IgG2 Antibodies against a Clinical Grade Plasmodium falciparum CSP Vaccine Antigen Associate with Protection against Transgenic Sporozoite Challenge in Mice

The availability of a highly purified and well characterized circumsporozoite protein (CSP) is essential to improve upon the partial success of recombinant CSP-based malaria vaccine candidates. Soluble, near full-length, Plasmodium falciparum CSP vaccine antigen (CS/D) was produced in E. coli under bio-production conditions that comply with current Good Manufacturing Practices (cGMP). A mouse immunogenicity study was conducted using a stable oil-in-water emulsion (SE) of CS/D in combination with the Toll-Like Receptor 4 (TLR4) agonist Glucopyranosyl Lipid A (GLA/SE), or one of two TLR7/8 agonists: R848 (un-conjugated) or 3M-051 (covalently conjugated). Compared to Alum and SE, GLA/SE induced higher CS/D specific antibody response in Balb/c mice. Subclass analysis showed higher IgG2:IgG1 ratio of GLA/SE induced antibodies as compared to Alum and SE. TLR synergy was not observed when soluble R848 was mixed with GLA/SE. Antibody response of 3M051 formulations in Balb/c was similar to GLA/SE, except for the higher IgG2:IgG1 ratio and a trend towards higher T cell responses in 3M051 containing groups. However, no synergistic enhancement of antibody and T cell response was evident when 3M051 conjugate was mixed with GLA/SE. In C57Bl/6 mice, CS/D adjuvanted with 3M051/SE or GLA/SE induced higher CSP repeat specific titers compared to SE. While, 3M051 induced antibodies had high IgG2c:IgG1 ratio, GLA/SE promoted high levels of both IgG1 and IgG2c. GLA/SE also induced more potent T-cell responses compared to SE in two independent C57/BL6 vaccination studies, suggesting a balanced and productive TH1/TH2 response. GLA and 3M-051 similarly enhanced the protective efficacy of CS/D against challenge with a transgenic P. berghei parasite and most importantly, high levels of cytophilic IgG2 antibodies were associated with protection in this model. Our data indicated that the cGMP-grade, soluble CS/D antigen combined with the TLR4-containing adjuvant GLA/SE warrants further evaluation for protective responses in humans

Chronic Platelet Activation and Acute Coronary Syndromes in 13 Middle-Aged Patients

We report on clinical, laboratory, and angiographic findings that appear to characterize a group of 13 middle-aged patients who suffered acute coronary syndromes (ACS) despite little angiographic evidence of atherosclerotic heart disease (ASHD) or other risk factors. Nine of the 13 were ≤46 years of age and the rest ranged to 59 years. All had evidence of platelet disorders (PD): seven had chronic immune thrombocytopenia (ITP), one had familial thrombocytopenia, and five had other disorders affecting platelets. Evidence of long-standing chronic platelet activation was the common feature of the group, as found by (i) elevated platelet microparticles (PMP), (ii) thrombocytopenia, and (iii) enhanced procoagulant activity of plasma. Data on the 7 with ITP were compared to 20 ITP without ACS: the former had higher PMP (p < 0.01) and platelet-associated IgM (p < 0.05) relative to the ITP patient controls. Another set of patient controls consisted of 20 ACS with documented ASHD: although activation indicators were abnormal also in this group relative to normal controls (p < 0.01), the PD group of 13 had more marked abnormalities in all tests (p < 0.03), particularly in PMP and thrombocytopenia (p < 0.01). The seven youngest in the PD group appeared to respond to antiplatelet therapy since no recurrence of coronary ischemia was seen in up to 3 years of observation. It is suggested that chronic platelet activation by antibodies or immune complex may predispose those in the PD group to ACS (e.g., when under stress) despite the absence of ASHD and few other known risk factors. The true incidence of this syndrome is unknown but may be substantial. Key Words: Chronic platelet activation-Platelet microparticles-Platelet.associated IgM-Immune thrombocytopenia-Acute coronary syndromes-Middle age

Roscoe Owen Brady, MD : Remembrances of co-investigators and colleagues

To celebrate the research visions and accomplishments of the late Roscoe O. Brady (1923-2016), remembrance commentaries were requested from several of his postdoctoral research fellows and colleagues. These commentaries not only reflect on the accomplishments of Dr. Brady, but they also share some of the backstories and experiences working in the Brady laboratory. They provide insights and perspectives on Brady's research activities, and especially on his efforts to develop an effective treatment for patients with Type 1 Gaucher disease. These remembrances illuminate Brady's efforts to implement the latest scientific advances with an outstanding team of young co-investigators to develop and demonstrate the safety and effectiveness of the first enzyme replacement therapy for a lysosomal storage disease. Brady's pursuit and persistence in accomplishing his research objectives provide insights into this remarkably successful physician scientist who paved the way for the development of treatments for patients with other lysosomal storage diseases