Table 1.

BOLD objectives and endpoints

Primary objective	Primary endpoint
To assess LD annual incidence rate in persons of all ages, races and ethnicities at potential phase III efficacy trial sites for the VLA15 vaccine in geographic regions that are endemic for LD, overall and by site.	The annual incidence rate of newly diagnosed LD in persons of all ages, races and ethnicities who are patients of the study sites’ GP/primary care practice, overall and by site.
Secondary objectives	Secondary endpoints
To assess LD annual incidence rate in persons of all ages, races and ethnicities at potential phase III efficacy trial sites for the VLA15 vaccine in geographic regions that are endemic for LD, by age, month of diagnosis and LD risk factor.	The annual incidence rate of newly diagnosed LD in persons of all ages, races and ethnicities at study sites by age, month of diagnosis and LD risk factor.
Describe the Borrelia genospecies/OspA serotype distribution of LD in persons of all ages, races and ethnicities at potential phase III efficacy trial sites for the VLA15 vaccine in geographic regions that are endemic for LD.	Proportion for each Borrelia genospecies/OspA serotypes of LD among participants with available genospecies/OspA serotype results.
Describe the proportion of LD cases by clinical manifestation category among persons of all ages, races and ethnicities at potential phase III efficacy trial sites for the VLA15 vaccine in geographic regions that are endemic for LD, by specific clinical manifestation category (ie, erythema migrans, neuroborreliosis, Lyme arthritis, Lyme carditis, borrelial lymphocytoma, acrodermatitis chronica atrophicans, LD ocular manifestations) and for all disseminated disease combined.	Proportion of newly diagnosed LD cases by specific clinical manifestation category (ie, erythema migrans, neuroborreliosis, Lyme arthritis, Lyme carditis, borrelial lymphocytoma, acrodermatitis chronica atrophicans, LD ocular manifestations) and for all disseminated disease combined.
To estimate the proportion of persons of all ages with newly diagnosed LD at potential phase III efficacy trial sites for the VLA15 vaccine who have conditions that would exclude their participation in the proposed phase III efficacy trial sites based on potential exclusion criteria (eg, immunosuppression), overall, by site, by age group, by season and by exclusion criteria.	The proportion of participants among persons of all ages, races and ethnicities with newly diagnosed LD who have conditions that would exclude their participation from the proposed phase III efficacy trial sites based on potential exclusion criteria (eg, immunosuppression), overall, by site, by age group, by season and by exclusion criteria.
Exploratory objectives	Exploratory endpoints
Describe the prevalence of LD risk factors (eg, time outdoors, pets, personal protective behaviours, occupational and leisure exposures) and potential phase III trial exclusion criteria among practice panel patients of all ages, races and ethnicities without current LD at potential phase III efficacy trial sites for the VLA15 vaccine, overall and by site.	Proportions of site practice panel patients of all ages, races, and ethnicities without current LD with key characteristics, (eg, self-reported specific LD risk factors and conditions that would exclude their participation from the potential phase III efficacy trial), overall, by age group and by site.
Describe signs and symptoms of LD and patient treatment journey for LD under current standard of care.	Time from symptom onset to diagnosis, duration of symptoms, treatment duration and type, number and type of medical visits and therapeutic procedures, and frequency of hospitalisation and mean length of stay.
Describe LD diagnostic testing practices under current standard of care.	Proportion of participants with standard of care LD diagnostic testing, overall and by type.
Estimate the ratio of LD incidence based on LD surveillance to LD incidence measured by this study by region and country.	Ratio of LD incidence from local LD surveillance system (in regions where available) to incidence of LD cases at study site(s) in that region.
To describe possible LD events with standard of care LD diagnosis without established LD clinical manifestations (ie, erythema migrans, neuroborreliosis, Lyme arthritis, Lyme carditis, borrelial lymphocytoma, acrodermatitis chronica atrophicans, LD ocular manifestations).	For standard of care LD diagnoses without established LD clinical manifestations, frequency and duration of symptoms experienced, frequency of physical exam findings by type and LD diagnostic testing results by type of test.
To describe LD impact on participants’ mental and physical functions and QoL.	Scores of physical, mental functions and QoL measured by SF-36, degree of pain, severity of pain of different body parts and degree of fatigue and its specific impact measured by FSS and SF-MPQ.
Objectives for assessment of persistent symptoms of LD including PTLD	Endpoints for assessment of persistent symptoms of LD including PTLD
To assess the proportion of suspected LD cases, by clinical manifestation (erythema migrans vs disseminated LD), that subsequently develop persistent symptoms, including PTLD.	Proportion of treated LD cases by clinical manifestation (erythema migrans vs disseminated LD that subsequently develop persistent symptoms, including PTLD).
To assess the severity of persistent symptoms (including PTLD) by clinical manifestation (erythema migrans and disseminated LD) among suspected LD cases.	Severity of persistent symptoms (including PTLD) by clinical manifestation (erythema migrans and disseminated LD) among suspected LD cases: pain severity (SF-MPQ and the pain subscale of the Medical Outcomes SF-36); fatigue severity (FSS); cognitive impairment (CFQ).
To compare the severity of symptoms among PTLD cases to those of patients with persistent symptoms that do not meet PTLD case definition.	Duration of persistent symptoms (including PTLD) by clinical manifestation (erythema migrans and disseminated LD).
To assess the impact of persistent symptoms (including PTLD) on health-related QoL between suspected LD cases in comparison with age-matched controls.	Symptom severity by subgroup (PTLD cases compared with treated LD cases with symptoms not meeting PTLD case definition, and participants with other non-LD diagnosis. SF-36, SF-MPQ, FSS and CFQ subscale scores and summary scores.
To assess the health resource use associated with persistent symptoms (including PTLD) among suspected LD cases.	Treatment duration and type, number and type of medical visits and therapeutic procedures, and frequency of hospitalisation, and mean length of stay.

BOLD, Burden of Lyme disease; CFQ, Cognitive Failures Questionnaire; FSS, Fatigue Severity Scale; GP, general practice; LD, Lyme disease; OspA, outer surface protein A; PTLD, post-treatment Lyme disease; QoL, quality of life; SF-36, 36-Item Short Form Survey; SF-MPQ, Short Form McGill Pain Questionnaire.