Immune Responses in Vaccinated Healthcare Workers with SARS-CoV-2 Breakthrough Infections

A new study out of Mexico found that vaccinated healthcare workers with SARS-CoV-2 breakthrough infection mount a coordinated, antigen-specific humoral response alongside a mixed pro- and anti-inflammatory cytokine signature. These immune patterns have immediate implications for occupational monitoring and serologic interpretation by helping distinguish vaccine-elicited antibodies from markers of recent infection.

A cohort study of 114 vaccinated healthcare workers with PCR-confirmed breakthrough SARS-CoV-2 infection measured antibody isotypes and a 13‑cytokine panel on serum sampled during acute illness. Specifically, N‑protein and RBD serology quantified IgM, IgA, and IgG and reported prevalences (anti‑NCP: IgM 93.8%, IgG 93.8%, IgA 28.1%; anti‑RBD: IgM 46.9%, IgG 100%, IgA 90.6%). Cytokine profiling was concurrent, linking humoral patterns with systemic inflammation.

Anti‑RBD IgG was the most consistently detectable isotype across the cohort (~100%), while anti‑RBD IgA was common (~91%) and IgM prevalence varied by antigen (anti‑NCP IgM ≈94% vs anti‑RBD IgM ≈47%), indicating antigen‑specific isotype bias. Atypical findings included isolated or antigen‑restricted IgM/IgA responses and delayed IgM in some vaccinated individuals. Hybrid exposure (vaccination plus infection) broadened early IgM detection.

Vaccinated SARS‑CoV‑2 cases showed concurrent rises in pro‑inflammatory mediators (IL‑6, IL‑8, TNF‑α, IFN‑γ, IL‑2) and regulatory cytokines (IL‑10, TGF‑β), consistent with a mixed activation state. Concurrent breakthrough infection cytokine profile analyses linked dual IgM positivity to NCP and RBD with significantly higher concentrations of IL‑6, IL‑8, TNF‑α, IFN‑γ, IL‑2, IL‑10 and TGF‑β; correlations were directionally consistent with broader IgM responses accompanying higher cytokine levels.

The combined serology and cytokine data support several operational implications for occupational health. Anti‑NCP IgM appears to be a useful marker of recent infection even in vaccinated staff, while anti‑RBD IgG/IgA are commonly vaccine‑induced and less specific for new infection. Prioritizing assays that include N‑protein IgM alongside select cytokines (IL‑6, IL‑8, IL‑10) can improve risk stratification and timing of repeat testing after exposure. Antigen‑specific isotype panels plus targeted cytokine measures better discriminate vaccine‑derived immunity from recent infection.

Key Takeaways:

• Breakthrough infections in vaccinated HCWs produce antigen‑specific isotype patterns and a mixed pro‑/anti‑inflammatory cytokine response.
• Anti‑NCP IgM and concurrent elevations in IL‑6/IL‑8/IL‑10 are associated with broader IgM responses and may indicate recent infection despite vaccination.
• Operational monitoring that combines N‑protein IgM testing with selective cytokine measures can improve discrimination of recent infection from vaccine‑induced seropositivity.
• Limitations include single‑center, cross‑sectional design and limited variant/longitudinal data; confirmatory multicenter longitudinal studies are needed.