Michael D. Decker

Efficacy of high-dose versus standard-dose influenza vaccine in older adults.

BACKGROUND As compared with a standard-dose vaccine, a high-dose, trivalent, inactivated influenza vaccine (IIV3-HD) improves antibody responses to influenza among adults 65 years of age or older. This study evaluated whether IIV3-HD also improves protection against laboratory-confirmed influenza illness. METHODS We conducted a phase IIIb-IV, multicenter, randomized, double-blind, active-controlled trial to compare IIV3-HD (60 μg of hemagglutinin per strain) with standard-dose trivalent, inactivated influenza vaccine (IIV3-SD [15 μg of hemagglutinin per strain]) in adults 65 years of age or older. Assessments of relative efficacy, effectiveness, safety (serious adverse events), and immunogenicity (hemagglutination-inhibition [HAI] titers) were performed during the 2011-2012 (year 1) and the 2012-2013 (year 2) northern-hemisphere influenza seasons. RESULTS A total of 31,989 participants were enrolled from 126 research centers in the United States and Canada (15,991 were randomly assigned to receive IIV3-HD, and 15,998 to receive IIV3-SD). In the intention-to-treat analysis, 228 participants in the IIV3-HD group (1.4%) and 301 participants in the IIV3-SD group (1.9%) had laboratory-confirmed influenza caused by any viral type or subtype associated with a protocol-defined influenza-like illness (relative efficacy, 24.2%; 95% confidence interval [CI], 9.7 to 36.5). At least one serious adverse event during the safety surveillance period was reported by 1323 (8.3%) of the participants in the IIV3-HD group, as compared with 1442 (9.0%) of the participants in the IIV3-SD group (relative risk, 0.92; 95% CI, 0.85 to 0.99). After vaccination, HAI titers and seroprotection rates (the percentage of participants with HAI titers ≥ 1:40) were significantly higher in the IIV3-HD group. Conclusions: Among persons 65 years of age or older, IIV3-HD induced significantly higher antibody responses and provided better protection against laboratory-confirmed influenza illness than did IIV3-SD. (Funded by Sanofi Pasteur; ClinicalTrials.gov number, NCT01427309.).

Comparative trial in infants of four conjugate Haemophilus influenzae type b vaccines

We performed a double-blind, randomized trial to compare the immunogenicity and reactogenicity of four conjugate Haemophilus influenzae type b vaccines given to infants 2, 4, and 6 months of age. Adverse reactions attributable to the vaccines were few and minor. The rates of systemic reactions did not differ among the various vaccines and were similar to those seen among children receiving conventional diphtheria-tetanus-pertussis vaccine. However, the four conjugate H. influenzae type b vaccines differed markedly in ability to stimulate antibody production. Mean antibody levels after three injections of polyribosylribitol phosphate conjugated with mutant diphtheria protein (PRP-CRM) or polyribosylribitol phosphate conjugated with tetanus toxoid (PRP-T) were 3.08 micrograms/ml and 3.64 micrograms/ml, respectively, significantly higher than those after the use of polyribosylribitol phosphate conjugated with outer-membrane protein of Neisseria meningitidis (PRP-OMP) (1.14 micrograms/ml) or polyribosylribitol phosphate conjugated with diphtheria toxoid (PRP-D) (0.28 microgram/ml). Only PRP-OMP produced a clinically pertinent elevation in antibody level after two injections (0.84 microgram/ml); the third injection of PRP-OMP produced a modest but statistically significant further elevation in mean antibody level (1.14 micrograms/ml). Only 29% of infants receiving PRP-D had antibody levels of 1 micrograms/ml, compared with 55%, 75%, and 83% of those receiving PRP-OMP, PRP-CRM, and PRP-T, respectively. We conclude that all four vaccines are safe and that all but PRP-D appear appropriate for use in a primary immunization series during infancy. The unique serologic response to PRP-OMP offers both advantages and disadvantages in comparison with PRP-CRM and PRP-T.

Central Venous Catheter Infections

When used wisely, central venous catheters are capable of providing vital circulatory access in any patient with a remarkably low risk of infection or major complication. Tunneled silicone catheters are the route of choice for long-term or outpatient use, particularly for oncology or TPN patients; insertion of such a catheter should occur early in the hospitalization of a newly diagnosed patient on chemotherapy. The greatest experience has accrued with the cuffed silicone catheters (for example, Broviac), but the totally implantable devices (for instance, Port-a-cath) may become the device of choice in pediatric outpatients. For infants, small, percutaneously inserted noncuffed silicone catheters appear to offer the greatest safety. Among acute care patients, percutaneous plastic central venous catheters fulfill a vital role but represent an important source of infection. Scrupulous technique, the minimizing of manipulation, and a readiness to replace the catheter at any suggestion of trouble are important to achieving the best results. Within a given design, it is generally best to use the smallest diameter catheter capable of performing the desired tasks. However, on the basis of currently available data, there need be no hesitation to use a multilumen catheter if the care of the patient demands multiple access ports. The various silicone catheters can usually be left in place while infection is treated, although fungal and certain other infections are more likely to require catheter removal. Percutaneous plastic catheters should be removed or changed over a wire if infection is suspected; if tip culture of the removed catheter is positive, and the catheter was replaced over a wire, then the replacement catheter should be promptly removed.

Respiratory Syncytial Virus Infection in Patients with Hematological Diseases: Single-Center Study and Review of the Literature

BACKGROUND Respiratory syncytial virus (RSV) causes significant mortality in patients with hematological diseases, but diagnosis and treatment are uncertain. METHODS We retrospectively identified RSV-infected patients with upper or lower respiratory tract infection (RTI) by culture, antigen testing, and polymerase chain reaction from November 2002 through April 2007. Patients with severe immunodeficiency (SID; defined as transplantation in the previous 6 months, T or B cell depletion in the previous 3 months, graft-versus-host disease [grade, >or=2], leukopenia, lymphopenia, or hypogammaglobulinemia) preferentially received oral ribavirin, intravenous immunoglobulin, and palivizumab. The remaining patients with moderate immunodeficiency (MID) preferentially received ribavirin and intravenous immunoglobulin. RESULTS We identified 34 patients, 22 of whom had upper RTI (10 patients with MID and 12 with SID) and 12 of whom had lower RTI (2 with MID and 10 with SID). Thirty-one patients were tested by polymerase chain reaction (100% of these patients had positive results; median RSV load, 5.46 log(10) copies/mL), 30 were tested by culture (57% had positive results), and 25 were tested by antigen testing (40% had positive results). RSV-attributed mortality was 18% (6 patients died) and was associated with having >or=2 SID factors (P=.04), lower RTI (P=.01), and preengraftment (P=.012). Among 12 patients with MID (7 of whom received treatment), no progression or death occurred. Nine patients with SID and upper RTI received treatment (7 patients received ribavirin, intravenous immunoglobulin, and palivizumab); infection progressed to the lower respiratory tract in 2 patients, and 1 patient died. Ten patients with SID and lower RTI were treated, 5 of whom died, including 4 of 6 patients who received ribavirin, intravenous immunoglobulin, and palivizumab. The duration of RSV shedding correlated with the duration of symptoms in patients with SID but exceeded symptom duration in patients with MID (P<.05). CONCLUSIONS Lower RTI, >or=2 SID criteria, and preengraftment are risk factors for RSV-attributed mortality. Polymerase chain reaction may optimize diagnosis and monitoring. Oral ribavirin therapy seems safe, but trials are needed to demonstrate its efficacy.

Establishment of Diagnostic Cutoff Points for Levels of Serum Antibodies to Pertussis Toxin, Filamentous Hemagglutinin, and Fimbriae in Adolescents and Adults in the United States

ABSTRACT Numerous reports have documented that serologic methods are much more sensitive than culture for the diagnosis of pertussis in adolescents and adults. However, a standardized serologic test for pertussis is not routinely available to most clinicians, and the serologic test levels or cutoff points correlated with diseases have not been determined. The goal of the present study was to examine the distribution of immunoglobulin G (IgG) levels against three Bordetella pertussis antigens (pertussis toxin [PT], filamentous hemagglutinin [FHA], and fimbria types 2 and 3 [FIM]) and to determine population-based antibody levels for the purpose of establishing such diagnostic cutoff points. Enzyme-linked immunosorbent assays (ELISAs) were performed with sera from >6,000 U.S. residents aged 6 to 49 years who participated in the Third National Health and Nutrition Examination Survey. Mixture models were developed to identify hypothesized exposure groups and establish diagnostic cutoffs. Quantifiable (>20 ELISA units/ml [EU]) anti-FHA and anti-FIM IgG antibodies were common (65 and 62% of individuals, respectively), but quantifiable anti-PT IgG antibodies were less frequent (16%). Given the distributions of antibody levels, an anti-PT IgG level of ≥94 EU was proposed as the diagnostic cutoff point. Application of this cutoff point to culture-confirmed illness in a prior study investigating cough illness yielded a high diagnostic sensitivity (80%) and specificity (93%). A standardized ELISA for anti-PT IgG with a single serum sample appears to be useful for the identification of recent B. pertussis infection in adolescents and adults with cough illness. The PT cutoff point will be further evaluated in prospective studies of confirmed B. pertussis infection.

Immune responses in infants whose mothers received Tdap vaccine during pregnancy.

Background: The effect of maternal Tdap vaccination on infant immunologic responses to routine pediatric vaccines is unknown. Methods: This was a cohort study of infants whose mothers received or did not receive Tdap vaccine during pregnancy. Maternal and cord blood samples were collected at delivery; infant blood samples were collected before and after primary series and booster dose of diphtheria, tetanus, and acellular pertussis (DTaP) and other vaccines. Geometric mean antibody concentrations or titers to pertussis, hepatitis B, tetanus, diphtheria, Haemophilus influenzae type b and polio antigens were measured. Mean maternal-to-cord blood antibody ratios were calculated. Results: At delivery, maternal and cord antibody concentrations to pertussis antigens were higher in the Tdap group (n = 16) than control group (n = 54; maternal: 1.9- to 20.4-fold greater; cord: 2.7- to 35.5-fold greater). Increased antibody concentrations persisted for infants at first DTaP (3.2- to 22.8-fold greater). After primary series, antibody concentrations to pertussis antigens were lower in Tdap group (0.7- to 0.8-fold lower), except for fimbriae types 2 and 3 (FIM) (1.5-fold greater). Antibody concentrations to pertussis antigens before and after booster dose were comparable (prebooster: Tdap group 1.0- to 1.2-fold higher than controls; postbooster: 0.9- to 1.0-fold lower). Differences in FIM values at these time points are difficult to interpret, due to varying FIM content among DTaP vaccines administered to infants in both groups. Conclusions: Maternal Tdap immunization resulted in higher pertussis antibody concentrations during the period between birth and the first vaccine dose. Although slightly decreased immune responses following the primary series were seen compared with controls, differences did not persist following the booster.

Acellular pertussis vaccines for infants.

Whole-cell vaccines, which are suspensions of killed Bordetella pertussis organisms, are among our most effective and least satisfactory vaccines. Before immunization was routine, pertussis was end...

Serologic response to standard inactivated influenza vaccine in human immunodeficiency virus-infected children

We compared the serologic response of 46 human immunodeficiency virus (HIV)-infected children and adolescents and 61 age-matched controls to standard trivalent inactivated influenza vaccine (A/Taiwan (H1N1), A/Shanghai (H3N2), B/Yamagata). Children were immunized according to the package insert recommendations before the 1990 to 1991 influenza season. Serum antibody titers to influenza A were determined before and 1 month after each vaccination and compared for study and control subjects. Serologic responses of HIV-infected participants were correlated with absolute CD4 counts and stage of HIV disease. Regardless of age or HIV status, all groups responded with significant increases in antibody to the influenza A strains (range, 2.1-fold to 11.8-fold), with the exception that antibody to H3N2 rose only 1.5-fold (P = 0.058) among HIV-positive subjects > or = 9 years old. Pre- and postimmunization antibody titers were significantly higher for controls than for HIV-positive subjects. There was no correlation between serologic responses and CD4 counts among HIV-infected subjects, but those with Centers for Disease Control and Prevention-defined acquired immunodeficiency syndrome responded significantly less well to vaccine. We conclude that HIV-infected children and adolescents produce significant antibody rises after inactivated influenza A vaccination but that their absolute antibody concentrations are lower than those seen in age-matched controls.

How soon after a prior tetanus-diphtheria vaccination can one give adult formulation tetanus-diphtheria-acellular pertussis vaccine?

Background: Adult formulation tetanus and diphtheria toxoids and acellular pertussis vaccines (Tdap) have been developed to prevent pertussis in adolescents and adults. There are concerns that unacceptable rates of severe injection site reactions, including Arthus-type reactions might occur if Tdap is administered too soon after a previous tetanus and diphtheria toxoid-containing vaccine formulated for infants and younger children (TD) or older children and adults (Td). Methods: To evaluate whether adverse reactions after Tdap might be related to time since last receipt of TD/Td, we performed an open label, province-wide, clinical trial comparing the reactogenicity of Tdap given 18 months–9 years versus ≥10 years after a previous TD/Td. Results: Seven thousand one hundred fifty-six children and adolescents were enrolled in the study (464–963 subjects per cohort), and 7001 had documented dates of the previous immunization within the specified intervals; adverse event data were provided by 5931 (84.7%). No whole limb swelling, Arthus-like reactions or serious adverse events related to vaccination were reported. No differences in reports of fever were found by interval since last immunization. Injection site erythema and swelling were slightly and statistically significantly increased among those participants with most recent prior TD/Td. Compared with the 10-year interval group, the maximum increase for any other group was ≤8.6% for any erythema, ≤6% for erythema >10 mm, ≤10.3% for any swelling, ≤6.9% for swelling >10 mm, ≤5.2% for any pain and ≤3.7% for moderate/severe pain. Conclusion: Although there is a slight increase in injection site events with decreasing interval since a previous immunization, Tdap can be safely administered at intervals of ≥18 months since a previous TD/Td vaccine.

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.