Non-clinical toxicity and immunogenicity evaluation of a Plasmodium vivax malaria vaccine using Poly-ICLC (Hiltonol®) as adjuvant.

Malaria caused byPlasmodium vivaxis a pressing public health problem in tropical and subtropical areas.However, little progress has been made toward developing a P. vivaxvaccine, with only three candidates being tested in clinical studies. We previously reported that one chimeric recombinant protein (PvCSP-All epitopes) containing the conserved C-terminus of the P. vivax Circumsporozoite Protein (PvCSP), the three variant repeat domains, and aToll-like receptor-3 agonist,Poly(I:C), as an adjuvant (polyinosinic-polycytidylic acid, a dsRNA analog mimicking viral RNA), elicits strong antibody-mediated immune responses in mice to each of the three allelic forms of PvCSP. In the present study, a pre-clinical safety evaluation was performed to identify potential local and systemic toxic effects of the PvCSP-All epitopes combined with the Poly-ICLC (Poly I:C plus poly-L-lysine, Hiltonol®) or Poly-ICLC when subcutaneously injected into C57BL/6 mice and New Zealand White Rabbits followed by a 21-day recovery period. Overall, all observations were considered non-adverse and were consistent with the expected inflammatory response and immune stimulation following vaccine administration. High levels of vaccine-induced specific antibodies were detected both in mice and rabbits. Furthermore, mice that received the vaccine formulation were protected after the challenge with Plasmodium berghei sporozoites expressing CSP repeats from P. vivax sporozoites (Pb/Pv-VK210). In conclusion, in these non-clinical models, repeated dose administrations of the PvCSP-All epitopes vaccine adjuvanted with a Poly-ICLC were immunogenic, safe, and well tolerated.

Qualitative Findings of a Nominal Group Process to Identify Critical Factors in New LIC Implementation.

OBJECTIVES: Medical schools considering longitudinal integrated clerkships (LICs) have access to literature that provides recommendations for planning, implementation, and sustainability. However, LIC development and implementation remain notoriously challenging. University of Utah's LIC development process was informed by the documented experiences of long-established LIC programs. A literature gap was identified pertaining to more recently implemented LICs. The aim of this study was to explore the experiences of faculty in the early stages of LIC development. METHODS: Thirteen representatives from eight LICs implemented after 2015 participated in 2 Zoom focus groups (5 participated in the first and the other 8 participated in the second). Participants were asked questions to assess key supports, barriers, and recommendations. Following the focus groups, participants were asked to rank the responses based on their level of importance. RESULTS: Highest ranked supports included stakeholder and partner involvement; a dedicated coordinator or team; and strong, committed leadership. Highest ranked barriers included difficulty recruiting preceptors and clinical sites; underestimation of the amount of work required to coordinate the LIC; and challenges in providing the needed faculty development. Top recommendations for new LICs included investing in the needs of clinical partners; staffing or assigning a dedicated coordinator early in the development and implementation process; and frequent communication with all stakeholders. CONCLUSION: Despite variation among the types of new LICs represented, there was consensus among participants on the importance of key supports, barriers, and recommendations. Knowledge of these factors can help new schools plan and allocate resources during their LIC development process. Participants found the focus group process and follow-up discussions useful and have formed an ongoing workgroup which meets quarterly.

A durable protective immune response to wild-type measles virus infection of macaques is due to viral replication and spread in lymphoid tissues.

Infection with wild-type (WT) measles virus (MeV) is an important cause of childhood mortality that leads to lifelong protective immunity in survivors. WT MeV and the live-attenuated MeV used in the measles vaccine (LAMV) are antigenically similar, but the determinants of attenuation are unknown, and protective immunity induced by LAMV is less robust than that induced by WT MeV. To identify factors that contribute to these differences, we compared virologic and immunologic responses after respiratory infection of rhesus macaques with WT MeV or LAMV. In infected macaques, WT MeV replicated efficiently in B and T lymphocytes with spreading throughout lymphoid tissues resulting in prolonged persistence of viral RNA. In contrast, LAMV replicated efficiently in the respiratory tract but displayed limited spread to lymphoid tissue or peripheral blood mononuclear cells. In vitro, WT MeV and LAMV replicated similarly in macaque primary respiratory epithelial cells and human lymphocytes, but LAMV-infected lymphocytes produced little virus. Plasma concentrations of interleukin-1ß (IL-1ß), IL-12, interferon-γ (IFN-γ), CCL2, CCL11, CXCL9, and CXCL11 increased in macaques after WT MeV but not LAMV infection. WT MeV infection induced more protective neutralizing, hemagglutinin-specific antibodies and bone marrow plasma cells than did LAMV infection, although numbers of MeV-specific IFN-γ- and IL-4-producing T cells were comparable. Therefore, MeV attenuation may involve altered viral replication in lymphoid tissue that limited spread and decreased the host antibody response, suggesting a link between lifelong protective immunity and the ability of WT MeV, but not LAMV, to spread in lymphocytes.

Recombinant Human Interleukin-15 and Anti-PD-L1 Combination Therapy Expands a CXCR3+PD1-/low CD8 T-Cell Subset in Simian Immunodeficiency Virus-Infected Rhesus Macaques.

BACKGROUND: The PD1/PD-L1 pathway contributes to the pathogenesis of human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection, and blockade of this pathway may have potential to restore immune function and promote viral control or elimination. In this study, we combined a checkpoint inhibitor anti-PD-L1 (Avelumab) and recombinant human interleukin-15 (rhIL-15) in SIV-infected rhesus macaques (RM). METHODS: The rhIL-15 was administered as continuous infusion in 2 cycles of 10 days in the context of weekly administration of anti-PD-L1 (Avelumab) in SIV-infected RM receiving combination antiretroviral therapy (cART). Safety, immunological parameters, and viral loads were monitored during the study. RESULTS: Administration of rhIL-15/anti-PD-L1 was safe and well tolerated. Treatment resulted in transient increases in proliferating (Ki67+) natural killer and CD8 T cells. In addition, treatment expanded a CXCR3+PD1-/low CD8 T-cell subset with the ability to secrete cytokines. Despite these effects, no changes in plasma viremia were observed after cART interruption. CONCLUSIONS: Expansion of the CXCR3+PD1-/low CD8 T-cell subset with functional capacity and potential to traffic to sites of viral reservoirs in SIV-infected rhesus macaques had no demonstrable effect on plasma viremia after cART interruption.

Agreement between the Apple Series 1, LifeTrak Core C200, and Fitbit Charge HR with Indirect Calorimetry for Assessing Treadmill Energy Expenditure.

The purpose of this study was to examine agreement in energy expenditure between the Apple Series 1 Watch, LifeTrak Core C200, and Fitbit Charge HR with indirect calorimetry during various treadmill speeds in young adults. Participants were a sample of college-aged students (mean age = 20.1 (1.7) years; 13 females, 17 males). Participants completed six structured 10-minute exercise sessions on a treadmill with speeds ranging from 53.6 m·min-1 to 187.7 m·min-1. Indirect calorimetry was used as the criterion. Participants wore the Apple Watch, LifeTrak, and Fitbit activity monitors on their wrists. Group-level agreement was examined using equivalence testing, relative agreement was examined using Spearman's rho, and individual-level agreement was examined using Mean Absolute Percent Error (MAPE) and Bland-Altman Plots. Activity monitor agreement with indirect calorimetry was supported using the Apple Watch at 160.9 m·min-1 (Mean difference = -2.7 kcals, 90% C.I.: -8.3 kcals, 2.8 kcals; MAPE = 11.9%; rs = 0.64) and 187.7 m·min-1 (Mean difference = 3.7 kcals, 90% C.I.: -2.2 kcals, 9.7 kcals; MAPE = 10.7%; rs = 0.72) and the Fitbit at 187.7 m·min-1 (Mean difference = -0.2 kcals, 90% C.I.: -8.8 kcals, 8.5 kcals; MAPE = 20.1%; rs = 0.44). No evidence for statistical equivalence was seen for the LifeTrak at any speed. Bland-Altman Plot Limits of Agreement were narrower for the Apple Series 1 Watch compared to other monitors, especially at slower treadmill speeds. The results support the utility of the Apple Series 1 Watch and Fitbit Charge HR for assessing energy expenditure during specific treadmill running speeds in young adults.

Measuring the validity and reliability of the Apple Watch as a physical activity monitor.

BACKGROUND: This study aimed to investigate the validity and reliability of the energy expenditure (EE) estimation of Apple Watch® among college students. METHODS: Thirty college students completed two sets of three 10-minute treadmill walking and running trials while wearing three Apple watches and being connected to indirect calorimetry. The walking trials were at speeds of 54, 80, and 107 m·min-1 while the running trials were at 134, 161, 188 m·min-1. Energy expenditure comparisons were made using Two-way ANOVA with repeated measures. Reliability was analyzed by Intraclass Correlation. RESULTS: There was no significant device x speed interactions (F (15, 696)=1.113, P=0.341) between the indirect calorimetry (criterion) and Apple Watch®. The lowest Inter-Class Correlation (ICC) scores were 0.49 (95%CI) at 54 while the highest were 0.72 (95%CI) at 107 and 134 m·min-1. CONCLUSIONS: Apple Watch® demonstrated a low to moderate validity and reliability on measuring EE.

Programed death-1/programed death-ligand 1 expression in lymph nodes of HIV infected patients: results of a pilot safety study in rhesus macaques using anti-programed death-ligand 1 (Avelumab).

OBJECTIVE: The programed death-1 (PD1)/programed death-ligand 1 (PD-L1) pathway plays a critical role in balancing immunity and host immunopathology. During chronic HIV/SIV infection, there is persistent immune activation accompanied by accumulation of virus-specific cells with terminally differentiated phenotypes and expression of regulatory receptors such as PD1. These observations led us to hypothesize that the PD1/PD-L1 pathway contributes to the functional dysregulation and ineffective viral control, and its blockade may be a potential immunotherapeutic target. METHODS: Lymph node biopsies from HIV-infected patients (n = 23) were studied for expression of PD1 and PD-L1. In addition, we assessed the safety and biological activity of a human anti-PD-L1 antibody (Avelumab) in chronically SIV-infected rhesus macaques. RESULTS: PD-L1 expression was observed in cells with myloid/macrophage morphology in HIV-infected lymph nodes. Administration of anti-PD-L1 was well tolerated, and no changes in body weights, hematologic, or chemistry parameters were observed during the study. Blockade of PD-L1 led to a trend of transient viral control after discontinuation of treatment. CONCLUSION: Administration of anti-PD-L1 in chronic SIV-infected rhesus macaques was well tolerated. Overall, these data warrant further investigation to assess the efficacy of anti-PD-L1 treatment on viral control in chronic SIV infection as a prelude to such therapy in humans.

Successful respiratory immunization with dry powder live-attenuated measles virus vaccine in rhesus macaques.

Measles remains an important cause of childhood mortality worldwide. Sustained high vaccination coverage is the key to preventing measles deaths. Because measles vaccine is delivered by injection, hurdles to high coverage include the need for trained medical personnel and a cold chain, waste of vaccine in multidose vials and risks associated with needle use and disposal. Respiratory vaccine delivery could lower these barriers and facilitate sustained high coverage. We developed a novel single unit dose, dry powder live-attenuated measles vaccine (MVDP) for respiratory delivery without reconstitution. We tested the immunogenicity and protective efficacy in rhesus macaques of one dose of MVDP delivered either with a mask or directly intranasal with two dry powder inhalers, PuffHaler and BD Solovent. MVDP induced robust measles virus (MeV)-specific humoral and T-cell responses, without adverse effects, which completely protected the macaques from infection with wild-type MeV more than one year later. Respiratory delivery of MVDP was safe and effective and could aid in measles control.

Transforming a Master of Public Health program to address public health practice needs.

The future of the constantly changing public health profession is tied to the development of practice skills through competency-based training. In this article, we describe a program change in the Master of Public Health program at East Stroudsburg University in northeastern Pennsylvania. The first goal of the program transition was to ensure that all program elements included the relevant vision, values, mission, goals, and objectives. The second goal was to use continuous data input and evaluation to incorporate opportunities for flexible assessments. The change process helped the university faculty define the program's vision and fostered an environment of community collaboration that guides training for public health professionals.