History of Syphilis May Attenuate Subsequent Treponema pallidum Infection

A team of researchers sought to identify the odds of detecting Treponema pallidum in individuals with previous syphilis vs those without prior syphilis infection.

Acquired immunity resulting from an initial episode of syphilis may attenuate subsequent infection with Treponema pallidum, according to study results published in Clinical Infectious Diseases.

To determine if a previous syphilis episode influences a subsequent syphilis episode, researchers analyzed data from individuals enrolled in a study of cerebrospinal fluid (CSF) abnormalities in syphilis conducted in Seattle, Washington, who were allowed to enroll again with subsequent syphilis infection. The researchers estimated that the odds of detecting T pallidum DNA in blood or ribosomal RNA (rRNA) in CSF at the index episode in individuals with previous syphilis were comparable to those in individuals without previous syphilis. The index episode “was defined as the most recent syphilis episode for which the study entry visit was performed within 30 days of the syphilis diagnosis date” and was included in the total number of syphilis episodes.

Of the 651 individuals included in the study, 96.1% were men who have sex with men, and 79.7% were people living with HIV. The median age was 39 years (interquartile range, 32-46). At the index visit, 57.3% had primary or secondary syphilis, and 42.7% had early latent or late latent syphilis. A total of 482 patients had 1 episode of syphilis, 121 had 2 episodes, and 48 had 3 or more episodes of syphilis.

Compared with primary and secondary syphilis, more individuals who had 3 or more syphilis episodes were diagnosed with early latent syphilis at their index episode compared with individuals who had 2 or fewer episodes (48.8% [21/43] vs 23.5% [108/459]; P <.001). Although this relationship lost significance when the rate of testing was considered, the trend persisted (adjusted odds ratio [aOR], 2.34; 95% CI, 0.86-6.38; P =.097).

Compared with individuals who had no previous syphilis, individuals who had previous syphilis at any stage had a significantly lower odds of detection of T palladium DNA in their blood (aOR, 0.17; 95% CI, 0.09-0.31; P <.001) and rRNA in CSF (aOR, 0.15; 95% CI, 0.07-0.35; P <.001) at the index episode. In addition, the odds of detecting T palladium DNA in blood and T palladium rRNA in CSF were higher among individuals with higher serum rapid plasma reagin titers (aOR, 1.30; 95% CI, 1.15-1.46; P <.001 and aOR, 1.49; 95% CI, 1.29-1.71; P <.001, respectively).

When restricting the analyses to 373 individuals with symptomatic syphilis, the odds of detecting T palladium DNA in blood and T palladium rRNA in CSF remained significantly lower among those with previous syphilis (aOR, 0.21; 95% CI, 0.090.47; P <.001 and aOR, 0.18; 95% CI, 0.06-0.54; P =.002, respectively).

Likewise, the odds of neurosyphilis at the index episode, defined as CSF white blood cells more than 20/μL or a reactive CSF-Venereal Disease Research Laboratory test, was significantly lower in individuals with previous syphilis (aOR, 0.54; 95% CI, 0.34-0.87; P =.01).

The findings held regardless of HIV status. “Our study suggests that acquired immune responses play an important role,” the researchers noted. “Future studies that compare host humoral and cellular immune responses during successive episodes of syphilis may help clarify the basis for our observations and may ultimately inform vaccine development,” they concluded.


Marra CM, Maxwell CL, Sahi SK, Tantalo LC, Dunaway SB, Lukehart SA. Previous syphilis alters the course of subsequent episodes of syphilis. Clin Infect Dis. Published online May 17, 2021. doi:10.1093/cid/ciab287