Complement Hyperactivation Is Mediated by Alternative and Lectin Pathways During Early Phase of Severe...

Area of Science:

• Immunology
• Virology
• Systems Biology

Background:

• The precise kinetics and pathways of complement activation in vaccinated individuals who contract COVID-19, particularly concerning severe disease, remain incompletely understood.
• The interplay between complement activation, thromboinflammation, and antibody responses in the context of vaccinated COVID-19 patients requires further elucidation.

Purpose of the Study:

• To dynamically model and analyze complement immune responses in a cohort of vaccinated individuals with varying COVID-19 severity.
• To investigate the temporal activation kinetics and specific pathways (classical, alternative, lectin) involved in complement activation during COVID-19 infection post-vaccination.
• To determine the relationship between complement activation, thromboinflammation, and virus-specific antibody levels in severe COVID-19 cases among vaccinated individuals.

Main Methods:

• Analysis of a vaccinated-infected cohort with mild to critical COVID-19.
• Application of a dynamic modeling approach to assess complement immune responses.
• Characterization of complement activation kinetics, pathways, and correlation with clinical parameters.

Main Results:

• Complement activation was observed to be earlier (7-14 days post symptom onset), more intense, and prolonged in severe and critical COVID-19 cases among vaccinated individuals.
• The alternative and lectin complement pathways, rather than the classical pathway, were identified as the primary mediators of this activation.
• Complement activation in severe vaccinated COVID-19 correlated with thromboinflammation but showed no significant association with virus-specific antibody responses.
• Factor Bb within the alternative pathway was identified as a crucial component in severe COVID-19 among the vaccinated.

Conclusions:

• Complement activation plays a significant role in the pathophysiology of severe COVID-19 in vaccinated individuals, primarily through the alternative and lectin pathways.
• The timing and intensity of complement activation, particularly involving the alternative pathway (Bb), are critical factors in severe disease.
• These findings highlight potential therapeutic windows for complement-targeted interventions and identify novel targets for managing severe COVID-19 in vaccinated populations.