David P. Greenberg

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.).

Treatment of children with congenital cytomegalovirus infection with ganciclovir.

Background. Congenital cytomegalovirus (CMV) infection affects ∼1% of live births in the US. Ten percent of these infants have symptoms at birth and another 10 to 15% acquire hearing loss or developmental problems. Congenital CMV is the most common cause of nonhereditary sensorineural hearing loss in children, and progressive hearing loss is common. To arrest the natural progression of congenital CMV, children referred to our center were treated with a prolonged course of ganciclovir. Methods. Medical records of children with congenital CMV who were treated with ganciclovir were reviewed to tabulate their presenting symptoms, duration of treatment, audiologic and developmental assessments and complications Results. We treated nine children with symptomatic CMV with iv ganciclovir at a median age of 10 days (range, 3 days to 11 months). Findings at diagnosis included microcephaly (five of nine); petechiae (five of nine); thrombocytopenia (seven of nine); and intracranial calcifications (six of eight). Hearing loss was noted before therapy in five of nine. The median duration of iv and subsequent oral ganciclovir was 1 year and 0.83 year, respectively. Median follow-up was 2 years (range, 1 to 7 years). No child had progression of hearing loss; improvement occurred in two. Seven children had at least one complication of ganciclovir therapy: central venous catheter/site infection (six); catheter malfunction (three); and neutropenia (one). Conclusion. Of nine children none treated with ganciclovir for congenital CMV had detectable progressive hearing loss. Complications associated with iv therapy occurred frequently. Currently available oral analogues of ganciclovir may facilitate earlier and more prolonged therapy for children with symptomatic congenital CMV and should be subjected to randomized controlled trials.

Bordetella Pertussis Infections in Vaccinated and Unvaccinated Adolescents and Adults, as Assessed in a National Prospective Randomized Acellular Pertussis Vaccine Trial (APERT)

BACKGROUND Acellular pertussis (aP) booster immunizations have been recommended for adolescents and older persons to enhance long-term protection and to possibly reduce community transmission of infections. METHODS This was a multicenter, randomized, double-blind vaccine trial in which one-half of the subjects received aP vaccine and one-half received hepatitis A vaccine (control subjects). All subjects were observed for almost 2 years for cough illnesses, and all underwent microbiologic and serologic studies for detection of pertussis infection. Immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies to pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae 2/3 were measured by enzyme-linked immunosorbent assay in serum samples obtained 1 and 12 months after immunization. Infection rates were determined with a variety of serologic criteria for control and vaccinated subjects. The incidence of prolonged cough illness was ascertained for subjects with and subjects without serologic evidence of infection. RESULTS Infection rates among control subjects are particularly representative of those in nonimmunized adults. Among control subjects, 0.4%-2.7% had increases in pertussis antibody of various types and degrees over 1 year, and 20%-46% had prolonged cough illnesses during this interval. Pertussis toxin antibody had the greatest specificity for detecting increases in antibody levels. Asymptomatic infections were approximately 5 times more common than clinical illnesses that met a strict clinical and microbiologic case definition. Relative to control subjects, aP-immunized subjects may have fewer increases in the antibody level (i.e., infections), especially for antibodies to fimbriae 2/3 (an antigen not in the vaccine). CONCLUSIONS Pertussis infections in older persons are largely asymptomatic. aP boosters confer protection for adolescents and adults against symptomatic pertussis and likely confer protection against mild and asymptomatic infections, and use of boosters may reduce transmission to others, especially infants.

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.

Pediatric experience with recombinant hepatitis B vaccines and relevant safety and immunogenicity studies

Yeast-derived recombinant hepatitis B vaccines have replaced plasma-derived vaccines in the United States and have now been given to millions of infants and children throughout the world. Routine immunization of infants in the United States with hepatitis B vaccine has been endorsed as the optimal means to prevent infection. The recombinant vaccines have an excellent safety record; most children have no adverse reactions whereas a few experience only minor local and systemic reactions that resolve within a short time. Both of the vaccines licensed in the United States are highly immunogenic in infants and children who complete a three dose vaccination sequence. Approximately 95 to 100% achieve protective levels of antibody to hepatitis B surface antigen (> or = 10 mIU/ml) after three doses. Immunization may begin at birth or at 1 to 2 months of age, and hepatitis B vaccine may be given simultaneously with other routine childhood vaccines. Antibody levels to hepatitis B surface antigen gradually wane over time, and the duration of maintaining protective levels correlates strongly with the peak level achieved. The protective efficacy against perinatal transmission from mothers who are positive for hepatitis B surface antigen and e antigen is 90 to 100% when the first dose of vaccine is administered at birth with hepatitis B immunoglobulin. In highly endemic populations immunization in infancy also protects against horizontal transmission from chronically infected family members. Studies currently in progress will determine the duration of protection, the potential need for booster doses and the feasibility of combining antigens in multivalent vaccines.

Safety and Immunogenicity of the American Academy of Pediatrics–Recommended Sequential Pneumococcal Conjugate and Polysaccharide Vaccine Schedule in Pediatric Solid Organ Transplant Recipients

Objective. Solid organ transplant recipients are at increased risk for invasive pneumococcal disease. The American Academy of Pediatrics recommends immunization with sequential pneumococcal vaccines for this group; however, data are lacking. Accordingly, this study was designed to evaluate the safety and immunogenicity of the recommended regimen. Methods. Pediatric solid organ transplant recipients (n = 25) between 2 and 18 years of age who had not previously received 7-valent conjugate pneumococcal vaccine (PCV7) were enrolled. These patients received 2 doses of the PCV7 and a single dose of the 23-valent polysaccharide pneumococcal vaccine (23V). Each vaccine dose was given 2 months apart. Healthy age-matched controls (n = 23) were enrolled for comparison. Controls received a single dose of PCV7 followed 2 months later by a single dose of 23V. Antibody concentrations to serotypes 1, 4, 5, 6B, 9V, 14, 18C, 19F, and 23F were measured by enzyme-linked immunosorbent assay prevaccination, 2 months after each vaccine dose and 5 to 7 months after 23V. Local and systemic reactions to each vaccine dose were recorded. Results. Systemic and injection-site reactions were comparable between the 2 groups. Significant rises in serotype-specific pneumococcal antibody geometric mean concentrations from prevaccination levels were observed in both groups; however, final antibody responses to serotypes 1, 4, 9V, 14, 18C, 19F, and 23F were significantly lower in solid organ transplant recipients compared with the control group. Antibody concentrations did not increase significantly among solid organ transplant patients after the second dose of PCV7. No additional increase in PCV7-associated serotype-specific antibody levels was observed after the 23V dose in both groups. Heart transplant recipients had lower antibody responses compared with liver transplant recipients. Conclusions. Although the pneumococcal vaccine regimen was safe and immunogenic among pediatric solid organ transplant recipients, the patients did not seem to benefit from the second dose of PCV7 or from the 23V dose given 2 months later. Additional studies are needed to determine the number of PCV7 doses and the interval between PCV7 and 23V to induce optimal responses.

Pertussis in adolescents: increasing incidence brings attention to the need for booster immunization of adolescents.

As a result of waning immunity and improved awareness, the reported incidence of pertussis is increasing among adolescents in the United States. Symptoms of pertussis are often mild and difficult to diagnose in adolescents, but these individuals can transmit the infection to schoolmates and family members, including high risk infants. Improvements in diagnosis and prevention of pertussis in adolescents are needed.

Health burden of pertussis in infants and children.

In countries with high rates of vaccination against pertussis, the incidence of this disease has decreased dramatically compared with the prevaccine era. However, pertussis still occurs in these countries, and severe morbidity and mortality are greatest among infants, particularly those who are unimmunized or incompletely immunized. Pertussis in older children and adults is perceived by many as being a mild disease, but it is a significant health burden in persons of all ages. Infants with pertussis experience the highest rates of hospitalization, complications and death. Severe complications include pneumonia, encephalopathy and meningoencephalitis. In addition, infants may experience weight loss, bronchitis, otitis media, apnea, cyanosis, inguinal hernia and rectal prolapse. It is essential to explore methods to prevent disease transmission to infants in the months before they complete their primary immunization series. The Global Pertussis Initiative was established to assess the true health burden of pertussis in infants and to suggest strategies to combat transmission and infection with Bordetella pertussis, which remains a significant public health concern.

Enhanced antibody responses in infants given different sequences of heterogeneous Haemophilus influenzae type b conjugate vaccines

To evaluate the safety and immunogenicity of differing sequences of heterogeneous Haemophilus influenzae type b (Hib) conjugate vaccines, we randomly assigned 300 infants to one of six vaccination schedules. At 2, 4, and 6 months of age, subjects were given single or heterogeneous vaccines: Hib polysaccharide (PRP) conjugated to mutant diphtheria toxin (HbOC), PRP conjugated to outer-membrane protein of Neisseria meningitidis (PRP-OMP), or PRP conjugated to tetanus toxoid (PRP-T). No serious reactions were attributable to immunization with heterogeneous vaccines, and there were few significant differences in the rates of minor adverse reactions among groups. PRP-OMP was the only vaccine that induced an antibody response after the first dose, but significant booster responses were not seen after the second and third doses. Subjects given PRP-T vaccine responded well after two doses, but three doses of HbOC vaccine were needed for an equivalent antibody response. All the Hib vaccine schedules evaluated were immunogenic, and schedules initiated by PRP-OMP vaccine at 2 months of age, followed by two doses of either HbOC or PRP-T vaccine at 4 and 6 months of age, induced the highest antibody levels after each dose. Such schedules may be the best for protecting infants and children who are at greatest risk of having invasive Hib disease, such as American Indian children.

Regional variation in the cost effectiveness of childhood hepatitis A immunization

Background. Routine childhood hepatitis A immunization is recommended in regions with incidence rates twice the national average, but it may be cost-effective in a wider geographic area. Objective. To evaluate the costs and benefits of potential hepatitis A immunization of healthy US children in regions with varying hepatitis A incidences. Methods. We considered vaccination of the 2000 US birth cohort in states defined by historic hepatitis A incidence rates. Infections among potential vaccinees and their personal contacts were predicted from age 2 through 85 years. Net vaccination costs were estimated from health system and societal perspectives and were compared with life-years saved and quality-adjusted life years (QALYs) gained using a 3% discount rate. Results. Nationally vaccination would prevent >75 000 cases of overt hepatitis A disease. Approximately two-thirds of health benefits would accrue to personal contacts rather than to vaccinees themselves. In states with incidence rates of ≥200%, 100 to 199%, 50 to 99% and <50% the national average, societal costs per QALY gained would be <