sharon sanders
Editor-in-Chief & President
SARS-CoV-2 Omicron BA.5: Evolving tropism and evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern.
Anupriya Aggarwal, Anouschka Akerman, Vanessa Milogiannakis, Mariana Ruiz Silva, View ORCID ProfileGregory J Walker, Andrea Kindinger, Thomas Angelovich, Melissa Churchill, Emily Waring, Supavadee Amatayakul-Chantler, Nathan Roth, Germano Coppola, Malinna Yeang, Tyra Jean, View ORCID ProfileCharles S.P. Foster, Alexandra Carey Hoppe, Mee Ling Munier, Daniel Christ, David Ross Darley, Gail Matthews, View ORCID ProfileWilliam D Rawlinson, Anthony D Kelleher, Stuart G Turville
doi: https://doi.org/10.1101/2022.07.07.22277128
This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
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To conclude, Omicron BA.5, like other omicron lineages, represents a continuing challenge for present vaccine strategies. Whilst many clinical studies have observed lower disease severity following infection in vaccine populations, the relative contributions of the Omicron variant phenotype and the efficacy of vaccine response to this observation was not readily clear 14. Whilst BA.1 and BA.2 are different in their transmissibility, their tropism towards cells of the upper respiratory tract is very similar. Mechanistically this change in tropism that moved efficient viral replication from the lung to bronchus is currently hypothesised to be a consequence of alternate protease usage away from the serine protease TMPRSS2 3,7,8,13. Curiously, the efficient use of TMPRSS2 is associated with prior furin cleavage of the S1 and S2 domains of Spike 3,12. The furin cleavage site is retained in Omicron lineages and acts as a functional substrate for furin when expressed as a separate peptide from the Spike (https://doi.org/10.1101/2022.04.20.488969). Therefore, conformational changes within the Spike of BA.1 and BA.2 would be consistent with the furin cleavage site being held in a conformation with limited furin accessibility.
In contrast, the small changes in the RBD of BA.5 appear to encourage furin cleavage in recent studies using pseudotyped viral platforms 15. This is consistent with observations for more efficient TMPRSS2 use, both herein and in animal models observing increased infection of the lung, in addition to increased disease severity 16. Curiously, the change in BA.5 not only gives the virus greater antibody evasion potential but concurrently has changed its tropism along with an increased transmission potential in the community.
Whilst observations of disease severity initially in South Africa were similar to other Omicron lineages 17, the increasing prevalence of BA.5 globally will now enable observations of disease severity across a range of immune backgrounds. Unfortunately, as we have observed herein, prior Omicron infections in those post-three vaccine doses have primarily increased potent responses to early pre-Omicron variants and have done little to increase breadth across Omicron lineages. Moving forward, vaccine strategies that can rapidly come online to increase breadth to current variants or can induce responsesto invariant epitopes that can future proof communities to emerging variants would be more pragmatic. In addition, whilst BA.5 appears to have evolved tropism towards pre-Omicron variant entry pathways, we will now need to look closely towards future variant trajectories and importantly if their tropism aligns with greater disease severity. If increased TMPRSS2 use is key to ranking variants for potential disease severity in the community, assays both herein and elsewhere will be able to resolve this changing TMPRSS2 tropism as soon as variants appear within the community through analysis of viral infectivity in primary nasopharyngeal swabs across TMPRSS2 cell lines. Figure Legends Figure 1. Humoral
https://www.medrxiv.org/content/10.1101/2022.07.07.22277128v1
Anupriya Aggarwal, Anouschka Akerman, Vanessa Milogiannakis, Mariana Ruiz Silva, View ORCID ProfileGregory J Walker, Andrea Kindinger, Thomas Angelovich, Melissa Churchill, Emily Waring, Supavadee Amatayakul-Chantler, Nathan Roth, Germano Coppola, Malinna Yeang, Tyra Jean, View ORCID ProfileCharles S.P. Foster, Alexandra Carey Hoppe, Mee Ling Munier, Daniel Christ, David Ross Darley, Gail Matthews, View ORCID ProfileWilliam D Rawlinson, Anthony D Kelleher, Stuart G Turville
doi: https://doi.org/10.1101/2022.07.07.22277128
This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
000000251
snip
To conclude, Omicron BA.5, like other omicron lineages, represents a continuing challenge for present vaccine strategies. Whilst many clinical studies have observed lower disease severity following infection in vaccine populations, the relative contributions of the Omicron variant phenotype and the efficacy of vaccine response to this observation was not readily clear 14. Whilst BA.1 and BA.2 are different in their transmissibility, their tropism towards cells of the upper respiratory tract is very similar. Mechanistically this change in tropism that moved efficient viral replication from the lung to bronchus is currently hypothesised to be a consequence of alternate protease usage away from the serine protease TMPRSS2 3,7,8,13. Curiously, the efficient use of TMPRSS2 is associated with prior furin cleavage of the S1 and S2 domains of Spike 3,12. The furin cleavage site is retained in Omicron lineages and acts as a functional substrate for furin when expressed as a separate peptide from the Spike (https://doi.org/10.1101/2022.04.20.488969). Therefore, conformational changes within the Spike of BA.1 and BA.2 would be consistent with the furin cleavage site being held in a conformation with limited furin accessibility.
In contrast, the small changes in the RBD of BA.5 appear to encourage furin cleavage in recent studies using pseudotyped viral platforms 15. This is consistent with observations for more efficient TMPRSS2 use, both herein and in animal models observing increased infection of the lung, in addition to increased disease severity 16. Curiously, the change in BA.5 not only gives the virus greater antibody evasion potential but concurrently has changed its tropism along with an increased transmission potential in the community.
Whilst observations of disease severity initially in South Africa were similar to other Omicron lineages 17, the increasing prevalence of BA.5 globally will now enable observations of disease severity across a range of immune backgrounds. Unfortunately, as we have observed herein, prior Omicron infections in those post-three vaccine doses have primarily increased potent responses to early pre-Omicron variants and have done little to increase breadth across Omicron lineages. Moving forward, vaccine strategies that can rapidly come online to increase breadth to current variants or can induce responsesto invariant epitopes that can future proof communities to emerging variants would be more pragmatic. In addition, whilst BA.5 appears to have evolved tropism towards pre-Omicron variant entry pathways, we will now need to look closely towards future variant trajectories and importantly if their tropism aligns with greater disease severity. If increased TMPRSS2 use is key to ranking variants for potential disease severity in the community, assays both herein and elsewhere will be able to resolve this changing TMPRSS2 tropism as soon as variants appear within the community through analysis of viral infectivity in primary nasopharyngeal swabs across TMPRSS2 cell lines. Figure Legends Figure 1. Humoral
https://www.medrxiv.org/content/10.1101/2022.07.07.22277128v1