Team:Shanghai HS/Description
Description
Background
Since 2019, the COVID has been spreading around the world and already caused millions of death. December 2020, Pfizer, Moderna, and Johnson & Johnson lead the first round of COVID vaccinations in the US, sending a beacon of hope through the darkness that the pandemic had caused. It seemed that the world was slowly moving along the path to recovery. However, as with any such virus, mutations are inevitable. New mutated variants of the coronavirus manifested themselves in various locations around the globe, threatening the safety that the vaccinations had promised.
In India, variant B.1.617, the infamous double mutation, appeared in March of this year, with not only higher transmissibility but also an ability to evade our immune system. In fact, a deadly second wave of the coronavirus spearheaded by the B.1.617 strain elevated the daily number of cases to a shocking 350,000, accumulating a total of more than 25 million cases from India, much worse than the first wave.
Mutant strain — B 1.1.7 & B 1.617
The “Indian variant” of SARS CoV-2, more accurately called B.1.617, has spread to many other countries including the UK.
Flashback to December 2020, Britain reported a highly contagious mutant strain of COVID-19 for the first time: the B.1.1.7 strain, which soon became the main strain in the London area. As of December 27, B.1.1.7 virus strains have been also detected in 16 other countries. A variant of concern shows evidence of increased transmissibility, greater disease severity, a substantial decrease in the neutralization of virus by antibodies from vaccination or past infection.
B.1.617
B.1.1.7
Structure and Pathology of Coronavirus
The coronavirus genome is comprised of ∼30000 nucleotides. It encodes four structural proteins, Nucleocapsid (N) protein, Membrane (M) protein, Spike (S) protein and Envelop (E) protein and several non-structural proteins. COVID-19 is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection may be asymptomatic or it may cause a wide spectrum of symptoms, such as mild symptoms of upper respiratory tract infection and life-threatening sepsis.
Pathology of Coronavirus
Structure of Coronavirus
Neutralizing antibody
Neutralizing antibodies can effectively control infection by blocking the interaction between the new coronavirus and the host cells. COVID-19 binds to the receptor ACE2 of the host cell through RBD of the spike protein on its surface. Therefore, the binding target of most neutralizing antibodies is the spike protein.
Neutralizing Antibody
Current Solution
Types of vaccine
In order to prevent the large spread of virus, different types of vaccine have been developed to cause the immune system creating antibodies to resist attacks from COVID-19.
1. Messenger RNA (mRNA) vaccine
This type of vaccine uses genetically engineered mRNA that will break down after teaching our immune cells how to make the S protein pieces that were found on the surface of the virus.
2. Viral vector vaccine
This type of vaccine uses a modified version of a different virus. After they enter into our cells, they will transfer important cell instructions from the COVID-19 virus for replicating the S protein.
Antibody
Antibodies are proteins made by the immune system to fight infections like viruses and may help to ward off future occurrences by those same infections. It contains a light chain and a heavy chain and it can be separated into the variable region and constant region which these two parts decide the specificity of the antibody. The variable region will decide whether this antibody can recognize the COVID-19. Some research proves that mAb treatment can reduce the amount of the SARS-CoV-2 virus in a person’s system.
Testing methods
1. Viral test
A viral test checks specimens from your nose or your mouth to find out if you are currently infected with the virus that causes COVID-19. There are two types which are NAATs, antigen tests and molecular (RT-PCR) tests. Molecular and antigen tests are performed using samples taken mainly from nose and throat using a long swab, or other respiratory specimens.
2. Antibody test
This test is done to find whether people have been infected in the past by checking the antibodies in the patient blood that defend against the attack of the virus. After infection with the COVID-19 virus, it can take two to three weeks to develop enough antibodies to be detected in an antibody test. Antibody tests may detect certain types of antibodies related to COVID-19 such as binding antibodies and neutralizing antibodies.
Theory
The S glycoprotein is the immunodominant target for previous NAbs, and comprises an N-terminal domain (NTD), a receptor-binding domain (RBD/S1B), and an S2 subunit. The SARS-CoV RBD [amino acids (aa) 338–506] consists of an S1B core domain (S1BCD) (aa 318–424) and a receptor-binding motif (RBM) (aa 438–498) that directly engages the human receptor hACE2. Meanwhile, The RBD is also a significant neutralization determinant in the inactivated SARS-CoV vaccine because it induces potent NAbs that block SARS-CoV entry.
It is well demonstrated that D614G mutation of SARS-CoV-2 spike protein, the major mutation detected to date, causing increased infectivity and case fatality. Furthermore, a recent study showed that D614G shifts S protein conformation toward an ACE2-binding fusion-competent state, and therefore may increase the infectivity of virus. Although the potency of RBD-directed NAbs against the D614G variant was not attenuated, the conformational shift toward an ACE2 binding-competent state induced by D614G could still influence the effectivity of some NAbs (e.g. Type-III NAbs which only bind the closed RBDs). The SARS-CoV-2 receptor ACE2 is highly conserved. The SARS-CoV-2 neutralizing antibody targeting ACE2 has been proved to strongly inhibit the replication of SARS-CoV-2 in vitro and in vivo without affecting the enzyme catalytic activity of ACE2.
In order to stay ahead of the virus, we must create an antibody that targets an area other than the spike protein. Our team believes the answer lies in the ACE2 receptor.
Goal
Pansolver Base team, we proposed a new antibody, proteins that can target and block the ACE2 receptor. Cooperating with the Shanghai Institute of Materia Medica (SIMM), we got the antibody X which was screened out from plenty of antibodies and was able to target and the ACE2 receptor. Consequently, mutation type as the virus is, the antibody X will effectively block the virus entry due to the close of the “door”.
We want to make sure that no matter how much the coronavirus mutates, the world has an antibody ready to combat it. Because as long as the coronavirus keeps mutating, it remains a threat to the entire world, and the Pansolver team is determined to neutralize that threat.
Future prospect
Thermal stability
We want to improve the thermal stability of our antibody X .
• Method 1: Modification of antibody molecular structure
Structural modification of antibody molecules based on the chemical modification sites has always been an important direction of stability optimization. It has been proved that the deamidation rate of Gln is much slower than that of ASN. Therefore, it is considered as a solution to remove the deamidation site or reduce the probability of deamidation effect by mutating ASN to Gln.
• Method 2: Optimization of production process
Under the condition of over acid or over alkali, the antibody will degrade in different ways. In pH 6.8 intravenous immunoglobulin (IGIV) preparation, the instability caused by pH can be improved by adding maltose stabilizer. In the CHO cell line system, scientists established a pH dependent kinetic model with six parameters as the main body, including the number of living cells, the number of apoptotic cells, the number of dead cells, the amount of product (mAb), the culture volume and the pH value, Then, an effective pH optimization strategy was developed in the production stage.
Inhalable nanobody
Pin-21 (Pittsburgh inhalable nanbody-21), the first type of nanobody has been invented, it is about three times smaller than the typical monoclonal antibody and has high stability, which makes it perfect for this treatment. The cost of nanobody production is very low, and it can be rapidly mass-produced to cope with the changing virus. In the future, Nanobody spray might become an effective treatment.
Ⅰnclinical trial
Systematic drug research is conducted in human body (patients or healthy volunteers) to confirm or reveal the effects, adverse reactions and / or absorption, distribution, metabolism and excretion of the test antibody, so as to determine the efficacy and safety of the test drug. Clinical trials are generally divided into phase I, II, III, IV clinical trials and EAP clinical trials.
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