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The Intractable SARS-CoV-2


Summary:


The coronavirus, SARS-CoV-2 is the causative organism of the COVID-19 pandemic. This virus is still circulating in more than 180 countries almost 2 years after initial infections were reported. It has ravaged the world and all walks of life, with incredible human costs and damage to the global economy.


The commonality of all 7 known human-infecting coronaviruses is that infection begins with viral spike protein attachment to human cell receptors. SARS-CoV-2 has caused a prolonged and sustained history of infection, different from previous coronaviruses. This may be partly due to evolving characteristics of the spike protein.


During virus replication, RNA nucleotides that code for amino acid building blocks produce the spike protein of SARS-CoV-2. These have mutated frequently over the course of the pandemic. Mutations translate into varying protein configurations, which can affect binding affinity to the human ACE-2 receptor. Mutations can also help to shorten viral replication cycles and increase transmissibility.


The first significant SARS-CoV-2 mutation was observed in Europe where the D614 virus mutated by replacing an Aspartic amino acid with a Glycine amino acid, resulting in the G614 variant. The G614 variant spike protein configuration allows easier binding to the human ACE-2 receptor, resulting in

an increase in virus infectivity by 70%. As the pandemic continues, multiple viral replications and mutations have occurred, resulting in more spike protein modifications. With every change, a more contagious variant can emerge. The most concerning mutation currently is the Delta variant, which is approximately 150% more contagious than the original wild-type (D614) SARS-CoV-2.


Currently, all vaccines approved for emergency use by WHO were formulated from the original D614 viral spike protein RNA. Upon vaccination, both antibodies and T cell-mediated immunity are effective in controlling the infection. However, with frequent mutations, some of the variants, such as the Delta variant, have shown to be able to weaken the neutralizing effects of antibodies. None of the variants, however, have any significant negative impact on vaccine-generated T cell immunity.


Similar to "common cold" Coronaviruses, SARS-CoV-2 initiates infection in the upper respiratory tract (URT).


All WHO-adopted SARS-CoV-2 vaccines are designed for intramuscular inoculation. These vaccines do not primarily address the prevention of infection, as they are developed to boost host immunity pathways to prevent disease progression. To prevent against initial viral URT infection, enhancement of “mucosal immunity” by intranasal vaccination rather than conventional intramuscular vaccination is the method of choice.


Prevention of initial infection is one method. Reduction of progression of the disease is another. In order for extension of viral infection into the lower respiratory tract (LRT), it must contend with innate immunity from cross-reactive memory CD4 and CD8 T lymphocytes. These lymphocytes are generated by ongoing exposure to common cold coronavirus infection (Rebecca et al., Nature Reviews in Immunology 20, 581-582(2020), Grifoni et al., 2020 Cell 181,1489-1501).


In their paper, Grifoni et al., demonstrated that pre-existing CD4 and CD8 memory T lymphocytes cross-reactive to SARSCoV- 2 are detected in 50% and 20% of healthy individuals without SARS-CoV-2 infection. Activated CD4 and CD8 lymphocytes were found in 100% and 70% of patients after SARS-CoV-2 infection. Both active and memory T cell responses focus not only on the viral spike protein component but also other viral structural and non-structural proteins.


Currently, the Delta variant is the most contagious among reported variants. It propagates effectively in the URT, however, more than 95% of progeny viruses are either confined to the URT or spread externally (by coughing, sneezing, etc.) to other individuals. This can allow for ongoing transmission of the virus and a disease course similar to the common cold, but less extensive infections extending into the LRT, especially in vaccinated individuals.


As more individuals are vaccinated to achieve global herd immunity, it is possible that SARS-CoV-2 may eventually exist as the fifth "common cold" Coronavirus among us.


Chia Wah Kiam Ph.D.

University of Toronto

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