Nanobodies can help us overcome the threat from SARS-CoV-2 variants
Major immunotherapeutic strategies in COVID-19 are now facing the emergence of multiple variants of concern (VOC), many of which contain RBD point mutants (RBD= Receptor Binding Domain seen on the spike protein of SARS-CoV-2) and can bypass the most potent neutralizing human antibodies.
Currently available vaccines are based largely on the wildtype “Wuhan” sequence spike antigen. But the emerging SARS-CoV-2 “variants of concern” with - potentially enhanced transmission, pathogenicity, immune escape, or a combination of all three -are showing resistance to neutralization by these vaccines.
Eric Topol on Twitter has summarized the immune evasiveness of these variants very well.
“The variants of concern/interest fall into a spectrum of immune evasiveness, with B.1.351 being most; B.1.1.7, B.1.429 least. This property pertains to the potential for reinfection & some reduction in vaccine efficacy. My prelim estimates based on publications/preprints, subject to change”
The current variants of concern are also well explained in this article by Science Mag — Immunity to SARS-CoV-2 variants of concern. I have put the key image here that explains everything.
DOI: 10.1126/science.abg7404. Link: https://science.sciencemag.org/content/371/6534/1103/tab-figures-data
Can Nanobodies help us overcome these variants of concern and their immune evasiveness?
Now, let’s study the preprint published by NCDIR researchers -“Nanobody Repertoires for Exposing Vulnerabilities of SARS-CoV-2” on BioRxiv on 10 April 2021. It provides us with plenty of hope on how we can overcome the threat of immune evasion demonstrated by the current variants of concern.
NCDIR or National Center for Dynamic Interactome is a biotechnology resource center with four labs that carry out cutting-edge research in molecular & cellular biology funded by a grant from the National Institutes of General Medical Sciences (NIGMS) of the National Institute of Health (NIH).
Researchers at NCDIR have generated and characterized a large set of potent high- affinity nanobodies that target the SARS-CoV-2 spike (both inside & outside the Receptor Binding Domain or RBD) and neutralize the virus.
These high-affinity nanobodies present excellent kinetic viral neutralization properties, which can be further enhanced by oligomerization.
This repertoire of nanobodies examines the Spike protein inside and outside the RBD and recognizing numerous sites where the antibodies can bind. In other words, these nanobodies scan the spike protein thoroughly and expose the vulnerability of the virus by revealing multiple neutralization targets. They could do it in pseudoviruses and authentic SARS-CoV-2, including in primary human airway epithelial cells.
Combinations of nanobodies (mixtures) show highly synergistic activities. Synergy is seen when the combination of drugs shows a greater effect than the sum of the individual effects of each drug. The biggest advantage of having a large repertoire of nanobodies is that you combine them in multiple ways and also that, these nanobodies show cooperative activity when combined leading to synergistic effects.
Current situation: threat vs hope
I had recently written quoting some articles which say that SARS-CoV-2 might be undergoing convergent evolution and may bring the pandemic to an end by playing all its best cards quickly.
Vaccines prepared in 2020 are working well but only against the variants that circulated in 2020. They are proving to be less effective against the 2021 variants, which are showing resistance.
At the same time, people who have recovered in 2021 from natural infection (from a new variant) are successfully cross-neutralizing ‘all’ other variants- the ones currently posing threat in 2021 as well as the past (2020) variants.
This is like an annual cycle where the newly acquired immunity (via natural infection or vaccines) is able to cover all current & past threats but not the future threats.
Now it depends on whether the virus will finish playing all its best cards in 2021 itself or will again generate some newer variants in 2022.
However, going by some reports, the virus is undergoing ‘convergent evolution’ and all its best cards may get over in 2021 itself (most likely scenario). Then we may need just another round (booster dose) of tweaked vaccines that will be able to cover all past, present, and future threats.
But if it’s not convergent evolution, and the virus goes on giving yearly surprises, then we may need annual vaccine shots.
Nanobodies can take care of the future threats:
As shown in the preprint, with a repertoire so large, affinity so high, and combinations so synergistic, these nanobodies can take care of the future threats too.
As concluded by the authors, Nanobodies and their mixtures are resistant to mutational escape shown by emerging variants of SARS-CoV-2. These nanobodies, therefore, can establish an exceptional resource for superior COVID-19 prophylactics and therapeutics.
Read the preprint here: Nanobody Repertoires for Exposing Vulnerabilities of SARS-CoV-2
