The coronavirus disease (COVID-19), caused by the pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread globally, infecting over 182 million people. In the process of dividing and replicating, errors in SARS-CoV-2's genetic makeup cause it to mutate. Virus mutations can affect its transmissibility and infectiousness. Some may help the virus evade the immune system, possibly making vaccines less effective, while others have little influence.
Researchers at the University of Cambridge, MRC-University of Glasgow Centre for Virus Research, The Pirbright Institute, MRC Laboratory of Molecular Biology, and Vir Biotechnology aimed to determine how SARS-CoV-2 evades the immune system, threatening the efficacy of developed vaccines.
The study, published in the journal Cell Reports, showed that the mutations in the virus, particularly the deletion of two amino acids H69/V70 seen in the Alpha variant (B.1.1.7), enables the virus to overcome weaknesses as it evolves.
The Alpha variant
Several new SARS-CoV-2 variants are spreading rapidly, and some fear this means that currently authorized vaccines for COVID-19 may not offer protection. Most of the variants involve the spike protein found on the virus surface, which facilitates attachment and entry into cells. Currently, all vaccines are directed against the spike protein.
The Alpha variant also called the B.1.1.7, emerged in the United Kingdom in late 2020. It contains spike protein substitutions N501Y, 69del, 70del, 144del, E484K, S494P, A570D, D614G, P681H, T716l, D1118H, and S982A. The notable characteristics of this variant of concern include a 50 percent increased transmission and potential increased severity.
In the study, the team analyzed global SARS-CoV-2 data and found that H69/V70 occurs independently, often emerging after a significant receptor-binding domain (RBD) amino acid replacement like Y453F and N439K, which are known to facilitate neutralizing antibody escape. They also impair angiotensin-converting enzyme 2 (ACE2) binding while sustaining an infectivity defect.
Under secure conditions, Professor Gupta and his colleagues used a harmless form of SARS-CoV-2 that cannot replicate but has the deletion of the key amino acid H69/V70 to investigate how the protein interacts with host cells and why the deletion is so important. The team tested the virus against blood samples from 15 people who have recovered from SARS-CoV-2 infection.
In their study, the researchers found that the deletion did not allow the virus to escape neutralizing antibodies acquired from previous infections or vaccinations. In fact, the deletion made the virus twice as infectious, making it more capable of attaching to and invading healthy cells.
In addition, the viral particles carrying the deletion had more mature spike proteins, allowing the virus to replicate more efficiently. Researchers discovered that deletions enabled viruses to not only escape the immune system but also compensate for mutations that caused negative effects. By doing so, the virus is able to penetrate gaps in the immune system's protective armor.
"We found that a two-amino-acid deletion, H69/V70, promotes SARS-CoV-2 spike incorporation into viral particles and increases infectivity by a mechanism that remains to be fully explained. This deletion has arisen multiple times and often after spike antibody escape mutations that reduce spike-mediated entry efficiency," the researchers explained in the study.
The team also warned that the Alpha variant mediates faster syncitium formation, which is dependent on the H69/V70 deletion. Further, the Alpha variant spike necessitates the H69/V70 for optimal infectivity. This means that the deletion makes it possible for the virus to tolerate and overcome many immune escape mutations while sustaining infectivity and its ability to fuse with host cells.
The study highlights that the spike H69/V70 does not confer escape from antibodies and enhances cleaved S2 and spike infectivity. Additionally, the Alpha variant of the B.1.1.7 variant requires H69/V70 for importance cleaved spike incorporation and infectivity, and its spike needs the H69/V70 for rapid syncytium formation.
To date, the virus has spread to 192 countries and territories, with a threat of emerging variants. The death toll has now reached over 3.94 million, with the United States reporting over 604,000 deaths.
The U.S. reports the highest number of cases, with 33.66 million infections, followed by India and Brazil, with more than 30.36 million and 18.55 million cases, respectively.