Epigenetic adjuvants: durable reprogramming of the innate immune system with adjuvants.

Development of effective vaccines is a critical global health priority. Stimulating antigen-specific B and T cells to elicit long-lasting protection remains the central paradigm of vaccinology. Adjuvants are components that enhance vaccine immunogenicity by targeting specific innate immune receptors and pathways. Recent data highlight the capacity of adjuvants to induce durable epigenetic reprogramming of the innate immune system to engender heightened resistance against pathogens. This raises the prospect of developing epigenetic adjuvants that, in addition to stimulating robust T and B cell responses, convey broad protection against diverse pathogens by training the innate immune system. In this review, we discuss our emerging understanding of the various vaccines and adjuvants and their effects on durable reprogramming of the innate immune response, their putative mechanisms of action, and the promise and challenges of developing epigenetic adjuvants as a universal vaccine strategy.

Assessing Preceptor and Student Perceptions of Remote Advanced Pharmacy Practice Experience Learning during the COVID-19 Pandemic.

The coronavirus disease 2019 pandemic created a major shift in learning modalities in the Advanced Pharmacy Practice Experience program. This descriptive study aimed to evaluate preceptor and student perceptions of remote learning experiences and student practice readiness upon completion of remote rotations. Preceptors and students who participated in partial to full remote experiential rotations between 17 August 2020 and 26 March 2021 were invited to complete an on-line survey. A cross-sectional survey consisted of closed-ended questions using a 5-point Likert scale assessing perception on adaptability, effectiveness of remote learning in advancing practice knowledge and skills, and confidence in students' practice readiness. A total of 29 preceptors and 43 students completed the survey (response rates of 67% and 57%, respectively). Approximately 70% of the remote rotations were practice-based, with ambulatory care representing the most frequently reported rotation by preceptors (38%) and students (28%). A high level of confidence in preceptor perception of their ability to adapt and provide effective remote experiences (average 4.28) matched with the students' high level of confidence with their preceptors' abilities (86% agree or strongly agree). Upon the completion of remote rotations, both preceptors and students felt confident in student practice readiness based on student ability to design and initiate individualized patient care plans or complete projects using evidence-based resources (79% and 86%, respectively). Most preceptors (69%) reported that students achieved the rotation objectives at the same level as students engaged in-person experiences. The limitations of remote learning included the absence of direct interactions. Overall, both preceptors and students reported achieving practice readiness with remote experiential learning experiences and felt the remote activities should be continued post-pandemic.

Adjuvanting a subunit SARS-CoV-2 vaccine with clinically relevant adjuvants induces durable protection in mice.

Adjuvants enhance the magnitude and the durability of the immune response to vaccines. However, there is a paucity of comparative studies on the nature of the immune responses stimulated by leading adjuvant candidates. In this study, we compared five clinically relevant adjuvants in mice-alum, AS03 (a squalene-based adjuvant supplemented with α-tocopherol), AS37 (a TLR7 ligand emulsified in alum), CpG1018 (a TLR9 ligand emulsified in alum), O/W 1849101 (a squalene-based adjuvant)-for their capacity to stimulate immune responses when combined with a subunit vaccine under clinical development. We found that all four of the adjuvant candidates surpassed alum with respect to their capacity to induce enhanced and durable antigen-specific antibody responses. The TLR-agonist-based adjuvants CpG1018 (TLR9) and AS37 (TLR7) induced Th1-skewed CD4+ T cell responses, while alum, O/W, and AS03 induced a balanced Th1/Th2 response. Consistent with this, adjuvants induced distinct patterns of early innate responses. Finally, vaccines adjuvanted with AS03, AS37, and CpG1018/alum-induced durable neutralizing-antibody responses and significant protection against the B.1.351 variant 7 months following immunization. These results, together with our recent results from an identical study in non-human primates (NHPs), provide a comparative benchmarking of five clinically relevant vaccine adjuvants for their capacity to stimulate immunity to a subunit vaccine, demonstrating the capacity of adjuvanted SARS-CoV-2 subunit vaccines to provide durable protection against the B.1.351 variant. Furthermore, these results reveal differences between the widely-used C57BL/6 mouse strain and NHP animal models, highlighting the importance of species selection for future vaccine and adjuvant studies.

Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine.

Despite the success of the BNT162b2 mRNA vaccine, the immunological mechanisms that underlie its efficacy are poorly understood. Here we analyzed the innate and adaptive responses to BNT162b2 in mice, and show that immunization stimulated potent antibody and antigen-specific T cell responses, as well as strikingly enhanced innate responses after secondary immunization, which was concurrent with enhanced serum interferon (IFN)-γ levels 1 d following secondary immunization. Notably, we found that natural killer cells and CD8+ T cells in the draining lymph nodes are the major producers of this circulating IFN-γ. Analysis of knockout mice revealed that induction of antibody and T cell responses to BNT162b2 was not dependent on signaling via Toll-like receptors 2, 3, 4, 5 and 7 nor inflammasome activation, nor the necroptosis or pyroptosis cell death pathways. Rather, the CD8+ T cell response induced by BNT162b2 was dependent on type I interferon-dependent MDA5 signaling. These results provide insights into the molecular mechanisms by which the BNT162b2 vaccine stimulates immune responses.

Adapting pharmacy experiential education during COVID-19: Innovating remote preceptor resources, tools, and patient care delivery beyond virtual meetings.

PURPOSE: To describe the innovative teaching practices, tools, and resources for remote learning developed by a school of pharmacy with a decentralized experiential program to empower and support preceptors in response to the coronavirus disease 2019 (COVID-19) pandemic. SUMMARY: As the pandemic has continued, there have been significant shifts in pharmacy workflow, staffing, and patient care delivery. Pharmacy students are slowly being reintegrated into these learning environments. Although preceptors are willing and eager to teach, many lack the resources, tools, and support to create remote learning experiences at their facilities. The University of the Pacific Thomas J. Long School of Pharmacy has a decentralized experiential education model in which faculty regional coordinators with clinical practices and diverse expertise are disseminated throughout California. This model allowed us to collaborate and understand preceptor needs from a local level. We created a preceptor COVID-19 guidance document, introduced innovative virtual playbooks to pivot up to 100% remote rotations, and promoted the layered learning model to integrate pharmacy residents into the remote teaching space. Communication and flexibility are key to ensure student and preceptor safety while maintaining high-quality advanced pharmacy practice experiences and preserving patient-student relationships in telehealth. CONCLUSION: Overall, we successfully created innovative solutions and leveraged our decentralized experiential model to meet the teaching and learning demands during an unanticipated crisis. We continue to adapt and plan to assess the effectiveness of the tools by administering surveys of preceptors and pharmacy students.

Rehabilitation of Patients with Platypnea-Orthodeoxia Syndrome in COVID-19 Pneumonia: Two Case Reports.

Platypnea-orthodeoxia syndrome, characterized by dyspnoea and arterial desaturation while upright, is a rare complication of acute respiratory distress syndrome. We report here 2 patients with COVID-19 pneumonia, who were diagnosed with platypnea-orthodeoxia syndrome during commencement of rehabilitation, 18 and 9 days respectively after admission to the intensive care unit. Both patients presented with normocapnic hypoxaemia. One patient required mechanical ventilation with supplemental oxygen during intensive care, while the other required high-flow nasal oxygen therapy. The manifestations of platypnea-orthodeoxia syndrome were most prominent during physiotherapy, when verticalization was attempted, and hindered further mobilization out of bed, including ambulation. This report describes the clinical manifestations of platypnea-orthodeoxia syndrome and the rehabilitative strategies carried out for these 2 patients. The platypnea-orthodeoxia syndrome in these patients resolved after 65 and 22 days respectively from the day of detection. This report highlights this potentially under-recognized phenomenon, which may be unmasked during rehabilitation of patients with COVID-19 pneumonia. Good functional outcomes were achieved with a combination of verticalization training with supplemental oxygen support, respiratory techniques training and progressive endurance and resistance training, whilst awaiting resolution of the platypneaorthodeoxia syndrome.

Treatment of severe COVID-19 with convalescent plasma in Bronx, NYC.

Convalescent plasma with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) antibodies (CCP) may hold promise as a treatment for coronavirus disease 2019 (COVID-19). We compared the mortality and clinical outcome of patients with COVID-19 who received 200 mL of CCP with a spike protein IgG titer ≥ 1:2430 (median 1:47,385) within 72 hours of admission with propensity score-matched controls cared for at a medical center in the Bronx, between April 13 and May 4, 2020. Matching criteria for controls were age, sex, body mass index, race, ethnicity, comorbidities, week of admission, oxygen requirement, D-dimer, lymphocyte counts, corticosteroid use, and anticoagulation use. There was no difference in mortality or oxygenation between CCP recipients and controls at day 28. When stratified by age, compared with matched controls, CCP recipients less than 65 years had 4-fold lower risk of mortality and 4-fold lower risk of deterioration in oxygenation or mortality at day 28. For CCP recipients, pretransfusion spike protein IgG, IgM, and IgA titers were associated with mortality at day 28 in univariate analyses. No adverse effects of CCP were observed. Our results suggest CCP may be beneficial for hospitalized patients less than 65 years, but data from controlled trials are needed to validate this finding and establish the effect of aging on CCP efficacy.

Clinical course and physiotherapy intervention in 9 patients with COVID-19.

Since the outbreak of the 2019 novel coronavirus (COVID-19), the role of physiotherapy for patients with COVID-19 infection has been highlighted by various international guidelines. Despite that, clinical information regarding the rehabilitation of patients with COVID-19 infection remains limited. In this case series, we provide a novel insight into the physiotherapy management in patients infected with COVID-19 in Singapore. The main findings are: (1) Respiratory physiotherapy interventions were not indicated in the majority of the patients with COVID-19 in this case series; (2) During rehabilitation, exertional or position-related desaturation is a common feature observed in critically ill patients with COVID-19 infection locally. This clinical phenomenon of exertional or positional-related desaturation has significantly slowed down the progression of rehabilitation in our patients. As such, it can potentially result in a significant burden on healthcare resources to provide rehabilitation to these patients. Based on these findings, we have highlighted several recommendations for the provision of rehabilitation in patients who are critically ill with COVID-19.