Skip to main content


U.S. flag
      An official website of the United States government
              Here’s how you know
        Here’s how you knowDot gov**Official websites use .gov**
                 A **.gov** website belongs to an official government organization in the United States.
                  HTTPS**Secure .gov websites use HTTPS**
                 A **lock** (A locked padlock) or **https://** means you’ve safely connected to the .gov website. Share sensitive information only on official, secure websites. 
  Menu Close
          HHS Search (ash)
    Search
        








  
  
    

  
      

                                      About HHS
    
                        
                              
      
      
      Programs & Services
    
                        
                              
      
      
      Grants & Contracts
    
                        
                              
      
      
      Laws & Regulations                  
Office of the Assistant Secretary for Health
  About OASH
    
                        
                                            
      
      
      Public Health Offices
    
                        
                                            
      
      
      Advisory Committees

              

    



Breadcrumb
    HHS
                              ASH Home
                              Advisory Committees
                              Tick-Borne Disease Working Group
                              Reports
                              Disease Prevention and Treatment Subcommittee Report to the TBDWG


    

    

    Navigate to:
  Tick-Borne Disease Working Group
                                            
            
            21st Century Cures Act
    
                                                  
                                            
            
      
      
      
      Charter
    
                                                  
                                            
            
      
      
      
      Meetings
    
                                                  
                                            
            
      
      
      
      Reports
    
                                                  
                                            
            
      
      
      
      Contact UsText resize icon

                    




Disease Prevention and Treatment Subcommittee Report to the TBDWG








  
  
    

  
      





Co-chairs: Dennis Dixon and Sunil Sood

*Information and opinions in this report do not necessarily reflect the opinions of the working group, the U.S. Department of Health and Human Services, or any other component of the Federal Government. Readers should not consider the report or any part of it to be guidance or instruction regarding the diagnosis, care, or treatment of tick-borne diseases or to supersede in any way existing guidance.* *All subcommittee members actively participated in the development of this report. Members voted to approve submission of the report to the Working Group and on the wording of each of the potential actions contained in the report. The vote to submit the report indicates general agreement with the content of the document, but it does not necessarily indicate complete agreement with each and every statement in the full report.*

Background

The Prevention and Treatment Subcommittee of the 2021-2022 Tick-Borne Disease Working Group convened to address advances and gaps in the prevention and treatment of tick-borne diseases (TBDs). Committee members were selected with expertise across the spectrum of TBDs in order to ensure current knowledge of the field and balanced representation. Care was made to include members with different perspectives on Lyme disease treatment, because that issue has consistently shown to generate divergent opinions in previous Tick-Borne Disease Working Group reports.

The subcommittee began by establishing the parameters of its mission, considering other subcommittees with possible overlap, and the published reports of previous Tick-Borne Disease Working Groups and their respective subcommittees. The following issues were discussed and used to develop a framework for the individual meetings and the final report:

The subcommittee acknowledged the extensive work conducted by previous subcommittees and the main working groups. The 2018 Report to Congress focused primarily on Lyme disease, while the 2020 Report to Congress was expanded to include more discussion of the other TBDs.
	In consideration of this work—the most recent report appearing less than one year before this subcommittee’s inaugural meeting—the group believed there was no need to repeat what had only recently been established. Therefore, extensive reviews of each priority area were not developed. Rather, presenters were charged with reviewing the content of previous reports, and providing updates on any subsequent advances, remaining gaps, or other issues they believed needed reinforcement.
	The subcommittee interpreted its mission in the prevention arena as exclusive of vector-control or reservoir-targeted measures, because another subcommittee was charged with issues of vector biology. Discussions of prevention presented here therefore are limited primarily to direct interventions in humans, such as vaccines and other methods of pre- and/or post-exposure prophylaxis.
	As the subcommittee members were specifically selected due to their individual areas of expertise, they would serve as the primary presenters for each identified priority area. Each presenter was free to tap the expertise of others on the panel in preparing their reviews. Outside presenters or discussants would be invited where needed.
	The subcommittee heeded the suggestion of the Tick-Borne Disease Working Group chairs that potential actions be limited in number. An effort was made to generate final potential actions that were broadly focused, where possible, and actionable. Toward that end, the subcommittee opted to consider all suggested action areas within each priority area using a broader framework to be discussed once all presentations were complete.Methods

Characteristics of the Subcommittee

During the public meeting on August 26, 2021, the Tick-Borne Disease Working Group selected Dennis M. Dixon, a federal representative, and Sunil K. Sood, a public representative, to serve as co-chairs of the Disease Prevention and Treatment Subcommittee.

The Subcommittee was composed of Federal (4), public health (6), academic (7), and patient (1) representatives (see Table 1). The expertise in TBD treatment and prevention is supported by more than 50 years of basic and applied research experience.

Subcommittee Meetings

The Subcommittee held seven two-hour virtual meetings (see Table 2). Members spent this time:

Considering relevant literature;
	Discussing current federal activities;
	Identifying gaps in knowledge and areas where federal funding is needed;
	Hearing from nine expert speakers (see Table 3); and
	Formulating their report to the Tick-Borne Disease Working Group.Public Comment and Inventory

Patients and advocates generously took the time to write to the Tick-Borne Disease Working Group and share their experience. The majority were concerned with Lyme disease, though alpha-gal syndrome also generated specific concern as well as other tick-borne infections, especially when present as Lyme disease coinfections. Concerns focused primarily on diagnostics and treatment. A number of people do not feel listened to by doctors, academicians, or the government.

There is a consensus that improved diagnostics are sorely needed if effective treatment is to be prescribed.  Limited case definitions may exclude many suffering people from a Lyme disease diagnosis. Furthermore, doctors should be aware of, and willing to treat, the myriad of Lyme disease coinfections. In general, correspondents indicated a need for improved medical education and physician awareness, coupled with a willingness for healthcare practitioners to listen to people who suffer with persistent Lyme disease.

Patients and advocates believe that physician adherence to limited and inadequate treatment options for Post-Treatment Lyme Disease Syndrome (PTLDS) cause undue physical and financial hardship. More treatment options should be accepted and covered by insurance. Disability coverage is needed as well.

The Prevention and Treatment Subcommittee of the 2021-2022 Tick-Borne Disease Working Group addressed these concerns from a scientific perspective but deferred potential actions on insurance reimbursement to the Subcommittee on Access to Care. As detailed in the priority chapters herein, substantial time was spent discussing the need to expand surveillance, reporting, and medical education. Although not elements of prevention and treatment directly, improving these areas was viewed as critical for knowing where to target prevention methods, in addition to the obvious need for accurate diagnosis to precede effective treatment.

Subcommittee members were all aware of continuing disagreements within the medical community regarding the presence of PTLDS and the best approaches to management. The Subcommittee co-chairs believed it was important to seat physicians with different opinions specifically to address the issue of Lyme disease treatment. That decision is reflected in Priority 6: Lyme Disease Treatment.

Some correspondents to the Tick-Borne Disease Working Group believed that new clinical trials are needed and that clinicaltrials.gov should be updated. This topic was addressed at various points during discussions of individual priority areas. The National Institutes of Health (NIH) consistently expressed its openness to more clinical trials and has mechanisms in place to address areas of need. A common theme was that the limited number of NIH-funded clinical trials and studies generally reflects an absence of proposals from the community and not a reluctance by NIH to fund meritorious research on Lyme disease and other TBDs.

Subcommittee Report Development

Potential topic areas identified at the Tick-Borne Disease Working Group meeting on August 26, 2021, related to TBD prevention and treatment included covering all the TBDs; vaccines; prophylaxis and treatment strategies; TBD treatment and prevention in children; clinical trials; primary, secondary, and tertiary prevention; biobanks; treatments needed; methods to comprehensively test treatment regimens against persistent disease; and therapeutics. During the Subcommittee’s first meeting (see Table 2: Meetings), the members voted that the main objective of the Subcommittee was not to revisit the complete biology or ecology of these pathogens, but rather to assess how they were addressed in the previous reports and identify key advances and remaining gaps, or areas that the Subcommittee believes should be reinforced in the areas of treatment and prevention.

The subcommittee explored the six identified areas that were not substantially covered in previous reports or that members believed required further exploration and update. These six areas are, therefore, the focus of this report:

Prevention and Treatment for Infections by the Rickettsiales
	Prevention and Treatment of Babesiosis
	Prevention and Treatment of Relapsing Fever/*Borrelia miyamotoi*Infection
	Prevention and Treatment for the Tick-Borne Viruses
	Prevention and Treatment of Alpha-gal Syndrome
	Lyme Disease Prevention
	Lyme Disease TreatmentMembers volunteered to develop and write content for each subtopic based on their expertise. The Priorities and Potential Actions were compiled by the Subcommittee over email and several meeting discussions.

Subtopic Member Assignments:

Prevention and Treatment for Infections by the Rickettsiales—Christopher Paddock
	Prevention and Treatment of Babesiosis and Relapsing Fever/*Borrelia miyamotoi*Infections— Peter Krause
	Prevention and Treatment for the Tick-Borne Viruses—Gregory Ebel
	Prevention and Treatment of Alpha-gal Syndrome—Scott Commins
	Lyme Disease Prevention—Mark Soloski
	Lyme Disease Treatment—Luis Marcos and Charlotte MaoBrief for the Working Group

During public meeting on February 28 and March 1, 2022, the Subcommittee co-chairs will present their final report to the Tick-Borne Disease Working Group using a PowerPoint template provided to them by the leadership and support team. The co-chairs worked with the support writer to populate the slide deck using content from the Subcommittee report. The presentation will be finalized after Subcommittee members provide feedback via email.

Table 1: Members of the Disease Prevention and Treatment Subcommittee
	Members
			Type
			Stakeholder Group
			Expertise*Subcommittee Co-Chair***Dennis Dixon, PhD**
			National Institute of Allergy and Infectious Diseases (NIAID), Rockville, MD
			Federal
			Academic Researcher
			Chief, Bacteriology and Mycology Branch, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), U.S. Department of Health and Human Services (HHS)*Subcommittee Co-Chair* **Sunil Sood, MD**
			South Shore University Hospital
			Bay Shore, NY
			Cohen Children’s Medical Center, Queens, NY
			Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY
			Public
			Medical Researcher
			Chair of Pediatrics, South Shore University Hospital; Attending Physician, Infectious Diseases, Cohen Children’s Medical Center; Professor of Pediatrics and Family Medicine, Zucker School of Medicine at Hofstra/Northwell*Working Group Co-Chair***Holiday Goodreau**
			LivLyme Foundation, Denver, CO
			Public
			Advocate, Family Member
			Executive Director, LivLyme Foundation; Co-creator, TickTracker*Working Group Co-Chair***Linen Hu, MD**
			Tufts University School of Medicine, Boston, MA
			Public
			Medical Researcher
			Professor of Microbiology and Medicine, Vice Dean for Research, Tufts University School of Medicine**Scott P. Commins, MD, PhD**
			University of North Carolina at Chapel Hill, Chapel Hill, NC
			Public
			Academic Researcher
			Assoc Professor of Medicine and Pediatrics, Section Chief, Allergy & Immunology, University of North Carolina School of Medicine**Gregory Ebel, ScD**
			Colorado State University, Fort Collins, Colorado
			Public
			Academic Researcher
			Professor, Colorado State University**Erol Fikrig, MD**
			Yale University School of Medicine, New Haven, CT
			Public
			Academic Researcher
			Professor of Medicine (Infectious Diseases) and Epidemiology (Microbial Diseases) and Microbial Pathogenesis, Yale Institute for Global Health; Section Chief, Infectious Diseases**Tony Galbo**
			Monticello, IL
			Public
			Advocate
			Advocate for Gabby’s Law in IL; Member, Congressionally Directed Medical Research Programs (CDMRP) Tick Borne Disease Programmatic Panel, Department of Defense**Peter J. Krause, MD**
			Yale University School of Public Health and Yale University of Medicine, New Haven, CT
			Public
			Academic Researcher
			Senior Research Scientist, Department of Epidemiology of Microbial Diseases, Yale University School of Public Health**Charlotte Mao, MD, MPH**
			Dean Center for Tick Borne Illness, Spaulding Rehabilitation Hospital, Massachusetts General Hospital, Pediatric Infectious Disease Division, Boston, MA
			Public
			Healthcare Provider, Medical Researcher
			Researcher and Physician, Dean Center for Tick Borne Illness, Spaulding Rehabilitation Hospital**Luis A. Marcos, MD, MPH**
			Stony Brook University, Stony Brook, NY
			Public
			Medical Researcher
			Director, Infectious Diseases Fellowship Program, Stony Brook University; Associate Professor of Medicine, Microbiology and Immunology, Stony Brook University Health Sciences Center School of Medicine**Christopher Paddock, MD, MPHTM**
			Rickettsial Zoonoses Branch, Centers for Disease Control and Prevention (CDC), Atlanta, GA
			Federal
			Medical Researcher
			Pathologist, Rickettsial Zoonoses Branch, Centers for Disease Control and Prevention**Paul Mead, MD, MPH**
			National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Bethesda, MD
			Federal
			Medical Researcher
			Chief, Bacterial Diseases Branch, Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases**Sam Perdue, PhD**
			National Institute of Allergy and Infectious Diseases (NIAID), Rockville, MD
			Federal
			Academic Researcher
			Section Chief, Basic Sciences and Program Officer, Rickettsial and Related Diseases, Bacteriology and Mycology Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), U.S. Department of Health and Human Services (HHS)**Mark Soloski, PhD**
			Johns Hopkins University School of Medicine, Baltimore, MD
			Public
			Academic Researcher
			Professor of Medicine, Johns Hopkins University School of Medicine, Lyme Disease Research Center, Johns Hopkins School of MedicineCharlie Stockman
			Public
			Advocate
			Lyme PatientTable 2: Overview of Disease Prevention and Treatment Subcommittee Meetings
	Meeting No.
			Date
			Present
			Topics Addressed#
			Month Day, Year
			List of names present1
			October 15, 2021
			Dennis Dixon (SC co-chair), Sunil Sood (SC co-chair), Linden Hu (WG co-chair), Gregory Ebel, Tony Galbo, Peter Krause, Charlotte Mao, Luis Marcos, Chris Paddock, Sam Perdue

			Sue Visser (CDC), Kimi Landry, Lauren Overman (DFO)
			Review of previous TBDWG and SC reports; treatment and prevention of rickettsioses; *Bartonella*as a Lyme coinfection2
			October 29, 2021
			Dennis Dixon (SC co-chair), Sunil Sood (SC co-chair), Holiday Goodreau (WG co-chair), Linden Hu (WG co-chair), Scott Commins, Gregory Ebel, Erol Fikrig, Tony Galbo, Peter Krause, Charlotte Mao, Luis Marcos, Christopher Paddock, Sam Perdue, Mark Soloski, Charlie Stockman
			Lauren Overman (DFO), Mike Kavounis (Contractor Support), Meghan Walsh (Contractor Support), Jay Weixelbaum (Contractor Support)
			Human babesiosis; *B. miyamotoi*infection3
			November 5, 2021
			Dennis Dixon (SC co-chair), Sunil Sood (SC co-chair), Linden Hu (WG co-chair), Scott Commins, Gregory Ebel, Tony Galbo, Peter Krause, Charlotte Mao, Luis Marcos, Christopher Paddock, Sam Perdue, Mark Soloski, Charlie Stockman
			Lauren Overman (DFO), Mike Kavounis (Contractor Support), Cat Thomson (Contractor Support
			Prevention and treatment of tick-borne viruses4
			November 12, 2021
			Dennis Dixon (SC co-chair), Linden Hu (WG co-chair), Scott Commins, Gregory Ebel, Erol Fikrig, Tony Galbo, Charlotte Mao, Christopher Paddock, Mark Soloski, Charlie Stockman
			Lauren Overman (DFO), Damon Kane (Contractor Support), Jay Weixelbaum (Contractor Support)
			Alpha-gal syndrome5
			November 17, 2021
			Dennis Dixon (SC co-chair), Sunil Sood (SC co-chair), Linden Hu (WG co-chair), Gregory Ebel, Erol Fikrig, Peter Krause, Charlotte Mao, Luis Marcos, Paul Mead, Christopher Paddock, Sam Perdue, Mark Soloski, Charlie Stockman
			Sabira Mohammed (Contractor Support), Gina Castelvecchi (Contractor Support), Meghan Walsh (Contractor Support)
			Lyme disease prevention6
			December 20, 2021
			Dennis Dixon (SC co-chair), Sunil Sood (SC co-chair), Linden Hu (WG co-chair), Tony Galbo, Peter Krause, Charlotte Mao, Luis Marcos, Sam Perdue
			Mike Kavounis (Contractor Support)
			Treatment of Lyme disease; treatment of Lyme disease and bartonellosis7
			January 21, 2022
			Dennis Dixon (SC co-chair), Sunil Sood (SC co-chair), Holiday Goodreau (WG co-chair), Scott Commins, Gregory Ebel, Erol Fikrig, Tony Galbo, Peter Krause, Charlotte Mao, Luis Marcos, Christopher Paddock, Sam Perdue, Mark Soloski, Charlie Stockman
			Alison Hinckley (Invited Speaker), Mike Kavounis (Contractor Support), Gina Castelvecchi (Contractor Support)
			CDC’s efforts in Lyme disease preventative development; discussion of SC potential actionsTable 3: Presenters to the Disease Prevention and Treatment Subcommittee
	Meeting No.
			Presenter(s)
			Topics Addressed
			Ok to Share?Name, education, affiliation1
			Christopher Paddock, MD, MPHTM, Centers for Disease Control and Prevention (CDC)
			Perspectives on the Control and Prevention of Tick-Borne Rickettsioses
			Yes1
			Sam Perdue, PhD, NIAID/NIH
			*Bartonella*as a co-infection
			Yes2
			Peter J. Krause, MD, Yale School of Public Health and Yale School of Medicine
			Human Babesiosis; *B. miyamotoi*Infection
			OK with revisions3
			Gregory Ebel, ScD, Colorado State University
			Non-Ecological/Behavioral Prevention and Treatment of Tick-Borne Viruses Enzootic in the U.S.
			Yes4
			Scott Commins, MD, PhD, University of North Carolina at Chapel Hill
			What Is Known about Treatment and Prevention of Alpha-gal Syndrome (AGS)
			Yes5
			Mark Soloski, PhD, Johns Hopkins University
			Lyme Disease Prevention
			Yes6
			Luis Marcos, MD, MPH, Stony Brook University
			Treatment of Lyme Disease
			Yes6
			Charlotte Mao, MD, MPH, Dean Center for Tick Borne Illness
			Treatment: Lyme Disease and Bartonellosis
			Yes7
			Alison Hinckley, PhD, National Center for Emerging and Zoonotic Infectious Diseases
			Toward a Potential Lyme Disease Vaccine or Preventive: CDC’s Ongoing Efforts
			YesTable 4: Votes Taken by the Disease Prevention and Treatment Subcommittee
	Meeting Number or Date
			Motion
			Result
			Minority ResponseIn Favor
			Opposed
			Abstained
			AbsentVia email
			Potential Action 1.1
			13
			0
			0
			0
			N/AVia email
			Potential Action 1.2
			13
			0
			0
			0
			N/AVia email
			Potential Action 1.3
			13
			0
			0
			0
			N/AVia email
			Potential Action 2.1
			13
			0
			0
			0
			N/AVia email
			Potential Action 2.2
			13
			0
			0
			0
			N/AVia email
			Potential Action 2.3
			13
			0
			0
			0
			N/AVia email
			Potential Action 3.1
			13
			0
			0
			0
			N/AVia email
			Potential Action 3.2
			13
			0
			0
			0
			N/AVia email
			Potential Action 3.3
			12
			1
			0
			0
			noneVia email
			Potential Action 3.4
			13
			0
			0
			0
			N/AVia email
			Potential Action 3.5
			13
			0
			0
			0
			N/AVia email
			Potential Action 3.6
			13
			0
			0
			0
			N/AResults and Findings

The subcommittee conducted seven conference calls spanning November 2021 to January 2022. Two of those calls were procedural, with the remaining calls covering six priority TBD prevention and treatment areas: (a) rickettsial infections, (b) babesiosis and relapsing fever/*B. miyamotoi*infection, (c) tick-borne viruses, (d) alpha-gal syndrome, (e) Lyme disease prevention, and (f) Lyme disease treatment.

The Priority Area descriptions below summarize the individual presentations made to the Subcommittee. Given the special importance of Lyme disease among the TBDs, the Subcommittee split that discussion into separate prevention and treatment priorities. Furthermore, the Subcommittee ensured that different treatment perspectives were presented.

These Priority Area summaries are intended to transparently and faithfully capture the presentations as they occurred, and do not imply universal agreement or consensus among the Subcommittee members. Rather, group consensus is reflected in the 12 final Subcommittee potential actions that were developed at the conclusion of all presentations and voted on by all members.

For consideration by the Tick-Borne Disease Working Group, the Disease Prevention and Treatment Subcommittee has identified six major priorities and twelve potential actions.

Priority 1: Prevention and Treatment for Infections by the Rickettsiales

Bacteria in the order rickettsiales are the second leading cause of tick-borne infections (referred to as “rickettsial diseases”) in the United States. Reported cases of human anaplasmosis, ehrlichiosis, and spotted fever rickettsioses have steadily increased, however cases are underrecognized and underreported.

*Anaplasma* *phagocytophilum,* *Ehrlichia,* and *Rickettsia* species are transmitted by different tick species, lead to different clinical presentations, and have distinct, though frequently overlapping, geographical distributions. While the true incidence is unknown, the diseases caused by this collection of bacteria result in significantly higher rates of hospitalization and death than Lyme disease yet remain clinically underappreciated.

*2018 Tick-Borne Disease Working Group Report*

The 2018 Tick-Borne Disease Working Group Report focused almost exclusively on Lyme disease. Rickettsiosis, ehrlichiosis, and anaplasmosis were discussed only as part of one subcommittee report on coinfections associated with Lyme disease. That report contained some general information on single pathogen infections but did not go into detail on treatment and prevention.

Several recommendations from the 2018 Report are relevant to the prevention and/or treatment of rickettsial diseases. Several recommendations involved supporting research of tick biology and TBD surveillance/epidemiology, which are critical for the prevention of rickettsial diseases (Tick-Borne Disease Working Group, 2018, Recommendations 3.1, 3.2, 3.4). Tick biology research will contribute to the development of tick-targeted prevention strategies. Increased surveillance will better inform the public on regional risks of rickettsial diseases and educate healthcare practitioners on including these diseases within differential diagnoses.

In the Prevention chapter, the 2018 Report focused on Lyme disease, but two recommendations are relevant to rickettsial diseases. Recommendation 4.1 addresses prevention through novel tick-control methods, an important part of a multi-pronged prevention strategy (Tick-Borne Disease Working Group, 2018, Recommendation 4.1). The 2021-2022 Changing Dynamics of Tick Ecology, Personal Protection, and Control Subcommittee will address tick control methods. The 2018 Report also urged that physicians and the public be better informed on regional and specific risks associated with TBDs (Tick-Borne Disease Working Group, 2018, Recommendation 4.4). After detailed discussion within the current working group, this was considered an important priority to be highlighted in our final potential actions. Education and awareness of tick-borne rickettsioses, leveraged by improved surveillance of these diseases, provides data critical for focused efforts at prevention.

The “Treatment” chapter of the 2018 Report also focused on Lyme disease, though one recommendation did encourage an increase in research on treatment for TBDs (Tick-Borne Disease Working Group, 2018, Recommendation 6.3). This broad, non-specific recommendation is therefore relevant to rickettsial diseases; the Subcommittee acknowledges the usefulness of this recommendation.

In summary, the 2018 Report, while mentioning rickettsial diseases within one subcommittee, made no recommendations specific to the treatment and prevention of these infections. Some recommendations broadly applicable to TBDs were indeed relevant to the current Disease Prevention and Treatment Subcommittee’s charge, and some will be reinforced in our final potential actions.

*2020 Tick-Borne Disease Working Group Report*

The 2020 Report both expanded on and complemented the 2018 version and included specific subcommittees focused on both Lyme disease and other TBDs. Two subcommittees were dedicated to rickettsial pathogens, one on *Ehrlichia/Anaplasma* and the other on *Rickettsia*(Ehrlichiosis and Anaplasmosis Subcommittee, 2020; Rickettsiosis Subcommittee, 2020). Both of these subcommittee reports provided extensive reviews on the state of the science for these pathogens. As with the 2018 Report, the 2020 Report also included recommendations on tick biology and surveillance, which are covered by the Changing Dynamics of Tick Ecology, Personal Protection, and Control Subcommittee.

In the Treatment chapter in the final 2020 Report, Recommendation 6.2 calls for increased research to improve treatment of a broader (i.e., non-Lyme) range of TBDs (Tick-Borne Disease Working Group, 2020, Recommendation 6.2). While this would pertain to the rickettsial diseases, they were not mentioned by name. There was no prevention chapter in the 2020 Report.

*Additional Issues*

In general, despite a thorough review of rickettsial pathogens and their clinical features, including diagnosis, treatment, and prevention in the related subcommittee reports, these recommendations were not sufficiently addressed within the final Tick-Borne Disease Working Group report. Research gaps and opportunities were discussed by the current Prevention and Treatment Subcommittee and are detailed below.

*Treatment*

The Subcommittee generally agreed that treatments are effective and available; new therapeutics for rickettsial diseases are not needed at this time. Doxycycline is effective against *Anaplasma*, *Ehrlichia,* and *Rickettsia*, and antibacterial resistance has not emerged as an issue.

There are, however, areas of treatment that could still be addressed. Foremost among these is that while doxycycline is highly effective, there is a lingering hesitancy among healthcare practitioners to prescribe the drug due to unfounded concerns of its use in children. In a recent study, 50% of U.S. physicians were reluctant to use doxycycline in children under age eight years, despite the potentially life-saving impact of this antibiotic and growing data that indicate short courses of doxycycline do not cause perceptible staining of permanent teeth (Pöyhönen et al., 2017). The Subcommittee agreed that enhanced educational efforts, targeted particularly for frontline healthcare practitioners (i.e., nurse practitioners, pediatricians, general practitioners, family medicine doctors, and emergency department physicians), is a critical need. While some Subcommittee members suggested retrospective case studies in children who received doxycycline to help allay concerns, most members considered the current data compelling enough, and additional studies could unnecessarily perpetuate doubt in the use of this potentially lifesaving antibiotic.

While not a treatment issue per se, considerable attention was paid to the need for improved surveillance and reporting of TBDs. Given the rapid clinical progression of many TBDs, particularly Rocky Mountain spotted fever (RMSF), physicians must be informed enough to suspect rickettsial infections in endemic areas.  Physicians can quickly initiate appropriate therapy to prevent onset of life-threatening manifestations.

New, non-antibiotic adjunctive therapies may be worth pursuing, especially in cases where antibiotic treatment has been delayed, but this was not considered a high priority by the Subcommittee. Rather, the focus should be on identifying and treating presumptive cases.

In addition to the rickettsiales, facultative intracellular bacteria of the genus *Bartonella* have been suggested to cause tick-borne illness or Lyme disease coinfections. Despite these reports, evidence is lacking to support transmission of *Borrelia henselae*, the predominant bacteria discussed in this framework. Most researchers in the field do not recognize tick transmission as a significant mode for *Bartonella*infection. The pathogen is still often cited as a coinfection with Lyme disease, so it will be further addressed in “Priority 6: Lyme Disease Treatment.”

*Current NIH Research on Rickettsial Disease Treatment*

There is little activity in the field, beyond a few grants supporting research to repurpose existing drugs or develop new ones to address late-stage symptoms that arise when initial treatment was delayed. Recently, efforts to develop nanobodies as therapeutics for ehrlichiosis and potentially other rickettsial infections have been reported (Zhang et al., 2021).

*Prevention*

The Subcommittee agreed that preventive approaches targeting the tick or reservoir likely had the best chance of commercial success. Anti-tick vaccine development, which will be discussed more in “Priority 5: Lyme Disease Prevention,” is an intriguing approach that could prevent multiple tick-borne infections with a single vaccine. Pathogen-specific vaccines, while potentially effective, are unlikely to be commercialized for any of the rickettsial diseases. It is possible, however, that multi-pathogen vaccines—for example those targeting pathogens transmitted by a single tick species—would have market viability and should be considered. In that light, research should continue with single pathogen approaches, which could be later combined into multivalent vaccines.

Canine vaccines against *Rickettsia rickettsii* could have considerable impact at mitigating large outbreaks or epidemic levels of RMSF that have been identified in the southwestern United States and northern Mexico during the past two decades. In these settings, cases of human disease result from zoonotic infections in dogs and massive populations of brown dog ticks (*Rhipicephalus sanguineus*). A canine vaccine against the pathogen could have targeted impact in these unique but highly relevant circumstances.

Potential roadblocks to vaccines include review requirements that single-pathogen vaccine viability be demonstrated before they can be combined into a multi-pathogen formulation. The relatively low incidence of rickettsial disease would pose issues for study enrollment requirements for vaccine trials. Perhaps a larger hurdle is difficulty in conducting a vaccine trial for a rickettsial disease, as the relatively low incidence would likely mandate a prohibitively large enrollment.

Priority 2: Prevention and Treatment of Babesiosis and Relapsing Fever/*Borrelia miyamotoi*Infections

Babesiosis

*Background*

Babesiosis is a worldwide disease caused by protozoan parasites of the genus *Babesia*(Vannier & Krause, 2012). There are more than 100 species of *Babesia*, 6 of which infect humans, while the others infect a wide array of wild and domestic animals. *Babesia* parasites invade and replicate within red blood cells. The main route of transmission is through the bite of an infected hard-bodied (*Ixodid*) tick. *Babesia* also can be transmitted via blood transfusion, organ transplantation, and perinatally from an infected mother to her fetus, but these routes of transmission are relatively rare. A diagnosis of babesiosis should be considered in patients living in an endemic area who are exposed to ticks and who present with typical symptoms, including fever, fatigue, sweats, chills, and headache. The diagnosis is confirmed by microscopic detection of *Babesia* on blood smears or polymerase chain reaction (PCR) amplification of *Babesia* DNA. A diagnosis also can be made with a four-fold rise in *Babesia* antibody titer in acute and convalescent sera. The current standard treatment of babesiosis is the combination of atovaquone/azithromycin or clindamycin/quinine as an alternative (Krause et al., 2021; Vannier & Krause, 2012).

*Summary of Evidence and Findings*

*Babesiosis is an emerging infection*

Babesiosis is an emerging TBD, with an increasing number of cases reported both in the United States and globally (Kumar et al., 2021). The geographic range of *Babesia* is expanding in the United States from epicenters in the Northeast and northern Midwest, where *Babesia* *microti* is endemic. Sporadic babesiosis cases due to *Babesia duncani* have been reported on the West Coast. Five cases of *Babesia divergens*–like babesiosis have been described in the Midwest and Far West. Internationally, sporadic cases of *B. divergens*, *B. ventorum, B. microti,*and*Babesia crassa–*like agent are reported in Europe. Endemic babesiosis due to *B. ventorum* and *B. crassa*–like agent occur in northeastern China and *B. microti* in southwestern China (Kumar et al., 2021). Rigorous epidemiological studies suggest that many more cases occur than are reported. Reinfection has been reported, but the contribution of reinfection to the emergence of babesiosis is unknown.

*Physicians lack familiarity with the disease and risk factors*

Because babesiosis is far less commonly reported than Lyme disease and is an emerging infection, many physicians lack an understanding of the dangers it can pose, especially for populations with risk factors for severe disease. Immunocompetent patients with babesiosis usually present with a moderate febrile illness, but about a quarter of adults and half of children experience mild or asymptomatic infection. In contrast, immunocompromised populations usually experience severe disease and often suffer complications, including severe anemia, shock, acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), congestive heart failure, renal failure, and/or coma. Immunocompromised patients also may experience persistent or relapsing illness lasting a year or longer despite multiple courses of antibiotic therapy (Krause et al., 2008). The fatality rate of immunocompromised patients can range from 4 to 27%, depending on their underlying condition. These include patients with asplenia, cancer, HIV/AIDS, patients on immunosuppressive drugs, and patients over 50 age years (Vannier & Krause, 2009). The role of various immunological responses that clear *Babesia* infection are not well-understood.

*Diagnosis is often delayed*

The diagnosis of a *Babesia* infection is often delayed for several reasons. People living and working in endemic areas, including physicians, are often unfamiliar with babesiosis. The disease has a long incubation period (1-4 weeks), and symptoms are nonspecific. There is no easily recognized symptom like the erythema migrans (EM) rash of Lyme disease that establishes the diagnosis.

*Treatment is less effective for immunocompromised patients.*

Mild to moderate cases of babesiosis can be successfully treated with a 7- to 10-day course of either atovaquone plus azithromycin or clindamycin plus quinine oral therapy (Krause et al., 2000). Hospitalized patients are similarly treated, except that the atovaquone or clindamycin is given intravenously. Symptoms typically abate within a few days. Highly immunocompromised patients may require months of antibiotic therapy, and some die despite treatment (Krause, 2019). Antibiotic resistance can develop during prolonged therapy, so there is a strong need to develop new therapies for the immunocompromised patient population.

*Current preventive measures are inadequate*

There is currently no vaccine or other therapeutic agent available to prevent *Babesia* infection in humans. Further research is needed to study immunogenic *Babesia* proteins, which could become the basis for a monoclonal antibody (mAb) therapy or vaccine. For example, 56 *B. microti*antigens were identified by screening a genome-wide cDNA phage library against patient sera (Verma et al., 2020).

*Potential actions to consider*

Many actions are available to reduce the incidence of human babesiosis and associated morbidity and mortality. These include:

Action through the One Health initiative to institute preventative ecological measures
	More effective surveillance of babesiosis cases
	Increased funds for research on anti-TBD vaccines (especially a multiplex vaccine for babesiosis, Lyme disease, and anaplasmosis) and anti-tick vaccines focused on tick salivary enzymes
	Education of physicians and the general public about the risks of severe babesiosis, especially in immunocompromised patients
	Funding for human studies and animal models and on immunologic factors important in clearing *Babesia*
	Development of point-of-care tests
	Development of repurposed drugs for immunocompromised patients (e.g., clofazimine, tafenoquine, quinolones) and novel therapies (e.g., mAbs)*Relapsing Fever/Borrelia miyamotoi Infection*

*Background*

Relapsing fever is an arthropod-borne infection caused by several species of spirochetes in the genus *Borrelia*found throughout the world (Krause et al., 2015). Two major types of relapsing fever are classified according to their arthropod vector, tick-borne relapsing fever (TBRF) and louse-borne relapsing fever (LBRF). TBRF may further be classified into soft tick-borne relapsing fever (STBRF) and hard tick-borne relapsing fever (HTBRF). STBRF has been reported in 12 Western states, most commonly in California, Washington State, and Colorado (Forrester et al., 2015). HTBRF is caused by *B. miyamoti*which is phylogenetically part of the relapsing fever spirochete group but has some phenotypic characteristics of Lyme borreliosis spirochetes*.*

The discovery of *B. miyamotoi* spirochetes in a variety of hard-bodied ticks greatly expands the potential geographic distribution of relapsing fever, and it is likely that *B. miyamotoi* will be found wherever Lyme disease is endemic. *B. miyamotoi*is an emerging infection with cases being reported over the past decade in North America, Asia, and Europe. *B. miyamotoi*infection is found in the blood but can also colonize the nervous system. It is transmitted by hard-bodied ticks (*Ixodes scapularis*, *Ixodes ricinius)*. Other potential routes of transmission include transfusion or transplacental infection. *B. miyamotoi*infection commonly presents as a fever with other flu-like symptoms. Patients typically do not develop the EM “bulls-eye” rash characteristic of *Borrelia burgdorferi*infection, although EM rash has been reported (Krause et al., 2015).  Complications of *B. miyamotoi*disease include relapsing fever and meningoencephalitis.

*Summary of evidence and findings*

*Geographic distribution of B. miyamotoi is not well understood*

Because there is no systematic reporting of *B. miyamotoi*cases, the geographic distribution of this disease is not well-characterized. In the United States, infections have been found in Connecticut, Massachusetts, Maine, New Jersey, New York, Rhode Island, Vermont, and Wisconsin (Jobe et al., 2016; Johnston et al., 2022; Krause et al., 2014). Internationally, cases have been reported in Austria, France, Germany, the Netherlands, Poland, Sweden, China, Japan, and Russia (Kubiak et al., 2021).

*Incidence and prevalence of B. miyamotoi infection are unclear*

The incidence and prevalence of *B. miyamotoi*are unclear. In a seroprevalence study of archived samples from southern New England residents collected from 1991 to 2012, 3.9% of samples from health individuals were positive for *B. miyamotoi,*suggesting that the pathogen infects more people than previously considered (Krause et al., 2014).  A new seroprevalence study for tick-borne illnesses in New England conducted in 2018 found that *B. miyamotoi*is widespread, albeit with a lower seroprevalence than Lyme disease and *B. microti* (Johnston et al., 2022). Not surprisingly, *B. miyamotoi*-seroreactive samples were detected in the same areas as *B. burgdorferi-* and *B. microti-*seroreactive samples.

*Clinical complications are not thoroughly understood, and those at greatest risk of complications are poorly defined*

Known complications of *B. miyamotoi*infection include relapsing fever and meningitis/meningoencephalitis. Other relapsing spirochetes (*B. hermsii, B. parkeri, B. parkeri, B. turicatae*) are associated with complications such as ARDS, cranial nerve palsy, and myocarditis. It is unclear whether these other complications occur in *B. miyamotoi*infections. Additionally, soft tick relapsing fever spirochetes can be transmitted through blood transfusion and placental infection. While there have been no reported cases of *B. miyamotoi*transmission via these alternative routes, a study using a mouse model of infection demonstrated that transfusion transmission of *B. miyamotoi* can occur with both fresh and stored murine-infected red blood cells (Krause et al., 2015). Finally, the risk factors for complications from *B. miyamotoi*are not well defined.

*Diagnosis of B. miyamotoi is often not considered*

*B. miyamotoi*disease has only recently been recognized and appears to be less common than Lyme disease or babesiosis. Many physicians and the general public are not familiar with *B. miyamotoi*disease. Additionally, symptoms are non-specific and often mild. Consequently, a diagnosis of *B. miyamotoi*is often not considered by physicians.

*Diagnostic assays are often unavailable*

A diagnosis of *B. miyamotoi*can be considered if a patient lives or travels in a region where other *Ixodes* tick-transmitted infections are endemic. Although *B. miyamotoi*spirochetes can be visualized in blood, microscopic assessment of blood smears is not a highly sensitive diagnostic method. PCR-based tests are sensitive and specific but less commonly available. Other means of detection of *B. miyamotoi*are serologic assays and inoculation of blood samples into laboratory mice; however, these are even less likely to be available for most diagnostic labs.

*Optimal treatment of B. miyamotoi is uncertain*

The antibiotics used for Lyme disease—doxycycline, amoxicillin, or ceftriaxone for 10-21 days— are also effective against *B. miyamotoi*infection, however, limited therapeutic studies have been carried out for *B. miyamotoi*infection. The optimal treatment regimen is unclear.

*Potential actions to consider*

Opportunities to reduce the incidence of *B. miyamotoi*infection and its associated morbidity include:

Action through One Health initiative to address ecological issues and collect data on seroprevalence and incidence
	Funding for research studies focused on central nervous system (CNS) infection, relapsing disease, and other potential complications of *B. miyamotoi* disease such as infection during pregnancy and blood transfusion transmission
	Investigation of risk factors for development of severe *B. miyamotoi* disease
	Education of healthcare workers and the public about *B. miyamotoi* infection
	Improved diagnostic assays for detection of *B. miyamotoi*infection
	Investigation of optimal treatment regimens for *B. miyamotoi* diseasePriority 3: Prevention and Treatment for the Tick-borne Viruses

Emerging tick-borne viruses (TBVs) include Powassan, Heartland, and Bourbon viruses. The central issue regarding these infections in the United States is that little is known about them due to the relative rarity of documented infections, as well as regulatory and funding challenges associated with researching them in an academic setting.

*Powassan Virus*

Powassan virus (POWV) is a tick-borne flavivirus first reported in 1958. It is the sole new world representative of the tick-borne encephalitis (TBE) serological complex within the flaviviruses. Infection in humans is notable for the severity of acute disease (~10% case fatality rate) and the high prevalence of severe long-term sequelae (Ebel, 2010). The virus perpetuates in nature in enzootic cycles involving small-medium sized vertebrates, including woodchucks, deer mice, white-footed mice, and shrews among others. The ticks that feed on these animals are the most important vectors and support maintenance in nature and transmission to humans via spillover from these enzootic cycles. Importantly, POWV is frequently isolated and/or detected in deer ticks (*Ixodes scapularis*), which feed frequently on people, and have driven the emergence of Lyme disease and other TBDs in recent decades. The seasonal and geographic distribution of human POWV cases supports the importance of deer ticks as vectors transmitting virus to human beings. Further, steady increases in annual caseloads of POWV and documented infection in deer indicates steady emergence due to association with these vectors (Nofchissey et al., 2013). Moreover, because of its association with deer ticks, POWV should be considered the most significant of the known TBVs in North America.

Treatment for acute POWV disease is supportive/palliative. Specific antiviral treatments do not exist despite considerable effort expended toward the development of anti-flaviviral compounds that interrupt or suppress virus replication. These drugs, however, generally have not been tested specifically against POWV. Therefore, the effectiveness of general approaches, including high dose corticosteroids and intravenous immunoglobulin therapy (IVIg) that have been proposed and assessed clinically in preliminary studies, is unclear. mAb therapies have been proposed and tested in mice. Use of mAbs in humans should be conducted with extreme care due to the well-documented propensity of flaviviruses for antibody-dependent enhancement (ADE), which can lead to more severe disease. For prevention of POWV disease, no vaccines have been licensed or are in clinical trials. However, vaccines are available for the prevention of other tick-borne encephalitis viruses (TBEVs) that are found in Eurasia. One of these (Ticovac®) from Pfizer was recently licensed in the United States for travelers to TBEV endemic regions. The effectiveness of this vaccine against POWV has not been conclusively demonstrated. Specific vaccines against POWV are under development using virus-like particles (VLPs), DNA and mRNA platforms. Some have been used to protect mice from challenge.

*Heartland Virus*

There have been about 50 cases of heartland virus (HRTV) in humans in the past decade. It is maintained in nature in transmission cycles that are poorly understood but appear to involve lone star ticks (*Amblyomma americanum*) as vectors to humans. The expansion of lone star ticks to the west and north may bring this virus into new localities, such that additional groups of people will be exposed in the future. Hence, heartland virus is an extremely important subject for ongoing research.

For prevention, there is no recent literature on the development of vaccines to prevent HRTV. Some literature examines preclinical vaccines for a related virus, severe fever with thrombocytopenia virus (SFTV). These include recombinant vesicular stomatitis virus (VSV), rabies vectored, and live-attenuated vaccines. The extent that these vaccines would prevent HRTV infection or reduce symptoms is unknown.

Minimal literature addresses the need for antiviral compounds targeting HRTV. An NF-κβ inhibitor (sc75741)and 2’-fluoro-2’-doxycycline have been studied in vitro and in vivo in mice (Mendoza et al., 2021; Smee et al., 2018). No human studies have been conducted.

*Bourbon Virus*

Bourbon virus has produced 5-10 known human cases (Kosoy et al., 2015; Savage et al., 2018). The infection may be clinically severe, particularly in older individuals with comorbidities. *A. americanum* are competent vectors. There are no vaccines or antiviral drugs in development, so treatment is supportive.

*Potential Actions to Consider*

*Powassan Virus*

Assess the efficacy of Ticovac® against POWV. Does Ticovac® cross protect against known POWV strains? This can be assessed with plaque reduction neutralization tests (PRNTs) using serum from immunized individuals.
	Evaluate the possibility of ADE in the context of postexposure prophylaxis treatment with a vaccine or mAbs.
	Develop a vaccine using Moderna’s mRNA technology and begin Phase I clinical trials.
	Evaluate the potential for vaccine use in clear geographic foci of transmission.
	Explore antiviral compounds as postexposure treatments under certain circumstances and test them in animal models.
	Consolidate and synthesize anti-POWV drug research.*Hartland Virus and Bourbon Viruses*

Develop vaccine candidates.
	Identify antiviral compounds for postexposure prophylaxis.
	Evaluate the possibility of ADE.
	Develop mAb therapies if ADE is not a concern.Priority 4: Prevention and Treatment of Alpha-gal Syndrome

Alpha-gal Syndrome (AGS) is an allergy to the carbohydrate galactose-alpha-1,3-galactose (“alpha-gal”) that is present in lower mammals such as cows, sheep, pigs, cats, and dogs (Levin et al., 2019). People who develop AGS most commonly report allergic reactions after eating beef, pork, or lamb (Commins et al., 2014). Unlike more traditional food allergies, reactions to alpha-gal occur 3-6 hours (or more) after consuming mammalian meat, and this prolonged delay frequently creates a challenge in diagnosis (Commins et al., 2014; Flaherty et al., 2017; Levin et al., 2019).

Although it is not fully established how AGS develops, accumulating evidence suggests that tick bites play a causal role (Commins et al., 2011). In the United States, the primary tick associated with AGS is *A. americanum*(the lone star tick) (Commins et al., 2011). However, in other areas of the world different species of ticks have been associated with the allergy (Chinuki et al., 2016; Levin et al., 2019; Van Nunen et al., 2009).

Accumulating data suggest that the incidence of AGS is on the rise, with the highest number of incidences reported in the southeast region of the United States, which correlates with the expanding geographic distribution of lone star ticks (Commins, 2016; Commins et al., 2011; Levin et al., 2019; Pattanaik et al., 2018). In 2009, there were 24 reported cases of AGS; however, more recent data documented more than34,000 cases from 2010 to 2018 in the United States alone, and AGS was identified as the leading cause of anaphylaxis in a southeastern registry of patients (Binder et al., 2021; Pattanaik et al., 2018). Thus, AGS likely represents the second most common cause of tick-borne illness behind only Lyme disease.

*2018 TBDWG Report*

The 2018 Report focused almost exclusively on Lyme disease. AGS was discussed as part of one subcommittee report and specifically mentioned in Recommendation 6.5: Improve the education and research on the pathogenesis of alpha-gal allergy, also known as the tick-caused “meat allergy” (Tick-Borne Disease Working Group, 2018, Recommendation 6.5).

Because tick bites appear to trigger the development of AGS, several recommendations of the 2018 Report pertaining to tick biology do have relevance to the prevention of AGS, including recommendations to support research on tick biology and TBD surveillance/epidemiology (Tick-Borne Disease Working Group, 2018, Recommendations 3.1, 3.2, 3.4). Increased funding for tick biology research may lead to tick-targeted prevention strategies, and increased surveillance will better inform the public on regional risks of human-biting ticks and educate healthcare practitioners on the need to include these diseases within differential diagnoses.

Recommendation 4.4 urges that physicians and the public be better informed on regional and specific risks associated with TBDs (Tick-Borne Disease Working Group, 2018, Recommendation 4.4). After detailed discussion within the current subcommittee, this was considered an important priority to address in our final potential actions.

In short, the 2018 Report, while mentioning AGS within one subcommittee, made no recommendations specific to the treatment and prevention of this condition. Some recommendations broadly applicable to TBDs were indeed relevant to the current Prevention and Treatment Subcommittee’s charge, and some of those will be reinforced in our final potential actions.

*2020 TBDWG Report*

The second iteration of TBDWG had an entire subcommittee devoted to AGS. Therefore, AGS received significant attention in the 2020 Report and recommendations from several chapters included AGS-based points (Tick-Borne Disease Working Group, 2020, Recommendations 4.4, 5.1, 7.5), including:

Recommendation 4.4: Provide HHS with resources to partner with national Integrated Delivery Networks (IDNs) (for example, Geisinger, Kaiser, etc.) to conduct a pilot feasibility study to leverage Electronic Medical Records (EMRs) using Best Practice Alerts at the patient point-of-care for Alpha-gal Syndrome in endemic areas (upholding patient confidentiality).
	Recommendation 5.1: Provide HHS with resources necessary to fund basic science research and clinical research to investigate the pathology of the human immune response following tick bites (e.g., Alpha-gal Syndrome [AGS])
	Recommendation 7.5: Generate broad awareness of Alpha-gal Syndrome through the following two mechanisms:
	Provide funding/support/resources necessary to create a National Tick-Borne Alpha-gal Syndrome Alert that is focused on awareness, prevention, and education regarding tick associated Alpha-gal Syndrome and that targets key stakeholder groups.
		Label foods/beverages, medications and medical products, cosmetics, etc. containing mammalian-derived components for the safety of consumers with Alpha-gal Syndrome.As with the 2018 Report, the 2020 Report also included recommendations on tick biology and surveillance, which are relevant to AGS.

*Treatment*

The Subcommittee generally agreed that because AGS is not known to be infectious, the primary treatment involves treating allergic reactions through guideline-based medical management. No controlled studies have been reported for allergen desensitization related to AGS. One promising aspect that has emerged recently is a line of genetically edited pigs that do not express alpha-gal. These “alpha-gal safe” animals have been approved by the U.S. Food and Drug Administration (FDA) and could represent a safe source of porcine medical products (e.g., heart valves) and pork meat for patients with AGS. Additional studies and testing are planned for safety of these mammals because the FDA approval was not based on an allergic indication but simply a non-alpha-gal one.

Another potential treatment that was discussed is omalizumab. This is an mAb commercially available for management of allergic asthma and treatment of chronic hives. The molecule works by binding the allergic class of antibody, IgE, and therefore could be useful in numerous IgE-mediated conditions such as AGS and other food allergies. Trials are under way with omalizumab in food allergy (peanut, tree nut) but none specifically addressing AGS.

Although not a treatment issue per se, considerable attention was paid to the need for improved surveillance and reporting of AGS. Given the importance of diagnosing AGS to prevent life-threatening allergic reactions, physicians must know to suspect the allergic syndrome in endemic areas.

*Prevention*

The Subcommittee agreed that preventive approaches targeting human-biting ticks had the best chance of success. Anti-tick vaccines are an intriguing approach that could prevent multiple tick-borne conditions with a single vaccine. This approach could be considered one of creating “tick resistance” in humans by vaccinating with tick salivary or other factors to induce an anti-tick immune response. Given the remarkable rise in AGS cases, powering a clinical trial for AGS anti-tick vaccine would be feasible.

Priority 5: Lyme Disease Prevention

*Overview/Introduction*

Current approaches to the prevention of Lyme disease rely largely on strategies that increase awareness of the threat of tick bites in tick-infested areas, promote the prudent use of proper clothing and/or repellent, and introduce measures that focus on controlling the major animal reservoirs of *B. burgdorferi*. While these approaches are and will continue to be cornerstones to the prevention of human Lyme disease, the Subcommittee focused its attention on current and new approaches that show promise as prophylactic approaches in the prevention of Lyme disease in the human host. These include new and emerging vaccines, the development of borreliacidal human mAbs and the use of small molecules. The committee noted several fundamental gaps in knowledge on the most relevant components of the human host immune response, which are important to understand to fully develop prevention strategies. These will be elaborated in the narrative below.

*Anti-Borrelia Vaccines*

The use of vaccines in the prevention of human infectious disease is well established and has been re-emphasized due to the current SARS-CoV-2 pandemic. In 1998 the Lyme disease vaccine Lymerix targeting OspA was licensed and made available, but it was removed from the market in 2002 due to a range of complex factors including the concern of the initiation of a self-reactive (autoimmune) process. The complexities of the history of Lymerix have been discussed in numerous forums and will not be elaborated here. We will focus on promising current and future vaccine approaches.

A new vaccine, VLA15, contains recombinant OspA proteins from several *Borrelia* strains found in the United States and Europe and has been engineered to remove the amino acids thought to drive a potential autoimmune response. VLA15 was developed by Valneva SE, which has partnered with Pfizer, and is currently under study in a Phase II clinical trial (Valneva, active trial). Preclinical studies and current trials have also shown great promise (Comstedt et al., 2017). In addition to this vaccine, an effective canine vaccine using chimeric antigens has been developed by the Marconi lab, and this strategy has been proposed as an effective human vaccine approach (Camire et al., 2021; O'Bier et al., 2021).

Research on the development of effective vaccines against human Lyme disease should be expanded. This will include the use of next generation vaccine platforms such as mRNA-based approaches but also other vaccine platforms such as the use of viral vectors, peptide-based vaccines, and attenuated/mutant strains of *Borrelia*. Also, the success of future effective vaccine strategies is strictly dependent on a deep understanding of elements of the human immune response that are most effective in providing protection against *Borrelia*. The *Borrelia* genome has more than 1,700 open reading frames and according to UniPro encodes more than 1,250 proteins. However, at this time, only two of these proteins (OspA and OspC) have been utilized in vaccine development. In addition, studies on the T-cell response in human Lyme disease have largely been focused on immune targets in Lyme arthritis, a manifestation of late Lyme disease. Therefore, many knowledge gaps exist in our understanding of the adaptive immune response, most notably the T-cell response during the early acute phase of disease. Gaps also exist in the identification of those elements that correlate with and contribute to the resolution of infection and the development of long-lasting immunity. Additional studies needed for understanding the immune response include (a) studies examining the range of bacterial proteins that serve as key immune targets for both T and B cell immunity in the acute phase, (b) research on the complexity of T and B cell effectors that are generated during immune response, and (c) the identification of elements that can be correlated with potent immunity. These studies should utilize relevant preclinical animal models to lay the groundwork but also employ human samples from well-defined patient cohorts. Funding support of studies of this nature will yield insights that will inform not only the development of a new generation of Lyme vaccines but also the evolution of human mAb-based therapies in Lyme disease that will be discussed below.

*Anti-Tick Vaccines*

The spirochaete *B. burgdorferi* is transmitted during the bite of an *Ixodes* tick. During this process the tick also transmits saliva containing several salivary gland proteins that have a range of biological properties (Hovius et al., 2007). Interestingly, several tick proteins have been shown to be antibody targets in forestry workers repeatedly exposed to ticks, and it has been reported that multiple tick bites reduced the likelihood of contracting Lyme borreliosis in humans (Trentelman et al., 2021). Importantly, anti-tick immunity induced by vaccination with tick proteins in animal models has been shown to alter and even arrest tick feeding (Matias et al., 2021; Rego et al., 2019; Sajid et al., 2021). Because the *Ixodes* tick can transmit viral, protozoan, and bacterial pathogens, the development of an anti-tick vaccine has enormous potential to reduce the incidence of a range of TBDs. Further development of this approach deserves strong support, which should include defining immune targets using relevant animal models and employing well-defined human cohorts, understanding the human immune response to tick proteins, and developing a safe and specific vaccine approach that will merit clinical trials.

*Human Monoclonal Antibody Based Protection*

Several pathogen-specific human mAbs have been developed to be used as therapeutics. This approach in the treatment of SARS-CoV-2 infection has been well documented. A human mAb (2217LS) reactive to OspA has been developed and engineered to retain an extended blood half-life (Schiller et al., 2021; Wang et al., 2016). This reagent has proven effective in rodent and primate models, has been proposed to be used as a pre-treatment for at risk individuals, and is now undergoing Phase I trials (MassBiologics, active trial). This approach, which can impact both prevention and treatment of other tick-borne pathogens, deserves support. As mentioned above for the development of Lyme vaccines, the advancement of this approach will also benefit from a deeper understanding of the range of relevant immune targets in Lyme disease and a fundamental understanding of immune mechanisms in human TBDs.

*Small Molecules and/or Antibiotics as Prevention*

Opinions vary on the use of antibiotics as a prophylactic measure for individuals at risk for Lyme disease. The major concerns center around the development of antibiotic-resistant bacteria and alterations in the host microbiome. To our knowledge antibiotic resistance has not been observed for *B. burgdorferi* and thus may not be a major clinical concern. A recent study using a high throughput selective screen of soil compounds against *B. burgdorferi* led to the rediscovery of hygromycin A as a potent antibiotic against *Borrelia* (Leimer et al., 2021). The antibiotic’s mechanism of action on *Borrelia* is novel and would not have been predicted; it is active in a mouse model and does not significantly alter the microbiome. This raises the possibly that, with proper support, other antibiotics, natural products, and/or small molecules could be discovered that have selective borreliacidal activity and leave the host microbiome unaltered. This will require support for both basic mechanistic and translational studies to develop such compounds as both prevention and treatment measures.

*Centers for Disease Control and Prevention Activities Related to Lyme Disease Prevention*

From a presentation made by Alison Hinckley on January 21, the subcommittee learned about Centers for Disease Control and Prevention (CDC) activities conducted or planned regarding potential Lyme disease vaccines or preventives. CDC is working in three areas: (a) describing the burden of Lyme disease; (b) laying the groundwork for an Advisory Committee on Immunization Practices (ACIP) review; and (c) communicating to healthcare providers and the public.

Dr. Hinckley described several recently published studies describing analytic efforts to estimate the burden of Lyme disease, in terms of number of annual diagnoses in the United States and the cost of the disease to the average patient, as well as society. Dr. Hinckley also described several recent published efforts that evaluate the acceptability of a potential Lyme disease vaccine among healthcare practitioners and the public. When more information is available regarding the efficacy of a potential vaccine, CDC will use all these data to develop an estimate of cost or benefit of a Lyme disease vaccine to society. All of these data will be considered by ACIP when developing recommendations for use of a vaccine.

In the coming one to two years, in anticipation of at least one vaccine completing a Phase III trial and being approved as safe and effective by FDA, CDC will also work to assemble and oversee an ACIP workgroup charged with collection, analysis, and preparation of information for presentation, discussion, deliberation, and vote by the ACIP in an open public forum. Throughout this entire process, CDC has been and will continue to communicate what is known (and unknown) about any potential vaccines or preventives. Once approved, CDC will work diligently to increase awareness of the vaccine among the public and clinicians as an effective tool for Lyme disease prevention in the United States.

*Summary*

There are gaps in knowledge on the molecular targets of B and T cells, the role of effector T cells, and the mechanisms that promote long-lasting protective immunity in human Lyme disease.
	There is a need to develop vaccines and/or human mAbs as prevention using knowledge on the most potent immune targets and effector mechanisms
	Vaccine development needs to utilize Next-Gen platforms (for example, mRNA based) in vaccine development and support the development of chimeric/multi subunit-based approaches that can target multiple TBDs.
	Tick-based vaccines show great potential and could prevent a range of TBDs; further research and development needs to be supported.
	New small molecules, natural products, and/or antibiotics that are borreliacidal and do not alter the host microbiome should be identified. We recommend the use of such molecules, if the basic science is supportive for them to be tested as preventative measures.Priority 6: Lyme Disease Treatment

*Treatment Perspective 1*

Lyme disease, a multisystem inflammatory disorder caused by the spirochetes in the *B. burgdorferi sensu lato complex*, is the most reported vector-borne disease in the United States (Schwartz et al., 2017). Lyme disease is treated with antimicrobials to resolve the acute infection, avoid complications, and prevent a relapse of the initial infection. Treatment with appropriate antibiotics early in *B. burgdorferi* infection is very effective at preventing the development of later clinical manifestations such as neurological disease (for example, cranial neuritis, radiculoneuritis, mononeuropathy, lymphocytic meningitis, or encephalopathy), cardiovascular disease (for example, carditis with atrioventricular block), or mono-oligoarticular arthritis (Arvikar & Steere, 2015). Length of antibiotic therapy depends on the clinical syndrome or stage of Lyme disease: 7-14 days for EM, and 14-28 days for other forms of invasive infection or later clinical manifestations (Lantos et al., 2021).

Following the acute phase of infection, recent treatment trials among patients with EM have estimated that approximately 10 to 20% of patients treated for Lyme disease experience lingering symptoms that may progress to PTLDS (Turk et al., 2019). Importantly, the pathogenesis of and the exact molecular mechanisms underlying this condition remain unknown, but autoantigens and/or CNS sensitization have been postulated to play a role (Maccallini et al., 2018), which means that antimicrobials may not necessarily provide benefit. PTLDS is an important evolving public health problem. The cumulative prevalence of PTLDS by 2020 is predicted to increase to approximately 2 million (DeLong et al., 2019). Prior reports from this committee have recommended research into the origin of long-term symptoms that develop into PTLDS. In addition, the report from 2020 recommended to “encourage clinical trials on early and persistent Lyme disease.” Furthermore, the most recent guidelines of the Infectious Diseases Society of America recognize that PTLDS/Chronic Lyme Disease requires further studies to understand it and to develop therapeutic strategies (Lantos et al., 2021). PTLDS may be more common after Lyme disease than previously thought (Aucott et al., 2022), which should be the focus of most clinical research efforts.

Coinfections with Lyme disease may occur, most commonly *Babesia* infection. Further studies should investigate coinfections and whether they can complicate Lyme disease or prolong symptoms, as seen in PTLDS.

*Issues*

Our understanding of PTLDS is incomplete. Multiple trials have been conducted on this syndrome using multiple antibiotics and with prolonged courses. However, symptoms are not completely alleviated by antibiotics, which suggests that antimicrobials may not be the treatment of choice for this syndrome. There is a need for a better understanding of the pathogenesis of PTLDS to help design interventions to alleviate the suffering of these patients.

In addition, coinfections may play a role in clinical outcomes, prolonged symptoms, and complications.

*Evidence and Findings*

Even though doxycycline is a very efficacious antibiotic for acute EM, some patients may develop complications from the initial infection on this therapy, such as Bell’s palsy (Marcos & Yan, 2017). Close follow-up of patients who clinically fail doxycycline therapy is advised.

The most common manifestation of Lyme disease seen in emergency department in endemic areas is EM (48.6%), followed by neurological complications (20.1%), arthritis (14.3%), and carditis (3.8%) (Khoo et al., 2017). This underscores that about half of Lyme disease patients will likely require more than 14 days of antimicrobials for disseminated Lyme disease (for example, joints, heart, brain, peripheral nerves). In addition, EM may go undetected in at least one-quarter of people infected with *B. burgdorferi*, which may explain why about one-half of the patients in emergency rooms present with dissemination of the initial infection.

In addition, coinfections with other TBDs may play a role in severity of Lyme disease. For instance, serological studies indicate that coinfection with *B. microti*and *B. burgdorferi*is common in humans (Wormser et al., 2019). In endemic regions, 25% of babesiosis patients also had Lyme disease and about 20% of Lyme disease cases reported coinfection with *Babesia* (Diuk-Wasser et al., 2016). Little is known about the impact of co-infection of *B. burgdorferi* with *B. microti* because studies are limited and largely confined to artificial needle inoculation of inbred mice. A study showed that when mice were coinfected with *B. microti* and *B. burgdorferi*, the presence of *Babesia*enhanced the severity of Lyme disease, while the presence of *B. burgdorferi* appeared to limit the effects of *Babesia* (Bhanot & Parveen, 2019). Co-infection with *Babesia* may also impact the development of PTLDS; in some studies, nearly half of patients with PTLDS had evidence of past infection with *Babesia* (Horowitz & Freeman, 2019). This suggests that in some cases persistent symptoms of PTLDS, including neurocognitive deficits in verbal memory and processing speed, may be related to coinfections (Horowitz & Freeman, 2019; Touradji et al., 2019). Anecdotal cases indicate that disseminated Lyme disease with mild *Babesia* disease may have worse outcomes and longer-term symptoms, which merits further investigation.

A search on Medline from 2018 to 2021 for recent human clinical trials for Lyme disease and co-infections revealed some interesting findings described in the following paragraphs. A study in Sweden showed that sequelae after Bell’s palsy due to Lyme disease can range between 7-20% on post-treated cases with doxycycline regardless of the concomitant use of steroids (Avellan & Bremell, 2021), which points out the potential for permanent damage of the peripheral nerves after Lyme disease, regardless of the use of steroids.

Physicians have used extended doxycycline treatment regimens in endemic areas, although this is not recommended. A single dose of doxycycline as prophylaxis after an engorged deer tick bite remains the standard of care, which has been confirmed in a new study (Harms et al., 2021). More than one day of doxycycline as prophylaxis against Lyme disease is not recommended.

For PTLDS, the need for further antibiotic therapy is controversial. Side effects from new medications for this purpose have been documented. Disulfiram has been used for PTLDS, and toxicities have been reported in patients (Trautmann et al., 2020).  For persistent symptoms, prolonged use of antibiotics may not be effective to reduce symptoms of PTLDS patients or to lead to better cognitive performance (Berende et al., 2019), which suggests the need for other approaches for symptom relief.

Lyme neuroborreliosis (neurological Lyme disease) may be treated with either oral doxycycline or intravenous ceftriaxone. A study from Finland showed that either antibiotic resulted in equal improvement in patients with neuroborreliosis (Kortela et al., 2021).

New studies continue to show that either oral doxycycline or intravenous ceftriaxone are equally effective for treating early disseminated Lyme disease (Stupica et al., 2018), suggesting again that antibiotics are highly effective for the early stages of Lyme disease. Furthermore, the choice of antibiotic therapy for initial EM does not change treatment response, as seen in a meta-analysis published in 2018 (Torbahn et al., 2018). All these findings suggest that antibiotic therapies work very well for syndromes following the initial infection, as well as for disseminated disease.

The main controversy in Lyme disease pertains to the relief of symptoms in those developing PTLDS. Prolonged antibiotic therapy may cause more harm than benefit. Therefore, future research based on non-antimicrobial interventions are needed. In addition, the role of initial coinfections needs to be studied in prospective well-designed cohort studies.

*Treatment Perspective 2*

*2018 Tick-Borne Disease Working Group Report*

In the 2018 Report, Lyme disease treatment and therapeutics were the focus of two subcommittees; *Bartonella* coinfection was discussed in a third subcommittee that addressed other TBDs and co-infections. In the 2018 final report, treatment-related recommendations relevant to Lyme or *Bartonella* disease included calls for the following:

Research to better understand disease pathogenesis in patients with persistent symptoms despite standard treatment regimens for Lyme/TBD (Tick-Borne Disease Working Group, 2018, Recommendation 6.1)
	Improved education and research on transmission (including via pregnancy) and treatment of other TBDs and coinfections (Tick-Borne Disease Working Group, 2018, Recommendation 6.3)
	Clinical trials to fill any research gaps in target groups or areas (Tick-Borne Disease Working Group, 2018, Recommendation 6.4), including:
	optimal treatment strategies for patients with Lyme neuroborreliosis, PTLDS, or coinfections who remain ill after standard antibiotic treatment
		pediatric population (better understand potential manifestations in those who remain ill despite standard treatment)
		pregnant women with Lyme and coinfections (with goal of establishing additional safe and approved treatment options)
	The treatment chapter notes that *Bartonella* can be a significant complicating coinfection in human TBDs, regardless of whether it is transmitted by tick, flea, lice, or other insect, and deems support of *Bartonella*research “vital” to determine most appropriate therapeutic regimens.*2020 Tick-Borne Disease Working Group Report*

In the 2020 Report, Lyme disease treatment was primarily addressed by one subcommittee. Another subcommittee addressed *Babesia* and other key tick-borne pathogens. *Bartonella* was not discussed at the subcommittee level, presumably because it already received a fair amount of attention in 2018 at the subcommittee level and in the final report.

The Treatment chapter of the 2020 Report included two main recommendations: (a) encourage clinical trials on early and persistent Lyme disease, and (b) conduct additional research to address gaps in our capacity to treat a broader range of TBDs (Tick-Borne Disease Working Group, 2020, Recommendations 6.1, 6.2). *Bartonella* is not mentioned in the final report.

The Clinician and Public Education, Patient Access to Care chapter addressed diverging views on treatment in two recommendations that called for:

Government websites, educational materials, and seminars on Lyme disease to communicate the existence of divergent views on treatment (and diagnosis) based on differing interpretations of the state of the science (Tick-Borne Disease Working Group, 2020, Recommendation 7.1)
	Support for CDC’s development of a Lyme disease curriculum and continuing medical education modules that incorporate feedback from scientists, clinicians, and patients with diverse scientific and clinical experiences (Tick-Borne Disease Working Group, 2020, Recommendation 7.2)Three separate minority responses were written for this chapter, reflecting considerable differing opinions regarding the chapter’s content.

In the Epidemiology and Surveillance chapter, Lyme disease treatment in pregnancy was addressed parenthetically in a call for further evaluation of non-tick bite Lyme disease transmission, including maternal-fetal transmission (Tick-Borne Disease Working Group, 2020, Recommendation 8.3). Several cited studies were interpreted as showing (a) limited evidence linking gestational Lyme disease to adverse pregnancy outcomes, and (b) a seemingly favorable infant prognosis with prompt diagnosis and appropriate antibiotic treatment of gestational Lyme disease; however, untreated gestational disease was associated with higher rates of adverse pregnancy outcomes.

*Issues Considered in This Treatment Perspective*

In total, the two prior Tick-Borne Disease Working Groups and their multiple subcommittees well-summarized major treatment-related issues for Lyme disease and bartonellosis, including associated gaps and opportunities for education and research in these areas. However, two specific treatment-related gaps that were not addressed or warrant some additional emphasis include:

Neuropsychiatric syndromes including Pediatric Acute-onset Neuropsychiatric Syndrome/Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANS/PANDAS) presentations. Research is needed to better understand the possible role of Lyme disease and *Bartonella* infections in the pathogenesis of neuropsychiatric syndromes, as well as optimal diagnosis and treatment.
	Lyme disease in pregnancy: This topic was addressed in recommendations of both prior Working Groups but is repeated here to reinforce the magnitude of the gap between existing and necessary research/knowledge in this area and to add some points of emphasis.*Evidence and Findings*

*Neuropsychiatric manifestations*

A group of researchers in the 1980s described five children with psychiatric manifestations of CNS Lyme disease, all who were infected before age 10 and developed psychiatric symptoms 1-8 years later, including irritability, wide mood swings, drop in school grades, loss of friends, frank psychosis, auditory hallucinations, personality changes, sleep disturbances, and anorexia nervosa-like syndrome (Pachner, 1986; Pachner & Steere, 1987). The anorexia-like syndrome occurred in a 12-year-old boy with a history of treated Lyme arthritis whose knee symptoms resolved with antibiotic treatment. Two months later, he became withdrawn, depressed, and began obsessive dieting and exercising with weight loss of 14 kg, leading to psychiatric hospitalization and a diagnosis of anorexia nervosa. His symptoms suggest the possibility of this being a PANS-like presentation. Lyme serology was enzyme immunoassay (EIA) positive with immunoblot reactivity to multiple *B. burgdorferi* proteins, including OspA and OspB. Cerebrospinal fluid (CSF) studies, head imaging, and electroencephalogram (EEG) were normal. He was treated with intravenous penicillin for 14 days with symptom improvement within several weeks and resolution over the next several months, which was sustained out to three years at time of publication (Pachner et al, 1989).

These and other cases of “third stage” CNS Lyme disease led Pachner to compare this type of late neuroborreliosis to neurosyphilis. Both are spirochetal diseases that can present in multiple ways, including a primarily psychiatric form (Pachner & Steere, 1987), and cases might go unrecognized due to the lack of earlier detected stages.  He noted that spirochetal brain diseases can mimic many other neurological diseases, and that centuries of lessons learned from syphilis can be applied to Lyme disease (Pachner, 1988). A caveat is that these reports are from the early days of understanding the pathogenesis of *B. burgdorferi* infection.

Since these initial studies, there have been approximately 300 peer-reviewed publications  on neuropsychiatric manifestations of Lyme disease, excluding papers on dementia  (Bransfield et al., 2019).  Patients experience a wide range of complicated and fluctuating symptoms affecting mood, behavior, cognition, and physiology. A retrospective case review of youth with bipolar disorder from a single New Jersey psychiatric practice found high rates of tick-borne illness, with the author suggesting some evidence of gene-environment interaction associated with tick-borne illness and bipolar disorder. The proportion of bipolar youth seropositive for at least one tick-borne pathogen or Bartonella was 72% (20/27). Some of these patients met criteria for PANS/PANDAS (Greenberg, 2018).

Inevitably, seropositivity to Lyme disease can be coincidental in endemic areas, and there are no systematic studies that correlate serological evidence of infection with these manifestations. When patients have psychiatric diagnoses that predate the onset of other Lyme disease symptoms or have psychiatric symptoms alone, it can be especially difficult to determine the root cause of neuropsychiatric manifestations (Belman et al., 1993). The IDSA 2020 guidelines panel reviewed the literature on children presenting with developmental, behavioral, or psychiatric disorders. The panel suggested against routinely testing for Lyme disease, citing lack of any data to support a causal relationship between tick-borne infections and childhood developmental delay or behavioral disorders such as attention deficit hyperactivity disorder (ADHD), PANDAS, learning disabilities, and psychiatric disorders (low quality evidence) (Lantos et al., 2021). The recommendation against routinely testing for Lyme disease was a weak recommendation, which can be construed as allowing testing to be considered, with anticipation of better quality evidence in the future. The guideline also stated that because of the low pretest probability of Lyme disease in this population, testing children in the absence of more specific signs of Lyme disease will lead to a high proportion of false-positive results.  For adults with psychiatric illness, IDSA  strongly recommends against routine testing for Lyme disease. In contrast, the 2016 American Psychiatric Association guidelines recommend that initial psychiatric evaluation include assessment of past or current infectious disease, including Lyme disease if locally endemic (Silverman et al., 2016).

Research is needed to better understand the possible role of Lyme disease and *Bartonella,* and in addition the role of other postulated infections in the pathogenesis, optimal diagnosis, and treatment of neuropsychiatric syndromes, including those diagnosed with PANS/PANDAS. The evidence base in peer-reviewed PubMed publications for *Borrelia* and *Bartonella* as potential triggers of PANS is currently limited to just one survey study and three case reports (Breitschwerdt et al., 2019; Cross et al., 2021; Kinderlehrer, 2021). In a survey of 698 patients with a clinical diagnosis of PANS, 5% had confirmed or suspected *B. burgdorferi*infection, and 4% self-reported “Lyme confection” (Calaprice et al., 2017). There is some overlap between manifestations of the rheumatologic presentations of Lyme disease and *Bartonella*infections (Maman et al., 2007).

*Bartonella*, even if it is not tick-borne, is a common concomitant infection with *Borrelia*, and can therefore impact treatment decisions. There is a large research gap regarding the role and treatment of *Bartonella*.

An integrative treatment approach is often indicated to address what can be termed “Lyme disease complex.” This “multiple hits model” of illness is seen in patients with persistent symptoms who may have multiple intercurrent infections, toxic exposures, or other predispositions. Symptom relief is an important part of complementary treatment to enhance patient quality of life. For example, non-restorative sleep can impose stress that advances disease progression. Sleep is needed to remove neurotoxic waste products that accumulate in the CNS during waking hours (Xie et al., 2013). Therefore, patients who are taught to practice good sleep hygiene may recover more quickly. There is a big gap in our understanding of the efficacy of such non-pharmaceutical interventions.

Gestational Lyme Disease

Gestational Lyme disease is being discussed by other subcommittees including the Clinical Presentation and Pathogenesis and Diagnostics Subcommittees of this year’s Tick-Borne Disease Working Group, so this is being mentioned only to note that Lyme disease transmission and treatment during pregnancy are research areas of unmet need.

There are  several reports of early neonatal death with spirochetes demonstrated in multiple organs on infant autopsy, sometimes confirmed as *B. burgdorferi* by culture or immunohistochemistry (Lavoie et al, 1987; MacDonald, 1989; MacDonald et al, 1987; Weber et al, 1988 ); however, there remain many unanswered basic questions such as prevalence and incidence of maternal and infant infection, the most effective maternal treatment(s) to prevent transmission and the range of potential health risks and long-term adverse outcomes for infants (Lambert, 2020).

An early study from CDC and university-based researchers found a concerningly high rate of adverse infant outcomes (5/19 or 26%).  The authors note that causality of *B. burgdorferi* in any of the adverse outcomes could not be established; however, there notably was no placenta or infant testing for *B. burgdorferi*at birth in four of the five cases (Markowitz et al., 1986).  Similarly, heterogenous outcomes were reported in later studies, including cardiac and ureter malformations, hypospadias, respiratory distress, cavernous hemangioma, and cerebral bleeding.  Again, a causal role of *B. burgdorferi*could not be established, but infant testing included serology only (no PCR or culture), and placentas were not tested (Lakos & Solymosi, 2010; Maraspin et al., 2020).  Researchers often comment that the wide variety of anomalies seen in such studies argues against a causal link. However, an alternate explanation could be that the true spectrum of congenital Lyme disease has not been defined.

A more recent systematic review showed maternal treatment for gestational Lyme disease was associated with significantly fewer adverse outcomes in treated (11%, CI 7-16%) versus untreated (50%, CI 30-70%), providing “indirect evidence of an association between gestational Lyme and adverse birth outcomes” (Waddell et al., 2018).  Of note, the lower adverse outcome rate of 11% (CI 7% - 16%) is still a sizable rate.

Importantly, there is a very limited evidence base to guide maternal antibiotic treatment for gestational Lyme disease or of evaluation and follow-up for the potentially infected infant.  U.S. consensus recommendations exist to guide management of pregnant women and infants at risk for syphilis, HIV, Zika, and several other congenital infections, but there is no such guidance for Lyme disease.

Potential Actions

*General*

**Potential Action 1.1:** Improve regional surveillance and reporting of tick-borne diseases, including alpha-gal syndrome, and expand physician and public education to ensure that health care providers consider the potential for tick-borne diseases in their patients.

Table 5: Vote on Potential Action 1.1
	Number in Favor
			**Number Opposed**
			Number Abstained
			Number Absent13
			0
			0
			0**Potential Action 1.2:** Understand the full spectrum of clinical manifestations of Lyme disease and other tick-borne diseases, to include microbial, immunologic, allergic (e.g., alpha-gal), and other biological determinants of outcomes of these diseases, including coinfections.

Table 6: Vote on Potential Action 1.2
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent13
			0
			0
			0**Potential Action 1.3:** Support research to better understand the magnitude and outcomes of co-infections and vertical transmission of tick-borne diseases.

Table 7: Vote on Potential Action 1.3
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent13
			0
			0
			0*Minority Responses*

There were no minority responses recorded.

*Treatment*

**Potential Action 2.1:** Improve treatment and management options for alpha-gal syndrome, including methods to desensitize patients to tick salivary factors and the use of alpha-gal deficient livestock for use as sources of food and pharmaceutical products.

Table 9: Vote on Potential Action 2.1
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent13
			0
			0
			0**Potential Action 2.2:** Develop antimicrobial compounds and antibody therapies with therapeutic potential for acute and persistent infections with domestic tick-borne pathogens. Establish a plan for identifying top candidates and carrying development at least through animal models.

Table 10: Vote on Potential Action 2.2
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent13
			0
			0
			0**Potential Action 2.3:** Increase research into the causes of persistent post-treatment symptoms attributed to tick-borne diseases, including Lyme disease, and identify or develop appropriate therapeutic approaches, including non-pharmaceutical interventions, to improve treatment outcomes.

Table 10: Vote on Potential Action 2.3
	Number in Favorh
			Number Opposedh
			Number Abstainedh
			Number Absenth13
			0
			0
			0*Minority Responses*

There were no minority responses recorded

*Prevention*

**Potential Action 3.1:** Increase development of “anti-tick” human vaccines and novel tick-control methods to provide protection against multiple tick-borne diseases.

Table 11: Vote on Potential Action 3.1
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent13
			0
			0
			0**Potential Action 3.2:** Establish correlates of protection and assess putative vaccine antigens for potential use in multivalent, multipathogen vaccines.  Assess cross-protective potential of existing tickborne encephalitis vaccines against Powassan virus.

Table 14: Vote on Potential Action 3.2
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent13
			0
			0
			0**Potential Action 3.3:** Require labeling of foods and food products for ingredients that are of non-primate mammal origin to prevent alpha-gal IgE response in sensitized individuals.

Table 15: Vote on Potential Action 3.3
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent12
			1
			0
			0**Potential Action 3.4:** Specifically target the development of Lyme disease vaccines and immunotherapeutics that move beyond OspA/OspC, and include the use of next-gen platforms (e.g. mRNA).

Table 16: Vote on Potential Action 3.4
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent13
			0
			0
			0**Potential Action 3.5:** Assess the role of new and existing therapeutic compounds in post-exposure prophylaxis for tick-borne diseases and their effects on long-term outcomes.

Table 16: Vote on Potential Action 3.5
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent13
			0
			0
			0**Potential Action 3.6:** Investigate novel methods for blood screening and pathogen inactivation for tick-borne disease pathogens that are transmitted through blood transfusion to improve the safety of the blood supply.

Table 16: Vote on Potential Action 3.5

Table 16: Vote on Potential Action 3.5
	Number in Favor
			Number Opposed
			Number Abstained
			Number Absent13
			0
			0
			0Appendix

References and Citations

Arvikar, S. L., & Steere, A. C. (2015). Diagnosis and treatment of Lyme arthritis. *Infect Dis Clin North Am*,*29*(2), 269-280. https://doi.org/10.1016/j.idc.2015.02.004

Aucott, J. N., Yang, T., Yoon, I., Powell, D., Geller, S. A., & Rebman, A. W. (2022). Risk of post-treatment Lyme disease in patients with ideally-treated early Lyme disease: A prospective cohort study. *Int J Infect Dis*,*116*, 230-237. https://doi.org/10.1016/j.ijid.2022.01.033

Avellan, S., & Bremell, D. (2021). Adjunctive Corticosteroids for Lyme Neuroborreliosis Peripheral Facial Palsy-A Prospective Study With Historical Controls. *Clin Infect Dis*,*73*(7), 1211-1215. https://doi.org/10.1093/cid/ciab370

Belman, A. L., Iyer, M., Coyle, P. K., & Dattwyler, R. (1993). Neurologic manifestations in children with North American Lyme disease. *Neurology*,*43*(12), 2609-2614. https://doi.org/10.1212/wnl.43.12.2609

Berende, A., Ter Hofstede, H. J. M., Vos, F. J., Vogelaar, M. L., van Middendorp, H., Evers, A. W. M., Kessels, R. P. C., & Kullberg, B. J. (2019). Effect of prolonged antibiotic treatment on cognition in patients with Lyme borreliosis. *Neurology*,*92*(13), e1447-e1455. https://doi.org/10.1212/wnl.0000000000007186

Bhanot, P., & Parveen, N. (2019). Investigating disease severity in an animal model of concurrent babesiosis and Lyme disease. *Int J Parasitol*,*49*(2), 145-151. https://doi.org/10.1016/j.ijpara.2018.06.006

Binder, A. M., Commins, S. P., Altrich, M. L., Wachs, T., Biggerstaff, B. J., Beard, C. B., Petersen, L. R., Kersh, G. J., & Armstrong, P. A. (2021). Diagnostic testing for galactose-alpha-1,3-galactose, United States, 2010 to 2018. *Annals of Allergy, Asthma & Immunology*,*126*(4), 411-416.e411. https://doi.org/https://doi.org/10.1016/j.anai.2020.12.019

Bransfield, R. C., Cook, M. J., & Bransfield, D. R. (2019). Proposed Lyme Disease Guidelines and Psychiatric Illnesses. *Healthcare (Basel, Switzerland)*,*7*(3), 105. https://doi.org/10.3390/healthcare7030105

Breitschwerdt, E. B., Greenberg, R., Maggi, R. G., Mozayeni, B. R., Lewis, A., & Bradley, J. M. (2019). Bartonella henselae Bloodstream Infection in a Boy With Pediatric Acute-Onset Neuropsychiatric Syndrome. *J Cent Nerv Syst Dis*,*11*, 1179573519832014. https://doi.org/10.1177/1179573519832014

Calaprice, D., Tona, J., Parker-Athill, E. C., & Murphy, T. K. (2017). A Survey of Pediatric Acute-Onset Neuropsychiatric Syndrome Characteristics and Course. *J Child Adolesc Psychopharmacol*,*27*(7), 607-618. https://doi.org/10.1089/cap.2016.0105

Camire, A. C., Hatke, A. L., King, V. L., Millership, J., Ritter, D. M., Sobell, N., Weber, A., & Marconi, R. T. (2021). Comparative analysis of antibody responses to outer surface protein (Osp)A and OspC in dogs vaccinated with Lyme disease vaccines. *Vet J*,*273*, 105676. https://doi.org/10.1016/j.tvjl.2021.105676

CDC. (2017). *Lyme Disease (Borrelia burgdorferi) 2017 Case Definition*. https://ndc.services.cdc.gov/case-definitions/lyme-disease-2017/#:~:text=An%20exposure%20in%20a%20high,the%20previous%20three%20reporting%20years

Chinuki, Y., Ishiwata, K., Yamaji, K., Takahashi, H., & Morita, E. (2016). Haemaphysalis longicornis tick bites are a possible cause of red meat allergy in Japan. *Allergy*,*71*(3), 421-425. https://doi.org/10.1111/all.12804

Commins, S. P. (2016). Invited Commentary: Alpha-Gal Allergy: Tip of the Iceberg to a Pivotal Immune Response. *Curr Allergy Asthma Rep*,*16*(9), 61. https://doi.org/10.1007/s11882-016-0641-6

Commins, S. P., James, H. R., Kelly, L. A., Pochan, S. L., Workman, L. J., Perzanowski, M. S., Kocan, K. M., Fahy, J. V., Nganga, L. W., Ronmark, E., Cooper, P. J., & Platts-Mills, T. A. (2011). The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose. *J Allergy Clin Immunol*,*127*(5), 1286-1293.e1286. https://doi.org/10.1016/j.jaci.2011.02.019

Commins, S. P., James, H. R., Stevens, W., Pochan, S. L., Land, M. H., King, C., Mozzicato, S., & Platts-Mills, T. A. (2014). Delayed clinical and ex vivo response to mammalian meat in patients with IgE to galactose-alpha-1,3-galactose. *J Allergy Clin Immunol*,*134*(1), 108-115. https://doi.org/10.1016/j.jaci.2014.01.024

Comstedt, P., Schüler, W., Meinke, A., & Lundberg, U. (2017). The novel Lyme borreliosis vaccine VLA15 shows broad protection against Borrelia species expressing six different OspA serotypes. *PLOS ONE*,*12*(9), e0184357. https://doi.org/10.1371/journal.pone.0184357

Cross, A., Bouboulis, D., Shimasaki, C., & Jones, C. R. (2021). Case Report: PANDAS and Persistent Lyme Disease With Neuropsychiatric Symptoms: Treatment, Resolution, and Recovery. *Frontiers in psychiatry*,*12*, 505941-505941. https://doi.org/10.3389/fpsyt.2021.505941

DeLong, A., Hsu, M., & Kotsoris, H. (2019). Estimation of cumulative number of post-treatment Lyme disease cases in the US, 2016 and 2020. *BMC Public Health*,*19*(1), 352. https://doi.org/10.1186/s12889-019-6681-9

Diuk-Wasser, M. A., Vannier, E., & Krause, P. J. (2016). Coinfection by Ixodes Tick-Borne Pathogens: Ecological, Epidemiological, and Clinical Consequences. *Trends Parasitol*,*32*(1), 30-42. https://doi.org/10.1016/j.pt.2015.09.008

Ebel, G. D. (2010). Update on Powassan virus: emergence of a North American tick-borne flavivirus. *Annu Rev Entomol*,*55*, 95-110. https://doi.org/10.1146/annurev-ento-112408-085446

Ehrlichiosis and Anaplasmosis Subcommittee. (2020). Report to the Tick-Borne Disease Working Group. https://www.hhs.gov/ash/advisory-committees/tickbornedisease/reports/ehrlichiosis-and-anaplasmosis-subcommittee-report-2020/index.html

Flaherty, M. G., Kaplan, S. J., & Jerath, M. R. (2017). Diagnosis of Life-Threatening Alpha-Gal Food Allergy Appears to Be Patient Driven. *Journal of Primary Care & Community Health*,*8*(4), 345-348. https://doi.org/10.1177/2150131917705714

Forrester, J. D., Kjemtrup, A. M., Fritz, C. L., Marsden-Haug, N., Nichols, J. B., Tengelsen, L. A., Sowadsky, R., DeBess, E., Cieslak, P. R., Weiss, J., Evert, N., Ettestad, P., Smelser, C., Iralu, J., Nett, R. J., Mosher, E., Baker, J. S., Van Houten, C., Thorp, E., . . . Mead, P. (2015). Tickborne relapsing fever - United States, 1990-2011. *MMWR Morb Mortal Wkly Rep*,*64*(3), 58-60.

Greenberg, R. (2018). Aggressiveness, violence, homicidality, homicide, and Lyme disease. *Neuropsychiatric disease and treatment*,*14*, 1253-1254. https://doi.org/10.2147/NDT.S168751

Hansen, K., & Lebech, A. M. (1992). The clinical and epidemiological profile of Lyme neuroborreliosis in Denmark 1985-1990. A prospective study of 187 patients with Borrelia burgdorferi specific intrathecal antibody production. *Brain*,*115 ( Pt 2)*, 399-423. https://doi.org/10.1093/brain/115.2.399

Horowitz, R. I., & Freeman, P. R. (2019). Precision medicine: retrospective chart review and data analysis of 200 patients on dapsone combination therapy for chronic Lyme disease/post-treatment Lyme disease syndrome: part 1. *Int J Gen Med*,*12*, 101-119. https://doi.org/10.2147/ijgm.S193608

Hovius, J. W., van Dam, A. P., & Fikrig, E. (2007). Tick-host-pathogen interactions in Lyme borreliosis. *Trends Parasitol*,*23*(9), 434-438. https://doi.org/10.1016/j.pt.2007.07.001

Jobe, D. A., Lovrich, S. D., Oldenburg, D. G., Kowalski, T. J., & Callister, S. M. (2016). Borrelia miyamotoi Infection in Patients from Upper Midwestern United States, 2014-2015. *Emerg Infect Dis*,*22*(8), 1471-1473. https://doi.org/10.3201/eid2208.151878

Johnston, D., Kelly, J. R., Ledizet, M., Lavoie, N., Smith, R. P. J., Parsonnet, J., Schwab, J., Lee, G., Espich, S., Maciejewski, K. R., Deng, Y., Majam, V., Zheng, H., Sougrnooma, B., Kumar, S., & Krause, P. J. (2022). Geographic Dispersion of *Borrelia miyamotoi, Borrelia burgdorferi* and *Babesia microti*in New England. *Clinical Infectious Diseases*.

Khoo, T., Spallone, A., Lier, A., Abul, Y., Wellins, A.-M., Weinbaum, F., Luft, B., & Marcos, L. A. (2017, 10/6/2017). *Lyme Disease in Hispanics in Long Island, New York: A New Health Disparity in the U.S.* Infectious Diseases Society of America (IDSA): ID Week 2017, San Diego, CA.

Kinderlehrer, D. A. (2021). Anorexia Nervosa Caused by Polymicrobial Tick-Borne Infections: A Case Study. *Int Med Case Rep J*,*14*, 279-287. https://doi.org/10.2147/imcrj.S311516

Kortela, E., Kanerva, M. J., Puustinen, J., Hurme, S., Airas, L., Lauhio, A., Hohenthal, U., Jalava-Karvinen, P., Nieminen, T., Finnilä, T., Häggblom, T., Pietikäinen, A., Koivisto, M., Vilhonen, J., Marttila-Vaara, M., Hytönen, J., & Oksi, J. (2021). Oral Doxycycline Compared to Intravenous Ceftriaxone in the Treatment of Lyme Neuroborreliosis: A Multicenter, Equivalence, Randomized, Open-label Trial. *Clinical Infectious Diseases*,*72*(8), 1323-1331. https://doi.org/10.1093/cid/ciaa217

Kosoy, O. I., Lambert, A. J., Hawkinson, D. J., Pastula, D. M., Goldsmith, C. S., Hunt, D. C., & Staples, J. E. (2015). Novel thogotovirus associated with febrile illness and death, United States, 2014. *Emerg Infect Dis*,*21*(5), 760-764. https://doi.org/10.3201/eid2105.150150

Krause, P. J. (2019). Human babesiosis. *International Journal for Parasitology*,*49*(2), 165-174. https://doi.org/https://doi.org/10.1016/j.ijpara.2018.11.007

Krause, P. J., Auwaerter, P. G., Bannuru, R. R., Branda, J. A., Falck-Ytter, Y. T., Lantos, P. M., Lavergne, V., Meissner, H. C., Osani, M. C., Rips, J. G., Sood, S. K., Vannier, E., Vaysbrot, E. E., & Wormser, G. P. (2021). Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA): 2020 Guideline on Diagnosis and Management of Babesiosis. *Clin Infect Dis*,*72*(2), e49-e64. https://doi.org/10.1093/cid/ciaa1216

Krause, P. J., Gewurz, B. E., Hill, D., Marty, F. M., Vannier, E., Foppa, I. M., Furman, R. R., Neuhaus, E., Skowron, G., Gupta, S., McCalla, C., Pesanti, E. L., Young, M., Heiman, D., Hsue, G., Gelfand, J. A., Wormser, G. P., Dickason, J., Bia, F. J., . . . Spielman, A. (2008). Persistent and Relapsing Babesiosis in Immunocompromised Patients. *Clinical Infectious Diseases*,*46*(3), 370-376. https://doi.org/10.1086/525852

Krause, P. J., Hendrickson, J. E., Steeves, T. K., & Fish, D. (2015). Blood transfusion transmission of the tick-borne relapsing fever spirochete Borrelia miyamotoi in mice. *Transfusion*,*55*(3), 593-597. https://doi.org/https://doi.org/10.1111/trf.12879

Krause, P. J., Lepore, T., Sikand, V. K., Gadbaw, J., Burke, G., Telford, S. R., Brassard, P., Pearl, D., Azlanzadeh, J., Christianson, D., McGrath, D., & Spielman, A. (2000). Atovaquone and Azithromycin for the Treatment of Babesiosis. *New England Journal of Medicine*,*343*(20), 1454-1458. https://doi.org/10.1056/NEJM200011163432004

Krause, P. J., Narasimhan, S., Wormser, G. P., Barbour, A. G., Platonov, A. E., Brancato, J., Lepore, T., Dardick, K., Mamula, M., Rollend, L., Steeves, T. K., Diuk-Wasser, M., Usmani-Brown, S., Williamson, P., Sarksyan, D. S., Fikrig, E., & Fish, D. (2014). Borrelia miyamotoisensu lato Seroreactivity and Seroprevalence in the Northeastern United States. *Emerging Infectious Diseases*,*20*(7), 1183-1190. https://doi.org/10.3201/eid2007.131587

Kubiak, K., Szczotko, M., & Dmitryjuk, M. (2021). Borrelia miyamotoi-An Emerging Human Tick-Borne Pathogen in Europe. *Microorganisms*,*9*(1). https://doi.org/10.3390/microorganisms9010154

Kumar, A., O'Bryan, J., & Krause, P. J. (2021). The Global Emergence of Human Babesiosis. *Pathogens (Basel, Switzerland)*,*10*(11), 1447. https://doi.org/10.3390/pathogens10111447

Lakos, A., & Solymosi, N. (2010). Maternal Lyme borreliosis and pregnancy outcome. *Int J Infect Dis*,*14*(6), e494-498. https://doi.org/10.1016/j.ijid.2009.07.019

Lambert, J. S. (2020). An Overview of Tickborne Infections in Pregnancy and Outcomes in the Newborn: The Need for Prospective Studies. *Frontiers in medicine*,*7*, 72-72. https://doi.org/10.3389/fmed.2020.00072

Lantos, P. M., Rumbaugh, J., Bockenstedt, L. K., Falck-Ytter, Y. T., Aguero-Rosenfeld, M. E., Auwaerter, P. G., Baldwin, K., Bannuru, R. R., Belani, K. K., Bowie, W. R., Branda, J. A., Clifford, D. B., DiMario, F. J., Halperin, J. J., Krause, P. J., Lavergne, V., Liang, M. H., Meissner, H. C., Nigrovic, L. E., . . . Zemel, L. S. (2021). Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease. *Clin Infect Dis*,*72*(1), 1-8. https://doi.org/10.1093/cid/ciab049

Lavole, P. E., Lattner, B. P., Duray, P. H., Malawista, S. E., Barbour, A. G., & Johnson, R. C. (1987). Culture positive seronegative transplacental Lyme borreliosis infant mortality. *Arthritis and Rheumatism*,*30*(4 Suppl.), S50-S50. https://eurekamag.com/research/028/030/028030915.php

Leimer, N., Wu, X., Imai, Y., Morrissette, M., Pitt, N., Favre-Godal, Q., Iinishi, A., Jain, S., Caboni, M., Leus, I. V., Bonifay, V., Niles, S., Bargabos, R., Ghiglieri, M., Corsetti, R., Krumpoch, M., Fox, G., Son, S., Klepacki, D., . . . Lewis, K. (2021). A selective antibiotic for Lyme disease. *Cell*,*184*(21), 5405-5418.e5416. https://doi.org/10.1016/j.cell.2021.09.011

Levin, M., Apostolovic, D., Biedermann, T., Commins, S. P., Iweala, O. I., Platts-Mills, T. A. E., Savi, E., van Hage, M., & Wilson, J. M. (2019). Galactose α-1,3-galactose phenotypes: Lessons from various patient populations. *Ann Allergy Asthma Immunol*,*122*(6), 598-602. https://doi.org/10.1016/j.anai.2019.03.021

Maccallini, P., Bonin, S., & Trevisan, G. (2018). Autoimmunity against a glycolytic enzyme as a possible cause for persistent symptoms in Lyme disease. *Med Hypotheses*,*110*, 1-8. https://doi.org/10.1016/j.mehy.2017.10.024

MacDonald, A. B. (1986). Human fetal borreliosis, toxemia of pregnancy, and fetal death. *Zentralbl Bakteriol Mikrobiol Hyg A*,*263*(1-2), 189-200. https://doi.org/10.1016/s0176-6724(86)80122-5

MacDonald, A. B. (1989). Gestational Lyme borreliosis. Implications for the fetus. *Rheum Dis Clin North Am*,*15*(4), 657-677.

MacDonald, A. B., Benach, J. L., & Burgdorfer, W. (1987). Stillbirth following maternal Lyme disease. *N Y State J Med*,*87*(11), 615-616.

Maggi, R. G., Ericson, M., Mascarelli, P. E., Bradley, J. M., & Breitschwerdt, E. B. (2013). Bartonella henselae bacteremia in a mother and son potentially associated with tick exposure. *Parasites & Vectors*,*6*(1), 101. https://doi.org/10.1186/1756-3305-6-101

Maluki, A., Breitschwerdt, E., Bemis, L., Greenberg, R., Mozayeni, B. R., Dencklau, J., & Ericson, M. (2020). Imaging analysis of Bartonella species in the skin using single-photon and multi-photon (second harmonic generation) laser scanning microscopy. *Clin Case Rep*,*8*(8), 1564-1570. https://doi.org/10.1002/ccr3.2939

Maman, E., Bickels, J., Ephros, M., Paran, D., Comaneshter, D., Metzkor-Cotter, E., Avidor, B., Varon-Graidy, M., Wientroub, S., & Giladi, M. (2007). Musculoskeletal manifestations of cat scratch disease. *Clinical infectious diseases : an official publication of the Infectious Diseases Society of America*, *45*(12).

Maraspin, V., Cimperman, J., Lotric-Furlan, S., Pleterski-Rigler, D., & Strle, F. (1999). Erythema migrans in pregnancy. *Wien Klin Wochenschr*,*111*(22-23), 933-940.

Maraspin, V., Lusa, L., Blejec, T., Ružić-Sabljić, E., Pohar Perme, M., & Strle, F. (2020). Course and Outcome of Erythema Migrans in Pregnant Women. *Journal of clinical medicine*,*9*(8), 2364. https://doi.org/10.3390/jcm9082364

Marcos, L. A., & Yan, Z. (2017). Progression of Lyme disease to Bell's Palsy despite treatment with doxycycline. *Int J Infect Dis*,*62*, 81-83. https://doi.org/10.1016/j.ijid.2017.07.004

Markowitz, L. E., Steere, A. C., Benach, J. L., Slade, J. D., & Broome, C. V. (1986). Lyme Disease During Pregnancy. *JAMA*,*255*(24), 3394-3396. https://doi.org/10.1001/jama.1986.03370240064038

MassBiologics. (April 2021 - ). *First Clinical Study of the Safety and Blood Levels of a Human Monoclonal Antibody (2217LS) Against Lyme Disease Bacteria in Healthy People*. https://clinicaltrials.gov/ct2/show/results/NCT04863287

Matias, J., Kurokawa, C., Sajid, A., Narasimhan, S., Arora, G., Diktas, H., Lynn, G. E., DePonte, K., Pardi, N., Valenzuela, J. G., Weissman, D., & Fikrig, E. (2021). Tick immunity using mRNA, DNA and protein-based Salp14 delivery strategies. *Vaccine*,*39*(52), 7661-7668. https://doi.org/10.1016/j.vaccine.2021.11.003

Mendoza, C. A., Yamaoka, S., Tsuda, Y., Matsuno, K., Weisend, C. M., & Ebihara, H. (2021). The NF-κB inhibitor, SC75741, is a novel antiviral against emerging tick-borne bandaviruses. *Antiviral Res*,*185*, 104993. https://doi.org/10.1016/j.antiviral.2020.104993

Nofchissey, R. A., Deardorff, E. R., Blevins, T. M., Anishchenko, M., Bosco-Lauth, A., Berl, E., Lubelczyk, C., Mutebi, J. P., Brault, A. C., Ebel, G. D., & Magnarelli, L. A. (2013). Seroprevalence of Powassan virus in New England deer, 1979-2010. *Am J Trop Med Hyg*,*88*(6), 1159-1162. https://doi.org/10.4269/ajtmh.12-0586

O'Bier, N. S., Hatke, A. L., Camire, A. C., & Marconi, R. T. (2021). Human and Veterinary Vaccines for Lyme Disease. *Curr Issues Mol Biol*,*42*, 191-222. https://doi.org/10.21775/cimb.042.191

Osler, W. (1894). *On chorea and choreiform affections*. Blakiston Company.

Pachner, A. R. (1986). Spirochetal diseases of the CNS. *Neurol Clin*,*4*(1), 207-222.

Pachner, A. R. (1988). Borrelia burgdorferi in the nervous system: the new "great imitator". *Ann N Y Acad Sci*,*539*, 56-64. https://doi.org/10.1111/j.1749-6632.1988.tb31838.x

Pachner AR, Duray P, Steere AC Central nervous system manifestations of Lyme disease Arch Neurol 1989 Jul;46(7):790-5. doi: 10.1001/archneur.1989.00520430086023.

Pachner, A. R., & Steere, A. C. (1987). CNS manifestations of third stage Lyme disease. *Zentralbl Bakteriol Mikrobiol Hyg A*,*263*(3), 301-306. https://doi.org/10.1016/s0176-6724(87)80081-0

Pattanaik, D., Lieberman, P., Lieberman, J., Pongdee, T., & Keene, A. T. (2018). The changing face of anaphylaxis in adults and adolescents. *Ann Allergy Asthma Immunol*,*121*(5), 594-597. https://doi.org/10.1016/j.anai.2018.07.017

Pöyhönen, H., Nurmi, M., Peltola, V., Alaluusua, S., Ruuskanen, O., & Lähdesmäki, T. (2017). Dental staining after doxycycline use in children. *The Journal of antimicrobial chemotherapy*,*72*(10), 2887-2890. https://doi.org/10.1093/jac/dkx245

Rego, R. O. M., Trentelman, J. J. A., Anguita, J., Nijhof, A. M., Sprong, H., Klempa, B., Hajdusek, O., Tomás-Cortázar, J., Azagi, T., Strnad, M., Knorr, S., Sima, R., Jalovecka, M., Fumačová Havlíková, S., Ličková, M., Sláviková, M., Kopacek, P., Grubhoffer, L., & Hovius, J. W. (2019). Counterattacking the tick bite: towards a rational design of anti-tick vaccines targeting pathogen transmission. *Parasites & Vectors*,*12*(1), 229. https://doi.org/10.1186/s13071-019-3468-x

Rickettsiosis Subcommittee. (2020). Report to the Tick-Borne Disease Working Group. https://www.hhs.gov/ash/advisory-committees/tickbornedisease/reports/rickettsiosis-subcomm-2020/index.html

Sajid, A., Matias, J., Arora, G., Kurokawa, C., DePonte, K., Tang, X., Lynn, G., Wu, M.-J., Pal, U., Strank Norma, O., Pardi, N., Narasimhan, S., Weissman, D., & Fikrig, E. (2021). mRNA vaccination induces tick resistance and prevents transmission of the Lyme disease agent. *Science Translational Medicine*,*13*(620), eabj9827. https://doi.org/10.1126/scitranslmed.abj9827

Savage, H. M., Godsey, M. S., Jr., Panella, N. A., Burkhalter, K. L., Manford, J., Trevino-Garrison, I. C., Straily, A., Wilson, S., Bowen, J., & Raghavan, R. K. (2018). Surveillance for Tick-Borne Viruses Near the Location of a Fatal Human Case of Bourbon Virus (Family Orthomyxoviridae: Genus Thogotovirus) in Eastern Kansas, 2015. *J Med Entomol*,*55*(3), 701-705. https://doi.org/10.1093/jme/tjx251

Schiller, Z. A., Rudolph, M. J., Toomey, J. R., Ejemel, M., LaRochelle, A., Davis, S. A., Lambert, H. S., Kern, A., Tardo, A. C., Souders, C. A., Peterson, E., Cannon, R. D., Ganesa, C., Fazio, F., Mantis, N. J., Cavacini, L. A., Sullivan-Bolyai, J., Hu, L. T., Embers, M. E., . . . Wang, Y. (2021). Blocking Borrelia burgdorferi transmission from infected ticks to nonhuman primates with a human monoclonal antibody. *The Journal of Clinical Investigation*,*131*(11). https://doi.org/10.1172/JCI144843

Schlesinger, P. A., Duray, P. H., Burke, B. A., Steere, A. C., & Stillman, M. T. (1985). Maternal-fetal transmission of the Lyme disease spirochete, Borrelia burgdorferi. *Ann Intern Med*,*103*(1), 67-68. https://doi.org/10.7326/0003-4819-103-1-67

Schwartz, A. M., Hinckley, A. F., Mead, P. S., Hook, S. A., & Kugeler, K. J. (2017). Surveillance for lyme disease—United States, 2008–2015. *MMWR Surveillance Summaries*,*66*(22), 1.

Silverman, J. J., Galanter, M., Jackson-Triche, M., Jacobs, D. G., Lomax, J. W., Riba, M. B., Tong, L. D., Watkins, K. E., Fochtmann, L. J., Rhoads, R. S., Yager, J., Vergare, M. J., Nininger, J. E., Craig, T. J., Cowley, D., Ghaemi, N., Kahn, D. A., Oldham, J. M., Pato, C. N., . . . Hunziker, J. W. (2016). *The American Psychiatric Association Practice Guidelines for the Psychiatric Evaluation of Adults*. American Psychiatric Association. https://psychiatryonline.org/doi/pdf/10.1176/appi.books.9780890426760

Smee, D. F., Jung, K. H., Westover, J., & Gowen, B. B. (2018). 2'-Fluoro-2'-deoxycytidine is a broad-spectrum inhibitor of bunyaviruses in vitro and in phleboviral disease mouse models. *Antiviral Res*,*160*, 48-54. https://doi.org/10.1016/j.antiviral.2018.10.013

Stiernstedt, G., Gustafsson, R., Karlsson, M., Svenungsson, B., & Sköldenberg, B. (1988). Clinical manifestations and diagnosis of neuroborreliosis. *Annals of the New York Academy of Sciences*,*539*, 46-55. https://doi.org/10.1111/j.1749-6632.1988.tb31837.x

Stiernstedt, G., Sköldenberg, B., Gårde, A., Kolmodin, G., Jörbeck, H., Svenungsson, B., & Carlström, A. (1987). Clinical manifestations of Borrelia infections of the nervous system. *Zentralbl Bakteriol Mikrobiol Hyg A*,*263*(3), 289-296. https://doi.org/10.1016/s0176-6724(87)80079-2

Stupica, D., Velušček, M., Blagus, R., Bogovič, P., Rojko, T., Cerar, T., & Strle, F. (2018). Oral doxycycline versus intravenous ceftriaxone for treatment of multiple erythema migrans: an open-label alternate-treatment observational trial. *Journal of Antimicrobial Chemotherapy*,*73*(5), 1352-1358. https://doi.org/10.1093/jac/dkx534

Tick-Borne Disease Working Group. (2018). Report to Congress. https://www.hhs.gov/sites/default/files/tbdwg-report-to-congress-2018.pdf

Tick-Borne Disease Working Group. (2020). Report to Congress. https://www.hhs.gov/sites/default/files/tbdwg-2020-report_to-ongress-final.pdf

Torbahn, G., Hofmann, H., Rücker, G., Bischoff, K., Freitag, M. H., Dersch, R., Fingerle, V., Motschall, E., Meerpohl, J. J., & Schmucker, C. (2018). Efficacy and Safety of Antibiotic Therapy in Early Cutaneous Lyme Borreliosis: A Network Meta-analysis. *JAMA Dermatol*,*154*(11), 1292-1303. https://doi.org/10.1001/jamadermatol.2018.3186

Touradji, P., Aucott, J. N., Yang, T., Rebman, A. W., & Bechtold, K. T. (2019). Cognitive Decline in Post-treatment Lyme Disease Syndrome. *Archives of Clinical Neuropsychology*,*34*(4), 455-465. https://doi.org/10.1093/arclin/acy051

Trautmann, A., Gascan, H., & Ghozzi, R. (2020). Potential Patient-Reported Toxicities With Disulfiram Treatment in Late Disseminated Lyme Disease. *Front Med (Lausanne)*,*7*, 133. https://doi.org/10.3389/fmed.2020.00133

Trentelman, J. J. A., Tomás-Cortázar, J., Knorr, S., Barriales, D., Hajdusek, O., Sima, R., Ersoz, J. I., Narasimhan, S., Fikrig, E., Nijhof, A. M., Anguita, J., & Hovius, J. W. (2021). Probing an Ixodes ricinus salivary gland yeast surface display with tick-exposed human sera to identify novel candidates for an anti-tick vaccine. *Scientific Reports*,*11*(1), 15745. https://doi.org/10.1038/s41598-021-92538-9

Turk, S. P., Lumbard, K., Liepshutz, K., Williams, C., Hu, L., Dardick, K., Wormser, G. P., Norville, J., Scavarda, C., McKenna, D., Follmann, D., & Marques, A. (2019). Post-treatment Lyme disease symptoms score: Developing a new tool for research. *PLOS ONE*,*14*(11), e0225012. https://doi.org/10.1371/journal.pone.0225012

Valneva, G. A. (December 2018 - ). *Immunogenicity and Safety Study of a Vaccine Against Lyme Borreliosis, in Healthy Adults Aged 18 to 65 Years. Randomized, Controlled, Observer-blind Phase 2 Study.* https://clinicaltrials.gov/ct2/show/results/NCT03769194?view=results

Van Nunen, S. A., O'Connor, K. S., Clarke, L. R., Boyle, R. X., & Fernando, S. L. (2009). An association between tick bite reactions and red meat allergy in humans. *Med J Aust*,*190*(9), 510-511. https://doi.org/10.5694/j.1326-5377.2009.tb02533.x

Vannier, E., & Krause, P. J. (2009). Update on babesiosis. *Interdisciplinary perspectives on infectious diseases*,*2009*, 984568-984568. https://doi.org/10.1155/2009/984568

Vannier, E., & Krause, P. J. (2012). Human babesiosis. *N Engl J Med*,*366*(25), 2397-2407. https://doi.org/10.1056/NEJMra1202018

Verma, N., Puri, A., Essuman, E., Skelton, R., Anantharaman, V., Zheng, H., White, S., Gunalan, K., Takeda, K., Bajpai, S., Lepore, T. J., Krause, P. J., Aravind, L., & Kumar, S. (2020). Antigen Discovery, Bioinformatics and Biological Characterization of Novel Immunodominant Babesia microti Antigens. *Scientific Reports*,*10*(1). https://doi.org/10.1038/s41598-020-66273-6

Waddell, L. A., Greig, J., Lindsay, L. R., Hinckley, A. F., & Ogden, N. H. (2018). A systematic review on the impact of gestational Lyme disease in humans on the fetus and newborn. *PLOS ONE*,*13*(11), e0207067-e0207067. https://doi.org/10.1371/journal.pone.0207067

Wang, Y., Kern, A., Boatright, N. K., Schiller, Z. A., Sadowski, A., Ejemel, M., Souders, C. A., Reimann, K. A., Hu, L., Thomas, W. D., Jr., & Klempner, M. S. (2016). Pre-exposure Prophylaxis With OspA-Specific Human Monoclonal Antibodies Protects Mice Against Tick Transmission of Lyme Disease Spirochetes. *The Journal of Infectious Diseases*,*214*(2), 205-211. https://doi.org/10.1093/infdis/jiw151

Weber, K., Bratzke, H. J., Neubert, U., Wilske, B., & Duray, P. H. (1988). Borrelia burgdorferi in a newborn despite oral penicillin for Lyme borreliosis during pregnancy. *Pediatr Infect Dis J*,*7*(4), 286-289. https://doi.org/10.1097/00006454-198804000-00010

Wormser, G. P., McKenna, D., Scavarda, C., Cooper, D., El Khoury, M. Y., Nowakowski, J., Sudhindra, P., Ladenheim, A., Wang, G., Karmen, C. L., Demarest, V., Dupuis, A. P., 2nd, & Wong, S. J. (2019). Co-infections in Persons with Early Lyme Disease, New York, USA. *Emerg Infect Dis*,*25*(4), 748-752. https://doi.org/10.3201/eid2504.181509

Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Sleep drives metabolite clearance from the adult brain. Science. 2013 Oct 18;342(6156):373-7. doi: 10.1126/science.1241224.PMID: 24136970

Zhang, W., Lin, M., Yan, Q., Budachetri, K., Hou, L., Sahni, A., Liu, H., Han, N.-C., Lakritz, J., Pei, D., & Rikihisa, Y. (2021). An intracellular nanobody targeting T4SS effector inhibits <em>Ehrlichia</em> infection. *Proceedings of the National Academy of Sciences*,*118*(18), e2024102118. https://doi.org/10.1073/pnas.2024102118

                    
  


Content created by Office of Infectious Disease and HIV/AIDS Policy (OIDP) Content last reviewed July 13, 2022Back to top
    Contact HHS
    
                        
                                            
      
      
      Careers
    
                        
                                            
      
      
      HHS FAQs
    
                        
                                            
      
      
      Nondiscrimination NoticeHHS Archive
    
                        
                                            
      
      
      Accessibility Statement
    
                        
                                            
      
      
      Privacy Policy
    
                        
                                            
      
      
      Viewers & PlayersBudget/Performance
    
                        
                                            
      
      
      Inspector General
    
                        
                                            
      
      
      Web Site Disclaimers
    
                        
                                            
      
      
      EEO/No Fear ActFOIA
    
                        
                                            
      
      
      The White House
    
                        
                                            
      
      
      USA.gov
    
                        
                                            
      
      
      Vulnerability Disclosure Policy
        Sign Up for Email Updates

Receive the latest updates from the Secretary, Blogs, and News Releases.

Sign Up
  HHS Headquarters
          200 Independence Avenue, S.W.
                  Washington, D.C. 20201
                  Toll Free Call Center: 1-877-696-6775​Disclaimer Policy: Links with this icon () mean that you are leaving the HHS website.
              The Department of Health and Human Services (HHS) cannot guarantee the accuracy of a non-federal website.
                  Linking to a non-federal website does not mean that HHS or its employees endorse the sponsors, information, or products presented on the website. HHS links outside of itself to provide you with further information.
                  You will be bound by the destination website's privacy policy and/or terms of service when you follow the link.
                  HHS is not responsible for Section 508 compliance (accessibility) on private websites.For more information on HHS's web notification policies, see Website Disclaimers.
              Continue
                  Go back