Websites of interest: Coronavirusgov. Travel Restrictions. Covid treatments CDC case tracker CDC covid-19 county check (check levels of Covid-19 in your county)
Find Covid-19 Medications and clinics (rapid treatment of COVID-19 is very important. This site from hhs.gov provides a map which displays pharmacies, clinics with safe and effective COVID-19 medicaitons)
Clinical Trials: VIR-7831 (antibody)
Introduction
COVID-19 is a new coronavirus detected first in 2019, in Wuhan City, Hubei Province, China.. It is not the same as the coronaviruses that commonly circulate among humans and cause mild illness, like the common cold. The first infections were linked to a live animal market.
COVID-19 was later named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the beta coronavirus family. It is the seventh known coronavirus to infect humans; four of these coronaviruses (229E, NL63, OC43 and HKU1) only cause slight symptoms of the common cold. Coversely, the other three, SARS-CoV, MERS-CoV and SARS-CoV-2, are able to cause severe symptoms and even death, with fatality rates of 10%, 37% and 5%, respectively. (Huang Acta Pharmacologica Sinica 41 (1141-1149 (2020).
Structure/pathological agent
COVID-19 is cuased by a novel virus strain, SARS-CoV-2, an enveloped, positive-sense, single-standed RNA betocoronavirus of the family Coronaviridae.
Sequence analysis of SARS-CoV-2 isolates suggests that the 30kb genome encodes as many as 14 open reading frames (Orfs). The 5′ Orf1a/Orf1ab encodes polyproteins, which are auto-proteolytically processed into 16 non-structural proteins (Nsp1-16) which form the replicase/transcriptase complex (RTC). The RTC consists of multiple enzymes, including the papain-like protease (Nsp3), the main protease (Nsp5), the Nsp7-Nsp8 primase complex, the primary RNA-dependent RNA polymerase (Nsp12), a helicase/triphosphatase (Nsp13), an exoribonuclease (Nsp14), an endonuclease (Nsp15), and N7- and 2’O-methyltransferases (Nsp10/Nsp16). At the 3′ end of the viral genome,a s many as 13 Orfs are expressed form nine predicted sub-genomic RNAs. These includes four structural proteins: Spke (S), Envelope (E), Membrane (Ma) and Nucleocapsid (N), and nine putative accessory factors. In genetic omposition, the SARS-CoV-2 genome is very simialr to SARS-CoV; each has an Orf1ab encoding 16 predicted Nsps and each has the fourt typical coronavirus structural proteins. However, they differ in their complement of 3′ open reading frames:
Cell entry (S (“Spike”) Protein): A large number of glycosylated S proteins cover the surface of SARS-CoV-2 and bind to the host cell receptor angiotensin-coverting enzyme 2 (ACE2), mediating viral cell entry. When the S protein binds to the receptor, TM protease serine 2 (TMPRSS2), a type 2 TM serine protease located on the host cell membrane, promotes virus entry into the cell by activating the S protein. Once the virus enters the cell, the viral RNA is released, polyproteins are translated form the RNA genome and replication and transcription of the viral RNA genome occur via protein cleavage and assembly of the replicase-transcriptase complex. (Huang Acta Pharmacologica Sinica 41 (1141-1149 (2020).
The spike (S) protein of coronaviruses facilitates viral entry into target cells. Entry depends on binding of the surface unit, S1, of the S protein to a cellular receptor, which facilitates viral attachment to the surface of target cells. In addition, entry requires S protein priming by cellular proteases, which entails S protein cleavage at the S1/S2 and the S2’ site and allows fusion of viral and cellular membranes, a process driven by the S2 subunit . SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. See Hoffman
With a size of 180-200 kDa, the S protein consists of an extracellular N-terminus, a transmembrane (TM) domain anchored in the viral membrane, and a short intracellular C terminal segment. S normally exists in a metastable, prefusion conformation; once the virus interacts with the host cell, extensive structural rearrangement of the S protein occurs, allowing the virus to fuse with a host cell membrane. The spikes are also coated with polysaccharide molecuels to camouglage them, evading surveillance of the host immune system during entry. (Huang Acta Pharmacologica Sinica 41 (1141-1149 (2020).
The total lenght of the S protein is 1273 aa and consists of a signal peptide (amino acids 1-13) located at the N-termnus, the S1 subunit (14-685 residues) and the S2 subunit (686-1273 residues). The last two regions are responsible for receptor binding and membrane fusion, respectively. (Huang Acta Pharmacologica Sinica 41 (1141-1149 (2020).
Replication/transcription:
–RNA-dependent RNA polymerase (RdRp) is an enzyme that synthesizes RNA from an RNA template. It is a critical component for the replication and transcription of all RNA viruses, as host cells do not possess this enzyme. The function of RdRp makes it a major therapeutic target for antiviral drugs, such as those used to treat COVID-19.
As with all positive strand RNA viruses, an RdRp lies at the core of the viral replication machinery and for CoVs this is the nsp12 protein. The pivotal role of nsp12 in the viral life-cycle, lack of host homologues and high level of sequence and structural conservation makes it an optimal target for therapeutics.
RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is the prime interest for
drug development due to its high conservation of amino acids within the beta-coronaviridae
virus family. Several RdRp inhibitors including remdesivir, sofosbuvir, galidesivir, tenofovir, and ribavirin have been tested for their efficacy against SARS-CoV-2; however, the first available antiviral treatments were 3C-like protease inhibitors such as lopinavir/ritonavir. While only remdesivir has been approved by WHO as an antiviral drug to treat COVID-19, all the RdRp inhibitors further develop a selective pressure on the virus that may contribute to the emergence of drug resistance as they all are nucleoside analogs and have a common mechanism of action. (Mandall, “Evolution of Antiviral Drug Resistance in SARS-CoV-2”)
Transmission/People at most risk
People at most risk for COVID-19 are older adults (65 years and older) and people who have serious underlying medical conditions such as heart disease, diabestes and lung disease.
COVID-19 seems to spread easily and sustainably in the community in some affected geographic areas.
Symptoms
The symptoms from COVID-19 can last from a few days to several weeks. Current guideleines recommend staying home for at elast five days or until symptoms have resolved.
Infection with COVID-19 can result in Acute Respiratory Distress Syndrome (ARDS), which may lead to long-term reduction in lung function, arrhythmia, and death.
Treatment options:
Most people with COVID-19 do not need a prescription, but oral antiviral treatment optins are available to treat mild to moderate COVID-19 in people who are more likely to get very sick. This can include older adults ages 50 and over, people who are unvaccinated, those with certain medial conditions (like chronic lung or heart disease) or those who have a weakened immune system. As with the flue, recoveirng from COVID-19 requires resting and staying hydrated. For a fever or body aches, ibuprofen or acetaminophen can help. Mucinex (guaifenesin) or Robitussin may help with cough and congestion.
Oral Antivirals:
oral antivirals are pills that stops the virus that causes COVID-19 form kaing copies. One antiviral is called Paxlovid and another is called Lagevrio (also knonw as monupiravir). Paxlovid is for adults and children 12 and older, weighing at least 88 poouns whoa re at high risk of getting very sick ffrom COVID-19 and who have mild to moderate symptoms. Lagevrio is for adults 18 years and older who are a t high risk fir gettubg vert sick from COVID-19 and who do not have access to other outpatient treatment options. If you are eligible, start using oral antivirals as soon as possible, no later than 5 days after your first symptoms appears. These pills are taken two time a day for 5 days.
Antiviral medications (Lagevrio [molnupiravir], Paxlovid [nirmatrelvir and ritonavir], and Veklury [remdesivir]) and monoclonal antibodies (bebtelovimab) are available to treat COVID-19 in persons who are at increased risk for severe illness,** including older adults, unvaccinated persons, and those with certain medical conditions. Antiviral agents reduce risk for hospitalization and death when administered soon after diagnosis. The federal Test to Treat initiative facilitates rapid, no-cost access to oral COVID-19 treatment for eligible persons who receive a positive SARS-CoV-2 test result. Recent expansion of prescribing authority of Paxlovid to pharmacists intends to further facilitate access. See CDC article
IL-6 receptor antogonists: Actemra (tocilizumab) was approved by the FDA in 2010 as the first IL-6 receptor antagonist autorized for rheumatoid arthritis. . Genentech, a member of the Roche Group has launched a Phase III trail to assess its marketed arthritis drug Actemra (tocilizumab) as a treatment for adults with severe COVID-19.
Neuraminidase inhibitors (NAIs).
–Tamiflu (Oseltamivir): is used to treat symptoms cause by the flue virus (influenza). It helps make the stymptoms such as cough, sore throat, ever/chills,e tc less sever and shortens the recovery time by 1-2 days. The drug was developed by Gilead Sciences and is marketed by Genentech. It is part of a COVID-19 clinical trial being held at Rajavithi University in Bangkok, Thailand. The trail combines protease inhibitors, Tamiflue and favipiravir with chloroquine, a drug used to treat malaria.
Nucleoside analogues (NAs): A promising class of RdRp inhibitors are nucleoside analogues (NAs), small molecule drugs that are metabolised intracellularly into their active ribonucleoside 5′-triphosphate (RTP) forms and incorporated into the nascent viral RNA by error-prone viral RdRps. This can disrupt RNA synthesis directly via chain termination, or can lead to the accumulation of deleterious mutations in the viral genome. For CoVs, the situation is complicated by the post-replicative repair capacity provided by the nsp14 exonuclease (ExoN) that is essential for maintaining the integrity of their large ~30 kb genomes.
–Remdescivir by Gilead Sciences is a nucleotide analog with broad spectrum antiviral activity against Ebola, Marburg, MERS and SARS. Remdesivir is a polymerase (RdRP) inhibitor and recent data suggests a new nucleotide analog may be effective agaisnt SARS-CoV-2 infection in laboratory animals.
—-Remdesivir+dexamethasone was associated with a significant reduction in 14- and 28-day mortality compared to dexamethasone alone in patients hospitalized for COVID-19 across all levels of baseline respiratory support, including IMV/ECMO. However, the use of remdesivir+dexamethasone still has low clinical practice uptake. In addition, these data suggest a need to update the existing guidelines. Global Center for Health Security
–Favipiravir is an influenza drug marketed by a subsidiary of FujiFilm, which has shown encouraging results in Chinese clinical trails in 340 COVID-19 patients.
Anti-VEGF: Avastin (bevacizumab) is a recombinant humanized mAb against VEGF. It is approved to treat several fomrs of cancer, including colorectal, non-small cell lumch cancer (NSCLS), kidney cancer, cervical cancer, ovarian cancer and recurrent glioblastoma. Amgen’s Mvasis, the generic version of Geentech’s Avastin is being tested in at least one clinical trail in China against COVID-19 penumonia.
Neutralizing antibodies: primarily target the trimeric spike (S) glycoproteins on teh viral surface that mediate entry into host cells. The S protein has two functional subunits that mediate cell attachment (the S1 fusion of the viral and cuellular membrane (the S2 subunit). Potent neutralizing antibodies often target the receptor interaciton site in S1, disabling receptor interactions. The spike proteins of SARS-CoV-2 (SARS2-S; 1273 residues, strain Wuhan-Hu-1) and SARS-CoV (SARS-S, 1255 residues strain Urbani) are 77.5% identical by primary amino acid sequence, are structurally very similar and commonly bind the human angiotensin coverting enyzme 2 (ACD2) protein as a host receptor through their S1 domain.
–Bamianivimab (Eli Lilly):
Bamlanivimab is a recombinant, neutralizing human IgG1 monoclonal antibody (mAb) directed against the spike protein of SARS-CoV-2. It was designed to block viral attachment and entry into human cells, thus neutralizing the virus. Bamlanivimab was developed from an antibody that was discovered from the blood of a recovered COVID-19 patient using AbCellera’s pandemic response platform, in partnership with the Vaccine Research Center (VRC) at the National Institutes for Allergy and Infectious Diseases (NIAID). Within one week of receiving the sample, AbCellera screened over five million antibody-producing cells to identify and isolate approximately 500 unique antibodies that bind to SARS-CoV-2. The binding antibodies were then tested by AbCellera, the VRC, and Eili Lilly to find those most effective in neutralizing the virus. Bamlanivimab was selected as the lead candidate from this group of antibodies and was both the first therapeutic candidate specifically developed against SARS-CoV-2 to enter human clinical trials in North America, and to receive EUA from the FDA. Bamlanivimab alone and/or administered with etesevimab were authorized under special use pathways in more than 22 countries. In the U.S.. (See US Patent Nos: 11,370,828 and US 11,447,541).
–Sotrovimab (GlaxoSmithKline): was approved by the FDA on May 26, 2021 for emergency use for teh treatment of mild to moderate COVID-19 in adults and pediatric patients who are at high risk for progression to severe COVID-19. It is a recombinant human IgG1k monoclonal antibody that binds to a conserved epitope on the spike protein receptor binding domain of SARS-CoV-2. Sotrovimab does nto compete with human ACE2 receptor binding.
Sotrovimab is effective against the Omnicron variant and can be administered in house
Polymerease inhibitors: work by stopping the viru’s genetic material from being replicated accurately. It fools the enzyme (called a polymerease) responsible for replciating the virus’s RNA so that it inserts errors or mutations. The mtuations then get replicated until there are so many mutations that the virus can no longer survive.
–Molnupiravir (Merck): is an antiviral originally developed to treat flu viruses.
Protease inhibitors: block an enzyme called a protease that cuts apart long strands of nonfuncitonal viral proteins into smaller, functional proteins.
–-Paxlovid: (Pfizer): is a combination of PF007321332 and an exisitng drug called ritonavir. Both are protease inhibitors. PF007321332 is the star of the show in the drug duo because it works on the virus itself, while ritonavir stops other enzymes form destroying PF-007321332. As with Merck’s Molnupivavir, treatment should start within five days of symptoms. It is important to ask for this treatment as soon as you know you have Covid.
Total revenues for Pfizer increased by 7% (4 billion) to 63.6 billion in 2024 primarily driven by Paxovid. (see form 10-K)
Vitamins: Resveratrol, quercetin, famotidine, NAC and melatinin.
HIV medications: Abbvies HIV medication Kaletra (Aluvia) which is a combination of antiviral drugs Iopinavir and ritonavir has been used against coronavirus. But one clincial trial showed that clinical symptoms did not improve with the drug.
Cancer Drugs:
–Acalabrutimib: rapid improvements in actutely ill patients with COVID-19 has been seen by adminsitering this cancer drug.
Diagnostics/Detection:
Antibody tests:
The FDA first approved antibody test for COVID-19 was granted to Cellex. The test is perforemd on a blood sample taken from a patient’s veine.
Mayo Blinic has developed its own antibody test.
Standorm Medicine have developed an antibody test that was luanched April 6 at Standord Health Care. The test provides resutls in 2-3 days.
Ortho Clinical Diagnostics has release a COVID-19 VITROS antibody test.
Testing for the corona-virus itself
–Saliva Test. Vault Saliva Test (can be done at home)
The FDA has approved Rutgers’ RUCDR infinite Biologics for its test that uses saliva. The test was developed by RUCDR with Spectrum Solutions and Accurate Idagnostic Labs.
–Swab tests (test for current infection)
–Rapid Testing (15 minutes of less)
Sofia SARS antigen. Innova Rapid Antigen Testing
–Testing of Buildings and Sites rather than People:
Testing for Covid & Flu simultaneously:
Healgen Rapid Check COVID-19/Flu A&B Antigen Test is available without a prescription.
Vaccination:
August 2024: The FDA approved and granted emergency use authorization (EUA) for updated mRNA COVID-19 vaccines (2024-2025 formula) manufactured by ModernaTX Inc. and Pfizer Inc. to include a monovalent (single) component that corresponds to the Omicron variant KP.2 strain of SARS-CoV-2. The mRNA COVID-19 vaccines have been updated with this formula to more closely target currently circulating variants and provide better protection against serious consequences of COVID-19, including hospitalization and death. See FDA news
mRNA vaccines contain material from the virus that causes COVID-19 that gives our cells instructions for how to make a harmless protein that is unique to the virus. After our cells make copies of the protein, they destroy the genetic material from the vaccine. Our bodies recognize that the protein should not be there and build T-lymphocytes and B-lymphocytes that will remember how to fight the virus that causes COVID-19 if we are infected in the future. Protein subunit vaccines include harmless pieces (proteins) of the virus that causes COVID-19 instead of the entire germ. Once vaccinated, our bodies recognize that the protein should not be there and build T-lymphocytes and antibodies that will remember how to fight the virus that causes COVID-19 if we are infected in the future. Vector Virus Vaccines contain a modified version of a different virus than the one that causes COVID-19. Inside the shell of the modified virus, there is material from the virus that causes COVID-19. This is called a “viral vector.” Once the viral vector is inside our cells, the genetic material gives cells instructions to make a protein that is unique to the virus that causes COVID-19. Using these instructions, our cells make copies of the protein. This prompts our bodies to build T-lymphocytes and B-lymphocytes that will remember how to fight that virus if we are infected in the future. See CDC
Drug Resistance Mechanisms:
High replication rate, multiple mutations, immune escape strategies, incomplete suppression, drug pressure, and prolonged exposure due to overuse, along with global spread, are the major causes behind the rapid emergence of drug resistance in SARS-CoV-2 (Mandall, “Evolution of Antiviral Drug Resistance in SARS-CoV-2”)
Glycan-Associated:
The spike protein of SARS-CoV-2 and its mammalian receptor ACE2 are both highly glycosylated. Notably, these glycans are essentially involved in and responsible for viral infectivity as well as in host immune dodging, thus playing an important role in the development of drug resistance. Importantly, spike protein glycans alter their binding affinity towards ACE2 by modulating the conformation and stability that directly affects viral infectivity leading to resistance development. (Mandall, “Evolution of Antiviral Drug Resistance in SARS-CoV-2”)
Mutations in Nsp12:
Nsp12 is an essential part of the SARS-CoV-2 RNA polymerase involved in the RNA
synthesis initiation of genetic replication. Nsp12 forms a functional RdRp complex by
interacting with nsp7 and nsp8, which regulate the replication–transcription complex. Due
to its crucial role in SARS-CoV-2 replication, nsp12 has been recognized and targeted as the
main target for antivirals. Importantly, mutations in the active site of nsp12 could play a
significant role in SARS-CoV-2 resistance development against antivirals. (Mandall, “Evolution of Antiviral Drug Resistance in SARS-CoV-2”)
Immune Response:
A close interaction between the virus SARS-CoV-2 and the immune system of an individual results in a diverse clinical manifestation of the COVID-19 disease. While adaptive immune
responses are essential for SARS-CoV-2 virus clearance, the innate immune cells, such as macrophages, may contribute, in some cases, to the disease progression. Macrophages have
shown a significant production of IL-6, suggesting they may contribute to the excessive inflammation in COVID-19 disease. Macrophage Activation Syndrome may further explain the high serum levels of CRP, which are normally lacking in viral infections. In adaptive immune responses, it has been revealed that cytotoxic CD8 + T cells exhibit functional exhaustion patterns, such as the expression of NKG2A, PD-1, and TIM-3. Since SARS-CoV-2 restrains antigen presentation by downregulating MHC class I and II molecules and, therefore, inhibits the T cell- mediated immune responses, humoral immune responses also play a role.