The use of a P. falciparum specific coiled-coil domain to construct a self-assembling protein nanoparticle vaccine to prevent malaria.

The parasitic disease malaria remains a major global public health concern and no truly effective vaccine exists. One approach to the development of a malaria vaccine is to target the asexual blood stage that results in clinical symptoms. Most attempts have failed. New antigens such as P27A and P27 have emerged as potential new vaccine candidates. Multiple studies have demonstrated that antigens are more immunogenic and are better correlated with protection when presented on particulate delivery systems. One such particulate delivery system is the self-assembling protein nanoparticle (SAPN) that relies on coiled-coil domains of proteins to form stable nanoparticles. In the past we have used de novo designed amino acid domains to drive the formation of the coiled-coil scaffolds which present the antigenic epitopes on the particle surface. Here we use naturally occurring domains found in the tex1 protein to form the coiled-coil scaffolding of the nanoparticle. Thus, by engineering P27A and a new extended form of the coiled-coil domain P27 onto the N and C terminus of the SAPN protein monomer we have developed a particulate delivery system that effectively displays both antigens on a single particle that uses malaria tex1 sequences to form the nanoparticle scaffold. These particles are immunogenic in a murine model and induce immune responses similar to the ones observed in seropositive individuals in malaria endemic regions. We demonstrate that our P27/P27A-SAPNs induce an immune response akin to the one in seropositive individuals in Burkina Faso. Since P27 is highly conserved among different Plasmodium species, these novel SAPNs may even provide cross-protection between Plasmodium falciparum and Plasmodium vivax the two major human malaria pathogens. As the SAPNs are also easy to manufacture and store they can be delivered to the population in need without complication thus providing a low cost malaria vaccine

Malaria Resilience in South America: Epidemiology, Vector Biology, and Immunology Insights from the Amazonian International Center of Excellence in Malaria Research Network in Peru and Brazil

The 1990s saw the rapid reemergence of malaria in Amazonia, where it remains an important public health priority in South America. The Amazonian International Center of Excellence in Malaria Research (ICEMR) was designed to take a multidisciplinary approach toward identifying novel malaria control and elimination strategies. Based on geographically and epidemiologically distinct sites in the Northeastern Peruvian and Western Brazilian Amazon regions, synergistic projects integrate malaria epidemiology, vector biology, and immunology. The Amazonian ICEMR’s overarching goal is to understand how human behavior and other sociodemographic features of human reservoirs of transmission— predominantly asymptomatically parasitemic people—interact with the major Amazonian malaria vector, Nyssorhynchus (formerly Anopheles) darlingi, and with human immune responses to maintain malaria resilience and continued endemicity in a hypoendemic setting. Here, we will review Amazonian ICEMR’s achievements on the synergies among malaria epidemiology, Plasmodium-vector interactions, and immune response, and how those provide a roadmap for further research, and, most importantly, point toward how to achieve malaria control and elimination in the Americas

Comparison of the Metabolic Effects of Ritonavir-Boosted Darunavir or Atazanavir Versus Raltegravir, and the Impact of Ritonavir Plasma Exposure: ACTG 5257

Background. Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24)

Comparison of the Metabolic Effects of Ritonavir-Boosted Darunavir or Atazanavir Versus Raltegravir, and the Impact of Ritonavir Plasma Exposure: ACTG 5257

Background. Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24)

Immunoregulation in human malaria: the challenge of understanding asymptomatic infection

Asymptomatic Plasmodium infection carriers represent a major threat to malaria control worldwide as they are silent natural reservoirs and do not seek medical care. There are no standard criteria for asymptomaticPlasmodium infection; therefore, its diagnosis relies on the presence of the parasite during a specific period of symptomless infection. The antiparasitic immune response can result in reducedPlasmodium sp. load with control of disease manifestations, which leads to asymptomatic infection. Both the innate and adaptive immune responses seem to play major roles in asymptomatic Plasmodiuminfection; T regulatory cell activity (through the production of interleukin-10 and transforming growth factor-β) and B-cells (with a broad antibody response) both play prominent roles. Furthermore, molecules involved in the haem detoxification pathway (such as haptoglobin and haeme oxygenase-1) and iron metabolism (ferritin and activated c-Jun N-terminal kinase) have emerged in recent years as potential biomarkers and thus are helping to unravel the immune response underlying asymptomatic Plasmodium infection. The acquisition of large data sets and the use of robust statistical tools, including network analysis, associated with well-designed malaria studies will likely help elucidate the immune mechanisms responsible for asymptomatic infection

Risk of aortic aneurysm and dissection following exposure to fluoroquinolones, common antibiotics, and febrile illness using a self-controlled case series study design: Retrospective analyses of three large healthcare databases in the US

Objective Recent observational studies suggest increased aortic aneurysm or dissection (AAD) risk following fluoroquinolone (FQ) exposure but acknowledge potential for residual bias from unreported patient characteristics. The objective of our study is to evaluate the potential association between FQ, other common antibiotics and febrile illness with risk of AAD using a self-controlled case series (SCCS) study design. Design Retrospective database analysis–SCCS. Setting Primary and Secondary Care. Study population 51,898 patients across 3 US claims databases (IBM® MarketScan® commercial and Medicare databases, Optum Clinformatics). Exposure FQ or other common antibiotics or febrile illness. Outcome AAD. Methods We studied patients with exposures and AAD between 2012 and 2017 in 3 databases. Risk windows were defined as exposure period plus 30 days. Diagnostic analyses included p-value calibration to account for residual error using negative control exposures (NCE), and pre-exposure outcome analyses to evaluate exposure-outcome timing. The measure of association was the incidence rate ratio (IRR) comparing exposed and unexposed time. Results Most NCEs produced effect estimates greater than the hypothetical null, indicating positive residual error; calibrated p (Cp) values were therefore used. The IRR following FQ exposure ranged from 1.13 (95% CI: 1.04–1.22 –Cp: 0.503) to 1.63 (95% CI: 1.45–1.84 –Cp: 0.329). An AAD event peak was identified 60 days before first FQ exposure, with IRR increasing between the 60- to 30- and 29- to 1-day pre-exposure periods. It is uncertain how much this pre-exposure AAD event peak reflects confounding versus increased antibiotic use after a surgical correction of AADs. Conclusion This study does not confirm prior studies. Using Cp values to account for residual error, the observed FQ-AAD association cannot be interpreted as significant. Additionally, an AAD event surge in the 60 days before FQ exposure is consistent with confounding by indication, or increased use of antibiotics post-surgery. Registration NCT03479736. </jats:sec

Risk of aortic aneurysm and dissection following exposure to fluoroquinolones, common antibiotics, and febrile illness using a self-controlled case series study design: Retrospective analyses of three large healthcare databases in the US.

ObjectiveRecent observational studies suggest increased aortic aneurysm or dissection (AAD) risk following fluoroquinolone (FQ) exposure but acknowledge potential for residual bias from unreported patient characteristics. The objective of our study is to evaluate the potential association between FQ, other common antibiotics and febrile illness with risk of AAD using a self-controlled case series (SCCS) study design.DesignRetrospective database analysis-SCCS.SettingPrimary and Secondary Care.Study population51,898 patients across 3 US claims databases (IBM® MarketScan® commercial and Medicare databases, Optum Clinformatics).ExposureFQ or other common antibiotics or febrile illness.OutcomeAAD.MethodsWe studied patients with exposures and AAD between 2012 and 2017 in 3 databases. Risk windows were defined as exposure period plus 30 days. Diagnostic analyses included p-value calibration to account for residual error using negative control exposures (NCE), and pre-exposure outcome analyses to evaluate exposure-outcome timing. The measure of association was the incidence rate ratio (IRR) comparing exposed and unexposed time.ResultsMost NCEs produced effect estimates greater than the hypothetical null, indicating positive residual error; calibrated p (Cp) values were therefore used. The IRR following FQ exposure ranged from 1.13 (95% CI: 1.04-1.22 -Cp: 0.503) to 1.63 (95% CI: 1.45-1.84 -Cp: 0.329). An AAD event peak was identified 60 days before first FQ exposure, with IRR increasing between the 60- to 30- and 29- to 1-day pre-exposure periods. It is uncertain how much this pre-exposure AAD event peak reflects confounding versus increased antibiotic use after a surgical correction of AADs.ConclusionThis study does not confirm prior studies. Using Cp values to account for residual error, the observed FQ-AAD association cannot be interpreted as significant. Additionally, an AAD event surge in the 60 days before FQ exposure is consistent with confounding by indication, or increased use of antibiotics post-surgery.RegistrationNCT03479736