Junctionless versus inversion-mode lateral semiconductor nanowire transistors.

This paper reports on gate-all-around silicon nanowire field-effect transistors (FETs) built in a lateral configuration, which represent the ultimate scaling limit of triple-gate finFET devices and allow a less disruptive CMOS scaling path in terms of processing and circuit layout design. We address several of their critical technological challenges, looking in particular at doping strategies. A comprehensive review of junctionless versus inversion-mode type of transistors is here presented, evaluating the impact on the devices' operation mode and on device properties such as: variability, reliability, noise, DC and analog/RF performance. We also discuss the potential for further manufacturable co-integration options.

Size dependence of microscopic Hall sensor detection limits.

In this paper the magnetic field detection limits of microscopic Hall sensors are investigated as a function of their lateral size. Hall sensors fabricated from GaAs/AlGaAs heterostructures and silicon are experimentally investigated at different temperatures using Hall effect and noise spectrum measurements. At room temperature a clear size dependence of the detection limit is observed, whereas at low temperatures this dependence is found to disappear. The results are explained using the theory of noise in semiconductors.

Immunization of mice by recombinant OspA preparations and protection against Borrelia burgdorferi infection induced by Ixodes ricinus tick bites.

The wide distribution of Borrelia burgdorferi, the spirochete causing Lyme borreliosis, represents a human health hazard in many areas of the world. Vaccination has been proposed as an effective prevention strategy. Vaccination experiments were conducted with preparations of recombinant outer surface protein A (OspA) derived from Borrelia burgdorferi strain ZS7. Mice received three doses (1 microgram each) of the antigens adsorbed to aluminum hydroxide. A strong immune response to the vaccine antigen was observed. Mice were challenged after immunization, using Ixodes ricinus nymphal ticks infected with Borrelia burgdorferi strain ZS7. Infection was investigated by ear biopsy culture, xenodiagnosis with uninfected larvae and serological response to Borrelia burgdorferi antigens. All unimmunized control animals were found to be infected, while all immunized animals were found to be protected against infection by Borrelia burgdorferi. In addition, most adult ticks derived from nymphs that fed on immunized mice were found to be free of spirochetes.

Site-specific alterations in the B oligomer that affect receptor-binding activities and mitogenicity of pertussis toxin.

Pertussis toxin plays a major role in the pathogenesis of whooping cough and is considered an important constituent of vaccines against this disease. It is composed of five different subunits associated in a molar ratio 1S1:1S2:1S3:2S4:1S5. The S1 subunit is responsible for the ADP-ribosyltransferase activity of the toxin. The B moiety, composed of S2 through S5, recognizes and binds to the target cell receptors and has some ADP-ribosyltransferase-independent activities such as mitogenicity. Site-directed mutagenesis of subunits S2 and S3 allowed us to identify amino acid residues involved in receptor binding. Of all the modifications generated, the deletion of Asn 105 in S2 and of Lys 105 in S3 resulted in the more drastic reduction of binding to haptoglobin and CHO cells, respectively. A holotoxin carrying both deletions presented a mitogenicity reduced to an undetectable level. The combination of these B oligomer mutations with two substitutions in the S1 subunit led to the production of a toxin analog with reduced ADP-ribosyltransferase-dependent and -independent activities including mitogenicity. As shown by immunoprecipitation with various monoclonal antibodies, the mutant holotoxin was correctly assembled and antigenically similar to the native toxin. This toxin analog induced toxin-neutralizing antibodies at the same level as the holotoxin carrying only mutations in the S1 subunit, and may therefore be considered a useful candidate for the development of a new generation vaccine against whooping cough.

Development of an acellular pertussis vaccine and its administration as a booster in healthy adults.

An acellular pertussis vaccine which contains highly purified pertussis toxoid (PT) and filamentous haemagglutinin (FHA) has been developed. These proteins have been shown to be stable, with essentially no significant reversion of the pertussis toxoid after a new detoxification procedure. Two clinical trials using this vaccine as a booster in 45 healthy adults have been performed. Results show that the vaccine was well tolerated, causing essentially mild, transient symptoms after administration. It induced an increase in anti-PT and anti-FHA antibody titres in all vaccinees.

Lack of induction of IgE and IgG antibodies to yeast in humans immunized with recombinant hepatitis B vaccines.

Yeast-derived hepatitis B vaccines (partially purified or highly purified) at different dosages and a plasma-derived hepatitis B vaccine (control) were injected into 50 young volunteers 3 times at monthly intervals. Before and 4 weeks after this series of immunizations, blood samples were drawn and tested for presence of IgE and IgG antibodies against yeast antigens. No rise in IgE antibodies against Saccharomyces cerevisiae antigens nor in IgG antibodies against Candida albicans antigens was found. Together with former clinical results this underlines the experience that type I and type III reactions against putative yeast contaminants apparently play no major role after immunization with recombinant hepatitis B vaccines.

Immunological properties of recombinant HBsAg produced in yeast.

Although currently available plasma-derived vaccines (PDV) against hepatitis B based on the surface antigen of the virus (HBsAg) are well-tolerated and effective, their supply is limited and time-consuming controls are necessary to assess their safety. It is therefore desirable that an alternative source of HBsAg be found. Recombinant DNA technology has provided the possibility of obtaining HBsAg in large quantities. However, it is important that a recombinant DNA hepatitis B vaccine be not only antigenically similar but also elicits a similar immune response in humans. Using the Ausria kit, the recombinant DNA vaccine of SmithKline Biologicals produced in yeast appears to have a higher antigenic content than a reference plasma-derived HBsAg preparation of similar purity when compared at equivalent protein concentrations. In competition experiments, however, antibodies obtained by immunization with PDV similarly recognized yeast-derived and plasma-derived antigens. Monoclonal antibodies directed to the common a determinant of the whole virus were also used to identify distinct epitopes on the recombinant DNA vaccine. The yeast-derived HBsAg is therefore antigenically similar to plasma-derived HBsAg. The yeast-derived vaccine (YDV) was highly immunogenic in mice, rabbits, goats, monkeys, chimpanzees, and humans. High titres of anti-HBs were reached in humans after three doses administered at 0, 1, and 6 months. The antibodies raised in humans after three doses of YDV were predominantly directed to the common a determinant. Competition studies using monoclonal antibodies raised against the whole virus showed that the antibodies had the same specificity as the antibodies induced by PDV. The affinity for the plasma-derived antigen of antibodies stimulated by YDV and PDV and antibodies present in the sera of convalescent subjects were also similar. Finally, competition experiments showed that the antibodies induced in humans by YDV and antibodies from convalescent subjects were directed to the same binding sites of the plasma-derived antigen. These studies indicate that the yeast-derived vaccine is immunologically similar to the plasma-derived vaccines both in vitro and in vivo and can therefore be expected to have similar protective efficacy.

Reactogenicity and immunogenicity of different lots of a yeast-derived hepatitis B vaccine.

Several lots of a yeast-derived hepatitis B vaccine at different doses and a 20 micrograms dose of plasma-derived vaccine were tested in young healthy adults and compared with respect to risk of hypersensitivity reactions, reactogenicity, and immunogenicity. No signs of hypersensitivity either pre-existing or vaccine-induced were observed. Reactogenicity was low and similar in all vaccine groups. It was not dose related and unaffected by the number of injections. Immunogenicity was evaluated for a 0, 1, 2, and 12 month vaccination schedule. Seroconversion rates (greater than or equal to 10 IU/l) were not significantly different between the purified yeast- and plasma-derived vaccines one month after the second vaccination whereas the percentage of seroconversion was slightly lower in the groups receiving only partly purified recombinant vaccines. Although geometric mean titres induced by the plasma-derived vaccine were somewhat higher after the first months, the antibody titres induced by the recombinant vaccine were at least as high as those elicited by a plasma-derived vaccine following the booster dose.

Production in yeast of hepatitis B surface antigen by R-DNA technology.

Yeast synthesizes the surface antigen protein of Hepatitis B virus when the structural gene is fused to the promoter from the ARG3 gene. Analysis of extracts and total cells shows that the primary translation product can be identified as a poorly antigenic monomer with an estimated molecular weight of 22K. In cell extracts Y-HBsAg is in the form of 20 nm particles which, like serum derived particles, are highly immunogenic in mice and monkeys. Yeast derived surface antigen is thus a viable alternative to the present serum derived HBV vaccines.

Expression of hepatitis B surface antigen in yeast.

The genomes of HBV viruses of two different serotypes were cloned in E. coli. Sequences coding for the major polypeptides of surface antigen (HBsAg) were fused with the 5' end of a cloned yeast arg3 gene. When introduced into yeast, on a suitable vector, the hybrid gene directed the synthesis of a fusion protein. Crude extracts of such strains were shown to contain HBsAg like material having physical properties characteristic of the antigen isolated from the plasma of chronic human carriers, as judged by isopycnic and rate zonal centrifugation. Furthermore, these extracts readily elicit specific anti-HBsAg antibodies in rabbits. Further manipulations of the 5' part of the arg3 gene resulted in the introduction of a unique restriction site located in the 5' non translated leader sequence. The resulting vector was used to construct a recombinant plasmid directing the synthesis of the mature (226 amino acids) HBsAg polypeptide.

Evaluation in young children of the Urabe Am 9 strain of live attenuated mumps vaccine in comparison with the Jeryl Lynn strain.

Urabe Am 9, a new strain of mumps vaccine, originally developed in Japan, was evaluated in children 14 to 20 months of age in a comparative trial with the Jeryl Lynn strain. Both vaccines performed well. The antibody responses were measured using a neutralization test and a haemolysis-in-gel test. The seroconversion rates at six weeks, as detected with either one or both tests, were 55/58 (94.8%) after the Urabe Am 9 and 58/60 (96.7%) after the Jeryl Lynn vaccine. Only mild infrequent adverse reactions were observed. It is concluded that both strains of live attenuated mumps vaccine are immunogenic and well-tolerated in this age group.

Comparison of the Urabe Am 9-Schwarz and Jeryl Lynn-Moraten combinations of mumps-measles vaccines in young children.

Two mumps-measles vaccine combinations were evaluated for their reactogenicity and immunogenicity in children aged 14 to 20 months. The Urabe Am 9-Schwarz combination vaccine was given to 108 double seronegative children. The seroconversion rate at six weeks after vaccination was 99.1% for measles (haemagglutination-inhibition test) and 92.6% for mumps (neutralization and haemolysis-in-gel tests). The Jeryl Lynn-Moraten vaccine was administered to 85 double seronegative children; the seroconversion rates were 95.3% for measles and 83.5% for mumps. The reported post-vaccination signs and symptoms resembled those seen after monovalent measles vaccine but were more accentuated. Fever over 37.5 C degrees was reported in 66.7% and unusual restlessness and irritability in 68.5% of the Urabe Am 9-Schwarz double seronegative vaccines compared to 55.3% (p less than 0.05) and 54.1% (p less than 0.05), respectively, in the recipients of the Jeryl Lynn-Moraten vaccine. These relatively high reaction rates probably reflect the close observation of the children by their parents during the study. Nevertheless, the tendency towards increased reaction rate and, possibly, reduced immunogenicity of bivalent mumps-measles vaccines as compared to the corresponding single vaccines should be taken into account in the planning of large scale vaccination of young children.