Vaccines and drugs must be adapted to fight new SARS-CoV-2 mutants, the study says.

Severe Acute Respiratory Syndrome that Caused the 2019 Coronavirus Disease (COVID-19) Pandemic A New Review of New Concerns (VOC) for Coronavirus 2 (SARS-CoV-2) is an Existing Treatment for the Virus And constantly reassess the usefulness of the virus and develop new ones.

Articles published online in the journal VirusPoints out the need to harness the power of genomic sequencing to identify important mutations in order to adapt prophylactic and therapeutic measures accordingly.

Pathogenesis of COVID-19

The novel coronavirus has four major structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N). Among these, spikes mediate viral invasion, bind to the host cell receptor angiotensin converting enzyme 2 (ACE2), and cause subsequent viral cell membrane fusion, causing the virus to invade the host cell.

Peplomers are immune-dominant antigens Neutralizing antibody It is specifically directed to the receptor binding domain (RBD). But it’s not the only one that provokes an immune response, starting with innate immune cells, macrophages, and monocytes.

This releases pro-inflammatory cytokines at the site of infection and also stimulates the adaptive immune response mediated by CD4 + and CD8 + T cells. Cytotoxic T cells kill infected cells and prevent the spread of the virus.

Severe or severe COVID-19 results from an dysregulated immunoinflammatory response, Cytokine storm, Leads to tissue and organ damage. This is most prominently manifested by symptoms of acute respiratory distress syndrome (ARDS) or sepsis, as well as collateral coagulation abnormalities and multiple organ failure.

Appearance of VOC

Several vaccines and monoclonal antibodies have been developed to address this threat, and many more. However, VOCs show mutations in spike antigens, allowing the virus to escape antibody-mediated recognition and destruction by the immune system. Alternatively, such mutations may improve the infectivity or toxicity of the virus.

The D614G strain was the first VOC to be noted in January 2020. It spread all over the world at a dazzling speed, became the dominant strain, replaced the original Wuhan strain, and its virus compatibility increased. This is indicated by the low cycle threshold of this positive reverse transcriptase-polymerase chain reaction (RT PCR) with VOCs.

The 20I / 501Y.V1 (B.1.1.7) strain appeared almost a year later in December 2020 and had 17 mutations. Similarly, it has spread rapidly to more than 150 countries. This was defined by the RBD N501Y mutation and other mutations, where the spike conformation changed at the interface between the two spike subunits. It is also 82% more contagious and probably toxic than previous mutants, but remains susceptible to neutralization by vaccine-induced antibodies.

Interestingly, there is an ORF8 Q27stop mutation that divides the ORF8 gene, allowing the virus to accumulate more downstream mutations. Since the ORF8 protein is involved in antigenic escape, this mutation may be responsible for the continued susceptibility of this VOC to antibodies.

Later variants 20H / 501Y.V2 and 20J / 501Y.V3 (B.1.351 and P.1 respectively) share the N501Y mutation with 20I / 501Y.V1. These also include several escape mutations, especially the E484K mutation, which allows antibody escape by structurally modifying the peplomer. 20H / 501Y.V2 is also highly infectious.

Recently, it has been reported that 20I / 501Y.V1 acquired an E484K mutation, and in some cases, it conferred the strain on its antigenic ability.

Other VOI

Since then, other mutants of interest (VOI) have emerged, such as 19B / 501Y in January 2021, with the N501Y and H655Y mutations found in the P.1 strain. Transmission of the virus from mink farmers to farm mink also induced the Y453F mutation in the receptor-binding motif of RBD. This is an escape mutation and is also found in the CAL20C variant. It also shows N501T mutations that may stabilize the viral receptor complex.

The CAL20C variant reported in California is well known for its L452R mutation, which can avoid neutralization with monoclonal antibodies (mAbs). Share line B with B.1.429 and B.1.427. This mutation is also present in strain A.27 (19B / 501Y VOI), along with the Q677H mutation near the furin cleavage site, which may help the virus adapt to the host and replicate faster.

Many other variants have been reported in smaller clusters, but remain stable infrequently or disappear in a few months. However, the 0A / 484Q variant (lineage B.1.617) has an L452R that is common to the CAL.20C variant and the E484Q, as well as the E484K mutation for biological effects. The presence of so-called double mutants can make them more contagious and resistant to antibody neutralization. This variant is now rapidly spreading to many parts of the world.

These mutations not only alter the biology of the virus with respect to the immune response, but also result in the appearance of multiple different strains within a single individual. This is called a quasi-species of the virus and can affect tissue tropism.

Wide organizational orientation

SARS-CoV-2 is primarily a respiratory virus, but it also affects many other organs such as the kidney (which expresses ACE2 100 times higher than lung tissue), heart, blood vessels, liver, brain, and gastrointestinal tract. Gives. Other receptors suspected of allowing the virus to invade host cells include neuropilin-1 (NRP-1) and a wide range of CD147 molecules.

Some mutations also form tissue tropism in the virus and may regulate the interaction of the virus with specific tissue-specific cell receptors. Gastrointestinal involvement can increase its spread through faeces, but this remains unproven by rigorous experimentation.

Effects of mutations on vaccine and antibody efficacy

Current vaccines are highly dependent on the spike antigen of the Wuhan strain. These include messenger ribonucleic acid (mRNA) vaccines that encode spike proteins, adenovirus vector spike vaccines, and inactivated virus vaccines.

The new vaccine may also incorporate the N protein, which has been reported to be highly immunogenic. The nonstructural protein NSP3 is another potential vaccine antigen because it is conserved among coronaviruses and can provoke a CD4 + mediated response.

Monoclonal antibodies have been used to prevent or treat COVID-19, including those with weakened immunity and those who are not protected. Two anti-RBDM Abs have been approved by the Food and Drug Administration. That is, the combination of Bamlanivimab (LY-CoV555 or LY3819253) and Casilivimab (REGN10933) + Imdevimab (REGN10987) was approved by Eli-Lilly and Regeneron, respectively.

The combination of mAbs has been shown to be able to supplement antibody resistance by SARS-CoV-2 VOCs. This is because at least one of the cocktail ingredients is always active against the virus, even if the neutralizing effect is reduced. For example, the combination of REGN 10933 + REGN 10987, CoV2-2196 + CoV2-2130, and LY-CoV 555 + CB6 all show this pattern, but the last combination is less effective against 20H / 501Y.V2. is showing.

However, in the case of the Wash SA-B.1351 strain, the presence of a compensatory mutation in K417N prevents this resistance.

Convalescent plasma The S982A mutation of the S2 spike subunit slightly increases neutralization resistance, but remains effective against most mutants. Again, the 20H / 501Y.V2 variant differs significantly in resistance to antibodies in convalescent plasma and antisera of vaccine recipients. This is associated with an E484K mutation that affects immune-dominant epitopes.

This may be the case for the 20J / 501Y.V3 variant and other variants that contain this mutation.

What is the impact?

Studies have shown that B.1.351, P.1 strains, and B.1.1.7 with E484K mutations are from a vaccination perspective because of convalescent sera, animal immune sera, and potential resistance to humans. It is a source of concern.Serum from vaccinated patients.. “

Vaccine antigens must be selected to induce both innate and adaptive immunity, but vaccines should stimulate an abnormal Th2 skew response that may be associated with antibody-dependent enhancement enhancement (ADE). It will not be.

To counter new VOCs, vaccines need to be updated regularly, as is under development with most major vaccines currently available. Many manufacturers have announced plans to release booster vaccines based on neutralization-resistant strains such as 20H / 501Y.V2.

Antibody cocktails also need to utilize more epitopes, especially highly conserved epitopes, to prevent mutation avoidance. Animal reservoirs need to be identified to prevent their potential spread to humans.

Genomic sequencing efforts are important in the fight against viruses and are further promoted to identify such VOCs, contain pandemics, and implement appropriate strategies that enable recovery of global health and economic activity. need to do it.