Drug-Induced Conformational Dynamics of P-Glycoprotein Underlies the Transport of Camptothecin Analogs.

P-glycoprotein (Pgp) plays a pivotal role in drug bioavailability and multi-drug resistance development. Understanding the protein's activity and designing effective drugs require insight into the mechanisms underlying Pgp-mediated transport of xenobiotics. In this study, we investigated the drug-induced conformational changes in Pgp and adopted a conformationally-gated model to elucidate the Pgp-mediated transport of camptothecin analogs (CPTs). While Pgp displays a wide range of conformations, we simplified it into three model states: 'open-inward', 'open-outward', and 'intermediate'. Utilizing acrylamide quenching of Pgp fluorescence as a tool to examine the protein's tertiary structure, we observed that topotecan (TPT), SN-38, and irinotecan (IRT) induced distinct conformational shifts in the protein. TPT caused a substantial shift akin to AMPPNP, suggesting ATP-independent 'open-outward' conformation. IRT and SN-38 had relatively moderate effects on the conformation of Pgp. Experimental atomic force microscopy (AFM) imaging supports these findings. Further, the rate of ATPase hydrolysis was correlated with ligand-induced Pgp conformational changes. We hypothesize that the separation between the nucleotide-binding domains (NBDs) creates a conformational barrier for substrate transport. Substrates that reduce the conformational barrier, like TPT, are better transported. The affinity for ATP extracted from Pgp-mediated ATP hydrolysis kinetics curves for TPT was about 2-fold and 3-fold higher than SN-38 and IRT, respectively. On the contrary, the dissociation constants (KD) determined by fluorescence quenching for these drugs were not significantly different. Saturation transfer double difference (STDD) NMR of TPT and IRT with Pgp revealed that similar functional groups of the CPTs are accountable for Pgp-CPTs interactions. Efforts aimed at modifying these functional groups, guided by available structure-activity relationship data for CPTs and DNA-Topoisomerase-I complexes, could pave the way for the development of more potent next-generation CPTs.

Baseline characteristics and comorbidities in the CAnadian REgistry for Pulmonary Fibrosis.

BACKGROUND: The CAnadian REgistry for Pulmonary Fibrosis (CARE-PF) is a multi-center, prospective registry designed to study the natural history of fibrotic interstitial lung disease (ILD) in adults. The aim of this cross-sectional sub-study was to describe the baseline characteristics, risk factors, and comorbidities of patients enrolled in CARE-PF to date. METHODS: Patients completed study questionnaires and clinical measurements at enrollment and each follow-up visit. Environmental exposures were assessed by patient self-report and comorbidities by the Charlson Comorbidity Index (CCI). Baseline characteristics, exposures, and comorbidities were described for the overall study population and for incident cases, and were compared across ILD subtypes. RESULTS: The full cohort included 1285 patients with ILD (961 incident cases (74.8%)). Diagnoses included connective tissue disease-associated ILD (33.3%), idiopathic pulmonary fibrosis (IPF) (24.7%), unclassifiable ILD (22.3%), chronic hypersensitivity pneumonitis (HP) (7.5%), sarcoidosis (3.2%), non-IPF idiopathic interstitial pneumonias (3.0%, including idiopathic nonspecific interstitial pneumonia (NSIP) in 0.9%), and other ILDs (6.0%). Patient-reported exposures were most frequent amongst chronic HP, but common across all ILD subtypes. The CCI was ≤2 in 81% of patients, with a narrow distribution and range of values. CONCLUSIONS: CTD-ILD, IPF, and unclassifiable ILD made up 80% of ILD diagnoses at ILD referral centers in Canada, while idiopathic NSIP was rare when adhering to recommended diagnostic criteria. CCI had a very narrow distribution across our cohort suggesting it may be a poor discriminator in assessing the impact of comorbidities on patients with ILD.

Ten-year trends in direct costs of asthma: a population-based study.

INTRODUCTION: There is little information on recent trends in the economic burden of asthma. Our objective was to estimate the excess costs of asthma and their trend in British Columbia, Canada, from 2002 to 2011. METHODS: A retrospective cohort of individuals aged 5-55 years was constructed from the provincial administrative health databases, consisting of patients with physician-diagnosed asthma and a propensity-score-matched comparison sample from the general population. Total direct medical costs were calculated as the sum of hospitalizations, outpatient visits and medication costs, adjusted to 2012 Canadian dollars ($). Excess costs were defined as the difference in costs between the asthma and comparison groups. RESULTS: A total of 341 457 individuals (mean age at entry 27.3, 54.1% female) were equally divided into the asthma and comparison groups. Excess costs in patients with asthma were $1028.0 (95% CI $982.7-$1073.4) per patient-year (PY). Medications contributed to the greatest share of excess costs ($471.7/PY), whereas hospitalization and outpatient costs were, respectively, $272.2/PY and $284.1/PY. Only $192.9/PY was attributable to asthma itself. There was a 2.9%/year increase in excess costs (P < 0.001), a combination of asthma-attributable costs declining by 0.8%/year while nonasthma excess costs increasing by 3.8%/year. The most dramatic trend was observed in asthma-related outpatient costs, which decreased by %6.6/year. CONCLUSIONS: A significant share of excess costs in asthma is not attributable to the disease itself. The pattern of costs changed significantly during the study period. The burden of comorbid conditions should be considered in developing evidence-based policies for management of patients with asthma.

The differences in short- and long-term varicella-zoster virus (VZV) immunoglobulin G levels following varicella vaccination of healthcare workers measured by VZV fluorescent-antibody-to-membrane-antigen assay (FAMA), VZV time-resolved fluorescence immunoassay and a VZV purified glycoprotein enzyme immunoassay.

Healthcare workers (HCWs) reporting no history of varicella frequently receive varicella vaccination (vOka) if they test varicella-zoster virus (VZV) immunoglobulin G (IgG) negative. In this study, the utilities of VZV-IgG time-resolved fluorescence immunoassay (VZV-TRFIA) and a commercial VZV-IgG purified glycoprotein enzyme immunoassay (gpEIA) currently used in England for confirming VZV immunity have been compared to the fluorescent-antibody-to-membrane-antigen assay (FAMA). A total of 110 HCWs received two doses of vOka vaccine spaced 6 weeks apart and sera collected pre-vaccination (n = 100), at 6 weeks post-completion of vaccination (n = 86) and at 12-18 months follow-up (n = 73) were analysed. Pre-vaccination, by FAMA, 61·0% sera were VZV IgG negative, and compared to FAMA the sensitivities of VZV-TRFIA and gpEIA were 74·4% [95% confidence interval (CI) 57·9-87·0] and 46·2% (95% CI 30·1-62·8), respectively. Post-completion of vaccination the seroconversion rate by FAMA was 93·7% compared to rates of 95·8% and 70·8% determined by VZV-TRFIA and gpEIA, respectively. At 12-18 months follow-up seropositivity rates by FAMA, VZV-TRFIA and gpEIA were 78·1%, 74·0% and 47·9%, respectively. Compared to FAMA the sensitivities of VZV-TRFIA and gpEIA for measuring VZV IgG following vaccination were 96·4% (95% CI 91·7-98·8) and 74·6% (95% CI 66·5-81·6), respectively. Using both FAMA and VZV-TRFIA to identify healthy adult VZV susceptibles and measure seroconversion showed that vOka vaccination of HCWs is highly immunogenic.

Glucocorticoid-induced osteoporosis management among seniors, by year, sex, and indication, 1996-2012.

UNLABELLED: We identified that glucocorticoid-induced osteoporosis management (bone mineral density testing or osteoporosis treatment) among seniors improved among men (2 to 23 %) and women (10 to 48 %) between 1996 and 2007, and then remained relatively stable through to 2012. Differences were also noted by indication (from a low of 21 % for respiratory conditions to a high of 41 % for rheumatic conditions). PURPOSE: The aim of our study was to describe the proportion of chronic oral glucocorticoid (GC) users that receive osteoporosis management (bone mineral density test or osteoporosis treatment) by sex and over time. METHODS: We identified community-dwelling older adults initiating chronic oral GC therapy in Ontario using pharmacy data from 1996 to 2012. Chronic GC use was defined as greater than or equal to two oral GC prescriptions dispensed and ≥450 mg prednisone equivalent over a 6-month period. Osteoporosis management within 6 months of starting chronic GC therapy was examined by sex, year, indication for therapy, and osteoporosis management history. Results were summarized using descriptive statistics. RESULTS: We identified 72,099 men and 95,975 women starting chronic oral GC therapy (mean age = 74.9 years, SD = 6.5). Approximately two thirds of patients (65 %) received ≥900 mg within the 6-month chronic use window. GC-induced osteoporosis management increased from 2 to 23 % (men) and 10 to 48 % (women) between 1996 and 2007, and then remained relatively stable through to 2012. A higher proportion of patients with prior osteoporosis management were managed within 6 months (56 % men, 67 % women) of chronic GC use, compared to patients without prior management (12 % men, 23 % women). Patients with rheumatic disease were managed most commonly (41 %), and patients with respiratory conditions were managed least commonly (21 %). CONCLUSIONS: GC-induced osteoporosis management improved significantly over time for both sexes yet remains low. Significant care gaps by sex and between clinical areas represent a missed opportunity for fracture prevention among patients requiring chronic GC therapy.

Hypersomnia subtypes, sleep and relapse in bipolar disorder.

BACKGROUND: Though poorly defined, hypersomnia is associated with negative health outcomes and new-onset and recurrence of psychiatric illness. Lack of definition impedes generalizability across studies. The present research clarifies hypersomnia diagnoses in bipolar disorder by exploring possible subgroups and their relationship to prospective sleep data and relapse into mood episodes. METHOD: A community sample of 159 adults (aged 18-70 years) with bipolar spectrum diagnoses, euthymic at study entry, was included. Self-report inventories and clinician-administered interviews determined features of hypersomnia. Participants completed sleep diaries and wore wrist actigraphs at home to obtain prospective sleep data. Approximately 7 months later, psychiatric status was reassessed. Factor analysis and latent profile analysis explored empirical groupings within hypersomnia diagnoses. RESULTS: Factor analyses confirmed two separate subtypes of hypersomnia ('long sleep' and 'excessive sleepiness') that were uncorrelated. Latent profile analyses suggested a four-class solution, with 'long sleep' and 'excessive sleepiness' again representing two separate classes. Prospective sleep data suggested that the sleep of 'long sleepers' is characterized by a long time in bed, not long sleep duration. Longitudinal assessment suggested that 'excessive sleepiness' at baseline predicted mania/hypomania relapse. CONCLUSIONS: This study is the largest of hypersomnia to include objective sleep measurement, and refines our understanding of classification, characterization and associated morbidity. Hypersomnia appears to be comprised of two separate subgroups: long sleep and excessive sleepiness. Long sleep is characterized primarily by long bedrest duration. Excessive sleepiness is not associated with longer sleep or bedrest, but predicts relapse to mania/hypomania. Understanding these entities has important research and treatment implications.

Probing the Mechanisms Underlying the Transport of the Vinca Alkaloids by P-glycoprotein.

The efficacy of many cancer drugs is hindered by P-glycoprotein (Pgp), a cellular pump that removes drugs from cells. To improve chemotherapy, drugs capable of evading Pgp must be developed. Despite similarities in structure, vinca alkaloids (VAs) show disparate Pgp-mediated efflux ratios. ATPase activity and binding affinity studies show at least two binding sites for the VAs: high- and low-affinity sites that stimulate and inhibit the ATPase activity rate, respectively. The affinity for ATP from the ATPase kinetics curve for vinblastine (VBL) at the high-affinity site was 2- and 9-fold higher than vinorelbine (VRL) and vincristine (VCR), respectively. Conversely, VBL had the highest Km (ATP) for the low-affinity site. The dissociation constants (KDs) determined by protein fluorescence quenching were in the order VBL < VRL< VCR. The order of the KDs was reversed at higher substrate concentrations. Acrylamide quenching of protein fluorescence indicate that the VAs, either at 10 µM or 150 µM, predominantly maintain Pgp in an open-outward conformation. When 3.2 mM AMPPNP was present, 10 µM of either VBL, VRL, or VCR cause Pgp to shift to an open-outward conformation, while 150 µM of the VAs shifted the conformation of Pgp to an intermediate orientation, between opened inward and open-outward. However, the conformational shift induced by saturating AMPPNP and VCR condition was less than either VBL or VRL in the presence of AMPPNP. At 150 µM, atomic force microscopy (AFM) revealed that the VAs shift Pgp population to a predominantly open-inward conformation. Additionally, STDD NMR studies revealed comparable groups in VBL, VRL, and VCR are in contact with the protein during binding. Our results, when coupled with VAs-microtubule structure-activity relationship studies, could lay the foundation for developing next-generation VAs that are effective as anti-tumor agents. A model that illustrates the intricate process of Pgp-mediated transport of the VAs is presented.

Chronic stressors and trauma: prospective influences on the course of bipolar disorder.

BACKGROUND: Exposure to life stress is known to adversely impact the course of bipolar disorder. Few studies have disentangled the effects of multiple types of stressors on the longitudinal course of bipolar I disorder. This study examines whether severity of chronic stressors and exposure to trauma are prospectively associated with course of illness among bipolar patients. METHOD: One hundred and thirty-one participants diagnosed with bipolar I disorder were recruited through treatment centers, support groups and community advertisements. Severity of chronic stressors and exposure to trauma were assessed at study entry with in-person interviews using the Bedford College Life Event and Difficulty Schedule (LEDS). Course of illness was assessed by monthly interviews conducted over the course of 24 months (over 3000 assessments). RESULTS: Trauma exposure was related to more severe interpersonal chronic stressors. Multiple regression models provided evidence that severity of overall chronic stressors predicted depressive but not manic symptoms, accounting for 7.5% of explained variance. CONCLUSIONS: Overall chronic stressors seem to be an important determinant of depressive symptoms within bipolar disorder, highlighting the importance of studying multiple forms of life stress.

Varicella in the neonatal ICU due to the Varicella vaccine Oka strain.

BACKGROUND: Varicella vaccination of non-immune post-partum women is recommended to reduce the risk of chickenpox in mothers and their infants. Though rare, transmission of the varicella vaccine strain vOka can occur from recent vaccinees to non-immune contacts who usually develop mild chickenpox. METHODS/RESULTS: Here we describe an infant hospitalized in the neonatal ICU with vaccine-strain varicella due to transmission from their mother who received the varicella vaccine post-partum. We describe the infection prevention and control strategies implemented to prevent further transmission. CONCLUSION: Vaccine-strain varicella transmission from mother to infant is a rare event and its occurrence in the neonatal ICU setting can be challenging. Anticipatory guidance for mothers vaccinated in the postpartum period and support of parents of an infected infant are recommended.

Identifying individuals with physcian diagnosed COPD in health administrative databases.

Chronic Obstructive Pulmonary Disease (COPD) is a common chronic respiratory disease responsible for significant morbidity and mortality. Population-based health administrative databases provide a powerful and unbiased way of studying COPD in the population, however, their ability to accurately identify patients with this disease must first be confirmed. The objective was to validate population-based health administrative definitions of COPD. Previously abstracted medical records of adults over the age of 35 randomly selected from primary care practices in Ontario, Canada were reviewed by an expert panel to establish if an individual did or did not have a diagnosis of COPD. These reference designations were then linked to each individual's respective health administrative database record and compared with predefine health administrative data definitions of COPD. Concepts of diagnostic test evaluation were used to calculate and compare their test characteristics. The most sensitive health administrative definition of COPD was 1 or more ambulatory claims and/or 1 or more hospitalizations for COPD that yielded a sensitivity of 85.0% (95% confidence interval 77.0 to 91.0) and a specificity of 78.4% (95% confidence interval 73.6 to 82.7). As number of ambulatory claims in the definition increased, sensitivity decreased and specificity increased. Individuals with COPD can be accurately identified in health administrative data, and therefore it may be used to create an unbiased population cohort for surveillance and research. This offers a powerful means of generating evidence to inform strategies that optimize the prevention and management of COPD.

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

Reasons patients present to the emergency department might change during epidemics and be a valuable component of a disease surveillance system.

We hypothesize that the frequency of reasons patients present to the emergency department will change during epidemics and might be a valuable component of a disease surveillance system. We found support for this hypothesis over a two-year period with high frequency days of fever clustering during two periods of increased hospital influenza activity, but not during any other period during the two-years. This methodology appears to be superior to the previous use of triage nurses defining patients with symptom complexes. Such a system could result in online monitoring, be independent of the medical personnel (use of admission secretary), and might be able to identify various epidemics including increased hospital disease activity due to bio-terror attacks, influenza, and food poisoning. This would have important implications for limiting the spread of disease and for the acute planning of distribution of medical resources. Studies are warranted in various settings to determine whether or not changes in the daily frequencies of reasons patients present to the ED will allow identification of epidemics.

Herpes zoster-associated encephalitis: clinicopathologic report of 12 cases and review of the literature.

Herpes-zoster associated encephalitis (HZAE) is an uncommon complication of herpes zoster. Over 8 years, we evaluated 12 patients with this clinical diagnosis. The majority of our patients were elderly, immunosuppressed, and found to have disseminated skin lesions prior to the onset of CNS symptoms. All patients had abnormal EEGs, and CSF pleocytosis was found in most. In the seven patients who were tested, specific antibody to the varicella-zoster membrane antigen (FAMA) was detected in spinal fluid during the course of the illness. Although three patients died during the period of active infection, the virus could not be definitively implicated as the cause of death. These HZAE patients could not be distinguished from our other herpes zoster patients on the basis of age, initially involved dermatome, or mortality rate. However, among herpes zoster patients who survived, duration of hospitalization was significantly longer in those with a diagnosis of HZAE. All surviving HZAE patients had a slow but eventual return to their prior cognitive status.

Symposium on infectious complications of neoplastic disease (Part II). Immunoprophylaxis of varicella-zoster infections.

Because it is possible to identify groups of persons with a high risk of varicella development and also because it is possible to anticipate when an attack may occur, immunoprophylaxis for varicella has met with great success. In contrast, the nature of zoster--its unpredictability and low attack rate--makes immunoprophylaxis much more difficult to implement. Varicella may be modified by administration of varicella-zoster immune globulin within three days of a known exposure to the virus. Although interferon has not yet been used in an attempt to prevent or modify varicella in humans, it has been used successfully to abort an outbreak of simian varicella in a monkey colony. Thus it might be clinically useful, particularly for those who cannot be given varicella-zoster immune globulin within three days of exposure. Transfer factor has also been shown to induce at least partial immunity to varicella in children with leukemia. The duration of this protection is unknown, and further study of the efficacy of transfer factor against both varicella and possibly even against zoster seems warranted. Live attenuated varicella vaccine, although still experimental, seems now to be the most practical way to prevent severe varicella in high-risk persons. The vaccine is safe and immunogenic, even in children with underlying leukemia who are still receiving chemotherapy. Studies in Japan, Europe, and the United States have shown that most vaccinated leukemic children who are exposed are protected against severe disease, although mild breakthrough cases have been reported. Varicella vaccine's potential to cause zoster remains under study.

Seroepidemiologic survey of varicella: Value of specific fluorescent antibody test.

The sensitive varicella-zoster fluorescent antibody to membrane antigen (V-Z FAMA) test was used in a seroepidemiologic survey of two outbreaks of varicella involving 30 children. The attack rate of varicella based on clinical observations alone was 60%. The attack rate based on clinical and serological observations lay between 78% and 82%, after excluding those children who had detectable antibody at the time of exposure. No subclinical varicella infection was observed in this small series of patients. No boost in antibody response was observed in immunes who were exposed to varicella. No patients with detectable V-Z antibody by FAMA at the time of exposure developed clinical varicella. The V-Z FAMA test provided helpful information about the immune status of persons exposed to varicella.

Live attenuated varicella vaccine use in immunocompromised children and adults.

Live attenuated varicella vaccine has been administered to 307 children with leukemia in remission and to 86 healthy adults. The vaccine was well tolerated and immunogenic. The major side effect in leukemic children receiving maintenance chemotherapy was development of a vaccine-associated rash. Vaccinees in whom a rash developed were potentially somewhat infectious to others about 1 month after immunization. Vaccination was not associated with an increase in the incidence of herpes zoster or in relapse of leukemia. Vaccination provided excellent protection against severe varicella. It was associated with a significant decrease in the attack rate of chickenpox following an intimate exposure to varicella-zoster virus, conferring about 80% protection in leukemic children. The cases of breakthrough varicella that occurred were mild. Thus, the vaccine may either prevent or modify varicella in high-risk individuals. It may also have use for prevention of nosocomial varicella.

Antibody to Varicella-Zoster virus in parturient women and their offspring during the first year of life.

A nursery outbreak of varicella is reported. Serum from 200 parturient women and 131 of their offspring were studied for antibody to varicella-zoster (V-Z) virus to analyze their immunity to varicella. Antibody titers were measured by the sensitive fluorescent antibody to membrane antigen (FAMA) technique. It was found that approximately 5% to 16% of women of child-bearing age in New York City are susceptible to varicella. Women from Puerto Rico or other subtropical and tropical areas are more likely to be susceptible (16%) than others (5%). Infants born to mothers with detectable V-Z FAMA titers almost always had detectable V-Z antibody at birth. In serial serum specimens obtained from 67 initially seropositive babies during the first year of life, it was found that by 6 months of age most infants were no longer passively protected against varicella. These observations may explain why varicella is not uncommonly observed in young babies.

Transcatheter embolotherapy of maternal pulmonary arteriovenous malformations during pregnancy.

STUDY OBJECTIVES: To determine if transcatheter embolotherapy is safe and effective for the treatment of pulmonary arteriovenous malformations during pregnancy. DESIGN: Prospective study. SETTING: Specialized hereditary hemorrhagic telangiectasia centers at Yale University School of Medicine and St. Michael's Hospital, University of Toronto. PATIENTS: Seven pregnant women (age range, 24 to 34 years; gestational age range, 16 to 36 weeks) undergoing transcatheter embolotherapy. INTERVENTIONS: Transcatheter embolotherapy in all patients. MEASUREMENTS AND RESULTS: Thirteen pulmonary arteriovenous malformations in seven patients were embolized with detachable silicone balloons and/or stainless steel coils without incident. The estimated fetal radiation dose ranged from < 50 to 220 mrad. No complications of pulmonary arteriovenous malformations occurred in any of the patients after transcatheter embolotherapy. The mothers went on to deliver healthy babies in all cases. CONCLUSIONS: Transcatheter embolotherapy of maternal pulmonary arteriovenous malformations performed by an experienced radiologist appears to be safe and effective after 16 weeks of gestational age.

Present and future challenges of immunizations on the health of our patients.

A recent analysis demonstrated a change in incidence approaching 100% for diseases against which we routinely immunize in the United States. At present, measles, mumps, rubella, invasive Haemophilus disease, poliomyelitis, diphtheria and tetanus are well-controlled but not eliminated. Diseases that now pose special problems include pertussis, hepatitis A and B and varicella. The incidence of pertussis surged in 1994, possibly in part because of waning immunity in the immunized population. Acellular pertussis vaccines are available for booster doses in children but are not now recommended for adults. Licensure of acellular pertussis vaccines for primary immunization of infants is eagerly awaited. Recombinant hepatitis B vaccine has been licensed for more than 10 years but there has been little change in disease incidence in the United States. Routine immunization of infants is now recommended but concerns exist about cost and persistence of immunity into adolescence. Inactivated hepatitis A vaccines appear to be highly effective in preventing clinical hepatitis and controlling epidemics. Potential target populations include military personnel, day-care attendees and travelers. Hepatitis A vaccine may be recommended for all children after approval by the United States Food and Drug Administration and if a combination vaccine becomes available. A live, attenuated varicella vaccine developed in 1974 and unlicensed in the United States is safe and highly effective in preventing varicella in healthy and immunocompromised populations. It also appears to reduce subsequent development of herpes zoster. Vaccines against pneumococci (conjugate vaccine), respiratory syncytial virus, rotavirus, tuberculosis and human immunodeficiency virus are needed. Research and technology to develop these vaccines must be developed, and efficient delivery mechanisms must be created and implemented.