The predictive role of symptoms in COVID-19 diagnostic models : A longitudinal insight

Acknowledgements 2019nCoV-302 Study Group Members: The NVX-CoV2373-2019nCoV-302 clinical trial was a collective group effort across multiple institutions and locations. Below is a list of sites and staff that significantly contributed to the implementation and conduct of the NVX-CoV2373-2019nCoV-302 clinical trial.Peer reviewe

Safety and efficacy of the NVX-CoV2373 coronavirus disease 2019 vaccine at completion of the placebo-controlled phase of a randomized controlled trial

Background: The recombinant protein-based vaccine, NVX-CoV2373, demonstrated 89.7% efficacy against coronavirus disease 2019 (COVID-19) in a phase 3, randomized, observer-blinded, placebo-controlled trial in the United Kingdom. The protocol was amended to include a blinded crossover. Data to the end of the placebo-controlled phase are reported. Methods: Adults aged 18–84 years received 2 doses of NVX-CoV2373 or placebo (1:1) and were monitored for virologically confirmed mild, moderate, or severe COVID-19 (onset from 7 days after second vaccination). Participants who developed immunoglobulin G (IgG) against nucleocapsid protein but did not show symptomatic COVID-19 were considered asymptomatic. Secondary outcomes included anti-spike (S) IgG responses, wild-type virus neutralization, and T-cell responses. Results: Of 15 185 participants, 13 989 remained in the per-protocol efficacy population (6989 NVX-CoV2373, 7000 placebo). At a maximum of 7.5 months (median, 4.5) postvaccination, there were 24 cases of COVID-19 among NVX-CoV2373 recipients and 134 cases among placebo recipients, a vaccine efficacy of 82.7% (95% confidence interval [CI], 73.3%–88.8%). Vaccine efficacy was 100% (95% CI, 17.9%–100.0%) against severe disease and 76.3% (95% CI, 57.4%–86.8%) against asymptomatic disease. High anti-S and neutralization responses to vaccination were evident, together with S-protein–specific induction of interferon-γ secretion in peripheral blood T cells. Incidence of serious adverse events and adverse events of special interest were similar between groups. Conclusions: A 2-dose regimen of NVX-CoV2373 conferred a high level of ongoing protection against asymptomatic, symptomatic, and severe COVID-19 through >6 months postvaccination. A gradual decrease of protection suggests that a booster may be indicated. Clinical Trials Registration: EudraCT, 2020-004123-16

Safety and Efficacy of the NVX-CoV2373 Coronavirus Disease 2019 Vaccine at Completion of the Placebo-Controlled Phase of a Randomized Controlled Trial

Acknowledgements The study and article were funded by Novavax. We would like to thank all the study participants for their commitment to this study. We also acknowledge the investigators and their study teams for their hard work and dedication. In addition, we would like to thank the National Institute for Health Research, representatives from the Department of Health and Social Care laboratories and NHS Digital and the members of the UK Vaccine Task Force. Editorial support was provided by Kelly Cameron of Ashfield MedComms, an Inizio company Funding This work was funded by Novavax, and the sponsor had primary responsibility for study design, study vaccines, protocol development, study monitoring, data management, and statistical analyses. All authors reviewed and approved the manuscript before submission. LF reports a position as a prior full-time employee, now contractor to Novavax re-imbursed hourly for work performed on this study and in analyses and drafting this report. IC reports providing medical writing support for this work as an employee of NovavaxPeer reviewedPublisher PD

Safety and efficacy of the NVX-CoV2373 coronavirus disease 2019 vaccine at completion of the placebo-controlled phase of a randomized controlled trial

Background: The recombinant protein-based vaccine, NVX-CoV2373, demonstrated 89.7% efficacy against coronavirus disease 2019 (COVID-19) in a phase 3, randomized, observer-blinded, placebo-controlled trial in the United Kingdom. The protocol was amended to include a blinded crossover. Data to the end of the placebo-controlled phase are reported. Methods: Adults aged 18–84 years received 2 doses of NVX-CoV2373 or placebo (1:1) and were monitored for virologically confirmed mild, moderate, or severe COVID-19 (onset from 7 days after second vaccination). Participants who developed immunoglobulin G (IgG) against nucleocapsid protein but did not show symptomatic COVID-19 were considered asymptomatic. Secondary outcomes included anti-spike (S) IgG responses, wild-type virus neutralization, and T-cell responses. Results: Of 15 185 participants, 13 989 remained in the per-protocol efficacy population (6989 NVX-CoV2373, 7000 placebo). At a maximum of 7.5 months (median, 4.5) postvaccination, there were 24 cases of COVID-19 among NVX-CoV2373 recipients and 134 cases among placebo recipients, a vaccine efficacy of 82.7% (95% confidence interval [CI], 73.3%–88.8%). Vaccine efficacy was 100% (95% CI, 17.9%–100.0%) against severe disease and 76.3% (95% CI, 57.4%–86.8%) against asymptomatic disease. High anti-S and neutralization responses to vaccination were evident, together with S-protein–specific induction of interferon-γ secretion in peripheral blood T cells. Incidence of serious adverse events and adverse events of special interest were similar between groups. Conclusions: A 2-dose regimen of NVX-CoV2373 conferred a high level of ongoing protection against asymptomatic, symptomatic, and severe COVID-19 through >6 months postvaccination. A gradual decrease of protection suggests that a booster may be indicated

Safety, immunogenicity, and efficacy of a COVID-19 vaccine (NVX-CoV2373) co-administered with seasonal influenza vaccines: an exploratory substudy of a randomised, observer-blinded, placebo-controlled, phase 3 trial

Background: Safety and immunogenicity of COVID-19 vaccines when co-administered with influenza vaccines have not yet been reported. Methods: A sub-study on influenza vaccine co-administration was conducted as part of the phase 3 randomised trial of NVX-CoV2373’s safety and efficacy; ~400 participants meeting main study entry criteria, with no contraindications to influenza vaccination, were enroled. After randomisation to receive NVX-CoV2373 or placebo, sub-study participants received an open-label influenza vaccine at the same time as the first dose of NVX-CoV2373. Reactogenicity was evaluated for 7 days post-vaccination plus monitoring for unsolicited adverse events (AEs), medically-attended AEs (MAAEs), and serious AEs (SAEs). Vaccine efficacy against COVID-19 was assessed. Findings: Sub-study participants were younger (median age 39; 6.7 % ≥65 years), more racially diverse, and had fewer comorbid conditions than main study participants. Reactogenicity events more common in co-administration group included tenderness (70.1% vs 57.6%) or pain (39.7% vs 29.3%) at injection site, fatigue (27.7% vs 19.4%), and muscle pain (28.3% vs 21.4%). Rates of unsolicited AEs, MAAEs, and SAEs were low and balanced between the two groups. Co-administration resulted in no change to influenza vaccine immune response, while a reduction in antibody responses to the NVX-CoV2373 vaccine was noted. Vaccine efficacy against COVID-19 was 87.5% (95% CI: -0.2, 98.4) in those 18-<65 years in the sub-study while efficacy in the main study was 89.8% (95% CI: 79.7, 95.5).  Interpretation: This is the first study to demonstrate safety, immunogenicity, and efficacy of a COVID-19 vaccine when co-administered with influenza vaccines

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Selectively Assertive: Interventions of India’s Supreme Court to Enforce Environmental Laws

We examine why India’s Supreme Court has selectively intervened to enforce environmental laws. While the Indian Judiciary has substantial political insulation, judges recognize the need for tactical balancing to preserve the legitimacy of their institution. We examine four cases: judicial interventions to check water pollution from tanneries and to phase out diesel engines, and judicial non-intervention to prevent degradation of wetlands and to check crop burning in states adjacent to Delhi. We suggest that judges intervened to correct enforcement failure when they do not anticipate pushback from organized constituencies. Where judicial action imposes costs on a large number of actors and motivates protests from organized groups, the justices have tended to overlook enforcement failures. In sum, in spite of political insulation, judges remain attentive to the popular mood and interest-group politics

Should India’s Supreme Court Enforce Regulations?

Should the Indian judiciary involve itself in the business of overseeing regulatory enforcement? Might such sustained interventions eventually degrade the political insulation of the judiciary that allows it to interpret the law as an expert, legitimate, and neutral actor? The rise of populism across the world poses serious challenges to democracy, pluralism, and free trade. It also challenges the willingness and the ability of regulators to enforce the law. Such lack of enforcement has led institutions such as the Supreme Court of India to intervene, often in response to public interest litigation in which citizens approach the court directly for relief. Politicians often enact regulations in response to policy crises, but they sometimes have fewer incentives to enforce them when counter pressure builds against such measures. As political scientists Theodore Lowi and James Q. Wilson have pointed out, regulations can face counter pressures if they impose concentrated and visible costs on specific constituencies to create less visible, long-term benefits for a large number of people. For example, opposition to environmental regulations—and more recently to climate policies—falls in this category because restrictions on carbon emissions can slow development but will help protect the future of the planet. At the local level, land use and zoning regulations often encounter populist backlash against those who seek to enforce these regulations. Anticipating the tension between populism and sound regulatory policy, many countries create specialized, politically insulated regulatory and administrative agencies. In the judicial sphere, several countries provide important safeguards for their judiciaries, giving them the autonomy needed to interpret the law without pandering to public opinion. In the Indian context, safeguards have included security of tenure and emoluments, a judicial appointment process that limits executive interference, and difficulties in sanctioning judges. The good news is that judicial insulation often works well, and judiciaries have often been seen as a critical bulwark against the erosion of rule of law. Recent judgments by the Supreme Court of India—involving mining activity in Goa and the sealing of illegal structures in Delhi—underline the crucial role the courts play in enforcing important but unpopular laws opposed by organized and visible constituencies, including political parties. The mining industry plays an important part in the economy of Goa, a state located on the western shore of India. Although mining provides employment and contributes to the state’s budget, mining has long had significantly deleterious environmental impacts on Goan ecology and traditional livelihoods. For example, in 2013, an expert appraisal committee appointed by the Ministry of Environment, Forests and Climate Change submitted a report that assessed 137 mining leases and found that the majority of the mines had flouted the terms of their environmental permits. After a series of legal challenges in lower courts, in 2014 the Supreme Court lifted a mining ban with the caveat that illegal mining could not be condoned. Errant miners would need to apply for fresh leases and environmental permits from the state government. However, a separate set of directions from the Bombay High Court empowered the state government to renew some 88 of the contested licenses, which it issued without fresh environmental permits and without being subject to an auction process. When these decisions were challenged before the Supreme Court in February 2018, the Court canceled the renewal of mining licenses and banned mining activity. The Court ordered a bidding process for fresh licenses and made several assertions of its power to review executive decisions to serve the public purpose. In response, all Goan political parties have come out against the mining ban, pointing to its adverse economic impact. Indeed, this has become a raging political issue in the state of Goa. As of now, the Supreme Court has shown its willingness to withstand the political pressure by taking a decision of this magnitude. The Goan mine owners affected by the decision, however, have indicated that they will file a review petition before the Court. In another instance, the Supreme Court intervened to remove unauthorized construction in the capital city of Delhi. Unauthorized constructions are a visible sign of India’s “messy and hidden” urbanization and have been blamed for tragic accidents such as fires in the Upahaar cinema, the Bawana industrial area, and in Kamala Mills. On numerous occasions, courts have criticized civic authorities for being either unwilling or unable to check violations and punish those flouting municipal safety norms. However, directions from a Supreme Court appointed committee compelled local authorities in Delhi to shut down several commercial establishments that have flouted building codes and environmental regulations. In response to this sealing drive to shut down the irregular constructions, the Delhi government proposed changes to the Delhi Master Plan 2021 which would have led to a retrospective legalization of these buildings. The Supreme Court ordered a stay on these amendments and castigated the Delhi Government for attempting to strong-arm the Court. The sealing drive has stirred up huge amounts of controversy: All of Delhi’s political parties have been making every effort to nullify these orders. The traders, the constituency most directly affected by the sealing of unauthorized construction, have vocally opposed the sealing drive, organizing strikes to protest. Associations of home owners have supported the sealing drive and the Supreme Court’s actions, but they do not have the political clout of the traders and the politicians. Still, the Supreme Court is not bending to the sustained campaign against its enforcement actions. The Indian judiciary’s enforcement of mining and construction regulations demonstrate its willingness to wade into contentious regulatory enforcement issues, an approach that has some similarity to the U.S. federal judiciary’s active role in enforcing school desegregation. Yet these examples of enforcement raise troubling questions about the extent to which the judiciary should step outside of its traditional role of interpreting the law and intervene in regulatory processes traditionally within the remit of the executive and the legislature. Should such interventions by the Supreme Court be celebrated as reflecting a robust judiciary committed to the rule of law? Or might these interventions undermine the citizenry’s deference to the judiciary because the judges are involved in street-level political battles? Governmental regulators are supposed to enforce the law; judges do not have the skills to do so. Sustained involvement by judges in regulatory enforcement can potentially undermine their legitimacy. Yet, one might also argue that it is the courts’ responsibility to act when state authorities either refrain from enforcing the law or condone its flagrant violations. Thus, it is not clear where should the line be drawn. And who should draw it? Will it be preemptive self-regulation by the judiciary or would a political backlash force the judiciary to retreat? Ultimately, the three branches of government must perform their assigned roles. This division of powers poses a short-term problem when the executive branch fails to perform its role in enforcement. Judicial substitution for executive inaction does not, however, bode well for the long-term legitimacy of the judicial branch

Should India’s Supreme Court Enforce Regulations?

Should the Indian judiciary involve itself in the business of overseeing regulatory enforcement? Might such sustained interventions eventually degrade the political insulation of the judiciary that allows it to interpret the law as an expert, legitimate, and neutral actor? The rise of populism across the world poses serious challenges to democracy, pluralism, and free trade. It also challenges the willingness and the ability of regulators to enforce the law. Such lack of enforcement has led institutions such as the Supreme Court of India to intervene, often in response to public interest litigation in which citizens approach the court directly for relief. Politicians often enact regulations in response to policy crises, but they sometimes have fewer incentives to enforce them when counter pressure builds against such measures. As political scientists Theodore Lowi and James Q. Wilson have pointed out, regulations can face counter pressures if they impose concentrated and visible costs on specific constituencies to create less visible, long-term benefits for a large number of people. For example, opposition to environmental regulations—and more recently to climate policies—falls in this category because restrictions on carbon emissions can slow development but will help protect the future of the planet. At the local level, land use and zoning regulations often encounter populist backlash against those who seek to enforce these regulations. Anticipating the tension between populism and sound regulatory policy, many countries create specialized, politically insulated regulatory and administrative agencies. In the judicial sphere, several countries provide important safeguards for their judiciaries, giving them the autonomy needed to interpret the law without pandering to public opinion. In the Indian context, safeguards have included security of tenure and emoluments, a judicial appointment process that limits executive interference, and difficulties in sanctioning judges. The good news is that judicial insulation often works well, and judiciaries have often been seen as a critical bulwark against the erosion of rule of law. Recent judgments by the Supreme Court of India—involving mining activity in Goa and the sealing of illegal structures in Delhi—underline the crucial role the courts play in enforcing important but unpopular laws opposed by organized and visible constituencies, including political parties. The mining industry plays an important part in the economy of Goa, a state located on the western shore of India. Although mining provides employment and contributes to the state’s budget, mining has long had significantly deleterious environmental impacts on Goan ecology and traditional livelihoods. For example, in 2013, an expert appraisal committee appointed by the Ministry of Environment, Forests and Climate Change submitted a report that assessed 137 mining leases and found that the majority of the mines had flouted the terms of their environmental permits. After a series of legal challenges in lower courts, in 2014 the Supreme Court lifted a mining ban with the caveat that illegal mining could not be condoned. Errant miners would need to apply for fresh leases and environmental permits from the state government. However, a separate set of directions from the Bombay High Court empowered the state government to renew some 88 of the contested licenses, which it issued without fresh environmental permits and without being subject to an auction process. When these decisions were challenged before the Supreme Court in February 2018, the Court canceled the renewal of mining licenses and banned mining activity. The Court ordered a bidding process for fresh licenses and made several assertions of its power to review executive decisions to serve the public purpose. In response, all Goan political parties have come out against the mining ban, pointing to its adverse economic impact. Indeed, this has become a raging political issue in the state of Goa. As of now, the Supreme Court has shown its willingness to withstand the political pressure by taking a decision of this magnitude. The Goan mine owners affected by the decision, however, have indicated that they will file a review petition before the Court. In another instance, the Supreme Court intervened to remove unauthorized construction in the capital city of Delhi. Unauthorized constructions are a visible sign of India’s “messy and hidden” urbanization and have been blamed for tragic accidents such as fires in the Upahaar cinema, the Bawana industrial area, and in Kamala Mills. On numerous occasions, courts have criticized civic authorities for being either unwilling or unable to check violations and punish those flouting municipal safety norms. However, directions from a Supreme Court appointed committee compelled local authorities in Delhi to shut down several commercial establishments that have flouted building codes and environmental regulations. In response to this sealing drive to shut down the irregular constructions, the Delhi government proposed changes to the Delhi Master Plan 2021 which would have led to a retrospective legalization of these buildings. The Supreme Court ordered a stay on these amendments and castigated the Delhi Government for attempting to strong-arm the Court. The sealing drive has stirred up huge amounts of controversy: All of Delhi’s political parties have been making every effort to nullify these orders. The traders, the constituency most directly affected by the sealing of unauthorized construction, have vocally opposed the sealing drive, organizing strikes to protest. Associations of home owners have supported the sealing drive and the Supreme Court’s actions, but they do not have the political clout of the traders and the politicians. Still, the Supreme Court is not bending to the sustained campaign against its enforcement actions. The Indian judiciary’s enforcement of mining and construction regulations demonstrate its willingness to wade into contentious regulatory enforcement issues, an approach that has some similarity to the U.S. federal judiciary’s active role in enforcing school desegregation. Yet these examples of enforcement raise troubling questions about the extent to which the judiciary should step outside of its traditional role of interpreting the law and intervene in regulatory processes traditionally within the remit of the executive and the legislature. Should such interventions by the Supreme Court be celebrated as reflecting a robust judiciary committed to the rule of law? Or might these interventions undermine the citizenry’s deference to the judiciary because the judges are involved in street-level political battles? Governmental regulators are supposed to enforce the law; judges do not have the skills to do so. Sustained involvement by judges in regulatory enforcement can potentially undermine their legitimacy. Yet, one might also argue that it is the courts’ responsibility to act when state authorities either refrain from enforcing the law or condone its flagrant violations. Thus, it is not clear where should the line be drawn. And who should draw it? Will it be preemptive self-regulation by the judiciary or would a political backlash force the judiciary to retreat? Ultimately, the three branches of government must perform their assigned roles. This division of powers poses a short-term problem when the executive branch fails to perform its role in enforcement. Judicial substitution for executive inaction does not, however, bode well for the long-term legitimacy of the judicial branch