The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling.

Mutations in the neurofibromatosis type II (NF2) tumor suppressor predispose humans and mice to tumor development. The study of Nf2+/- mice has demonstrated an additional effect of Nf2 loss on tumor metastasis. The NF2-encoded protein, merlin, belongs to the ERM (ezrin, radixin, and moesin) family of cytoskeleton:membrane linkers. However, the molecular basis for the tumor- and metastasis- suppressing activity of merlin is unknown. We have now placed merlin in a signaling pathway downstream of the small GTPase Rac. Expression of activated Rac induces phosphorylation and decreased association of merlin with the cytoskeleton. Furthermore, merlin overexpression inhibits Rac-induced signaling in a phosphorylation-dependent manner. Finally, Nf2-/- cells exhibit characteristics of cells expressing activated alleles of Rac. These studies provide insight into the normal cellular function of merlin and how Nf2 mutation contributes to tumor initiation and progression.

The mammalian ShcB and ShcC phosphotyrosine docking proteins function in the maturation of sensory and sympathetic neurons.

Shc proteins possess SH2 and PTB domains and serve a scaffolding function in signaling by a variety of receptor tyrosine kinases. There are three known mammalian Shc genes, of which ShcB and ShcC are primarily expressed in the nervous system. We have generated null mutations in ShcB and ShcC and have obtained mice lacking either ShcB or ShcC or both gene products. ShcB-deficient animals exhibit a loss of peptidergic and nonpeptidergic nociceptive sensory neurons, which is not enhanced by additional loss of ShcC. Mice lacking both ShcB and ShcC exhibit a significant loss of neurons within the superior cervical ganglia, which is not observed in either mutant alone. The results indicate that these Shc family members possess both unique and overlapping functions in regulating neural development and suggest physiological roles for ShcB/ShcC in TrkA signaling.

axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase.

Using a sensitive transfection-tumorigenicity assay, we have isolated a novel transforming gene from the DNA of two patients with chronic myelogenous leukemia. Sequence analysis indicates that the product of this gene, axl, is a receptor tyrosine kinase. Overexpression of axl cDNA in NIH 3T3 cells induces neoplastic transformation with the concomitant appearance of a 140-kDa axl tyrosine-phosphorylated protein. Expression of axl cDNA in the baculovirus system results in the expression of the appropriate recombinant protein that is recognized by antiphosphotyrosine antibodies, confirming that the axl protein is a tyrosine kinase. The juxtaposition of fibronectin type III and immunoglobulinlike repeats in the extracellular domain, as well as distinct amino acid sequences in the kinase domain, indicate that the axl protein represents a novel subclass of receptor tyrosine kinases.

Mitogenesis and endocytosis: What's at the INTERSECTIoN?

Endocytosis is a regulated physiological process by which cell surface proteins are internalized along with extracellular factors such as nutrients, pathogens, peptides, toxins, etc. The process begins with the invagination of small regions of the plasma membrane which ultimately form intracellullar vesicles. These internalized vesicles may shuttle back to the plasma membrane to recycle the membrane components or they may be targeted for degradation. One role for endocytosis is in the attenuation of receptor signaling. For example, desensitization of activated membrane bound receptors such as G-protein coupled receptors (GPCRs) or receptor tyrosine kinases (RTKs) occurs, in part, through endocytosis of the activated receptor. However, accumulating evidence suggests that endocytosis also mediates intracellular signaling. In this review, we discuss the experimental data that implicate endocytosis as a critical component in cellular signal transduction, both in the initiation of a signal as well as in the termination of a signal. Furthermore, we focus our attention on a recently described adaptor protein, intersectin (ITSN), which provides a link to both the endocytic and the mitogenic machinery of a cell. Thus, ITSN functions at a crossroad in the biochemical regulation of cell function.

Overexpression of matrix Gla protein mRNA in malignant human breast cells: isolation by differential cDNA hybridization.

Genetic alterations are involved in the development of human breast cancer. We sought to isolate genes that are differentially expressed or suppressed in cultured human breast carcinoma cells as compared to cultured normal human breast epithelial cells by employing differential screening of selected cDNA libraries. Analysis of several clones thus isolated revealed that the matrix Gla protein (MGP) gene is overexpressed in the breast cancer cell line 600 PEI, though is transcribed at lower levels in most other mammary derived cultures. MGP requires vitamin K dependent gamma-carboxylation for its known function and thus can be inhibited by vitamin K antagonists. This raises the possibility that MGP may be among those factors that when inhibited by vitamin K antagonists reduce metastases in experimental models. Among the gene whose transcription is consistently suppressed upon mammary transformation were fibronectin and the type I keratin, K14. Differential cDNA screening therefore is an effective method of identifying genes involved in various aspects of mammary cell transformation.

Testing for antibody to hepatitis A to decrease the cost of hepatitis A prophylaxis with immune globulin or hepatitis A vaccines.

BACKGROUND: The introduction of new vaccines to prevent hepatitis A infection raises the question of the cost of these vaccines relative to immune globulin when short-term protection against hepatitis A is required. Since the prevalence of hepatitis A antibodies (anti-HAV) in the US population increases rapidly with age, testing for anti-HAV may decrease the cost of vaccination programs. METHODS: A cost-analysis model was developed that incorporates the cost of immune globulin or hepatitis A vaccine, the number of doses of vaccine, the cost of testing for anti-HAV in either commercial or public-sector laboratories, and the prevalence of anti-HAV in the general population by age. RESULTS: In comparison with hepatitis A vaccines, with expected costs between $10 and $25 per dose, use of immune globulin for postexposure prophylaxis or preexposure short-term (< or = 6 months) prophylaxis is much less expensive for all age groups. Testing for anti-HAV does not significantly diminish the cost of immune globulin regimens. In contrast, if anti-HAV testing is performed in a public-sector laboratory at $10 per test, and hepatitis A vaccine costs $10 per dose, testing reduces vaccination costs in those 40 years of age or older for a two-dose vaccine regimen and in those 30 years of age or older for a three-dose regimen. At the other end of the spectrum, if vaccine costs $35 per dose, commercial testing for anti-HAV at $25 per person reduces the costs in those 30 years of age or older if either a two- or three-dose regimen is elected. However, vaccine savings are realized in those 10 years and older if public-sector testing is performed and three doses of vaccine at $35 per dose are utilized. In an intermediate scenario of public-sector testing and vaccines costing $25 per dose, the cost would also be reduced in those 30 years old or older. CONCLUSIONS: Testing for anti-HAV in frequent travelers, international government, business, and volunteer workers, military personnel, etc, may be an effective means of decreasing costs of hepatitis A prevention.

Intracranial blastomycoma.

Although meningitis is the most common form of central nervous system (CNS) blastomycosis, solitary mass lesions are not an infrequent presentation. Four of our patients presented with focal neurological deficits as a result of single intracranial mass lesions. Only 1 had clearcut evidence of extraneural blastomycosis. One was a coal miner, another worked with soil samples, and one was an engineer for a wood pulp company. All were previously healthy and 2 had diabetes. Complement fixation and immunodiffusion tests were negative in all 4 patients, and white blood cell counts and erythrocyte sedimentation rates were normal. Wet mount of tissue obtained intraoperatively by aspiration demonstrated the organism in 2 cases, culture from a lung lesion made the diagnosis in 1 case, and stain and culture of ventricular fluid revealed the organisms in the fourth case. Multiple cultures of cerebrospinal fluid from lumbar puncture were negative. All 4 patients survived. Amphotericin B alone was curative in 2 cases; surgical removal alone was curative in 1. All 4 computerized tomographic scans revealed isodense or slightly hyperdense single mass lesions with homogeneous contrast enhancement and surrounding edema, and tumor was the preoperative diagnosis in 2 cases. Such scans should suggest CNS blastomycoma in patients from the endemic area, despite the lack of other systemic manifestations. Diagnosis nevertheless rests on the characteristic histopathologic appearance in tissues and/or culture. Solitary intracranial blastomycomas may be less rare than previously thought; at our institution, we observed 4 cases in 4 years.

Rationale for clinical trials evaluating ceftriaxone in the therapy of bacterial meningitis.

Ceftriaxone is a promising antimicrobial agent in the therapy of bacterial meningitis. The rationale for the clinical evaluation of ceftriaxone in patients with meningitis is based on the following favorable characteristics: ceftriaxone has excellent in vitro activity (MBC90 0.25 microgram/ml or less) against the major meningeal pathogens including meningococci, pneumococci, group B streptococci, Hemophilus influenzae, and Escherichia coli, but it is inactive against Listeria monocytogenes; ceftriaxone is rapidly bactericidal within purulent cerebrospinal fluid in experimental animal models of meningitis induced by pneumococci, group B streptococci, H. influenzae, and E. coli; against most of the major meningeal pathogens, the activity attained in cerebrospinal fluid in human subjects with bacterial meningitis is high (1:512 or greater) and active concentrations of ceftriaxone persist in cerebrospinal fluid for prolonged periods compared with those of other cephalosporins; the results of clinical trials reported to date in patients with meningitis are encouraging. Ceftriaxone deserves further clinical evaluation in the treatment of bacterial meningitis; the optimal dose, frequency of administration, and duration of therapy remain to be determined.

The PTB domain: a modular domain with multiple function.

The convergence of cell biology, virology, biochemistry, molecular biology and genetics, has resulted in an increased understanding of the mechanisms by which cells communicate with each other and their environment. It has become clear that signal transduction is not just a linear, stepwise activation of enzymatic cascades. Rather, signal transduction involves the specific temporal and spatial assembly of multiprotein complexes within a cell, thereby leading to specific outcomes such as growth, differentiation and apoptosis. Abrogation of these complexes can lead to diseases such as cancer. The discovery of modular protein recognition domains, eg, Src homology 2 (SH2) and SH3 domains, led to the notion that these domains promote the assembly of multiprotein signaling complexes. The phosphotyrosine binding (PTB) domain, also known as a phosphotyrosine interaction domain, was originally described as an alternative to the SH2 domain for recognition of tyrosine phosphorylated ligands. However, recent experiments suggest that this domain is more versatile than originally described and is capable of binding a broad range of ligands including phospholipids and nonphosphorylated proteins. Thus, PTB domains possess a high degree of flexibility in ligand binding, thereby allowing for a wider range of interactions with cellular targets.

Hepatitis B vaccine booster dose: low-dose recombinant hepatitis B vaccines as a booster dose.

BACKGROUND: The timing and best regimen for a booster dose of hepatitis B vaccine have not been determined. METHODS: Two studies were conducted to determine the response to a booster dose of 5 micrograms recombinant hepatitis B vaccine. In the first study, a 5 micrograms (0.5 ml) dose of Recombivax HB was administered intramuscularly 38 months after the initial dose to 71 volunteers. In a second study, we offered a 5 micrograms dose recombinant hepatitis B vaccine, either Recombivax HB (0.5 ml) or Engerix B (0.25 ml), to students who had previously been immunized with three doses of vaccine. RESULTS: In the first study, among the 44 persons for whom postbooster sera were available, the geometric mean concentration of anti-hepatitis B surface antigens increased from 42 to 2090 mIU/ml after the 5 micrograms (0.5 ml) dose of Recombivax. In the second study, after a 5 micrograms (0.5 ml) dose of Recombivax, the geometric mean concentration increased from 43 to 990 mIU/ml (n = 48), and in the group that received a 5 micrograms (0.25 ml) dose of Engerix B, the concentration increased from 83 to 2337 mIU/ml (n = 45) (p = 0.18 for postdose concentrations). CONCLUSION: A 5 micrograms dose of recombinant vaccine results in an excellent booster response at a cost one fourth to one half that of a full 1 ml dose of vaccine.

Prevalence of hepatitis B virus among health care workers in Belize, Central America.

A seroprevalence survey of hepatitis B virus (HBV) markers was conducted among health care workers in Belize to help determine the epidemiology of hepatitis B and to determine if screening before immunization might lower vaccine costs. Of the 330 workers tested, 94 (29%) were positive for antibody to HBV core antigen (anti-HBc) and three (1%) had HBV surface antigen. The presence of anti-HBc increased significantly with age from 12% in those 18-24 years old to 52% in those > or = 50 years old. The rate was 17% of 48 men compared with 30% of 282 women (P = 0.05). Rates increased with years of medical service and were higher among nurses (69 of 228; 30%) and nonprofessional staff (15 of 44; 34%) than among physicians (0 of 20). The presence of anti-HBc also differed significantly among ethnic groups: Mestizo, 4%; Creole, 33% and Garifuna, 57%. Rates differed by district ranging from 3% in a northern district (mostly Mestizo) to 67% in a southern district (mostly Garifuna). Parental exposure to hepatitis B through needle stick injuries and blood transfusions was not associated with anti-HBc. Multiple logistic regression analysis confirmed ethnicity, district of residence, and age as the best predictors of anti-HBc in health care workers. Cost analysis suggests that because of regional differences in exposure, testing of health care workers for anti-HBc in the Belize and Stann Creek districts in southern Belize before hepatitis B immunization would result in vaccine program cost savings.

Prevalence of antibody to Trypanosoma cruzi in three populations in Belize.

Cross-sectional studies were conducted to determine the prevalence of antibody to Trypanosoma cruzi, the agent of Chagas' disease among three populations in Belize. Specimens were tested using a second-generation enzyme-linked immunoassay (EIA). Confirmatory testing with three single-antigen EIAs and a radioimmunoprecipitation assay (RIPA) were performed. Five (0.5%) of 962 blood donors at the Belize City Hospital were reactive including four (6%) of 65 donors from countries known to be endemic for Chagas' disease and one (0.1%) of 861 from Belize (P < 0.001). Among 467 healthy members of the Belize Defense Force, none were reactive. The third group included workers and families primarily from other Central American countries living on a banana plantation in a rural area of the country. Twenty-seven (6.1%) of 442 sera were reactive. The prevalence was 5.3% of 75 < 15 years of age, 4.2% of 236 15-34 years of age, and 9.7% of 124 > or = 35 years of age (P = 0.11, by chi-square for trend). The prevalence was similar in males (6.7% of 280) and females (5.8% of 154). The prevalence of those born in Belize (4 of 56, 7.1%) was similar with that of those born in El Salvador (9 of 110, 8.2%), Guatemala (6 of 117, 5.1%), and Honduras (8 of 129, 6.2%). Of the four persons with reactive sera who were born in Belize, the immigrant mother of one was also reactive, suggesting possible congenital transmission. Among 31 sera repeatedly reactive by EIA to T. cruzi that were further studied, 22 (71%) were reactive by at least two of three single-antigen confirmatory EIAs and 29 (94%) by RIPA. Additional studies should focus on the epidemiology of T. cruzi and ways to reduce risk of transfusion-related infections in Belize.

Seroprevalence of hepatitis B virus among school-age children in the Stann Creek District of Belize, Central America.

Adults in the Stann Creek District of Belize have a high prevalence of hepatitis B virus (HBV) infection, but the age of onset of these infections is unclear. We conducted a seroprevalence study of hepatitis B markers among Stann Creek school-age children to provide information for planning a hepatitis B vaccine program. The overall prevalence in 587 students was high for antibody to hepatitis B core antigen (anti-HBc) (43.3%) and hepatitis B surface antigen (HBsAg) (7.7%). There was marked variation of anti-HBc by school and by the predominant ethnic groups attending those schools. Maya had the highest prevalence (76%), followed by Mestizo (50%), Garifuna (37%), and Creole (25%). Children less than nine years of age attending the rural primary schools (mostly Mayan and Mestizo) had significantly higher prevalence of anti-HBc than did children attending the urban primary school (mostly Garifuna and Creole) (P < 0.05). Anti-HBc was found in 42% and 36% of students at the two high schools. Of the five schools tested, only at the urban primary school did anti-HBc positivity increase with age. Based on an analysis of the cost of serologic screening before immunization compared with mass vaccination, preimmunization serologic screening resulted in vaccine program cost savings in four of the five schools. Because most children in the rural areas contract hepatitis B before entering school, immunization against HBV should be integrated into the routine infant immunization program.

Safety, immunogenicity, and efficacy of a malaria sporozoite vaccine administered with monophosphoryl lipid A, cell wall skeleton of mycobacteria, and squalane as adjuvant.

A Plasmodium falciparum circumsporozoite protein (PfCSP) recombinant fusion protein, R32NS1(81), formulated with monophosphoryl lipid A, cell wall skeleton of mycobacteria, and squalane (Detox) was administered to 12 volunteers. One volunteer had malaise and self-limited painful induration at the injection site after the second dose and declined further immunization. The other 11 volunteers tolerated the three doses of 1,230 micrograms of vaccine, but most complained of sore arms; in five cases the pain or malaise was severe enough to interfere with work or sleep. Two weeks after the third dose of vaccine, four of the 11 immunized volunteers had > or = 14 micrograms/ml of antibodies to the repeat region of the PfCSP in their serum. Two of these four volunteers did not develop P. falciparum parasitemia when challenged by the bite of five mosquitoes carrying P. falciparum sporozoites. The seven volunteers with lower levels of antibodies and 11 of 11 controls developed parasitemia. These data are consistent with other studies, and indicate that vaccine-induced antibodies against the repeat region of PfCSP can prevent effective sporozoite infection of hepatocytes in humans. The challenge is to improve the immunogenicity of PfCSP-based vaccines, and to develop methods for including PfCSP peptides as components of multitarget malaria vaccines.

Hepatitis B virus, human immunodeficiency virus type-1, and syphilis among women attending prenatal clinics in Belize, Central America.

Women and their infants may benefit from therapeutic interventions when hepatitis B, human immunodeficiency virus (HIV), or syphilis are detected during the prenatal period. We initiated hepatitis B and HIV screening of women attending prenatal clinics in Belize. Risk factor assessment information for hepatitis B infection and demographic data were determined by interview. Of 543 evaluable women, 81 (14.9%) were seropositive for hepatitis B core antibody (anti-HBc); one woman had asymptomatic hepatitis B surface antigenemia. Antibodies to HIV-1 were detected in one woman. Reactive syphilis serologies were detected in 15 (2.8%) women. Anti-HBc seroprevalence varied by district (range 3.1-43.5%) and by ethnicity (range 0.0-40.9%). Significant identified risks for anti-HBc seropositivity from univariate analyses included being of the Garifuna ethnic group, residence or birth in the Stann Creek or Toledo districts, a reactive syphilis serology, a household size of eight or greater, and five or more lifetime sexual partners. Multivariate analyses identified ethnicity and a reactive rapid plasma reagin as the best predictors of anti-HBc seropositivity. Highly variable differences in anti-HBc prevalence by district may permit the targeting of limited public health resources for education, screening, and prevention programs.

PIP: A cross-sectional study of 543 pregnant women attending prenatal clinics in Belize's 6 districts in a 6-week period in 1993 detected highly variable prevalences of hepatitis B virus (HBV) markers. 81 sera specimens (14.9%) were positive for anti-hepatitis B core antigen (anti-HBc); one woman had asymptomatic hepatitis B surface antigenemia. No HBV markers were detected in the sera of the 1 woman with human immunodeficiency virus (HIV)-1 infection. 15 women (2.8%) had reactive syphilis serologies. Serologic evidence of exposure to HBV was significantly associated with the following sociodemographic factors: single status, age 30-34 years, household size exceeding 8, 5 or more lifetime sexual partners, geographic location (residence in the Stann Creek or Toledo districts), and ethnicity (Garifuna, Creole, and Mayan). In the multivariate analysis, ethnicity and a reactive syphilis result were the only independent predictors of anti-HBc seroprevalence. Anti-HBc seroprevalence varied by district from 3.1-43.5%, with the highest rate in Stann Creek, and by ethnicity from 0 to 40.9%, with the highest rate among the Garifuna. Prevalences were substantially lower among Mestizo-Spanish from the northern and western districts of Orange Walk, Corozal, and Cayo. The overall low prevalence of HBsAg does not support a nationwide prenatal screening program, especially given limited public health care resources. However, this study's findings suggest the feasibility of HBV screening of pregnant women among the Garifuna, Creole, Mayan, and immigrant populations of Belize's Stann Creek and Toledo districts.

Epidemiology of acute hepatitis in the Stann Creek District of Belize, Central America.

Hepatitis is common in the Stann Creek District of southern Belize. To determine the etiologies, incidence, and potential risk factors for acute jaundice, we conducted active surveillance for cases. Cases of jaundice diagnosed by a physician within the previous 6 weeks were enrolled. Evaluation included a questionnaire and laboratory tests for hepatitis A, B, C, D, and E, a blood film for malaria, and a serologic test for syphilis. Etiologies of jaundice among 62 evaluable patients included acute hepatitis A, 6 (9.7%), acute hepatitis B, 49 (79.0%), hepatitis non-A-E, 2 (3.2%), and malaria, 5 (8.1%). There were no cases of acute hepatitis E. One patient each with antibody to hepatitis C and D were detected. The annualized incidence of hepatitis A was 0.26 per 1,000. All cases of hepatitis A were in children 4-16 years of age. The annualized incidence of hepatitis B, 2.17 per 1,000, was highest in adults aged 15-44 years (4.4 per 1,000) and was higher in men (36 cases; 3.09 per 1,000) than women (13 cases; 1.19 per 1,000). Four (31%) of the women with hepatitis B were pregnant. The annualized incidence was significantly higher in Mestizo (6.18 per 1000) and Maya (6.79 per 1,000) than Garifuna (0.38 per 1,000) or Creole (0.36 per 1,000). Persons with hepatitis B were significantly more likely to be born outside of Belize (82%), had been in Belize < 5 years (73%), and lived and worked in rural areas (96%) than was the general population. Of those > or = 14 years of age with hepatitis B, only 36% were married. Few persons admitted to transfusions, tattoos, IV drug use, multiple sexual partners, visiting prostitutes, or sexually transmitted diseases. Only 1 of 49 had a reactive test for syphilis. Six patients were hospitalized (including 3 with acute hepatitis B and one with hepatitis A), and none to our knowledge died. Acute hepatitis B is the most common cause of viral hepatitis in the Stann Creek District, but the modes of transmission remain obscure. Infants, women attending prenatal clinics, and new workers are potential targets for immunization with hepatitis B vaccine.

An outbreak of enterically transmitted non-A, non-B hepatitis in Pakistan.

An epidemic of enterically transmitted non-A, non-B hepatitis occurred at a college in Sargodha, Pakistan in early 1987. There were 133 clinical cases, an attack rate of approximately 20%. Though the disease was relatively mild, all clinical cases required hospitalization and prolonged convalescence. Nearly all cases were associated with a single water source. The epidemic ended when the water supply was improved. This is the 4th described epidemic of non-A, non-B hepatitis in Pakistan.

The prevalence of hepatitis A, B and C infection among different ethnic groups in Belize.

Little is known about the prevalence of infection with hepatitis viruses in Belize, Central America. We conducted a serologic survey among members of the Belize Defence Force (BDF), which is composed of the five major ethnic groups in Belize, to estimate prevalence rates of hepatitis A, B, and C among military-aged men and women in Belize. Of approximately 600 men and women in the BDF, 492 (82%) completed a questionnaire and blood collection. Antibody to hepatitis A was found in 94%, with similar rates by age, sex, rank, and ethnicity. Antibody to hepatitis B core antigen (anti-HBc) was found in 31%. Rates of anti-HBc varied significantly among the ethnic groups with the lowest rates in Mestizo (5%) and Mayan Indians (9%), and significantly higher rates among Creoles (30%) and Garifuna (56%). Rates increased with increasing age from 28% in those 18-24 years old to 35% in those > or = 35 years old (P = 0.07, by chi-square test for trend). Hepatitis B surface antigen was found in 21 (4%) overall. Antibody to hepatitis C was found in two (0.4%). In this young healthy population, exposure to hepatitis A before the age of 18 is almost universal, while exposure to hepatitis B is related to age and ethnic origin.

Epidemiology, preventive services, and illnesses of international travelers.

Medical preparation of travelers to overseas locations is an important part of military medical care. We reviewed pre-travel records of patients attending the travel clinic at the National Naval Medical Center (NNMC) and used a post-travel questionnaire to determine the most frequent medical problems associated with international travel. Among 1,416 individuals who received pre-travel care at NNMC, there were 760 (54%) males and 656 (46%) females, the median patient age was 48 years, the most common reason for travel was pleasure, and the median duration of travel was 21 days. The most common destinations were Asia (27%), Africa (15%), Europe (13%), Central America/Caribbean (12%), and South America (11%). The median number of immunizations prescribed was three. Malaria chemoprophylaxis was prescribed to 45%. The average cost of vaccines and medications to medically prepare a traveler was $67. Among 271 (82%) who returned the post-travel questionnaire, the most common illnesses reported were diarrhea (23%) and upper respiratory infections (19%); medical treatment was sought by 9%. Properly informed, military physicians can provide a valuable service at a reasonable cost to reduce the risk of travel-acquired medical problems and illnesses.

Randomized controlled trial of concurrent hepatitis A and B vaccination.

Hepatitis A and B viruses are threats to deployed military forces. The objective of this study was to determine the feasibility of concurrent vaccination against hepatitis A and B viruses. One hundred five healthy persons, 20 to 49 years of age and without serologic markers to hepatitis A or B viruses, were randomized to receive an inactivated hepatitis A vaccine (HEP A; 25 units in 0.5 mL), recombinant hepatitis B vaccine (HEP B; 10 micrograms in 1.0 mL), or both (HEP A & B) concurrently in separate arms. Vaccines were administered intramuscularly at 0, 1, and 6 months. Sera obtained at 1, 2, 6, 7, and 12 months after the first dose were tested for quantitative antibody to hepatitis A virus (anti-HAV) and antibody to hepatitis B surface antigen. Local reactions (e.g., pain) were reported by less than half of the volunteers and were similar at the site of HEP A, whether given alone or concurrently. However, more persons complained of pain (usually mild) at the HEP B site when HEP B was given concurrently with HEP A compared with HEP B alone (43% vs. 15%, 34% vs. 9%, and 42% vs. 15% for doses 1, 2, and 3, respectively; p < 0.05 for each dose). Among persons immunized with HEP A alone or HEP A & B, the proportion with > or = 10 mIU/mL anti-HAV was 83% in both groups 1 month after dose 1 and 100% at months 2, 7, and 12. The geometric mean concentrations of anti-HAV increased from 21 mIU/mL at month 1 to 2,649 and 2,312 mIU/mL in the HEP A and HEP A & B groups, respectively, at month 7. The response to HEP B was similar whether administered alone or concurrently. Antibody responses were similar in those receiving HEP A or HEP B concurrently or alone, but more subjects reported pain (usually mild) at the HEP B site after concurrent vaccination than after HEP B alone. Further work should be conducted to approve HEP A for patients younger than 2 years of age and to develop combined HEP A and HEP B vaccines in the United States.