SARS-CoV2

Cellular Responses to SARS-CoV-2

1. Both CD4 and CD8 T cell responses occur within 1-2 weeks of symptom onset 2. Th1 CD4 T cells will produce IFN-gamma, 3. CTL will produce IFN-gamma and TNF-alpha Both Th1 and CTL can be induced by spike, membrane, and nucleocapsid proteins along with non-structural proteins 4. Cross reactivity may exist with T cells 5. Breath and Strength of the immune response correlates with more severe disease

FDA approved treatments for COVID-19

1. COVID-19 Convalescent plasma: Hospitalized COVID-19 2. Veklury (remdesivir): Hospitalized 3. Bamlanivimab: mild to moderate COVID-19 4. Barcitinib with remdesivir: Hospitalized 5. Casivirimab + imdevimab: mild to moderate COVID-19 for patients who are at high risk

Humoral Response to SARS-CoV-2

1. IgM, IgA, IgG titers increase after the first week(s) following symptom onset and may persist from weeks to months after infection (3-6 months) 2. Will still have mem B cells after infection 3. Neutralizing antibodies are made against S1 and Nucleocapsid surface proteins on SARS-CoV-2 4. Low A.b response is associated with viral clearing while higher A.b response is associated with more serious disease Pre-existing A.b may help

What kind of immune response is desired from a vaccine?

1. Neutralizing A.b would be ideal Would want A.b that induce phagocytosis, ADCC, and complement 2. CD4 T cells to induce isotype switching for IgG and IgA A.b and memory B cell formation Also want CD4 to secrete IFN-gamma 3. CTL to kill infected cells

Pfizer/biotech Vaccine

A US/German Vaccine that is a lipid-nanoparticle formulated RNA vaccine Resulted in CD4/CD8 responses and neutralizing IgG A.b against RBD in S1 of the spike protein Deemed safe and effective, UK approved 95% effective stored at -70 degrees celsius

Bamlanivimab

A monoclonal A.b treatment for non-hospitalized COVID 19 patients with mild or moderate cases neutralizing IgG monoclonal A.b that binds the S1 RBD portion of the spike protein More safe and effective to use than convalescent plasma

Sars-CoV-2 Structural biology

A relatively larger virus with a 30 kilobasepair RNA genome Encodes structural proteins: 1. Nucleocapsid: encapsule genome 2. Spike: interaction with the host via attachment 3. Envelope: structural envelope proteins to help form shape and maintain size 4. Membrane: Structural envelop proteins to help form shape and maintain size

SARS-CoV

A virus that persisted primarily in Asia from Nov 2002 - July 2003 Originated in bats- palm Cilvets and then humans 8098 cases with 800 deaths (higher fatality rate then CoV2) Tropic to lower airways

Novavax vaccine

Adjuvanted spike glycoprotein in a synthetic nanoparticlesubunit vaccine Neutralizing response to spike protein but T cell response unknown Efficacy not known

ACE-2 expression and location of COVID-19 in body

Angiotensin-converting enzyme 2 is expressed in the lungs, small intestine, kidneys, and heart of humans Need ACE-2R with the host proteases TMPRSS2 is coexpressed with ACE-2R in nasal epithelial cells, lungs, and bronchial branches explaining the upper respiratory tropism of SARS-Cov2

Casirivimab and imdevimab

Artificial antibody cocktail developed by Regeneron used to treat mild to moderate COVID 19 that are at risk for serious disease Uses two monoclonal A.b against the spike protein to ensure the virus can escape via a single mutation Used by Trump

Sinovac vaccine

Chemically inactivated whole virus vaccine Anti-RBD and neutralizing responses but no cellular responses reported efficacy unknown

Sinopharm/ Wuhan and Beijing Institute of Biological Products

Chinese vaccines that use Inactivated whole virus with alum adjuvant Both showed neutralizing response but no cellular responses measured Been approved by various countries and is being administered Efficacy unknown

Epidemiology of SARS-CoV2

Global Case Number = 67,189,474 Global Fatalities = 1,538,097 America has 14 million cases with about 280 thousand deaths Minnesota is one of the hot spots within the United States right now Rising cases may be due to cold weather and clustering of people indoors

SARS-CoV2 Therapeutic Drugs research

In early December 359 therapeutic drugs are in clinical trials Repurposed Drugs make up the majority of those drugs which includes 1. Anti-viral drugs: Inhibit Viral entry, exit, or replication 2. Immune modulatory drugs: anti-inflammatory drugs like corticosteroids, anti-IL6, anti-IL-5, anti-IFN-alpha

Moderna / National institute of Allergy and Infectious Disease Vaccine

Lipid nanoparticle RNA vaccine Resulted in CD8 response, margnial Th1 and neutralizing IgG 94% effective and is stored at -40 degrees Celsius

Why did MERS and SARS-CoV not lead to a pandemic?

MERS and SARS are tropic to the lower airways which makes them less infectious and less contagious of a disease Also both of these corona-viruses have peak viral loads after symptom onset which allows people to properly isolate

MERS-CoV

Middle East Respiratory Syndrome Coronavirus Originated in Saudi Arabia in 2012 until present Jumped from Dromedary Camel to humans 2494 cases and 858 deaths making it the most lethal of the three coronaviruses Tropic to lower airways

Sars-CoV-2 general

Originated in Wuhan in Dec 2019 Jumped from Bats to a (pangolin) to humans Tropic to upper airways which makes it more infectious because people are exhaling more virus Symptoms begin to show AFTER viral peak which leads to asymptomatic spreading

Convalescent plasma

Plasma purified from patients who have recovered from COVID 19 and have specific A.b against SARS-CoV2 The first available treatment that was used as a filler until better treatments come along May cause adverse effects however 1. A.b mediated enhancement of infection 2. Allergic transfusion reaction 3. Transfusion-associated acute lung injury due to anti-HLA A.b in serum

University of Oxford/ Astrazeneca vaccine

Replication deficient chimpanzee adeno-vectored vaccine Resulted in IFN-gamma T cell response and neutralizing IgG paused a few times but were deemed unrelated issues to vaccine 1/2 dose plus a full dose deemed 90% effective which may be due to T cell overstimulation Stored at 2-8 degrees Celsius

Janssen Pharmaceutical companies of Johnson and Johnson vaccine

Replication-deficient adenovirus serotype 26 vectored vaccine CD4/CD8 and neutralizing response Efficacy unknown

Gamaleya vaccine

Russian vaccine that uses Recombinant adenovirus serotype 26 and Sputnik 5 vectors in two doses CD4/CD8 and neutralizing response 92% effective out of 20 COVID cases so unknown how it will apply to the greater population

Why may low A.b responses against SARS-Cov2 be associated with higher viral clearance?

The reason is still unknown but there's been speculation that pre-existing A.b against seasonal corona viruses may offer some degree of cross protection which may dampen the effects of COVID-19 This would lead to less A.b needed to be produced Could explain why children do well with this pandemic

Sars-CoV-2 entry

The spike protein binds to angiotensin-converting enzyme 2 (ACE2) receptor Host proteases like host transmembrane proteases serine (TMPRSS2) will cleave the spike protein into two fragments 1. S1 will catalyze cell attachment and is the sight for neutralizing antibodies 2. S2 will mediate cell fusion with the outercapsule and the cell membrane for viral genome release

Corona virus pathogenicity

There have been 5 human corona viruses that have lower pathogenicity Three have high pathogenicity and can lead towards a cytokine storm due to an over-activated immune system which can lead to multiple organ failure and death 1. Severe-acute-respiratory syndrome coronavirus 2. Middle East respiratory syndrome related coronavirus 3. SARS-Cov2

COVID-19 vaccine guideline for FDA

They are looking for a vaccine that balances humoral and cell mediated responses considered efficacious when 50% of people from disease not infection Would be ideal if only two doses were need 2-4 weeks apart

Corona Viruses

This is a large family of enveloped ssRNA viruses They infect both mammals and birds and typically result in respiratory illness Is transmitted primarily through droplets from coughing and sneezing patients and will result in a mild upper respiratory infection like the common cold Three relatively new strains lead to more serious infection