How COVID-19 Vaccines Affect Immune Responses During Breakthrough Infections

Background Introduction

As the COVID-19 pandemic continues, an increasing number of infections are “breakthrough infections,” occurring in individuals who have been vaccinated or previously infected with SARS-CoV-2. Although vaccination has significantly reduced the risk of infection and disease severity, breakthrough infections still spread among high-risk populations and may lead to Long COVID. Therefore, understanding the immune response during breakthrough infections is crucial for optimizing vaccine strategies and treatment methods.

Previous studies have mainly focused on how vaccines enhance adaptive immunity, but the role of innate immunity in controlling viral infections and coordinating immune responses is equally important. Innate immune cells, such as monocytes and natural killer (NK) cells, not only directly participate in antiviral responses but also influence overall immune responses by regulating adaptive immune cell activity. However, how prior vaccination or infection alters innate immune responses, particularly the activity and function of innate immunity during breakthrough infections, remains unclear.

To fill this knowledge gap, a research team from Stanford University published a study titled “Prior vaccination prevents overactivation of innate immune responses during COVID-19 breakthrough infection” in Science Translational Medicine, providing detailed insights into how vaccination affects innate and adaptive immune responses during breakthrough infections.

Research Team and Publication Information

The study was conducted by Leslie Chan, Kassandra Pinedo, Mikayla A. Stabile, and other researchers from Stanford University School of Medicine, Harvard T.H. Chan School of Public Health, and other renowned institutions. The paper was published in Science Translational Medicine on January 29, 2025.

Research Process and Results

1. Study Subjects and Experimental Design

The study recruited three groups of participants:
1. Unvaccinated Infected Individuals (UVI): Mainly infected during the Delta variant wave from April to December 2021.
2. Vaccinated Infected Individuals (VI): Infected during the same Delta variant wave and fully vaccinated (primarily with Pfizer or Moderna vaccines).
3. Healthy Controls (HC): Healthy individuals without SARS-CoV-2 infection.

The researchers performed single-cell RNA sequencing (scRNA-seq), mass cytometry, and Olink plasma proteomics on peripheral blood mononuclear cells (PBMCs) and plasma samples from participants. These techniques were used to study innate and adaptive immune responses in unvaccinated and vaccinated individuals during breakthrough infections.

2. Single-Cell Transcriptomic Analysis

Using scRNA-seq, the researchers found that monocytes and NK cells had lower transcriptional activity during breakthrough infections. Compared to unvaccinated infected individuals, vaccinated individuals exhibited reduced migration potential in monocytes and lower proliferative activity in NK cells. Additionally, females showed stronger innate immune cell activity during breakthrough infections.

3. Functional Analysis of Monocytes

The study revealed that monocytes in vaccinated individuals exhibited lower inflammatory responses at the transcriptional level. For example, classical monocytes (CD14+ monocytes) and non-classical monocytes (CD16+ monocytes) showed fewer upregulated genes during breakthrough infections. Moreover, monocytes in vaccinated individuals had lower expression of metabolism-related genes, such as those involved in lipid metabolism and purine nucleotide biosynthesis, suggesting that vaccination suppresses inflammatory responses by altering metabolic pathways.

4. Transcriptomic and Functional Analysis of NK Cells

NK cells play a critical role in the early stages of viral infection. The study found that NK cells in unvaccinated individuals exhibited stronger upregulation of genes related to cell cycle and activation, while vaccinated individuals had lower NK cell proliferative activity. This indicates that vaccination limits NK cell proliferation, reducing the risk of excessive inflammatory responses.

5. Cell-Cell Communication Analysis

Through cell-cell communication network analysis, the researchers identified enhanced immunosuppressive signals from monocytes and NK cells to adaptive immune cells (e.g., B cells and T cells) in vaccinated individuals. These signals may help control the overactivation of adaptive immune responses, thereby preventing immunopathological damage.

6. Sex-Based Differences

The study found that females exhibited significantly stronger innate immune cell activity during breakthrough infections, particularly in monocytes and NK cells. Mass cytometry and plasma proteomics further validated these findings, showing that females had stronger inflammatory responses and immune cell activation during breakthrough infections.

Conclusions and Significance

This study reveals how vaccination modulates innate immune cell activity to suppress excessive inflammatory responses during breakthrough infections, protecting individuals from severe disease. It also highlights the critical role of sex differences in immune responses, suggesting that future vaccine strategies should consider sex-specific approaches.

Key Highlights

1. Role of Innate Immunity in Breakthrough Infections: The study systematically explores how vaccination alters the activity of monocytes and NK cells to regulate immune responses during breakthrough infections.
   
2. Importance of Sex Differences: Females exhibited stronger innate immune responses during breakthrough infections, providing a basis for sex-specific vaccine design.
   
3. Regulation of Cell-Cell Communication: The study reveals how innate immune cells send immunosuppressive signals to control the overactivation of adaptive immune responses.
   

Practical Value

This study provides important insights for future vaccine design, particularly in how to reduce the risk and severity of breakthrough infections by modulating innate immune responses. Additionally, the findings on sex differences offer scientific evidence for the development of personalized vaccine strategies.

Summary

This research deepens our understanding of immune responses post-vaccination and provides critical clues for optimizing COVID-19 vaccine strategies. By uncovering the key role of innate immune cells in breakthrough infections, the study offers new scientific insights for addressing SARS-CoV-2 and its variants in the future.