SARS-CoV-2 lineage-dependent temporal phylogenetic distribution and viral load in immunocompromised and immunocompetent individuals

Abstract

Objectives: Mutational dynamics of SARS-CoV-2 in immunocompromised hosts, although well documented, remain a relatively unexplored mechanism. This study aims to compare the viral replication load and genetic diversity of SARS-CoV-2 in immunocompromised patients and non-immunocompromised individuals (NICs) from two major hospitals in Paris from January 2021 to May 2023.

Methods: Cycle threshold (CT) values were measured by TaqPath COVID-19 RT-PCR (Thermo Fisher Scientific). The SARS-CoV-2 whole-genomes from 683 immunocompromised patients and 296 NICs was sequenced using Oxford Nanopore Technologies and used to determine lineage and mutational profile.

Results: All immunocompromised patients, but not oncology patients, had lower SARS-CoV-2 viral loads than NICs. The genetic distribution of SARS-CoV-2 was homogeneous between immunocompromised individuals and NICs, with more mutations in immunocompromised patients (IRR = 1,013). Indeed, extensive genomic analysis revealed several mutations specifically associated with immunosuppression status, such as S: T95I, S:N764K, M:Q19E and ORF10:L37F. Conversely, the S: R346K and NSP13:T127N mutations were more common in NICs.

Conclusion: Immunocompromised patients have lower viral loads, probably due to their later diagnosis compared to NICs and oncology patients, who have better access to on-site SARS-CoV-2 testing and follow-up. In addition, mutational profiles differ between the two groups, with immunocompromised hosts accumulating more mutations compared to NICs.

Keywords: Immunocompromised host; SARS-CoV-2; Single mutation analysis; Viral load; Whole-Genome sequencing.

Fig. 1

Whole-genome analysis and single mutation analysis (A) Multiple correspondence analysis shows no distinct mutation profile between controls and immunocompromised patients. Sequences form clusters according to their lineage and their similarities from one lineage to another, such as BA.2 and its sub-lineage BA.5 and BQ.1 (B). Single mutation analysis display on the volcano plot, showing three amino acid substitutions in the Spike protein and three substitutions in the M, ORF10 and NSP3 proteins. Substitutions S: R346K and NSP3:T127N are positively associated to NICs group and S: T95I, S:N764K, ORF10: L37F and M: Q19E are positively associated to immunocompromised patients group (C)

Fig. 2

Boxplot comparing the number of mutations at diagnosis across different patient groups stratified by immunosuppression type. The groups include patients with autoimmune or inflammatory diseases, hematological oncology, HIV infection, intensive care admission, oncology, respiratory diseases, treatment with rituximab, and solid organ transplantation, as well as controls. The boxplots represent the median, interquartile range (IQR), and the range of observed values, with outliers shown as individual points. Notably, patients admitted to intensive care exhibit a higher number of mutations compared to most other groups, while controls have a lower average mutation count