A Research and Development (R&D) Roadmap for Broadly Protective Coronavirus Vaccines: A Pandemic Preparedness Strategy

Broadly protective coronavirus vaccines are an important tool for protecting against future SARS-CoV-2 variants and could play a critical role in mitigating the impact of future outbreaks or pandemics caused by novel coronaviruses. The Coronavirus Vaccines Research and Development (R&D) Roadmap (CVR) is aimed at promoting the development of such vaccines. The CVR, funded by the Bill & Melinda Gates Foundation and The Rockefeller Foundation, was generated through a collaborative and iterative process, which was led by the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota and involved 50 international subject matter experts and recognized leaders in the field. This report summarizes the major issues and areas of research outlined in the CVR and identifies high-priority milestones. The CVR covers a 6-year timeframe and is organized into five topic areas: virology, immunology, vaccinology, animal and human infection models, and policy and finance. Included in each topic area are key barriers, gaps, strategic goals, milestones, and additional R&D priorities. The roadmap includes 20 goals and 86 R&D milestones, 22 of which are ranked as high priority. By identifying key issues, and milestones for addressing them, the CVR provides a framework to guide funding and research campaigns that promote the development of broadly protective coronavirus vaccines.

A research and development (R&D) roadmap for broadly protective coronavirus vaccines: A pandemic preparedness strategy.

Broadly protective coronavirus vaccines are an important tool for protecting against future SARS-CoV-2 variants and could play a critical role in mitigating the impact of future outbreaks or pandemics caused by novel coronaviruses. The Coronavirus Vaccines Research and Development (R&D) Roadmap (CVR) is aimed at promoting the development of such vaccines. The CVR, funded by the Bill & Melinda Gates Foundation and The Rockefeller Foundation, was generated through a collaborative and iterative process, which was led by the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota and involved 50 international subject matter experts and recognized leaders in the field. This report summarizes the major issues and areas of research outlined in the CVR and identifies high-priority milestones. The CVR covers a 6-year timeframe and is organized into five topic areas: virology, immunology, vaccinology, animal and human infection models, and policy and finance. Included in each topic area are key barriers, gaps, strategic goals, milestones, and additional R&D priorities. The roadmap includes 20 goals and 86 R&D milestones, 26 of which are ranked as high priority. By identifying key issues, and milestones for addressing them, the CVR provides a framework to guide funding and research campaigns that promote the development of broadly protective coronavirus vaccines.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Dose, Infection, and Disease Outcomes for Coronavirus Disease 2019 (COVID-19): A Review.

The relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) dose, infection, and coronavirus disease 2019 (COVID-19) outcomes remains poorly understood. This review summarizes the existing literature regarding this issue, identifies gaps in current knowledge, and suggests opportunities for future research. In humans, host characteristics, including age, sex, comorbidities, smoking, and pregnancy, are associated with severe COVID-19. Similarly, in animals, host factors are strong determinants of disease severity, although most animal infection models manifest clinically with mild to moderate respiratory disease. The influence of variants of concern as it relates to infectious dose, consequence of overall pathogenicity, and disease outcome in dose-response remains unknown. Epidemiologic data suggest a dose-response relationship for infection contrasting with limited and inconsistent surrogate-based evidence between dose and disease severity. Recommendations include the design of future infection studies in animal models to investigate inoculating dose on outcomes and the use of better proxies for dose in human epidemiology studies.

Population testing for COVID-19: an approach for infection prevention

BackgroundPopulation screening with highly sensitive diagnostic tools, such as nucleic acid amplification testing (NAAT), can enable early identification and isolation of cases and reduce transmission of SARS-CoV-2.ObjectiveTo describe the results of a rigorous, large-scale COVID-19 testing and monitoring program with confirmatory processes and adjudication of positive results.DesignDescriptive Epidemiology StudySetting32 U.S. National Football League (NFL) Clubs during the 2020 seasonParticipantsNFL players and staffMethodsThe NFL/NFL Players Association instituted a COVID-19 Testing and Surveillance Program for the 2020 Season, which included daily testing for players and staff, full medical follow-up and adjudication of cases. Clinical adjudication was based on subsequent daily testing, symptoms, and clinical history;persons remained in isolation during adjudication.ResultsBetween August 1 and November 14, 2020, a total of 632,370 RT-PCR tests were administered to 11,668 individuals;270 (2.4%) confirmed cases were observed. PPVs of the initial positive result ranged from 73–82% across RT-PCR platforms. Initial positive results were positive on re-processing 61–79% of the time. PPV increased when both results were positive to >95%;however, initial positives that were negative on confirmatory processing resulted in true cases a portion of the time, depending on machine and population prevalence. High Ct values (33 to 37) could indicate onset of infection. Infected individuals were identified and isolated early in infection, preventing spread.InterventionsDaily or frequent testing using three NAAT platforms, rapid point-of-care testing, and symptom monitoring.Main Outcome MeasurementsCOVID-19 infection.ConclusionRoutine RT-PCR testing allowed early detection of infection. Cycle threshold values provided a useful guidepost for understanding results. Confirmatory processing of initial positive values significantly improved PPV. Antigen POC testing was unable to reliably rule out COVID-19 early in infection. Adjudication processes were able to confirm or rule out SARS-CoV-2.

BSAC Vanguard Series: the future of ADVOCACY on AMR.

The COVID public health emergency has brought home how vulnerable we are to forces beyond our control. We are losing our ability to treat infectious diseases for a number of reasons, including antimicrobial resistance (AMR). AMR is a 'slow-moving' threat, which makes it harder to recognize and address. The situation has not been helped by the difficulty we have had in seeing the actions and health of everyone on this planet as interconnected. The COVID pandemic has changed this. Despite the dire predictions of the effect of AMR in the future, we still have time to change course. Advocacy by scientists and health professionals is a powerful tool in this process, but there are pitfalls and it must be used wisely. In this article I suggest a number of ways in which this can be achieved.

Optimizing SARS-CoV-2 Surveillance in the United States: Insights From the National Football League Occupational Health Program.

BACKGROUND: Evidence to understand effective strategies for surveillance and early detection of SARS-CoV-2 is limited. OBJECTIVE: To describe the results of a rigorous, large-scale COVID-19 testing and monitoring program. DESIGN: The U.S. National Football League (NFL) and the NFL Players Association (NFLPA) instituted a large-scale COVID-19 monitoring program involving daily testing using 2 reverse transcription polymerase chain reaction (RT-PCR) platforms (Roche cobas and Thermo Fisher QuantStudio), a transcription-mediated amplification platform (Hologic Panther), and an antigen point-of-care (aPOC) test (Quidel Sofia). SETTING: 32 NFL clubs in 24 states during the 2020 NFL season. PARTICIPANTS: NFL players and staff. MEASUREMENTS: SARS-CoV-2 test results were described in the context of medically adjudicated status. Cycle threshold (Ct) values are reported when available. RESULTS: A total of 632 370 tests administered across 11 668 persons identified 270 (2.4%) COVID-19 cases from 1 August to 14 November 2020. Positive predictive values ranged from 73.0% to 82.0% across the RT-PCR platforms. High Ct values (33 to 37) often indicated early infection. For the first positive result, the median Ct value was 32.77 (interquartile range, 30.02 to 34.72) and 22% of Ct values were above 35. Among adjudicated COVID-19 cases tested with aPOC, 42.3% had a negative result. Positive concordance between aPOC test result and adjudicated case status increased as viral load increased. LIMITATIONS: Platforms varied by laboratory, and test variability may reflect procedural differences. CONCLUSION: Routine RT-PCR testing allowed early detection of infection. Cycle threshold values provided a useful guidepost for understanding results, with high values often indicating early infection. Antigen POC testing was unable to reliably rule out COVID-19 early in infection. PRIMARY FUNDING SOURCE: The NFL and the NFLPA.

A Research and Development (R&D) roadmap for influenza vaccines: Looking toward the future.

Improved influenza vaccines are urgently needed to reduce the burden of seasonal influenza and to ensure a rapid and effective public-health response to future influenza pandemics. The Influenza Vaccines Research and Development (R&D) Roadmap (IVR) was created, through an extensive international stakeholder engagement process, to promote influenza vaccine R&D. The roadmap covers a 10-year timeframe and is organized into six sections: virology; immunology; vaccinology for seasonal influenza vaccines; vaccinology for universal influenza vaccines; animal and human influenza virus infection models; and policy, finance, and regulation. Each section identifies barriers, gaps, strategic goals, milestones, and additional R&D priorities germane to that area. The roadmap includes 113 specific R&D milestones, 37 of which have been designated high priority by the IVR expert taskforce. This report summarizes the major issues and priority areas of research outlined in the IVR. By identifying the key issues and steps to address them, the roadmap not only encourages research aimed at new solutions, but also provides guidance on the use of innovative tools to drive breakthroughs in influenza vaccine R&D.

Observed Versus Expected COVID-19 Infections Among National Football League Players During the 2020 Season.

BACKGROUND: The National Football League (NFL) and National Football League Players Association implemented a set of strict protocols for the 2020 season with the intent to mitigate COVID-19 risk among players and staff. In that timeframe, the league's 32 teams completed 256 regular season games and several thousand meetings and practices. In parallel, community cases of COVID-19 were highly prevalent. We assess the risk of holding a 2020 NFL season by comparing community and player COVID-19 infections. METHODS: We used county-level COVID-19 test data from each team to establish baseline distributions of infection rates expected to occur in a population similar in age and sex to NFL players. We used a binomial distribution to simulate expected infections in each community cohort and compared these findings with observed COVID-19 infections in players. RESULTS: Over a 5-month period (1 August 2020 to 2 January 2021), positive NFL player infections (n = 256) were 55.7% lower than expected when compared with simulations from NFL community cohorts. For 30 of 32 teams (94%), observed counts fell at or below expectation, including 28 teams (88%) for which rates were lower. Two teams fell above baseline expectation. CONCLUSIONS: The NFL/NFLPA protocols that governed team facilities, travel, gameday, and activities outside of the workplace were associated with lower infection rates among NFL players compared with the surrounding community. The NFL's 2020-2021 season are consistent with the hypothesis that robust testing and behavioral protocols support a safe return to sport and work.

Shifting the paradigm: using disease outbreaks to build resilient health systems

[...]events push weak health systems to a breaking point, as witnessed during recent outbreaks of cholera, drug-resistant tuberculosis, Ebola virus disease and Zika virus disease.1–4 The current COVID-19 pandemic is testing the response and resilience of health systems worldwide, including well-resourced systems in Europe and North America, where health institutions and public health agencies are operating beyond capacity, diagnostics are lacking, triage systems are faltering, personal protective equipment are insufficient, and front-line health workers are facing risks of disease and death.5 Building responsive and resilient health systems is an imperative for the global health community. [...]many aspects of outbreak response lay the groundwork for health system strengthening (HSS), such as enhancing surveillance systems and training the health workforce.12 Over the last two decades, numerous mechanisms, frameworks and agreements have been developed to promote health systems that are resilient to outbreaks and major health emergencies, such as the International Health Regulations (IHR)—an agreement between 196 countries to work together to mitigate global health security threats and a cornerstone of efforts aimed at ensuring sufficient health system infrastructure to detect, assess and report major events impacting public health.13 Through the IHR, in 2016 the Joint External Evaluations were created to identify critical gaps within health systems and prioritise actions to enhance preparedness and response within a country.14 There is not yet a framework, toolkit or formalised targets for HSS activities during outbreaks. [...]during the current COVID-19 pandemic the USA approved a US$2 trillion-dollar stimulus bill, of which US$157 billion was directly allocated to the health system and research.15 While it is critical and ethically necessary to prioritise immediate response activities, the organisational infrastructure, capacity and networks which typically result from these investments could be leveraged to also strengthen health systems, in particular those components that are directly impacted during the outbreak, such as health information systems, healthcare services, medical and public health workforce, supply chain management and essential medicines and vaccines. Lessons could be learned from industries, such as military, nuclear, oil and gas and aviation that have similar high-pressure and complex environments as the biomedically oriented institutions and experience major events and disasters, and have used methodologies to effectively address acute challenges while building better, more sustainable systems and processes along the way.16 Methodologies like systems analysis and applied systems thinking could be adapted and used during an acute response to both further enhance response effectiveness and strengthen health systems.16 We have identified 10 activities that could be implemented during health emergencies to ensure that health systems are strengthened during the response.

Pandemic diseases preparedness and response in the age of COVID-19-a symposium report.

For years, experts have warned that a global pandemic was only a matter of time. Indeed, over the past two decades, several outbreaks and pandemics, from SARS to Ebola, have tested our ability to respond to a disease threat and provided the opportunity to refine our preparedness systems. However, when a novel coronavirus with human-to-human transmissibility emerged in China in 2019, many of these systems were found lacking. From international disputes over data and resources to individual disagreements over the effectiveness of facemasks, the COVID-19 pandemic has revealed several vulnerabilities. As of early November 2020, the WHO has confirmed over 46 million cases and 1.2 million deaths worldwide. While the world will likely be reeling from the effects of COVID-19 for months, and perhaps years, to come, one key question must be asked, How can we do better next time? This report summarizes views of experts from around the world on how lessons from past pandemics have shaped our current disease preparedness and response efforts, and how the COVID-19 pandemic may offer an opportunity to reinvent public health and healthcare systems to be more robust the next time a major challenge appears.

The relationship of large city out-of-hospital cardiac arrests and the prevalence of COVID-19.

BACKGROUND: Though variable, many major metropolitan cities reported profound and unprecedented increases in out-of-hospital cardiac arrest (OHCA) in early 2020. This study examined the relative magnitude of those increases and their relationship to COVID-19 prevalence. METHODS: EMS (9-1-1 system) medical directors for 50 of the largest U.S. cities agreed to provide the aggregate, de-identified, pre-existing monthly tallies of OHCA among adults (age >18 years) occurring between January and June 2020 within their respective jurisdictions. Identical comparison data were also provided for corresponding time periods in 2018 and 2019.  Equivalent data were obtained from the largest cities in Italy, United Kingdom and France, as well as Perth, Australia and Auckland, New Zealand. FINDINGS: Significant OHCA escalations generally paralleled local prevalence of COVID-19. During April, most U.S. cities (34/50) had >20% increases in OHCA versus 2018-2019 which reflected high local COVID-19 prevalence. Thirteen observed 1·5-fold increases in OHCA and three COVID-19 epicenters had >100% increases (2·5-fold in New York City). Conversely, cities with lesser COVID-19 impact observed unchanged (or even diminished) OHCA numbers. Altogether (n = 50), on average, OHCA cases/city rose 59% during April (p = 0·03). By June, however, after mitigating COVID-19 spread, cities with the highest OHCA escalations returned to (or approached) pre-COVID OHCA numbers while cities minimally affected by COVID-19 during April (and not experiencing OHCA increases), then had marked OHCA escalations when COVID-19 began to surge locally. European, Australian, and New Zealand cities mirrored the U.S. experience. INTERPRETATION: Most metropolitan cities experienced profound escalations of OHCA generally paralleling local prevalence of COVID-19.  Most of these patients were pronounced dead without COVID-19 testing. FUNDING: No funding was involved. Cities provided de-identified aggregate data collected routinely for standard quality assurance functions.

Infectious Disease Threats: A Rebound To Resilience.

The US has experienced a series of epidemics during the past five decades. None has tested the nation's resilience like the coronavirus disease 2019 (COVID-19) pandemic, which has laid bare critical weaknesses in US pandemic preparedness and domestic leadership and the nation's decline in global standing in public health. Pandemic response has been politicized, proven public health measures undermined, and public confidence in a science-based public health system reduced. This has been compounded by the large number of citizens without ready access to health care, who are overrepresented among infected, hospitalized, and fatal cases. Here, as part of the National Academy of Medicine's Vital Directions for Health and Health Care: Priorities for 2021 initiative, we review the US approach to pandemic preparedness and its impact on the response to COVID-19. We identify six steps that should be taken to strengthen US pandemic resilience, strengthen and modernize the US health care system, regain public confidence in government leadership in public health, and restore US engagement and leadership in global partnerships to address future pandemic threats domestically and around the world.

Development and deployment of COVID-19 vaccines for those most vulnerable.

Development of safe and effective COVID-19 vaccines is a global priority and the best hope for ending the COVID-19 pandemic. Remarkably, in less than 1 year, vaccines have been developed and shown to be efficacious and are already being deployed worldwide. Yet, many challenges remain. Immune senescence and comorbidities in aging populations and immune dysregulation in populations living in low-resource settings may impede vaccine effectiveness. Distribution of vaccines among these populations where vaccine access is historically low remains challenging. In this Review, we address these challenges and provide strategies for ensuring that vaccines are developed and deployed for those most vulnerable.

Critical Considerations for COVID-19 Vaccination of Refugees, Immigrants, and Migrants.

As COVID-19 vaccines are distributed across the United States, it is essential to address the pandemic's disproportionate impact on refugee, immigrant, and migrant (RIM) communities. Although the National Academies Press Framework for Equitable Allocation of COVID-19 Vaccine provides recommendations for an equitable vaccine campaign, implementation remains. Practical considerations for vaccine rollout include identifying and overcoming barriers to vaccination among RIM communities. To identify barriers, information regarding vaccine beliefs and practices must be incorporated into the pandemic response. To overcome barriers, effective communication, convenience of care, and community engagement are essential. Taking these actions now can improve health among RIM communities.

Implementation and Evolution of Mitigation Measures, Testing, and Contact Tracing in the National Football League, August 9-November 21, 2020.

The National Football League (NFL) and the NFL Players Association (NFLPA) began the 2020 football season in July, implementing extensive mitigation and surveillance measures in facilities and during travel and gameplay. Mitigation protocols* were evaluated and modified based on data from routine reverse transcription-polymerase chain reaction (RT-PCR) tests for SARS-CoV-2, the virus that causes coronavirus 2019 (COVID-19); proximity tracking devices; and detailed interviews. Midseason, transmission was observed in persons who had cumulative interactions of <15 minutes' duration, leading to a revised definition of high-risk contacts that required consideration of mask use, setting and room ventilation in addition to proximity and duration of interaction. The NFL also developed an intensive protocol that imposed stricter infection prevention precautions when a case was identified at an NFL club. The intensive protocol effectively prevented the occurrence of high-risk interactions, with no high-risk contacts identified for 71% of traced cases at clubs under the intensive protocol. The incorporation of the nature and location of the interaction, including mask use, indoor versus outdoor setting, and ventilation, in addition to proximity and duration, likely improved identification of exposed persons at higher risk for SARS-CoV-2 infection. Quarantine of these persons, along with testing and intensive protocols, can reduce spread of infection.