Application of Phylodynamic Tools to Inform the Public Health Response to COVID-19: Qualitative Analysis of Expert Opinions.

BACKGROUND: In the wake of the SARS-CoV-2 pandemic, scientists have scrambled to collect and analyze SARS-CoV-2 genomic data to inform public health responses to COVID-19 in real time. Open source phylogenetic and data visualization platforms for monitoring SARS-CoV-2 genomic epidemiology have rapidly gained popularity for their ability to illuminate spatial-temporal transmission patterns worldwide. However, the utility of such tools to inform public health decision-making for COVID-19 in real time remains to be explored. OBJECTIVE: The aim of this study is to convene experts in public health, infectious diseases, virology, and bioinformatics-many of whom were actively engaged in the COVID-19 response-to discuss and report on the application of phylodynamic tools to inform pandemic responses. METHODS: In total, 4 focus groups (FGs) occurred between June 2020 and June 2021, covering both the pre- and postvariant strain emergence and vaccination eras of the ongoing COVID-19 crisis. Participants included national and international academic and government researchers, clinicians, public health practitioners, and other stakeholders recruited through purposive and convenience sampling by the study team. Open-ended questions were developed to prompt discussion. FGs I and II concentrated on phylodynamics for the public health practitioner, while FGs III and IV discussed the methodological nuances of phylodynamic inference. Two FGs per topic area to increase data saturation. An iterative, thematic qualitative framework was used for data analysis. RESULTS: We invited 41 experts to the FGs, and 23 (56%) agreed to participate. Across all the FG sessions, 15 (65%) of the participants were female, 17 (74%) were White, and 5 (22%) were Black. Participants were described as molecular epidemiologists (MEs; n=9, 39%), clinician-researchers (n=3, 13%), infectious disease experts (IDs; n=4, 17%), and public health professionals at the local (PHs; n=4, 17%), state (n=2, 9%), and federal (n=1, 4%) levels. They represented multiple countries in Europe, the United States, and the Caribbean. Nine major themes arose from the discussions: (1) translational/implementation science, (2) precision public health, (3) fundamental unknowns, (4) proper scientific communication, (5) methods of epidemiological investigation, (6) sampling bias, (7) interoperability standards, (8) academic/public health partnerships, and (9) resources. Collectively, participants felt that successful uptake of phylodynamic tools to inform the public health response relies on the strength of academic and public health partnerships. They called for interoperability standards in sequence data sharing, urged careful reporting to prevent misinterpretations, imagined that public health responses could be tailored to specific variants, and cited resource issues that would need to be addressed by policy makers in future outbreaks. CONCLUSIONS: This study is the first to detail the viewpoints of public health practitioners and molecular epidemiology experts on the use of viral genomic data to inform the response to the COVID-19 pandemic. The data gathered during this study provide important information from experts to help streamline the functionality and use of phylodynamic tools for pandemic responses.

Genomics-informed outbreak investigations of SARS-CoV-2 using civet

The scale of data produced during the SARS-CoV-2 pandemic has been unprecedented, with more than 13 million sequences shared publicly at the time of writing. This wealth of sequence data provides important context for interpreting local outbreaks. However, placing sequences of interest into national and international context is difficult given the size of the global dataset. Often outbreak investigations and genomic surveillance efforts require running similar analyses again and again on the latest dataset and producing reports. We developed civet (cluster investigation and virus epidemiology tool) to aid these routine analyses and facilitate virus outbreak investigation and surveillance. Civet can place sequences of interest in the local context of background diversity, resolving the query into different 'catchments' and presenting the phylogenetic results alongside metadata in an interactive, distributable report. Civet can be used on a fine scale for clinical outbreak investigation, for local surveillance and cluster discovery, and to routinely summarise the virus diversity circulating on a national level. Civet reports have helped researchers and public health bodies feedback genomic information in the appropriate context within a timeframe that is useful for public health.

Implementation of genomic surveillance of SARS-CoV-2 in the Caribbean: Lessons learned for sustainability in resource-limited settings

The COVID-19 pandemic highlighted the importance of global genomic surveillance to monitor the emergence and spread of SARS-CoV-2 variants and inform public health decision-making. Until December 2020 there was minimal capacity for viral genomic surveillance in most Caribbean countries. To overcome this constraint, the COVID-19: Infectious disease Molecular epidemiology for PAthogen Control & Tracking (COVID-19 IMPACT) project was implemented to establish rapid SARS-CoV-2 whole genome nanopore sequencing at The University of the West Indies (UWI) in Trinidad and Tobago (T&T) and provide needed SARS-CoV-2 sequencing services for T&T and other Caribbean Public Health Agency Member States (CMS). Using the Oxford Nanopore Technologies MinION sequencing platform and ARTIC network sequencing protocols and bioinformatics pipeline, a total of 3610 SARS-CoV-2 positive RNA samples, received from 17 CMS, were sequenced in-situ during the period December 5th 2020 to December 31st 2021. Ninety-one Pango lineages, including those of five variants of concern (VOC), were identified. Genetic analysis revealed at least 260 introductions to the CMS from other global regions. For each of the 17 CMS, the percentage of reported COVID-19 cases sequenced by the COVID-19 IMPACT laboratory ranged from 0·02% to 3·80% (median = 1·12%). Sequences submitted to GISAID by our study represented 73·3% of all SARS-CoV-2 sequences from the 17 CMS available on the database up to December 31st 2021. Increased staffing, process and infrastructural improvement over the course of the project helped reduce turnaround times for reporting to originating institutions and sequence uploads to GISAID. Insights from our genomic surveillance network in the Caribbean region directly influenced non-pharmaceutical countermeasures in the CMS countries. However, limited availability of associated surveillance and clinical data made it challenging to contextualise the observed SARS-CoV-2 diversity and evolution, highlighting the need for development of infrastructure for collecting and integrating genomic sequencing data and sample-associated metadata.

Towards a global virus genomic surveillance network

The COVID-19 pandemic galvanized the field of virus genomic surveillance, demonstrating its utility for public health. Now, we must harness the momentum that led to increased infrastructure, training, and political will to build a sustainable global genomic surveillance network for other epidemic and endemic viruses. We suggest a generalizable modular sequencing framework wherein users can easily switch between virus targets to maximize cost-effectiveness and maintain readiness for new threats. We also highlight challenges associated with genomic surveillance, and when global inequalities persist. We propose solutions to mitigate some of these issues, including training and multilateral partnerships. Exploring alternatives to clinical sequencing can also reduce the cost of surveillance programs. Finally, we discuss how establishing genomic surveillance would aid control programs and potentially provide a warning system for outbreaks, using a global respiratory virus (RSV), an arbovirus (dengue virus), and a regional zoonotic virus (Lassa virus) as examples. Following technological advancements from past emergencies, global virus genomic surveillance increased to unprecedented levels during the COVID-19 pandemic. In their Perspective, Hill et all examine this infrastructure and discuss the importance of developing sustainable global genomic surveillance networks for other epidemic and endemic viruses to inform public health decision making.

Toward a global virus genomic surveillance network.

The COVID-19 pandemic galvanized the field of virus genomic surveillance, demonstrating its utility for public health. Now, we must harness the momentum that led to increased infrastructure, training, and political will to build a sustainable global genomic surveillance network for other epidemic and endemic viruses. We suggest a generalizable modular sequencing framework wherein users can easily switch between virus targets to maximize cost-effectiveness and maintain readiness for new threats. We also highlight challenges associated with genomic surveillance and when global inequalities persist. We propose solutions to mitigate some of these issues, including training and multilateral partnerships. Exploring alternatives to clinical sequencing can also reduce the cost of surveillance programs. Finally, we discuss how establishing genomic surveillance would aid control programs and potentially provide a warning system for outbreaks, using a global respiratory virus (RSV), an arbovirus (dengue virus), and a regional zoonotic virus (Lassa virus) as examples.

Genomics-informed outbreak investigations of SARS-CoV-2 using civet.

The scale of data produced during the SARS-CoV-2 pandemic has been unprecedented, with more than 13 million sequences shared publicly at the time of writing. This wealth of sequence data provides important context for interpreting local outbreaks. However, placing sequences of interest into national and international context is difficult given the size of the global dataset. Often outbreak investigations and genomic surveillance efforts require running similar analyses again and again on the latest dataset and producing reports. We developed civet (cluster investigation and virus epidemiology tool) to aid these routine analyses and facilitate virus outbreak investigation and surveillance. Civet can place sequences of interest in the local context of background diversity, resolving the query into different 'catchments' and presenting the phylogenetic results alongside metadata in an interactive, distributable report. Civet can be used on a fine scale for clinical outbreak investigation, for local surveillance and cluster discovery, and to routinely summarise the virus diversity circulating on a national level. Civet reports have helped researchers and public health bodies feedback genomic information in the appropriate context within a timeframe that is useful for public health.

Saliva-based methods for SARS-CoV-2 testing in low- and middle-income countries.

As the coronavirus disease 2019 (COVID-19) continues to disproportionately affect low- and middle-income countries, the need for simple, accessible and frequent diagnostic testing grows. In lower-resource settings, case detection is often limited by a lack of available testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To address global inequities in testing, alternative sample types could be used to increase access to testing by reducing the associated costs. Saliva is a sensitive, minimally invasive and inexpensive diagnostic sample for SARS-CoV-2 detection that is appropriate for asymptomatic surveillance, symptomatic testing and at-home collection. Saliva testing can lessen two major challenges faced by lower- and middle-income countries: constrained resources and overburdened health workers. Saliva sampling enables convenient self-collection and requires fewer resources than swab-based methods. However, saliva testing for SARS-CoV-2 diagnostics has not been implemented on a large scale in low- and middle-income countries. While numerous studies based in these settings have demonstrated the usefulness of saliva sampling, there has been insufficient attention on optimizing its implementation in practice. We argue that implementation science research is needed to bridge this gap between evidence and practice. Low- and middle-income countries face many barriers as they continue their efforts to provide mass COVID-19 testing in the face of substantial inequities in global access to vaccines. Laboratories should look to replicate successful approaches for sensitive detection of SARS-CoV-2 in saliva, while governments should act to facilitate mass testing by lifting restrictions that limit implementation of saliva-based methods.

La maladie à coronavirus 2019 (COVID-19) continue à affecter les pays à revenu faible et intermédiaire de manière disproportionnée, accentuant le besoin en tests diagnostiques simples, accessibles et fréquents. Dans les endroits disposant de ressources limitées, la détection des cas se heurte souvent au manque de tests disponibles pour le syndrome respiratoire aigu sévère (SARS-CoV-2). Afin de lutter contre les inégalités mondiales en la matière, d'autres types d'échantillons pourraient être exploités, dans le but d'améliorer l'accès au dépistage tout en diminuant les frais qu'il engendre. Les échantillons de salive offrent une méthode de diagnostic fiable, peu invasive et peu coûteuse pour détecter le SARS-CoV-2. Cette méthode est compatible avec le suivi des personnes asymptomatiques, le dépistage des personnes symptomatiques et la collecte d'échantillons à domicile. Les tests salivaires permettent d'atténuer deux problèmes majeurs rencontrés par les pays à revenu faible et intermédiaire: une pénurie de ressources et des soignants surmenés. En outre, les patients peuvent effectuer le prélèvement eux-mêmes et cette méthode nécessite moins de moyens que celle reposant sur l'écouvillonnage. Pourtant, les tests salivaires de détection du SARS-CoV-2 n'ont pas été déployés à grande échelle dans les pays à revenu faible et intermédiaire. Malgré les nombreuses études démontrant l'utilité des tests salivaires dans ces régions, les perspectives d'optimisation de leur mise en œuvre n'ont suscité que peu d'attention. Dans le présent document, nous affirmons que des recherches scientifiques sur leur exécution sont requises pour combler ce fossé entre les faits et la pratique. Les pays à revenu faible et intermédiaire sont confrontés à une multitude d'obstacles dans leurs efforts de dépistage massif de la COVID-19. Et ce, en dépit des profondes inégalités qu'ils subissent dans le monde en matière d'accès aux vaccins. Les laboratoires devraient tenter de reproduire les approches les plus efficaces pour détecter le SARS-CoV-2 dans la salive, tandis que les gouvernements devraient prendre des mesures favorisant un dépistage de masse en levant les restrictions qui entravent le déploiement des tests salivaires.

A medida que la enfermedad por coronavirus de 2019 (COVID-19) sigue afectando de manera desproporcionada a los países de ingresos bajos y medios, crece la necesidad de realizar pruebas de diagnóstico sencillas, accesibles y frecuentes. En entornos de bajos recursos, la detección de casos suele estar limitada por la falta de pruebas disponibles para diagnosticar el coronavirus del síndrome respiratorio agudo grave de tipo 2 (SARS-CoV-2). Para abordar las desigualdades globales en las pruebas, se podrían utilizar tipos de muestra alternativos para aumentar el acceso a las pruebas reduciendo los costes asociados. La saliva es una muestra de diagnóstico sensible, poco invasiva y económica para la detección del SARS-CoV-2 que es apropiada para la vigilancia asintomática, las pruebas sintomáticas y la obtención en el hogar. Las pruebas de saliva pueden reducir dos de los principales problemas a los que se enfrentan los países de ingresos bajos y medios: la escasez de recursos y la sobrecarga de trabajo del personal sanitario. La toma de muestras de saliva permite realizar fácilmente la obtención por cuenta propia y requiere menos recursos que los métodos con hisopos. Sin embargo, las pruebas de saliva para el diagnóstico del SARS-CoV-2 no se han aplicado a gran escala en los países de ingresos bajos y medios. Aunque varios estudios realizados en estos entornos han demostrado la utilidad del muestreo de saliva, no se ha prestado suficiente atención a la optimización de su aplicación en la práctica. En este sentido, se considera que la investigación científica sobre la implementación es necesaria para subsanar esta deficiencia entre la evidencia y la práctica. Los países de ingresos bajos y medios se enfrentan a muchas dificultades en sus esfuerzos por realizar pruebas masivas en relación con la COVID-19, a pesar de las grandes desigualdades en el acceso global a las vacunas. Los laboratorios deberían intentar reproducir los enfoques que han tenido éxito para la detección sensible de la infección por el SARS-CoV-2 en la saliva, mientras que los gobiernos deberían actuar para facilitar las pruebas masivas eliminando las restricciones que limitan la aplicación de los métodos de diagnóstico salival.

Saliva-based methods for SARS-CoV-2 testing in low- and middle-income countries Méthodes de dépistage salivaire du SARS-CoV-2 dans les pays à revenu faible et intermédiaire Métodos de diagnóstico salival para determinar la infección por el SARS-CoV-2 en países de ingresos bajos y medios طرق اختبار SARS-CoV-2 المعتمدة على اللعاب في الدول ذات الدخل المنخفض والدخل المتوسط 中低收入国家基于唾液的 SARS-CoV-2 检测方法 Методы тестирования на вирус SARS-CoV-2 на основе образцов слюны в странах с низким и средним уровнем дохода

As the coronavirus disease 2019 (COVID-19) continues to disproportionately affect low- and middle-income countries, the need for simple, accessible and frequent diagnostic testing grows. In lower-resource settings, case detection is often limited by a lack of available testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To address global inequities in testing, alternative sample types could be used to increase access to testing by reducing the associated costs. Saliva is a sensitive, minimally invasive and inexpensive diagnostic sample for SARS-CoV-2 detection that is appropriate for asymptomatic surveillance, symptomatic testing and at-home collection. Saliva testing can lessen two major challenges faced by lower- and middle-income countries: constrained resources and overburdened health workers. Saliva sampling enables convenient self-collection and requires fewer resources than swab-based methods. However, saliva testing for SARS-CoV-2 diagnostics has not been implemented on a large scale in low- and middle-income countries. While numerous studies based in these settings have demonstrated the usefulness of saliva sampling, there has been insufficient attention on optimizing its implementation in practice. We argue that implementation science research is needed to bridge this gap between evidence and practice. Low- and middle-income countries face many barriers as they continue their efforts to provide mass COVID-19 testing in the face of substantial inequities in global access to vaccines. Laboratories should look to replicate successful approaches for sensitive detection of SARS-CoV-2 in saliva, while governments should act to facilitate mass testing by lifting restrictions that limit implementation of saliva-based methods.

Global disparities in SARS-CoV-2 genomic surveillance.

Genomic sequencing is essential to track the evolution and spread of SARS-CoV-2, optimize molecular tests, treatments, vaccines, and guide public health responses. To investigate the global SARS-CoV-2 genomic surveillance, we used sequences shared via GISAID to estimate the impact of sequencing intensity and turnaround times on variant detection in 189 countries. In the first two years of the pandemic, 78% of high-income countries sequenced >0.5% of their COVID-19 cases, while 42% of low- and middle-income countries reached that mark. Around 25% of the genomes from high income countries were submitted within 21 days, a pattern observed in 5% of the genomes from low- and middle-income countries. We found that sequencing around 0.5% of the cases, with a turnaround time <21 days, could provide a benchmark for SARS-CoV-2 genomic surveillance. Socioeconomic inequalities undermine the global pandemic preparedness, and efforts must be made to support low- and middle-income countries improve their local sequencing capacity.

An evaluation of telephone versus videoconference consults for pre-treatment medication history taking by cancer pharmacists.

INTRODUCTION: The primary aim was to compare the successful completion rates of pre-treatment medication history consults conducted by pharmacists with patients either via an unscheduled telephone consult (current standard care) or a scheduled videoconference consult model. Secondary aims were to examine pharmacist perceptions of the telephone and videoconference consults and explore patient (+/- support person) perceptions of videoconference consults. METHOD: Completion data were collected and compared for the two modalities. In addition, pharmacists commented on any positive/negative factors impacting all consults. For the final 35 participants completing a videoconference consult, patients, support people, and pharmacists involved, completed a survey exploring perceptions and satisfaction. RESULTS: A significantly higher completion rate (p < 0.0001) was found for the videoconferencing model, with 94% (76 of 81) completed successfully compared to 72% (76 of 105) of the unscheduled telephone consults. Pharmacists reported multiple factors impacting the success of the telephone consults including scheduling issues and patient factors. Survey responses revealed that 100% of patients/support people and 82% of pharmacists reported satisfaction with videoconference consults. Surveyed participants noted some technical issues, however, the 'ability to show/view medication containers and/or labels' and 'convenience of scheduled time' were benefits of the videoconference model. DISCUSSION: Results indicate that pre-treatment medication history consults should be offered via videoconference to maximise success.

Generation of recombinant hyperimmune globulins from diverse B-cell repertoires.

Plasma-derived polyclonal antibody therapeutics, such as intravenous immunoglobulin, have multiple drawbacks, including low potency, impurities, insufficient supply and batch-to-batch variation. Here we describe a microfluidics and molecular genomics strategy for capturing diverse mammalian antibody repertoires to create recombinant multivalent hyperimmune globulins. Our method generates of diverse mixtures of thousands of recombinant antibodies, enriched for specificity and activity against therapeutic targets. Each hyperimmune globulin product comprised thousands to tens of thousands of antibodies derived from convalescent or vaccinated human donors or from immunized mice. Using this approach, we generated hyperimmune globulins with potent neutralizing activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in under 3 months, Fc-engineered hyperimmune globulins specific for Zika virus that lacked antibody-dependent enhancement of disease, and hyperimmune globulins specific for lung pathogens present in patients with primary immune deficiency. To address the limitations of rabbit-derived anti-thymocyte globulin, we generated a recombinant human version and demonstrated its efficacy in mice against graft-versus-host disease.