Immune Response in Moderate to Critical Breakthrough COVID-19 Infection After mRNA Vaccination

Area of Science:

• Immunology
• Virology
• Vaccinology

Background:

• Severe COVID-19 can occur despite vaccination due to SARS-CoV-2 variants of concern (VOCs).
• Vaccine breakthrough infections (VBI) with VOCs like the alpha variant pose a significant public health challenge.

Purpose of the Study:

• To investigate the cellular and humoral immune responses in patients experiencing VBI with the SARS-CoV-2 alpha variant.
• To compare immune responses in VBI patients to a vaccinated, uninfected control group.

Main Methods:

• Analysis of cellular immunity, including high-avidity spike (S)-reactive CD4+ and CD8+ T cells, against alpha variant and wild type (WT) SARS-CoV-2.
• Assessment of humoral immunity, specifically neutralizing antibody titers against the alpha variant.
• Comparison of immune responses at disease onset and during disease progression.

Main Results:

• Patients with moderate to fatal COVID-19 post-VBI showed no detectable high-avidity S-reactive T cells at disease onset.
• A robust T-cell response against nucleocapsid (N) and membrane (M) proteins was observed in VBI patients.
• Lower neutralizing antibody titers and delayed S-reactive T-cell responses were noted in VBI patients compared to controls.

Conclusions:

• The alpha variant exhibits reduced immunogenicity against the S-protein in VBI patients, necessitating further investigation.
• A stronger T-cell response to N- and M-proteins suggests their potential as alternative targets for future vaccines.
• Findings support the consideration of VBI patients in alternative vaccination strategies and the development of next-generation vaccines with broader antigenic targets.