EBNA-1 IgG Persistence After Primary EBV Infection
Yes, EBNA-1 IgG antibodies remain positive for life after the first Epstein-Barr virus infection in the vast majority of individuals. 1
Standard Serologic Pattern After Primary Infection
EBNA antibodies develop 1–2 months after primary infection and persist for life, making their presence a reliable marker of past EBV exposure (> 6 weeks prior). 1
The typical evolution follows a predictable sequence: VCA IgM and VCA IgG appear during acute infection, while EBNA antibodies emerge later and then remain detectable indefinitely. 1, 2
Once EBNA-1 IgG becomes positive, it indicates past infection and makes EBV an unlikely cause of current acute symptoms. 1
Important Exception: EBNA-Negative Individuals
Approximately 5–10% of EBV-infected individuals may fail to develop EBNA antibodies despite confirmed past infection, a critical caveat when interpreting serology. 1
This phenomenon occurs more frequently in immunocompromised patients (transplant recipients, HIV-positive individuals, those with congenital immunodeficiencies), who may lose previously positive EBNA antibodies during periods of cellular immune suppression. 3, 4
These "secondary anti-EBNA-1-negative cases" comprised 45% of all EBNA-negative/VCA-IgG-positive patients in one large study, highlighting that EBNA negativity does not always indicate acute infection. 3
Distinguishing Primary from Secondary EBNA Negativity
When encountering a patient with VCA IgG-positive but EBNA-negative serology, the key question is whether this represents acute primary infection or loss of EBNA in a previously infected person. 3
VCA IgG avidity testing provides the definitive answer: low avidity indicates acute primary infection (< 4 weeks), while high avidity indicates past infection with secondary EBNA loss. 3, 4, 5
The presence of VCA IgM together with EBNA negativity definitively indicates acute primary infection, regardless of VCA IgG avidity. 1
In contrast, high-avidity VCA IgG with EBNA negativity but without VCA IgM suggests immunosuppression-related loss of EBNA antibodies rather than acute infection. 3
Clinical Pitfalls to Avoid
Do not assume EBNA negativity always means acute infection—consider the patient's immune status and duration of symptoms. 3
In immunocompromised patients, quantitative EBV DNA viral load testing (> 10^2.5 copies/mg DNA in peripheral blood mononuclear cells) is preferred over serology for diagnosis and monitoring. 1, 2
Heterophile antibody (Monospot) testing can help differentiate: 94% of patients with true primary infection are heterophile-positive, while only 5% of those with serologic reactivation (high-avidity antibodies) are heterophile-positive. 5
Chronic Active EBV Infection Context
In rare cases of chronic active EBV infection (CAEBV), patients may show very high VCA IgG titers (≥ 1:640) with elevated early antigen (EA) IgG titers (≥ 1:160), often with detectable IgA antibodies to VCA and/or EA. 1, 2
CAEBV patients typically have persistent mononucleosis-like symptoms and elevated EBV DNA loads, but EBNA antibody patterns vary and are not the primary diagnostic criterion. 6