Research suggests profound SARS-CoV-2 mutations are rare even among immunosuppressed

A recent article posted to the medRxiv* preprint server assessed whether host traits like immunosuppression aids severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutational drift.

​​​​​​​Study: Immunosuppression as a hub for SARS-CoV-2 mutational drift. ​​​​​​​Image Credit: NIAID


Recently emerged SARS-CoV-2 variants of concern (VOCs) play a considerable role in the endurance of the coronavirus disease 2019 (COVID-19) pandemic. The persistent emergence of novel SARS-CoV-2 VOCs is a continuing worldwide health threat. While these VOCs are notorious for their incredible evolutionary jumps and ability to evade priorly acquired immunity, their origins are mostly unclear.

Spillover infections in vulnerable animals, extended infection in an immunocompromised human host, or a combination of the two are the current hypotheses regarding the mysterious origin of novel SARS-CoV-2 variants. During the infection course, intra-host SARS-CoV-2 mutations arise and accumulate. While most mutations are random, recent research has found different mutational trends influenced by the clinical characteristics of the host.

SARS-CoV-2 is exposed to positive selection during infection, resulting in numerous, significantly nonsynonymous mutations. The virus undergoes purifying selection during transmission, and many nonsynonymous intra-host single nucleotide variants (iSNVs) are not passed on to subsequent hosts. Furthermore, immunocompromised SARS-CoV-2 hosts are vulnerable to long-term viral shedding, which can continue for months and accrue mutations that aid immune evasion.

About the study

In the present study, to evaluate the impacts of immunity and host clinical factors on the intra-host SARS-CoV-2 evolution, the investigators coupled electronic health data of COVID-19 patients with whole-genome SARS-CoV-2 sequences in Israel.

The team retrieved anonymized electronic health data from Maccabi Healthcare Services (MHS) centralized computerized database. MHS is a state-mandated, non-profit health organization in Israel that covers and offers healthcare to 26.7% of the population. The study included the MHS members with a COVID-19-positive polymerase chain reaction (PCR) assay result, plus viral sequencing data from that test.

The demographic data collected include age, sex, and a coded residential socioeconomic, geographical statistical region allocated by the Central Bureau of Statistics of Israel. The acquired SARS-CoV-2-related information comprised COVID-19 vaccination dates and the reports of any COVID-19 PCR testing. Additionally, the scientists procured SARS-CoV-2-related death and hospitalization records.

The COVID-19-related data also comprised the viral sequencing of some PCR assays chosen by MHS at random. Further, the procured information consisted of data on immunocompromised conditions, hypertension, cardiovascular illnesses, obesity (described as a body mass index of 30 kg/m2 or greater), diabetes mellitus, chronic obstructive pulmonary disease, and chronic renal disease from automated registries of the MHS.


The team discovered slight but substantial changes in SARS-CoV-2 intra-host heterogeneity, influenced by host factors like smoking, age, and COVID-19 vaccination status. The lack of a strong link between host factors and intra-host mutation rate was in line with prior findings. However, the current analysis shows a positive association with age, whereas Li and companions' longitudinal investigation indicated a minor negative correlation.

The scientists believe the intra-host disparities in mutational rate were likely suggestive of changes in host-pathogen connections. Nonetheless, robust purifying selection possibly limited the transmissibility and influence of these variations on total viral evolution. Nonsynonymous iSNVs were nearly unique at the lower part of allelic frequency. Besides, the team found no indication of any iSNV fixation in the group across the broader viral population.

Surprisingly, SARS-CoV-2 genomes from immunosuppressed individuals were substantially identical to those from immunocompetent individuals. Only one of 31 immunosuppressed patients, a newly vaccinated female aged around 70 with a history of Hashimoto's thyroiditis, had a noticeable difference in viral genomes during the early COVID-19 course. The authors emphasize that the viral genome procured from this female was unusually mutated, with near-complete truncating of the accessory protein, open reading frame 3a (ORF3a).

On the whole, the present findings show that host factors have only a minimal impact on the intra-host evolutionary pace and trajectory of SARS-CoV-2, with even the bulk of immunosuppressed people carrying rather typical viral genomes. According to the investigators, significant evolutionary leaps, such as those seen in SARS-CoV-2 VOCs, were thought to be uncommon, even in immunodeficient hosts.


Collectively, the study findings suggest that host clinical factors such as smoking and COVID-19 vaccination status have a minor impact on intra-host SARS-CoV-2 variety. The analysis revealed that the appearance and fixing of high-effect SARS-CoV-2 mutations in immunosuppressed individuals were uncommon and were not limited to COVID-19 patients with protracted periods of viral shedding. 

Nevertheless, the researchers speculated that significant SARS-CoV-2 evolutionary alterations could occur early in infection. Interestingly, in an immunosuppressed lady recently vaccinated against COVID-19, they discovered a unique stop-gain mutation that resulted in the near-complete truncation of ORF3a.

Furthermore, the team concluded that the link between the fundamental clinical characteristics and intra-host evolution was still unknown and needs additional investigations. 

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Immunosuppression as a hub for SARS-CoV-2 mutational drift; Guy Shapira, Tal Patalon, Sivan Gazit, Noam Shomron. medRxiv preprint 2022, DOI:,

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: AIDS, Assay, Body Mass Index, Chronic, Chronic Obstructive Pulmonary Disease, Coronavirus, Coronavirus Disease COVID-19, covid-19, Diabetes, Diabetes Mellitus, Evolution, Frequency, Genome, Hashimoto's Thyroiditis, Healthcare, immunity, Immunosuppression, Mutation, Nucleotide, Obesity, Pandemic, Pathogen, Polymerase, Polymerase Chain Reaction, Protein, Renal disease, Research, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Smoking, Syndrome, Thyroiditis, Virus

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Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.

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