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Where did COVID-19 come from, and how to deal with it?

The London biotech fund 4BIO Capital has written a memo for its investors with an understandable, but knowledge-based review of the origin of the virus, domestic aspects and the current situation with drugs and vaccines. This text may be of interest to a wider audience.

Translator is not affiliated with the foundation

Introduction


The world is faced with the largest threat to human health almost exactly 100 years after the Spanish flu epidemic. Thanks to the development of technologies that ensure the rapid development of drugs and vaccines, teleworking and coordination, we can and should hope for a quick solution to the problem and a much smaller number of victims.

In this memo, you will learn about the nature of the virus and the epidemiology of COVID-19, the status of drug development and the risks that we see at the time of writing (March 20).

Main thought:Considering the significant similarities between receptor proteins and SARS-CoV and SARS-CoV-2 proteases, we believe that a significant part of the current crisis could have been prevented. Sponsoring the SARS-CoV study in the mid-2000s should not have stopped until a working vaccine and protease inhibitors were found. Sponsoring organizations, politicians, the pharmaceutical industry, and the venture capital community should do everything possible to prevent a similar story from happening with SARS-CoV-2.

Prerequisites. Fundamentals of Virology and Epidemiology


The causative agent of COVID-19 is SARS-CoV-2 from the coronavirus family. Its closest relatives are the SARS-CoV virus (their genomes are similar by about 79%), and the MERS-CoV virus with a similarity of 50%. These are enveloped viruses with a genome represented by single-stranded (+) RNA, the nucleocapsid of which forms a helical structure. The size of the coronavirus genome varies from approximately 27 to 34 kilobases (29.9 for SARS-CoV-2), and is the largest known RNA virus (the size of SARS-CoV-2 is 29.9 kilobases).

Compared with the seasonal influenza virus, SARS-CoV-2 is characterized by both a higher infectivity (basic reproductive number 2.0–2.5 versus 1.3 for influenza) and a higher severity of the disease, both in terms of the number of hospitalizations (~ 20% versus ~ 2%) and mortality (~ 3% versus ~ 0.1%). In this regard, SARS-CoV-2 also contrasts sharply with its immediate family, with much less severe symptoms than SARS-CoV and MERS-CoV (with mortality rates of about 10% and 35%, respectively).

The clinical manifestations of various CoV infections vary greatly depending on the specific type of coronavirus. Most of them occur in a mild form without symptoms, and can occur with symptoms of a cold and even result in death in 30% of cases (for example, when infected with MERS-CoV). Among the most common symptoms are colds, with fever, tonsillitis, primary viral pneumonia and / or bronchitis, as well as secondary bacterial pneumonia and / or bronchitis. SARS-CoV, better known as Severe Acute Respiratory Syndrome, or SARS, caused inflammation of the upper and lower respiratory tract. MERS-CoV, the Middle East respiratory syndrome, or MERS, manifested as fever, cough, shortness of breath, gastrointestinal disturbances (mainly diarrhea), with or without pneumonia.In some infected patients, the disease was asymptomatic. MERS was associated with high mortality, and the symptoms could progress to adult respiratory distress syndrome, multiple organ failure, and sepsis.



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Today, unlike the influenza virus, members of the coronavirus family have shown little ability to genetic reassortment. It is she who is responsible for the serious genetic changes that underlie the known influenza pandemics, to which humanity has not developed immunity.

Nevertheless, in the coronavirus family, special adaptation mechanisms have been developed that were observed in MERS-CoV and SARS-CoV, and are likely to manifest in SARS-CoV-2. Coronaviruses disrupt several stages of the primary immune response, including RNA detection, type 1 interferon signaling pathway, and STAT1 / 2 activation in the direction of interferon / interferon Ξ± receptors. Not only the severity of the disease depends on this, but also the uncharacteristically long incubation period (up to 14 days compared to 1–4 for the flu).

Currently, there is no reliable data on the existence of long-term immunity to SARS-CoV-2. A study (Bao et al., 2020) published on BioRxiv showed no re-infection in macaques after primary infection. However, the study was conducted on only 4 animals, and it considers only a short-term reaction. If SARS-CoV-2 behaves similarly to SARS-CoV and MERS-CoV, then SARS-CoV-specific immunoglobulin G and neutralizing antibodies are detected within 2 years after infection, which indicates the possibility of a long-term immunity in the patient.

Mortality


Although mortality from SARS-CoV-2 is significantly lower than from its immediate family (see statistics above), the number of deaths increases dramatically with age. The disease is largely asymptomatic in children and a large number of young people (it is estimated that in 50–70% of cases the disease is asymptomatic), but in the age group over 70, mortality ranges from 5 to 10% (depending on the quality of hospital care) .

Practical aspects


  • SARS-CoV-2 spreads through the air and is viable for several hours on various surfaces (the half-life in aerosol and copper is 1 hour, on cardboard for almost 4 hours, on steel - 6, on plastic - 7 hours: www.nejm .org / doi / 10.1056 / NEJMc2004973 );
  • SARS-CoV-2 62–70% , 0,5% ( ). ;
  • , SARS-CoV-2 37 , , , ( ., 2020). , SARS-CoV 60 , , SARS-CoV-2 , , ;
  • , COVID-19, , – , ;
  • Early reports from China indicate that intrauterine transmission of COVID-19 from pregnant women to the fetus does not occur, and SARS-CoV-2 does not pose a particular additional risk to pregnant women beyond the usual flu symptoms.

Treatment and vaccines: progress to date


In response to the epidemic, both scientific and industry communities have become extremely active. In particular, the early decoding of the sequence of the viral genome and the subsequent publication of the crystal structure of key surface proteins accelerated the work of researchers. Thanks to this, the development of drugs is carried out at a fairly fast pace.

Due to the rapidly deteriorating situation in the world, some old-generation drugs are not used for their intended purpose, despite the low level of evidence of their effectiveness. One of them is the inhalation of interferon alfa, and the other is the lopinavir / ritonavir combination, which was originally developed for the treatment of HIV (Jin et al., 2020). In addition, Gilead recently began clinical trials of the antiviral drug remdesivir, designed to treat Ebola. The studies of remdesivir aroused considerable interest among many observers of the biopharmaceutical industry and the scientific community due to its noticeable activity against COVID-19 in the laboratory (study by Wang, Cao, Jang et al.,2020) and the ability of Gilead to produce and accelerate the delivery of the drug to the market in the United States due to the existing infrastructure. In addition, the old antimalarial generic chloroquine showed some positive results among the first group of patients with COVID-19 in China (Coulson et al., 2020). Along with redeveloped drugs, at least 22 medical products are currently being developed at various pharmaceutical companies and research institutes specifically for COVID-19 therapy. As with drugs against other viruses, much of the effort is focused on finding protease inhibitors.Along with redeveloped drugs, at least 22 medical products are currently being developed at various pharmaceutical companies and research institutes specifically for COVID-19 therapy. As with drugs against other viruses, much of the effort is focused on finding protease inhibitors.Along with redeveloped drugs, at least 22 medical products are currently being developed at various pharmaceutical companies and research institutes specifically for COVID-19 therapy. As with drugs against other viruses, much of the effort is focused on finding protease inhibitors.

At the time of writing (March 20), at least 69 independent attempts to produce a vaccine against COVID-19 were made in the world, of which there are more than 20 in China. The three vaccines under development against COVID-19 are described below, which seem to us the most promising :

  1. On March 16, for 45 healthy volunteers, the first stage of clinical trials for the safety of the mRNA-1273 vaccine under study began. It was developed by the National Institute of Allergy and Infectious Diseases (NIAID) in collaboration with Moderna, Inc. The work was based on previous projects for the development of other stud vaccines on the surface of other coronaviruses, SARS and MERS. The active phase of the study will take at least 4 months, and subsequent follow-up - more than a year;
  2. 17 Pfizer Inc. BioNTech SE – BNT162. 2020 . 2018 , BNT162. , 13 2020 Pfizer , COVID-19;
  3. 26 Novavax ; -. - SARS MERS, - .

Other biotechnology companies and research institutes are also working to create a vaccine or drugs for the treatment of COVID-19. DNA vaccines (Inovio, Entos Pharma, etc.), protein-based vaccines (Sanofi, AJ Vaccines, etc.), viral vector-based vaccines (J & J, Altimmune, etc.), live attenuated vaccines are considered as vaccines. (Institute Pasteur, Codagenix). Several ways are used to search for treatment: neutralizing viral particles with antibodies (Takeda, NIH, etc.), small molecules (Insilico Medicine, Enanta Pharma, etc.), small interfering RNAs (Vir Biotech, Sirnaomics), and even cell therapy (Sorento Therapeutics) . While there is no forecast of the effectiveness and timing of the development of new drugs against COVID-19.

In general, we strongly believe that both ways of developing vaccines (new mRNA / DNA vaccines and classic viral vector vaccines) should be used, and it would be optimal if two or three vaccines can be used simultaneously. Now it’s completely unclear whether the commercial vaccine against COVID-19 can be successful, so at the moment cooperation is much preferable to competition.

Moreover, we believe that in the future, the main priority for charitable organizations and politicians should be getting a full-fledged working vaccine and therapeutic drugs in order to finally draw conclusions from the history of SARS-CoV. Success in producing cross-reactive CoV-CoV2 antibodies indicates that if we had a vaccine and a drug for SARS therapy, the situation could be completely different. However, unfortunately, the flow of investment in SARS research has dried up soon after the media turned its attention to other topics, and the work was never completed.

This time we have to do more.

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