COVID-19 Vaccine

COVID-19 Vaccine

COVID-19 Vaccine Research & Development, Drug Trials & Clinical Studies Wiki Courtesy WikiPedia. Sponsored by covid19southafrica.co.za

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COVID-19 Vaccine Wiki

COVID-19 vaccine is a hypothetical vaccine against coronavirus disease 2019 (COVID-19). Although no vaccine has completed clinical trials, there are multiple attempts in progress to develop such a vaccine. In late February 2020, the World Health Organization (WHO) said it did not expect a vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus, to become available in less than 18 months.[1] The Coalition for Epidemic Preparedness Innovations (CEPI) – which is organizing a US$2 billion worldwide fund for rapid investment and development of vaccine candidates[2] – indicated in April that a vaccine may be available under emergency use protocols by early 2021.[3]

By April 2020, 115 COVID-19 vaccine candidates were in development,[3][4] with two organizations having initiated Phase I-II safety and efficacy studies in human subjects.[5][6] Five vaccine candidates were in Phase I safety studies in April.[3]

COVID-19 Vaccine 2020 projects

COVID-19 was identified in December 2019.[7] A major outbreak spread around the world in 2020, leading to considerable investment and research activity to develop a vaccine.[7][8] Many organizations are using published genomes to develop possible vaccines against SARS-CoV-2.[7][9][10][11] In the United States, the Food and Drug Administration announced its intent “to use all of the regulatory flexibility granted to it by Congress to ensure the most efficient and timely development of vaccines to fight COVID-19.”[12]

Some 79 companies and academic institutions are involved in vaccine development,[4][3] with three of them receiving support from CEPI, including projects by the biotechnology companies Moderna,[13] and Inovio Pharmaceuticals, and the University of Queensland.[14] Five hundred clinical studies worldwide, across all stages of development on vaccine and therapeutic candidates for COVID-19, are registered with the World Health Organization Clinical Trial Registry, as of March 2020.[15]

In early March 2020, CEPI announced a US$2 billion funding goal in a global partnership between public, private, philanthropic, and civil society organisations to accelerate development of COVID-19 vaccines, with commitments to date by the governments of Denmark, Finland, Germany, Norway, and the UK.[2] Stated in April, imperatives of the CEPI initiative for vaccine development are speed, manufacturing capacity, deployment at scale, and global access.[3]

Technology platforms

In April, CEPI scientists reported that 10 different technology platforms were under research and development during early 2020 to create an effective vaccine against COVID-19.[3] Major platform targets advanced into Phase I safety studies include:

  • nucleic acid (DNA and RNA) (Phase I developer and vaccine candidate: Moderna, mRNA-1273)
  • viral vector (Phase I developer and vaccine candidate: CanSino Biologics, adenovirus type 5 vector)
  • virus-like particle involved in DNA replication (Phase I developer and vaccine candidate: Shenzhen Geno-Immune Medical Institute, LV-SMENP)

According to CEPI, the platforms based on DNA or messenger RNA offer considerable promise to alter COVID-19 antigen functions for strong immune responses, and can be rapidly assessed, refined for long-term stability, and prepared for large-scale production capacity.[3] Other platforms being developed in 2020 focus on peptides, recombinant proteins, live attenuated viruses, and inactivated viruses.[3]

In general, the vaccine technologies being developed for COVID-19 are not like vaccines already in use to prevent influenza, but rather are using “next-generation” strategies for precision on the COVID-19 infection mechanisms, while hastening development for eventually preventing infection with a new vaccine.[3] Vaccine platforms in development are also designed to address mechanisms for infection susceptibility to COVID-19 in specific population subgroups, such as the elderly, children, pregnant women, or people with existing weakened immune systems.[3]

CEPI classifies development stages for vaccines as either “exploratory” (planning and designing a candidate, with no evaluation in vivo yet), “preclinical” (in vivo evaluation with preparation for manufacturing a compound to test in humans), or initiation of Phase I safety studies in healthy people.[3]

Vaccine candidates

As reported by CEPI scientists in April, 115 total vaccine candidates are in early stages of development, with 78 confirmed as active projects (79, according to the Milken Institute[4]), and 37 others announced, but with little public information available (presumed to be in planning or being designed).[3] Of the 79 confirmed active projects,[4] 74 are either in “exploratory” or “preclinical” development, according to the early-April CEPI report.[3]

In April after the CEPI report was published, Phase I-II randomized, interventional trials for dosing and assessment for side effects began in Wuhan, China on the candidate vaccine, Ad5-nCoV (CanSino Biologics, table),[5] and in England on the candidate, ChAdOx1 nCoV-19.[6] Only five other trials on vaccine candidates are in Phase I human testing, as of mid-April.[3]

Phase I trials test primarily for safety and preliminary dosing in a few dozen healthy subjects, while Phase II trials – following success in Phase I – evaluate immunogenicity, dose levels (efficacy based on biomarkers) and adverse effects of the candidate vaccine, typically in hundreds of people.[16][17] A Phase I-II trial conducts preliminary safety and immunogenicity testing, is typically randomized, placebo-controlled, and at multiple sites, while determining more precise, effective doses.[17] Phase III trials typically involve more participants, including a control group, and test effectiveness of the vaccine to prevent the disease, while monitoring for adverse effects at the optimal dose.[16][17]

Clinical trials

COVID-19 Wiki: candidate vaccines in Phase I-II trials

Vaccine candidate (developer/sponsor)TechnologyPhase of trial (participants)LocationDuration
Ad5-nCoV (CanSino Biologics, Institute of Biotechnology of the Academy of Military Medical Sciences)recombinant adenovirus type 5 vectorPhase II interventional trial for dosing and side effects (500)Wuhan, ChinaMarch 2020 to December 2020
Ad5-nCoV (CanSino Biologics, Institute of Biotechnology of the Academy of Military Medical Sciences)recombinant adenovirus type 5 vectorPhase I (108)Wuhan, ChinaMarch 2020 to December 2020
ChAdOx1 nCoV-19 (University of Oxford)adenovirus vectorPhase I-II, randomized, placebo-controlled, multiple sites (510)England, United KingdomApril 2020 to May 2021
mRNA-1273 (Moderna, US National Institute of Allergy and Infectious Diseases)lipid nanoparticle dispersion containing messenger RNAPhase I (45)United StatesMarch 2020 to Spring-Summer 2021
Covid-19/aAPC (Shenzhen Geno-Immune Medical Institute)lentiviral vector, pathogen-specific artificial antigen presenting dendritic cellsPhase I (100)Shenzhen, ChinaMarch 2020 to 2023
LV-SMENP-DC (Shenzhen Geno-Immune Medical Institute)lentiviral minigene vaccine, dendritic cells modified with lentiviral vectorPhase I (100)Shenzhen, ChinaMarch 2020 to 2023
INO-4800 (Inovio Pharmaceuticals, CEPI)DNA plasmid delivered by electroporationPhase I (40)United StatesApril 2020 to November 2020

Preclinical research

Of 79 vaccine candidates in active development (confirmed as of early April 2020), 74 were not yet in human evaluation (still in “preclinical” research).[3][4]

  • Around 24 January 2020 in Australia, the University of Queensland announced that it is investigating the potential of a molecular clamp vaccine that would genetically modify viral proteins in order to stimulate an immune reaction.[14]
  • Around 24 January 2020 in Canada, the International Vaccine Centre (VIDO-InterVac) at the University of Saskatchewan announced the commencement of work on a vaccine, aiming to start human testing in 2021.[26]
  • Vaccine development projects were announced at the Chinese Center for Disease Control and Prevention on 26 January 2020,[27] and the University of Hong Kong on 28 January.[28]
  • Around 29 January 2020, Janssen Pharmaceutical Companies, led by Hanneke Schuitemaker, announced that it had begun work on developing a vaccine.[29] Janssen is co-developing an oral vaccine with its biotechnology partner, Vaxart.[30] On 18 March 2020, Emergent BioSolutions announced a manufacturing partnership with Vaxart to develop the vaccine.[31]
  • On 8 February 2020, the laboratory OncoGen in Romania published a paper on the design of a vaccine with similar technology to the one used for cancer neoantigen vaccination therapy.[32] On 25 March the head of the research institute announced that they had finalized the synthesis of the vaccine and were beginning the tests.[33]
  • On 27 February 2020, a Generex subsidiary company, NuGenerex Immuno-Oncology, announced they were beginning a vaccine project to create an Ii-Key peptide vaccine against COVID-19. They wanted to produce a vaccine candidate that could be tested in humans “within 90 days.”[34]
  • On 5 March 2020, Washington University in St. Louis announced its projects to develop a vaccine.[35]
  • On 5 March 2020, the United States Army Medical Research and Materiel Command at Fort Detrick and the Walter Reed Army Institute of Research in Silver Spring, both in western Maryland, announced they were working on a vaccine.[36]
  • Around 10 March 2020, Emergent Biosolutions announced that it had teamed with Novavax Inc. in the development and manufacture of a vaccine. The partners further announced plans for preclinical testing and a Phase I clinical trial by July 2020.[37]
  • On 12 March 2020, India’s Health Ministry announced they are working with 11 isolates, and that even on a fast track it would take at least around one-and-a-half to two years to develop a vaccine.[38]
  • On 12 March 2020, Medicago, a biotechnology company in Quebec City, Quebec, reported development of a coronavirus-like particle under partial funding from the Canadian Institutes for Health Research.[39][40][41] The vaccine candidate is in laboratory research, with human testing planned for July or August 2020.[40][41]
  • On 16 March 2020, the European Commission offered an 80 million investment in CureVac, a German biotechnology company, to develop a mRNA vaccine.[42] Earlier that week, The Guardian reported that the US President Donald Trump had offered CureVac “‘large sums of money’ for exclusive access to a Covid-19 vaccine”, against which the German government protested.[43]
  • On 17 March 2020, American pharmaceutical company Pfizer announced a partnership with German company BioNTech to jointly develop a mRNA-based vaccine.[44] mRNA-based vaccine candidate BNT162, currently in pre-clinical testing with clinical trials expected to begin in April 2020.[45]
  • In Italy on 17 March 2020, Takis Biotech, an Italian biotech company announced they will have pre-clinical testing results in April 2020 and their final vaccine candidate could begin human testing by fall.[46]
  • In France on 19 March 2020, the Coalition for Epidemic Preparedness Innovations (CEPI) announced a US$4.9 million investment in a COVID-19 vaccine research consortium involving the Institut Pasteur, Themis Bioscience (Vienna, Austria), and the University of Pittsburgh, bringing CEPI’s total investment in COVID-19 vaccine development to US$29 million.[47] CEPI’s other investment partners for COVID-19 vaccine development are Moderna, Curevac, Inovio, Novavax, the University of Hong Kong, the University of Oxford, and the University of Queensland.[47]
  • On 20 March 2020, Russian health officials announced that scientists have begun animal testing of six different vaccine candidates.[48]
  • Imperial College London researchers announced on 20 March 2020 that they are developing a self-amplifying RNA vaccine for COVID-19. The vaccine candidate was developed within 14 days of receiving the sequence from China.[49]
  • In late March, the Canadian government announced C$275 million in funding for 96 research projects on medical countermeasures against COVID-19, including numerous vaccine candidates at Canadian companies and universities, such as the Medicago and University of Saskatchewan initiatives.[39][40][26][41] Around the same time, the Canadian government announced C$192 million specifically for developing a COVID-19 vaccine, with plans to establish a national “vaccine bank” of several new vaccines that could be used if another coronavirus outbreak occurs.[40]
  • On 2 April 2020, researchers at the University of Pittsburgh School of Medicine reported on testing of PittCoVacc, a possible COVID-19 vaccine in mice, stating that “MNA delivered SARS-CoV-2 S1 subunit vaccines elicited potent antigen-specific antibody responses [in the mice] that were evident beginning 2 weeks after immunization.”[50][51]
  • In Canada on 16 April 2020, the University of Waterloo School of Pharmacy announced design of a DNA-based vaccine candidate as a possible nasal spray. Using bacteriophages, the DNA will be designed to replicate inside human bacteria to produce harmless virus-like particles, which may stimulate the immune system to produce antibodies against the SARS-CoV-2 virus.[52]

Supercomputer-assisted research

In March 2020, the US government, industry, and three universities pooled resources to access supercomputers from IBM, combined with cloud computing resources from Hewlett Packard Enterprise, Amazon, Microsoft, and Google.[53][54] The COVID-19 High Performance Computing Consortium is being used to forecast disease spread, model possible vaccines, and screen thousands of chemical compounds to design a COVID-19 vaccine or therapy.[53][54]

An additional consortium of Microsoft, six universities (including the Massachusetts Institute of Technology, a member of the first consortium), and the National Center for Supercomputer Applications in Illinois, working under the auspices of C3.ai, a company founded by billionaire software developer Thomas Siebel, are currently pooling their supercomputer resources for the same uses described above, along with developing medical protocols and strengthening public health strategies around the world, as well as awarding large grants to researchers who propose to use AI to carry out similar tasks by May. The consortium is called the C3.ai Digital Transformation Institute.[55][56]

Non-specific vaccine

Some vaccines have heterologous effects, also called non-specific effects. That means they can have benefits beyond the disease they prevent.[57] The anti-tuberculosis vaccine, BCG vaccine, is an example that is being tested to determine if it has a protective effect against COVID-19, pursuant to assertions that COVID-19 mortality was lower in countries having routine BCG vaccine administration.[58]

In March 2020, a randomized trial of BCG vaccine to reduce COVID-19 illness began in the Netherlands, seeking to recruit 1,000 healthcare workers.[59] A further randomized trial in Australia is seeking to enrol 4,170 healthcare workers.[60][61] Another 700 healthcare workers from Boston and Houston will be recruited in another trial,[62] and a further 900 healthcare workers in Egypt in a trial registered by a university in Cairo.[63]

Potential limitations

It is possible vaccines in development will not be safe or effective.[64] One study found that between 2006 and 2015, the success rate of obtaining approval from Phase I to successful Phase III trials was 16.2% for vaccines,[65] and CEPI indicates a potential success rate of only 10% for vaccine candidates in 2020 development.[3]

The rapid development and urgency of producing a vaccine for the COVID-19 pandemic may increase the risks and failure rate of delivering a safe, effective vaccine.[3] Early research to assess vaccine efficacy using COVID-19-specific animal models, such as ACE2transgenic mice, other laboratory animals, and non-human primates, indicate a need for biosafety-level 3 containment measures for handling live viruses, and international coordination to ensure standardized safety procedures.[3] An April 2020 CEPI report stated: “strong international coordination and cooperation between vaccine developers, regulators, policymakers, funders, public health bodies and governments will be needed to ensure that promising late-stage vaccine candidates can be manufactured in sufficient quantities and equitably supplied to all affected areas, particularly low-resource regions.”[3]

While the flu vaccine is typically mass-produced by injecting the virus into the eggs of chickens, this method will not work for the COVID-19 vaccine, as the SARS-CoV-2 virus cannot replicate inside eggs.[66]

Controversy of “challenge” studies

During the global emergency of the COVID-19 pandemic, strategies are under consideration to fast-track the timeline for licensing a vaccine against COVID-19, especially by compressing (to a few months) the usually lengthy duration of Phase II-III trials (typically, many years).[67][68][69] Following preliminary proof of safety and efficacy of a candidate vaccine in laboratory animals and healthy humans, controlled “challenge” studies may be implemented to bypass typical Phase III research, providing an accelerated path to license a vaccine for widespread prevention against COVID-19.[67][70] Challenge studies have been implemented previously for diseases less deadly than COVID-19 infection, such as common influenza, typhoid fever, cholera, and malaria.[68]

The design of a challenge study involves first, simultaneously testing a vaccine candidate for immunogenicity and safety in laboratory animals and healthy adult volunteers (100 or fewer) – which is usually a sequential process using animals first – and second, rapidly advancing its effective dose into a large-scale Phase II-III trial in previously-uninfected, low-risk volunteers (such as young adults), who would then be deliberately infected with COVID-19 for comparison with a placebo control group.[67][68][70] Following the challenge, the volunteers would be monitored closely in clinics with life-saving resources, if needed.[67][68] Volunteering for a vaccine challenge study during the COVID-19 pandemic is likened to the emergency service of healthcare personnel for COVID-19-infected people, firefighters, or organ donors.[67]

Although challenge studies are ethically questionable due to the unknown hazards for the volunteers of possible COVID-19 disease enhancement and whether the vaccine received has long-term safety (among other cautions), challenge studies may be the only option available as the COVID-19 pandemic worsens, according to some infectious disease experts,[67][68][70] to rapidly produce an effective vaccine that will minimize the projected millions of deaths worldwide from COVID-19 infection.[67][71]

COVID-19 Wiki vaccine drug development

COVID-19 drug development is the research process to develop a preventative vaccine or therapeutic prescription drug that would alleviate the severity of 2019-20 coronavirus disease (COVID-19). Internationally as of mid-April 2020, some 225 drug companies, biotechnology firms, university research groups, and health organizations were developing 115 vaccine candidates[1] and 145 potential therapies for COVID-19 disease in various stages of preclinical or clinical research.[2]

The World Health Organization (WHO),[3] European Medicines Agency (EMA),[4] US Food and Drug Administration (FDA),[5] and the Chinese government and drug manufacturers[6][7] were coordinating with academic and industry researchers to speed development of vaccines, antiviral drugs, and post-infection therapies.[8][9][10][11] The International Clinical Trials Registry Platform of the WHO recorded 536 clinical studies to develop post-infection therapies for COVID-19 infections,[12][13] with numerous established antiviral compounds for treating other infections under clinical research to be repurposed.[8][14][15][16][17] In March, the WHO initiated the “SOLIDARITY Trial” in 10 countries, enrolling thousands of people infected with COVID-19 to assess treatment effects of four existing antiviral compounds with the most promise of efficacy.[3][18] A dynamic, systematic review was established in April 2020 to track the progress of registered clinical trials for COVID-19 vaccine and therapeutic drug candidates.[13]

Vaccine and drug development is a multistep process, typically requiring more than five years to assure safety and efficacy of the new compound.[19] In February 2020, the WHO said it did not expect a vaccine against SARS-CoV-2 – the causative virus for COVID-19 – to become available in less than 18 months,[20] and conservative estimates of time needed to prove a safe, effective vaccine is one year (early 2021).[1][21] Several national regulatory agencies, such as EMA and FDA, approved procedures to expedite clinical testing.[5][22]

By April, four potential post-infection therapies – favipiravir, remdesivir, lopinavir and hydroxychloroquine (or chloroquine) – were in the final stage of human testing[2][3][16][23]Phase III-IV clinical trials – and five vaccine candidates had entered the first stage of human safety evaluation, Phase I.[1]

Drug development is the process of bringing a new infectious disease vaccine or therapeutic drug to the market once a lead compound has been identified through the process of drug discovery.[19] It includes laboratory research on microorganisms and animals, filing for regulatory status, such as via the FDA, for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug.[24][25] The entire process – from concept through preclinical testing in the laboratory to clinical trial development, including Phase I-III trials – to approved vaccine or drug typically takes more than a decade.[19][24][25]

New chemical entities

Development of a COVID-19 vaccine or therapeutic antiviral drug begins with matching a chemical concept to the potential prophylactic mechanism of the future vaccine or antiviral activity in vivo.[24][25][26]

covid-19 vaccine

Timeline showing the various drug approval tracks and research phases[19][24][27]

Drug design and laboratory testing

New chemical entities (NCEs, also known as new molecular entities or NMEs) are compounds that emerge from the process of drug discovery to specify a vaccine or antiviral candidate. These have promising activity against a biological target related to COVID-19 disease. At the beginning of vaccine or drug development, little is known about the safety, toxicity, pharmacokinetics, and metabolism of the NCE in humans.[19][24][25] It is the function and obligation of drug development to assess all of these parameters prior to human clinical trials to prove safety and efficacy. A further major objective of drug development is to recommend the dose and schedule for the first use in a human clinical trial (“first-in-human” [FIH] or First Human Dose [FHD], previously also known as “first-in-man” [FIM]).

In addition, drug development must establish the physicochemical properties of the NCE: its chemical makeup, stability, and solubility. Manufacturers must optimize the process they use to make the chemical so they can scale up from a medicinal chemist producing milligrams, to manufacturing on the kilogram and ton scale.[24][25] They further examine the product for suitability to package as capsules, tablets, aerosol, intramuscular injectable, subcutaneous injectable, or intravenous formulations. Together, these processes are known in preclinical and clinical development as chemistry, manufacturing, and control (CMC).[24]

Many aspects of drug development focus on satisfying the regulatory requirements of drug licensing authorities.[19] These generally constitute tests designed to determine the major toxicities of a novel compound prior to first use in humans.[19][24] It is a regulatory requirement that an assessment of major organ toxicity be performed (effects on the heart and lungs, brain, kidney, liver and digestive system), as well as effects on other parts of the body that might be affected by the drug (e.g., the skin if the new vaccine is to be delivered by skin injection). Increasingly, these tests are made using in vitro methods (e.g., with isolated cells), but many tests can only be made by using experimental animals to demonstrate the complex interplay of metabolism and drug exposure on toxicity.[24]

The information is gathered from this preclinical testing, as well as information on CMC, and submitted to regulatory authorities (in the US, to the FDA), as an Investigational New Drug (IND) or Biologics License Application application for a vaccine.[19][24][25][26] If the IND is approved, development moves to the clinical phase,[19] and the progress of performance in humans – if a vaccine under development in the United States – is monitored by the FDA in a “vaccine approval process.”[28]

Efforts to streamline drug discovery

Over 2018–20, new initiatives to stimulate vaccine and antiviral drug development included partnerships between governmental organizations and industry, such as the European Innovative Medicines Initiative,[29] the US Critical Path Initiative to enhance innovation of drug development,[30] and the Breakthrough Therapy designation to expedite development and regulatory review of promising candidate drugs.[31] To accelerate refinement of diagnostics for detecting COVID-19 infection, a global diagnostic pipeline tracker was formed.[32]

During March 2020, the Coalition for Epidemic Preparedness Innovations (CEPI) initiated an international COVID-19 vaccine development fund, with the goal to raise US$2 billion for vaccine research and development,[33] and committed to investments of US$100 million in vaccine development across several countries.[34] The Canadian government announced CA$275 million in funding for 96 research projects on medical countermeasures against COVID-19, including numerous vaccine candidates at Canadian universities,[35][36] with plans to establish a “vaccine bank” of new vaccines for implementation if another coronavirus outbreak occurs.[36][37]

Clinical trial phases

Clinical trial programs involve three, multiple-year stages toward product approval, and a fourth, post-approval stage for ongoing safety monitoring of the vaccine or drug therapy:[19][38]

  • Phase I trials, usually in healthy volunteers, determine safety and dosing.
  • Phase II trials are used to establish an initial reading of efficacy and further explore safety in small numbers of people having the disease targeted by the NCE.
  • Phase III trials are large, pivotal trials to determine safety and efficacy in sufficiently large numbers of people with the COVID-19 infection. If safety and efficacy are adequately proved, clinical testing may stop at this step and the NCE advances to the new drug application (NDA) stage to begin marketing.[19]
  • Phase IV trials are post-approval trials that may be a condition attached by the FDA, also called post-market surveillance studies. Until a vaccine is provided to the general population, all potential adverse events remain unidentified, requiring that vaccines undergo Phase IV studies with regular reports by the manufacturer to the Vaccine Adverse Event Reporting System (VAERS) to identify problems after use in the population begins.[28]

The process of defining characteristics of the drug does not stop once an NCE is advanced into human clinical trials. In addition to the tests required to move a novel vaccine or antiviral drug into the clinic for the first time, manufacturers must ensure that any long-term or chronic toxicities are well-defined, including effects on systems not previously monitored (fertility, reproduction, immune system, among others).[24][28] If a vaccine candidate or antiviral compound emerges from these tests with an acceptable toxicity and safety profile, and the manufacturer can further show it has the desired effect in clinical trials, then the NCE portfolio of evidence can be submitted for marketing approval in the various countries where the manufacturer plans to sell it.[19] In the United States, this process is called a “new drug application” or NDA.[19][24]

Adaptive designs for COVID-19 vaccine trials

A clinical trial design in progress may be modified as an “adaptive design” if accumulating data in the trial provide early insights about positive or negative efficacy of the treatment.[39][40] The global Solidarity and European Discovery trials of hospitalized people with severe COVID-19 infection apply adaptive design to rapidly alter trial parameters as results from the four experimental therapeutic strategies emerge.[12][41][42] Adaptive designs within ongoing Phase II-III clinical trials on candidate therapeutics may shorten trial durations and use fewer subjects, possibly expediting decisions for early termination or success, and coordinating design changes for a specific trial across its international locations.[40][43][44]

Failure rate

Most novel drug candidates (NCEs) fail during drug development, either because they have unacceptable toxicity or because they simply do not prove efficacy on the targeted disease, as shown in Phase II-III clinical trials.[19][24] Critical reviews of drug development programs indicate that Phase II-III clinical trials fail due mainly to unknown toxic side effects (50% failure of Phase II cardiology trials), and because of inadequate financing, trial design weaknesses, or poor trial execution.[43][45]

A study covering clinical research in the 1980-90s found that only 21.5% of drug candidates that started Phase I trials were eventually approved for marketing.[46] During 2006–15, the success rate of obtaining approval from Phase I to successful Phase III trials was under 10% on average, and 16.2% specifically for vaccines.[47] The high failure rates associated with pharmaceutical development are referred to as an “attrition rate”, requiring decisions during the early stages of drug development to “kill” projects early to avoid costly failures.[47][48]

Cost

Main article: Cost of drug development

One 2010 study assessed both capitalized and out-of-pocket costs for bringing a single new drug to market as about US$1.8 billion and $870 million, respectively.[49] A median cost estimate of 2015-16 trials for development of 10 anti-cancer drugs was $648 million.[50] In 2017, the median cost of a pivotal trial across all clinical indications was $19 million.[51]

The average cost (2013 dollars) of each stage of clinical research was US$25 million for a Phase I safety study, $59 million for a Phase II randomized controlled efficacy study, and $255 million for a pivotal Phase III trial to demonstrate its equivalence or superiority to an existing approved drug,[52] possibly as high as $345 million.[51] The average cost of conducting a 2015-16 pivotal Phase III trial on an infectious disease drug candidate was $22 million.[51]

The full cost of bringing a new drug (i.e., new chemical entity) to market – from discovery through clinical trials to approval – is complex and controversial.[24][25][51][53] In a 2016 review of 106 drug candidates assessed through clinical trials, the total capital expenditure for a manufacturer having a drug approved through successful Phase III trials was $2.6 billion (in 2013 dollars), an amount increasing at an annual rate of 8.5%.[52] Over 2003-13 for companies that approved 8-13 drugs, the cost per drug could rise to as high as $5.5 billion, due mainly to international geographic expansion for marketing and ongoing costs for Phase IV trials for continuous safety surveillance.[54]

Alternatives to conventional drug development have the objective for universities, governments, and the pharmaceutical industry to collaborate and optimize resources.[55]

COVID-19 Wiki Vaccine clinical trials overview: timelines in 2020

According to two organizations tracking clinical trial progress on potential therapeutic drugs for COVID-19 infections, 29 Phase II-IV efficacy trials were concluded in March or scheduled to provide results in April from hospitals in China – which experienced the first outbreak of COVID-19 in late 2019.[2][23] Seven trials were evaluating repurposed drugs already approved to treat malaria, including four studies on hydroxychloroquine or chloroquine phosphate.[23] Repurposed antiviral drugs make up most of the Chinese research, with 9 Phase III trials on remdesivir across several countries due to report by the end of April.[2][23] Other potential therapeutic candidates under pivotal clinical trials concluding in March-April are vasodilators, corticosteroids, immune therapies, lipoic acid, bevacizumab, and recombinant angiotensin-converting enzyme 2, among others.[23]

The COVID-19 Clinical Research Coalition has goals to 1) facilitate rapid reviews of clinical trial proposals by ethics committees and national regulatory agencies, 2) fast-track approvals for the candidate therapeutic compounds, 3) ensure standardised and rapid analysis of emerging efficacy and safety data, and 4) facilitate sharing of clinical trial outcomes before publication.[12] A dynamic review of clinical development for COVID-19 vaccine and drug candidates was in place, as of April.[13]

By March 2020, the international Coalition for Epidemic Preparedness Innovations (CEPI) committed to research investments of US$100 million across several countries,[34] and issued an urgent call to raise and rapidly invest $2 billion for vaccine development.[56] Led by the Bill and Melinda Gates Foundation with partners investing US$125 million and coordinating with the World Health Organization, the COVID-19 Therapeutics Accelerator began in March, facilitating drug development researchers to rapidly identify, assess, develop, and scale up potential treatments.[57] The COVID-19 Clinical Research Coalition formed to coordinate and expedite results from international clinical trials on the most promising post-infection treatments.[12] In early 2020, numerous established antiviral compounds for treating other infections were being repurposed or developed in new clinical research efforts to alleviate the illness of COVID-19.[2][8][14][15][23]

COVID-19 Wiki Vaccine Therapeutic candidates

Phase III-IV trials

Pivotal Phase III trials assess whether a candidate drug has efficacy specifically against a disease, and – in the case of people hospitalized with severe COVID-19 infections – test for an effective dose level of the repurposed or new drug candidate to improve the illness (primarily pneumonia) from COVID-19 infection.[3][12][58] For an already-approved drug (such as hydroxychloroquine for malaria), Phase III-IV trials determine in hundreds to thousands of COVID-19-infected people the possible extended use of an already-approved drug for treating COVID-19 infection.[23][58] As of early April 2020, 103 candidate therapeutics were in preclinical or a stage of Phase I-IV development,[2] with trial results for 29 drug candidates expected during April.[23]

International Solidarity and Discovery Trials

In March, the World Health Organization (WHO) launched the coordinated “Solidarity Trial” in 10 countries on five continents to rapidly assess in thousands of COVID-19 infected people the potential efficacy of existing antiviral and anti-inflammatory agents not yet evaluated specifically for COVID-19 illness.[3][18][59] The individual or combined drugs being studied are 1) lopinavirritonavir combined, 2) lopinavir–ritonavir combined with interferon-beta, 3) remdesivir or 4) (hydroxy)chloroquine in separate trials and hospital sites internationally.[3][18] With about 15% of people infected by COVID-19 having severe illness, and hospitals being overwhelmed during the pandemic, WHO recognized a rapid clinical need to test and repurpose these drugs as agents already approved for other diseases and recognized as safe.[3]

The Solidarity project is designed to give rapid insights to key clinical questions:[3][59]

  • Do any of the drugs reduce mortality?
  • Do any of the drugs reduce the time a patient is hospitalized?
  • Do the treatments affect the need for people with COVID-19-induced pneumonia to be ventilated or maintained in intensive care?
  • Could such drugs be used to minimize the illness of COVID-19 infection in healthcare staff and people at high risk of developing severe illness?

Enrolling people with COVID-19 infection is simplified by using data entries, including informed consent, on a WHO website.[3] After the trial staff determines the drugs available at the hospital, the WHO website randomizes the hospitalized subject to one of the trial drugs or to the hospital standard of care for treating COVID-19. The trial physician records and submits follow-up information about the subject status and treatment, completing data input via the WHO Solidarity website.[3] The design of the Solidarity trial is not double-blind – which is normally the standard in a high-quality clinical trial – but WHO needed speed with quality for the trial across many hospitals and countries.[3] A global safety monitoring board of WHO physicians examine interim results to assist decisions on safety and effectiveness of the trial drugs, and alter the trial design or recommend an effective therapy.[3][59] A similar web-based study to Solidarity, called “Discovery”, was initiated in March across seven countries by INSERM (Paris, France).[3][41]

During March, funding for the Solidarity trial reached US$108 million from 203,000 individuals, organizations and governments, with 45 countries involved in financing or trial management.[60]

Recovery Trial

During April, the British “Recovery Trial” was launched initially in 132 hospitals across the UK,[61] expanding to become the world’s largest COVID-19 clinical study involving 5400 infected people under treatment at 165 UK hospitals, as of 17 April.[62] The trial is examining different potential therapies for severe COVID-19 infection: lopinavir/ritonavir, low-dose dexamethasone (an anti-inflammatory steroid), hydroxychloroquine, and azithromycin (a common antibiotic).[63]

Tabulating late-stage treatment candidates

Numerous candidate drugs under study as “supportive” treatments to relieve discomfort during illness, such as NSAIDs or bronchodilators, are not included in the table below. Others in early-stage Phase II trials or numerous treatment candidates in Phase I trials,[2][23] are also excluded. Drug candidates in Phase I-II trials have a low rate of success (under 12%) to pass through all trial phases to gain eventual approval.[24][43] Candidates in Phase III trials for diseases related to COVID-19 infection – infectious and respiratory diseases – have a success rate of about 72%.[47]

COVID-19 Wiki: candidate drug treatments in Phase III-IV trials

Drug candidateDescriptionExisting disease approvalTrial sponsor(s)Location(s)Expected resultsNotes,
references[64]
Remdesivirantiviral; adenosine nucleotide analog inhibiting RNA synthesis in coronavirusesinvestigational[65]Gilead, WHO, INSERMChina, Japan initially; expanded internationally in Global Solidarity and Discovery TrialsApril (Chinese, Japanese trials) to mid-2020[2][23][41][66][67] Selectively provided by Gilead for COVID-19 emergency access.[64][68]
Hydroxychloroquine or chloroquineantiparasitic and antirheumatic; generic made by many manufacturersmalaria, rheumatoid arthritis, lupus (International)[69][70]CEPI, WHO, INSERMMultiple sites in China; Global Solidarity and Discovery Trials, Europe, internationalApril 2020 (Chinese trials); mid-2020multiple side effects, some severe, and possible death;[69][70][71] possible adverse prescription drug interactions;[69][70] trials[2][23][41]
Favipiravirantiviral against influenzainfluenza (China)[72]FujifilmChinaApril 2020[2][9][23][73]
Lopinavir/ritonavir without or with Rebifantiviral, immune suppressioninvestigational combination; lopinavir/ritonavir approved[74]CEPI, WHO, UK Government, Univ. of Oxford, INSERMGlobal Solidarity and Discovery Trials, multiple countriesmid-2020[2][23][41]
Sarilumabhuman monoclonal antibody against interleukin-6 receptorrheumatoid arthritis (USA, Europe)[75]RegeneronSanofiMultiple countriesSpring 2020[2][76]
ASC-09 + ritonavirantiviralcombination not approved; ritonavir approved for HIV[74]Ascletis PharmaMultiple sites in ChinaSpring 2020[2][77]
Tocilizumabhuman monoclonal antibody against interleukin-6 receptorimmunosuppression, rheumatoid arthritis (USA, Europe)[78]GenentechHoffmann-La RocheMultiple countriesmid-2020[2][23][79]

Hydroxychloroquine and chloroquine

Chloroquine is an anti-malarial medication that is also used against some auto-immune diseases. Hydroxychloroquine is more commonly available than chloroquine in the United States.[68] Although several countries use chloroquine or hydroxychloroquine for treatment of persons hospitalized with COVID-19, as of March 2020 the drug has not been formally approved through clinical trials in the United States.[68][80] Chloroquine has been recommended by Chinese, South Korean and Italian health authorities for the treatment of COVID-19,[81] although these agencies and the US CDC noted contraindications for people with heart disease or diabetes.[68][82] In the United States, the experimental treatment is authorized only for emergency use for patients who are hospitalized but are not able to receive treatment in a clinical trial.[83]

In February 2020, both drugs were shown to effectively reduce COVID-19 illness, but a further study concluded that hydroxychloroquine was more potent than chloroquine and had a more tolerable safety profile.[84][85] Preliminary results from a trial indicated that chloroquine is effective and safe in COVID-19 pneumonia, “improving lung imaging findings, promoting a virus-negative conversion, and shortening the disease course.”[86]

On 18 March, the WHO announced that chloroquine and the related hydroxychloroquine would be among the four drugs studied as part of the Solidarity clinical trial.[87]

Hydroxychloroquine and chloroquine have numerous, potentially serious, side effects, such as retinopathy, hypoglycemia, or life-threatening arrhythmia and cardiomyopathy.[69][71] Both drugs have extensive interactions with prescription drugs, affecting the therapeutic dose and disease mitigation.[69][70] Some people have allergic reactions to these drugs.[69][70]

On 12 April, a preliminary clinical trial conducted at a hospital in Brazil was stopped when several people given high doses of chloroquine for COVID-19 infection developed irregular heart rates, causing 11 deaths.[71][88]

Favipiravir

Chinese clinical trials in Wuhan and Shenzhen claimed to show that favipiravir was “clearly effective”.[89] Of 35 patients in Shenzhen tested negative in a median of 4 days, while the length of illness was 11 days in the 45 patients who did not receive it.[90] In a study conducted in Wuhan on 240 patients with pneumonia half were given favipiravir and half received umifenovir. The researchers found that patients recovered from coughs and fevers faster when treated with favipiravir, but that there was no change in how many patients in each group progressed to more advanced stages of illness that required treatment with a ventilator.[91]

On 22 March 2020, Italy approved the drug for experimental use against COVID-19 and began conducting trials in the three regions most affected by the disease.[92] The Italian Pharmaceutical Agency reminded the public that the existing evidence in support of the drug is scant and preliminary.[93]

COVID-19 Vaccine Strategies

Re-purposing approved drugs

See also: COVID-19 drug repurposing research

Drug repositioning (also called drug repurposing) – the investigation of existing drugs for new therapeutic purposes – is one line of scientific research followed to develop safe and effective COVID-19 treatments.[17][94] Several existing antiviral medications, previously developed or used as treatments for Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), HIV/AIDS, and malaria, are being researched as COVID-19 treatments, with some moving into clinical trials.[95]

During the COVID-19 outbreak, drug repurposing is the clinical research process of rapidly screening and defining the safety and efficacy of existing drugs already approved for other diseases to be used for people with COVID-19 infection.[14][17][96] In the usual drug development process,[19] confirmation of repurposing for new disease treatment would take many years of clinical research – including pivotal Phase III clinical trials – on the candidate drug to assure its safety and efficacy specifically for treating COVID-19 infection.[14][96] In the emergency of a growing COVID-19 pandemic, the drug repurposing process was being accelerated during March 2020 to treat people hospitalized with COVID-19.[3][14][17]

Clinical trials using repurposed, generally safe, existing drugs for hospitalized COVID-19 people may take less time and have lower overall costs to obtain endpoints proving safety (absence of serious side effects) and post-infection efficacy, and can rapidly access existing drug supply chains for manufacturing and worldwide distribution.[3][14][97] In an international effort to capture these advantages, the WHO began in mid-March 2020 expedited international Phase II-III trials on four promising treatment options – the SOLIDARITY trial[3][98][99] – with numerous other drugs having potential for repurposing in different disease treatment strategies, such as anti-inflammatory, corticosteroid, antibody, immune, and growth factor therapies, among others, being advanced into Phase II or III trials during 2020.[2][14][15][96][100]

In March, the United States Centers for Disease Control and Prevention (CDC) issued a physician advisory concerning remdesivir for people hospitalized with pneumonia caused by COVID-19: “While clinical trials are critical to establish the safety and efficacy of this drug, clinicians without access to a clinical trial may request remdesivir for compassionate use through the manufacturer for patients with clinical pneumonia.”[68]

Early-stage COVID-19 Wiki drug candidates

Preclinical research

The term “preclinical research” is defined by laboratory studies in vitro and in vivo, indicating a beginning stage for development of a preventative vaccine, antiviral or other post-infection therapies,[8] such as experiments to determine effective doses and toxicity, before a candidate compound is advanced for safety and efficacy evaluation in humans.[26][101] To complete the preclinical stage of drug development – then be tested for safety and efficacy in an adequate number of people infected with COVID-19 (hundreds to thousands in different countries) – is a process likely to require 1–2 years for COVID-19 vaccines and therapies, according to several reports in early 2020.[10][20][21][102][103][104] Despite these efforts, the success rate for drug candidates to reach eventual regulatory approval through the drug development process for treating infectious diseases is 19%.[47]

According to one source (as of mid-April 2020), most programs in preclinical research for developing COVID-19 drug candidates were for antibodies, antivirals, cell-based or RNA-based compounds, and scanning libraries of chemicals or existing drugs to repurpose the compound as a post-infection treatment against COVID-19.[2]

Antiviral drugs

Since SARS-CoV-2 is a virus, considerable scientific attention has been focused on repurposing approved anti-viral drugs that were developed for prior outbreaks such as MERS, SARS, and West Nile virus.[105]

Broad-spectrum agents

  • Ribavirin: ribavirin was recommended for COVID-19 treatment according to Chinese 7th edition guidelines[106]
  • Umifenovir: umifenovir was recommended for COVID-19 treatment according to Chinese 7th edition guidelines[106]

Interferons

Drugs tested on SARS

Antibiotics

Some antibiotics may be repurposed as COVID-19 treatments:[116][117]

Antiparasitics

Inhibitors

Genetic map of the Lily-Mottle virus: the wedges show where the protease breaks up the polyprotein. The principle may apply to the SARS-CoV-2 virus main protease

In March 2020, the main protease of the SARS-CoV-2 virus was identified as a target for post-infection drugs. This enzyme is essential to the host cell to reproduce the ribonucleic acid of the virus. To find the enzyme, scientists used the genome published by Chinese researchers in January 2020 to isolate the main protease.[122] Protease inhibitors approved for treating human immunodeficiency viruses (HIV) – lopinavir and ritonavir – have preliminary evidence of activity against the coronaviruses, SARS and MERS.[3][14] As a potential combination therapy, they are used together in two Phase III arms of the 2020 global Solidarity project on COVID-19.[3] A preliminary study in China of combined lopinavir and ritonavir found no effect in people hospitalized for COVID-19.[123]

COVID-19 Wiki (Pandemic)

This article is about the disease. For the virus, see Severe acute respiratory syndrome coronavirus 2. For the pandemic, see 2019–20 coronavirus pandemic.

Coronavirus disease 2019 (COVID-19)
Other namesCoronavirus COVID 2019-nCoV acute respiratory disease Novel coronavirus pneumonia[1][2]
Symptoms of COVID-19
Pronunciation/kəˈroʊnəˌvaɪrəs dɪˈziːz//ˌkoʊvɪdnaɪnˈtiːn, ˌkɒvɪd-/[3]
SpecialtyInfectious disease
SymptomsFever, cough, shortness of breath, loss of smell, none[4][5][6]
ComplicationsPneumonia, viral sepsis, acute respiratory distress syndrome, kidney failure
Usual onset2–14 days (typically 5) from infection
CausesSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
Risk factorsTravel, viral exposure
Diagnostic methodrRT-PCR testing, CT scan
PreventionHand washing, face coverings, quarantine, social distancing
TreatmentSymptomatic and supportive
Frequency3,303,296[7] confirmed cases
Deaths235,290 (7.1% of confirmed cases)[7]

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[8] The disease was first identified in December 2019 in Wuhan, the capital of China’s Hubei province, and has since spread globally, resulting in the ongoing 2019–20 coronavirus pandemic.[9][10] As of 1 May 2020, more than 3.3 million cases have been reported across 187 countries and territories, resulting in more than 235,000 deaths. More than 1.03 million people have recovered.[7]

Common symptoms include fever, cough, fatigue, shortness of breath, and both loss of smell and taste.[11][5][12][13] While the majority of cases result in mild symptoms, some progress to viral pneumonia, multi-organ failure, or cytokine storm.[9][14][15] The time from exposure to onset of symptoms is typically around five days but may range from two to fourteen days.[5][16]

The virus is primarily spread between people during close contact,[a] often via small droplets produced by coughing,[b] sneezing, or talking.[6][17][19] The droplets usually fall to the ground or onto surfaces rather than remaining in the air over long distances.[6] People may also become infected by touching a contaminated surface and then touching their face.[6][17] On surfaces, the amount of virus declines over time until it is insufficient to remain infectious, but it may be detected for hours or days.[6][19][20][21] It is most contagious during the first three days after the onset of symptoms, although spread may be possible before symptoms appear and in later stages of the disease.[22] The standard method of diagnosis is by real-time reverse transcription polymerase chain reaction (rRT-PCR) from a nasopharyngeal swab.[23] Chest CT imaging may also be helpful for diagnosis in individuals where there is a high suspicion of infection based on symptoms and risk factors; however, guidelines do not recommend using it for routine screening.[24][25]

Recommended measures to prevent infection include frequent hand washing, maintaining physical distance from others (especially from those with symptoms), covering coughs, and keeping unwashed hands away from the face.[26][27] In addition, the use of a face covering is recommended for those who suspect they have the virus and their caregivers.[28][29] Recommendations for face covering use by the general public vary, with some authorities recommending against their use, some recommending their use, and others requiring their use.[29][30][31] Currently, there is not enough evidence for or against the use of masks (medical or other) in healthy individuals in the wider community.[6]

Currently, there is no available vaccine or specific antiviral treatment for COVID-19.[6] Management involves the treatment of symptoms, supportive care, isolation, and experimental measures.[32] The World Health Organization (WHO) declared the 2019–20 coronavirus outbreak a Public Health Emergency of International Concern (PHEIC)[33][34] on 30 January 2020 and a pandemic on 11 March 2020.[10] Local transmission of the disease has occurred in most countries across all six WHO regions.[35]

Signs and symptoms

SymptomRange
Fever83–99%
Cough59–82%
Loss of appetite40–84%
Fatigue44–70%
Shortness of breath31–40%
Coughing up sputum28–33%
Muscle aches and pains11–35%

Fever is the most common symptom, although some older people and those with other health problems experience fever later in the disease.[4][36] In one study, 44% of people had fever when they presented to the hospital, while 89% went on to develop fever at some point during their hospitalization.[4][37]

Other common symptoms include cough, loss of appetite, fatigue, shortness of breath, sputum production, and muscle and joint pains.[4][5][38][39] Symptoms such as nausea, vomiting, and diarrhoea have been observed in varying percentages.[40][41][42] Less common symptoms include sneezing, runny nose, or sore throat.[43]

Some cases in China initially presented with only chest tightness and palpitations.[44]

A decreased sense of smell or disturbances in taste may occur.[45][46] Loss of smell was a presenting symptom in 30% of confirmed cases in South Korea.[13][47]

As is common with infections, there is a delay between the moment a person is first infected and the time he or she develops symptoms. This is called the incubation period. The incubation period for COVID‑19 is typically five to six days but may range from two to 14 days,[48][49] although 97.5% of people who develop symptoms will do so within 11.5 days of infection.[50]

A minority of cases do not develop noticeable symptoms at any point in time.[51][52] These asymptomatic carriers tend not to get tested, and their role in transmission is not yet fully known.[53][54] However, preliminary evidence suggests they may contribute to the spread of the disease.[55][56] In March 2020, the Korea Centers for Disease Control and Prevention (KCDC) reported that 20% of confirmed cases remained asymptomatic during their hospital stay.[56][57]

Cause

See also: Severe acute respiratory syndrome coronavirus 2

Transmission

Cough/sneeze droplets visualised in dark background using Tyndall scattering

Respiratory droplets produced when a man is sneezing visualised using Tyndall scatteringFile:COVID19 in numbers- R0, the case fatality rate and why we need to flatten the curve.webmPlay media A video discussing the basic reproduction number and case fatality rate in the context of the pandemic

As COVID-19 is a new disease, many aspects as to how it spreads are under investigation.[6][17][19] The disease is spread during close contact, often by small droplets produced during coughing, sneezing, or talking.[6][19] The droplets are transmitted, and cause new infection, when inhaled by people in close contact (1 to 2 metres, 3 to 6 feet). They are produced during breathing out, however as they are relatively heavy, they usually fall to the ground or surfaces.[6][19]

After the droplets fall to floors or surfaces, they still can infect other people, if they touch contaminated surfaces and then their eyes, nose or mouth with unwashed hands.[6] On surfaces the amount of active virus decreases over time until it can no longer cause infection.[19] However, experimentally, the virus can survive on various surfaces for some time, (for example copper or cardboard for a few hours, and plastic or steel for a few days).[19][21] Surfaces are easily decontaminated with household disinfectants which kill the virus outside the human body or on the hands.[6] Notably, however disinfectants or bleach should never be ingested or injected as a treatment or preventative measure for COVID-19, as this is harmful or potentially fatal.[58]

Sputum and saliva carry large amounts of virus.[6][17][19] Some medical procedures may result in the virus being transmitted easier than normal for such small droplets, known as airborne transmission.[6][19]

The virus is most contagious during the first three days after onset of symptoms, although spread is known to occur up to two days before symptoms appear (presymptomatic transmission) and in later stages of the disease.[17][19][59][60] Some people have been infected and recovered without showing symptoms, but uncertainties remain in terms of asymptomatic transmission.[19]

Although COVID-19 is not a sexually transmitted infection, kissing, intimate contact, and faecal oral routes are suspected to transmit the virus.[61][62]

Virology

Main article: Severe acute respiratory syndrome coronavirus 2

Illustration of SARSr-CoV virion

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel severe acute respiratory syndrome coronavirus, first isolated from three people with pneumonia connected to the cluster of acute respiratory illness cases in Wuhan.[63] All features of the novel SARS-CoV-2 virus occur in related coronaviruses in nature.[64] Outside the human body, the virus is killed by household soap, which bursts its protective bubble.[24]

SARS-CoV-2 is closely related to the original SARS-CoV.[65] It is thought to have a zoonotic origin. Genetic analysis has revealed that the coronavirus genetically clusters with the genus Betacoronavirus, in subgenus Sarbecovirus (lineage B) together with two bat-derived strains. It is 96% identical at the whole genome level to other bat coronavirus samples (BatCov RaTG13).[43] In February 2020, Chinese researchers found that there is only one amino acid difference in the binding domain of the S protein between the coronaviruses from pangolins and those from humans; however, whole-genome comparison to date found that at most 92% of genetic material was shared between pangolin coronavirus and SARS-CoV-2, which is insufficient to prove pangolins to be the intermediate host.[66]

Pathophysiology

In some, the disease may progress to pneumonia, multi-organ failure, and death.[67][68]

The lungs are the organs most affected by COVID‑19 because the virus accesses host cells via the enzyme angiotensin-converting enzyme 2 (ACE2), which is most abundant in type II alveolar cells of the lungs. The virus uses a special surface glycoprotein called a “spike” (peplomer) to connect to ACE2 and enter the host cell.[69] The density of ACE2 in each tissue correlates with the severity of the disease in that tissue and some have suggested that decreasing ACE2 activity might be protective,[70][71] though another view is that increasing ACE2 using angiotensin II receptor blocker medications could be protective and these hypotheses need to be tested.[72] As the alveolar disease progresses, respiratory failure might develop and death may follow.[71]

The virus also affects gastrointestinal organs as ACE2 is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelium[73] as well as endothelial cells and enterocytes of the small intestine.[74]

A number of neurological symptoms has been reported including seizures, stroke, encephalitis, and Guillain–Barré syndrome.[75] ACE2 is present in the brain, and there is growing evidence of neurological manifestations in people with COVID‑19. It is not certain if the virus can directly infect the brain by crossing the barriers that separate the circulation of the brain and the general circulation. Other coronaviruses are able to infect the brain via a synaptic route to the respiratory centre in the medulla, through mechanoreceptors like pulmonary stretch receptors and chemoreceptors (primarily central chemoreceptors) within the lungs.[76] It is possible that dysfunction within the respiratory centre further worsens the ARDS seen in COVID‑19 patients. Common neurological presentations include a loss of smell, headaches, nausea, and vomiting. Encephalopathy has been noted to occur in some patients (and confirmed with imaging), with some reports of detection of the virus after cerebrospinal fluid assays although the presence of oligoclonal bands seems to be a common denominator in these patients.[77]

Cardiovascular-related complications may include heart failure, irregular electrical activity, blood clots, and heart inflammation.[78] The virus can cause acute myocardial injury and chronic damage to the cardiovascular system.[79] An acute cardiac injury was found in 12% of infected people admitted to the hospital in Wuhan, China,[41] and is more frequent in severe disease.[80] Rates of cardiovascular symptoms are high, owing to the systemic inflammatory response and immune system disorders during disease progression, but acute myocardial injuries may also be related to ACE2 receptors in the heart.[79] ACE2 receptors are highly expressed in the heart and are involved in heart function.[79][81] A high incidence of thrombosis (31%) and venous thromboembolism (25%) have been found in ICU patients with COVID‑19 infections and may be related to poor prognosis.[82][83] Blood vessel dysfunction and clot formation (as suggested by high D-dimer levels) are thought to play a significant role in mortality, incidences of clots leading to pulmonary embolisms, and ischaemic events within the brain have been noted as complications leading to death in patients infected with SARS-CoV-2. Infection appears to set off a chain of vasoconstrictive responses within the body, constriction of blood vessels within the pulmonary circulation has also been posited as a mechanism in which oxygenation decreases alongside the presentation of viral pneumonia.[84]

Another common cause of death is complications related to the kidneys[84]—SARS-CoV-2 directly infects kidney cells, as confirmed in post-mortem studies. Acute kidney injury is a common complication and cause of death; this is more significant in patients with already compromised kidney function, especially in people with pre-existing chronic conditions such as hypertension and diabetes which specifically cause nephropathy in the long run.[85]

Autopsies of people who died of COVID‑19 have found diffuse alveolar damage (DAD), and lymphocyte-containing inflammatory infiltrates within the lung.[86]

Immunopathology

Although SARS-COV-2 has a tropism for ACE2-expressing epithelial cells of the respiratory tract, patients with severe COVID‑19 have symptoms of systemic hyperinflammation. Clinical laboratory findings of elevated IL-2, IL-7, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1-α (MIP-1α), and tumour necrosis factor-α (TNF-α) indicative of cytokine release syndrome (CRS) suggest an underlying immunopathology.[41]

Additionally, people with COVID‑19 and acute respiratory distress syndrome (ARDS) have classical serum biomarkers of CRS, including elevated C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer, and ferritin.[87]

Systemic inflammation results in vasodilation, allowing inflammatory lymphocytic and monocytic infiltration of the lung and the heart. In particular, pathogenic GM-CSF-secreting T-cells were shown to correlate with the recruitment of inflammatory IL-6-secreting monocytes and severe lung pathology in COVID‑19 patients.[88] Lymphocytic infiltrates have also been reported at autopsy.[86]

Diagnosis

Main article: COVID-19 testing

Demonstration of a nasopharyngeal swab for COVID-19 testing

CDCrRT-PCR test kit for COVID-19[89]

The WHO has published several testing protocols for the disease.[90] The standard method of testing is real-time reverse transcription polymerase chain reaction (rRT-PCR).[91] The test is typically done on respiratory samples obtained by a nasopharyngeal swab; however, a nasal swab or sputum sample may also be used.[23][92] Results are generally available within a few hours to two days.[93][94] Blood tests can be used, but these require two blood samples taken two weeks apart, and the results have little immediate value.[95] Chinese scientists were able to isolate a strain of the coronavirus and publish the genetic sequence so laboratories across the world could independently develop polymerase chain reaction (PCR) tests to detect infection by the virus.[9][96][97] As of 4 April 2020, antibody tests (which may detect active infections and whether a person had been infected in the past) were in development, but not yet widely used.[98][99][100] The Chinese experience with testing has shown the accuracy is only 60 to 70%.[101] The FDA in the United States approved the first point-of-care test on 21 March 2020 for use at the end of that month.[102]

Diagnostic guidelines released by Zhongnan Hospital of Wuhan University suggested methods for detecting infections based upon clinical features and epidemiological risk. These involved identifying people who had at least two of the following symptoms in addition to a history of travel to Wuhan or contact with other infected people: fever, imaging features of pneumonia, normal or reduced white blood cell count, or reduced lymphocyte count.[103]

A study asked hospitalised COVID‑19 patients to cough into a sterile container, thus producing a saliva sample, and detected the virus in eleven of twelve patients using RT-PCR. This technique has the potential of being quicker than a swab and involving less risk to health care workers (collection at home or in the car).[104]

Along with laboratory testing, chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection but are not recommended for routine screening.[24][25] Bilateral multilobar ground-glass opacities with a peripheral, asymmetric, and posterior distribution are common in early infection.[24] Subpleural dominance, crazy paving (lobular septal thickening with variable alveolar filling), and consolidation may appear as the disease progresses.[24][105]

In late 2019, WHO assigned the emergency ICD-10 disease codes U07.1 for deaths from lab-confirmed SARS-CoV-2 infection and U07.2 for deaths from clinically or epidemiologically diagnosed COVID‑19 without lab-confirmed SARS-CoV-2 infection.[106]

Typical CT imaging findings

CT imaging of rapid progression stage

Pathology

Few data are available about microscopic lesions and the pathophysiology of COVID‑19.[107][108] The main pathological findings at autopsy are:

Prevention

See also: 2019–20 coronavirus pandemic § Prevention, flatten the curve, and workplace hazard controls for COVID-19

Progressively stronger mitigation efforts to reduce the number of active cases at any given time—known as “flattening the curve“—allows healthcare services to better manage the same volume of patients.[112][113][114] Likewise, progressively greater increases in healthcare capacity—called raising the line—such as by increasing bed count, personnel, and equipment, helps to meet increased demand.[115]

Mitigation attempts that are inadequate in strictness or duration—such as premature relaxation of distancing rules or stay-at-home orders—can allow a resurgence after the initial surge and mitigation.[113][116]

Preventive measures to reduce the chances of infection include staying at home, avoiding crowded places, keeping distance from others, washing hands with soap and water often and for at least 20 seconds, practising good respiratory hygiene, and avoiding touching the eyes, nose, or mouth with unwashed hands.[117][118][119] The CDC recommends covering the mouth and nose with a tissue when coughing or sneezing and recommends using the inside of the elbow if no tissue is available.[117] Proper hand hygiene after any cough or sneeze is encouraged.[117] The CDC has recommended the use of cloth face coverings in public settings where other social distancing measures are difficult to maintain, in part to limit transmission by asymptomatic individuals.[120] The U.S. National Institutes of Health guidelines do not recommend any medication for prevention of COVID‑19, before or after exposure to the SARS-CoV-2 virus, outside of the setting of a clinical trial.[121]

Social distancing strategies aim to reduce contact of infected persons with large groups by closing schools and workplaces, restricting travel, and cancelling large public gatherings.[122] Distancing guidelines also include that people stay at least 6 feet (1.8 m) apart.[123] There is no medication known to be effective at preventing COVID‑19.[124] After the implementation of social distancing and stay-at-home orders, many regions have been able to sustain an effective transmission rate (“Rt“) of less than one, meaning the disease is in remission in those areas.[125] In a simple model l o g ( R t ) ≈ R t − 1 {\textstyle log(R_{t})\approx R_{t}-1} {\textstyle log(R_{t})\approx R_{t}-1} needs on average over time be kept at or below zero to avoid exponential growth.

As a vaccine is not expected until 2021 at the earliest,[126] a key part of managing COVID‑19 is trying to decrease and delay the epidemic peak, known as “flattening the curve“.[113] This is done by slowing the infection rate to decrease the risk of health services being overwhelmed, allowing for better treatment of current cases, and delaying additional cases until effective treatments or a vaccine become available.[113][116]

According to the WHO, the use of masks is recommended only if a person is coughing or sneezing or when one is taking care of someone with a suspected infection.[127] For the European Centre for Disease Prevention and Control (ECDC) face masks “… could be considered especially when visiting busy closed spaces …” but “… only as a complementary measure …”[128] Several countries have recommended that healthy individuals wear face masks or cloth face coverings (like scarves or bandanas) at least in certain public settings, including China,[129] Hong Kong,[130] Spain,[131] Italy (Lombardy region),[132] and the United States.[120]

Those diagnosed with COVID‑19 or who believe they may be infected are advised by the CDC to stay home except to get medical care, call ahead before visiting a healthcare provider, wear a face mask before entering the healthcare provider’s office and when in any room or vehicle with another person, cover coughs and sneezes with a tissue, regularly wash hands with soap and water and avoid sharing personal household items.[28][133] The CDC also recommends that individuals wash hands often with soap and water for at least 20 seconds, especially after going to the toilet or when hands are visibly dirty, before eating and after blowing one’s nose, coughing or sneezing. It further recommends using an alcohol-based hand sanitiser with at least 60% alcohol, but only when soap and water are not readily available.[117]

For areas where commercial hand sanitisers are not readily available, the WHO provides two formulations for local production. In these formulations, the antimicrobial activity arises from ethanol or isopropanol. Hydrogen peroxide is used to help eliminate bacterial spores in the alcohol; it is “not an active substance for hand antisepsis“. Glycerol is added as a humectant.[134]

Prevention efforts are multiplicative, with effects far beyond that of a single spread. Each avoided case leads to more avoided cases down the line, which in turn can stop the outbreak in its tracks.

File:COVID19 W ENG.ogv

Play media Handwashing instructions

Management

People are managed with supportive care, which may include fluid therapy, oxygen support, and supporting other affected vital organs.[135][136][137] The CDC recommends that those who suspect they carry the virus wear a simple face mask.[28] Extracorporeal membrane oxygenation (ECMO) has been used to address the issue of respiratory failure, but its benefits are still under consideration.[37][138] Personal hygiene and a healthy lifestyle and diet have been recommended to improve immunity.[139] Supportive treatments may be useful in those with mild symptoms at the early stage of infection.[140]

The WHO, the Chinese National Health Commission, and the United States’ National Institutes of Health have published recommendations for taking care of people who are hospitalised with COVID‑19.[121][141][142] Intensivists and pulmonologists in the U.S. have compiled treatment recommendations from various agencies into a free resource, the IBCC.[143][144]

Medications

See also: Coronavirus disease 2019 § Research

On May 1, 2020, the United States Food and Drug Administration gave an Emergency Use Authorization (not full approval) for use of remdesivir on hospital patients with severe COVID-19m after a randomized controlled trial performed by the National Institutes of Health found it reduced the average number of days spent in recovery.[145] Researchers continue working on more effective treatments and many vaccine candidates are in development or testing phases.

For symptoms, some medical professionals recommend paracetamol (acetaminophen) over ibuprofen for first-line use.[146][147][148] The WHO and NIH do not oppose the use of non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen for symptoms,[121][149] and the FDA says currently there is no evidence that NSAIDs worsen COVID‑19 symptoms.[150]

While theoretical concerns have been raised about ACE inhibitors and angiotensin receptor blockers, as of 19 March 2020, these are not sufficient to justify stopping these medications.[121][151][152][153] One study published on April 22 in Circulation Research found that COVID-19 patients with hypertension had lower all-cause mortality when on these drugs.[154]

Steroids, such as methylprednisolone, are not recommended unless the disease is complicated by acute respiratory distress syndrome.[155][156]

Medications to prevent blood clotting have been suggested for treatment,[82] and anticoagulant therapy with low molecular weight heparin appears to be associated with better outcomes in severe COVID‐19 showing signs of coagulopathy (elevated D-dimer).[157]

Protective equipment

See also: COVID-19 related shortages

COVID-19 Vaccine

The CDC recommends four steps to putting on personal protective equipment (PPE).[158]

Precautions must be taken to minimise the risk of virus transmission, especially in healthcare settings when performing procedures that can generate aerosols, such as intubation or hand ventilation.[159] For healthcare professionals caring for people with COVID‑19, the CDC recommends placing the person in an Airborne Infection Isolation Room (AIIR) in addition to using standard precautions, contact precautions, and airborne precautions.[160]

The CDC outlines the guidelines for the use of personal protective equipment (PPE) during the pandemic. The recommended gear is a PPE gown, respirator or facemask, eye protection, and medical gloves.[161][162]

When available, respirators (instead of facemasks) are preferred.[163] N95 respirators are approved for industrial settings but the FDA has authorised the masks for use under an Emergency Use Authorisation (EUA). They are designed to protect from airborne particles like dust but effectiveness against a specific biological agent is not guaranteed for off-label uses.[164] When masks are not available, the CDC recommends using face shields or, as a last resort, homemade masks.[165]

Currently, N95 masks may trap the virus but they are not able to kill it. One current project is testing a graphene-based composite ink to see whether it can kill the virus when applied to fabrics or existing N95 masks.[166]

Mechanical ventilation

Most cases of COVID‑19 are not severe enough to require mechanical ventilation or alternatives, but a percentage of cases are.[167][168] The type of respiratory support for individuals with COVID‑19 related respiratory failure is being actively studied for people in the hospital, with some evidence that intubation can be avoided with a high flow nasal cannula or bi-level positive airway pressure.[169] Whether either of these two leads to the same benefit for people who are critically ill is not known.[170] Some doctors prefer staying with invasive mechanical ventilation when available because this technique limits the spread of aerosol particles compared to a high flow nasal cannula.[167]

Severe cases are most common in older adults (those older than 60 years,[167] and especially those older than 80 years).[171] Many developed countries do not have enough hospital beds per capita, which limits a health system‘s capacity to handle a sudden spike in the number of COVID‑19 cases severe enough to require hospitalisation.[172] This limited capacity is a significant driver behind calls to flatten the curve.[172] One study in China found 5% were admitted to intensive care units, 2.3% needed mechanical support of ventilation, and 1.4% died.[37] In China, approximately 30% of people in hospital with COVID‑19 are eventually admitted to ICU.[4]

Acute respiratory distress syndrome

Main article: Acute respiratory distress syndrome

Mechanical ventilation becomes more complex as acute respiratory distress syndrome (ARDS) develops in COVID‑19 and oxygenation becomes increasingly difficult.[173] Ventilators capable of pressure control modes and high PEEP[174] are needed to maximise oxygen delivery while minimising the risk of ventilator-associated lung injury and pneumothorax.[175] High PEEP may not be available on older ventilators.

TherapyRecommendations
High-flow nasal oxygenFor SpO2 <93%. May prevent the need for intubation and ventilation
Tidal volume6mL per kg and can be reduced to 4mL/kg
Plateau airway pressureKeep below 30 cmH2O if possible (high respiratory rate (35 per minute) may be required)
Positive end-expiratory pressureModerate to high levels
Prone positioningFor worsening oxygenation
Fluid managementGoal is a negative balance of 0.5–1.0L per day
AntibioticsFor secondary bacterial infections
GlucocorticoidsNot recommended

Experimental treatment

See also: § Research

Research into potential treatments started in January 2020,[176] and several antiviral drugs are in clinical trials.[177][178] Remdesivir appears to be the most promising.[124] Although new medications may take until 2021 to develop,[179] several of the medications being tested are already approved for other uses or are already in advanced testing.[180] Antiviral medication may be tried in people with severe disease.[135] The WHO recommended volunteers take part in trials of the effectiveness and safety of potential treatments.[181]

The FDA has granted temporary authorisation to convalescent plasma as an experimental treatment in cases where the person’s life is seriously or immediately threatened. It has not undergone the clinical studies needed to show it is safe and effective for the disease.[182][183][184]

Information technology

See also: Contact tracing and Government by algorithm

In February 2020, China launched a mobile app to deal with the disease outbreak.[185] Users are asked to enter their name and ID number. The app can detect ‘close contact’ using surveillance data and therefore a potential risk of infection. Every user can also check the status of three other users. If a potential risk is detected, the app not only recommends self-quarantine, it also alerts local health officials.[186]

Big data analytics on cellphone data, facial recognition technology, mobile phone tracking, and artificial intelligence are used to track infected people and people whom they contacted in South Korea, Taiwan, and Singapore.[187][188] In March 2020, the Israeli government enabled security agencies to track mobile phone data of people supposed to have coronavirus. The measure was taken to enforce quarantine and protect those who may come into contact with infected citizens.[189] Also in March 2020, Deutsche Telekom shared aggregated phone location data with the German federal government agency, Robert Koch Institute, to research and prevent the spread of the virus.[190] Russia deployed facial recognition technology to detect quarantine breakers.[191] Italian regional health commissioner Giulio Gallera said he has been informed by mobile phone operators that “40% of people are continuing to move around anyway”.[192] German government conducted a 48 hours weekend hackathon with more than 42.000 participants.[193][194] Two million people in the UK used an app developed in March 2020 by King’s College London and Zoe to track people with COVID‑19 symptoms.[195] Also, the president of Estonia, Kersti Kaljulaid, made a global call for creative solutions against the spread of coronavirus.[196]

Psychological support

See also: Mental health during the 2019–20 coronavirus pandemic

Individuals may experience distress from quarantine, travel restrictions, side effects of treatment, or fear of the infection itself. To address these concerns, the National Health Commission of China published a national guideline for psychological crisis intervention on 27 January 2020.[197][198]

The Lancet published a 14-page call for action focusing on the UK and stated conditions were such that a range of mental health issues was likely to become more common. BBC quoted Rory O’Connor in saying, “Increased social isolation, loneliness, health anxiety, stress, and an economic downturn are a perfect storm to harm people’s mental health and wellbeing.”[199][200]

People avoiding hospitals even with heart attack symptoms

38% fewer persons in the United States have sought treatment for heart attack symptoms, which is very similar to a 40% reduction in Spain.[201]

There is also concern that persons with symptoms of a stroke are staying away, as are persons with appendicitis symptoms.[202]

The head of cardiology at the University of Arizona has stated, “My worry is some of these people are dying at home because they’re too scared to go to the hospital.”[202]

Prognosis

This article relies too much on references to primary sources. Please improve this by adding secondary or tertiary sources. (March 2020) (Learn how and when to remove this template message)
COVID-19 Vaccine

The severity of diagnosed COVID-19 cases in China[203]

COVID-19 Vaccine

Case fatality rates by age group:   China, as of 11 February 2020[204]   South Korea, as of 30 April 2020[205]   Spain, as of 29 April 2020[206]   Italy, as of 28 April 2020[207]

COVID-19 Vaccine

Case fatality rate in China depending on other health problems. Data through 11 February 2020.[204]

COVID-19 Vaccine

The number of deaths vs total cases by country and approximate case fatality rate[208]

The severity of COVID‑19 varies. The disease may take a mild course with few or no symptoms, resembling other common upper respiratory diseases such as the common cold. Mild cases typically recover within two weeks, while those with severe or critical diseases may take three to six weeks to recover. Among those who have died, the time from symptom onset to death has ranged from two to eight weeks.[43]

Children make up a small proportion of reported cases, with about 1% of cases being under 10 years and 4% aged 10–19 years.[19] They are likely to have milder symptoms and a lower chance of severe disease than adults; in those younger than 50 years the risk of death is less than 0.5%, while in those older than 70 it is more than 8%.[209][210][211] Pregnant women may be at higher risk for severe infection with COVID-19 based on data from other similar viruses, like SARS and MERS, but data for COVID-19 is lacking.[212][213] In China, children acquired infections mainly through close contact with their parents or other family members who lived in Wuhan or had traveled there.[209]

In some people, COVID‑19 may affect the lungs causing pneumonia. In those most severely affected, COVID-19 may rapidly progress to acute respiratory distress syndrome (ARDS) causing respiratory failure, septic shock, or multi-organ failure.[214][215] Complications associated with COVID‑19 include sepsis, abnormal clotting, and damage to the heart, kidneys, and liver. Clotting abnormalities, specifically an increase in prothrombin time, have been described in 6% of those admitted to hospital with COVID-19, while abnormal kidney function is seen in 4% of this group.[216] Approximately 20-30% of people who present with COVID‑19 demonstrate elevated liver enzymes (transaminases).[124] Liver injury as shown by blood markers of liver damage is frequently seen in severe cases.[217]

Some studies have found that the neutrophil to lymphocyte ratio (NLR) may be helpful in early screening for severe illness.[218]

Most of those who die of COVID‑19 have pre-existing (underlying) conditions, including hypertension, diabetes mellitus, and cardiovascular disease.[219] The Istituto Superiore di Sanità reported that out of 8.8% of deaths where medical charts were available for review, 97.2% of sampled patients had at least one comorbidity with the average patient having 2.7 diseases.[220] According to the same report, the median time between the onset of symptoms and death was ten days, with five being spent hospitalised. However, patients transferred to an ICU had a median time of seven days between hospitalisation and death.[220] In a study of early cases, the median time from exhibiting initial symptoms to death was 14 days, with a full range of six to 41 days.[221] In a study by the National Health Commission (NHC) of China, men had a death rate of 2.8% while women had a death rate of 1.7%.[222] Histopathological examinations of post-mortem lung samples show diffuse alveolar damage with cellular fibromyxoid exudates in both lungs. Viral cytopathic changes were observed in the pneumocytes. The lung picture resembled acute respiratory distress syndrome (ARDS).[43] In 11.8% of the deaths reported by the National Health Commission of China, heart damage was noted by elevated levels of troponin or cardiac arrest.[44] According to March data from the United States, 89% of those hospitalised had preexisting conditions.[223]

The availability of medical resources and the socioeconomics of a region may also affect mortality.[224] Estimates of the mortality from the condition vary because of those regional differences,[225] but also because of methodological difficulties. The under-counting of mild cases can cause the mortality rate to be overestimated.[226] However, the fact that deaths are the result of cases contracted in the past can mean the current mortality rate is underestimated.[227][228] Smokers were 1.4 times more likely to have severe symptoms of COVID‑19 and approximately 2.4 times more likely to require intensive care or die compared to non-smokers.[229]

Concerns have been raised about long-term sequelae of the disease. The Hong Kong Hospital Authority found a drop of 20% to 30% in lung capacity in some people who recovered from the disease, and lung scans suggested organ damage.[230] This may also lead to post-intensive care syndrome following recovery.[231]

Age0–910–1920–2930–3940–4950–5960–6970–7980-8990+
Canada as of 29 April[232]0.00.20.65.517.3
China as of 11 February[204]0.00.20.20.20.41.33.68.014.8
Denmark as of 30 April[233]0.24.515.924.839.9
Israel as of 30 April[234]0.00.00.50.51.42.89.324.533.327.3
Italy as of 28 April[207]0.10.00.10.30.92.69.824.229.024.7
Netherlands as of 25 April[235]0.00.30.10.20.51.57.623.230.029.3
Portugal as of 28 April[236]0.00.00.00.00.20.73.08.717.2
South Korea as of 30 April[205]0.00.00.00.20.20.82.610.424.3
Spain as of 29 April[206]0.30.40.20.30.61.44.713.720.821.6
Sweden as of 26 April[237]0.00.00.40.41.02.36.921.230.034.0
Switzerland as of 30 April[238]0.00.00.00.10.00.52.810.525.2
WA state as of 25 April[239]0.00.21.38.929.9
Age0–1920–4445–5455–6465–7475–8485+
United States as of 16 March[240]0.00.1–0.20.5–0.81.4–2.62.7–4.94.3–10.510.4–27.3
Note: The lower bound includes all cases. The upper bound excludes cases that were missing data.
0–910–1920–2930–3940–4950–5960–6970–7980+
Severe disease0.0
(0.0–0.0)
0.04
(0.02–0.08)
1.0
(0.62–2.1)
3.4
(2.0–7.0)
4.3
(2.5–8.7)
8.2
(4.9–17)
11
(7.0–24)
17
(9.9–34)
18
(11–38)
Death0.0016
(0.00016–0.025)
0.0070
(0.0015–0.050)
0.031
(0.014–0.092)
0.084
(0.041–0.19)
0.16
(0.076–0.32)
0.60
(0.34–1.3)
1.9
(1.1–3.9)
4.3
(2.5–8.4)
7.8
(3.8–13)
Total infection fatality rate is estimated to be 0.66% (0.39–1.3). Infection fatality rate is fatality per all infected individuals, regardless of whether they were diagnosed or had any symptoms. Numbers in parentheses are 95% credible intervals for the estimates.

Immunity

As of April 2020, it was unknown if past infection provides effective and long-term immunity in people who recover from the disease.[242][243] As those infected were reported to have developed protective antibodies, acquired immunity was presumed likely, based on the behaviour of other coronaviruses, in March 2020.[244] However, cases in which recovery from COVID‑19 was followed by positive tests for coronavirus at a later date have been reported.[245][246][247][248] These cases are believed to be lingering infection rather than reinfection,[248] or false positives due to remaining RNA fragments.[249] Long running research shows that some of the other in humans circulating coronaviruses are often capable of reinfection after roughly a year.[250][1]

History

Main article: Timeline of the 2019–20 coronavirus pandemic

The virus is thought to be natural and has an animal origin,[64] through spillover infection.[251] The actual origin is unknown, but by December 2019 the spread of infection was almost entirely driven by human-to-human transmission.[204][252] A study of the first 41 cases of confirmed COVID‑19, published in January 2020 in The Lancet, revealed the earliest date of onset of symptoms as 1 December 2019.[253][254][255] Official publications from the WHO reported the earliest onset of symptoms as 8 December 2019.[256] Human-to-human transmission was confirmed by the WHO and Chinese authorities by 20 January 2020.[257][258]

Epidemiology

Main article: 2019–20 coronavirus pandemic

Several measures are commonly used to quantify mortality.[259] These numbers vary by region and over time and are influenced by the volume of testing, healthcare system quality, treatment options, time since the initial outbreak, and population characteristics such as age, sex, and overall health.[260]

The death-to-case ratio reflects the number of deaths divided by the number of diagnosed cases within a given time interval. Based on Johns Hopkins University statistics, the global death-to-case ratio is 7.1% (235,290/3,303,296) as of 1 May 2020.[7] The number varies by region.[261]

Other measures include the case fatality rate (CFR), which reflects the percent of diagnosed individuals who die from a disease, and the infection fatality rate (IFR), which reflects the percent of infected individuals (diagnosed and undiagnosed) who die from a disease. These statistics are not time-bound and follow a specific population from infection through case resolution. Many academics have attempted to calculate these numbers for specific populations.[262]

Outbreaks have occurred in prisons due to crowding and an inability to enforce adequate social distancing.[263] In the United States, the prisoner population is aging and many of them are at high risk for poor outcomes from COVID-19 due to high rates of coexisting heart and lung disease, and poor access to high-quality healthcare.[263]

COVID-19 Vaccine

Total confirmed cases over time

COVID-19 Vaccine

Total deaths over time

COVID-19 Vaccine

Total confirmed cases of COVID‑19 per million people, 10 April 2020[264]

COVID-19 Vaccine

Total confirmed deaths due to COVID‑19 per million people, 10 April 2020[265]

Infection fatality rate

Our World in Data states that as of March 25, 2020, the infection fatality rate (IFR) cannot be accurately calculated.[266] In February, the World Health Organization estimated the IFR at 0.94%, with a confidence interval between 0.37 percent to 2.9 percent.[267] The University of Oxford Centre for Evidence-Based Medicine (CEBM) estimated a global CFR of 0.72 percent and IFR of 0.1 percent to 0.36 percent.[268] According to CEBM, random antibody testing in Germany suggested an IFR of 0.37% (0.12% to 0.87%) there, but there have been concerns about false positives.[268][269][270] Firm lower limits of infection fatality rates have been established in a number of locations. In New York City, with a population if 8.4 million, as of April 25, 16,673 (0.20% of the population) have died from COVID-19, and 20,800 (0.25% of the population) excess deaths have occurred, and in Bergamo province, where 0.57% of the population has died.[271][272][273] To get a better view on the number of people infected, initial antibody testing has been carried out but there are no valid scientific reports based on them yet and a newspaper article provides a survey.[274][275]

Sex differences

Main article: Gendered impact of the 2019–20 coronavirus pandemic

The impact of the pandemic and its mortality rate are different for men and women.[276] Mortality is higher in men in studies conducted in China and Italy.[277][278][279] The highest risk for men is in their 50s, with the gap between men and women closing only at 90.[279] In China, the death rate was 2.8 percent for men and 1.7 percent for women.[279] The exact reasons for this sex-difference are not known, but genetic and behavioural factors could be a reason.[276] Sex-based immunological differences, a lower prevalence of smoking in women, and men developing co-morbid conditions such as hypertension at a younger age than women could have contributed to the higher mortality in men.[279] In Europe, of those infected with COVID‑19, 57% were men; of those infected with COVID‑19 who also died, 72% were men.[280] As of April 2020, the U.S. government is not tracking sex-related data of COVID‑19 infections.[281] Research has shown that viral illnesses like Ebola, HIV, influenza, and SARS affect men and women differently.[281] A higher percentage of health workers, particularly nurses, are women, and they have a higher chance of being exposed to the virus.[282] School closures, lockdowns, and reduced access to healthcare following the 2019–20 coronavirus pandemic may differentially affect the genders and possibly exaggerate existing gender disparity.[276][283]

Society and culture

Name

During the initial outbreak in Wuhan, China, the virus and disease were commonly referred to as “coronavirus” and “Wuhan coronavirus”,[284][285][286] with the disease sometimes called “Wuhan pneumonia”.[287][288] In the past, many diseases have been named after geographical locations, such as the Spanish flu,[289] Middle East Respiratory Syndrome, and Zika virus.[290]

In January 2020, the World Health Organisation recommended 2019-nCov[291] and 2019-nCoV acute respiratory disease[292] as interim names for the virus and disease per 2015 guidance and international guidelines against using geographical locations (e.g. Wuhan, China), animal species or groups of people in disease and virus names to prevent social stigma.[293][294][295]

The official names COVID‑19 and SARS-CoV-2 were issued by the WHO on 11 February 2020.[296] WHO chief Tedros Adhanom Ghebreyesus explained: CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019).[297] The WHO additionally uses “the COVID‑19 virus” and “the virus responsible for COVID‑19” in public communications.[296] Both the disease and virus are commonly referred to as “coronavirus” in the media and public discourse.

Misinformation

Main article: Misinformation related to the 2019–20 coronavirus pandemic

After the initial outbreak of COVID‑19, conspiracy theories, misinformation and disinformation emerged regarding the origin, scale, prevention, treatment and other aspects of the disease and rapidly spread online.[298][299][300][301]

Other animals

Humans appear to be capable of spreading the virus to some other animals. A domestic cat in Liège, Belgium, tested positive after it started showing symptoms (diarrhoea, vomiting, shortness of breath) a week later than its owner, who was also positive.[302] Tigers at the Bronx Zoo in New York, United States, tested positive for the virus and showed symptoms of COVID‑19, including a dry cough and loss of appetite.[303] Minks at two farms in the Netherlands also tested positive for COVID-19.[304]

A study on domesticated animals inoculated with the virus found that cats and ferrets appear to be “highly susceptible” to the disease, while dogs appear to be less susceptible, with lower levels of viral replication. The study failed to find evidence of viral replication in pigs, ducks, and chickens.[305]

COVID-19 Vaccine Research

Main article: COVID-19 drug development

No medication or vaccine is approved to treat the disease.[180] International research on vaccines and medicines in COVID‑19 is underway by government organisations, academic groups, and industry researchers.[306][307] In March, the World Health Organisation initiated the “SOLIDARITY Trial” to assess the treatment effects of four existing antiviral compounds with the most promise of efficacy.[308]

There has been a great deal of COVID-19 research, involving accelerated research processes and publishing shortcuts to meet the global demand. To minimise the impact of misinformation, medical professionals and the public are advised to expect rapid changes to available information, and to be attentive to retractions and other updates.[309]

COVID-19 Vaccine

Main article: COVID-19 vaccine

There is no available vaccine, but various agencies are actively developing vaccine candidates. Previous work on SARS-CoV is being used because both SARS-CoV and SARS-CoV-2 use the ACE2 receptor to enter human cells.[310] Three vaccination strategies are being investigated. First, researchers aim to build a whole virus vaccine. The use of such a virus, be it inactive or dead, aims to elicit a prompt immune response of the human body to a new infection with COVID‑19. A second strategy, subunit vaccines, aims to create a vaccine that sensitises the immune system to certain subunits of the virus. In the case of SARS-CoV-2, such research focuses on the S-spike protein that helps the virus intrude the ACE2 enzyme receptor. A third strategy is that of the nucleic acid vaccines (DNA or RNA vaccines, a novel technique for creating a vaccination). Experimental vaccines from any of these strategies would have to be tested for safety and efficacy.[311]

On 16 March 2020, the first clinical trial of a vaccine started with four volunteers in Seattle, United States. The vaccine contains a harmless genetic code copied from the virus that causes the disease.[312]

Antibody-dependent enhancement has been suggested as a potential challenge for vaccine development for SARS-COV-2, but this is controversial.[313]

COVID-19 Vaccine Medications

Main article: COVID-19 drug repurposing research

At least 29 phase II–IV efficacy trials in COVID‑19 were concluded in March 2020 or scheduled to provide results in April from hospitals in China.[314][315] There are more than 300 active clinical trials underway as of April 2020.[124] Seven trials were evaluating already approved treatments, including four studies on hydroxychloroquine or chloroquine.[315] Repurposed antiviral drugs make up most of the Chinese research, with nine phase III trials on remdesivir across several countries due to report by the end of April.[314][315] Other candidates in trials include vasodilators, corticosteroids, immune therapies, lipoic acid, bevacizumab, and recombinant angiotensin-converting enzyme 2.[315]

The COVID‑19 Clinical Research Coalition has goals to 1) facilitate rapid reviews of clinical trial proposals by ethics committees and national regulatory agencies, 2) fast-track approvals for the candidate therapeutic compounds, 3) ensure standardised and rapid analysis of emerging efficacy and safety data and 4) facilitate sharing of clinical trial outcomes before publication.[316][317]

Several existing medications are being evaluated for the treatment of COVID‑19,[180] including remdesivir, chloroquine, hydroxychloroquine, lopinavir/ritonavir, and lopinavir/ritonavir combined with interferon beta.[308][318] There is tentative evidence for efficacy by remdesivir, as of March 2020.[319][320] Clinical improvement was observed in patients treated with compassionate-use remdesivir.[321] Remdesivir inhibits SARS-CoV-2 in vitro.[322] Phase III clinical trials are underway in the U.S., China, and Italy.[180][314][323]

In 2020, a trial found that lopinavir/ritonavir was ineffective in the treatment of severe illness.[324] Nitazoxanide has been recommended for further in vivo study after demonstrating low concentration inhibition of SARS-CoV-2.[322]

There are mixed results as of 3 April 2020 as to the effectiveness of hydroxychloroquine as a treatment for COVID‑19, with some studies showing little or no improvement.[325][326] The studies of chloroquine and hydroxychloroquine with or without azithromycin have major limitations that have prevented the medical community from embracing these therapies without further study.[124]

Oseltamivir does not inhibit SARS-CoV-2 in vitro and has no known role in COVID‑19 treatment.[124]

Anti-cytokine storm

Cytokine release syndrome (CRS) can be a complication in the later stages of severe COVID‑19. There is preliminary evidence that hydroxychloroquine may have anti-cytokine storm properties.[327]

Tocilizumab has been included in treatment guidelines by China’s National Health Commission after a small study was completed.[328][329] It is undergoing a phase 2 non-randomised trial at the national level in Italy after showing positive results in people with severe disease.[330][331] Combined with a serum ferritin blood test to identify cytokine storms, it is meant to counter such developments, which are thought to be the cause of death in some affected people.[332][333][334] The interleukin-6 receptor antagonist was approved by the FDA to undergo a phase III clinical trial assessing the medication’s impact on COVID‑19 based on retrospective case studies for the treatment of steroid-refractory cytokine release syndrome induced by a different cause, CAR T cell therapy, in 2017.[335] To date, there is no randomised, controlled evidence that tocilizumab is an efficacious treatment for CRS. Prophylactic tocilizumab has been shown to increase serum IL-6 levels by saturating the IL-6R, driving IL-6 across the blood-brain barrier, and exacerbating neurotoxicity while having no impact on the incidence of CRS.[336]

Lenzilumab, an anti-GM-CSF monoclonal antibody, is protective in murine models for CAR T cell-induced CRS and neurotoxicity and is a viable therapeutic option due to the observed increase of pathogenic GM-CSF secreting T-cells in hospitalised patients with COVID‑19.[337]

The Feinstein Institute of Northwell Health announced in March a study on “a human antibody that may prevent the activity” of IL-6.[338]

COVID-19 Vaccine Passive antibodies

Transferring purified and concentrated antibodies produced by the immune systems of those who have recovered from COVID‑19 to people who need them is being investigated as a non-vaccine method of passive immunisation.[339] This strategy was tried for SARS with inconclusive results.[339] Viral neutralisation is the anticipated mechanism of action by which passive antibody therapy can mediate defence against SARS-CoV-2. Other mechanisms, however, such as antibody-dependent cellular cytotoxicity and/or phagocytosis, may be possible.[339] Other forms of passive antibody therapy, for example, using manufactured monoclonal antibodies, are in development.[339] Production of convalescent serum, which consists of the liquid portion of the blood from recovered patients and contains antibodies specific to this virus, could be increased for quicker deployment.[340]

See also

Sources

COVID-19 Vaccine Development – WikiPedia

COVID-19 Drug Development – WikiPedia

Coronavirus disease 2019 – WikiPedia

This article uses material from the Wikipedia article “COVID-19 Vaccine”, which is released under the Creative Commons License.