Two consecutive randomized controlled pertussis booster trials in children initially vaccinated in infancy with an acellular vaccine: The first with a five-component Tdap vaccine to 5-year olds and the second with five- or monocomponent Tdap vaccines at age 14-15 years.

Prior study children from a DTaP efficacy trial were recruited at ages 5 and 15 years to randomized booster trials addressing immunogenicity and reactogenicity; 475 preschool children received mixed or separate injections of a reduced antigen vaccine (Tdap5, Sanofi Pasteur MSD) and an inactivated polio vaccine, and 230 adolescents received the same or another booster vaccine (Tdap1, SSI, Denmark). Pre-vaccination antibody concentrations against pertussis antigens were significantly higher at 15 than 5 years of age, probably due to natural boosting between the studies. Tdap5 induced comparable anti-PT concentrations at both ages, but antibody responses were significantly higher to filamentous haemagglutinin, pertactin and fimbriae 2/3 in adolescents. As expected, a higher amount of PT (Tdap1, 20µg) induced a stronger anti-PT response than a lower amount (Tdap5, 2.5µg). The frequency of adverse events was low and there were no serious adverse reactions. All local reactions had an early onset and a short duration. A large swelling or redness of more than half of the upper arm circumference was reported in 8/475 5-year-olds and in 6/230 15-year-olds. Children vaccinated with Tdap5 reported more moderate pain in adolescence than at preschool age, whereas itching was only reported in preschool children. Sweden introduced DTaP vaccines in 1996 after a 17-year hiatus with no general pertussis vaccination and pertussis was still endemic at the time of the studies. The frequency of adverse events was nevertheless low in both preschool children and adolescents and antibody responses were adequate. These studies document immunogenicity and reactogenicity in a trial cohort consecutively vaccinated with acellular pertussis vaccines from infancy to adolescence. The adolescent study was registered at ClinicalTrials.gov on 26 March 2009 (NCT00870350).

Accumulation of potentially toxic elements in road deposited sediments in residential and light industrial neighborhoods of Singapore.

Road deposited sediments (RDS) are a valuable environmental medium for characterizing contaminant levels in urban areas; and their associated potentially toxic elements (PTEs) can directly impact both human and aquatic health. In this study, RDS were collected from 15 co-located industrial and residential roads throughout Singapore to determine the effect of land use on contaminant levels. A second pilot study was designed to quantify the efficiency of road sweeping in removing different RDS grain size fractions from industrial and residential roads. The fine fraction (<63 µm) of all RDSs was analyzed for over 40 elements. Eleven elements that reflect geogenic and anthropogenic sources were examined in detail (Al, Co, Cr, Cu, Fe, Ni, Pb, Sb, Sc, Si, and Zn). Industrial RDS had statistically higher concentrations of Co, Cr, Fe, and Ni than residential RDS. Potentially toxic elements Cu, Pb, Sb, and Zn were enriched >10-fold at all locations compared to upper continental crust values. Concentrations of Cu, Pb and Zn exceeded aquatic sediment probable effect concentration levels, suggesting they could generate a toxic response in bottom-dwelling aquatic organisms. Traffic was equally heavy at both industrial and residential sites, but large trucks and machinery comprised a larger proportion of the traffic in the industrial areas. Traffic was not significantly correlated with the PTE (i.e., Cu, Pb, Sb and Zn) concentrations. Plausible anthropogenic contaminant sources include vehicles (e.g., brake and tire wear, vehicle emissions) and several industrial activities including metal works, oil processing, and waste incineration. Street sweeping was effective in removal of large organic debris and inorganic RDS, but it was ineffective in removing the geochemically important fraction, i.e., <125 µm.

High-efficiency particulate air filter test stand and aerosol generator for particle loading studies.

This manuscript describes the design, characterization, and operational range of a test stand and high-output aerosol generator developed to evaluate the performance of 30 x 30 x 29 cm(3) nuclear grade high-efficiency particulate air (HEPA) filters under variable, highly controlled conditions. The test stand system is operable at volumetric flow rates ranging from 1.5 to 12 standard m(3)/min. Relative humidity levels are controllable from 5%-90% and the temperature of the aerosol stream is variable from ambient to 150 degrees C. Test aerosols are produced through spray drying source material solutions that are introduced into a heated stainless steel evaporation chamber through an air-atomizing nozzle. Regulation of the particle size distribution of the aerosol challenge is achieved by varying source solution concentrations and through the use of a postgeneration cyclone. The aerosol generation system is unique in that it facilitates the testing of standard HEPA filters at and beyond rated media velocities by consistently providing, into a nominal flow of 7 standard m(3)/min, high mass concentrations (approximately 25 mg/m(3)) of dry aerosol streams having count mean diameters centered near the most penetrating particle size for HEPA filters (120-160 nm). Aerosol streams that have been generated and characterized include those derived from various concentrations of KCl, NaCl, and sucrose solutions. Additionally, a water insoluble aerosol stream in which the solid component is predominantly iron (III) has been produced. Multiple ports are available on the test stand for making simultaneous aerosol measurements upstream and downstream of the test filter. Types of filter performance related studies that can be performed using this test stand system include filter lifetime studies, filtering efficiency testing, media velocity testing, evaluations under high mass loading and high humidity conditions, and determination of the downstream particle size distributions.

New genotypes and factors associated with Cryptosporidium detection in mussels (Mytilus spp.) along the California coast.

A 3 year study was conducted to evaluate mussels as bioindicators of faecal contamination in coastal ecosystems of California. Haemolymph samples from 4680 mussels (Mytilus spp.) were tested for Cryptosporidium genotypes using PCR amplification and DNA sequence analysis. Our hypotheses were that mussels collected from sites near livestock runoff or human sewage outflow would be more likely to contain the faecal pathogen Cryptosporidium than mussels collected distant to these sites, and that the prevalence would be greatest during the wet season when runoff into the nearshore marine environment was highest. To test these hypotheses, 156 batches of sentinel mussels were collected quarterly at nearshore marine sites considered at higher risk for exposure to livestock runoff, higher risk for exposure to human sewage, or lower risk for exposure to both faecal sources. Cryptosporidium genotypes detected in Haemolymph samples from individual mussels included Cryptosporidium parvum, Cryptosporidium felis, Cryptosporidium andersoni, and two novel Cryptosporidium spp. Factors significantly associated with detection of Cryptosporidium spp. in mussel batches were exposure to freshwater outflow and mussel collection within a week following a precipitation event. Detection of Cryptosporidium spp. was not associated with higher or lower risk status for exposure to livestock faeces or human sewage sources. This study showed that mussels can be used to monitor water quality in California and suggests that humans and animals ingesting faecal-contaminated water and shellfish may be exposed to both host-specific and anthropozoonotic Cryptosporidium genotypes of public health significance.

Persistent itching nodules after the fourth dose of diphtheria-tetanus toxoid vaccines without evidence of delayed hypersensitivity to aluminium.

Studies in Gothenburg, Sweden, reported an exceptionally high rate of persistent itching nodules at the site of injection of aluminium containing vaccines, usually with positive epicutaneous tests to aluminium. When a new booster diphtheria-tetanus vaccine was introduced we performed a prospective cluster randomised active surveillance in 25,232 10-year-olds. Parental reports 6 months after vaccination with Duplex or diTeBooster were collected for 22,365 (88%) pupils in 851 schools. We identified 3-6 children per 10,000 with a local itching nodule persisting for at least 2 months. There were no significant differences between the vaccine groups. Contact allergy to aluminium was not detected. The findings support the use of the vaccine presently available in the Swedish vaccination program. Continued surveillance of persistent itching nodules and aluminium contact allergy is, however, warranted for vaccines containing pertussis toxoid and aluminium.

How to make sense of pertussis immunogenicity data.

Studies on serologic correlates to protection in pertussis were reviewed. Trials in the 1950s showed that agglutinogen titers correlated to protection of whole-cell vaccines, but postvaccination antibodies against pertussis toxin (PT) and against filamentous hemagglutinin did not in a later trial of acellular vaccines. However, in household studies nested in 2 recent trials, preexposure antibody levels against pertactin and against fimbriae correlated with protection against typical and mild pertussis, and anti-PT correlated only with protection against typical pertussis. These findings could be used by regulatory agencies to license pertussis vaccines. A reference laboratory for pertussis should distribute panels to control interlaboratory variation in recommended assays, and a minimal response should be set for each pertussis antigen. We conclude that 2 studies have shown correlates between measurable anti-pertactin, anti-fimbriae, and anti-PT antibody levels at exposure and individual protection against pertussis. We suggest that postvaccination response rates may be used as surrogate markers of protection.

[Vaccine protection of Swedish children. Time for revision of replacing doses of diphtheria, tetanus, polio and pertussis]. / Svenska barns vaccinskydd. Dags att se över påfyllnadsdoserna för difteri, stelkramp, polio och kikhosta.

The Swedish vaccination programme against diphtheria, tetanus, pertussis, polio and Haemophilus influenzae type b is characterized by few, widely spaced doses. Swedish schoolchildren have low diphtheria antibody levels compared to children in other countries. The introduction of acellular pertussis vaccine in 1996 has markedly cut the pertussis incidence in all ages except school-age children. There are now reasons to consider replacing the present fourth dose of inactivated polio vaccine given at 5 years of age and the diphtheria-tetanus toxoids given at 10 years of age with a combined diphtheria-tetanus-polio-acellular pertussis vaccine dose to be given at 5-6 years of age. A fifth dose of a DTPaPolio vaccine should be considered at 15-18 years of age.

The seroepidemiology of rubella in western Europe.

Most of the countries in western Europe have now implemented mass infant rubella immunization programmes, instead of or in addition to selective vaccination in order to achieve the elimination of congenital rubella syndrome. The European countries Denmark, England and Wales, Finland, France, Germany, Italy and the Netherlands undertook large, national serological surveys collecting several thousand serum specimens during 1994-8. Antibodies against rubella virus were detected by a variety of enzyme immuno-assays. Comparability of the assay results was achieved by a standardized methodology. The age- and sex-stratified serological results were related to the schedules, coverage of rubella vaccination and the incidence in these countries. The results show widely differing levels of immunity to rubella both in the general population and in the specific age groups of males and females. A low rate (< 5%) of susceptibles in childhood and adolescents of both sexes was obtained only in Finland and the Netherlands. Countries such as Italy with only moderate coverage for the infant immunization programme currently have both high susceptibility levels in the general population and in the at-risk population. The likelihood is of continued epidemics of rubella with cases of congenital rubella syndrome. The continued implementation of selective vaccination will help to offset the impact of this ongoing transmission and to protect women on reaching childbearing age.

The sero-epidemiology of diphtheria in Western Europe. ESEN Project. European Sero-Epidemiology Network.

Seven countries in Western Europe collected large, representative serum banks across the entire age range and tested them for diphtheria anti-toxin (sample size ranged from 2991 to 7715). Although a variety of assays were used, the results were all standardized to those of a reference laboratory and expressed in international units. The standardization process, and the availability of similar, large data sets allowed comparative analyses to be performed in which a high degree of confidence could be ascribed to observed epidemiological differences. The results showed that there were large differences in the proportion of adults with insufficient levels of protection amongst different countries. For instance, roughly 35% of 50- to 60-year-olds were found to be seronegative (titre < or = 0.01 IU/ml) in Finland compared with 70-75% in the United Kingdom. Furthermore, the proportion of seronegative adults would be expected to increase in some countries, notably Italy and the western part of Germany. In those countries with vaccination of military recruits there was a marked sex-related difference in the proportion of seropositive individuals. All countries have high levels of infant vaccine coverage (> 90%) but the accelerated schedule in the United Kingdom appears to result in lower anti-toxin titres than elsewhere. In Sweden, booster doses are not offered until 10 years of age which results in large numbers of children with inadequate levels of protection. Although the United Kingdom and Sweden both have higher proportions of seronegative children than elsewhere the likelihood of a resurgence of diphtheria in these countries seems remote.

Diphtheria antitoxin response to DTP vaccines used in Swedish pertussis vaccine trials, persistence and projection for timing of booster.

Data from two Swedish pertussis vaccine trials with various combination vaccines were used to compare anti-diphtheria antitoxin concentrations over time between different vaccines, vaccine lots and vaccine schedules. The immune responses were measured with a validated ELISA method.Results are given for 1326 children, born 1992, that were recruited to the placebo (DT)-controlled Trial I which used a 2, 4, 6 month schedule. Two DTP acellular and one DTP whole cell vaccine were used. No DT boosters were given until 5 years of age. Trial II recruited children born 1993-94 and compared three DTP acellular vaccines with one DTP whole cell vaccine. Results are given for 306 children in a 2, 4, 6 month schedule and for 531 children in a 3, 5, 12 month schedule. The latter schedule gave significantly higher diphtheria antitoxin concentrations post third dose. The various DTP acellular vaccines and an inefficacious DTP whole cell vaccine gave lower antitoxin concentrations than both an efficacious DTP whole cell vaccine and the DT vaccine. The larger differences in antigen response between vaccines was reduced in the course of time. Generally, an initial rapid decline of antitoxin concentration was followed by a slower decline; the change typically occurring when the antitoxin concentration reached 0.13-0.16 EU/ml. The time needed to reach this level was between 6 and 10 months based on the initial vaccine response.A "best-fit" combined exponential regression model was used to predict the optimal timing for booster vaccinations against diphtheria.Our data support a 3, 5, 12 month schedule followed by a fourth dose 4-5 years after the third dose, depending upon the vaccine used.

Bordetella pertussis, Bordetella parapertussis, Mycoplasma pneumoniae, Chlamydia pneumoniae and persistent cough in children.

Material collected during a prospective pertussis vaccine trial in 1992-95 was examined for Bordetella pertussis (culture and serology), Bordetella parapertussis (culture), Mycoplasma pneumoniae and Chlamydia pneumoniae (PCR). From 64% (99/155) of episodes with cough for less than 100 d, 115 aetiological agents were identified in one southern and one northern subset of DT-recipients. The most common single agent was B. pertussis, representing 56%(64/115), with a median cough period of 51 d, followed by M. pneumoniae 26%(30/115), 23 d, C. pneumoniae 17% (19/115), 26 d, and B. parapertussis 2% (2/115). For co-infections, the median duration of cough was about 60 d. Spasmodic cough for 21 d or more (clinical WHO criteria for pertussis) was present in 82% (41/50) of infections with B. pertussis as single agent, 38% (17/45) with B. parapertussis, 38% (5/13) with C. pneumoniae, 26% (5/19) with M. pneumoniae and 30%(17/56) in cases where no aetiology was found. In children with cough for more than 100 d (n = 78) using all vaccine arms, B. pertussis was responsible in 83% (65/78), in 21%(16/78) together with other agents. Acellular vaccines were more efficient against serious disease than whole cell vaccine. Antibiotic treatment was more common at the southern (34%) study site than at the northern one (12%). The findings indicate that diagnosis should rely on laboratory confirmation, both for rational treatment of an individual case and for monitoring outbreaks.

Marked decline in pertussis followed reintroduction of pertussis vaccination in Sweden.

Immunisation against pertussis with an acellular pertussis vaccine for children at 3, 5, and 12 months was included in the Swedish vaccination programme in January 1996, 17 years after the withdrawal of whole cell vaccine in 1979. Within months coverage r

Measuring protection; a case study of pertussis vaccines--Swedish Trial II: secondary non-randomized comparisons between two schedules of infant vaccination.

In a double-blind trial two-, three- and five-component acellular vaccines were compared to a British whole-cell vaccine: in areas using three doses at three, five and 12 months of age (3-5-12 schedule), 72,698 children and in areas using a two, four and six months schedule (2-4-6 schedule), 10,194 children were evenly randomized to the four groups. The background incidence of pertussis was higher in the 3-5-12 schedule areas than in the 2-4-6 schedule areas; in spite of this, the point estimates of the relative risks for the 3-5-12 schedule versus the 2-4-6 schedule were close to or below one for the multicomponent acellular and the whole-cell vaccine groups, indicating a lower overall risk of pertussis when the third dose was delayed. The risk of whooping cough according to parents was lowest for the five-component and whole-cell vaccine groups in both schedules. The delayed third dose elicited booster responses for filamentous haemagglutinin but not for the other pertussis antigens. For highly efficacious pertussis vaccines two doses in infancy followed by a third dose in the second year of life may be recommended.

Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis.

Vaccine efficacies against typical pertussis after household exposure to Bordetella pertussis were estimated to be 75.4% for an acellular five-component vaccine, 42.4% for an acellular two-component vaccine, and 28.5%, for a licensed US whole cell vaccine, compared to placebo. Logistic regression analyses demonstrated statistically significant correlations between clinical protection and the presence of IgG antibodies against pertactin, fimbriae 2/3 and pertussis toxin in pre-exposure sera. Multicomponent pertussis vaccines of proven high efficacy in recent Swedish NIAID-sponsored efficacy trials induced higher antibody levels against pertactin and fimbriae 2/3 than less efficacious vaccines. Anti-pertactin, anti-fimbriae 2/3, and anti-PT may be used as surrogate markers of protection for multicomponent acellular and whole-cell vaccines against pertussis.

Potential exposure to SV40 in polio vaccines used in Sweden during 1957: no impact on cancer incidence rates 1960 to 1993.

U.S. polio vaccines produced during the 1950s were potentially contaminated by simian virus 40 (SV40). Recently DNA from SV40 has been detected in brain ependymoma, pleural mesothelioma and osteosarcoma. In 1957, when national polio vaccination was started in Sweden, vaccine potentially contaminated with SV40 was given to approximately 700,000 individuals, mainly pre-school and school children born between 1946 and 1953. From 1958, a Swedish inactivated polio vaccine was exclusively used, which has been claimed to be free of SV40. We explored cancer incidence rates in the cohorts exposed to the potentially contaminated polio vaccines in Sweden. The Swedish Cancer Registry provided annual cancer incidence rates in five-year age groups for the years 1960-93. Cancer incidence in cohorts maximally exposed was followed during this period, and the incidence when these cohorts reached a specific age was compared to the incidence when unexposed cohorts reached the same age. For osteosarcoma and brain ependymoma overall age-standardised incidence rates were essentially unchanged between 1960 and 1993, and age specific rates were similar in the exposed and unexposed male and female cohorts. During the same period, overall age standardised incidence rates in males of brain cancers increased from 9.0 to 13.1 and of pleural mesotheliomas from 0.2 to 2.1 per 100,000. None of these increased rates was associated with the exposed cohorts. The use of potentially SV40 contaminated inactivated polio vaccines in Sweden has not been shown to be associated with increased cancer incidence. However, the exposed cohorts have not yet reached the age of increased risk of brain cancer or mesothelioma.