The important role for the immune system in shaping the evolution of SARS-CoV-2


Two studies published in the open-access journal PLOS Pathogens provide new evidence supporting an important role for the immune system in shaping the evolution of SARS-CoV-2, the virus that causes COVID-19.

These findings—and the novel technology behind them—improve understanding of how new SARS-CoV-2 strains arise, which could help guide treatment and vaccination efforts.

For the first study, Rachel Eguia of Fred Hutchinson Cancer Research Center in Seattle, Washington, and colleagues sought to better understand SARS-CoV-2 by investigating a closely related virus that has circulated widely for a far longer period of time: the common-cold virus 229E.

229E and SARS-CoV-2 are both in the coronavirus family, which features a “spike protein” that enables infection of human cells. A person who is infected with 229E develops an immune response against the spike protein that protects them from reinfection, but only for a few years.

Whether reinfection then occurs because the immune response wears off or because 229E evolves to escape it has been unclear.

Eguia and colleagues addressed this question by testing the activity of serum samples collected from patients in the 1980s-90s against spike proteins from both old 229E strains and strains that evolved later on. They found that the old spike proteins were vulnerable to the older sera. However, modern spike proteins were able to evade older sera while remaining vulnerable to sera from modern patients.

This analysis suggests that modern strains of 229E have accumulated spike protein mutations that enable them to evade older sera. These findings raise the possibility that SARS-CoV-2 and other coronaviruses could undergo similar evolution, and that COVID-19 vaccines may require periodic updates to remain effective against new strains.

The authors add, “The human common-cold coronavirus evolves over the span of years to decades to erode neutralization by human polyclonal serum antibodies. This work suggests that human coronaviruses undergo significant antigenic evolution that may contribute to eventual re-infections.”

For the second study, Sung Hee Ko of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, and colleagues developed new technology for genetic sequencing of the SARS-CoV-2 spike protein, enabling detection of multiple SARS-CoV-2 strains that may be present at the same time within a single infected patient.

Previous studies have used standard sequencing methods to produce a single genetic sequence from an individual patient, obscuring the potential presence of multiple SARS-CoV-2 strains. By contrast, the new technology highlights virus diversity within each patient and enables tracking of the evolution of new SARS-CoV-2 strains during acute infection.

Indeed, when the researchers applied the new method to human respiratory samples, they found new SARS-CoV-2 variants arising within the same patient over the course of acute infection. The precise mutations in these variants suggest that they arose in response to selective pressure from the immune system.

Future application of the new technology could improve understanding of how the evolution of new SARS-CoV-2 variants within a single patient impacts their outcomes. The findings also suggest that patients might see greater benefits from early treatment with antiviral drugs capable of targeting multiple strains, than from delayed treatment with a single antiviral drug.

The authors add, “We used new technology to show that coronavirus variants with mutated spike proteins can arise early in the course of infection. Our results suggest more virus evolution in each person than previously thought, with potential implications for clinical outcomes and for the emergence of transmissible variant strains.”

Together, these two studies deepen understanding of how new SARS-CoV-2 strains arise in response to immune system activity, potentially paving the way for additional research and improved treatment.

The novel SARS-CoV-2 coronavirus that causes COVID19 has surpassed 34 million infections worldwide within nine months of pandemic, resulting in more than one million deaths until September 2020 ( (1). In-depth characterization of this virus is urgently needed to improve outbreak surveillance, vaccine development and for effective treatments now and in the immediate future. SARS-CoV-2 is a positive single-stranded RNA virus (+ssRNA) with a crown-like appearance observed by electron microscopy that is due the presence of the of spike glycoproteins on the lipid bilayer envelope (2, 3).

Another three transmembrane proteins are incorporated into the envelope: small envelope protein (E), matrix protein (M), and nucleocapsid protein (N) (4). As seen with SARS-CoV-1, SARS-CoV-2 binds through its Spike glycoprotein to cell membrane-bound angiotensin-converting enzyme 2 (ACE2) for entry into host cells (5–8). Advancements in COVID19 treatments have been recently developed including Remdesivir, a nucleoside analog that inhibits viral RNA-dependent RNA polymerase and is an effective treatment to reduce viral titers in rhesus macaques that is clinically approved for COVID19 treatment (9).

As well, either wild-type or catalytically inactive ACE2 has been demonstrated to block viral entry in vitro, and are proposed as promising treatments (10, 11). A remaining question is how the human humoral immune response develops after SARS-CoV-2 infection. Studies in Iceland have shown that around 90% of infected patients develop antiviral antibodies that last up to four months (12), but it has also been suggested that around one third of the seropositive infections are asymptomatic and become antibody-negative early in the convalescence period (13).

Also, the unexpectedly low secondary infection risk reported for SARS-CoV-2 infection suggests innate immune responses are active in humans (14, 15). To explore host– SARS-CoV-2 interactions at the genetic level it is useful to analyze viral sequencing results per individual and at the population level. Initiatives such as GISAID ( (16, 17) and the Sequence Read Archive (SRA, have been storing SARS-CoV-2 sequencing datasets worldwide from the beginning of the pandemic starting in January 2020, allowing researchers to track fixed variants and follow viral evolution by geographical region.

The unprecedented amount of SARS-CoV-2 whole genome sequencing data can help to 1) characterize viral variants that occur within a given host, 2) understand variant fixation in a given population and 3) understand how the virus changes over time. In fact, the Spike protein mutation D614G global transition that occurred very recently was discovered in this way and is associated with higher viral titers and higher fatality rates (18, 19).

Thus, it is probable that more mutations are to be discovered by tracking SARS-CoV-2 genomic changes globally. In this study we aimed to characterize in depth intra-host variation and population-fixed variants worldwide up until the beginning of August 2020 by using over 76,000 SARS-CoV-2 sequences and 17,500 sequencing datasets from GISAID and SRA repositories, respectively. First, we found evidence for SARS-CoV-2 hypermutation, occurring in less than 2% of COVID19 patients.

This mechanism is predicted to inactivate the virus and is likely caused by host mechanisms involved APOBEC3G complexes and intra-host microdiversity, where G>T transversions and C>T transitions are frequent signatures observed both in hypermutant and non-hypermutant samples. These results suggest that SARS-CoV-2 is actively shaped by the host immune system to varying degrees. From a population context, several SARS-CoV-2 proteins such as Nsp2, 3C-like proteinase, ORF3a and ORF8 are under active evolution, evidenced by their increasing πN/ πS ratios.

Noteworthy, most of the population-fixed variants in SARS-CoV-2 are predicted to destabilize viral proteins, as already reported for other RNA viruses. Of these variants, those occurring in the ORF3a (Q57H), Nucleocapsid (I292T, RG203KR) and Spike protein (V1176F) have a positive association with increased mortality ratios in populations from Saudi-Arabia and Brazil, respectively. In particular, the V1176F variant co-occurs with the D614G mutation in the Spike protein mutation in Brazil and arose independently in at least in three independent SARS-CoV-2 clades.

This variant is predicted to stabilize the SARS-CoV-2 Spike trimmer complex and confer flexibility to the stalk domain of the trimmer, potentially facilitating Spike binding properties to ACE2. Also, this variant is associated with increased mortality ratios in Brazil and is increasingly spreading throughout the world. Similarly, the emerging variant S477N occurring in the Receptor Binding Domain, dramatically increase its frequency and became dominant in Australia within two months. Experimental data support that S477N increase both fitness and binding to ACE2 receptor, explaining its selection among other viruses in Australia. S477N also is presently spreading across countries and is associated with higher fatalities throughout the world. We propose that these variants are novel mutations occurring in SARS-CoV-2 and their spread may pose serious concerns in public health in the future of the pandemic.

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More information: Ko SH, Bayat Mokhtari E, Mudvari P, Stein S, Stringham CD, Wagner D, et al. (2021) High-throughput, single-copy sequencing reveals SARS-CoV-2 spike variants coincident with mounting humoral immunity during acute COVID-19. PLoS Pathog 17(4): e1009431.

Eguia RT, Crawford KHD, Stevens-Ayers T, Kelnhofer-Millevolte L, Greninger AL, Englund JA, et al. (2021) A human coronavirus evolves antigenically to escape antibody immunity. PLoS Pathog 17(4): e1009453.


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