# Complement Hyperactivation Is Mediated by Alternative and Lectin Pathways During Early Phase of Severe Vaccination‐Omicron BA.5 Infection

## TL;DR

The study shows that severe vaccination-BA.5 Omicron infections trigger early and prolonged complement activation via alternative and lectin pathways, linked to thromboinflammation but not antibody responses.

## Contribution

The study identifies alternative and lectin pathways as key drivers of complement hyperactivation in severe vaccination-BA.5 Omicron infections.

## Key findings

- Complement activation occurs earlier and lasts longer in severe vaccination-BA.5 Omicron cases.
- Alternative and lectin pathways mediate complement activation in severe cases, not the classical pathway.
- Complement activation correlates with thromboinflammation but not with virus-specific antibody responses.

## Abstract

Complement temporal activation kinetics, activation pathways, and their relationship with thromboinflammation and antibody responses in severe vaccination‐COVID‐19 remains unclear. Based on a vaccinated‐infected cohort, we analyzed complement immune responses across mild to critical COVID‐19 cases by a dynamic model. Our results showed that complement activation was earlier (7–14 days post symptom onset), more intense and lasted longer in severe and critical vaccination‐COVID‐19, mediated by alternative and lectin pathways instead of classical pathway. Moreover, complement activation in severe vaccination‐COVID‐19 was related to thromboinflammation but not to the virus‐specific antibody response. Our study elucidated the kinetics of complement activation in vaccination‐COVID‐19 infection, revealing that Bb in alternative pathway were crucial in severe vaccination‐COVID‐19. These findings indicate the optimal timing for implementing complement activation‐targeted interventions in the management of severe vaccination‐COVID‐19 and provide more potential therapeutic targets.