In December 2019, coronavirus disease (Covid-19) was first reported in China [1]. The epidemic, originating in Wuhan, China, started on December 12 2019, causing 2,794 laboratory-confirmed infections and, by 26 January 2020, these infections had resulted in 80 deaths.
Whole sequencing results of the original Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), MN908947 [2] and MT007544 [3], were reported on March 18 2020 and June 25 2020, respectively. Both sequences are of the first generation strain of SARS-Cov-2, referred to after as D614. D614 refers to the 614th amino acid, aspartate or “D”, from the coding DNA sequence (CDS) of the spike protein, 21563 to 25384. The spike protein produces a surface glycoprotein and a structural protein and the protein ID that we used is “QHD43416”.
On March 1 2020, only 9.9% of the 6244 global cases of the 2nd generation strain of SARS-Cov-2, referred to after as G614, but this rapidly increased to 54% of cases by March 10 2020, causing G614 to become the dominant strain[4].
On June 21 2020, the World Health Organization (WHO) Situation Report recorded over 8.7 million COVID-19 cases and 460,000 deaths. As of today, the numbers are still increasing daily [4].
On August 20 2020 [4] and October 8 2020, detailed sequencing data of the G614 strain of SARS-CoV-2 was reported [5]. The protein IDs are “7KDK_A”, “7LX5_B” [6] and “7KEC_C”, which are trimer proteins. The authors mentioned that SARS-CoV-2 G614 is a 3 RBD down Spike Protein Trimer without the P986-P987 stabilizing mutations (S-GSAS-D614G). However, after detailed analysis it was observed that the non-mutated status, D6147, stilled existed in the detailed sequencing data of the LX5-B protein ID. It is not known whether this interferes with the function of the other two units which have already mutated to G614, in this trimer.
Seven months later, in October 2020, the Delta type became the domain strain over others and by January 2021, 78 million people had been infected, and more than 1.7 million patients had died [7], showing a nine fold increase in cases and a four fold increase in deaths over a 6 month duration. Two years later, the pandemic is still ongoing.
Normally when a person is infected, they are able to generate sufficient IgG to protect them within 14 days. This gained immunity should protect against the infection, lead to recovery, and also reduce the success of transmission from one person to another.
Therefore, why has SARS-CoV-2 remained as an epidemic for 2 years? The major reason should, at least, be that the generated antibody, IgG, could not protect the host against re-infection through new mutant strains of SARS-CoV-2.
The antigens in the spike protein of SARS-CoV-2 have not remained stable over the last 2 years, with mutations shifting from D614, to G614, to Delta, and finally to Omicron.
The epidemic data has shown that the G614 mutation was the next generation of D614 and that the G614 mutation had higher infectivity [8] and higher toxicity to humans. It become more capable of survival and evasion of the previously generated immunity in humans.
There are many papers discussing the evolution of the antigens, from D614, to G614, to Delta, and to Omicron but a limited number papers demonstrate a reason as to why D614 mutated to G614, then from G614 to Delta, and from Delta to Omicron.
Once an antigen invades the human body, the immune system will generate a specific antibody against the antigen. When the same antigen wants to invade the human body again for a second time, it must have evolved through mutations that allow it to evade the established immune system or it will fail to infect the human body.
Normally, one antigen matches one antibody and, although cross-reactions between antigens and antibodies does exist, the efficiency might not be as good as the original antigen-antibody pairing. Antibody-Dependent Enhancement (ADE) may occur due to such cross reactions. We hyposthesize that the matching of antigen and antibodies is very similar to the pairing of locks and keys.
If a person has a key to open the lock of his or her apartment, this key should not have the ability to open another lock to someone elses apartment. However, a master key can exist which has the ability to open the locks of all apartments. The master ket will be very similar to any of the apartment keys, but should be a little bit smaller is size to allow for entry into all locks.
We suggest that the same rule might fit the evolution of antigens. The evolved antigen needs to be similar but smaller compared to the non-mutant original antigen and we found this to be true, at least in the case of the mutation from D614 to G614, from G614 to Delta, and from Delta to Omicron. As “G” is the smallest amino acid among all 20 amino acids, and, therefore, “smaller” than “D”, this leads to G614 being smaller than D614. Delta type is also smaller than G614, and Omicron smaller than Delta.
This paper will try to identify a reason as to why a mutation occurred at position D614, but not in other positions and why the order was first from D614 to G614, second from G614 to Delta, third to Omicron.