Importance The coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial increase in hospitalizations for pneumonia with multiorgan disease. This review discusses current evidence regarding the pathophysiology, transmission, diagnosis, and management of COVID-19. Observations SARS-CoV-2 is spread primarily via respiratory droplets during close face-to-face contact. Infection can be spread by asymptomatic, presymptomatic, and symptomatic carriers. The average time from exposure to symptom onset is 5 days, and 97.5% of people who develop symptoms do so within 11.5 days. The most common symptoms are fever, dry cough, and shortness of breath. Radiographic and laboratory abnormalities, such as lymphopenia and elevated lactate dehydrogenase, are common, but nonspecific. Diagnosis is made by detection of SARS-CoV-2 via reverse transcription polymerase chain reaction testing, although false-negative test results may occur in up to 20% to 67% of patients; however, this is dependent on the quality and timing of testing. Manifestations of COVID-19 include asymptomatic carriers and fulminant disease characterized by sepsis and acute respiratory failure. Approximately 5% of patients with COVID-19, and 20% of those hospitalized, experience severe symptoms necessitating intensive care. More than 75% of patients hospitalized with COVID-19 require supplemental oxygen. Treatment for individuals with COVID-19 includes best practices for supportive management of acute hypoxic respiratory failure. Emerging data indicate that dexamethasone therapy reduces 28-day mortality in patients requiring supplemental oxygen compared with usual care (21.6% vs 24.6%; age-adjusted rate ratio, 0.83 [95% CI, 0.74-0.92]) and that remdesivir improves time to recovery (hospital discharge or no supplemental oxygen requirement) from 15 to 11 days. In a randomized trial of 103 patients with COVID-19, convalescent plasma did not shorten time to recovery. Ongoing trials are testing antiviral therapies, immune modulators, and anticoagulants. The case-fatality rate for COVID-19 varies markedly by age, ranging from 0.3 deaths per 1000 cases among patients aged 5 to 17 years to 304.9 deaths per 1000 cases among patients aged 85 years or older in the US. Among patients hospitalized in the intensive care unit, the case fatality is up to 40%. At least 120 SARS-CoV-2 vaccines are under development. Until an effective vaccine is available, the primary methods to reduce spread are face masks, social distancing, and contact tracing. Monoclonal antibodies and hyperimmune globulin may provide additional preventive strategies. Conclusions and Relevance As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. Many aspects of transmission, infection, and treatment remain unclear. Advances in prevention and effective management of COVID-19 will require basic and clinical investigation and public health and clinical interventions.

/pdf/pathophysiology-transmission-diagnosis-and-treatment-of-2o6dok06xg.pdf

Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Alongside investigations into the virology of SARS-CoV-2, understanding the fundamental physiological and immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and rational design of effective therapies. Here, we provide an overview of the pathophysiology of SARS-CoV-2 infection. We describe the interaction of SARS-CoV-2 with the immune system and the subsequent contribution of dysfunctional immune responses to disease progression. From nascent reports describing SARS-CoV-2, we make inferences on the basis of the parallel pathophysiological and immunological features of the other human coronaviruses targeting the lower respiratory tract - severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Finally, we highlight the implications of these approaches for potential therapeutic interventions that target viral infection and/or immunoregulation.

/pdf/the-trinity-of-covid-19-immunity-inflammation-and-10rwiwjpt5.pdf

The trinity of COVID-19: immunity, inflammation and intervention.

Background Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. Methods This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. Results The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P Conclusions The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2035389

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) has resulted in an unprecedented public health crisis. There are currently no SARS-CoV-2-specific treatments or vaccines available due to the novelty of the virus. Hence, rapid development of effective vaccines against SARS-CoV-2 are urgently needed. Here we developed a pilot-scale production of a purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc), which induced SARS-CoV-2-specific neutralizing antibodies in mice, rats and non-human primates. These antibodies neutralized 10 representative SARS-CoV-2 strains, suggesting a possible broader neutralizing ability against SARS-CoV-2 strains. Three immunizations using two different doses (3 μg or 6 μg per dose) provided partial or complete protection in macaques against SARS-CoV-2 challenge, respectively, without observable antibody-dependent enhancement of infection. These data support clinical development of SARS-CoV-2 vaccines for humans.

https://science.sciencemag.org/content/sci/early/2020/05/05/science.abc1932.full.pdf

Development of an inactivated vaccine candidate for SARS-CoV-2.

COVID-19 Vaccine Hesitancy Worldwide: A Concise Systematic Review of Vaccine Acceptance Rates.

Developing Covid-19 Vaccines at Pandemic Speed An ideal vaccine platform would support development from viral sequencing to clinical trials in less than 16 weeks, demonstrate elicitation of consist...

https://www.nejm.org/doi/pdf/10.1056/NEJMp2005630?articleTools=true

Developing Covid-19 Vaccines at Pandemic Speed.

The COVID-19 pandemic is estimated to have killed six to 18 million persons.1Wang H Paulson KR Pease SA et al.Estimating excess mortality due to the COVID-19 pandemic: a systematic analysis of COVID-19-related mortality, 2020–21.Lancet. 2022; 399: 1513-1536Summary Full Text Full Text PDF PubMed Scopus (116) Google Scholar This pandemic exposed major gaps in our global health security architecture that must be addressed to keep infectious disease outbreaks from becoming pandemics, and to effectively respond when they occur.2Duff JH Liu A Saavedra J et al.A global public health convention for the 21st century.Lancet Public Health. 2021; 6: e428-e433Summary Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 3Gostin LO Moon S Meier BM Reimagining global health governance in the age of COVID-19.Am J Public Health. 2020; 110: 1615-1619Crossref PubMed Scopus (31) Google Scholar To address these gaps, WHO member states created the Intergovernmental Negotiating Body to negotiate a treaty or international health agreement on pandemic prevention, preparedness, and response. These negotiations are currently underway, and an initial working draft of a proposed legal instrument has been made public.4WHOA/INB/2/3: Working draft, presented on the basis of progress achieved, for the consideration of the Intergovernmental Negotiating Body at its second meeting. World Health Organization, Geneva2022Google ScholarA major gap in existing international health agreements is the scarcity of accountability mechanisms to independently and objectively assess and monitor compliance as well as to incentivise or sanction country non-compliance with agreed-upon regulations. For a global agreement to succeed in preventing and mitigating pandemics, standards must be set, and countries and international bodies held accountable to their commitments and obligations under those standards.Accountability mechanisms are safeguards to ensure that all parties remain answerable for their respective obligations. The selection of which accountability mechanisms will be most useful for a global health agreement will depend on the substance of what is negotiated by countries. Countries determine how seriously to take normative instruments when they choose to include accountability mechanisms. To ensure equity, countries must have access to the technical, financial, and technological resources they require to achieve compliance under the agreement.To promote compliance, a framework of accountability must include transparency, monitoring, and oversight mechanisms. While transparency requires member states to share information, independent monitoring and oversight allows for verification and to obtain a clear idea of the state of compliance with international law. For this purpose, we recommend an impartial international oversight body that is independent from WHO because an international representative body might be subject to greater political influence (eg, when donor countries fail to comply with legally binding regulations, or when the director of that body is subject to re-election by members).5Panel for a Global Public Health ConventionThe pandemic convention we need now—a call to action.https://gphcpanel.org/the-pandemic-convention-we-need-now/Date: 2022Date accessed: April 25, 2022Google ScholarIn addition to transparency, monitoring, and oversight, accountability is not achievable without robust system of incentives and disincentives. There could be non-financial incentives for compliance, including reputation, priority access to limited resources and treaty voting rights. Low-income and middle-income countries will also require financial support to develop their capacity to prevent, prepare, and respond to outbreaks and pandemics. Such funding can be used as incentives to increase compliance by tying funding for subsequent years to milestone achievements, such as it is done by the Global Fund to Fight AIDS, Tuberculosis, and Malaria.6Jain S Zorzi N Investing for impact: the global fund approach to measurement of AIDS response.AIDS Behav. 2017; 21: 91-100Crossref PubMed Scopus (6) Google ScholarDisincentives are challenging because member states will often not agree to a system that includes sanctions. However, there are existing mechanisms that can be incorporated into a system of accountability that can have a similar effect. For example, Article IV of the International Monetary Fund (IMF) requires periodic assessments of countries' internal economic stability as well as how a country's economic instability might impact the larger world economy.7Takagi S IMF Bilateral Financial Surveillance. International Monetary Fund, Washington, DC2018Google Scholar Because pandemics create substantial risks to national and international economic stability, compliance with preparedness and response requirements under international law can be included as criteria for evaluating countries under existing Article IV mechanisms. Although the resulting IMF consultation reports might not directly affect a country's economy, a country's credit ratings by private agencies is influenced by the IMF reports.8Lombardi D The development dimension of IMF lending policies.Ital J Int Aff. 2007; 42: 95-113Google ScholarIn a meta-analysis of 224 studies evaluating 53 unique legally binding international agreements,9Hoffman S, Baral P, Van Katwyk S. Do international treaties matter? A systematic field-wide evidence synthesis of effects. Proc Natl Acad Sci (in press).Google Scholar Steven Hoffman and colleagues concluded that international agreements without accountability do not achieve their goals. A legally binding international agreement on pandemic prevention and management is most likely to prevent the next pandemic if effective accountability mechanisms are instituted. We acknowledge that some countries will be unwilling to sign onto an agreement with accountability, but an agreement without it will be unlikely to make a difference to the future health of the world.10Hoffman SJ Ottersen T Addressing antibiotic resistance requires robust international accountability mechanisms.J Law Med Ethics. 2015; 43: 53-64Crossref PubMed Scopus (18) Google Scholar We hope that if a small number of countries are willing to sign an agreement with accountability, in time more and more countries will join, as has often happened in economic and trade agreements.A global system to prevent pandemics that merely relies on the good will of countries is not sufficient—as shown by the current system's inability to prevent the spread of SARS-COV-2. The accountability of countries and international bodies is essential for a global public health system to prevent outbreaks from becoming pandemics. The COVID-19 pandemic is estimated to have killed six to 18 million persons.1Wang H Paulson KR Pease SA et al.Estimating excess mortality due to the COVID-19 pandemic: a systematic analysis of COVID-19-related mortality, 2020–21.Lancet. 2022; 399: 1513-1536Summary Full Text Full Text PDF PubMed Scopus (116) Google Scholar This pandemic exposed major gaps in our global health security architecture that must be addressed to keep infectious disease outbreaks from becoming pandemics, and to effectively respond when they occur.2Duff JH Liu A Saavedra J et al.A global public health convention for the 21st century.Lancet Public Health. 2021; 6: e428-e433Summary Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 3Gostin LO Moon S Meier BM Reimagining global health governance in the age of COVID-19.Am J Public Health. 2020; 110: 1615-1619Crossref PubMed Scopus (31) Google Scholar To address these gaps, WHO member states created the Intergovernmental Negotiating Body to negotiate a treaty or international health agreement on pandemic prevention, preparedness, and response. These negotiations are currently underway, and an initial working draft of a proposed legal instrument has been made public.4WHOA/INB/2/3: Working draft, presented on the basis of progress achieved, for the consideration of the Intergovernmental Negotiating Body at its second meeting. World Health Organization, Geneva2022Google Scholar A major gap in existing international health agreements is the scarcity of accountability mechanisms to independently and objectively assess and monitor compliance as well as to incentivise or sanction country non-compliance with agreed-upon regulations. For a global agreement to succeed in preventing and mitigating pandemics, standards must be set, and countries and international bodies held accountable to their commitments and obligations under those standards. Accountability mechanisms are safeguards to ensure that all parties remain answerable for their respective obligations. The selection of which accountability mechanisms will be most useful for a global health agreement will depend on the substance of what is negotiated by countries. Countries determine how seriously to take normative instruments when they choose to include accountability mechanisms. To ensure equity, countries must have access to the technical, financial, and technological resources they require to achieve compliance under the agreement. To promote compliance, a framework of accountability must include transparency, monitoring, and oversight mechanisms. While transparency requires member states to share information, independent monitoring and oversight allows for verification and to obtain a clear idea of the state of compliance with international law. For this purpose, we recommend an impartial international oversight body that is independent from WHO because an international representative body might be subject to greater political influence (eg, when donor countries fail to comply with legally binding regulations, or when the director of that body is subject to re-election by members).5Panel for a Global Public Health ConventionThe pandemic convention we need now—a call to action.https://gphcpanel.org/the-pandemic-convention-we-need-now/Date: 2022Date accessed: April 25, 2022Google Scholar In addition to transparency, monitoring, and oversight, accountability is not achievable without robust system of incentives and disincentives. There could be non-financial incentives for compliance, including reputation, priority access to limited resources and treaty voting rights. Low-income and middle-income countries will also require financial support to develop their capacity to prevent, prepare, and respond to outbreaks and pandemics. Such funding can be used as incentives to increase compliance by tying funding for subsequent years to milestone achievements, such as it is done by the Global Fund to Fight AIDS, Tuberculosis, and Malaria.6Jain S Zorzi N Investing for impact: the global fund approach to measurement of AIDS response.AIDS Behav. 2017; 21: 91-100Crossref PubMed Scopus (6) Google Scholar Disincentives are challenging because member states will often not agree to a system that includes sanctions. However, there are existing mechanisms that can be incorporated into a system of accountability that can have a similar effect. For example, Article IV of the International Monetary Fund (IMF) requires periodic assessments of countries' internal economic stability as well as how a country's economic instability might impact the larger world economy.7Takagi S IMF Bilateral Financial Surveillance. International Monetary Fund, Washington, DC2018Google Scholar Because pandemics create substantial risks to national and international economic stability, compliance with preparedness and response requirements under international law can be included as criteria for evaluating countries under existing Article IV mechanisms. Although the resulting IMF consultation reports might not directly affect a country's economy, a country's credit ratings by private agencies is influenced by the IMF reports.8Lombardi D The development dimension of IMF lending policies.Ital J Int Aff. 2007; 42: 95-113Google Scholar In a meta-analysis of 224 studies evaluating 53 unique legally binding international agreements,9Hoffman S, Baral P, Van Katwyk S. Do international treaties matter? A systematic field-wide evidence synthesis of effects. Proc Natl Acad Sci (in press).Google Scholar Steven Hoffman and colleagues concluded that international agreements without accountability do not achieve their goals. A legally binding international agreement on pandemic prevention and management is most likely to prevent the next pandemic if effective accountability mechanisms are instituted. We acknowledge that some countries will be unwilling to sign onto an agreement with accountability, but an agreement without it will be unlikely to make a difference to the future health of the world.10Hoffman SJ Ottersen T Addressing antibiotic resistance requires robust international accountability mechanisms.J Law Med Ethics. 2015; 43: 53-64Crossref PubMed Scopus (18) Google Scholar We hope that if a small number of countries are willing to sign an agreement with accountability, in time more and more countries will join, as has often happened in economic and trade agreements. A global system to prevent pandemics that merely relies on the good will of countries is not sufficient—as shown by the current system's inability to prevent the spread of SARS-COV-2. The accountability of countries and international bodies is essential for a global public health system to prevent outbreaks from becoming pandemics. We declare no competing interests. ÁG is former Secretary-General of the Organisation of Economic Cooperation and Development (OECD), JDM is former President of the Republic of Ghana, LCM is former President of Costa Rica, JH is former President of the World Health Assembly, and BMS is former Chair of the Ebola Interim Assessment Panel. 

Jane Halton

Papers

Developing Covid-19 Vaccines at Pandemic Speed.

An effective pandemic treaty requires accountability

Governance of health emergencies