Student reflections on an interdisciplinary pandemics course utilising systems thinking.

ISSUE ADDRESSED: The complexity and uncertainty of the COVID-19 pandemic highlights the need to change training of public health professionals in higher education by shifting from siloed specialisations to interdisciplinary collaboration. At the end of 2020 and 2021, public health professionals collaboratively designed and delivered, a week-long intensive course-Public Health in Pandemics. The aim of this research study was to understand whether the use of systems thinking in the design and delivery of the course enabled students to grasp the interdisciplinary nature of contemporary health promotion and public health practice. RESEARCH METHODS: Two focus group interviews (n = 5 and 3/47) and a course opinion survey (n = 11/47) were utilised to gather information from students regarding experiences and perceptions of course design and delivery, and to determine if students felt better able to understand the complex nature of pandemics and pandemic responses. MAJOR FINDINGS: Students provided positive feedback on the course and believed that the course design and delivery assisted in understanding the complex nature of health problems and the ways in which health promotion and public health practitioners need to work across sectors with diverse disciplines for pandemic responses. CONCLUSIONS: The use of an integrated interdisciplinary approach to course design and delivery enabled students used systems thinking to understand the complexity in preparing for and responding to a pandemic. This approach may have utility in preparing an agile, iterative and adaptive health promotion and public health workforce more capable of facing the challenges and complexity in public health.

Attributes of national governance for an effective response to public health emergencies: Lessons from the response to the COVID-19 pandemic.

Background: The Coronavirus Disease 2019 (COVID-19) pandemic takes variable shapes and forms in different regions and countries. This variability is explained by several factors, including the governance of the epidemic. We aimed to identify the key attributes of governance in response to the COVID-19 pandemic and gain lessons for an effective response to public health emergencies. Methods: We employed a mixed-methods design. We mapped the attributes of governance from well-established governance frameworks. A negative binomial regression was conducted to identify the effect of the established governance measures on the epidemiology of the COVID-19 pandemic. We used publicly available data on COVID-19 cases and deaths in countries around the world. Document review was conducted to identify the key approaches and attributes of governance during the pre-vaccine era of the response to the COVID-19 pandemic. We conducted a thematic analysis to identify key attributes for effective governance. Results: The established governance measures, including generation of intelligence, strategic direction, regulation, partnership, accountability, transparency, rule of law, control of corruption, responsiveness, effectiveness, efficiency, equity, ethics, and inclusiveness, are necessary but not sufficient to effectively respond to and contain the COVID-19 pandemic. Additional attributes of national governance were identified: 1) agile, adaptive, and transformative governance; 2) collective (collaborative, inclusive, cooperative, accountable, and transparent) governance; 3) multi-level governance; 4) smart and ethical governance: sensible, pragmatic, evidence-based, political, learner, and ethical. Conclusions: The current governance frameworks and their attributes are not adequate to contain the COVID-19 pandemic. We argue that countries need agile, adaptable, and transformational, collaborative, multi-level, smart and ethical governance to effectively respond to emerging and re-emerging public health threats. In addition, an effective response to public health emergencies depends not only on national governance but also on global governance. Hence, global health governance should be urgently renewed through a paradigm shift towards universal health coverage and health security to all populations and in all countries. This requires enhanced and consistent global health diplomacy based on knowledge, solidarity, and negotiation.

Analysis of the COVID-19 pandemic: lessons towards a more effective response to public health emergencies.

BACKGROUND: The pandemic of Coronavirus Disease 2019 (COVID-19) is a timely reminder of the nature and impact of Public Health Emergencies of International Concern. As of 12 January 2022, there were over 314 million cases and over 5.5 million deaths notified since the start of the pandemic. The COVID-19 pandemic takes variable shapes and forms, in terms of cases and deaths, in different regions and countries of the world. The objective of this study is to analyse the variable expression of COVID-19 pandemic so that lessons can be learned towards an effective public health emergency response. METHODS: We conducted a mixed-methods study to understand the heterogeneity of cases and deaths due to the COVID-19 pandemic. Correlation analysis and scatter plot were employed for the quantitative data. We used Spearman's correlation analysis to determine relationship strength between cases and deaths and socio-economic and health systems. We organized qualitative information from the literature and conducted a thematic analysis to recognize patterns of cases and deaths and explain the findings from the quantitative data. RESULTS: We have found that regions and countries with high human development index have higher cases and deaths per million population due to COVID-19. This is due to international connectedness and mobility of their population related to trade and tourism, and their vulnerability related to older populations and higher rates of non-communicable diseases. We have also identified that the burden of the pandemic is also variable among high- and middle-income countries due to differences in the governance of the pandemic, fragmentation of health systems, and socio-economic inequities. CONCLUSION: The COVID-19 pandemic demonstrates that every country remains vulnerable to public health emergencies. The aspiration towards a healthier and safer society requires that countries develop and implement a coherent and context-specific national strategy, improve governance of public health emergencies, build the capacity of their (public) health systems, minimize fragmentation, and tackle upstream structural issues, including socio-economic inequities. This is possible through a primary health care approach, which ensures provision of universal and equitable promotive, preventive and curative services, through whole-of-government and whole-of-society approaches.

Mapping a Pandemic: SARS-CoV-2 Seropositivity in the United States (preprint)

Asymptomatic SARS-CoV-2 infection and delayed implementation of diagnostics have led to poorly defined viral prevalence rates. To address this, we analyzed seropositivity in US adults who have not previously been diagnosed with COVID-19. Individuals with characteristics that reflect the US population (n = 11,382) and who had not previously been diagnosed with COVID-19 were selected by quota sampling from 241,424 volunteers (ClinicalTrials.gov NCT04334954). Enrolled participants provided medical, geographic, demographic, and socioeconomic information and 9,028 blood samples. The majority (88.7%) of samples were collected between May 10th and July 31st, 2020. Samples were analyzed via ELISA for anti-Spike and anti-RBD antibodies. Estimation of seroprevalence was performed by using a weighted analysis to reflect the US population. We detected an undiagnosed seropositivity rate of 4.6% (95% CI: 2.6 - 6.5%). There was distinct regional variability, with heightened seropositivity in locations of early outbreaks. Subgroup analysis demonstrated that the highest estimated undiagnosed seropositivity within groups was detected in younger participants (ages 18-45, 5.9%), females (5.5%), Black/African American (14.2%), Hispanic (6.1%), and Urban residents (5.3%), and lower undiagnosed seropositivity in those with chronic diseases. During the first wave of infection over the spring/summer of 2020 an estimate of 4.6% of adults had a prior undiagnosed SARS-CoV-2 infection. These data indicate that there were 4.8 (95% CI: 2.8-6.8) undiagnosed cases for every diagnosed case of COVID-19 during this same time period in the United States, and an estimated 16.8 million undiagnosed cases by mid-July 2020.

Recombinant production of a functional SARS-CoV-2 spike receptor binding domain in the green algae Chlamydomonas reinhardtii (preprint)

Recombinant production of viral proteins can be used to produce vaccine antigens or reagents to identify antibodies in patient serum. Minimally, these proteins must be correctly folded and have appropriate post-translation modifications. Here we report the production of the SARS-CoV-2 spike protein Receptor Binding Domain (RBD) in the green algae Chlamydomonas. RBD fused to a fluorescent reporter protein accumulates as an intact protein when targeted for ER-Golgi retention or secreted from the cell, while a chloroplast localized version is truncated, lacking the amino terminus. The ER-retained RBD fusion protein was able to bind the human ACE2 receptor, the host target of SARS-CoV-2, and was specifically out-competed by mammalian cell-produced recombinant RBD, suggesting that the algae produced proteins are sufficiently post-translationally modified to act as authentic SARS-CoV-2 antigens. Because algae can be grown at large scale very inexpensively, this recombinant protein may be a low cost alternative to other expression platforms.

SARS-CoV-2 binding and neutralizing antibody levels after vaccination with Ad26.COV2.S predict durable protection in rhesus macaques (preprint)

The first COVID-19 vaccines have recently gained authorization for emergency use.1,2 At this moment, limited knowledge on duration of immunity and efficacy of these vaccines is available. Data on other coronaviruses after natural infection suggest that immunity to SARS-CoV-2 might be short lived,3,4 and preliminary evidence indicates waning antibody titers following SARS-CoV-2 infection.5 Here we model the relationship between immunogenicity and protective efficacy of a series of Ad26 vectors encoding stabilized variants of the SARS-CoV-2 Spike (S) protein in rhesus macaques6,7,8 and validate the analyses by challenging macaques 6 months after immunization with the Ad26.COV2.S vaccine candidate that has been selected for clinical development. We find that Ad26.COV2.S confers durable protection against replication of SARS-CoV-2 in the lungs that is predicted by the levels of S-binding and neutralizing antibodies. These results suggest that Ad26.COV2.S could confer durable protection in humans and that immunological correlates of protection may enable the prediction of durability of protection.

A single dose of replication-competent VSV-vectored vaccine expressing SARS-CoV-2 S1 protects against virus replication in a hamster model of severe COVID-19 (preprint)

The development of effective countermeasures against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the agent responsible for the COVID-19 pandemic, is a priority. We designed and produced ConVac, a replication-competent vesicular stomatitis virus (VSV) vaccine vector that expresses the S1 subunit of SARS-CoV-2 spike protein. We used golden Syrian hamsters as animal model of severe COVID-19 to test the efficacy of the ConVac vaccine. A single vaccine dose elicited high levels of SARS-CoV-2 specific binding and neutralizing antibodies; following intranasal challenge with SARS-CoV-2, animals were protected from weight loss and viral replication in the lungs. No enhanced pathology was observed in vaccinated animals upon challenge, but some inflammation was still detected. The data indicate rapid control of SARS-CoV-2 replication by the S1-based VSV-vectored SARS-CoV-2 ConVac vaccine.

Global health security and universal health coverage: Understanding convergences and divergences for a synergistic response.

BACKGROUND: Global health security (GHS) and universal health coverage (UHC) are key global health agendas which aspire for a healthier and safer world. However, there are tensions between GHS and UHC strategy and implementation. The objective of this study was to assess the relationship between GHS and UHC using two recent quantitative indices. METHODS: We conducted a macro-analysis to determine the presence of relationship between GHS index (GHSI) and UHC index (UHCI). We calculated Pearson's correlation coefficient and the coefficient of determination. Analyses were performed using IBM SPSS Statistics Version 25 with a 95% level of confidence. FINDINGS: There is a moderate and significant relationship between GHSI and UHCI (r = 0.662, p<0.001) and individual indices of UHCI (maternal and child health and infectious diseases: r = 0.623 (p<0.001) and 0.594 (p<0.001), respectively). However, there is no relationship between GHSI and the non-communicable diseases (NCDs) index (r = 0.063, p>0.05). The risk of GHS threats a significant and negative correlation with the capacity for GHS (r = -0.604, p<0.001) and the capacity for UHC (r = -0.792, p<0.001). CONCLUSION: The aspiration for GHS will not be realized without UHC; hence, the tension between these two global health agendas should be transformed into a synergistic solution. We argue that strengthening the health systems, in tandem with the principles of primary health care, and implementing a "One Health" approach will progressively enable countries to achieve both UHC and GHS towards a healthier and safer world that everyone aspires to live in.

The N-terminal domain of spike glycoprotein mediates SARS-CoV-2 infection by associating with L-SIGN and DC-SIGN (preprint)

The widespread occurrence of SARS-CoV-2 has had a profound effect on society and a vaccine is currently being developed. Angiotensin-converting enzyme 2 (ACE2) is the primary host cell receptor that interacts with the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Although pneumonia is the main symptom in severe cases of SARS-CoV-2 infection, the expression levels of ACE2 in the lung is low, suggesting the presence of another receptor for the spike protein. In order to identify the additional receptors for the spike protein, we screened a receptor for the SARS-CoV-2 spike protein from the lung cDNA library. We cloned L-SIGN as a specific receptor for the N-terminal domain (NTD) of the SARS-CoV-2 spike protein. The RBD of the spike protein did not bind to L-SIGN. In addition, not only L-SIGN but also DC-SIGN, a closely related C-type lectin receptor to L-SIGN, bound to the NTD of the SARS-CoV-2 spike protein. Importantly, cells expressing L-SIGN and DC-SIGN were both infected by SARS-CoV-2. Furthermore, L-SIGN and DC-SIGN induced membrane fusion by associating with the SARS-CoV-2 spike protein. Serum antibodies from infected patients and a patient-derived monoclonal antibody against NTD inhibited SARS-CoV-2 infection of L-SIGN or DC-SIGN expressing cells. Our results highlight the important role of NTD in SARS-CoV-2 dissemination through L-SIGN and DC-SIGN and the significance of having anti-NTD neutralizing antibodies in antibody-based therapeutics.

A Workflow of Integrated Resources to Catalyze Network Pharmacology Driven COVID-19 Research (preprint)

Motivation: In the event of an outbreak due to an emerging pathogen, time is of the essence to contain or to mitigate the spread of the disease. Drug repositioning is one of the strategies that has the potential to deliver therapeutics relatively quickly. The SARS-CoV-2 pandemic has shown that integrating critical data resources to drive drug-repositioning studies, involving host-host, host-pathogen and drug-target interactions, remains a time-consuming effort that translates to a delay in the development and delivery of a life-saving therapy. Results: Here, we describe a workflow we designed for a semi-automated integration of rapidly emerging datasets that can be generally adopted in a broad network pharmacology research setting. The workflow was used to construct a COVID-19 focused multimodal network that integrates 487 host-pathogen, 74,805 host-host protein and 1,265 drug-target interactions. The resultant Neo4j graph database named "Neo4COVID19" is accessible via a web interface and via API calls based on the Bolt protocol. We believe that our Neo4COVID19 database will be a valuable asset to the research community and will catalyze the discovery of therapeutics to fight COVID-19. Availability: https://neo4covid19.ncats.io . Keywords: SARS-CoV-2, COVID-19, network pharmacology, graph database, Neo4j, data integration, drug repositioning