A phase 1 study of the safety, reactogenicity, and immunogenicity of a Schistosoma mansoni vaccine with or without glucopyranosyl lipid A aqueous formulation (GLA-AF) in healthy adults from a non-endemic area.

BACKGROUND: Schistosomiasis caused by Schistosoma mansoni (Sm) is a chronic, debilitating and potentially deadly neglected tropical disease. The licensure of a vaccine to prevent schistosomiasis would represent a major breakthrough in public health. METHODS: The safety and immunogenicity of a candidate Sm vaccine were assessed in this phase I, double-blind, dose-escalation trial. Seventy-two healthy Sm-naïve 18-50 year olds were randomized to receive 3 doses ∼ 8 weeks apart of saline placebo, or 10 µg, 30 µg, or 100 µg of recombinant Sm-Tetraspanin-2 vaccine formulated on aluminum hydroxide adjuvant (Sm-TSP-2/Al) with or without 5 µg of glucopyranosyl lipid A aqueous formulation (GLA-AF). Clinical and serologic responses were assessed for 1 year after dose 3. RESULTS: Vaccines were safe and well-tolerated. The most common reactions were injection site tenderness and pain, and headache and fatigue. Tenderness and pain were more frequent in groups receiving vaccine with GLA-AF than placebo (p = 0.0036 and p = 0.0014, respectively). Injection site reactions among those given Sm-TSP-2/Al with GLA-AF lasted 1.22 and 1.33 days longer than those receiving Sm-TSP-2/Al without GLA-AF or placebo (p < 0.001 for both). Dose- and adjuvant-related increases in serum IgG against Sm-TSP-2 were observed. Peak IgG levels occurred 14 days after dose 3. Seroresponse frequencies were low among recipients of Sm-TSP-2/Al without GLA-AF, but higher among subjects receiving 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF. More seroresponses were observed among those given 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF compared to placebo (p = 0.023 and p < 0.001, respectively). Seroresponse frequencies were 0%, 30%, 50%, and 89%, respectively, among those given placebo, or 10 µg, 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF, suggesting a dose-response relationship for Sm-TSP-2/Al with GLA-AF (p = 0.0001). CONCLUSIONS: Sm-TSP-2/Al with or without GLA-AF was safe and well tolerated in a Sm-naïve population. A vaccine like the one under development may represent our best hope to eliminating this neglected tropical disease.

Effect of recent seasonal influenza vaccination on serum antibody responses to candidate pandemic influenza A/H5N1 vaccines: A meta-analysis.

Recent studies have suggested that among those receiving seasonal influenza vaccine (SIV), reduced immunogenicity is observed in recently vaccinated (RV; within the past season or 2) persons when compared with those not recently vaccinated (NRV). We performed a meta-analysis to assess the effect of recent immunization with SIV on serum H5 hemagglutination inhibition (HAI) antibody responses after influenza A/H5N1 vaccination using data from a series of randomized controlled trials. The primary outcome was seroconversion measured by HAI assays following receipt of 2 doses of H5N1 vaccine. The geometric mean titer (GMT) of serum HAI antibody after vaccination was the secondary outcome. Analyses were performed using propensity score (PS) matching. The PS for each individual in the meta-analysis cohort was calculated using logistic regression and covariates included age, gender, race, antigen dose, adjuvant, statin use and vaccine manufacturer. 2015 subjects enrolled in 7 clinical trials were eligible for inclusion in the meta-analysis cohort; among these, 915 (45%) were RV. 901 RV subjects were matched (1:1) with replacement to a subject who was NRV. Subjects who received SIV within the previous season were significantly less likely to seroconvert following H5N1 vaccination (adjusted odds ratio 0.76; 95%CI 0.60-0.96; p = 0.024), and the GMT was 18% higher among NRV subjects (GM ratio of HAI antibody 1.18; 95%CI 1.04-1.33; p = 0.008). Further work is needed to better define the effects of, and mechanisms contributing to, reduced immune responses to H5N1 vaccine among RV subjects.

[Kurt Seidel (1914-1990) : Between medicine and politics]. / Kurt Seidel (1914-1990) : Zwischen Medizin und Politik.

Prof. Dr. med. Kurt Seidel played an outstanding role in the post-war history of rheumatology in eastern Germany. This is documented by the textbook articles and review articles written by him, by the foundation and leadership over many years of the working and research group of rheumatology in Jena, by his role in the formation of the divided society of the German Democratic Republic (GDR) and by the preparation of its chronical in 1984. An appreciation of his achievements against the background of the scientific political circumstances prevailing at that time is documented through a dissertation.

[Originators and eponyms of dermatomyositis : Ernst Leberecht Wagner (1821-1888) and Heinrich Unverricht (1853-1912)]. / Erstbeschreiber und Namensgeber der Dermatomyositis : Ernst Leberecht Wagner (1821-1888) und Heinrich Unverricht (1853-1912).

Dermatomyositis is a rare muscle disease that was first described by Ernst Leberecht Wagner and Heinrich Unverricht.After providing a survey on both scientists' life works, this contribution describes the most significant subsequent works on the diagnostics and classification of clinical symptoms and the progress of the disease that the author has been observing for more than three decades.Polymyositis/dermatomyositis (also known as Unverricht-Wagner or Wagner-Unverricht syndrome) was described in two publications by Ernst Leberecht Wagner in 1863 and 1887. Wagner was - probably uniquely in Germany - consecutively professor of pathology and also, as a successor to K. A. Wunderlich, of internal medicine at the University of Leipzig. The most frequently used designation for polymyositis/dermatomyositis today was originated by Heinrich Unverricht in 1891. After his education in his home town of Breslau, Unverricht was first employed as head of the clinic for internal medicine in Jena. From 1886 he was a professor in Dorpat, but he left this university when the language of teaching was changed to Russian in 1892. Unverricht then became the first director of the newly founded Sudenburg Hospital in Magdeburg (Medical Academy from 1954 to 1991).During the subsequent decades, further medical scientists have studied the disease and brought about today's precise classification criteria for diagnostics - based on Wagner's and Unverricht's findings.

[Max Hirsch founder of rheumatology in Germany: banished and murdered]. / Max Hirsch, Begründer der Rheumatologie in Deutschland: Vertrieben und ermordet.

The Jewish physician and scientist Dr. Max Hirsch (1875-1941) made a substantial contribution to consolidation of the foundations of his professional discipline, balneology, and in particular developed the social aspects. He recognized the economic significance of diseases of the musculoskeletal system very early on and gathered important ideas from abroad. Together with the department head in the Prussian Ministry of Education and Cultural Affairs, the Privy Councillor Prof. Dr. Eduard Dietrich and later alone, he was editor of various balneological journals. He worked as general secretary of the Deutsche Gesellschaft für Rheumatologie (German Society of Rheumatology) from the beginning of its existence (1927) and created the publication series Veröffentlichungen der Deutschen Gesellschaft für Rheumabekämpfung (Publications of the German Society against Rheumatism) and Rheuma-Jahrbuch (Annual review of rheumatology) in 1929, 1930 and 1931 and organized seven rheumatology congresses up to 1933. After the accession to power of the National Socialists, Max Hirsch and Eduard Dietrich were deposed from office. Hirsch emigrated to Latvia via Switzerland and the Soviet Union with his wife and one son where they were murdered in the course of the Jewish pogrom. The second son escaped with his family to Sweden.

Investigators' perspectives on translating human microbiome research into clinical practice.

BACKGROUND: Human microbiome research has the potential to transform the practice of medicine, fundamentally shifting the ways in which we think not only about human health, illness and disease, but also about clinical practice and public health interventions. Drawing from a larger qualitative study on ethical, legal and social dimensions of human microbiome research, in this article, we document perspectives related to the translation of human microbiome research into clinical practice, focusing particularly on implications for health, illness and disease. METHODS: We conducted 60 in-depth, semi-structured interviews (2009-2010) with 63 researchers and National Institutes of Health project leaders ('investigators') involved with human microbiome research. The interviews explored a range of ethical, legal and social implications of human microbiome research, including investigators' perspectives on potential strategies for translating findings to clinical practice. Using thematic content analysis, we identified and analyzed emergent themes and patterns. RESULTS: We identified 3 themes: (1) investigators' general perspectives on the clinical utility of human microbiome research, (2) investigators' perspectives on antibiotic use, overuse and misuse, and (3) investigators' perspectives concerning future challenges of translating data to clinical practice. CONCLUSION: The issues discussed by investigators concerning the clinical significance of human microbiome research, including embracing a new paradigm of health and disease, the importance of microbial communities, and clinical utility, will be of critical importance as this research moves forward.

[The enterprising Irishman Bernard Connor (1666-1698)]. / Der unternehmungslustige Ire Bernard Connor (1666-1698).

In the thesis of the Irish physician Bernard Connor (1666-1698) from 1693 in Rheims he describes the torso of a man whose bones were joined together due to ankylosing spondylitis which is considered to be the first example of such skeletal findings. This communication must however be seen in connection with earlier and similar observations following soon after, which were published in the German and especially in the English literature. This further put into question the eponym of Strümpell-Marie-Bechterew disease commonly used in Germany for a long time. However, Bernard Connor was also a very interesting personality of the seventeenth century for other medical and historical reasons. With natural science oriented publications he attracted the opposition of the Clergy. In his 3-volume history of Poland where he worked for several months as the personal physician to King John III Sobieski, which was also published in German, he described very graphically not only the current political and social situation but also the medicine of the country which he found to be very backward. This stands in contrast to the exemplary achievements in rheumatology in Poland under European standards at the end of the twentieth century which are described and exemplified by some exceptional personalities.

Safety and immunogenicity of a recombinant nonglycosylated erythrocyte binding antigen 175 Region II malaria vaccine in healthy adults living in an area where malaria is not endemic.

Erythrocyte binding antigen region II (EBA-175) is a conserved antigen of Plasmodium falciparum that is involved in binding of the parasite to the host's erythrocytes. We evaluated the safety and immunogenicity of a recombinant EBA-175 vaccine with aluminum phosphate adjuvant in healthy young adults living in the United States. Eighteen subjects/group received ascending doses (5, 20, 80, or 160 µg) of the vaccine at 0, 1, and 6 months; 8 subjects received placebo. Most of the injection site and systemic reactions were mild to moderate in intensity. After 2 or 3 doses of the vaccine at any concentration, antibody levels measured by enzyme-linked immunosorbent assay were significantly higher than those for the placebo group. Sera from subjects who received 3 doses of the vaccine at any concentration inhibited the growth of erythrocyte-stage P. falciparum at low levels compared to sera from placebo recipients or preimmune sera. In conclusion, the EBA-175 vaccine with adjuvant was safe and immunogenic in malaria-naïve subjects.

[The High Priest of gout - Sir Alfred Baring Garrod (1819-1907)]. / Der Hohepriester der Gicht - Sir Alfred Baring Garrod (1819-1907).

The name of Sir Alfred Baring Garrod is linked with the first detection of uric acid in blood and its accumulation in sufferers from gout as well as the formulation of the term rheumatoid arthritis. The disease concept formulated by him initially (especially in Germany) caused confusion and much discussion but has now become accepted worldwide. Garrod's work on gout delivered important contributions to the elucidation of pathophysiological problems of the symptoms. Furthermore, he made a great contribution to the reorganization of the British Pharmacopoeia. One of his sons, the also knighted Sir Archibald Edward Garrod, initially continued the work of his father in the field of rheumatology and thereby made it really known. Later he developed his own research field with the establishment of the genetics of metabolism and introduced here the term inborn errors of metabolism.

Comparative immunogenicity of recombinant influenza hemagglutinin (rHA) and trivalent inactivated vaccine (TIV) among persons > or =65 years old.

Alternative substrates for influenza vaccine production are needed to ensure adequate supplies. We evaluated the relative safety and immunogenicity of recombinant hemagglutinin (rHA) or trivalent inactivated vaccine (TIV) among 869 > or =65-year-old subjects in a randomized clinical trial. Virologic surveillance for influenza-like illness (ILI) was conducted during the 2006-2007 epidemic. Vaccines were well tolerated. Seroconversion rates vs. influenza A/H1N1 and H3N2 antigens were superior in the rHA group, but were inferior vs. influenza B; however, results for influenza B are confounded since the vaccine antigens were different. ILI frequencies were low and similar in both groups. Studies assessing relative immunogenicity of vaccines using identical B Ags are warranted.

Safety, reactogenicity and immunogenicity of Francisella tularensis live vaccine strain in humans.

We evaluated the safety, reactogenicity and immunogenicity of escalating doses of a new Francisella tularensis Live Vaccine Strain (LVS) lot by scarification (SCAR) or subcutaneously (SQ) in humans. Subjects (N=10/group) received one dose of LVS via SCAR at 10(5),10(7) or 10(9)cfu/ml or SQ at 10(2), 10(3),10(4) or 10(5)cfu/ml; 14 subjects received placebo. All doses/routes were well tolerated. When compared to placebo, vaccination with 10(7) SCAR and 10(9) SCAR resulted in significantly higher serologic response frequencies, as measured by ELISA for IgG, IgM, IgA and microagglutination; whereas vaccination with 10(5) SCAR, 10(7) SCAR 10(9) SCAR and 10(5) SQ elicited a significantly higher interferon-gamma response frequency.

[A.I. Nesterow (1895-1979) and Russian rheumatology]. / A.I. Nesterow (1895-1979) und die russische Rheumatologie.

Alongside several important Russian scientists of the 18th century (G.I. Sokolski, S.P. Botkin), W.T. Talalajew - with his work on cardiac rheumatoid nodules - and W.M. Bechterew, the namesake of ankylosing spondylitis, made significant contributions to international rheumatology. While the Dutchman Jan van Breemen (1874-1961) was busy founding international rheumatology, Russian rheumatology played an at least equally important role in Europe, attracting much attention with the brilliant organisation of the 4th Congress of the International League Against Rheumatism (ILAR) in Moscow in 1934. The later institutionalised and perfectly organised rheumatological care in the giant empire is inextricably linked with the name of Anatoli Innokentjewitsch Nesterow. He founded a large institute in Moscow and, together with his many students, laid the foundations for a network of rheumatological dispensaries in Russia and the former Soviet Republic. Moreover, as the leading centre for the Working Group of Rheumatologists in socialist countries, he and his colleagues also gave specialist work in the GDR the impetus it needed. His life and work, as well as that of his congenial successor, W. A. Nassonova, are described, partially on the basis of personal encounters.

[The pathologists: Aschoff, Klinge and Gräff]. / Die Pathologen: Aschoff, Klinge, Gräff.

The article presents three pathologists who have made important contributions to the understanding of rheumatic diseases. Ludwig Aschoff's (1866-1942) work formed the foundation and was for a long time at the centre of the discussion on pathology of rheumatic diseases. Impetus was added from a rheumatological perspective by the discovery of the Aschoff nodule as an indicator of rheumatic myocarditis. Thus, newly manifested rheumatic carditis is only diagnosed when rheumatic nodules are found. Fritz Klinge (1892-1974), following in Aschoff's footsteps, broke new ground in rheumatology in Germany. From extensive animal tests at a Leipzig institute he induced inflammatory reactions, necrosis and cell proliferation which, due to repeated sensitization, lead to arthritis and periarthritis. He identified therein a relationship to human rheumatism, which he considered to be caused by an allergic (hyperergic) reaction of the mesenchyme. In his opinion, the varying manifestations of rheumatic fever and rheumatoid arthritis presented one and the same pathological event. His main achievements were to close the gap between method-related deficits in morphology and the myriad clinical observations in the field of"rheumatic" diseases and to create a pathoanatomic platform for"rheumatism". Siegfried Gräff (1899-1947) was a strong critic of Klinge. He only ever relied on individual post mortem observations and was skeptical of animal testing in a rheumatological context. He considered"rheumatism" as a symptom, refuting its status as a disease. He distinguished rheumatic fever, as characterized by the Aschoff granuloma, from a second"rheuma-symptom" disease group, namely non-specific chronic polyarthritis (rheumatoid arthritis).