Breakthrough Infections with Multiple Lineages of SARS-CoV-2 Variants Reveals Continued Risk of Severe Disease in Immunosuppressed Patients

Abstract

The pandemic of COVID-19 caused by SARS-CoV-2 infection continues to spread around the world. Vaccines that elicit protective immunity have reduced infection and mortality, however new viral variants are arising that may evade vaccine-induced immunity or cause disease in individuals who are unable to develop robust vaccine-induced responses. Investigating the role of viral variants in causing severe disease, evading vaccine-elicited immunity, and infecting vulnerable individuals is important for developing strategies to control the pandemic. Here, we report fourteen breakthrough infections of SARS-CoV-2 in vaccinated individuals with symptoms ranging from asymptomatic/mild (6/14) to severe disease (8/14). High viral loads with a median Ct value of 19.6 were detected in the nasopharyngeal specimens from subjects regardless of disease severity. Sequence analysis revealed four distinct virus lineages, including alpha and gamma variants of concern. Immunosuppressed individuals were more likely to be hospitalized after infection (p = 0.047), however no specific variant was associated with severe disease. Our results highlight the high viral load that can occur in asymptomatic breakthrough infections and the vulnerability of immunosuppressed individuals to post-vaccination infections by diverse variants of SARS-CoV-2.

Keywords: COVID-19; SARS-CoV-2; breakthrough infections; immunosuppression; post-vaccination infections; variants of concern.

Figure 1

Sequence analyses reveal multiple lineages of SARS-CoV-2 variants associated with breakthrough infections in this study. Phylogenetic tree depicting the lineages of the thirteen SARS-CoV-2 genomic sequences. The complete genome nucleotide sequence obtained from each subject was analyzed with NextClade software (https://clades.nextstrain.org/tree, accessed on 21 July 2021) for clade assignment. WHO designation of variants of concern (VOC) are given in parenthesis. Hospitalized subjects are indicated with a red circle and number; subjects with mild/asymptomatic disease are indicated with a black circle and number.

Figure 2

Multiple mutations in the SARS-CoV-2 spike gene were identified in subjects with breakthrough infections. Schematic diagram of the SARS-CoV-2 spike with functional domains highlighted in color. NTD: N-terminal domain; RBD: receptor-binding domain; CTD1 and CTD2: C-terminal domain 1 and 2; FP: fusion peptide; HR1: heptad repeat 1; CH: central helix; CD: connector domain; HR2: heptad repeat 2; TM: transmembrane domain; CT: cytoplasmic tail. The amino acid substitutions deduced from the nucleotide sequence detected in each subject are shown in the boxes and colored according to their location in the spike sequence. Subject numbers in red are the hospitalized cases.