Can You Get Mono Again After Having It Once?
No, you typically cannot get infectious mononucleosis (mono) again after having it once, because after primary EBV infection you develop lifelong immunity with persistent EBV-specific antibodies and memory T cells that prevent reinfection with the same virus. 1, 2
Understanding EBV Immunity After Mono
Over 90% of adults worldwide have been infected with EBV and maintain lifelong immunity, indicated by the presence of IgG antibodies to viral capsid antigen (VCA) and Epstein-Barr nuclear antigen (EBNA) that persist indefinitely after the initial infection 1, 3
After primary EBV infection, you develop robust EBV-specific T cell immune responses, with both CD8+ and CD4+ T cells functioning as cytotoxic cells that defend against the virus and prevent symptomatic reinfection 4
The virus remains dormant in your body for life (latent infection in B cells), but your immune system keeps it under control, preventing you from developing the clinical syndrome of mono again 5, 4
Important Caveats and Exceptions
Chronic Active EBV (CAEBV) - A Rare Exception
A very small subset of patients can develop Chronic Active EBV infection (CAEBV), which is NOT the same as getting mono again, but rather represents ongoing viral reactivation with persistent IM-like symptoms lasting months to years 6
CAEBV is characterized by unusually high antibody titers (IgG against VCA ≥1:640 and EA ≥1:160), increased viral loads in peripheral blood (>10^2.5 copies/mg DNA), and serious complications including hemophagocytic lymphohistiocytosis or lymphoproliferative disorders 6
This condition is extremely rare and represents immune dysfunction, not reinfection 6
Immunocompromised Patients
Patients on immunosuppressive therapy face increased risk of severe EBV reactivation and lymphoproliferative disorders, particularly those on thiopurines, where fatal cases have been reported 1
In immunocompromised patients with suspected EBV reactivation, immunomodulator therapy should be reduced or discontinued if possible, and antiviral therapy with ganciclovir or foscarnet may be considered in severe cases 1
What About Mono-Like Symptoms Again?
If you develop mono-like symptoms again (fever, sore throat, lymphadenopathy, fatigue), it is NOT EBV reinfection but rather a different pathogen 7
Other causes of mononucleosis-like illness include: cytomegalovirus (CMV) infection, acute HIV infection, Toxoplasma gondii infection, and adenovirus infection 1, 7
Testing approach for recurrent mono-like symptoms: If heterophile antibody test is negative and EBV serologies show past infection (positive EBNA with negative IgM), pursue alternative diagnoses including CMV, HIV, and toxoplasmosis 1, 2
Clinical Bottom Line
The presence of positive EBNA antibodies with negative VCA IgM indicates past EBV infection and immunity, not current acute disease, as EBNA antibodies appear late in EBV infection and persist indefinitely 2. You cannot get the same EBV mono twice under normal circumstances with a functioning immune system.