#17,097
In the summer of 2021, just months after the release of the mRNA vaccines, many world leaders were optimistically touting the `imminent end of the pandemic' (see UK PM: COVID Restrictions To End July 19th).
Tempering those expectations, the UK's SAGE (Scientific Advisory Group for Emergencies) on COVID released a series of detailed reports on the SARS-CoV-2 pandemic, and where they thought things might go from there.
The most prescient of these reports was filed under Long term evolution of SARS-CoV-2, 26 July 2021, but this 15-page PDF was titled:
Can we predict the limits of SARS-CoV-2 variants and their phenotypic consequences?
As eradication of SARS-CoV-2 will be unlikely, we have high confidence in stating that there will always be variants. The number of variants will depend on control measures.
We describe hypothetical scenarios by which SARS-CoV-2 could further evolve and acquire, through mutation, phenotypes of concern, which we assess according to possibility. For this purpose, we consider mutations in the ‘body’ of the virus (the viral genes that are expressed in infected cells and control replication and cell response), that might affect virus fitness and disease severity, separately from mutations in the spike glycoprotein that might affect virus transmission and antibody escape.
We assess which scenarios are the most likely and what impact they might have and consider how these scenarios might be mitigated. We provide supporting information based on the evolution of SARS-CoV-2, human and animal coronaviruses as well as drawing parallels with other viruses.
While our pharmaceutical cupboard isn't entirely bare, treatment options have decreased markedly over the past 9 months (see FDA: The COVID-19 Treatment Guidelines Panel’s Statement on Omicron Subvariants and Anti-SARS-CoV-2 Monoclonal Antibodies), and newer variants could further erode our medical armamentarium against COVID.
As much as people want BA.5 to be COVID's last hurrah, SARS-CoV-2 continues to mutate and evolve, often generating new subvariants that are even better at evading existing immunity (either from vaccination, prior infection, or both) than previous iterations.
All of which brings us to a new preprint out of China which finds that a new round of Omicron subvariants (including BQ.1.1.10, BA.4.6.3, XBB, and CH.1.1) show the highest level of immune escape seen to date.Not surprisingly, with thousands of subvariants vying for an increasingly smaller pool of susceptible hosts, the variants best able to evade existing immunity are the ones that flourish, while more susceptible variants do not.
Immunity isn't a simple binary on/off switch, meaning that even low levels of immunity may be enough to keep some people from falling ill, and others out of the ICU. But the greater the degree of immune escape, the less effective vaccines, monoclonal antibodies, and immunity from past infection become.
As the SAGE group envisioned, three years into this pandemic we find ourselves locked into a continually escalating arms race with the virus, with no end in sight.
I've only posted the excerpt from the 44-page (and highly technical) preprint. Follow the link to read it in its entirety.
Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution
Yunlong Cao, Fanchong Jian, Jing Wang, Yuanling Yu, Weiliang Song, Ayijiang Yisimayi, Jing Wang, Ran An, Xiaosu Chen, Na Zhang, Yao Wang, Peng Wang, Lijuan Zhao, Haiyan Sun, Lingling Yu, Sijie Yang, Xiao Niu, Tianhe Xiao, Qingqing Gu, Fei Shao, Xiaohua Hao, Yanli Xu, Ronghua Jin, Zhongyang Shen, Youchun Wang, Xiaoliang Sunney Xie
doi: https://doi.org/10.1101/2022.09.15.507787
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Abstract
Continuous evolution of Omicron has led to a rapid and simultaneous emergence of numerous variants that display growth advantages over BA.5. Despite their divergent evolutionary courses, mutations on their receptor-binding domain (RBD) converge on several hotspots. The driving force and destination of such convergent evolution and its impact on humoral immunity remain unclear.Here, we demonstrate that these convergent mutations can cause striking evasion of neutralizing antibody (NAb) drugs and convalescent plasma, including those from BA.5 breakthrough infection, while maintaining sufficient ACE2 binding capability.BQ.1.1.10, BA.4.6.3, XBB, and CH.1.1 are the most antibody-evasive strain tested, even exceeding SARS-CoV-1 level. To delineate the origin of the convergent evolution, we determined the escape mutation profiles and neutralization activity of monoclonal antibodies (mAbs) isolated from BA.2 and BA.5 breakthrough-infection convalescents.Importantly, due to humoral immune imprinting, BA.2 and especially BA.5 breakthrough infection caused significant reductions in the epitope diversity of NAbs and increased proportion of non-neutralizing mAbs, which in turn concentrated humoral immune pressure and promoted convergent evolution. Moreover, we showed that the convergent RBD mutations could be accurately inferred by integrated deep mutational scanning (DMS) profiles, and the evolution trends of BA.2.75/BA.5 subvariants could be well-simulated through constructed convergent pseudovirus mutants.Together, our results suggest current herd immunity and BA.5 vaccine boosters may not provide good protection against infection. Broad-spectrum SARS-CoV-2 vaccines and NAb drugs development should be highly prioritized, and the constructed mutants could help to examine their effectiveness in advance.
Competing Interest Statement
X.S.X. and Y.C. are inventors on the provisional patent applications of BD series antibodies, which includes BD30-604 (DXP-604), BD55-5840 (SA58) and BD55-5514 (SA55). X.S.X. and Y.C. are founders of Singlomics Biopharmaceuticals. Other authors declare no competing interests.
