JN.1’s rock-and-roll party

JN.1’s rock-and-roll party results in an accumulation of various mutations, preparing the spike protein to trigger steric immune evasion. This evolutionary shift poses a formidable threat to public health.

Currently circulating JN.1 clade lineages are highly infectious, primarily spreading through asymptomatically infected Covid-19 (C-19) vaccinees. This has led to sustained high viral infection rates,  despite the relatively low mutation rate of SARS-CoV-2 (SC-2). Simultaneously, polyreactive, nonneutralizing IgM Abs (PNNAbs) in C-19 vaccinees are hindering trans infection at the lower respiratory tract.

This prevention of trans infection protects C-19 vaccinees from severe C-19 disease caused by highly infectious Omicron descendants. Interestingly, these are the same antibodies (Abs) that previously contributed to the enhanced infectiousness of early Omicron variants at the level of the upper respiratory tract. These PNNAbs come to bear in the presence of high titers of poorly neutralizing (i.e., low affinity) Abs (https://pubmed.ncbi.nlm.nih.gov/34384810/). PNNAbs are presumably produced by B cells lacking memory, and titers sufficient to inhibit SC-2 virulence can therefore only be sustained for as long as the levels of the poorly neutralizing Abs remain high enough to stimulate their production. Consequently, a significant decline in the titers of these poorly neutralizing Abs automatically implies a waning of the PNNAbs. When the concentration of the latter falls below a minimal threshold for virulence inhibition, they exert suboptimal immune pressure on a small antigenic site (so-called ‘enhancing site’) comprised within the N-terminal domain of the spike (S) protein (S-NTD) to which these Abs attach upon recognizing viral particles adsorbed to migratory dendritic cells (https://bit.ly/3NYokkE; chapter 6.1).

Suboptimal immune pressure, concentrated on a small antigenic site and occurring collectively within a highly C-19 vaccinated population, causes a high level of immune selection pressure on the virus. This immune selection pressure is not variant-specific, as the targeted antigenic site within the S-NTD is highly conserved among all SC-2 variants. A high infection rate combined with high and widespread variant-nonspecific immune selection pressure on viral (trans) infectiousness explains why many immune escape variants are now rapidly emerging, co-circulating and being transmitted. Competition between a multitude of selected immune escape variants reduces the chance that any specific mutation is transmitted. This situation also enables the virus to accumulate multiple genetic changes during the viral transmission chain, facilitating reshuffling of the amino acid composition of the S protein to selectively accommodate a particular set of site-specific O-glycosylations on the S protein. The targeted change in the S glycosylation profile is likely to cause steric hindrance in the attachment of the virulence-inhibiting Abs to dendritic cell-tethered virions while preserving their fusogenic capacity (https://www.voiceforscienceandsolidarity.org/scientific-blog/predictions-gvb-on-evolution-c-19-pandemic). Mutations enabling the accommodation of such a specific glycosylation pattern would allow the newly emerging variant to lift the blockade on viral virulence in C-19 vaccinees and thereby evade immune protection from severe illness.

Reports of spectacular mutations are currently accumulating. These mutations are not limited to the S protein but also affect other viral proteins involved in viral reproduction, clearance of viral-infected cells, and even cell metabolic processes, including those that regulate post-translational glycosylation during processing of viral glycoproteins in virus-infected cells. On the other hand, shifts in the distribution of distinct O-linked sugars may already occur as a direct consequence of amino acid mutations (https://bit.ly/3NYokkE; chapter 3.4.1).

Given that the S protein is responsible for viral (trans)infectiousness and is, therefore, indispensable for initiating the virus reproduction cycle at the upper and/ or lower respiratory tract, it is not surprising that variants escaping Abs targeting the S protein have a much higher potential for successful transmission compared to variants harboring mutations in proteins involved in other stages of the viral lifecycle. It is therefore reasonable to assume that the transformative mutation that will ultimately unleash the virus’s virulence in highly C-19 vaccinated populations will occur in/ on its S protein.

In conclusion: The virus is now rapidly accruing substantial genetic diversity to accommodate a new,  sweet, but unexpected, ally that will give it a new face, one that eludes recognition of the immune subversive mutation by the immune systems of numerous fully vaccinated individuals and likely unleashes the virus’s full virulence.

- Society in highly C-19 vaccinated countries will be caught off guard!-