Safety, reactogenicity and immunogenicity of a novel pneumococcal protein-based vaccine in adults : a phase I/II randomized clinical study

Background: New vaccines containing highly conserved Streptococcus pneumoniae proteins such as pneumolysin toxoid (dPly) and histidine-triad protein D (PhtD) are being developed to provide broader protection against pneumococcal disease. This study evaluated the safety, reactogenicity and immunogenicity of different pneumococcal protein-containing formulations in adults. Methods: In a phase I double-blind study (www.clinicaltrials.gov: NC100707798), healthy adults (18-40 years) were randomized (1:2:2:2:2:2:2) to receive two doses of one of six investigational vaccine formulations 2 months apart, or a single dose of the control 23-valent pneumococcal polysaccharide vaccine (23PPV; Pneumovax23 (TM), Sanofi Pasteur MSD) followed by placebo. The investigational formulations contained dPly alone (10 or 30 mu g), or both dPly and PhtD (10 or 30 mu g each) alone or combined with the polysaccharide conjugates of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV; Synflorix (TM), GlaxoSmithKline Vaccines). Two groups primed with a formulation containing dPly and PhtD (10 or 30 mu g each) continued to the follow-up phase II study (NCT00896064), in which they received a booster dose at 5-9 months after primary vaccination. Results: Of 156 enrolled and vaccinated adults, 146 completed the primary immunization and 43 adults received a booster dose. During primary and booster vaccination, for any formulation, 39.5 degrees C (oral temperature) was reported. Unsolicited adverse events considered causally related to vaccination were reported following <= 33.3% of investigational vaccine doses. No serious adverse events were reported for adults receiving investigational vaccine formulations. Formulations containing dPly with or without PhtD were immunogenic for these antigens; polysaccharide conjugate-containing formulations were also immunogenic for those 10 polysaccharides. Conclusion: Investigational vaccine formulations containing dPly and PhtD were well tolerated and immunogenic when administered to healthy adults as standalone protein vaccine or combined with PHiD-CV conjugates

Immunogenicity of pneumococcal conjugate vaccine formulations containing pneumococcal proteins, and immunogenicity and reactogenicity of co-administered routine vaccines - A phase II, randomised, observer-blind study in Gambian infants.

BACKGROUND: Two conserved pneumococcal proteins, pneumolysin toxoid (dPly) and pneumococcal histidine triad protein D (PhtD), combined with 10 polysaccharide conjugates from the pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) in two investigational pneumococcal vaccine (PHiD-CV/dPly/PhtD) formulations were immunogenic and well-tolerated when administered to Gambian children. Here, we report immunogenicity of the polysaccharide conjugates, and immunogenicity and reactogenicity of co-administered routine vaccines. METHODS: In this phase II, controlled, observer-blind, single-centre study, healthy infants aged 8-10 weeks were randomised (1:1:1:1:1:1) to six groups. Four groups received 3+0 schedule (2-3-4 months [M]) of PHiD-CV/dPly/PhtD (10 or 30 µg of each protein), PHiD-CV, or 13-valent pneumococcal conjugate vaccine; and two groups received 2+1 schedule (2-4-9 M) of PHiD-CV/dPly/PhtD (30 µg of each protein) or PHiD-CV. All infants received diphtheria-tetanus-whole cell pertussis-hepatitis B-Haemophilus influenzae type b (DTPw-HBV/Hib) and oral trivalent polio vaccines (OPV) at 2-3-4 M, and measles, yellow fever, and OPV vaccines at 9 M. We evaluated immune responses at 2-5-9-12 M; and reactogenicity 0-3 days post-vaccination. RESULTS: 1200 infants were enrolled between June 2011 and May 2012; 1152 completed the study. 1 M post-primary vaccination, for each PHiD-CV serotype except 6B and 23F, ≥97.4% (3+0 schedule) and ≥96.4% (2+1 schedule) of infants had antibody concentrations ≥0.2 μg/mL. Immune responses were comparable between groups within the same vaccination schedules. Observed antibody geometric mean concentrations (GMCs) increased by 1 M post-primary vaccination compared to pre-vaccination. In the following months, GMCs and opsonophagocytic activity titres waned, with an increase post-booster for the 2+1 schedule. Immune responses to protein D and, DTPw-HBV/Hib, OPV, measles, and yellow fever vaccines were not altered by co-administration with pneumococcal proteins. Reactogenicity of co-administered vaccines was comparable between groups and did not raise concerns. CONCLUSION: Immune responses to the 10 PHiD-CV polysaccharide conjugates and co-administered vaccines were not altered by addition of dPly and PhtD. ClinicalTrials.gov identifier NCT01262872

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Towards a Sociological Understanding of Research Ethics

Zgodnie z tezą, że kompetencje etyczne stanowią ważną cechę kompetencji merytorycznych badaczy terenowych, a doświadczane przez nich dylematy etyczne mają charakter dylematów metodologiczno-teoretycznych, autorzy artykułu naświetlają problem połączenia refleksji etycznej z paradygmatem socjologii jakościowej. Argumentują, że wydzielenie jej jako specjalności normatywnej i filozoficznej, która dominuje w kodeksach etycznych, niesie ze sobą zagrożenie traktowania jej w inny sposób niż pozostałe zagadnienia obecne w socjologicznych badaniach i refleksjach oraz może prowadzić do istotnej straty poznawczej. Autorzy podkreślają możliwość i potrzebę rozwijania etyki badań w paradygmacie socjologii jakościowej, poszukując inspiracji u źródeł socjologii: u Webera, Durkheima i w szkole chicagowskiej. Krytycznie odnoszą się do nadziei, że tworzenie kodeksów etycznych jest skutecznym sposobem samoregulacji środowisk naukowych, wskazując na znaczenie specyficznych historycznych, społecznych i językowych kontekstów ich tworzenia oraz osadzenie ich w normatywnej wizji życia społecznego, która nie jest zgodna z duchem socjologii interpretatywnej. W konsekwencji opowiadają się za ujmowaniem zagadnień etycznych podkreślających podmiotowość, sytuacyjność, procesualność i komunikacyjny charakter zarówno działań badaczy w terenie, jak i działań instytucji akademickich w tym zakresie.According to the thesis that ethical competence is an important part of professional competence of social researchers and that ethical dilemmas are often experienced by them as methodological and theoretical dilemmas, the authors of the article highlight the problem of lack of link between ethical reflection and the paradigm of qualitative sociology. They argue that the separation of this topic within mainly normative-philosophical domain, which dominates in ethical codes, carries a risk of treating it differently than other issues of sociological investigation and can lead to a significant loss of its cognitive value. Instead, the authors emphasize the possibility and the need to develop research ethics within the paradigm of qualitative sociology, looking for an inspiration in the works of Max Weber, Emile Durkheim, the Chicago School, Norman Denzin and Martyn Hammersley among others. They are critical to the hope that creation of ethical codes is an effective way of scientific communities’ self-regulation, stressing the importance of specific historical, social and linguistic contexts of their creation. Consequently, the authors emphasize subjective, situational, processual, and discursive character of ethics-oriented activities, undertaken both by researchers in the field, and by academic institutions in this regard

Ethical Issues and Risk in Fieldwork. Introduction

We wprowadzeniu autorzy proponują ujęcie kwestii etycznych w kategoriach ryzyka, które towarzyszy prowadzeniu badań terenowych. Spojrzenie na badania od strony ryzyka pomaga po części uporządkować dyskurs o różnych zagrożeniach pojawiających się w toku nawiązywania interakcji badawczych, a także kieruje uwagę na powiązane sprawy identyfikowania i komunikowania ryzyka oraz podejmowania kwestii etycznych. Jedną z najważniejszych cech relacji badawczej, która utrudnia definitywne rozstrzyganie problemów etycznych, jest to, że nawiązywana jest ona w zmieniających się okolicznościach, niepowtarzalnych i zaskakujących sytuacjach, a także wobec zderzenia różnych systemów etycznych, które mogą dzielić zarówno badaczy i badanych, jak i różne podmioty w obrębie obu stron badawczej relacji. Jest już wiele danych pokazujących, że badania terenowe przynoszą nieoczekiwane zagrożenia etyczne zarówno dla jednostek, jak i zbiorowości, są bowiem prowadzone zarówno na poziomie kontaktu twarzą w twarz między jednostkami, jak i pomiędzy zbiorowościami o odmiennych formach społecznej organizacji. W sytuacji kiedy badacze nie mogą zniwelować różnic istniejących między zbiorowościami, które reprezentują i które badają, sami ponoszą ciężar ich istnienia. To musi wywoływać skutki poznawcze, emocjonalne, moralne i osobiste zarówno dla nich, jak i ich informatorów. Stąd w świetle istniejącej wiedzy można powiedzieć, że tego rodzaju ryzyko w badaniach terenowych jest nieuniknione i trzeba uczyć się je akceptować. Natomiast nie wiadomo jeszcze, jakie skutki dla organizacji badań przyniesie rozwijanie i instytucjonalizowanie dyskursów etycznych w obrębie nauk społecznych, które może wpływać nie tylko na kontrolę ryzyka, ale także na dokonywanie wyboru tematów i metod badawczych, profilowanie instytucji badawczych i polityki finansowania badań.In the introduction the authors propose framing ethical issues in terms of different risks which accompany fieldwork. This approach helps to organize ethical problems that emerge during qualitative research and directs our attention to the complementary issues of risk communication and ethical discourse within sociology. It seems that one of the most important features of the relationship emerging during qualitative research is that they appear in changing circumstances, unique situations and have unexpected consequences both for individuals and collectivities. They proceed both within face-to-face contact and within a clash of different forms of social organization and ethical systems. When it is impossible for a researcher to deal with the differences between collectivities directly, he or she bears the burden of these differences on the personal level during the fieldwork. It must cause different kinds of cognitive, emotional, moral, and personal results for both the researchers and their informants. In the light of current knowledge the risk during fieldwork seems to be inevitable and must be accepted, but, still the impact of developing of ethical discourses on controlling this risk and on research organization (for example in selecting research subjects, research methods, and research funding politics) is unclear

Safety, reactogenicity, and immunogenicity of a 12-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine in healthy toddlers: results from a phase I, randomized trial

As a stepping stone toward evaluation in infants, the safety and immunogenicity of an investigational 12-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (12vPHiD-CV) was assessed in toddlers. 12vPHiD-CV contains CRM197-conjugated capsular polysaccharides of serotypes 6A and 19A in addition to capsular polysaccharides of the 10 serotypes in PHiD-CV. In this phase I, double-blind, multicenter study (NCT01485406) conducted in Germany, 61 healthy toddlers aged 12–23 months previously primed with three PHiD-CV doses were randomized (1:1) to receive one dose of 12vPHiD-CV or PHiD-CV. Safety and reactogenicity of 12vPHiD-CV were assessed in terms of occurrence of grade 3 vaccination-related solicited and unsolicited adverse events (AEs) and vaccination-related serious AEs. Immune responses were evaluated 1 month post-vaccination. Grade 3 solicited local AEs (all considered vaccination-related) were reported for two (6.5%, redness) and three (9.7%, swelling) toddlers in the 12vPHiD-CV group and one (3.4%, swelling) in the PHiD-CV group. Grade 3 vaccination-related solicited general AEs were only reported in the PHiD-CV group. No grade 3 unsolicited or serious AEs were reported. For PHiD-CV serotypes, 100% of toddlers in both groups had antibody concentrations ≥0.2 µg/mL 1 month post-vaccination, and antibody geometric mean concentrations increased from pre-boosting. For serotypes 6A and 19A, antibody responses tended to be higher in the 12vPHiD-CV than the PHiD-CV group. A single dose of 12vPHiD-CV administered in toddlers was well tolerated and no safety concerns were identified. Immune responses were comparable to those induced by PHiD-CV when administered in toddlers previously primed with three doses of PHiD-CV

Prevention of otitis media: Now a reality?

Acute otitis media (AOM), one of the most common childhood diseases, is associated with a substantial medical, social and economic burden. Non-typeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae are the two main causes of bacterial OM. The 7-valent pneumococcal CRM197-conjugate vaccine (7vCRM, Prevnar (TM)/Prevenar (TM), Wyeth) demonstrated efficacy against AOM caused by vaccine pneumococcal serotypes. Protection against overall AOM was also observed with an 11-valent pneumococcal protein D-conjugate vaccine (11Pn-PD) in the Pneumococcal Otitis EfficacyTrial (POET). Following POET, an optimized 10-valent pneumococcal non-typeable H. influenzae protein D-conjugate vaccine (PHiD-CV; Synflorix (TM), GlaxoSmithlKline Biologicals) was developed. This vaccine includes serotypes 1, 5, and 7F, in addition to those already included in 7vCRM, and was recently licensed in Europe for active immunization against invasive disease and AOM caused by S. pneumoniae in infants and children from 6 weeks up to 2 years of age. The use of protein D as carrier protein permits avoidance of possible interferences known to occur with some conjugate vaccines, and has the added potential benefit of providing protection against NTHi. This review seeks to highlight the recent advances in the field of OM vaccination, with a focus on data regarding the recently licensed PHiD-CV. (C) 2009 Published by Elsevier Ltd