Due to their complex genetic diversity, a universal vaccine is nearly impossible for HIV, influenza, or hepatitis viruses. But how about SARS-CoV-2?
* Image adapted from Darwin, 1845 (public domain). Darwin’s finches (also called Galapagos finches) are known for their diversity in beak shapes and functions.
Viruses undergo more frequent mutations due to their quicker life cycle compared to, for example, bacteria or humans. Mutations increase the genetic diversity of a biological entity, which makes it harder to eliminate.
The influenza virus, for example, requires seasonal vaccines to put it under control. The human immunodeficiency virus (HIV) and hepatitis C virus (HCV) have no successful vaccines. Genetically diverse bacteria like Staphylococcus aureus or Acinetobacter baumannii are also difficult to treat as they quickly gain antibiotic resistance genes.
How genetically diverse is the novel coronavirus, SARS-CoV-2? And this answer will determine how challenging it is to make a vaccine for the virus.
Genetic diversity of SARS-CoV-2
A paper published in the PNAS, a high-ranking journal, in September provides an answer as stated obviously in their title, “A SARS-CoV-2 vaccine candidate would likely match all currently circulating variants.”
In this study, 12 researchers at the Walter Reed Army Institute of Research in Maryland compared 27,977 SARS-CoV-2 sequences from 84 countries. Bioinformatics analyses found just two dominant mutations: P4715L and D614G with 69.3 and 69.4% prevalence, respectively, that co-occur. And the D614G one is probably the more important one in driving SARS-CoV-2 evolution, the authors theorized.
There is barely any data on the P4715L mutation — proline (P) at position 4715 mutated to leucine (L). In contrast, the D614G mutation — aspartic acid (D) at position 614 mutated into glycine (G) — is famous in the scientific literature for causing Covid-19 reinfection and enhancing its infectivity in human cells.
An encouraging finding is that no mutation has drastically altered the receptor-binding domain (RBD) of the viral spike protein. This means that all circulating variants or strains of SARS-CoV-2 still use the ACE2 receptor as an entry point into human cells. It also means that a vaccine targeting the RDB, which current vaccines in development do, would be universal for SARS-CoV-2.
Further, comparing the first 30 SARS-CoV-2 genomes sampled from Wuhan at the beginning of the outbreak to the thousands of genomes sampled at a later date did not reveal much diversity. And comparing genomes sampled weekly observed that SARS-CoV-2 genomic diversity, they wrote, “tended to narrow over time rather than diverge.”
An encouraging finding is that no mutation has drastically altered the receptor-binding domain (RBD) of the viral spike protein.
Why? Most coronaviruses, including the novel one, have a nonstructural protein 14 (nsp14) that follows the virus’s RNA polymerase — an enzyme that makes RNA genes. In this process, the nsp14 cuts out mutated genes as the RNA polymerase synthesizes them. This keeps the overall mutation rate 10-fold lower than a typical RNA virus. (Viruses use DNA or RNA as their genes, and RNA viruses have a higher mutation rate than DNA viruses.)
“Viral diversity has challenged vaccine development efforts for other viruses such as HIV-1, influenza, or Dengue, but these viruses each constitute a more diverse population than SARS-CoV-2 viruses,” the authors concluded. “We can therefore be cautiously optimistic that viral diversity should not be an obstacle for the development of a broadly protective SARS-CoV-2 vaccine.”
Genetic diversity of current relevant viruses
The study above has also drawn phylogenetic evolutionary trees depicting the genetic diversities of SARS-CoV-2 and HIV-1 (see figure below). “Both trees shown on the same scale is to illustrate the extent of diversity that needs to be covered by an HIV-1 vaccine compared to what a SARS-CoV-2 vaccine will need to cover,” the researchers stated.
(For SARS-CoV-2, its genetic diversity is the small dot in the middle of part A. Clearly, making a SARS-CoV-2 vaccine will not be as impossible as for HIV-1.)
Virologists thus say the low genetic diversity of the novel coronavirus is its ‘Achilles heel’ — its biggest weakness. Neutralize its RBD, and it’s done.
In a commentary of this study, “Low genetic diversity may be an Achilles heel of SARS-CoV-2,” researchers at the HIV Dynamics & Replication Program at the National Cancer Institute at Frederick shared more data on the genetic diversities of the surface glycoprotein — that binds to a cell receptor to initiate infection — of viruses of public health concern. They illustrated their genomic analyses below with the sphere size correlating to genetic diversity.
- Red spheres: Human coronaviruses with no available vaccines: SARS-CoV-2 causes Covid-19, and the rest causes the common cold that may advance to more severe infection if it reaches the lower respiratory tract.
- Dark blue spheres: Viruses with moderate genetic diversity — mumps, hepatitis B virus (HBV), and measles — and successful vaccines.
- Light blue sphere: The influenza A virus with high genetic diversity and available seasonal vaccines, albeit with limited efficacy.
- Green spheres: Viruses with immense genetic diversity — HIV-1 and hepatitis C virus (HCV) —and no reliable vaccines.
Despite the initial worries about mutating SARS-CoV-2, its genetic diversity is still lower than many other viruses of public health importance. Looking at the surface glycoprotein only — that interact with human cell receptors — the diversity of SARS-CoV-2 is >100-fold lower than HBV and measles and >400-fold lower than HIV-1, influenza A, and hepatitis viruses. Virologists thus say the low genetic diversity of the novel coronavirus is its ‘Achilles heel’ — its biggest weakness. Neutralize its RBD, and it’s done.
“We can therefore be cautiously optimistic that viral diversity should not be an obstacle for the development of a broadly protective SARS-CoV-2 vaccine.”
As a coronavirus, SARS-CoV-2 has a robust system that disfavors mutations. Based on 27,977 genomes sampled from 84 countries, research finds that SARS-CoV-2 is not genetically diverse. Analyzing only the surface glycoprotein that binds to and infects human cells, SARS-CoV-2 has a genetic diversity of hundreds of fold lower than other viruses of public health concern. Importantly, viral genetic diversity is also an indicator of how arduous it would be to make its vaccine. So the vaccine prospects of SARS-CoV-2 are many times better than, say, HIV-1, influenza, or hepatitis viruses.*
This article was originally published here with modifications.