T cell vaccinology: Exploring the known unknowns

The objective of modern vaccine development is the safe generation of protective long-term immune memory, both prophylactic and therapeutic. Live attenuated vaccines generate potent cellular and humoral immunity 0005, 0010 and 0015, but numerous problems exist with these vaccines, ranging from production and storage issues to adverse reactions and reversion to virulence. Subunit vaccines are safer, more stable, and more amenable to mass production. However the protection they produce is frequently inferior to live attenuated vaccines and is typically confined to humoral, and not cellular immunity. Unfortunately, there are presently no subunit vaccines available clinically that are effective at eliciting cellular responses let alone cellular memory [4]. This article will provide and overview of areas of investigation that we see as important for the development of vaccines with the capacity to induce robust and enduring cellular immune responses.     

Physical measures and biomarker collection in health surveys: Propensity to participate

Population-based surveys have long been a key tool for health researchers, policy makers and program managers. The addition of bio-measures, including physical measures and specimen collection, to self-reported health and health behaviors can increase the value of the research for health sciences. At the same time, these bio-measures are likely to increase the perceived burden and intrusiveness to the respondent. Relatively little research has been reported on respondent willingness to participate in surveys that involve physical measures and specimen collection and whether there is any associated non-response bias.This paper explores the willingness of respondents to participate in surveys that involve physical measures and biomarkers. A Census-balanced sample of nearly 2000 adults from a national mobile panel of persons residing in the U.S. were interviewed. Willingness to participate in six specific bio-measures was assessed. The survey finds a high correlation in the willingness of respondents to participate among these specific bio-measures. This suggests there is a general propensity towards (and against) bio-measures among potential respondents, despite some differences in willingness to participate in the more sensitive, intrusive or burdensome biomarkers. This study finds the general propensity to participate in bio-measures is correlated with a number of key measures of health and illness. This suggests that the inclusion of biomarkers in health surveys may introduce some bias in key measures that need to be balanced against the value of the additional information.     

Ziltivekimab for Treatment of Anemia of Inflammation in Patients on Hemodialysis: Results from a Phase 1/2 Multicenter,Randomized, Double-Blind,Placebo-Controlled Trial

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SERCA2a gene therapy in heart failure: an anti-arrhythmic positive inotrope

Therapeutic options that directly enhance cardiomyocyte contractility in chronic heart failure (HF) therapy are currently limited and do not improve prognosis. In fact, most positive inotropic agents, such as β-adrenoreceptor agonists and PDE inhibitors, which have been assessed in HF patients, cause increased mortality as a result of arrhythmia and sudden cardiac death. Cardiac sarcoplasmic reticulum Ca²⁺-ATPase2a (SERCA2a) is a key protein involved in sequestration of Ca²⁺ into the sarcoplasmic reticulum (SR) during diastole. There is a reduction of SERCA2a protein level and function in HF, which has been successfully targeted via viral transfection of the SERCA2a gene into cardiac tissue in vivo. This has enhanced cardiac contractility and reduced mortality in several preclinical models of HF. Theoretical concerns have been raised regarding the possibility of arrhythmogenic adverse effects of SERCA2a gene therapy due to enhanced SR Ca²⁺ load and induction of SR Ca²⁺ leak as a result. Contrary to these concerns, SERCA2a gene therapy in a wide variety of preclinical models, including acute ischaemia/reperfusion, chronic pressure overload and chronic myocardial infarction, has resulted in a reduction in ventricular arrhythmias. The potential mechanisms for this unexpected beneficial effect, as well as mechanisms of enhancement of cardiac contractile function, are reviewed in this article.     

Nicorandil: do the dermatological and gastrointestinal risks outweigh the benefits?

Background Nicorandil has been available in the U.K. since 1994 for the prophylaxis and treatment of angina. Since the first reported case of nicorandil‐associated oral ulceration in 1997 complications elsewhere in the gastrointestinal tract have been reported. Objectives Our case series highlights this serious drug complication. Methods We reviewed the records of all patients referred to our specialist stoma dermatology clinic who had stoma surgery for diverticular disease and all patients referred with persistent parastomal or perianal ulceration that was not attributable to Crohn’s disease or pyoderma gangrenosum. Patient demographics, nicorandil ingestion, bowel involvement, stoma type, cutaneous ulceration and outcome were recorded. Results A total of 36 patients had stoma surgery performed as a consequence of diverticular disease. The proportion of patients taking nicorandil (in all cases at a dose of 40 mg or more daily) was one third, higher than expected. There was a higher incidence of enteric fistula formation and bowel perforation among those taking nicorandil, 92% (11/12) and 50% (6/12), respectively, compared with those not on the drug, 0% and 21% (5/24), respectively. In addition, parastomal ulceration was seen more often in those taking nicorandil, 100% (12/12), compared with those not, 8% (2/24). Even without a history of diverticular disease we observed a high incidence of bowel perforation and parastomal and/or perianal ulceration among patients taking nicorandil. In the vast majority of cases ulceration healed upon cessation of nicorandil. Conclusions For those with diverticular disease taking nicorandil is strongly associated with fistula formation or bowel perforation; as such the risk‐benefit equation for nicorandil needs careful consideration given that other nitrates are available.     

Coiled-coil irregularities of the M1 protein structure promote M1–fibrinogen interaction and influence group A Streptococcus host cell interactions and virulence

Group A Streptococcus (GAS) is a human pathogen causing a wide range of mild to severe and life-threatening diseases. The GAS M1 protein is a major virulence factor promoting GAS invasiveness and resistance to host innate immune clearance. M1 displays an irregular coiled-coil structure, including the B-repeats that bind fibrinogen. Previously, we found that B-repeat stabilisation generates an idealised version of M1 (M1*) characterised by decreased fibrinogen binding in vitro. To extend these findings based on a soluble truncated version of M1, we now studied the importance of the B-repeat coiled-coil irregularities in full length M1 and M1* expressed in live GAS and tested whether the modulation of M1–fibrinogen interactions would open up novel therapeutic approaches. We found that altering either the M1 structure on the GAS cell surface or removing its target host protein fibrinogen blunted GAS virulence. GAS expressing M1* showed an impaired ability to adhere to and to invade human endothelial cells, was more readily killed by whole blood or neutrophils and most importantly was less virulent in a murine necrotising fasciitis model. M1-mediated virulence of wild-type GAS was strictly dependent on the presence and concentration of fibrinogen complementing our finding that M1–fibrinogen interactions are crucial for GAS virulence. Consistently blocking M1–fibrinogen interactions by fragment D reduced GAS virulence in vitro and in vivo. This supports our conclusion that M1–fibrinogen interactions are crucial for GAS virulence and that interference may open up novel complementary treatment options for GAS infections caused by the leading invasive GAS strain M1.