COVID and the Common Cold Notes

Respiratory and Gastrointestinal Systems

Learning Outcomes

• Identify the origins and causes of common cold.
• Identify the origins and causes of human coronavirus infections.
• Explain the approaches used to develop human coronavirus vaccines.
• Outline the effects of Long Covid-19 infection and the limitation of our current understanding.
• List practices that help to limit the spread of human coronavirus infections.

Overview of Viral Infections

• Common Cold:
  • Rhinoviruses
  • Parainfluenza virus
  • Respiratory syncytial virus
• Gingivostomatitis:
  • Herpes simplex type 1
  • Epstein-Barr virus
• Eye infections:
  • Herpes simplex virus
  • Adenovirus
  • Cytomegalovirus
• Pharyngitis:
  • Adenovirus
• Parotitis:
  • Mumps virus
• Pneumonia:
  • Influenza virus, Types A and B
  • Parainfluenza virus
  • Respiratory syncytial virus
  • Adenovirus
  • SARS coronavirus
• Gastroenteritis:
  • Adenovirus
  • Rotavirus
  • Norovirus
  • Astrovirus
  • Coronavirus
• Hepatitis:
  • Hepatitis virus types A, B, C, D, E
• Pancreatitis:
  • Coxsackie B virus
• Cardiovascular:
  • Coxsackie B virus
• Encephalitis/meningitis:
  • JC virus
  • Measles
  • LCM virus
  • Arbovirus
  • Rabies
• Myelitis:
  • Poliovirus
  • HTLV-I
• Brain inflammation:
  • Cytomegalovirus
• Skin infections:
  • Varicella zoster virus
  • Human herpesvirus 6
  • Smallpox
  • Molluscum contagiosum
  • Human papillomavirus
  • Parvovirus B19
  • Rubella
  • Measles
  • Coxsackie A virus
• Sexually transmitted diseases:
  • Herpes simplex type 2
  • Human papillomavirus
  • HIV
• Warts:
  • Human papillomavirus
• Virus transmitted by infected saliva through bite or wound:
  • Rabies

Viral Replication

• Viruses depend on living cells to propagate.
• They enter host cells and redirect the cell's metabolism.
• They substitute the cell's RNA with their own and produce more viruses internally.

Common Cold

• Defined by NICE as a mild, self-limiting, upper respiratory tract infection characterized by nasal stuffiness and discharge, sneezing, sore throat, and cough.
• The term has been used for centuries, often associated with the belief that exposure to cold causes symptoms.
• Respiratory viruses like rhinoviruses were discovered in the 1950s as the cause of the common cold, providing a scientific explanation.
• All known respiratory viruses can produce the illness complex recognized as the common cold.

Iceberg of Virus Infection

• The illness complex recognized as a common cold is only a part of what is often called the iceberg of virus infection.
• Ascending severity of disease:
  • Asymptomatic
  • Common Cold
  • Flu-like illness
  • Pneumonia
  • Death/Respiratory Failure
• The threshold of symptom severity for self-diagnosis is a common cold.

Characteristics

• Common cold is often referred to as a “head cold,” meaning the symptoms are located in the upper airways.
• More severe symptoms indicate a “flu-like illness.”

Risk factors for common cold

• Sex
• Age
• Smoking & alcohol
• Immune status
• Sociability
• Crowding
• Exercise
• Sleep
• Nutrition
• Stress
• Season
• Chilling

Treatments for Common Cold

• No vaccines for the common cold exist yet.

Morbidity and mortality

• Morbidity and mortality are often not fully appreciated due to the familiarity of the syndrome and complexity caused by hundreds of different serotypes of the virus.
• Human respiratory syncytial virus (RSV)
  • One death in every 50 attributable to RSV infection in children aged 0–60 months and one death in every 28 for children aged 28 days–6 months.
  • RSV causes a substantial burden of disease in those aged over 65 years, and in 2015, it was estimated that RSV and other respiratory viruses caused 1.2 million deaths in the elderly, with RSV being the most common cause of death.
• Rhinoviruses
  • Rhinoviruses are the most common cause of the common cold.
  • There is increasing evidence that rhinoviruses are responsible for considerable morbidity and mortality, especially as regards exacerbation of asthma.
  • Respiratory viruses believed to be restricted to upper respiratory tract infections due to temperature sensitivity are a common cause of lower respiratory infections.

Origins & Causes of Human Coronavirus Infections

• COVID19 or SARS-CoV-2 did not come from nowhere! It is a zoonotic disease that can be transmitted from other species to humans.
• Many coronaviruses infect humans:
  • Original sources are bats and rodents.
  • The first 4 listed cause mild disease (common colds).
  • SARS-CoV (2003-04) and MERS-CoV (2012) caused severe epidemics.
  • Most (all?) have secondary hosts from which they infected humans.
• Pangolin-CoV is about 91% identical to SARS-CoV-2.
• Bat RaTG13, SARS-CoV-2 & pangolin-CoV are extremely similar.
• Pangolin-CoV & SARS-CoV-2 have similar binding motifs.

COVID-19 Structure & Life Cycle

• S, E, and M proteins are built in the rough ER and embedded in the membrane there.
• N proteins are made in the cytoplasm.
• Assembly is thought to occur between the RER and Golgi.
• Assembly is completed in the Golgi.
• The virus is shed via exocytosis.
• Viral genes are coded on one, single-stranded RNA molecule in each virion.
• Key proteins:
  • Spike (S): cell entry.
  • Envelope (E): embedded in membrane derived from the host cell.
  • Nucleocapsid (N): Protects viral genome.
  • Membrane protein (M): Most abundant structural protein.

COVID19: Risk Factors

• Crowding
• Sociability
• Exercise
• Immune status
• Age
• Smoking & alcohol
• Sex
• Sleep
• Nutrition
• Stress
• Season

Treatments for COVID19

• COVID19 light to mild symptoms are treated similarly to the common cold.
• The FDA has authorized or approved several antiviral medications used to treat mild to moderate COVID-19 in people more likely to get very sick.
  • Antiviral medications target specific parts of the virus to stop it from multiplying in the body once someone is infected, helping to prevent severe illness and death.
• The Infectious Diseases Society of America provides Guidelines on the Treatment and Management of Patients with COVID-19 for healthcare providers to help them work with their patients and determine the best treatment options.
• Treatment options:
  • Nirmatrelvir with Ritonavir (Paxlovid):
    • Antiviral
    • Adults; children ages 12 years and older
    • Start as soon as possible; must begin within 5 days of when symptoms start
    • Taken at home by mouth (orally)
  • Veklury (remdesivir):
    • Antiviral
    • Adults and children
    • Start as soon as possible; must begin within 7 days of when symptoms start
    • Intravenous (IV) infusions at a healthcare facility for 3 consecutive days
  • Molnupiravir (Lagevrio):
    • Antiviral
    • Adults
    • Start as soon as possible; must begin within 5 days of when symptoms start
    • Taken at home by mouth (orally)

Practices to Limit the Spread of Human Coronavirus Infections

• COVID-19 Vaccines
• Practicing core prevention strategies:
  • Wash your hands with soap and water or use hand sanitizer regularly
  • Open windows and doors if you meet people inside, or meet them outside instead
  • Stay at least 2 meters away from people (particularly indoors or in crowded places)
  • Work from home if you can, or talk to your employer about how they can help reduce your risk at work
  • Wear a face covering when it's hard to stay away from other people
  • Think about asking people to wear a face covering or take a rapid lateral flow test if you're meeting them inside
• Pre-exposure Prophylaxis (Medication for Preventing COVID-19)
  • The FDA has authorized a preventive monoclonal antibody for people who are moderately or severely immunocompromised, ages 12 years and older, and weigh at least 88 pounds.
  • In addition to vaccination, Pemivibart (Pemgarda™) may provide another layer of protection against COVID-19 and can be given at least 2 weeks after receiving a COVID-19 vaccine.

How to Avoid Spreading COVID-19

• If you have symptoms of COVID-19 or have tested positive:
  • Cover your mouth and nose when you cough or sneeze and encourage children to do this
  • Regularly clean surfaces you touch often (such as door handles and remote controls) and in shared spaces, such as kitchens or bathrooms
  • Try to stay away from other people, including those you live with, until you feel better
  • Let people who need to come into your home know that you’ve tested positive or have symptoms
  • Think about asking friends, family, or neighbors to get food and other essentials for you
  • Avoid indoor or crowded places (including public transport or large social gatherings) or places where there is not much fresh air if you need to leave your home
  • Wear a face covering when it's hard to stay away from other people
  • Let healthcare professionals know about your positive test result or symptoms if you’re asked to attend an appointment in person

Approaches Used to Develop Human Coronavirus Vaccines

• Antibody-dependent enhancement

  • Homotypic or heterotypic serotype virus attack
  • Vaccinated individual get infected of cells with FcRs
  • Antibody (non-neutralizing Abs or neutralizing Abs under suboptimal concentration)
  • Formation of immune complex
  • Replication and amplification of virus
  • Release of IL-4, IL-13, IL-5, etc.
  • Poor stimulation of NK cells and CTLs
  • Release of proinflammatory cytokines
  • Activation of C1q
  • Release of eosinophil chemoattractant
  • Tμ2 cell, Eosinophil, Neutrophil, Lymphocyte
  • Inflammatory infiltration
  • Activation of inflammatory response
  • T2-type immunopathology

7 Strategies for COVID-19 Vaccines

1. Viruses are physically or chemically inactivated but preserve the integrity of the virus particle, which serves as the immunogen
2. Virus is attenuated by in vitro or in vivo passage or reverse-genetic mutagenesis. The resulting virus becomes non-pathogenic or weakly pathogenic but retains immunogenicity by mimicking live virus infection
3. Key viral proteins or peptides that can be manufactured in vitro in bacteria, yeast, insect or mammalian cell
4. For DNA vaccines, viral antigen(s) encoded by a recombinant DNA plasmid are produced in host cells via a sequential transcription- to-translation process. For mRNA vaccines, viral antigen(s) are synthesized by in vitro transcription and they produce viral antigen(s) in the cytoplasm through direct protein translation in vivo.
5. Viral gene(s) are cloned into non-replicating or replicating virus vectors (such as adenovirus). The antigen(s) are produced by transduced host cells after immunization
6. Structural viral proteins are co-expressed to form non- infectious particles as the vaccine immunogen. They resemble real virions but they lack the virus genome

Virus Infectivity

Notes

*Symptomatic individuals shed the virus during the first 2 to 3 days of infection. | Viral shedding occurs 24 hours before symptoms appear, peaking around day 3 of illness. Viral shedding occurs 2 to 3 days before symptoms appear, peaking around day 3 of illness. However, there can be viral shedding without ever developing symptoms.

Current vaccines under development and their major antigen targets

STRATEGY; CONSTRUCT ; DEVELOPER; B AND T CELL RESPONSESA; CLINICAL STAGE; CLINICAL TRIAL IDENTIFIER; FIRST REPORTED

• WHOLE VIRUS; INACTIVATED VIRUS(PICOVACC); Sinovac, with National Institute for Communicable Disease Control and Prevention, China; Induction of S-specific, RBD-specific and N-specific IgG, and nAbs in mice, rats and NHPs; no induction of either TH1 or TH2 cell responses in NHPs; induction of RBD-specific IgG and nAbs in humans; no obvious vaccine-induced T cell responses in humans; Phase III; NCT04456595; 6 May 2020.
• WHOLE VIRUS; INACTIVATED VIRUS; Wuhan Institute of Biological Products, Sinopharm, with Wuhan Institute of Virology, Chinese Academy of Sciences, China; Induction of virus-specific IgG and Abs in humans; no induction of either TH1 or TH2 cell responses in humans; Phase III; NCT04582344, NCT04617483, ChiCTR2000034780, ChiCTR2000039000, NCT04612972; 13 Aug 2020.
• WHOLE VIRUS; INACTIVATED VIRUS(BBIBP-CORV); Beijing Institute of Biological Products, Sinopharm, with;; Induction of Abs in rabbits, guinea pigs, rats, mice, NHPs and humans; no induction of either TH1 or TH2 cell responses in NHPs; Phase III; NCT04612972, ChiCTR2000034780, NCT04560881; 6 Jun 2020.
• WHOLE VIRUS; INACTIVATED VIRUS; Institute of Viral Disease Control and Prevention, China Institute of Medical Biology, Chinese Academy of Medical Sciences, China; Induction of S-specific and N-specific IgG and Abs in humans; Phase I/II; NCT04470609; 9 Nov 2020.
• S PROTEIN; VIRUS VECTOR (AD5) ;CanSino Biological Inc. with Beijing Institute of Biotechnology, China; Induction of RBD-specific IgG and Abs in humans; induction of TH1 cell responses; Phase III; NCT04526990, NCT04540419; 22 May 2020.
• S PROTEIN; VIRUS VECTOR (CHADOX1); University of Oxford, with AstraZeneca, UK; ; ISRCTN89951424, NCT04516746, NCT04540393, ;; Induction of RBD-specific IgG and Abs in humans; induction of TH1 cell responses; Phase III; ISRCTN89951424, NCT04516746, NCT04540393,; 20 Jul 2020.
• S PROTEIN; VIRUS VECTOR (AD26 AND AD5); Gamaleya Research Institute, Russia; Induction of S-specific IgG and nAbs in mice and NHPs; induction of high TH1 cell responses but low TH2 cell responses in mice; induction of S-specific IgG and nabs in humans, with nAb titres similar to convalescent plasma; Phase III; NCT04530396, CTRI/2020/08/027170; 4 Sep 2020.
• S PROTEIN; DNA; Inovio Pharmaceuticals, with International Vaccine Institute, South Korea; Induction of RBD-specific IgG and Abs in humans, with nab titres similar to convalescent plasma; induction of IENY-associated T cell responses; Phase II; NCT04642638, ChiCTR2000040146; 20 May 2020.
• PROTEIN SUBUNIT; S-2P; Clover Biopharmaceuticals, with GSK and Dynavax, China; Induction of S-trimer-binding antibodies and nabs in mice and NHPs; induction of high TH1 cell responses but low TH2 cell responses in mice; Phase I; NCT04405908; 21 Sep 2020.
• PROTEIN SUBUNIT; LNP-MRNA; Moderna, with National Institute of Allergy and Infectious Diseases, USA; Induction of S-specific IgG and nAbs in mice, NHPS and humans, with nab titres higher than convalescent plasma; induction of high TH1 cell responses but low TH2 cell responses in mice, NHPs and humans; Phase III; NCT04470427; 14 Jul 2020.
• PROTEIN SUBUNIT; LNP-MRNA; BioNTech, with Fosun Pharma and Pfizer, Germany; Induction of S1-specific IgG and Abs in humans, with Ab titres higher than convalescent plasma; Phase III; NCT04368728; 20 Aug 2020.
• PROTEIN SUBUNIT (CHO); Full-length S with two proline substitutions (K986P and V987P); Novavax, USA with;; Phase III; NCT04611802; 30 Jun 2020.
• VIRUS-VECTORED (AD26); Full-length S with two proline substitutions (K986P and V987P); Janssen Pharmaceutical Companies, USA;; Induction of S-specific IgG and Abs in mice, NHPs and humans, with nab titres in humans higher than convalescent plasma; induction of high TH1 cell responses but low TH2 cell responses in mice, NHPS and humans; Phase III; ISRCTN14722499; 30 Jul 2020.
• PROTEIN SUBUNIT (BACULOVIRUS/SF9); RBD (residues 319-545); West China Hospital, Sichuan University, China Induction of RBD-specific IgG and Abs in mice, rabbits and NHPs; induction of both Tн1 and TH2 cell responses in mice; Phase II; ChiCTR2000039994; 29 Jul 2020.
• LNP-MRNA; RBD (residues 319-541) PLA Academy of Military Sciences, with Walvax Biotech and Suzhou Abogen Biosciences, China Induction of RBD-specific IgG and nabs in mice and NHPs; induction of high TH1 cell responses in mice and NHPs but low TH2 cell responses Phase I; ChiCTR2000034112, ChiCTR2000039212; 23 Jul 2020.
• PROTEIN SUBUNIT (CHO); RBD-dimer (residues 319-537 as tandem repeat) Anhui Zhifei Longcom Biopharmaceutical, with Institute of Microbiology, Chinese Academy of Sciences, China Induction of RBD-specific IgG and Abs in mice; no induction of either TH1 or TH2 cell responses in mice Phase III; ChiCTR2000040153; 28 Jun 2020.
• LNP-MRNA RBD-trimer (trimerized by addition of T4 fibritin foldon domain); BioNTech, with Eosun Pharma and Pfizer, Germany Induction of RBD-specific IgG and nabs in humans, with nob titres higher than convalescent plasma; induction of high Tн1 cell responses but low TH2 cell responses in humans; Phase I/II;NCT04537949; 12 Aug 2020.