs. non-black participants. We found arm motion limitation, itching, pain, swelling and tenderness were more likely to occur in participants with the highest anti-PA IgG concentrations. In the SQ study group, redness and swelling were more common for obese participants compared to participants who were not overweight. Females had significantly higher proportions of all AEs compared to males. Menstrual phase was not associated with any AEs. CONCLUSIONS: Female and non-black participants had a higher proportion of AVA associated AEs and higher anti-PA IgG concentrations. Antibody responses to other vaccines may also vary by sex and race. Further studies may provide better understanding for higher proportions of AEs in women and non-black participants.

Effect of reduced dose schedules and intramuscular injection of anthrax vaccine adsorbed on immunological response and safety profile: a randomized trial.

OBJECTIVE: We evaluated an alternative administration route, reduced schedule priming series, and increased intervals between booster doses for anthrax vaccine adsorbed (AVA). AVA's originally licensed schedule was 6 subcutaneous (SQ) priming injections administered at months (m) 0, 0.5, 1, 6, 12 and 18 with annual boosters; a simpler schedule is desired. METHODS: Through a multicenter randomized, double blind, non-inferiority Phase IV human clinical trial, the originally licensed schedule was compared to four alternative and two placebo schedules. 8-SQ group participants received 6 SQ injections with m30 and m42 "annual" boosters; participants in the 8-IM group received intramuscular (IM) injections according to the same schedule. Reduced schedule groups (7-IM, 5-IM, 4-IM) received IM injections at m0, m1, m6; at least one of the m0.5, m12, m18, m30 vaccine doses were replaced with saline. All reduced schedule groups received a m42 booster. Post-injection blood draws were taken two to four weeks following injection. Non-inferiority of the alternative schedules was compared to the 8-SQ group at m2, m7, and m43. Reactogenicity outcomes were proportions of injection site and systemic adverse events (AEs). RESULTS: The 8-IM group's m2 response was non-inferior to the 8-SQ group for the three primary endpoints of anti-protective antigen IgG geometric mean concentration (GMC), geometric mean titer, and proportion of responders with a 4-fold rise in titer. At m7 anti-PA IgG GMCs for the three reduced dosage groups were non-inferior to the 8-SQ group GMCs. At m43, 8-IM, 5-IM, and 4-IM group GMCs were superior to the 8-SQ group. Solicited injection site AEs occurred at lower proportions in the IM group compared to SQ. Route of administration did not influence the occurrence of systemic AEs. A 3 dose IM priming schedule with doses administered at m0, m1, and m6 elicited long term immunological responses and robust immunological memory that was efficiently stimulated by a single booster vaccination at 42 months. CONCLUSIONS: A priming series of 3 intramuscular doses administered at m0, m1, and m6 with a triennial booster was non-inferior to more complex schedules for achieving antibody response.

Enrollment in YFV Vaccine Trial: An Evaluation of Recruitment Outcomes Associated with a Randomized Controlled Double-Blind Trial of a Live Attenuated Yellow Fever Vaccine.

This investigation evaluated several factors associated with diverse participant enrollment of a clinical trial assessing safety, immunogenicity, and comparative viremia associated with administration of 17-D live, attenuated yellow fever vaccine given alone or in combination with human immune globulin. We obtained baseline participant information (e.g., sociodemographic, medical) and followed recruitment outcomes from 2005 to 2007. Of 355 potential Yellow Fever vaccine study participants, 231 cases were analyzed. Strong interest in study participation was observed among racial and ethnically diverse persons with 36.34% eligible following initial study screening, resulting in 18.75% enrollment. The percentage of white participants increased from 63.66% (prescreened sample) to 81.25% (enrollment group). The regression model was significant with white race as a predictor of enrollment (OR=2.744, 95% CI=1.415-5.320, p=0.003).In addition, persons were more likely to enroll via direct outreach and referral mechanisms compared to mass advertising (OR=2.433, 95% CI=1.102-5.369). The findings indicate that racially diverse populations can be recruited to vaccine clinical trials, yet actual enrollment may not reflect that diversity.

Health-related quality of life in the CDC Anthrax Vaccine Adsorbed Human Clinical Trial.

BACKGROUND: After the Department of Defense implemented a mandatory anthrax vaccination program in 1998 concerns were raised about potential long-term safety effects of the current anthrax vaccine. The CDC multicenter, randomized, double-blind, placebo-controlled Anthrax Vaccine Adsorbed (AVA) Human Clinical Trial to evaluate route change and dose reduction collected data on participants' quality of life. Our objective is to assess the association between receipt of AVA and changes in health-related quality of life, as measured by the SF-36 health survey (Medical Outcomes Trust, Boston, MA), over 42 months after vaccination. METHODS: 1562 trial participants completed SF-36v2 health surveys at 0, 12, 18, 30 and 42 months. Physical and mental summary scores were obtained from the survey results. We used Generalized Estimating Equations (GEE) analyses to assess the association between physical and mental score difference from baseline and seven study groups receiving either AVA at each dose, saline placebo at each dose, or a reduced AVA schedule substituting saline placebo for some doses. RESULTS: Overall, mean physical and mental scores tended to decrease after baseline. However, we found no evidence that the score difference from baseline changed significantly differently between the seven study groups. CONCLUSIONS: These results do not favor an association between receipt of AVA and an altered health-related quality of life over a 42-month period.

Immunogenicity and safety of varying dosages of a monovalent 2009 H1N1 influenza vaccine given with and without AS03 adjuvant system in healthy adults and older persons.

BACKGROUND: Adjuvanted vaccines have the potential to improve influenza pandemic response. AS03 adjuvant has been shown to enhance the immune response to inactivated influenza vaccines. METHODS: This trial was designed to evaluate the immunogenicity and safety of an inactivated 2009 H1N1 influenza vaccine at varying dosages of hemagglutinin with and without extemporaneously mixed AS03 adjuvant system in adults ≥ 18 years of age. Adults were randomized to receive 2 doses of 1 of 5 vaccine formulations (3.75 µg, 7.5 µg, or 15 µg with AS03 or 7.5 µg or 15 µg without adjuvant). RESULTS: The study population included 544 persons <65 years of age and 245 persons ≥ 65 years of age. Local adverse events tended to be more frequent in the adjuvanted vaccine groups, but severe reactions were uncommon. In both age groups, hemagglutination inhibition antibody geometric mean titers after dose one were higher in the adjuvanted groups, compared with the 15 µg unadjuvanted group, and this difference was statistically significant for the comparison of the 15 µg adjuvanted group with the 15 µg unadjuvanted group. CONCLUSIONS: AS03 adjuvant system improves the immune response to inactivated 2009 H1N1 influenza vaccine in both younger and older adults and is generally well tolerated. ClinicalTrials.gov NCT00963157.

Safety and immune responses in children after concurrent or sequential 2009 H1N1 and 2009-2010 seasonal trivalent influenza vaccinations.

BACKGROUND: Administering 2 separate vaccines for seasonal and pandemic influenza was necessary in 2009. Therefore, we conducted a randomized trial of monovalent 2009 H1N1 influenza vaccine (2009 H1N1 vaccine) and seasonal trivalent inactivated influenza vaccine (TIV; split virion) given sequentially or concurrently in previously vaccinated children. METHODS: Children randomized to 4 study groups and stratified by age received 1 dose of seasonal TIV and 2 doses of 2009 H1N1 vaccine in 1 of 4 combinations. Injections were given at 21-day intervals and serum samples for hemagglutination inhibition antibody responses were obtained prior to and 21 days after each vaccination. Reactogenicity and adverse events were monitored. RESULTS: All combinations of vaccines were safe in the 531 children enrolled. Generally, 1 dose of 2009 H1N1 vaccine and 1 dose of TIV, regardless of sequence or concurrency of administration, was immunogenic in children ≥ 10 years of age; children <10 years of age required 2 doses of 2009 H1N1 vaccine. CONCLUSIONS: Vaccines were generally well tolerated. The immune responses to 2009 H1N1 vaccine were adequate regardless of the sequence of vaccination in all age groups but the sequence affected titers to TIV antigens. Two doses of 2009 H1N1 vaccine were required to achieve a protective immune response in children <10 years of age. CLINICAL TRIALS REGISTRATION: NCT00943202.

Safety and immunogenicity of influenza A H5 subunit vaccines: effect of vaccine schedule and antigenic variant.

BACKGROUND: The current US national stockpile of influenza H5 vaccine was produced using the antigen from the strain A/Vietnam/1203/2004 (a clade 1 H5 virus). Recent H5 disease has been caused by antigenically divergent H5 viruses, including A/Indonesia/05/2005 (a clade 2 H5 virus). METHODS: The influence of schedule on the antibody response to 2 doses of H5 vaccines (one a clade 1 hemagglutinin protein [HA] vaccine and one a clade 2 HA vaccine) containing 90 µg of antigen was evaluated in healthy adults 18-49 years of age. RESULTS: Two doses of vaccine were required to induce antibody titers ≥ 1:10 in most subjects. Accelerated schedules were immunogenic, and antibody developed after vaccinations on days 0 and 7, 0 and 14, and 0 and 28, with the day 0 and 7 schedule inducing lower titers than those induced with the other schedules. With mixed vaccine schedules of clade 1 followed by clade 2 vaccine administration, the first vaccination primed for a heterologous boost. The heterologous response was improved when the second vaccination was given 6 months after the first, compared with the response when the second vaccination was given after an interval of 1 month. CONCLUSIONS: An accelerated vaccine schedule of injections administered at days 0 and 14 was as immunogenic as a vaccine schedule of injections at days 0 and 28, but both schedules were inferior to a vaccine schedule of injections administered at 0 and 6 months for priming for heterologous vaccine boosting. Clinical Trial Registry Number: NCT00703053.

Safety, efficacy, and immunogenicity of an inactivated influenza vaccine in healthy adults: a randomized, placebo-controlled trial over two influenza seasons.

BACKGROUND: Seasonal influenza imposes a substantial personal morbidity and societal cost burden. Vaccination is the major strategy for influenza prevention; however, because antigenically drifted influenza A and B viruses circulate annually, influenza vaccines must be updated to provide protection against the predicted prevalent strains for the next influenza season. The aim of this study was to assess the efficacy, safety, reactogenicity, and immunogenicity of a trivalent inactivated split virion influenza vaccine (TIV) in healthy adults over two influenza seasons in the US. METHODS: The primary endpoint of this double-blind, randomized study was the average efficacy of TIV versus placebo for the prevention of vaccine-matched, culture-confirmed influenza (VMCCI) across the 2005-2006 and 2006-2007 influenza seasons. Secondary endpoints included the prevention of laboratory-confirmed (defined by culture and/or serology) influenza, as well as safety, reactogenicity, immunogenicity, and consistency between three consecutive vaccine lots. Participants were assessed actively during both influenza seasons, and nasopharyngeal swabs were collected for viral culture from individuals with influenza-like illness. Blood specimens were obtained for serology one month after vaccination and at the end of each influenza season's surveillance period. RESULTS: Although the point estimate for efficacy in the prevention of all laboratory-confirmed influenza was 63.2% (97.5% confidence interval [CI] lower bound of 48.2%), the point estimate for the primary endpoint, efficacy of TIV against VMCCI across both influenza seasons, was 46.3% with a 97.5% CI lower bound of 9.8%. This did not satisfy the pre-specified success criterion of a one-sided 97.5% CI lower bound of >35% for vaccine efficacy. The VMCCI attack rates were very low overall at 0.6% and 1.2% in the TIV and placebo groups, respectively. Apart from a mismatch for influenza B virus lineage in 2005-2006, there was a good match between TIV and the circulating strains. TIV was highly immunogenic, and immune responses were consistent between three different TIV lots. The most common reactogenicity events and spontaneous adverse events were associated with the injection site, and were mild in severity. CONCLUSIONS: Despite a good immune response, and an average efficacy over two influenza seasons against laboratory-confirmed influenza of 63.2%, the pre-specified target (lower one-sided 97.5% confidence bound for efficacy > 35%) for the primary efficacy endpoint, the prevention of VMCCI, was not met. However, the results should be interpreted with caution in view of the very low attack rates we observed at the study sites in the 2005-2006 and 2006-2007, which corresponded to relatively mild influenza seasons in the US. Overall, the results showed that TIV has an acceptable safety profile and offered clinical benefit that exceeded risk. TRIAL REGISTRATION: NCT00216242.

The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8+ T cell response.

The live yellow fever vaccine (YF-17D) offers a unique opportunity to study memory CD8(+) T cell differentiation in humans following an acute viral infection. We have performed a comprehensive analysis of the virus-specific CD8(+) T cell response using overlapping peptides spanning the entire viral genome. Our results showed that the YF-17D vaccine induces a broad CD8(+) T cell response targeting several epitopes within each viral protein. We identified a dominant HLA-A2-restricted epitope in the NS4B protein and used tetramers specific for this epitope to track the CD8(+) T cell response over a 2 year period. This longitudinal analysis showed the following. 1) Memory CD8(+) T cells appear to pass through an effector phase and then gradually down-regulate expression of activation markers and effector molecules. 2) This effector phase was characterized by down-regulation of CD127, Bcl-2, CCR7, and CD45RA and was followed by a substantial contraction resulting in a pool of memory T cells that re-expressed CD127, Bcl-2, and CD45RA. 3) These memory cells were polyfunctional in terms of degranulation and production of the cytokines IFN-gamma, TNF-alpha, IL-2, and MIP-1beta. 4) The YF-17D-specific memory CD8(+) T cells had a phenotype (CCR7(-)CD45RA(+)) that is typically associated with terminally differentiated cells with limited proliferative capacity (T(EMRA)). However, these cells exhibited robust proliferative potential showing that expression of CD45RA may not always associate with terminal differentiation and, in fact, may be an indicator of highly functional memory CD8(+) T cells generated after acute viral infections.

Effects of a reduced dose schedule and intramuscular administration of anthrax vaccine adsorbed on immunogenicity and safety at 7 months: a randomized trial.

CONTEXT: In 1999, the US Congress directed the Centers for Disease Control and Prevention to conduct a pivotal safety and efficacy study of anthrax vaccine adsorbed (AVA). OBJECTIVE: To determine the effects on serological responses and injection site adverse events (AEs) resulting from changing the route of administration of AVA from subcutaneous (s.q.) to intramuscular (i.m.) and omitting the week 2 dose from the licensed schedule. DESIGN, SETTING, AND PARTICIPANTS: Assessment of the first 1005 enrollees in a multisite, randomized, double-blind, noninferiority, phase 4 human clinical trial (ongoing from May 2002). INTERVENTION: Healthy adults received AVA by the s.q. (reference group) or i.m. route at 0, 2, and 4 weeks and 6 months (4-SQ or 4-IM; n = 165-170 per group) or at a reduced 3-dose schedule (3-IM; n = 501). A control group (n = 169) received saline injections at the same time intervals. MAIN OUTCOME MEASURES: Noninferiority at week 8 and month 7 of anti-protective antigen IgG geometric mean concentration (GMC), geometric mean titer (GMT), and proportion of responders with a 4-fold rise in titer (%4 x R). Reactogenicity outcomes were proportions of injection site and systemic AEs. RESULTS: At week 8, the 4-IM group (GMC, 90.8 microg/mL; GMT, 1114.8; %4 x R, 97.7) was noninferior to the 4-SQ group (GMC, 105.1 microg/mL; GMT, 1315.4; %4 x R, 98.8) for all 3 primary end points. The 3-IM group was noninferior for only the %4 x R (GMC, 52.2 microg/mL; GMT, 650.6; %4 x R, 94.4). At month 7, all groups were noninferior to the licensed regimen for all end points. Solicited injection site AEs assessed during examinations occurred at lower proportions in the 4-IM group compared with 4-SQ. The odds ratio for ordinal end point pain reported immediately after injection was reduced by 50% for the 4-IM vs 4-SQ groups (P < .001). Route of administration did not significantly influence the occurrence of systemic AEs. CONCLUSIONS: The 4-IM and 3-IM regimens of AVA provided noninferior immunological priming by month 7 when compared with the 4-SQ licensed regimen. Intramuscular administration significantly reduced the occurrence of injection site AEs. Trial Registration clinicaltrials.gov Identifier: NCT00119067.

Safety and immunogenicity of concurrent administration of live attenuated influenza vaccine with measles-mumps-rubella and varicella vaccines to infants 12 to 15 months of age.

OBJECTIVE: This study evaluated the safety, tolerability, and immunogenicity of live attenuated influenza vaccine administered concurrently with measles-mumps-rubella vaccine and varicella vaccine to healthy children 12 to 15 months of age. METHODS: Children were assigned randomly to receive (1) measles-mumps-rubella vaccine, varicella vaccine, and intranasal placebo on day 0, followed by 1 dose of live attenuated influenza vaccine on days 42 and 72; (2) measles-mumps-rubella, varicella, and live attenuated influenza vaccines on day 0, followed by a second dose of live attenuated influenza vaccine on day 42 and intranasally administered placebo on day 72; or (3) 1 dose of live attenuated influenza vaccine on days 0 and 42, followed by measles-mumps-rubella and varicella vaccines on day 72. Serum samples were collected before vaccination on days 0, 42, and 72. Reactogenicity events and adverse events were collected through day 41 after concurrent vaccinations and through day 10 after administration of live attenuated influenza vaccine or placebo alone. RESULTS: Among 1245 (99.5%) evaluable children, seroresponse rates and geometric mean titers for measles-mumps-rubella vaccine and varicella vaccine were similar with concurrent administration of live attenuated influenza vaccine or placebo (seroresponse rates of > or = 96% for measles-mumps-rubella vaccine and > or = 82% for varicella vaccine in both groups). Hemagglutinin-inhibiting antibody geometric mean titers and seroconversion rates to influenza strains in live attenuated influenza virus vaccine were similar after the vaccine was administered alone (seroconversion rates of 98%, 92%, and 44% for H3, B, and H1 strains, respectively) or with measles-mumps-rubella and varicella vaccines (seroconversion rates of 98%, 96%, and 43%). The incidences of reactogenicity events and adverse events were similar among treatment groups. CONCLUSIONS: Concurrent administration of live attenuated influenza vaccine with measles-mumps-rubella vaccine and varicella vaccine provided equivalent immunogenicity, compared with separate administration, and was well tolerated.

Vaccine effectiveness against medically attended, laboratory-confirmed influenza among children aged 6 to 59 months, 2003-2004.

OBJECTIVES: Influenza is a leading cause of illness among children. Studies rarely have measured influenza vaccine effectiveness among young children, particularly when antigenic match between vaccine and circulating viruses is suboptimal. We assessed vaccine effectiveness against medically attended, laboratory-confirmed influenza for children who were aged 6 to 59 months during the 2003-2004 influenza season. METHODS: In a case-control study that was conducted in a single pediatric practice, case patients who were aged 6 to 59 months and had laboratory-confirmed influenza were age matched 1:2 to eligible control subjects. Vaccination status was ascertained as of the date of the case patient's symptom onset. Conditional logistic regression was used to calculate vaccine effectiveness, adjusting for underlying medical conditions and health care usage. RESULTS: We identified 290 influenza case patients who were seen for medical care from November 1, 2003, to January 31, 2004. Vaccine effectiveness among fully vaccinated children, compared with unvaccinated children, was 49%. Partially vaccinated children who were aged 6 to 23 months had no significant reduction in influenza (vaccine effectiveness: -70%), but partially vaccinated children who were aged 24 to 59 months had a significant (65%) reduction in influenza, compared with unvaccinated children. CONCLUSIONS: Full vaccination provided measurable protection against laboratory-confirmed influenza among children who were aged 6 to 59 months during a season with suboptimal vaccine match. No vaccine effectiveness was identified with partial vaccination among children who were aged 6 to 23 months, affirming that children need to be fully vaccinated to obtain protective effects. These results strengthen the evidence of the vaccine's ability to reduce substantially the burden of disease in this age group.

Rotavirus infection alters peripheral T-cell homeostasis in children with acute diarrhea.

The patterns of gene expression and the phenotypes of lymphocytes in peripheral blood mononuclear cells (PBMC) from children with diarrhea caused by rotavirus and healthy children were compared by using DNA microarray, quantitative PCR, and flow cytometry. We observed increased expression of a number of genes encoding proinflammatory cytokines and interferon or interferon-stimulated proteins and demonstrated activation of some genes involved in the differentiation, maturation, activation, and survival of B lymphocytes in PBMC of patients with rotavirus infection. In contrast, we observed a consistent pattern of lower mRNA levels for an array of genes involved in the various stages of T-cell development and demonstrated a reduction in total lymphocyte populations and in the proportions of CD4 and CD8 T lymphocytes from PBMC of patients. This decreased frequency of T lymphocytes was transient, since the proportions of T lymphocytes recovered to almost normal levels in convalescent-phase PBMC from most patients. Finally, rotavirus infection induced the activation and expression of the early activation markers CD83 and CD69 on a fraction of CD19 B cells and the remaining CD4 and CD8 T lymphocytes in acute-phase PBMC of patients; the expression of CD83 continued to be elevated and was predominantly exhibited on CD4 T lymphocytes in convalescent-phase PBMC. On the basis of these findings at the molecular, phenotypic, and physiologic levels in acute-phase PBMC, we conclude that rotavirus infection induces robust proinflammatory and antiviral responses and B-cell activation but alters peripheral T-cell homeostasis in children.

Experience with MCV-4, a meningococcal, diphtheria toxoid conjugate vaccine against serogroups A, C, Y and W-135.

Invasive disease due to Neisseria meningitidis continues to cause debility and death worldwide in otherwise healthy individuals. Disease epidemiology varies globally, but most cases are due to serogroups A, B, C, W-135 or Y. MenactraTM (MCV-4), a quadrivalent, meningococcal diphtheria-conjugate vaccine against serogroups A, C, Y, and W-135, was licensed in the USA for individuals 11-55 years of age. Published results of clinical trials demonstrated robust immune responses that correlate with indicators of protection. MCV-4-induced antibody persist for up to 3 years after administration and anamnestic responses to revaccination. The vaccine was well tolerated; the most common reactions were transient, mild injection-site reactions and headache. MCV-4 should provide significant clinical benefits in the future.

Invasive infections with Haemophilus influenzae serotype a containing an IS1016-bexA partial deletion: possible association with virulence.

BACKGROUND: Recent reports of invasive Haemophilus influenzae non-b capsular serotypes in the era since development of conjugate vaccines have prompted concern about serotype replacement. Unusual clusters of invasive infection due to H. influenzae serotype a with clinical features that resemble those of infection due to H. influenzae serotype b have been described. A unique feature often associated with more-virulent H. influenzae serotype a isolates is the IS1016-bexA partial deletion, which was previously identified in the capsule locus of H. influenzae serotype b strains. We report the clinical, epidemiologic, and molecular genetic features of 2 cases of severe disease caused by H. influenzae serotype a. METHODS: Invasive H. influenzae isolates were serotyped with standard serological methods, and molecular typing was done with PCR. The capsular genotype of each isolate was characterized with PCR, partial sequencing, and Southern blot hybridization. Further strain typing was performed with pulsed-field gel electrophoresis. RESULTS: We identified 2 children with severe invasive disease due to H. influenzae serotype a. Both H. influenzae serotype a isolates contained the identical pulsed-field gel electrophoresis pattern and capsular genotype. An IS1016-bexA partial deletion in the capsule gene locus similar to that found in H. influenzae serotype b was identified in both isolates by means of PCR and sequencing of the IS1016-bexA junction. CONCLUSIONS: We describe 2 cases of severe invasive disease due to H. influenzae serotype a with the putative virulence-enhancing IS1016-bexA partial deletion and duplication of the capsule locus. Our data support the hypothesis that this mutation may be associated with virulence in non-b capsular serotypes of H. influenzae.

Vancomycin use in hospitalized pediatric patients.

OBJECTIVES: To assess vancomycin utilization at children's hospitals, to determine risk factors for vancomycin use and length of therapy, and to facilitate adapting recommendations to optimize vancomycin prescribing practices in pediatric patients. METHODS: Two surveys were conducted at Pediatric Prevention Network hospitals. The first (Survey I) evaluated vancomycin control programs. The second (Survey II) prospectively reviewed individual patient records. Each hospital was asked to complete questionnaires on 25 consecutive patients or all patients for whom vancomycin was prescribed during a 1-month period. RESULTS: In Survey I, 55 of 65 (85%) hospitals reported their vancomycin control policies. Three quarters had specific policies in place to restrict vancomycin use. One half had at least 3 vancomycin restriction measures. In Survey II, personnel at 22 hospitals reviewed 416 vancomycin courses, with 2 to 25 (median = 12) patients tracked per hospital. Eighty-two percent of the vancomycin prescribed was for treatment of neonatal sepsis, fever/neutropenia, fever of unknown origin, positive blood culture, pneumonia, or meningitis. In an additional 6% (26/416), vancomycin was prescribed for patients with beta-lactam allergies and in 13% (56/416) for prophylaxis. Median duration of prophylaxis was 2 days (range: 1-15 days). Almost half (196, 47%) of the patients who received vancomycin were in intensive care units; 27% of the vancomycin courses were initiated by neonatologists and 19% by hematologists/oncologists. The predominant risk factor at the time of vancomycin initiation was the presence of vascular catheters (322, 77%); other host factors included cancer chemotherapy (55, 13%), transplant (30, 7%), shock (24, 6%), other immunosuppressant therapy (17, 4%), or hyposplenic state (2, <1%). Other clinical considerations were severity of illness (96, 23%), uncertainty about diagnosis (51, 12%), patient not responding to current antibiotic therapy (40, 10%), or implant infection (13, 3%). When vancomycin was initiated, blood cultures were positive in 85 patients (20%); cultures from other sites were positive in 45 (11%), and Gram stains of body fluids were positive in 37 (9%). In 29 (7%) patients, organisms sensitive only to vancomycin were isolated before vancomycin initiation. Reasons for discontinuing vancomycin included: therapeutic course completed (125, 30%), negative cultures (106, 25%), alternative antibiotics initiated (75, 18%), illness resolved (14, 3%), or patient expired (13, 3%). Final results of blood culture isolates resistant to beta-lactam antibiotics included 48 coagulase-negative staphylococcus, 5 Staphylococcus aureus, and 10 other species. CONCLUSIONS: At children's hospitals, vancomycin is initiated for therapy in patients who have vascular catheters and compromised host factors. Only 7% had laboratory-confirmed beta-lactam-resistant organisms isolated at the time vancomycin was prescribed. Efforts to modify empiric vancomycin use in children's hospitals should be targeted at intensivists, neonatologists, and hematologists. Initiatives to decrease length of therapy by decreasing the number of surgical prophylaxis doses and days of therapy before laboratory results may decrease vancomycin exposure.

Revaccination of healthy nonresponders with hepatitis B vaccine and prediction of seroprotection response.

Sixty healthy nonresponders were randomized to receive intramuscular (IM) high dose hepatitis B virus (HBV) vaccine versus IM standard dose HBV vaccine plus granulocyte-macrophage colony-stimulating factor (GM-CSF) at 0-2 months. Antibody to hepatitis B surface antigen was measured 1 month after each dose and 3 months after the last dose. Two regimens were equivalent in eliciting seroprotection in nonresponders. Weight-height index (WHI) <39 and alanine transaminase (ALT) <39 mg/dl predicted which nonresponders would seroconvert. A three-dose regimen of standard dose HBV vaccine plus GM-CSF may be a useful for seroprotection of healthy nonresponders.