Can sick people be used as an early warning system despite vaccination?​

Breakthrough infections could provide early evidence of mutations in later dominant variants. This is what scientists from the Spanish National Research Council (CSIC) and the Fundación Jiménez Díaz report in a preprint of the “Journal of Clinical Investigation” that has not yet been peer-reviewed by experts.

In a pilot study, Brenda Martnez-González and Celia Perales took a nasopharyngeal swab from five symptomatic infected people who had been vaccinated twice with the BioNTech/Pfizer vaccine during the third wave of the pandemic but died in April 2021 infected with the alpha variant during the fourth wave. In addition, they looked at five people who had COVID-19 but had not been vaccinated.

The researchers found a number of mutations in the genome sequences relevant to the spike protein, which were later also present in the Delta plus, Iota and omicron variants. 

All of these variants had supplanted previous dominant virus versions and were declared “variants of interest” (VOI) or “variants of concern” (VOC) by health authorities: Iota in March 2021, Delta-Plus in May 2021 and Omicron in November 2021.

Further development of the coronavirus variants in immunocompromised patients

Mutations and an RNA replication machinery that does not have error correction – which is common in DNA double strands – ensure that different amino acid is suddenly encoded in the SARS-CoV-2 genome or that certain amino acids are even completely removed. All of this can affect the three-dimensional structure of the protein and, for example, ensure that the spike protein binds better to the ACE-2 receptor on body cells.

Normally, viruses don’t have much time to mutate in patients’ bodies before the immune system destroys the virus. However, if the immune system takes much longer because it cannot completely get rid of the viruses, then they have more time for helpful mutations, which subsequently prevail if they give the viruses an advantage. 

Scientists suspect that many of the dominant coronavirus variants developed in immunocompromised patients.

Some of the virus variants in the body are very rare, with just a few percent or less than one percent of people having them. The Spanish research team used a powerful, so-called “ultra-deep sequencing” method that is better at finding these rare gene variants.

Get an overview of the many mutants

Only one vaccinated person had the omicron mutation, yet it made up 12.64 percent of the virus material tested. The other mutations were discovered in both vaccinated and unvaccinated persons at lower, mostly equivalent rates. The researchers conclude that the vaccine had no effect on the virus’s selective pressure. The VOI and VOC highlighted are not sequential and clearly separate variants, according to their findings.

“This work underscores the need to analyze virus populations at high resolution and in depth to get an overview of the many mutants that coexist in each infected individual,” says Esteban Domingo, a researcher at the Severo Ochoa Center for Molecular Biology (CBMSO- CSIC UAM). “These analyzes could allow us to track down potentially relevant mutations or mutation sets before they become part of dangerous variants.” 

So-called escape mutations are particularly problematic with regard to the development of COVID-19 vaccines adapted to new variants. These help the pathogen to escape a targeted immune reaction.

Whether and how it can be predicted which mutation will prevail and ensure the dominance of a variant remains to be seen. If this succeeds, it would be conceivable to develop adapted vaccines at an early stage, especially with mRNA technology, which can be adapted relatively quickly. For this, however, broader studies on the early detection of mutations with many more test persons are first necessary.

For Domingo and co-author Celia Perales, it was already clear in an earlier article when the best vaccination period would be: “The composition and dynamics of the viral mutation spectra show us that vaccination campaigns against the COVID-19 disease should be started at a time when disease incidence is low to avoid selection of escape mutants,” they wrote in the Journal of Virology last March.

Source: 10.1172/JCI157700

Image Credit: Getty

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