Can Borrelia C6 peptide and VlsE IgG stay positive after infection is no longer active?

Borrelia C6 peptide and VlsE IgG assays measure host humoral recognition of Borrelia antigens, not the presence of living organisms. In a 74-year-old with a positive result, the central interpretive issue is therefore whether the clinical picture supports current Lyme borreliosis rather than treating seropositivity as evidence of active infection.

Clinical evidence

• The claim is strongly supported: C6/VlsE IgG may persist long after infection has resolved or been effectively treated. At 8–15 years after treated Lyme disease, anti-VlsE IR6 antibodies remained detectable in approximately 50% of people with prior early disease and 83% with prior late disease.
• Persistence is also documented earlier after treatment: in one C6 cohort, 19 of 25 participants who were positive before treatment remained positive at six months.
• Antibody concentrations can decline without becoming negative. In a 45-person cohort, 80% had at least a fourfold decline in C6 titer after treatment, but falling titers do not establish eradication, and persistent positivity does not establish treatment failure.

Mechanistic interpretation

• C6 is derived from IR6, a conserved and strongly immunogenic region of the VlsE protein. Antibodies to this region can reflect durable antigen-specific immune memory after prior exposure.
• However, IR6 epitopes may be poorly accessible on intact spirochetes. Thus, C6/VlsE reactivity is evidence of immune recognition, not proof of protective immunity, viable organisms, or ongoing tissue infection.

Diagnostic implications

• IDSA/AAN/ACR guidance and longitudinal studies agree that C6/VlsE serology alone cannot distinguish active Lyme disease from remote, resolved infection.
• Specificity is incomplete: reported cross-reactivity includes Borrelia miyamotoi, with one summary reporting cross-reaction rates of 5% for C6 and 3% for a VlsE-based assay.

Bottom line

• A positive C6 or VlsE IgG result can remain positive for years after inactive infection and should not alone be interpreted as persistent infection, treatment failure, or an indication for treatment.