TBDWG May 10, 2018 - Meeting Summary

Welcome, Background, Announcements
Recap of Public Meeting 3 and Overview of Recent Activities
Meeting Purpose and Goals
Subcommittee Presentations
   Disease Vectors, Surveillance, and Prevention
   Pathogenesis, Transmission, and Treatment
   Testing and Diagnostics
   Access to Care Services and Support to Patients
   Vaccine and Therapeutics
   Other Tick-Borne Diseases and Co-Infections
Public Comment
Closing and Next Steps
Appendix: TBDWG Members and HHS Staff

Note: For context and clarity, speaker credentials will be included upon first mention in each meeting’s summary. Subsequently, individuals will be referenced by their first names to equalize expertise across the many diverse disciplines represented in this document. All perspectives and expertise, including patient-lived experience, is valued equally. Speaking on a first-name basis helps the Tick-Borne Disease Working Group ensure that all voices are heard and valued based on merit and without the bias of titles, eminence, or prestige.

Welcome

John Aucott, Tick-Borne Disease Working Group Chair, Associate Professor for the Division of Rheumatology at Johns Hopkins University School of Medicine, and Director of the Johns Hopkins Lyme Disease Clinical Research Center, welcomed participants to the meeting. He thanked the 14 working group members, 53 working group subcommittee members, expert speakers, HHS staff, contractors, and other contributors who have supported the Tick-Borne Disease Working Group.

Announcements

Richard Wolitski, Director of the Office of HIV/AIDS and Infectious Disease Policy, Office of the Assistant Secretary for Health, announced that, on May 9, he turned over the role of Designated Federal Officer (DFO) for the Tick-Borne Disease Working Group to James Berger, Director of the Office of HIV/AIDS and Infectious Disease Policy, Office of the Assistant Secretary for Health. James has been the alternate DFO since the project began. Kaye Hayes, Acting Deputy Director of the Office of HIV/AIDS and Infectious Disease Policy, is the new alternate DFO. John then conducted roll call. The meeting started with a quorum (see Appendix for attendance).

Background

Kristen Honey, Tick-Borne Disease Working Group Vice Chair; Senior Policy Analyst for the Office of Management and Budget, Executive Office of the President; Senior Research Scholar for Stanford University; and member of the Stanford University Lyme Disease Working Group, described what the Tick-Borne Disease Working Group intends to accomplish and reviewed the vision and core values that the group adopted during Public Meeting 3.

The Tick-Borne Disease Working Group is making history. The TBDWG report to Congress will be the first report to Congress under the 21st Century Cures Act on tick-borne illness. The report brings together many perspectives about tick-borne disease, including patient and patient advocate perspectives. The Tick-Borne Disease Working Group is creating new tools, like the Inventory of Federal Actions, which will assess federal efforts to address tick-borne diseases. Additionally, the Tick-Borne Disease Working Group is working to shift the focus from problems and blame to solutions, collaboration, and development of better care and outcomes for patients.

During Public Meeting 3, the Tick-Borne Disease Working Group adopted the following shared vision:

A nation free of tick-borne diseases where new infections are prevented and
infected patients have access to affordable care that restores health.

The Tick-Borne Disease Working Group also identified the following core values:

• Respect: everyone is valued
• Innovation: shifting the paradigm, finding a better way
• Honesty and Integrity: find the truth, tell the truth
• Excellence: quality, real-world evidence underlies decision-making
• Compassion: finding solutions to relieve suffering
• Collaboration: work with citizens and patients as partners
• Accountability: the buck stops here

Recap of Public Meeting 3 and Overview of Recent Activities

John reviewed Public Meeting 3 and the Tick-Borne Disease Working Group’s accomplishments since then.

One working group member and three subcommittee members have changed since the previous meeting. All four new members are patients or former patients. John introduced the new working group member, Robert Sabatino, Founder and Executive Director of Lyme Society, Inc.

As part of Public Meeting 3, the six subcommittees met concurrently in separate virtual break-out groups. During the subcommittee meetings, the subcommittee members introduced themselves to one another. Following introductions, the subcommittees reviewed the draft inventory requests that were later sent to the U.S. Departments of Health and Human Services (HHS), Defense (DoD), and Veterans Affairs (VA). They also began to identify the priorities they would focus on in their reports to the Tick-Borne Disease Working Group.

John described the composition of the six subcommittees. Each subcommittee has two co-chairs, and at least one co-chair is a working group member. Across the subcommittees, there are 53 subcommittee members. The Tick-Borne Disease Working Group, together with the subcommittee membership, totals 67 people and represents diverse perspectives. One in four working group and subcommittee members is a patient or family member of people who have experienced tick-borne disease. Each subcommittee includes at least one patient.

John listed the co-chairs for each of the six subcommittees, as shown in the following Table.

Subcommittee	Co-Chairs
Disease Vectors, Surveillance, and Prevention	Ben Beard, MS, PhD, Deputy Director, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention (CDC) Pat Smith, President, Lyme Disease Association
Pathogenesis, Transmission, and Treatment	Wendy Adams, MBA, Research Grant Director, Bay Area Lyme Foundation Captain Estella Jones, DVM, Acting Deputy Director for the Office of Counter Terrorism and Emerging Threats, FDA
Testing and Diagnostics	Lise Nigrovic, MD, MPH, Co-Director of Population Science Center, Institutional Centers for Clinical and Translational Research; Senior Associate Physician in Medicine, Boston Children's Hospital David Roth, JD, Retired senior managing director of a private equity firm (Blackstone)
Access to Care Services and Support to Patients	Paula Jackson Jones, President & Co-Founder, Midcoast Lyme Disease Support & Education Commander Scott “Coop” Cooper, MMSc, PA-C, Lead Officer and Senior Technical Advisor for Medicare Hospital Health and Safety Regulations, Centers for Medicare and Medicaid Services
Vaccine and Therapeutics	Dennis Dixon, PhD, Chief, Bacteriology and Mycology Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health and Human Services Robert Smith, MD, MPH, Director, Vector-Borne Disease Laboratory, Maine Medical Center Research Institute; Director, Division of Infectious Diseases, Department of Medicine, Maine Medical Center; Professor of Medicine, Tufts University School of Medicine
Other Tick-Borne Diseases and Co-Infections	Richard Horowitz, MD, Medical Director, Hudson Valley Healing Arts Center Allen Richards, PhD, Director, Rickettsial Diseases Research Program, Naval Medical Research Center, U.S. Department of Defense

• David Roth is now a co-chair for the Testing and Diagnostics Subcommittee.
• Paula Jackson Jones is now a co-chair for the Access to Care Services and Patient Support Subcommittee.
• Sherrill Franklin, Patient Advocate and Small Business Owner, is a new member of the Access to Care Services and Patient Support Subcommittee.

The subcommittee reports to the Tick-Borne Disease Working Group are complete and available online. The subcommittees produced their reports within a strenuous timeframe, meaning there was not sufficient time for publication-level editing of the reports. These reports will inform the Tick-Borne Disease Working Group’s report to Congress. Within their reports, the subcommittees identified current efforts to address tick-borne disease, gaps in efforts and knowledge, and opportunities to expand work. The reports also highlight potential actions for addressing tick-borne disease. Each subcommittee did extensive literature reviews, heard presentations from outside experts, and gathered information from patients to include in the reports. Now that the subcommittee reports are complete, the subcommittees will no longer meet weekly. The Tick-Borne Disease Working Group has asked the subcommittee co-chairs to remain available to answer content questions or provide input. They will provide any such inputto the Tick-Borne Disease Working Group in writing, and the input will be available to the public.

Meeting Purpose and Goals

The focus of Public Meeting 4 was to review the subcommittee reports. The co-chairs of each subcommittee presented their work. The presentations were pre-decisional, meaning the subcommittees were presenting their reports to the Tick-Borne Disease Working Group for consideration.

The Tick-Borne Disease Working Group’s report to Congress will not mirror the content of the subcommittee reports; rather, the subcommittee reports are one of many information sources the Tick-Borne Disease Working Group will use to develop the final report. Other information sources will include:

• other quantitative data from surveillance, research, and program monitoring and evaluation;
• other qualitative data, including case studies, patient or provider accounts, and public comment;
• an inventory of federal activities from HHS, DoD, and VA.

John provided an example of the impact of public comment on the Tick-Borne Disease Working Group’s efforts, and Kristen reviewed the timeline for the Tick-Borne Disease Working Group’s reporting to Congress. The Tick-Borne Disease Working Group will submit the report to Congress and the HHS Secretary in December 2018. It will be the first of three reports throughout the 6-year duration of the Tick-Borne Disease Working Group. Subsequent reports are due every 2 years.

The first report will function as more than a report; it will establish new processes, procedures, and federal infrastructure to yield benefits in the future. The second report will entail a more comprehensive literature review and federal inventory of data. The third report will further improve and update the information.

The Tick-Borne Disease Working Group’s membership will evolve over time. After the publication of the first report, HHS will again seek public nominations for Tick-Borne Disease Working Group members. Some members may remain in the Tick-Borne Disease Working Group, while others may rotate out.

The Tick-Borne Disease Working Group is conducting the first-ever inventory of federal activities related to tick-borne disease. The inventory will examine federal research and development, funding, and the number of employees who work on this issue. The subcommittees helped design the inventory requests, which the Tick-Borne Disease Working Group sent to HHS, DoD, and VA. Their responses are due May 11, 2018. The Tick-Borne Disease Working Group will provide a report on information received through the inventory at the next meeting on May 15 and 16, 2018, and determine how to integrate the responses into the report.

During working group meetings, members of the public can provide comments during a 30- to 60-minute window. Input is limited to 3 minutes per person. Public comments from the previous working group meetings are in the process of being posted on the HHS website. Public comments can also be sent to [email protected]. The Tick-Borne Disease Working Group has received many written comments, which will be made publicly available after personally identifiable information has been removed.

Kristen emphasized the importance of the human dimension of tick-borne disease. Behind every data point is human experience. The Tick-Borne Disease Working Group intends to integrate stories of lived experience with data to present a full picture of the issue. She shared her own experiences as a survivor of Lyme disease. Diverse perspectives, experiences, and knowledge are crucial to realize the Tick-Borne Disease Working Group’s vision.

The Tick-Borne Disease Working Group has not yet finalized its mission statement. Kristen asked for a working group member to volunteer to create draft mission statements that the Tick-Borne Disease Working Group can vote on during the next meeting. Robert Sabatino volunteered.

Subcommittee Presentations

Each of the six subcommittees presented their reports to the Tick-Borne Disease Working Group.

Disease Vectors, Surveillance, and Prevention

Pat Smith and Ben Beard presented an overview of Disease Vectors, Surveillance, and Prevention Subcommittee’s report to the Tick-Borne Disease Working Group.

Background

The Disease Vectors, Surveillance, and Prevention Subcommittee examined the biology and ecology of tick vectors, human disease surveillance, and prevention approaches. Pat described challenges related to each of these three areas.

Challenges related to disease vectors include the following.

• In recent decades, distribution of the tick vectors of human and animal illnesses has increased steadily and significantly.
• Due to the lack of a coordinated national tick vector surveillance program, there are significant gaps in information on local distributions of tick vectors. This information is badly needed for educating the public health community, health care providers, and the general public about local disease risk.
• There is a need to better understand the pathogens and vectors associated with tick-borne diseases, particularly in the southern and western United States.
• Introduction of exotic tick species and pathogens poses additional risk.

Challenges related to surveillance include the following.

• Lyme disease is underreported, which is further complicated by a case definition that requires laboratory and supportive clinical data for confirmation of later-stage cases.
• Underreporting and inconsistencies in state surveillance data significantly hamper efforts to raise public awareness of the magnitude of the problem and evaluate prevention effectiveness.

New methods and products are badly needed for killing and repelling ticks, as are controlled field trials that measure epidemiologic outcomes to provide data-driven prevention recommendations. Challenges related to prevention include the following.

• Primary prevention of tick-borne diseases relies on methods of reducing exposure to infected ticks.
• Data on the effectiveness of methods for killing and repelling ticks is very limited.
• The internet frequently provides misinformation, directing those at risk to ineffective, potentially harmful prevention methods.

A major challenge across all three areas is the critical lack of federal funding. Current federal funding to support surveillance and prevention activities, as well as basic and applied research on tick biology, ecology, and control is severely inadequate to address one of the largest public health problems in the United States.

Methods

Subcommittee member expertise included the following areas.

• tick biology and ecology,
• microbiology,
• human and tick surveillance,
• tick-borne disease prevention and control,
• public and health care provider education,
• advocacy,
• patient education and support, and
• Congressional affairs.

To inform the report to the Tick-Borne Disease Working Group, the subcommittee held 10 meetings and heard 3 formal presentations from subject matter experts. Subcommittee members contributed to the report through independent literature reviews and individual knowledge.

The subcommittee identified five priority issues to address in the report and split into five subgroups to address each priority and draft that portion of the report. During weekly subcommittee calls, subgroups had the opportunity to seek input from the entire subcommittee. Once the sections were complete, a professional writer from the HHS contractor synthesized the sections into a cohesive report.

Final Votes

The subcommittee approved the overall report unanimously, with two minority reports. All but one of the potential actions were approved unanimously, with the other potential action approved by majority, with seven in favor, three opposed, two abstaining, and one absent.

Priority Issues and Potential Actions

The subcommittee identified five priority issues and corresponding potential actions. The priority issues are of equal importance, but the potential actions for each issue are prioritized. Below, potential actions are listed under the corresponding priority issue.

Priority Issue 1: Increase understanding of the geographic distribution of tick vectors, disease ecology, and vectorial capacity; how these are changing over time; and the key entomological determinants of risks to humans, including tick behavior and vector competence.

1. Fund tick environment-habitat-host research, including emphasis on vector surveillance studies that can be compared across sites and over time, research on enzootic cycles that sustain tick-borne pathogens, and investigation of vectors and hosts outside the Midwest and Northeast focal points.
2. Support tick abatement programs by funding stand-alone tick control programs or integrating tick control into existing local and regional mosquito control efforts, establishing partnerships to promote new tick-control inventions, and enhancing the Small Business Innovation Research program to incentivize new solutions.
3. Fund research on modern molecular and genetic techniques to disrupt tick-borne disease infection and transmission and develop and disseminate vaccines.
4. Fund research on pathogen-binding receptors and regulatory factors that enable tick-borne pathogens to infect the tick tissues, proliferate, and survive for transmission to humans and animals.
5. Fund research into creating a genetically modified tick population for release in highly endemic regions.

Priority Issue 2: Develop novel safe and effective tick- or host-targeted interventions to reduce human disease incidence.

1. Conduct further studies of proven tick control measures to validate them for preventing human diseases.
2. Evaluate effective, natural tick control products and repellents.
3. Assess integrated tick management tools that are most effective for vector control while minimizing negative environmental impacts and pesticide resistance.
4. Continue to study and develop tick and pathogen control measures to impact pathogen prevalence in ticks and animal reservoir hosts.
5. Assess barriers to public adoption of prevention practices.

Priority Issue 3: Improve national disease surveillance and reporting and examine the potential role of other data sources and patient registries in defining national disease burdens and trends.

1. Supplement and integrate traditional public health surveillance data with other data sources, such as tick surveillance data, tick testing data, companion animal tick-borne disease testing data, medical claims data, weather data, other patient data sources, and data from other federal agencies.
2. Have public health authorities formally recognize and provide resources for regular studies to estimate the actual number of tick-borne disease cases.
3. Have public health authorities formally recognize alternative, validated, systematic approaches to tick-borne disease surveillance, such as systematic sampling of tick-borne disease reports for investigation that reduce the burden on tick-borne disease reporters but allow for comparability of surveillance findings across states and over time.
4. Simplify and encourage reporting of tick-borne disease cases to public health agencies through providing an electronic forum for exchanging health data and offering education and incentives for reporting.
5. Require public health authorities to annually, and when opportune, inform doctors, insurers, health departments, the press, and the public not to use Lyme disease surveillance criteria for diagnostic purposes.
   • Minority report 3.5.1: The subcommittee developed Potential Action 3.5 to address a minority response related to concern about the Council of State and Territorial Epidemiologists and CDC Lyme surveillance case definition and its misuse in clinical diagnosis. The minority report states that misuse of the overly narrow surveillance case definition led to widespread failure by physicians to diagnose and treat Lyme disease in patients who did not meet the surveillance criteria, as well as concerns about the federal government’s failure to clarify proper use of the case definition.

Priority Issue 4: Detect, identify, and characterize novel and emerging pathogens in ticks, including Bartonella, and the transmission risks from ticks to humans.

1. Create an integrated surveillance and response system by combining all medically important vectors, primarily mosquitoes and ticks, within one comprehensive operational scheme.
2. Establish an interdisciplinary technical committee between the American Medical Association, the Veterinary Medical Association, and the Entomological Society of America to provide guidance on studying and validating tick-borne pathogens and vectors.
3. Establish a global tick microbiome consortium to further characterize microbiomes for exotic tick species in the United States.
4. Establish a state and federal tick-borne disease council to develop best practices for disseminating science-based information, including interactive sites for tick identification in real time.
5. Study each of the major zoonotic tick-borne diseases in different ecosystems using harmonized protocols to understand the variability in qualitative and quantitative characteristics of ecological drivers.

Priority Issue 5: Improve prevention education for patients and physicians.

1. Focus prevention education on practices and activities with positively measured outcomes and encourage innovation in science-based prevention education.
2. Expand CDC-supported regional Centers of Excellence in Vector-Borne Disease.
3. Incentivize innovation in K-12 learning and evaluate the effectiveness of learning resources.
4. Invest in programs that already effectively link tick sciences to lived experiences, and update targeted public health intervention programs to address gaps in knowledge and prevention.
   • Minority Report 5.4.1: The minority response to Potential Action 5.4 urges removal of the word “already,” on the grounds that it limits the potential action to programs already in place for decades, which would create difficulties for areas of the country characterized as having low tick populations or low rates of tick-borne disease.

5. Develop best practice tick control training materials for pest control operators and make continuing education compliance a requirement for licensure.

Challenges and Limitations

Challenges and limitations to the subcommittee’s work included:

• a lack of time to research, draft, review, and revise the report before presenting it to the Tick-Borne Disease Working Group;
• inadequate time to discuss overlap with other subcommittees (for example, the subcommittee debated whether the negative impact of the surveillance case definition on diagnosis and treatment can be addressed through surveillance and reporting actions, or if this issue relates more closely to clinical diagnosis);
• instructions that sometimes seemed unclear and appeared to vary slightly across documents;
• limitations on the number of priority issues the subcommittee could include in the report; and
• an assigned topic that spanned three different areas, which limited the depth of work the subcommittee could accomplish in each area.

Discussion

The subcommittee co-chairs responded to questions and comments from Tick-Borne Disease Working Group members and other subcommittee co-chairs. The main discussion points are summarized below.

The group discussed the controversy over whether ticks can transmit Bartonella to humans. While ticks are known to contain Bartonella, and humans do get infected with Bartonella, scientists have not yet determined whether it is transmitted by ticks or in some other way. For that reason, the subcommittee suggested the potential action to conduct more research into the possible role of ticks in transmission of Bartonella and other pathogens.

Ben elaborated on the subcommittee’s vision for the Centers of Excellence. CDC initiated the Centers of Excellence program amidst the response to the Zika virus. The program was designed to address three needs in responding to vector-borne diseases: public health entomologists, operational research to develop new tools, and building a network of academic centers and state and local health departments. Centers of Excellence for tick-borne diseases would help develop responses to the increasing distribution and incidence of tick-borne diseases and the exotic disease threat from exotic tick species. They could help launch a vector-surveillance network for ticks.

Rich remarked on the importance of increased national surveillance, with an emphasis on its uses for alpha-gal allergy. In other parts of the world, the bush tick has been associated with alpha-gal allergy. However, alpha-gal allergy is not normally a nationally reportable disease, which makes surveillance of this issue important to improve understanding of it. Using technology to report on it, like the new tick tracker app that was recently released, may be helpful.

The group discussed the weakness of the current diagnostic test, in the context of the need for epidemiological studies to understand who is actually affected by tick-borne disease. In its report, the subcommittee discussed the evolution of the two-tiered approach and how it became the standard for surveillance and diagnostics. Case definitions are necessarily restrictive, but are meant to be used for surveillance, not diagnostics. Currently, CDC is conducting a study to see to what extent the surveillance definition is misused throughout the United States. One possible solution is to change the surveillance definition, and another is to provide education for physicians. Pat reiterated the subcommittee minority report’s call for the federal government to be proactive about educating physicians about the proper use of the case definition.

Rob commented that vector surveillance, including tracking vector range expansion and determining infection prevalence, is important to determining the areas of greatest risk. Human diseases tend to lag behind the vector’s establishment in an area. In Maine, researchers found that an area would reach a threshold of ticks before tick-borne disease began to appear in humans. Pat added that, due to lack of funding, some states are providing average case numbers to CDC, and CDC cannot report out those numbers. This trend makes identifying areas of risk difficult and is one of the reasons the subcommittee drafted a potential action to look at new ways of standardizing reporting.

The group then discussed erythema migrans (EM) rashes as surveillance signs for Lyme disease. Because these symptoms are highly associated with Lyme disease, they are helpful surveillance markers. However, many people with Lyme disease never develop a rash, so the presence of a rash is not an accurate diagnostic criterion.

Pathogenesis, Transmission, and Treatment

Wendy Adams and Estella Jones presented an overview of the Pathogenesis, Transmission, and Treatment Subcommittee’s report to the Tick-Borne Disease Working Group.

Background

Due to time constraints, the subcommittee concentrated solely on pathogenesis, transmission, and treatment as they relate to Borrelia (B.) burgdorferi. They focused on:

• how a B. burgdorferi infection causes pathology in an infected host;
• how B. burgdorferi establishes and maintains an infection in the host; and
• early, acute, and continuing signs and symptoms.

Limited knowledge of human pathophysiology impedes patient care, and additional research into pathogenesis is needed. Basic mechanisms of immune evasion are not well-understood. Animal models are useful, but no single animal model reflects the spectrum of human disease. Understanding molecular mechanisms may inform therapeutic choices. For example, studies have shown inter-cellular infection in vitro in different cell types, but there is no definitive evidence in vivo. Further, more knowledge is needed about the potential role of pro-inflammatory cytokines, B. burgdorferi lipoproteins, autoantibodies, and cross-reactive antibodies; whether strain variations impact therapeutic outcomes; and whether the addition of other pathogens affects the disease process, diagnosis, or treatment. Additionally, clinicians need better tools to diagnose and treat patients.

Within the report, the subcommittee avoided the term “post-treatment Lyme disease syndrome” (PTLDS) because it is a narrow definition that, while useful for clinical research, suggests that a patient who received treatment no longer has an infection. Due to the rigorous timeline, the subcommittee did not examine transmission as closely as the other two topics.

Methods

The subcommittee held 13 meetings to discuss the subject matter and heard 11 presentations from experts in microbiology, immunology, and animal models, and clinicians. Subcommittee members culled scientific literature, government websites, patient registries, and clinical experience to inform the report. Because the federal agencies who received the Tick-Borne Disease Working Group inventory had not returned their responses yet, the subcommittee was unable to review, in detail, the previous government activities related to pathogenesis, transmission, and treatment of tick-borne diseases.

To develop the report to the Tick-Borne Disease Working Group, the subcommittee first identified priority issues and formed a subgroup to explore each priority in detail. Each subgroup drafted a section of the report and incorporated feedback from other subcommittee members. During weekly meetings, the subcommittee discussed what information to include from the presentations and reviewed report outlines and drafts.

Final Votes

All final votes on the report content and potential actions were unanimous.

Priority Issues and Potential Actions

Based on the key issues identified, the subcommittee focused on the following three priorities and corresponding potential actions. Potential actions are listed below each priority issue. The second and third priorities share the same potential actions.

Priority Issue 1: What mechanisms of B. burgdorferi pathogenesis allow it to persist in some animal species despite a competent immune system and/or antimicrobial therapy?

1. Promote research on animal models of B. burgdorferi infection and the mechanisms of disease processes in humans, with emphasis on pathologies and mechanisms that are not well-understood, such as neuroborreliosis.
2. Pursue further study of B. burgdorferi survival mechanisms during infection and its tolerance to antibiotics and other stresses.

Priority Issue 2: What is the pathogenesis of persistent symptoms in antibiotic-naïve and antibiotic-treated patients? Are there biomarkers to determine the continuing presence of infection?

1. To ensure clinical trials are representative of diverse patients, conduct trials using more inclusive entry criteria to represent the heterogeneity of patients and include different treatment approaches. Use innovative, patient-centered trial designs.
2. Develop and disseminate to diverse stakeholder groups more comprehensive education materials that highlight the diverse symptomology, expanding geography of infecting ticks, and limitations of current testing procedures.

Priority Issue 3: What are the best treatment regimens for acute Lyme disease and for patients with ongoing symptoms who have or have not been previously treated?

• See the potential action items under the Priority Issue 2.

Challenges and Limitations

Challenges and limitations to the subcommittee’s work included:

• insufficient time to thoroughly research all three subcommittee topics, especially transmission;
• a lack of responses to the federal agency inventory, which the subcommittee needed to provide a detailed picture of federal efforts; and
• inadequate nomenclature for continuing signs and symptoms of Lyme disease after initial treatment.

Discussion

The subcommittee co-chairs responded to questions and comments from working group members and other subcommittee co-chairs. The main discussion points are summarized below.

The group discussed the lack of understanding about the role of co-infection as a significant challenge. For example, there is evidence that anaplasma and borreliosis can work together to suppress the immune system and that unrelated sources of inflammation can exacerbate Lyme disease symptoms, but more research is needed. A study on biomarkers of PTLDS shows some promise about using biomarkers for prognostic indicators for patients who continue to experience symptoms following treatment.

As far as animal models, non-human primates are the most appropriate, but using them as animal models presents ethical and cost concerns. Mice are used frequently, and some experts have suggested rabbits as potential neuroborreliosis models. Balance must be achieved between developing animal models and researching disease in patients.

In response to a question about obstacles to human translational research, Wendy noted that there is no broad clinical trial network for Lyme disease like there is for many other disease groups. Such a network needs to be established prior to clinical trials to ensure different therapies and geographic areas are tested.

David raised the issue of the role of diagnostics in creating a well-characterized cohort for a clinical trial. Wendy agreed that poor diagnostics make creating a well-characterized cohort difficult. There is a need for direct detection of Lyme disease, rather than reliance on passive antibody tests, since animal antibody responses to the same pathogen can vary. She added that development of a test for cerebral spinal fluid could help diagnose neuroborreliosis.

Testing and Diagnostics

Lise Nigrovic and David Roth presented an overview of the Testing and Diagnostics Subcommittee’s report to the Tick-Borne Disease Working Group.

Background

Lyme disease is the most commonly reported vector-borne disease, with CDC estimates of over 300,000 infections per year and an average annual increase in cases of 6%. Biological and technical challenges to the diagnosis of Lyme disease limit the opportunities for early identification and treatment. Currently, CDC recommends diagnosis based on the presence of either an EM “bulls-eye” rash or a positive two-tiered serology test in an appropriate clinical scenario. Fewer than half of all patients have a typical bulls-eye rash, making diagnosis difficult. Therefore, patients must rely on health care professionals who suspect they have Lyme disease to have serologic testing done. Current serology has limitations that can result in negative tests in patients who have Lyme disease. With federal support, better diagnostics could be rapidly developed and/or adapted from diagnostics for other diseases.

The Testing and Diagnostics Subcommittee focused solely on Lyme disease in its research for the report to the Tick-Borne Disease Working Group.

Methods

The subcommittee held 11 conference calls, supplemented by electronic correspondence. They hosted three presentations from experts in the field, but primarily used their meetings as a platform to prepare the report to the Tick-Borne Disease Working Group.

To develop the report, the subcommittee identified priority areas and assigned a subgroup to write a portion of the report for each priority area. The subcommittee completed the report through discussion and collaborative editing. When subcommittee members disagreed on a statement, the subcommittee rephrased that section to achieve consensus.

Final Votes

The subcommittee unanimously voted in favor of the report to the Tick-Borne Disease Working Group, with no minority reports or amendments. One member abstained from voting on potential actions related to NIH funding, due to a potential conflict of interest.

Priority Issues and Potential Actions

The subcommittee identified three priority issues. The co-chairs described their research findings related to each priority issue and the corresponding potential actions.

Priority Issue 1: Existing gaps in current diagnostic approaches

The current two-tiered serology diagnostic system is more than 30 years old. It is the only FDA- and CDC-approved laboratory test for Lyme disease, but it can lead to missed or incorrect diagnoses. Diagnostic test performance may vary among different laboratories or test kits. The current test sometimes provides false negative and false positive results. Test performance in patients without a bulls-eye rash has not been rigorously evaluated. Gaps in provider education may lead to delayed diagnosis of Lyme disease in patients. These shortcomings result from technical limitations, like cross-reactivity between tests for Lyme disease and for other infectious diseases, and biological limitations related to how the human immune system reacts to infection with B. burgdorferi.

The subcommittee identified the following potential action to address existing gaps in current diagnostic approaches.

1. Increase appropriations to NIH and other federal organizations to fund research that will advance the development of better-performing diagnostic tests. NIH and other federal organizations may then take advantage of current and existing peer-review processes to evaluate the feasibility and impact of proposed research projects, including projects that will:
   • support translational research leading to the development of improved diagnostic tests;
   • rapidly translate new diagnostics into test platforms that can be submitted for evaluation by FDA for clearance or approval; and
   • encourage scientists to repurpose existing technologies available for diagnosis of other diseases, such as cancer and non-Lyme infectious diseases.

2. Develop new (or increase support for existing) bio-sample repositories to support basic research and test validation.

Priority Issue 2: Identification of technologies that could improve the state of diagnostic testing

Approaches to Lyme disease diagnosis fall into two general categories: (1) direct testing, which detects the pathogen, and (3) indirect testing, which evaluates the host response to the infection. The current diagnostic system is an indirect test. The main types of direct tests are cultures and polymerase chain reaction (PCR) tests. In clinical samples, Borrelia can be at low levels and difficult to detect through direct testing. Indirect testing requires development of detectable levels of antibodies to B. burgdorferi, which takes time and makes diagnosis during the first few weeks difficult. The second-tier immune blot of the current serologic approach relies on subjective interpretation, which introduces variability in results. Indirect testing ultimately depends on the test’s composition and ability of the host’s immune system to respond to infection.

The subcommittee conducted an inventory of diagnostic approaches to Lyme disease. The approaches include proteomics, multiplex next-generation DNA/RNA sequencing, metagenomic next-generation DNA/RNA sequencing, culture-based methods, nanopore sequencing, metabolomics, transcriptomics, next-generation serologic assays, microfluidics, and cytokine release assays. Further work is needed to investigate the best approach moving forward.

Potential actions for this priority include the following.

1. Increase funding for discovery and development of diagnostics for Lyme disease.
2. Foster public-private partnerships and open source data-sharing and support prize-based competitions for the development of diagnostics for Lyme disease.

Priority Issue 3: Inclusion of special populations in clinical studies

Special populations are those who have not traditionally been included in studies to evaluate diagnostic tests. For example, approximately half to more than half of new Lyme disease cases occur in children, but few children have participated in studies. Other special populations include:

• under-represented minorities,
• patients from areas considered non-endemic for Lyme disease,
• immunocompromised patients,
• pregnant women, and
• neonates born to women who were infected during pregnancy.

Potential actions related to including special populations in clinical studies are as follows.

1. Encourage the inclusion of special populations in future federally funded Lyme disease research.
2. Provide federal funds for the development of high-quality Lyme disease biobanks that include samples and data from special populations, especially children.

Develop and disseminate high-quality online provider education modules that address the diagnosis of tick-borne illness in general, and special populations more specifically.

Challenges and Limitations

Limited time and resources for completing the report led to generalizing language in some sections of the report, because the subcommittee lacked time to review all of the literature on their topic. In some cases, the subcommittee settled for consensus when members may have had different opinions so they could submit the report on time. Another challenge the subcommittee faced was limited interaction with the other subcommittees. Because diagnostics affect many efforts related to tick-borne disease, all subcommittees could have benefited from integrated discussion on connected topics.

Discussion

The subcommittee co-chairs responded to questions and comments from working group members and other subcommittee co-chairs. The main discussion points are summarized below.

Pat stated that, while new diagnostics are an important goal for the future, those new approaches will have to have clear, lengthy approval processes. In the meantime, current patients must rely on the flawed test that is currently required. To address this challenge, potential actions should urge the federal government to drop the requirement to use the existing test or permit laboratories to report out the bands they actually see during testing, rather than those that fit into a pre-determined list of bands. Another potential action should be to convene all stakeholders to examine real-world evidence to develop better diagnostics. Pat requested that the working group members think about this potential action and discuss it at the next meeting. John voiced support for forwarding this suggestion to Congress. Rich added that a validated screening questionnaire that identifies migratory pain symptoms and looking at Borrelia-specific bands may suffice until new diagnostic approaches are in place. For this to happen, clinicians must understand the hallmark symptoms of Lyme disease, and laboratories must be permitted to report out the bands they see.

Wendy Adams asked about any prioritization of technologies for diagnosis, which led directly into Dennis remarking that the need for better diagnostics is a challenge for many diseases. Over the past decade, NIH has issued regular and recurring general solicitations that focus on addressing bacterial diseases, and the outcomes of those efforts often fail to match up with the inputs. This trend indicates the diagnostic challenges result from not merely a lack of funding, but a larger scientific dilemma. David responded that there may be other ways beyond requests for proposals to attract interest in solving the scientific challenges. For example, cash-based prizes could be offered for developing successful diagnostic technologies for Lyme disease. The subcommittee has not yet received a clear picture of what percentage of NIH funding supports indirect methods versus direct methods, but it is important that direct technologies be prioritized.

Pat observed that another challenge is the adherence to diagnostic criteria that were intended to be surveillance guidelines only. She expressed her belief that the federal government has not been open to new diagnostic technologies, such as the approach studied by Schutzer et al in 1990. Dennis responded that lack of interest is not the reason for delay, but rather the lengthy, rigorous scientific review process. The technology must pass competitive peer review to receive funding. Right now, NIH has two parties interested in developing diagnostic technology for Lyme disease.

Rob questioned the statement that the current test was only validated with people who had the EM rash. The test is most reactive in people who have Lyme arthritis, and most Lyme arthritis patients never had a rash or were not diagnosed with Lyme disease. He stated that the current test, while less than ideal, is helpful to clinicians for people seen after about a month of infection.

Rich suggested enhancing the current two-tiered serology test by creating a diagnostic algorithm that indicates next steps in cases where a patient has a classic presentation of Lyme disease and other diseases have been ruled out, but the initial tests are negative. Clinicians need guidance on how to move through tests and when to use them. Kristen added that creating a simple decision tree would help guide clinicians more immediately while the algorithm is in development.

The group discussed the Western blot test. Wendy remarked that using the Western blot test, irrespective of the ELISA test results, could help physicians in the short-term by providing data in spite of a negative ELISA report. Rob said that replacing the Western blot with more easily reproducible testing would be beneficial. As long as Lyme disease diagnostics rely on antibody testing, the ideal scenario is to conduct two highly reproducible, specific tests together to achieve the same sensitivity and specificity. Blots present a challenge for physicians because they are more subjective and less standardized than other types of tests.

David reiterated the importance of interaction across subcommittees to discuss and make connections between overlapping efforts. John responded that the working group meeting set for the following week would provide an opportunity for this level of discussion.

Access to Care Services and Support to Patients

Paula and Scott Cooper presented an overview of the Access to Care Services and Support to Patients Subcommittee’s report to the Tick-Borne Disease Working Group.

Background

Many patients experience delays receiving a diagnosis and accessing care. The subcommittee investigated barriers to diagnosis and treatment for patients with Lyme disease and examined best practices for advancing care and support for patients and their loved ones. The subcommittee defined access to care as including diagnosis and treatment of the disease(s) and any associated symptoms and co-infections.

A patient’s ability to access care depends on:

• recognition of Lyme and other tick-borne diseases at all stages of disease and of the overall degree of associated morbidity and mortality;
• ability to accurately and affordably diagnose the disease(s);
• ability to appropriately and affordably treat the disease(s);
• education of patients, the public, and health care providers; and
•  availability of accurate, appropriate, and affordable diagnosis and treatment for all patients, particularly those at highest risk and those who are most vulnerable.

Currently, many of the direct patient resources, like financial assistance, support groups, and referrals to Lyme-literate providers, come from advocacy groups. These groups also serve as catalysts for legislative work and political and social activism. Advocacy groups typically comprise current and former patients and their loved ones, caregivers, health care practitioners, and community members. Some focus their efforts locally, while others support a national audience.

Many states offer free or reduced care programs to those who qualify, but most do not cover doctors’ visits or treatment for Lyme disease. However, some national organizations and companies provide financial assistance for testing and treatment for those who qualify.

Advocacy groups often host free educational events on diagnosis and treatment that offer information, products, and services for patients and the community. Additionally, many state and national advocacy groups, nonprofit organizations, and associations offer educational information on their websites and through their apps.

Methods

The ten member subcommittee participated in nine conference calls and held nine presentations by subject matter experts, including an investigative writer, clinicians, and patient advocates. To develop the report to the Tick-Borne Disease Working Group, the subcommittee reviewed journal articles and other publications and studied public comments and patient stories. To draft the report, subcommittee members split into multiple writing subgroups.

Final Votes

The subcommittee voted to approve the report without additional comment. Nine members voted in favor and one abstained. The member who abstained had submitted material for the report outside the established process, so the group did not have a chance to discuss the material. The subcommittee plans to review that content within a few days of this meeting and include it as a minority report addendum if needed.

Priority Issues and Potential Actions

The subcommittee identified three priority issues. The co-chairs described their research findings related to each priority issue and the corresponding potential actions.

Priority Issue 1: Awareness and education

The subcommittee assigned potential actions for this issue to several different audience sectors. Potential actions are listed below each sector.

1. Public education
   1. Provide education regarding prevention and recognition of tick-borne diseases, ticks, tick bites and how to remove a tick correctly. Develop audience-specific messaging and outreach.
   2. Create a more comprehensive and interactive website at the federal level.
   3. Include a tick-borne disease curriculum in the school system, especially in endemic regions.
   4. Treat Lyme disease and other tick-borne diseases as chronic illnesses. Even without definitive science determining the exact cause, there is agreement that debilitating symptoms linger after treatment for at least 20 percent of Lyme disease patients. The approach for other chronic conditions is to address and manage the medical, social, economic, and psychological challenges faced by those with chronic conditions or chronic symptoms. Lyme and tick-borne illness should be no exception.

2. Patient education
   1. Add existing resources to state public health webpages and behavioral health associations.
   2. Use public service announcements to educate people.
   3. Have pamphlets available at doctors’ offices that use patient-friendly language and outline symptoms.
   4. Inform patients that they may experience any number of symptoms in differing intensity and advise them of the distinct types of rashes.
   5. Dispel myths, promote reality, and continually update information that is promoted to providers and the public.

3. Provider education
   1. Provide formal and continuing education on tick-borne diseases, starting in medical schools and allied health programs and including, but not limited to, behavioral health practitioners, nurses, family nurse practitioners, physician assistants, and nurse assistants.

4. Legislation
   1. Implement mandatory insurance coverage for diagnosis and treatment of tick-borne disease.
   2. Enforce existing laws.
   3. Establish laws to protect patients’ rights, including informed consent regarding the two published standards of care for Lyme disease.
   4. Establish laws to protect physicians who wish to treat according to clinical criteria and/or International Lyme and Associated Diseases Society (ILADS) guidelines.
   5. Implement federal demographic reporting. Include a Lyme disease/tick-borne disease checkbox on health forms within government health care institutions and programs to gather accurate data about the prevalence, health impact, and cost of tick-borne diseases.
   6. Hold Congressional hearings to gather data and correct Lyme public health and human rights issues. Legislative oversight and investigative hearings may be critical to correct the issues facing tick-borne disease patients.
   7. Adapt Maryland’s Patient Information Disclosure Act as a model for legislation. This legislation requires notifying patients when any diagnostic test performed lacks a high level of reliability.

Priority Issue 2: Access to affordable medical care

The subcommittee assigned potential actions for this priority area to several different issues. Potential actions are listed below each issue.

1. Federal and state government barriers, such as improper use of the CDC surveillance criteria for diagnosis, two different sets of guidelines for standards of care (Infectious Diseases Society of America (IDSA) and ILADS), and state licensing boards
   1. Revert to the 2011 language on the CDC website that distinguished surveillance criteria from diagnostic criteria.
   2. Post ILADS guidelines for standards of care on the CDC website.
   3. Draw attention to the footnote on the IDSA guidelines, which states that the guidelines are not meant to account for individual variation nor replace clinical judgment and that adherence is voluntary.
   4. Allocate more balanced funding for tick-borne diseases to match communication from the federal government.
   5. Establish tick-borne disease Centers of Excellence.
   6. Hold a Congressional hearing about tick-borne diseases.
   7. Allocate increased funding for tick-borne disease research, treatment, and prevention in a way that is proportional to cancer and HIV/AIDS.
   8. Implement protections from job discrimination due to tick-borne diseases.
   9. Implement protections for students of all ages from discrimination due to tick-borne diseases.
   10. Increase research funding through the DoD Congressionally Directed Medical Research Program.

2. Insurance blocks that result in denied services and treatment or out-of-pocket costs for patients
   1. Require insurance to cover Lyme disease treatment and testing.
   2. Streamline the reimbursement process for patients.
   3. Streamline the patient/doctor appeal process.
   4. Include mental health coverage for addressing issues related to tick-borne disease

3. Underrepresented and high-risk populations
   1. Ensure equal health care provisions across demographics.
   2. Produce educational materials in multiple languages.
   3. Require entities who receive federal funds to provide education for patients and the public.
   4. Educate OB/GYN doctors about potential gestational transmission during pregnancy and prepare practitioners to address other forms of transmission between humans as more becomes known about this issue.

Priority Issue 3: Access to proper diagnosis and treatment

The subcommittee assigned potential actions for this priority area to two different issues. Potential actions are listed below each issue.

1. Proper diagnosis and treatment, including protection for patients against exploitation through costly, unproven, and extreme treatments and access to affordable, reliable diagnostic tools.
   1. Fund research toward the accurate diagnosis and treatment of all stages of tick-borne diseases.
   2. Improve physician training, especially in endemic areas.
   3. Include tick-borne disease education with mental health training.
   4. Introduce informed consent forms into medical visits.

2. Affordable treatment options that protect patients from traveling to another state to receive treatment or from forgoing treatment due to prohibitive costs
   1. Update medical coding to include codes for chronic Lyme disease and co-infections.
   2. Expand insurance coverage for complementary and alternative treatments and visits.

Challenges and Limitations

While the subcommittee had a literature base to draw from related to connections between Lyme disease and psychiatric illness, there is a lack of data on the patient experience. Given the complexities of tick-borne diseases and the controversies surrounding them, the timeline for developing the report was also a challenge.

Discussion

The subcommittee co-chairs responded to questions and comments from working group members and other subcommittee co-chairs. The main discussion points are summarized below.

The group discussed the possibility of the federal government gathering information and providing funds to unify nonprofit educational efforts and steer them toward a shared vision. Kristen mentioned that CDC provides trainings for educators, which could be a channel for enhancing education about tick-borne diseases. Rich noted that Rotary International has helped address disease epidemics in the past by raising their own resources. To reduce the burden on the federal government, Rotary International or a similar group may be able to help coordinate education efforts across advocacy groups.

Pat remarked that some of the potential actions, particularly the one related to protecting students from discrimination, apply at the state level, rather than the federal level. Educational systems have often been ignorant about Lyme disease. In some cases, schools charge students with truancy when they are too sick from Lyme disease to attend class, and there have been instances of the school reporting the issue to family services and the child being removed from the home. In some states, school doctors can overrule what a student’s own physician recommends. To help resolve these issues, the Tick-Borne Disease Working Group may need to recommend that the U.S. Department of Education become involved in preventing discrimination against children with Lyme disease.

Vaccine and Therapeutics

Dennis Dixon and Rob Smith presented an overview of the Vaccine and Therapeutics Subcommittee’s report to the Tick-Borne Disease Working Group.

Background

The subcommittee focused on products available through pharmacies, including compound pharmacies. They also considered products in clinical development. The subcommittee divided therapeutics into two categories: (1) antimicrobials, which target pathogens, and (2) non-antimicrobial therapeutics, which help manage symptoms.

The Lyme disease vaccine was introduced in 1998 and went through a large analyzed clinical trial with 10,000 people. After one million doses were given to 400,000 people, it was voluntarily withdrawn due to market reasons. The large challenge facing new vaccines being developed today is the intersection of science, policy, and public perception, particularly in regards to overcoming the legacy of a vaccine that was a commercial failure.Potential human-targeted vaccine concepts include those that are based on the bacterial antigens OspA, OspB, or OspA/OspC or those that target tick salivary antigens. A potential vaccine that may be close to introduction is a multivalent OspA vaccine, which could prevent against the six most common B. burgdorferi serotypes in the United States and Europe. This vaccine was designed to omit hLFA-1 (human leukocyte function-associated antigen-1), an epitope that was a common point of concern for LYMErix. The Phase 1 trial of this potential vaccine recently concluded, with no safety concerns noted thus far.

Experts are also exploring other reservoir-targeted and tick antigen-targeted vaccines. Field trials have demonstrated proof of principle for the use of OspA-based vaccination of rodents as a possible strategy for interrupting transmission of B. burgdorferi in the environment. Additional studies and/or modeling would help show what the potential vaccine’s effect would be in different circumstances.

Barriers to acceptance of a new Lyme disease vaccine include:

• public concerns regarding safety and efficacy, cost (insurance coverage), and convenience (e.g., durability of immunity and the need for booster vaccinations),
• industry concerns regarding commercial withdrawal of LYMErix, and
• competing priorities in the public health sector.

Potential strategies for overcoming these obstacles include the following.

• Share epidemiologic rationales. For example, note that the geographic range of ticks is expanding and the number of tick-borne disease cases is rising. Point out that health care costs related to diagnosing and treating tick-borne disease continue to rise, and studies indicate that a Lyme disease vaccine would be cost effective.
• Because children are a high-risk population for Lyme disease, they need to be included in clinical trials for a new vaccine. Clinical trials should also determine the frequency of boosters, if they are needed.
• Involve stakeholders before the vaccine is introduced to improve communication and generate support.

Randomized control trials support the use of oral antibiotics to treat most cases of B. burgdorferi infection, including cephalosporins; tetracyclines; penicillins; and, to a lesser extent, macrolides. Intravenous treatments are typically only used to treat severe Lyme disease, neuroborreliosis, and relapsed Lyme arthritis. Ongoing research through in vitro and in vivo animal studies is exploring additional antibiotic options.

Challenges to antimicrobial therapies include the following.

• Antibiotic choices are more limited for women who are pregnant or breastfeeding and for pediatric patients, and are very limited for treatment of some co-infections.
• Symptoms may persist following standard antibiotic treatments.
• Trials to date have not demonstrated a therapeutic benefit for antibiotic treatment of PTLDS, compared to the associated adverse effects.
• Trials of treatment for PTLDS have not included children.

Non-antimicrobial therapies help patients manage various symptoms following treatment. For persistent antibiotic-refractory Lyme arthritis, methotrexate and hydroxychloroquine are used.

• Challenges to non-antimicrobial therapies include the following.
• The mechanisms of pathogenesis of persistent symptoms are not clear, though a lot of research is currently underway.
• There is a lack of clinical data on the effectiveness on symptom relief of many non-antimicrobial therapeutics for Lyme disease and PTLDS.

Methods

The subcommittee held 10 meetings and heard 10 presentations from experts on clinical data about vaccines and therapeutics that are in use or under investigation. A writer from the HHS contractor drafted a summary of each meeting to help track important concepts and discussion points. Subcommittee members achieved consensus on the report to the Tick-Borne Disease Working Group after reviewing it individually.

Final Votes

All subcommittee members voted to approve the report to the Tick-Borne Disease Working Group and the list of potential action items.

Priority Issues and Potential Actions

The subcommittee identified two priority issues. The co-chairs described their research findings related to each priority issue and the corresponding potential actions.

Priority 1: Human vaccine to prevent Lyme disease

Potential actions include the following.

1. Identify current barriers to public and industry acceptance of vaccines for Lyme disease and address concerns as part of the process.
2. Support the continued development of human Lyme disease vaccines.

Priority 2: Therapeutics for PTLDS

A potential action to address this issue is as follows.

1. Continue research into the pathogenesis (that is, immune response, cross-reactivity, autoimmunity, and bacterial persistence) of persistent symptoms in patients who have received standard treatment regimens

Discussion

The subcommittee co-chairs responded to questions and comments from working group members and other subcommittee co-chairs. The main discussion points are summarized below.

Pat observed that many patients reported becoming ill after receiving the LYMErix vaccine. While some believe a certain OspA epitope caused the problem, she expressed concern that insufficient research has been done to determine the exact cause, because the existence of problems was never acknowledged. FDA has now fast-tracked Valneva, a potential new vaccine that will use six OspA antigens. She finds this disconcerting, as she believes the organisms that will be used in the vaccine are not well-understood. The subcommittee report cites no evidence of increased adverse effects in vaccine recipients compared to those who received a placebo. However, there are numerous accounts from patients about reporting adverse events to their doctors following vaccination and being told their experience was not an adverse event. Safety must be the top priority in introducing a new vaccine, and people from all stakeholder groups must be involved. This involvement should start with diverse representation on the subcommittee.

Dennis responded that the subcommittee had a patient representative and a member who is a patient family member. He disagreed about the lack of scientific understanding, stating that the scientific concerns have been thoroughly addressed. He noted that looking forward to the safety and efficacy of new vaccines is more important and will prevent more suffering and deaths than continuing to resurrect concerns about a vaccine that was withdrawn. Rob added that because moving a new vaccine through development stages and regulatory approvals takes a long time, starting over on a new vaccine due to suspicions about a previous vaccine would significantly delay a potentially useful prevention instrument. Bringing in different stakeholders to ensure a safe, successful vaccine was a main focal point of the subcommittee’s discussions. 

The group discussed a potential vaccine against tick salivary proteins, including whether down-regulation of OspA and up-regulation of OspC interfere with the vaccine’s efficacy. They also discussed trials on retreatment for PTLDS. Within those trials, Wendy identified a primary focus on EM rashes as the endpoint and a secondary focus on symptom resolution. She noted that improvement of fatigue was confirmed across both trials. Dennis did not interpret the studies as focusing on the EM rashes as the endpoint, but rather on a combination of assessment of the patient and follow-up. They agreed that resolution of the EM rash is not a useful endpoint, since this symptom often resolves without treatment.

Other Tick-Borne Diseases and Co-Infections

Richard Horowitz and Allen Richards presented an overview of the Other Tick-Borne Diseases and Co-Infections Subcommittee’s report to the Tick-Borne Disease Working Group.

Background

The subcommittee focused on diagnosing tick-borne diseases and co-infections, treatment for these conditions, and the alpha-gal allergy.

Co-infections of ticks with human and animal pathogens is more widespread than is commonly recognized by medical professionals and the public. Ticks now often contain multiple tick-borne pathogens, which can be transmitted with a single tick bite, and some tick-borne infections can be transmitted within a very short period of time after a bite. Transmission of some tick-borne diseases is also possible through blood transfusion, solid organ transplantation, and maternal-fetus transmission. Increased awareness about coinfections with appropriate testing and treatment is important to help decrease morbidity and mortality from other tick-borne diseases and co-infections. In persistently symptomatic patients, more than one tick-borne disease is often present. These pathogens can affect humans acutely and chronically.

Based primarily on high morbidity and mortality rates, the subcommittee chose to focus on the following diseases and topics:

• Anaplasma or Ehrlichia,
• Babesia (Babesia microti, Babesia duncani),
• Other Borrelia (relapsing fever borrelia (hard/soft ticks) and B. burgdorferi sensu lato spp),
• Rickettsia (Rocky Mountain spotted fever),
• Deer tick virus (Powassan virus),
• Bartonella species, and
• Other pathogens (the role of Mycoplasma infections in Lyme disease patients).

Methods

The subcommittee participated in 12 meetings and listened to 12 presentations from subject matter experts. They reviewed over 200 journal articles and studied public comments, patient stories, and clinical case studies. To draft the report to the Tick-Borne Disease Working Group, the subcommittee split into three writing groups, with each subgroup focused on one key theme. The subcommittee finalized the report through multiple rounds of comments and revisions.

Final Votes

The subcommittee members passed all potential actions included in the report. Of the 36 potential actions, 33 passed unanimously, with one abstention. Of the three potential actions remaining, two members opposed two of the actions, and one member opposed the other. Reasons for opposition included:

• the potential action falls outside the scope of the subcommittee’s charge and
• new assays should be less of a priority than implementing existing assays or determining their predictive value.

Priority Issues and Potential Actions

The subcommittee categorized priority issues under three key themes: diagnosis, treatment, and alpha-gal allergy.

Diagnosis

Priority issue 1: Education – The following gaps were identified in education.

• Health care providers need education about clinical diagnosis, when to order diagnostic tests, and what the results mean.
• Clinical testing laboratories need education about selecting appropriate and well-validated diagnosis assays and what the results mean.
• Patients, patient family members, and the public need education about other tick-borne diseases and coinfections.
• There is a need for studies examining the incidence of concurrent tick-borne infections and investigation into the natural history of untreated tick-borne diseases, issues with persistence, and the potential role of coinfections.

Potential actions include the following.

1. Conduct studies to answer important questions about the natural history of other tick-borne diseases and co-infections, and the human immune response to infections.
2. Educate health care providers, patients, and the public.
3. Create a tick-borne diseases and co-infections multi-site Tick-Borne Disease Working Group to develop a collaborative, standardized approach to data collection, and conduct longitudinal cohort natural history studies of sequela and complications of treated infections.

Priority issue 2: Clinical diagnosis – Current gaps in clinical diagnosis include:

• a lack of clinical algorithms and guidance and
• the need for a comprehensive list of signs and symptoms, differential diagnoses, and laboratory tests for each infection to confirm or rule out the diagnosis.

A potential action includes the following.

1. Develop flow chart algorithms for clinical diagnosis of other tick-borne diseases and co-infections.

Priority issue 3: Laboratory testing – Gaps in this area are as follows.

• Few diagnostic tests have undergone interlaboratory comparisons using a defined sample panel developed by an independent agency with well characterized samples of known provenance.
• New, more sensitive, specific assays need to be available onsite.
• Selecting the right samples for specific infections may require the use of other samples, like skin biopsies. Using multiple combinations of methodologies multiple times may be helpful.
• Timelines for testing need to be described.

Testing is often performed using non-FDA-approved laboratories, while other laboratories are not well-validated. The predictive value of laboratory-developed tests is not known unless there is independent evaluation of the predictive values. Additionally, a laboratory’s methods may not be fully disclosed. This lack of openness and objectivity about assays can pose a challenge to effective laboratory testing. Having known positive samples that are well-characterized is important to effective testing.

Potential actions include the following.

1. Develop flow charts or algorithms for clinical diagnosis and laboratory testing for acute and chronic illnesses.
2. Promote independent validation of laboratory-developed tests using panels of control samples that are assessed blindly.
3. Establish realistic goals for new tests.
4. Examine ways to optimize sampling.
5. Develop new and better tests in acute and chronic presentations based on the needs identified from systematic review.
6. Expand the number of externally validated assays to provide complete coverage of other tick-borne diseases and coinfections.

Priority issue 4: Surveillance – The main gap identified related to surveillance is the need for more and improved systematic surveillance studies for other tick-borne diseases and coinfections.

A potential action includes the following.

1. Increase resources available for surveillance, including collaborative projects centering on surveillance or recognition of tick-borne diseases, at the state level.

Treatment

Priority issue 2.1: Anaplasma or Ehrlichia – This condition can range from asymptomatic to severe febrile illness. It rarely results in death. Clinicians should look for fever with low white cell counts, low platelet counts, and elevated liver functions. The pathology seen for Anaplasma or Ehrlichia is increased inflammation. Delayed treatment can lead to severe clinical outcomes.

Potential actions include the following.

1. Educate health care providers on the use of doxycycline.
2. Dedicate resources to determine mechanisms of immune suppression and pro-inflammatory mechanisms post-infection.

Priority issue 2.2: Babesia – There are over 100 species of Babesia, with B. microti and B. duncani being the most common in the United States. B. duncani poses a diagnostic challenge, since only 13 well-defined clinical samples exist. Patients often have a sudden onset of malarial symptoms.

Potential actions include the following.

1. Increase resources to improve diagnostics and broaden Babesia species testing panels to allow for greater genetic diversity.
2. Provide health care education for doctors and subspecialists on the signs, symptoms, risks, laboratory evaluation, and treatment challenges of Babesiosis.
3. Conduct laboratory research and clinical trials to evaluate new treatment regimens for Babesiosis, since resistance to standard regimens has been reported.
4. Conduct research on immunotherapy/human monoclonal antibodies to control parasitemia while on drug treatment.

Priority issue 2.3: Other Borrelia species – The subcommittee focused on the Borrelia species B. miyamotoi and B. burgdorferi sensu lato spp. The frequency of these species of Borrelia is increasing. Antibody testing for Lyme disease cannot detect these infections. There are gaps in knowledge regarding the incidence of B. miyamotoi and challenges related to its persistence.

Potential actions include the following.

1. Improve public education on the prevention of tick bites, and educate health care providers on the signs, symptoms, and transmission of Borrelia.
2. Expand routine testing panels, such as those used for chronic fatigue and fibromyalgia, to see if Borrelia species play a role.
3. Evaluate the efficacy of treatment regimens against relapsing fever Borrelia transmitted by hard and soft ticks, especially when different coinfections are present, since persistent infection has been reported.

Priority area 2.4: Powassan virus – The Powassan virus may result in asymptomatic infection. However, 50 percent of survivors with neurological symptoms have severe, permanent neurological symptoms, and 10 percent of infections are fatal. The risk of this infection is increasing. There are gaps in understanding of how the virus is transmitted. Further, no effective treatments exist for Powassan virus.

Potential actions include the following.

1. Increase resources for research into effective treatment.
2. Conduct research on animal models about modes of transmission and whether persistence exists after an acute infection.

Priority area 2.5: Rocky Mountain spotted fever – Rocky Mountain spotted fever is difficult to diagnose in early stages due to non-specific symptoms. It is a severe disease that can lead to cardiac and respiratory symptoms, renal failure, seizure, coma, bladder and bowel problems, and learning disabilities. It is important to treat presumptively and immediately with doxycycline.

Potential actions include the following.

1. Educate health care providers on the non-specific signs and symptoms of Rocky Mountain spotted fever and the importance of using doxycycline immediately.
2. Treat the condition presumptively and never delay or stop treatment.

Priority area 2.6: Bartonella – Bartonella is difficult to detect through standard testing because it has multiple species and subspecies, and the pathogens evade and manipulate the immune system. Bartonella can range from benign to life threatening, and can persist and relapse post-treatment. Fleas are the vectors for this disease, but Bartonella has been found in ticks. Gaps include a lack of knowledge about the mode of transmission, difficulty establishing proof of infection, and lack of effective treatment.

Potential actions include the following.

1. Improve and expand diagnostic assays and determine the effect on immunity.
2. Conduct trials to evaluate more effective treatments.
3. Allocate resources to improve and expand research into the interaction between simultaneous infecting pathogens and the effect on the immune response of two or more pathogens.
4. Conduct animal and human clinical trials to evaluate more effective treatment protocols, as Bartonella has been shown to persist despite single or combination therapy.
5. Allocate resources for research to determine the risk of transmitting multiple tick-borne pathogens via the blood supply.

Priority area 2.7: The role of other pathogens, like Mycoplasma, and the role of other inflammation sources – Mycoplasma are difficult to detect by standard testing because there are multiple species, and the pathogens manipulate the immune system. Mycoplasma is also known to persist and can relapse post-treatment. Approximately 70 percent of Lyme disease patients have been found to have systemic mycoplasma infections. Gaps in knowledge exist related to transmission and whether Mycoplasma exacerbates the symptoms of PTLDS, and establishing proof of infection is difficult.

Potential actions include the following.

1. Review the role of overlapping causes of inflammation in Lyme disease patients, such as Mycoplasma infections and environmental toxins. These have both been associated with autoimmune phenomenon.
2. Conduct research on the role of free radical oxidative stress and cytokine production during tick-borne infection. Downstream effects of inflammation may result in disabling symptoms. Allocate resources to conduct clinical trials to identify contributing causes and confounding factors.

Alpha-gal allergy

Bites from a Lone Star tick (and other ticks) can result in an allergy to mammalian products, leading to an anaphylactic reaction that can be life threatening. Gaps include a lack of surveillance, lack of education and awareness about preventing tick bites, and a lack of awareness on avoiding triggers for those who have the allergy.

Potential actions include the following.

1. Increase education and awareness pre-diagnosis and counseling after diagnosis. Labelling on food may be inadequate.
2. Dedicate additional resources to vector control.
3. Increase funding for immunologic and animal model research to identify and better understand the tick proteins that cause alpha-gal meat allergy.

Challenges and Limitations

The timeframe for developing the report to the Tick-Borne Disease Working Group was challenging. There was insufficient time to hear presentations on all the desired topics while also writing the report, as well as insufficient time for editing the report. Subcommittee members would have liked more time to discuss several issues related to diagnostics and treatment.

Discussion

The subcommittee co-chairs responded to questions and comments from working group members and other subcommittee co-chairs. The main discussion points are summarized below.

Pat commented that surveillance activities impact all tick-borne diseases. She shared an example of a young girl who died from Rocky Mountain spotted fever because the state insisted the condition did not exist there.

Rob disputed the subcommittee’s characterization of B. miyamotoi as a Lyme-like illness and stated that it is more like anaplasma or Ehrlichia.

The group discussed the controversy regarding whether ticks transmit Bartonella and the need for more research about its transmission. Currently, there is insufficient data to support it as a tick-transmitted infection. Rob pointed out that pathogens found in ticks are not necessarily transmitted by ticks. Rich responded that the subcommittee chose to include Bartonella in its report despite a lack of data because many clinicians have detected it in patients with persistent symptoms through PCR and RNA testing.

Paula remarked that, given the unreliable diagnostic tools currently available for tick-borne diseases, education and awareness efforts should emphasize the clinical aspect of diagnosis so doctors can recognize signs and symptoms in their patients. Rich agreed, and reiterated the need for diagnostic algorithms that health care providers can use.

The group discussed environmental stressors and toxins as overlapping causes of inflammation. Rich stated that the majority of his patients test positive for heavy metals, like mercury. Many patients are beginning to show evidence of multiple mold toxins. He noted the importance of not looking at Lyme disease in isolation, but considering the possible roles of other tick-borne infections, co-infections, and toxins. More clinical research is needed on toxins as a compounding factor.

Paula and Rich discussed the need for better long-term studies on the effectiveness of the common practice of prescribing one to two doxycycline pills to patients who report a tick bite but are not yet symptomatic.

Ben described an observational study CDC is currently conducting to identify novel agents causing tick-borne illness.

Public Comment

During the public comment period, 11 attendees provided brief comments.

Theresa Denham:  Access to care begins with recognizing what the disease is. There is a need to adopt a single, standard definition to use in surveillance and provide alternative mechanisms for reporting tick-borne disease since some states do not cooperate. Tick-borne diseases are severely underreported in Oregon. Oregon is not considered an endemic area, and the message that the number of cases in Oregon is fairly low has created a barrier to diagnosis and care. The state did not agree to a statewide sampling study despite available funding. Patients are told they do not have the disease, so it goes unreported. In 2014, only 2 percent of Lyme disease patients in Oregon both received the care they needed and had their cases reported. It is important to examine how states report incidence of tick-borne diseases. Changes made at the federal level will not make a difference if states refuse to recognize the presence of tick-borne disease.

Allison Caruana:  The battle against tick-borne diseases cannot be won on a scientific front alone, but also require a sociopolitical front. There is a need to acknowledge the real science of tick-borne diseases and properly fund efforts to address them. Allison disputed the understanding of tick-borne diseases as caused by bacteria. Rather, she stated they are viral diseases. She pointed to the study Linear Plasmids of Borrelia Burgdorferi Have Telomeric Structure Sequences Similar to Those of Eukaryotic Virus and a statement from Allen Steere in which he announced the discovery of a new viral disease called Lyme disease.

Jill Aurbach:  Until tick research becomes the main focus, ticks and their pathogens will continue to spread. New pathogens are continuously being discovered. A Lyme disease vaccine alone will not stop new pathogens or other tick-borne diseases beyond Lyme disease. Jill urged the Tick-Borne Disease Working Group to establish an agenda to stop ticks and tick-borne diseases from spreading geographically. She called for research that emphasizes reduction in tick populations and pathogens and blocking a tick’s ability to transmit pathogens to humans and other creatures.

Enid Haller:  Enid presented suggestions to enhance the credibility of the Tick-Borne Disease Working Group and its products. The misused surveillance criteria and concerns about too many shortcuts taken in development of the LYMErix vaccine have led to public distrust of Lyme leadership. The Tick-Borne Disease Working Group could earn trust by:

• publishing all notes and reports from the subcommittees;
• publishing notices about public meetings well in advance, and ensuring the meeting agenda allows time for open question and answer sessions with more time for members of the pubic to speak;
• ensuring that working group members disclose conflicts of interest;
• publishing historical records of HHS and DoD findings;
• allowing for open communication across subcommittees; 
• releasing HHS and DoD documents for subcommittees to review; and
• allowing her to serve as a watchdog over the government process.

Lonnie Marcum:  Lonnie shared the story of her daughter’s struggle to be diagnosed with a tick-borne disease. She observed that the story is not unique, and that misdiagnosis of tick-borne disease seems to be the norm in California. She shared that the medical system they worked with seemed more willing to condemn her daughter to a lifetime of anti-seizure, antidepressant, and pain medication, rather than give her a life-saving prescription for doxycycline. She noted a tendency to downplay the far-reaching effects of other tick-borne diseases, besides Lyme disease, that occur outside the northeastern United States. Lyme disease is not the only disease to fear from a tick bite, and the public needs to know more about the other risks. Testing needs to cover other tick-borne pathogens. Today, the technology exists to design highly sensitive tests capable of detecting multiple pathogens, and the public needs a test that does much more than detecting one species of Borrelia.

Beth Carrison-van der Heide:  Beth thanked the Tick-Borne Disease Working Group for addressing alpha-gal allergy and reiterated the severe consequences of the condition. For example, children with the allergy may have difficulty attending school if the cafeteria is cooking meat, due to the airborne exposure to the allergen. People with alpha-gal are often unable to participate in vaccinations, since many vaccines contain mammalian products. Beth described her experience of being in the hospital, unable to speak on her own behalf, and receiving medication after medication that perpetuated her condition due to mammalian ingredients. She requested that, for upcoming working group meetings, the Tick-Borne Disease Working Group provide speakers with more notice when they are approved to provide comments, so they can prepare their comments.

Laura Hovind:  Laura stated that the OspA vaccine causes immune suppression, which leads to the chronic seronegative form of Lyme disease because OspA is a fungal endotoxin. She shared her perception that the vaccine caused the neurologic disease, which was then excluded from the Lyme disease case definition. She expressed her belief that the millions of dollars channeled to research efforts to develop OspA-based vaccines will be futile, since an OspA vaccine was never a viable option. Further, testing will never be accurate until the falsified case definition is thrown out. She added that patients feel they are being treated as a commodity and are tired of seeing inadequate results in response to tick-borne disease.

Teri Schnitzel:  People who have tick-borne diseases are desperate to regain their lives, families, careers, and health. Many are unable to work, yet they do not qualify for financial assistance. The United States combated the Zika virus quickly and effectively, and Lyme disease deserves the same level of effort. However, Lyme disease patients are largely ignored by the medical world or told they do not understand the disease and they do not have it because their tests came back negative. Insurance companies deny them coverage. These patients desperately need help. They need reliable testing and more research. They need CDC to rewrite the Lyme disease guidelines so doctors who read them will begin to believe the patients.

Ira Aurbach:  While it is encouraging to see diverse views represented on the Tick-Borne Disease Working Group, some of the hard-lined mindsets about tick-borne disease seemed to emerge during the subcommittees’ presentations. For example, the two-pill doxycycline study should not be endorsed. CDC attempted to replicate the results of the study and failed, yet the CDC website currently advises a single dose of 200mg of doxycycline within 72 hours of a tick bite. That advice needs to change, and the Tick-Borne Disease Working Group must help stop the misleading of people through information that does not work.

Gary Sweeney:  Gary described the adverse effects of delayed diagnosis on patients’ health, family, and finances. His daughter endured a 10-year battle to be diagnosed and treated for Lyme disease in a non-endemic area. Her test results were positive according to CDC and IDSA guidelines, presenting two of the three required IgM bands. However, her test result was labeled as negative due to clinical symptoms persisting for more than several months. A common thread of delayed diagnosis due to extremely outdated testing protocols leaves many patients untreated and at risk. Funding for research, treatment, and prevention is woefully inadequate, and information gaps still exist related to the basic biology of Borrelia and its interaction with the human immune system. He praised the Tick-Borne Disease Working Group for its efforts thus far and urged them to impartially make informed decisions to bring about real change from the status quo of dismissive treatment and misinformation.

Nicole Flatt:  Nicole said that transparency is essential to conversations about tick-borne diseases moving forward. She stated that Lyme disease causes immune wreckage via immune suppression from septic tick bites that extends far beyond persistent spirochete infection, and that the LYMErix vaccine caused chronic Lyme because OspA is a sepsis-inducing fungal antigen.

Closing and Next Steps

John remarked that the subcommittee reports brought together experts and stakeholders with diverse backgrounds and perspectives. There was a high degree of agreement on the potential actions.

Between now and the next Tick-Borne Disease Working Group meeting, the Tick-Borne Disease Working Group will:

• identify the most important findings, challenges, gaps, and potential actions from the subcommittee reports;
• review public comments and other information sources to inform the final report to Congress; and
• analyze data from the Inventory of Federal Actions (due May 11) for inclusion in the final report.

Kristen described the upcoming Tick-Borne Disease Working Group meeting. The next meeting will be held in-person on May 15 and 16 at the Hilton Crystal City Conference Center in Arlington, VA. The meeting will be live-streamed online for those who cannot attend in person. The deadline to sign up to present public comment at this meeting is May 10. The meeting will focus on the Tick-Borne Disease Working Group’s report to Congress. They will review the report outline, template, and layout and discuss key elements of the report content. Kristen presented a detailed timeline of the report’s development.

The meeting was adjourned.

Appendix: TBDWG Members and HHS Staff

TBDWG Members

Chair
John N. Aucott, MD, Associate Professor, Division of Rheumatology, Johns Hopkins University School of Medicine; Director, Johns Hopkins Lyme Disease Clinical Research Center

Vice-Chair
Kristen T. Honey, PhD, PMP, Senior Policy Analyst, Office of Management and Budget, Office of the Federal Chief Information Officer, Executive Office of the President; Senior Research Scholar, Stanford University; Member, Stanford University Lyme Disease Working Group

Wendy A. Adams, MBA, Research Grant Director, Bay Area Lyme (BAL) Foundation 

Charles Benjamin (Ben) Beard, PhD, Deputy Director, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services; Associate Editor, Emerging Infectious Diseases

Commander Scott Cooper, PA-C, MMSc, Senior Technical Advisor and Lead Officer for Medicare Hospital Health and Safety Regulations, Centers for Medicare and Medicaid Services, U.S. Department of Health and Human Services

Dennis M. Dixon, PhD, Chief, Bacteriology and Mycology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health and Human Services

Richard I. Horowitz, MD, Hudson Valley Healing Arts Center; member, World Health Organization’s Ad Hoc Committee for Health Equity

David Leiby, PhD, Chief, Product Review Branch, Center for Biologicals Evaluation and Research, U.S. Food and Drug Administration, U.S. Department of Health and Human Services (temporarily stood in for Captain Estella Jones, DVM, Acting Deputy Director, Office of Counterterrorism and Emerging Threats, U.S. Food and Drug Administration, U.S. Department of Health and Human Services)

Lise E. Nigrovic, MD, MPH, Director, Population Health Sciences and Health Services Research Center of the Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital; Chair, Pediatric Emergency Medicine Collaborative Research Committee, American Academy of Pediatrics

Allen L. Richards, PhD, Director, Rickettsial Diseases Research Program, Naval Medical Research Center, U.S. Department of Defense

Robert Sabatino, Founder and Executive Director, Lyme Society Inc.

Vanila M. Singh, MD, MACM, Chief Medical Officer, Office of the Assistant Secretary for Health, U.S. Department of Health and Human Services (absent)

Patricia Smith, President, Lyme Disease Association

Robert Smith, MD, MPH, FACP, FIDSA, Director and Co-Founder, Vector-Borne Disease Laboratory, Main Medical Center Research Institute; Director, Division of Infectious Diseases, Maine Medical Center

HHS Support Staff Present

Designated Federal Officer
James Berger, MS, MT (ASCP), SBB, Senior Blood and Tissue Policy Advisor, Office of HIV/AIDS and Infectious Disease Policy, Office of the Assistant Secretary for Health, U.S. Department of Health and Human Services

Alternate Designated Federal Officer
B. Kaye Hayes, MPA, Deputy Director, Office of HIV/AIDS and Infectious Disease Policy, Office of the Assistant Secretary for Health, U.S. Department of Health and Human Services

Debbie Seem, RN, MPH, Public Health Analyst, Office of HIV/AIDS and Infectious Disease Policy, Office of the Assistant Secretary for Health, U.S. Department of Health and Human Services

Selena Gonzales, MPH, ORISE Fellow, Office of HIV/AIDS and Infectious Disease Policy, Office of the Assistant Secretary for Health, U.S. Department of Health and Human Services

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