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. 2024 Dec 31;20(1):2399382.
doi: 10.1080/21645515.2024.2399382. Epub 2024 Sep 10.

Genomic insights into mRNA COVID-19 vaccines efficacy: Linking genetic polymorphisms to waning immunity

Min-Jia Hsieh  1 , Ping-Hsing Tsai  2 , Pin-Hsuan Chiang  3 , Zih-Kai Kao  4 , Zi-Qing Zhuang  3 , Ai-Ru Hsieh  5 , Hsiang-Ling Ho  6   7 , Shih-Hwa Chiou  2   8 , Kung-Hao Liang  2   9   10   11 , Yu-Chun Chen  1   3   8   12
Affiliations

Genomic insights into mRNA COVID-19 vaccines efficacy: Linking genetic polymorphisms to waning immunity

Min-Jia Hsieh et al. Hum Vaccin Immunother. .

Abstract

Genetic polymorphisms have been linked to the differential waning of vaccine-induced immunity against COVID-19 following vaccination. Despite this, evidence on the mechanisms behind this waning and its implications for vaccination policy remains limited. We hypothesize that specific gene variants may modulate the development of vaccine-initiated immunity, leading to impaired immune function. This study investigates genetic determinants influencing the sustainability of immunity post-mRNA vaccination through a genome-wide association study (GWAS). Utilizing a hospital-based, test negative case-control design, we enrolled 1,119 participants from the Taiwan Precision Medicine Initiative (TPMI) cohort, all of whom completed a full mRNA COVID-19 vaccination regimen and underwent PCR testing during the Omicron outbreak. Participants were classified into breakthrough and protected groups based on PCR results. Genetic samples were analyzed using SNP arrays with rigorous quality control. Cox regression identified significant single nucleotide polymorphisms (SNPs) associated with breakthrough infections, affecting 743 genes involved in processes such as antigenic protein translation, B cell activation, and T cell function. Key genes identified include CD247, TRPV1, MYH9, CCL16, and RPTOR, which are vital for immune responses. Polygenic risk score (PRS) analysis revealed that individuals with higher PRS are at greater risk of breakthrough infections post-vaccination, demonstrating a high predictability (AUC = 0.787) in validating population. This finding confirms the significant influence of genetic variations on the durability of immune responses and vaccine effectiveness. This study highlights the importance of considering genetic polymorphisms in evaluating vaccine-induced immunity and proposes potential personalized vaccination strategies by tailoring regimens to individual genetic profiles.

Keywords: COVID-19; genetic polymorphisms; long-term memory CD8+ T cells; mRNA-based vaccines; waning immunity.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
GWAS flowchart of participant selection.
Figure 2.
Figure 2.
The characterization of genetic variants associated with vaccine effectiveness decreasing after three doses.
Figure 3.
Figure 3.
Variant-affected genes regulate the activity fighting against SARS-CoV-2.
Figure 4.
Figure 4.
Patients with a high PRS are more susceptible to COVID-19 even after vaccination.
See this image and copyright information in PMC

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