Despite the end of the pandemic, COVID-19 continues to pose a serious health threat. Most individuals have established robust immune protection and do not develop severe disease but the infection can still lead to marked and sometimes long-lasting disease symptoms.
The researchers discovered that the pirola variant, in contrast the all previously circulating omicron variants, enters lung cells with high efficiency and uses the cellular enzyme TMPRss2 for entry, thereby exhibiting surprising parallels to variants alpha, beta, gamma and delta that circulated during the first years of the pandemic. The improved entry into lung cells might indicate that the virus is more aggressive but production of new, infectious viral particles in infected cells was reduced, which may limit spread and pathogenic potential.
The researchers report in the journal Cell that the pirola variant is resistant against all therapeutic antibodies and efficiently evades antibody responses in vaccinated individuals with and without breakthrough infection. However, the virus was appreciably inhibited by antibodies elicited by the new, XBB.1.5-adpated mRNA vaccine.
In summary, the results show that four years after the start of the pandemic the virus is still capable of profound changes and can reacquire properties that may promote the development of severe disease.
The spread of SARS-CoV-2 is associated with the constant emergence of new viral variants. These variants have acquired mutations in the spike protein, which allow evasion of neutralizing antibodies in vaccinated and convalescent individuals. The emergence of viral variants started with the alpha variant followed by the beta, gamma and delta variants.
At the end of the year 2021 the omicron variant became globally dominant, which, based on genome sequence, differed markedly from previously circulating variants. However, the virus had to pay a price for this massive change. Thus, the omicron variant evades neutralizing antibodies and is transmitted with high efficiency but has lost the ability to efficiently use a host cell enzyme, the protease TMPRSS2, for lung cell entry. As a consequence, the omicron variant induces pneumonia less frequently.
Pirola: A quantum leap in SARS-CoV-2 evolution
Descendants of the omicron variant dominated globally until the end of the year 2023. New variants frequently differed only by few mutations from their predecessors and there was evidence that viruses circulating in 2023 had only limited options to evade antibody pressure in the human population. Therefore, the discovery of a new SARS-CoV-2 omicron subvariant, pirola (BA.2.86), which, based on genome sequence, strongly differed from other circulating viruses drew a lot of attention.
The pirola variant, analogous to the omicron variant, likely arose in immunocompromised patients and presents a quantum leap in SARS-CoV-2 evolution. The spike protein of the pirola variant harbors more than 30 mutations relative to its precursor variant, BA.2, and it is largely unknown how these mutations affect the biological properties of the virus.
A team of researchers from the German Primate Center (DPZ) led by Markus Hoffmann and Stefan Pöhlmann addressed this question jointly with the research groups of Christian Drosten (Charité, Berlin), Georg Behrens (Hannover Medical School), Luka Cicin-Sain (Helmholtz Center for Infection Research, Braunschweig) and Hans-Martin Jäck (Friedrich-Alexander-University Erlangen Nuremberg).
Pirola can infect lung cells more efficiently
The researchers discovered that the pirola variant, in contrast to all previously circulating omicron subvariants, enters lung cells with high efficiency and in a TMPRSS2-dependent manner. Further, they could demonstrate that mutations S50L and K356T in the spike protein of the pirola variant are important for the highly efficient lung cell entry.
“It is noteworthy that two years after the global dominance of the omicron variant, which fails to robustly enter lung cells, now a quite different virus is spreading and that this virus is able to again enter lung cells with high efficiency. If the augmented lung cell entry translates into more severe disease upon infection with the pirola variant remains to be investigated in animal models,” says Pöhlmann, head of the Infection Biology Unity of the German Primate Center.
Pirola replicates less well than its predecessors
SARS-CoV-2 infected cells produce new virus particles many of which, but not all, are able to infect new cells. The researchers provided evidence that cells infected by the pirola variant are less well able than cells infected with previous variants to produce intact viral particles. “The relatively inefficient production of infectious particles by cells infected with the pirola variant was surprising,” says Hoffmann, the lead contact of the study.
“It will be interesting to analyze which mechanism is responsible. Maybe the infected cells produce defective interfering particles, which regulate spread of the pirola variant and contribute to antibody evasion.”
Therapeutic antibodies are ineffective against pirola
Recombinantly produced neutralizing antibodies were successfully used for COVID-19 prophylaxis and therapy. However, due to the emergence of viral variants with mutations in the antibody binding sites most of those antibodies are not active against currently circulating variants. The present study shows that the pirola variant is no exception—none of the tested antibodies was able to neutralize the virus.
“These results show that the development of new, broad spectrum antibodies is an important task,” says Hoffmann.
New, adapted vaccine protects against pirola
The pirola variant was also able to evade antibodies induced by vaccination or infection but with less efficiency than the contemporaneously circulating Eris variant (EG.5.1). However, antibodies induced by vaccination with the new XBB.1.5-adapted vaccine were able to appreciably inhibit both the pirola and the Eris variant.
“These results suggest that the XBB.1.5-adpated vaccine might induce a robust, although likely short-lived, protection against infection with the pirola variant,” says Hoffmann.
“In this context it is interesting that subvariants of pirola are currently globally on the rise that harbor an additional mutation in the spike protein, which may increase antibody evasion. The virus is in the process of optimizing itself and the consequences of this optimization should be studied,” adds Lu Zhang, first author of the study.
More information: Lu Zhang et al, SARS-CoV-2 BA.2.86 enters lung cells and evades neutralizing antibodies with high efficiency, Cell (2024). DOI: 10.1016/j.cell.2023.12.025

News
Unlocking hidden soil microbes for new antibiotics
Most bacteria cannot be cultured in the lab-and that's been bad news for medicine. Many of our frontline antibiotics originated from microbes, yet as antibiotic resistance spreads and drug pipelines run dry, the soil [...]
By working together, cells can extend their senses beyond their direct environment
The story of the princess and the pea evokes an image of a highly sensitive young royal woman so refined, she can sense a pea under a stack of mattresses. When it comes to [...]
Overworked Brain Cells May Hold the Key to Parkinson’s
Scientists at Gladstone Institutes uncovered a surprising reason why dopamine-producing neurons, crucial for smooth body movements, die in Parkinson’s disease. In mice, when these neurons were kept overactive for weeks, they began to falter, [...]
Old tires find new life: Rubber particles strengthen superhydrophobic coatings against corrosion
Development of highly robust superhydrophobic anti-corrosion coating using recycled tire rubber particles. Superhydrophobic materials offer a strategy for developing marine anti-corrosion materials due to their low solid-liquid contact area and low surface energy. However, [...]
This implant could soon allow you to read minds
Mind reading: Long a science fiction fantasy, today an increasingly concrete scientific goal. Researchers at Stanford University have succeeded in decoding internal language in real time thanks to a brain implant and artificial intelligence. [...]
A New Weapon Against Cancer: Cold Plasma Destroys Hidden Tumor Cells
Cold plasma penetrates deep into tumors and attacks cancer cells. Short-lived molecules were identified as key drivers. Scientists at the Leibniz Institute for Plasma Science and Technology (INP), working with colleagues from Greifswald University Hospital and [...]
This Common Sleep Aid May Also Protect Your Brain From Alzheimer’s
Lemborexant and similar sleep medications show potential for treating tau-related disorders, including Alzheimer’s disease. New research from Washington University School of Medicine in St. Louis shows that a commonly used sleep medication can restore normal sleep patterns and [...]
Sugar-Coated Nanoparticles Boost Cancer Drug Efficacy
A team of researchers at the University of Mississippi has discovered that coating cancer treatment carrying nanoparticles in a sugar-like material increases their treatment efficacy. They reported their findings in Advanced Healthcare Materials. Over a tenth of breast [...]
Nanoparticle-Based Vaccine Shows Promise in Fighting Cancer
In a study published in OncoImmunology, researchers from the German Cancer Research Center and Heidelberg University have created a therapeutic vaccine that mobilizes the immune system to target cancer cells. The researchers demonstrated that virus peptides combined [...]
Quantitative imaging method reveals how cells rapidly sort and transport lipids
Lipids are difficult to detect with light microscopy. Using a new chemical labeling strategy, a Dresden-based team led by André Nadler at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) and [...]
Ancient DNA reveals cause of world’s first recorded pandemic
Scientists have confirmed that the Justinian Plague, the world’s first recorded pandemic, was caused by Yersinia pestis, the same bacterium behind the Black Death. Dating back some 1,500 years and long described in historical texts but [...]
“AI Is Not Intelligent at All” – Expert Warns of Worldwide Threat to Human Dignity
Opaque AI systems risk undermining human rights and dignity. Global cooperation is needed to ensure protection. The rise of artificial intelligence (AI) has changed how people interact, but it also poses a global risk to human [...]
Nanomotors: Where Are They Now?
First introduced in 2004, nanomotors have steadily advanced from a scientific curiosity to a practical technology with wide-ranging applications. This article explores the key developments, recent innovations, and major uses of nanomotors today. A [...]
Study Finds 95% of Tested Beers Contain Toxic “Forever Chemicals”
Researchers found PFAS in 95% of tested beers, with the highest levels linked to contaminated local water sources. Per- and polyfluoroalkyl substances (PFAS), better known as forever chemicals, are gaining notoriety for their ability [...]
Long COVID Symptoms Are Closer To A Stroke Or Parkinson’s Disease Than Fatigue
When most people get sick with COVID-19 today, they think of it as a brief illness, similar to a cold. However, for a large number of people, the illness doesn't end there. The World [...]
The world’s first AI Hospital, developed in China is transforming healthcare
Artificial Intelligence and its developments have had a revolutionary impact on society, and healthcare is not an exception. China has made massive strides in AI integrated healthcare, and continues to do so as AI [...]