The evolution of transmissible variants harboring mutations consistent with immune escape in mild community COVID-19 cases

In a recent study posted to the medRxiv* preprint server, researchers investigate whether transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants developed during SARS-CoV-2 infection by culturing and sequencing SARS-CoV-2 strains obtained from serial oral and nasal samples of community-residing coronavirus disease 2019 (COVID-19) patients.

Study: Rapid emergence of transmissible SARS-CoV-2 variants in mild community cases. Image Credit: joshimerbin/Shutterstock.com
Study: Rapid emergence of transmissible SARS-CoV-2 variants in mild community cases. Image Credit: joshimerbin/Shutterstock.com

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

Previous studies have reported that SARS-CoV-2 mutations develop over weeks to months of SARS-CoV-2 infection among hospitalized patients suffering from hematological malignancies or other immunosuppressive conditions and among community residents with advanced immunodeficiency.

It is reported that immune-evasive variants of SARS-CoV-2 emerge in case of inadequate SARS-CoV-2 suppression by the immunological system among profoundly immunocompromised individuals, enabling the evolutionary development of non-synonymous amino acid substitutions or mutations.

About the study

In the present study, researchers investigated whether self-resolving and mild SARS-CoV-2 infections among community residents could give rise to immune-evasive SARS-CoV-2 variants while shedding infectious SARS-CoV-2.

The study was conducted from May 2021 to October 2021, in the period of SARS-CoV-2 Delta variant of concern (VOC) predominance in the United Kingdom (UK). For the study, 343 ATACCC study participants, who were community-dwelling individuals with symptomatic polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection, were enrolled within 5.0 days of the onset of symptoms. Among the individuals, 23% (n=78) of Delta VOC-exposed individuals had SARS-CoV-2-positive PCR reports at >1.0 time points, and for 32 out of 78 cases, the growth phase of SARS-CoV-2 was captured.

Nasopharyngeal swan specimens obtained from the patients were subjected to lateral flow tests (LFTs) and plaque assays for SARS-CoV-2 culture. Whole-genome sequencing (WGS) was performed for 11 out of 32 individuals with ≥4.0 consecutive specimens comprising >1,000.0 SARS-CoV-2 ribonucleic acid (RNA) copies per mL on quantitative reverse transcription-PCR (RT-qPCR).

SARS-CoV-2 mutation detection criteria were as follows: (i) the identification of a mutation in ≥5.0% of the sequenced reads in a specific site and (ii) time-associated changes in the proportion of SARS-CoV-2 mutation, and (iii) availability of previously published reports reporting the mutant as an immune-evasive variant.

Results

Of 11 cases, nine (three and six unvaccinated and vaccinated, respectively) shed infectious SARS-CoV-2 for five days. No mutants fulfilling the criteria were identified, albeit one patient developed the open-reading frame (ORF)1ab:T283I mutation that is reported to result in neutral effects. Two vaccinated patients showed persistent infectious SARS-CoV-2 throughout the sampling periods despite SARS-CoV-2-negative LFT reports in the later period of the infection.

Of note, both cases, A and B, developed multiple and significant SARS-CoV-2 mutations, DA55-C67 and DF54-Q62insL, in SARS-CoV-2 ORF7a, that prevents the insertion of the anti-SARS-CoV-2 serine incorporator-5 (SERINC-5) host protein into budding SARS-CoV-2 virions, and the S255F and D253G mutations in the SARS-CoV-2 spike (S) N-terminal domain (NTD), conferring immune-evasiveness to the virus.

Remarkably, both case individuals were diabetic and obese, with elevated body mass index (BMI) values of 27 to 28, whereas the other cases with regular SARS-CoV-2 culture and RT-PCR reports did not have type 2 diabetes. Nevertheless, both cases had good blood sugar control, with HbA1c values lesser than 48.0 mmol per mL for four years before the infection. None of the individuals suffered from immunosuppression or recurring infections and showed spontaneous recovery from mild SARS-CoV-2 infection without requiring hospitalization.

Case B demonstrated viral load increases when the SARS-CoV-2 mutations were initially identifiable, with elevations in plaque-forming units (PFU) values in the plaque assays and SARS-CoV-2 RNA load in RT-PCR that couldn’t be explained by sampling variabilities. SARS-CoV-2 rebound reportedly correlates with the immune-evasive variant emergence, and the temporal association indicates that immune-evasive mutant development drove prolonged SARS-CoV-2 shedding.

Of interest, the findings indicated that case A and case B individuals were infected initially by various haplotypes of one quasi-species. It is not likely that the mutations identified in the initial stage of infection returned to ancestral states. Therefore, their relative reductions in frequency during the infection course can be explained better by increased frequency under immunological pressures of more haplotypes of the original type devoid of such deletions.

Conclusion

Overall, the study findings showed that community-dwelling contacts of COVID-19 patients could swiftly develop culturable and viable SARS-CoV-2 mutations, conferring immune-evasiveness during the regular course of SARS-CoV-2 infections within 14.0 days of the onset of COVID-19.

The study findings indicate the feasibility of immune-evasive mutations in community residents with COVID-19 without major immunosuppression. Further research must explore type II diabetes as a risk factor for immune-evasive SARS-CoV-2 variant emergence.

*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:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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