254 Robert A. Aronowitz vaccines was that SKB’s LYMErix contained an aluminum adjuvant (often used to boost immunity), while Connaught’s ImuLyme did not (which theoretically might lead to fewer side effects). In order to max- imize the signal-to-noise ratio in a disease whose diagnostic criteria and boundaries had long been subject to intense controversy, both trials used narrow, objective criteria for what would constitute a Lyme disease case in the study population. “Definite” Lyme disease was defined as the presence of erythema migrans (EM, the characteristic LD rash) or objective neurologic, musculoskeletal, or cardiovascular manifestations of LD, plus laboratory and/or biopsy confirmation (of rash) of infection. Such criteria maximized the specificity of the diagnosis and minimized the possibility of mistakenly seeing no preventive effect of a vaccine when one existed, which might result if many wrong or questionable cases were counted as LD. The results from the two trials suggested that both vaccines were safe and effective. Numbers of nontrivial adverse reactions were similar in controls and subjects. Subjects who received the full three doses had at least a 75 percent reduction in definite LD compared with the controls, and in the second year of the LYMErix trial (the only one to study this question), there were no cases of asymptomatic infection (defined by laboratory evidence of infection without symptoms) in the treated group. The absence of asymptomatic seropositives among the vaccinated could be understood as powerful evidence of vaccine efficacy because asymptomatic seropositive cases are ascertained only by objective measures, unlike clinical diagnoses, which might be counted mistakenly on the basis of how trial subjects perceived and reported symptoms and sought medical care and of differences in physicians’ diagnostic practices. The trials also produced a disturbing picture of the inaccuracy of clin- ical diagnosis. In both trials, only a small fraction of initially suspected cases were confirmed as definite Lyme disease (in the 10% to 20% range), suggesting widespread overdiagnosis (or, alternatively, that the diagnos- tic criteria were too narrow). Because these data were from the carefully observed conditions of a well-funded clinical trial, a much larger prob- lem certainly existed in everyday clinical practice. At the same time, a high percentage (30%) of cases confirmed by biopsies of skin rashes in the LYMErix trial were not accompanied by positive serology, sug- gesting that underdiagnosis was also present in the world outside trials, especially when clinicians depended on serology, for example, in cases presenting without the characteristic rash or after the rash was gone.