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- Three vaccines to combat Covid-19 have shown several positive results
- Replication of the virus takes place within cells
- Blocking entry to cells prevents more virus from being produced.
The latest results from the Phase 3 Covid-19 vaccine trials have been very positive.
These have shown that vaccination of people with the SARS-CoV-2 spike protein gene can induce excellent protective immunity.
The spike protein is the focus of most Covid-19 vaccines, as it is the part of the virus that allows it to enter our cells.
Virus replication only occurs within cells, so blocking entry prevents more viruses from being produced.
If a person has antibodies that can recognize the spike protein, this should stop the virus in its tracks.
The three most advanced vaccines (from Oxford / AstraZeneca, Pfizer / BioNTech, and Moderna) work by making our own cells make copies of the spike protein of the virus.
The Oxford vaccine accomplishes this by introducing the spike protein gene through a harmless adenovirus vector.
The other two vaccines deliver the spike protein gene directly as mRNA wrapped in a nanoparticle.
When our own cells produce the spike protein, our immune response will recognize it as foreign and begin to produce antibodies and T cells that specifically attack it.
Read more: The Pfizer vaccine has just been approved: this will be the next few months
However, the SARS-CoV-2 virus is more complicated than just a spike protein.
In fact, there are four different proteins that make up the general structure of the virus particle: spike, envelope (E), membrane (M), and nucleocapsid (N).
In a natural infection, our immune system recognizes all these proteins to varying degrees.
So how important are immune responses to these different proteins? Does it matter that the first vaccines won’t replicate them?
After SARS-CoV-2 infection, researchers have found that we actually produce the most antibodies against the N protein, not the spike protein.
This is the same for many different viruses that also have N proteins.
But how antibodies to protein N protect us from infection has been a long-standing mystery.
This is because the N protein is only found within the virus particle, wrapped around the RNA.
Therefore, Protein N antibodies cannot block virus entry, will not be measured in neutralization assays that test this in the laboratory, and have therefore been largely overlooked.
New mechanism discovered
Our latest work from the MRC Molecular Biology Laboratory in Cambridge has revealed a new mechanism for how antibodies to protein N can protect against viral diseases.
We have studied another virus that contains an N protein called lymphocytic choriomeningitis virus and we have shown a surprising role for an unusual antibody receptor called TRIM21.
While antibodies are normally thought to only work outside of cells, TRIM21 is only found inside cells.
We have shown that protein N antibodies that enter cells are recognized by TRIM21, which then grinds down the associated protein N.
Below, small N protein fragments are shown on the surface of infected cells.
T cells recognize these fragments, identify the cells as infected, and then kill the cell and consequently any virus.
Read more: Coronavirus: explanation of B and T cells
We hope that this recently identified role for N protein antibodies in protection against virus infection is important for SARS-CoV-2, and work is underway to explore this further.
This suggests that vaccines that induce N protein antibodies, as well as spike antibodies, could be valuable, as they would stimulate another way that our immune response can eliminate SARS-CoV-2.
Adding protein N to SARS-CoV-2 vaccines could also be helpful because protein N is very similar between different coronaviruses, much more so than spike protein.
This means that it is possible that a protective immune response against the N protein of SARS-CoV-2 also offers some protection against other related coronaviruses, such as Mers.
Another potential benefit that may arise from the inclusion of protein N in SARS-CoV-2 vaccines is due to the low mutation rates observed in the protein N sequence.
Some changes in the SARS-CoV-2 sequence have been reported during the course of this pandemic, with the most significant changes occurring in the spike protein.
There is some concern that if the peak sequence is altered too much, new vaccines will be required.
This could be similar to the current need for annual flu vaccine updates.
However, since the sequence of protein N is much more stable than the peak, vaccines that include a component targeting protein N are likely to be effective longer.
The first wave of SARS-CoV-2 vaccines provides genuine hope that this virus can be controlled through vaccination.
From here on, it will be a constant quest to develop even better vaccines that can remain effective against an evolving virus.
Future vaccines will likely focus on more than the SARS-CoV-2 spike protein, and the N protein is a promising target to add to current strategies that are being considered.
Sarah L Caddy, Clinical Researcher in Viral Immunology and Veterinary Surgeon, University of Cambridge. This article is republished from The conversation under a Creative Commons license. Read the Original article.
Image Credit: CDC, Pexels
