Faculty Bibliography

Primary vesicoureteral reflux (pVUR) is one of the most common causes of pediatric kidney failure. Linkage scans suggest that pVUR is genetically heterogeneous with two loci on chromosomes 1p13 and 2q37 under autosomal dominant inheritance. Absence of pVUR in parents of affected individuals raises the possibility of a recessive contribution to pVUR. We performed a genome-wide linkage scan in 12 large families segregating pVUR, comprising 72 affected individuals. To avoid potential misspecification of the trait locus, we performed a parametric linkage analysis using both dominant and recessive models. Analysis under the dominant model yielded no signals across the entire genome. In contrast, we identified a unique linkage peak under the recessive model on chromosome 12p11-q13 (D12S1048), which we confirmed by fine mapping. This interval achieved a peak heterogeneity LOD score of 3.6 with 60% of families linked. This heterogeneity LOD score improved to 4.5 with exclusion of two high-density pedigrees that failed to link across the entire genome. The linkage signal on chromosome 12p11-q13 originated from pedigrees of varying ethnicity, suggesting that recessive inheritance of a high frequency risk allele occurs in pVUR kindreds from many different populations. In conclusion, this study identifies a major new locus for pVUR and suggests that in addition to genetic heterogeneity, recessive contributions should be considered in all pVUR genome scans

BACKGROUND: The objective of this study is to assess whether hepatitis A vaccine is immunogenic and well tolerated when administered to 12-month-old children alone or concomitantly with other routinely administered pediatric vaccines. METHODS: Six hundred seventeen healthy 12-month-old children were randomized to receive dose 1 of hepatitis A vaccine given alone or concomitantly with measles-mumps-rubella vaccine and varicella vaccine and dose 2 of hepatitis A vaccine given alone or concomitantly with diphtheria-tetanus-acellular pertussis vaccine and optionally with oral or inactivated poliovirus vaccine. Participants were followed for clinical adverse experiences and serologic responses to all vaccine antigens. Antibody responses were compared with historical controls for some indices. RESULTS: The safety profile was generally comparable whether hepatitis A vaccine was administered alone or concomitantly with other vaccines. When administered alone, the hepatitis A seropositivity rate was 98.3% and 100% for dose 1 and dose 2, respectively, and after dose 2 was similar to historical rates and the geometric mean titers were similar between initially seropositive and initially seronegative subjects (6207 and 6810 mIU/mL, respectively). After concomitant administration with hepatitis A vaccine, antibody responses to measles, mumps, rubella, diphtheria, tetanus and filamentous hemagglutinin (98.8%, 99.6%, 100%, 98.6%, 100% and 83.3%, respectively) were similar to historical controls and response to poliovirus was demonstrated, but immune responses to varicella zoster virus (79%) and pertussis toxoid (76%) were inferior to historical controls. CONCLUSIONS: Hepatitis A vaccine is highly immunogenic and generally well tolerated when administered to healthy children as young as 12 months of age regardless of initial hepatitis A serostatus and can be administered concomitantly with measles-mumps-rubella vaccine and oral or inactivated poliovirus vaccine

BACKGROUND: This clinical trial was conducted to demonstrate that each of 3 consistency lots of a combined measles, mumps, rubella and varicella vaccine (MMRV) would be well tolerated, induce clinically acceptable and similar immune responses to each antigen and induce immune responses similar to measles, mumps and rubella vaccine (MMR) administered concomitantly with varicella vaccine (V). An additional objective was to evaluate the persistence of antibodies 1 year postvaccination. METHODS: Study participants 12 to 23 months of age received a single injection of either one of 3 consistency lots of MMRV or MMR + V administered at separate injection sites. RESULTS: A total of 3,928 healthy children were enrolled at study sites in the United States and Canada. Immune responses to measles, mumps, rubella and varicella in children immunized with each of 3 lots of MMRV were similar and the combined response to all 3 lots was comparable to that of the control group. The 1-year antibody persistence rates for measles, mumps, rubella and varicella viruses were each greater than 95% and comparable among the recipients of the 3 consistency lots of MMRV and the control group. All vaccines were generally well tolerated during the 42 days after vaccination and the overall incidence of adverse experiences was comparable between recipients of MMRV and MMR + V. Rates of fever (temperature >or=38.9 degrees C oral equivalent or tactile) were greater in recipients of MMRV than in recipients of MMR + V (39.1% versus 33.1%, P = 0.001). Fevers were transient and there was no difference in the incidence of febrile seizures. CONCLUSIONS: MMRV was generally well tolerated and had comparable immunogenicity and overall safety profiles to MMR + V administered concomitantly. Long-term persistence of antibodies after receipt of MMRV is expected based on similar antibody titers against all 4 antigens 1 year postvaccination compared with recipients of MMR and V

The Kiryas Joel community in Monroe, N.Y. was the site of the first clinical trial which proved the protective efficacy of hepatitis A vaccine. The vaccine used was VAQTA J. Med. Virol (hepatitis A vaccine, inactivated). In the 9 years since the trial ended vaccination of infants reaching 2 years of age has continued along with monitoring for hepatitis A cases. The prevaccine pattern of frequent outbreaks has converted to a sustained pattern of no outbreaks, despite sporadic introduction of hepatitis A into the community in nonvaccinees. Community use of VAQTA in children 2 years of age and older has proven capable of providing long-term prevention of hepatitis A outbreaks in a formerly frequently affected community despite prolonged sporadic introduction of the virus

An Hasidic Jewish community has experienced recurrent hepatitis A outbreaks since 1980. To assess risk factors for illness during a 1985-6 outbreak, the authors reviewed case records and randomly selected 93 households for an interview and serologic survey. In the outbreak, 117 cases of hepatitis A were identified, with the highest attack rate (4.2%) among 3-5 year olds. Among the survey households, the presence of 3-5 year olds was the only risk factor that increased a household's risk of hepatitis A (indeterminant relative risk, P = 0.02). Furthermore, case households from the outbreak were more likely to have 3-5 years olds than were control households from the survey (odds ratio = 16.4, P < 0.001). Children 3-5 years old were more likely to have hepatitis A and may have been the most frequent transmitters of hepatitis A in this community. Hepatitis A vaccination of 3-5 year olds can protect this age group and might prevent future outbreaks in the community

The experience to date with the Merck inactivated hepatitis A vaccine in healthy children 2-16 years old is reviewed. Comparison of response to increasing doses indicates that an intramuscular dose of 25 units results in seroconversion of 99% of children by week 4 following a single dose. Antibody persistence rate is nearly 100% six months later, whether or not a second priming dose is given at week 8. This vaccine has proven highly immunogenic in children and has a favourable safety/tolerability profile. It should be useful for pre-exposure prophylaxis and control of hepatitis A, and should eventually replace immune globulin (Ig) for this indication

The worldwide experience to date with VAQTA, a highly purified formalin-inactivated hepatitis A vaccine containing alum-adjuvant, is reviewed. No serious adverse experience related to vaccination has been reported. The vaccine has proven highly immunogenic, with seroconversion detectable after a single dose in 90-99% of children 2-16 years old, and of adults under 77 kg (170 lb) body weight. There is a trend toward lower one-dose seroconversion rates with increasing age and with weight > 77 kg. Early seroconversion in the latter groups may require two 25-unit doses given 2, 4 or 8 weeks apart, or a higher priming dose. Seroconversion induced by this vaccine has been shown to signify protection from clinical hepatitis A disease. The few vaccines whose titers have waned to borderline levels responded anamnestically to a booster, suggesting that the vaccine induces an immune memory response and should provide long-term protection

The performance of vaccine protective efficacy trials is often more complex than reports of final results suggest. The current article reviews the background, planning and preparations for the Monroe, NY, protective efficacy trial of a formalin-inactivated, alum-adjuvanted hepatitis A vaccine (VAQTA, manufactured by Merck Research Laboratories). The vaccine trial was carried out at Kiryas Joel, a Hasidic Jewish community which had experienced numerous annual outbreaks in a local environment with similarities to day-care centers. Careful communication, and cooperation of community leadership, a flexible technical resource team, and knowledge of an epidemic already ongoing in a sister community whose members were due to arrive for summer holidays, permitted rapid and efficient completion of the trial with a striking demonstration of protection after a single vaccine dose

BACKGROUND. Although inactivated hepatitis A vaccine is known to be well tolerated and immunogenic in healthy children and adults, its efficacy has yet to be established. METHODS. To evaluate the efficacy of the hepatitis A vaccine in protecting against clinically apparent disease, we conducted a double-blind, placebo-controlled trial in an Hasidic Jewish community in upstate New York that has had recurrent outbreaks of hepatitis A. At the beginning of a summer outbreak, 1037 healthy seronegative children 2 to 16 years of age were randomly assigned to receive one intramuscular injection of a highly purified, formalin-inactivated hepatitis A vaccine or placebo. A case was defined by the presence of typical signs and symptoms, a diagnostic increase in IgM antibody to hepatitis A, and a serum concentration of alanine aminotransferase at least twice the upper limit of normal. Cases occurring greater than or equal to 50 days after the injection were included in the evaluation of efficacy. The children were followed for a mean of 103 days. RESULTS. A total of 519 children received vaccine, and 518 received placebo. The vaccine was well tolerated, with no serious adverse reactions. From day 50 after the injection, 25 cases of clinically apparent hepatitis A occurred in the placebo group and none in the vaccine group (P less than 0.001), confirming that the vaccine had 100 percent protective efficacy. Before day 21, seven cases occurred in the vaccine group and three cases in the placebo group. After that time, there were no cases among vaccine recipients and 34 cases among placebo recipients. CONCLUSIONS. The inactivated purified hepatitis A vaccine that we tested is well tolerated, and a single dose is highly protective against clinically apparent hepatitis A