Vaccines & Theraputics Report- May 2018

Table 3: Presenters to the Vaccines and Therapeutics Subcommittee

Table 4: Votes Taken by the Vaccines and Therapeutics Subcommittee

Potential Actions

The most prevalent tick-borne infection is Lyme disease, which can be expensive to diagnose and treat. Complications of the disease include heart block, arthritis, and neurologic illness. Additionally, some patients experience persistent fatigue and other symptoms after treatment. The geographic range of risk for Lyme disease continues to increase, as does the number of cases. Risk of infection in the northeastern United States is considered to be primarily peridomestic, as the disease is often acquired in residential yards and adjoining land. Preventive strategies—including personal protective measures, such as tick avoidance, use of repellents and protective clothing, or use of acaricides on lawns—have not been demonstrated to consistently lower peridomestic risk of Lyme disease.

In the United States, Lyme disease is caused by Borreliella burgdorferi sensu stricto, which is transmitted to humans by two species of Ixodes ticks. These ticks are prolific disease vectors because they can infect multiple hosts within a single life cycle, and they can withstand adverse environmental conditions.

Given the prevalence of Lyme disease and the low rates of success with currently employed preventive measures, there is an urgent need for vaccines that would help prevent Lyme disease and perhaps other infections transmitted by Ixodes species in humans. Effective Lyme disease vaccines are feasible, as demonstrated by LYMErix and the success of veterinary Lyme disease vaccines. Further, studies have indicated that a Lyme disease vaccine would be cost effective. (See Appendix A for more information about how the various types of Lyme disease vaccines might work.)

Opportunities for Development of Lyme Disease Vaccines

B. burgdorferi, the spirochete that causes Lyme disease, produces outer surface protein A (OspA) in unfed ticks. Once the infected tick has been exposed to a blood meal, OspA production is downregulated and production of outer surface protein C (OspC) and other spirochete antigens is upregulated, a process that allows B. burgdorferi to be transmitted and establish infection in humans. The spirochete demonstrates a remarkably effective corkscrew motility and has other adaptive features that help it to evade host immunity, disseminate, and colonize tissue. Ultimately, that process supports persistent infection, leading to the health problems associated with Lyme disease.

OspA-based vaccines block transmission of B. burgdorferi by killing the spirochete in ticks, whereas OspA/OspC-based vaccines presumably work by killing the spirochete in both ticks and mammals.

Prospects for a New OspA-Based Vaccine Against Lyme Disease

LYMErix, an OspA-based vaccine that helped protect humans against Lyme disease, was released in 1998, but voluntarily withdrawn in 2002 because of low demand, weak recommendations, and class-action lawsuits. As noted by Stanley Plotkin, MD, Emeritus Professor of Pediatrics, University of Pennsylvania, the vaccine was efficacious, and levels of protective antibody were determined. Levels were more robust in children than adults. Dr. Plotkin believes the vaccine could have been more individually and epidemiologically effective had it been used in children. However, no pediatric studies were conducted for LYMErix prior to the vaccine’s release.

A criticism of the vaccine was that it may have required yearly administration, and a safety concern was possible mimicry between OspA and human leukocyte function antigen-1 (hLFA-1). However, there was no evidence of increased adverse effects in vaccine recipients compared with placebo recipients, and laboratory researchers ultimately concluded that there was no evidence for reactions based on homology with the human antigen.

Research into new vaccines for the prevention of Lyme disease in humans is ongoing. For example, a new OspA vaccine is in development that performed well in early trials. It has the advantages of inclusion of antigens of several European genotypes of B. burgdorferi sensu lato and deletion of the hLFA-1 epitope. Data produced by Valneva showed that a vaccine composed of the LA-2 portions of OspA from six Borreliella species that can cause Lyme disease evoked antibody responses to all six. Comparisons are being made with serum responses to LYMErix, which contained OspA only from B. burgdorferi sensu stricto.

A New Approach to Developing an OspA/OspC-Based Vaccine for Humans

Beyond the OspA vaccine, additional vaccines could be developed using other antigens that are shown to protect against Lyme disease. Protein sequencing of B. burgdorferi shows that all OspA types in North America and Europe are closely related. In contrast, OspC types differ in terms of their amino acid sequences. More important, only some OspC variants elicit cross-reactivity, which has complicated efforts to develop OspA/OspC-based vaccines.

To address the lack of OspC cross-reactivity, Richard Marconi, PhD, Professor, Department of Microbiology & Immunology, Virginia Commonwealth University School of Medicine, and colleagues conducted an epitope mapping analysis and discovered that the L5 and H5 epitopes are the regions of OspC that trigger antibody responses in mice. Both epitopes are also the most hypervariable parts of OspC. Based on these discoveries, researchers decided to join the L5 and H5 epitopes and create a brand-new protein called a chimeritope.

Ultimately, efforts to create usable chimeritopes proved successful in the development of VANGUARD crLyme, a subcutaneous OspA/OspC-based vaccine for dogs. The vaccine helps prevent canine Lyme disease by inhibiting B. burgdorferi transmission from ticks and eliciting antibodies against B. burgdorferi.

Based on the experience in veterinary studies, Dr. Marconi maintains that the chimeritope approach to vaccine development has the potential to result in a Lyme disease vaccine for humans and perhaps be adapted to include immunogens for co-infecting pathogens.

Anti-Tick Vaccines: Another Area of Promise

Utpal Pal, PhD, Professor and Director, Veterinary Medical Sciences Graduate Program, University of Maryland College of Agriculture and Natural Resources, discussed the possibility that administering anti-tick vaccines to both animal hosts and humans could help double efforts to prevent transmission of the organism that causes Lyme disease.

Tick feeding is a slow, multi-stage process that begins with a bite and ends a few days later with full engorgement of the tick. B. burgdorferi resides in the tick’s gut prior to a blood meal. After tick feeding has begun, the pathogen migrates to the salivary glands, and the tick injects salivary gland antigens into its host. Ticks are most vulnerable during the blood meal. For that reason, the ideal anti-tick vaccine would interfere with tick physiology during feeding or prevent feeding altogether. An advantage of such an approach is that it could theoretically prevent transmission of Lyme disease, anaplasmosis, and babesiosis by interruption of tick feeding, as most pathogens that are transmitted by I. scapularisusually require more than 24 hours of feeding to infect a host.

Dr. Pal is involved in research around vaccines that target three major categories of tick salivary-gland antigens, or proteins. Those three categories include attachment proteins, immunomodulatory proteins, and allergy or physiology proteins.

Attachment proteins facilitate the tick’s blood meal. A vaccine that neutralizes attachment proteins leads to inflammation at the tick site, thereby resulting in impaired blood feeding.

Immunomodulatory proteins affect host immune response. Vaccines that target those proteins work by reducing transmission and/or acquisition of B. burgdorferi; reducing or partially controlling spirochete load; or impairing tick feeding.

Allergy or physiology proteins facilitate tick engorgement or regulate important functions, such as blood coagulation, food digestion, and inflammatory and immune responses. A vaccine that targets those proteins can impact transmission of B. burgdorferi.

Additional research has been done using anti-tick vaccines based on tick gut antigens, tick gut barrier antigens, and ubiquitous tick antigens.

Two vaccines that are based on the gut antigen Bm86 are already available for veterinary use in Australia and certain parts of Latin America. Another gut protein of interest to researchers is a tick receptor for B. burgdorferi outer surface protein A (TROSPA). Research suggests that blocking TROSPA can reduce B. burgdorferi colonization of the tick as well as pathogen transmission to the host. Additionally, one type of salivary gland antigen that causes inflammatory and immune responses at the tick site also tends to cross-react with gut antigens, thereby rupturing the tick gut and killing engorged ticks.

Tick gut barrier antigens are a relatively new area of research. Strategies targeting these types of proteins can either interfere with transmission or impair pathogen persistence.

Ubiquitous tick antigens that impact pathogen transmission include subolesin and ferritin. Subolesin-targeted vaccination impairs tick feeding and oviposition, whereas ferritin-targeted vaccination helps reduce tick feeding, oviposition, and fertility.

Dr. Pal notes that including a combination of tick proteins—in addition to selected B. burgdorferiproteins that assist in pathogen transmission, such as BBA52—as components of an anti-tick vaccine would help ensure prevention of pathogen transmission, impairment of the blood meal engorgement process, or the killing of ticks. However, given the small size of many tick antigens, it is likely that anti-tick vaccines would require either an adjuvant or multivalence to help ensure a high degree of immunogenicity.

Reservoir Targeted Vaccines

Some researchers have advocated for integrated tick management strategies that would use vaccines to interrupt enzootic transmission of B. burgdorferi. Such strategies might involve vaccines that target tick salivary gland proteins or OspA-based reservoir targeted vaccines (RTVs) that are administered orally to mice via bait.

The work of Maria Gomes-Solecki, DVM, Associate Professor, Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, has primarily focused on the Escherichia coli OspA RTV. Data from field trials conducted in 2007 through 2012 in Millbrook, New York, demonstrate that deployment of the vaccine over 3 to 5 years significantly reduces the prevalence of infection among ticks in the environment. These promising data have been partially corroborated by the results of two 12-month field studies conducted by Jean Tsao, PhD, from 1998 through 2002 in Connecticut.

The advantage of using E. coli as a delivery vehicle for an RTV is that the bacteria do not reproduce outside specialized culture conditions. Therefore, the E. coli OspA RTV is safe for distribution in peridomestic areas. The vaccine’s main disadvantage is that it requires multiple doses to be immunogenic and protective, and significant protection requires multi-year consecutive use. However, ecologists report that the typical mouse spends most of its life in proximity to the area where it was born. Therefore, it is reasonable to expect that mice will continue to mobilize around E. coli OspA RTV bait stations and ingest the multiple doses that are required for immunogenicity.

The Vaccinia virus-delivered OspA RTV has been the focus of work by Linden Hu, MD. Unlike the E. coli OspA RTV, the Vaccinia virus-delivered OspA RTV requires only one dose for immunogenicity and protection. Vaccinia is a replicating virus that is considered less safe than E. coli for distribution in peridomestic areas. However, in a key study of the Vaccinia virus-delivered OspA RTV, no Vaccinia or OspA was detected in the soil at any time.

According to Dr. Gomes-Solecki, the best ecological approach to Lyme disease prevention would be a two-pronged strategy that leverages the strengths of each RTV. She envisions distribution of the E. coliOspA RTV to local governments and pest management companies for use in backyards and deployment of a virus-delivered OspA RTV in non-populated wild areas to provide barriers against expansion of the Lyme disease spirochete into new territory.

Currently, the E. coli OspA RTV is in the process of being licensed by the U.S. Department of Agriculture for commercial application. The virus-delivered OspA RTV is awaiting final testing for efficacy and safety.

Survey findings suggest that an RTV-based approach is likely to appeal to persons who are younger, have children and pets at home, and are ecologically conscious. More research is needed to determine the cost-effectiveness of RTVs and the amount of land that would require protection to prevent expansion of the Lyme disease spirochete. The scientific community also awaits the release of data regarding possible unintended consequences of an E. coli OspA RTV.

Currently Available Antimicrobial Drugs for Lyme Disease

A number of antimicrobial drugs are used to treat Lyme disease. A list of those antimicrobial drugs whose use is supported in randomized controlled clinical trials (RCTs) can be found in Appendix B.

According to Subcommittee Co-Chair Robert P. Smith, MD, MPH, Director, Vector-Borne Disease Laboratory, Maine Medical Center Research Institute, the ideal antibiotic for Lyme disease treatment would be highly effective in treatment of individuals diagnosed with different stages of infection. Relapse after treatment would be rare. Other desirable characteristics would include ease of administration, a low side-effect profile, and low cost. Additionally, the ideal antibiotic would not promote the development of bacterial resistance, and it would be safe and effective for use in children, women who are pregnant or breastfeeding, and immunocompromised patients.

Multiple North American and European RCTs have compared the effectiveness of available antibiotics for treatment of different stages of Lyme disease. These trials demonstrate that oral doxycycline, amoxicillin, and cefuroxime axetil are all effective and generally well tolerated in the treatment of patients with early Lyme disease. Macrolides, such as azithromycin, appear to be slightly less efficacious. For treatment of neuroborreliosis, use of intravenous (IV) ceftriaxone, IV cefotaxime, or IV penicillin is supported by RCTs, and in one European RCT, oral doxycycline and IV ceftriaxone were equally efficacious. Several relatively small RCTs demonstrated similar efficacy of oral agents (that is, doxycycline or amoxicillin) and IV penicillin or ceftriaxone for Lyme arthritis. Adverse effects may occur with any antibiotic regimen, but are generally less frequent or severe with oral antibiotic treatment than with IV regimens.

As Juan C. Salazar, MD, MPH, FAAP, Professor and Chair, Department of Pediatrics, University of Connecticut Health Center, noted in his discussion of antibiotic use in special populations, the agents noted above to be effective in RCTs are also used in children and during pregnancy and lactation, with the exception of doxycycline, which is not preferred in children younger than 8 years and is contraindicated during pregnancy. Treatment recommendations do not change in immunocompromised individuals.

Non-Antimicrobial Drugs for Late-Lyme Arthritis and PTLDS

As John Aucott, MD, Director, Johns Hopkins Lyme Disease Clinical Research Center, has reported, several non-antimicrobial drugs are used off label in two categories of patients—those with antibiotic-refractory late-Lyme arthritis and others with post-treatment Lyme disease syndrome (PTLDS). Medications used to treat antibiotic-refractory late-Lyme arthritis include hydroxychloroquine, methotrexate, and biologicals, whereas a plethora of medications are used to treat pain, fatigue, and cognitive symptoms in patients with PTLDS. A complete list of the medications can be found in Appendix C.

There are several underlying reasons for the wide range of approaches to care for patients who have PTLDS. Key reasons include patient and physician uncertainty as to the cause of PTLDS symptoms with attendant medical ambiguity as to how to respond. Although patients with PTLDS show no evidence of anatomic neurologic damage, deficits in cognitive processing can be measured during neurocognitive testing. Availability of FDA-approved drugs to treat PTLDS might help address some of these issues.

Compounded Medications

According to Richard Horowitz, MD, Medical Director, Hudson Valley Healing Arts Center, one or more tick-borne infections—in combination with environmental toxins—can increase autoimmune manifestations and inflammation. In turn, inflammation and its downstream effects contribute to fatigue, pain, and neuropsychiatric symptoms in patients with Lyme disease.

In his practice, Richard uses compounded medications and herbal preparations intended to help block the production of inflammatory cytokines, lower inflammation, and increase detoxification in patients with persistent Lyme disease symptoms. Also, compounding allows for flexible dosing. Additionally, some compounded medications may be available in liposomal formulations; others may be free of dyes or excipients.

Appendix D includes a list of the compounded medications and herbal preparations that Dr. Horowitz uses to combat inflammation and the detrimental effects of exposure to endogenous and exogenous toxins. He advises clinicians to evaluate all possible sources of inflammation in a patient with Lyme disease and tailor treatment accordingly.

Opportunities for Development of New Therapeutics for Lyme Disease

In its discussions, the subcommittee considered the role that bacterial persistence might play in Lyme arthritis and PTLDS. Bacterial persistence is a widespread phenomenon that was first reported in the medical literature in 1942. In cases of bacterial persistence, antibiotic-tolerant cells, which are referred to as “persister cells,” are present in small amounts despite antimicrobial treatment, and they are less susceptible to antibiotics than normal antibiotic-sensitive cells.

In his presentation to the subcommittee, Felipe C. Cabello, MD, Professor of Microbiology and Immunology, New York Medical College, discussed the presence of persister cells in bacteria in general and specifically in B. burgdorferi. He commented on the widespread occurrence of persistence in bacteria, its potential relevance to antibiotic treatment failures in several bacterial infections, and the search for antimicrobials to eliminate persister cells. He also showed data from published studies suggesting that the bacterial organism’s growth phase influences its susceptibility to antimicrobials and generation of persister cells, and that these phenomena have been shown to occur in B. burgdorferi in vitro and in animal models.

According to Dr. Cabello, the prevalence of B. burgdorferi persister cells appears to be influenced by the organism’s population density and growth phase as well as by mechanisms that increase its adaptability to metabolic and nutritional challenges encountered in the mammalian and tick host. He concluded by recommending investigation of the possible role of persistence in patients with late manifestations of Lyme disease, including Lyme arthritis and PTLDS.

In another presentation, Monica E. Embers, PhD, Director, Vector-Borne Diseases Core, Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University School of Medicine, discussed research attesting to the persistence of B. burgdorferi in animal models, such as dogs, mice, and non-human primates. Specifically, there is evidence of persistent, intact, metabolically active B. burgdorferi after antimicrobial treatment of disseminated infection in rhesus macaques. The evidence to date in the studies she summarized includes visual demonstration in specifically stained tissue sections and molecular demonstration by assays such as polymerase chain reaction for nucleic acid, as well as assays that detect transcriptional activity. Of note, none of the summarized studies included evidence of viability by growth on culture media.

Histopathologic findings in rhesus macaques could be attributable to residual inflammation in and around tissues that harbor a low burden of persistent host-adapted spirochetes and/or residual spirochetal antigens. However, foci of inflammation are quite rare. More research is needed to determine whether the presence of such rare foci can be the source of systemic illness and, if so, what the mechanism might be.

Discussion

To improve public health with respect to Lyme disease, there is a need for a safe and effective human vaccine as well as therapeutics that target the causes of persistent symptoms in patients with Lyme disease. Accordingly, the subcommittee has identified the following priority areas for future exploration and discussion.

1. Human vaccines for Lyme disease should be a top priority focus for the next phase of the Tick-Borne Disease Working Group initiative.
2. Assessment of therapeutics for PTLDS should be an area of priority. A prerequisite for that assessment is an understanding of disease etiology (that is, underlying causes and mechanisms) in individual patients, including children and adolescents.

Human Vaccines for Lyme Disease

Vaccines have changed the course of infectious diseases and saved countless lives, and are accordingly a proven public health mainstay. Unfortunately, for many key infectious diseases, such as tuberculosis, malaria, and HIV, effective and widely adopted vaccines remain elusive. The once-licensed LYMErix vaccine for human Lyme disease was effective (with nearly 80% efficacy) for the first year following two doses. Public and scientific concerns over the issue of cross-reactivity with human tissue limited public uptake. As a result, company support was withdrawn. Subsequent scientific studies and analyses minimized and essentially addressed scientific concerns, yet public concerns remain. Addressing current barriers to acceptance by both the general public and industry will be essential to helping ensure successful reintroduction of a Lyme disease vaccine for humans. Success is likely to require a combination of scientific progress; company, public, and federal agency engagement; and patient advocacy.

Scientific opportunities abound for microbe-targeted vaccines, such as newer approaches to enhance immunogenicity, the removal of components thought by some to harbor autoimmune potential, and the targeting of additional species of Borrelliela. The latter two objectives have already been met in several vaccine candidates. The subcommittee envisions a tiered approach to vaccine introduction—that is, spurring the release of an OspA- and/or OspA/C-based vaccine(s), which could be available on a shorter timeline as development of other approaches continues. To narrow the focus of vaccine research among many of the identified immunogens, an early step is the testing of immunogenicity and vaccine efficacy in animal hosts given an infected (multiple strain) tick challenge. Opportunities to prevent infection using reservoir (mouse) host targeted and vector (tick) targeted vaccine strategies as part of an integrated tick management approach also deserve continued evaluation based upon the scientific work noted above.

Antimicrobial and Non-Antimicrobial Therapeutics for Lyme Disease

A deeper understanding of what causes PTLDS is needed to select appropriate treatment for patients who continue to experience clinical signs and symptoms following treatment with currently available antibiotics. The causes may differ among patients. Multiple RCTs have documented the efficacy of currently available antimicrobials for treatment of acute Lyme disease in well-defined patient populations and for treatment of the most common extra-cutaneous presentations—that is, neuroborreliosis and Lyme arthritis. Nevertheless, there are sub-populations of patients who develop PTLDS after undergoing recommended treatment. Additionally,to date, none of the currently available non-antimicrobial therapeutics have label indications for relief of pain, fatigue, and cognitive symptoms resulting from infection with B. burgdorferi or for treatment of the infection itself, and efficacy studies for such therapeutics are very limited.

Dr. Aucott presented data documenting how patients with PTLDS feel and function. Clearly, more needs to be done to address the signs and symptoms of PTLDS, which usually differ from the clinical manifestations (such as rash, neuropathy, or joint swelling) typically associated with untreated infection. Ideally, the approach would be based upon a clearer understanding of the genesis of PTLDS symptoms in each patient. Causes to consider include effects of a protracted host immune response, other causes of autoimmunity or cross-reactivity, collateral effects of prior antibiotic treatments, and systemic responses to bacterial persistence. With direction provided by increased scientific evaluation of the pathogenesis of illness, evidence-based therapeutics can be more effectively developed. Emphasis on understanding the causes of disease and improving symptom management represent opportunities to move beyond some of the ongoing controversy regarding strategies for treatment of PTLDS.

Appendix A. How Vaccines Might Help Prevent Lyme Disease

OspA Vaccines

• Block transmission of B. burgdorferi by killing the spirochete in ticks

OspA/OspC-Based Vaccines

• Block transmission of B. burgdorferi by killing the spirochete in both ticks and mammals

Anti-Tick Vaccines

• Neutralize the tick’s attachment proteins that facilitate a blood meal, which impairs tick feeding
• Target the tick’s immunomodulatory proteins that affect host immune response, which:
  • Reduces transmission and/or acquisition of the causative organism
  • Reduces or partially controls spirochete load
  • Impairs tick feeding
• Target allergy or physiology proteins that facilitate tick engorgement or regulate important functions, which impacts pathogen transmission
• Block a tick receptor for B. burgdorferi OspA, which:
  • Reduces pathogen colonization of the tick
  • Reduces pathogen transmission to the host
• Cause a cross-reaction with tick gut antigens, which:
  • Ruptures the tick gut
  • Kills engorged ticks
• Target tick gut barrier antigens, which:
  • Interferes with transmission
  • Impairs pathogen persistence
• Target ubiquitous tick antigens, which:
  • Impairs tick feeding
  • Interferes with the tick’s ability to lay eggs
  • Decreases tick fertility

Reservoir Targeted Vaccines

• Kill the spirochete in ticks that feed on mice
• Reduce the prevalence of infection among ticks and mice in the treated environment

Appendix B. Antimicrobial Drugs in Current Use for Treatment of Lyme Disease with Documented Efficacy in RCTs

Oral

• Tetracyclines (doxycycline)
• Penicillins (amoxicillin, phenoxymethylpenicillin)
• Cefuroxime axetil
• Macrolides (azithromycin)

Intravenous

• Ceftriaxone
• Cefotaxime
• Penicillin

Appendix C. Non-Antimicrobial Drugs Used Off-Label to Treat Lyme Disease

Antibiotic-Refractory Late Lyme Arthritis

• Hydroxychloroquine
• Methotrexate
• Biologicals
• Compounded medications

PTLDS Symptoms

Pain[1]

• Drugs for musculoskeletal and joint pain
  • Acetaminophen
  • Non-steroidal anti-inflammatory drugs
  • Muscle relaxants
  • Topical analgesics, such as lidocaine patches, capsaicin cream, and diclofenac gel
  • Note that opiates are not indicated
• Musculoskeletal anti-inflammatory drugs
  • Prednisone (used but not recommended)
  • Hydroxychloroquine
• Drugs for neuropathic pain
  • Gabapentin
  • Pregabalin
  • Compounded pain creams
• Drugs approved for fibromyalgia
  • Pregabalin
  • Duloxetine hydrochloride
  • Milnacipran hydrochloride
• Compounded medications

Fatigue[2]

• Dopamine-norepinephrine reuptake inhibitors, such as bupropion
• Stimulants
  • Adderall®
  • Modafinil
• Drugs to treat sleep disruption
  • Tricyclic antidepressants (not FDA-approved)
  • Other sleep aids
• Compounded medications

Cognitive Symptoms[3]

• Drugs typically used to treat attention-deficit/hyperactivity disorder
  • Methylphenidate
  • Adderall®
• Stimulants
  • Adderall®
  • Modafinil
• Drugs to treat sleep disruption
  • Tricyclic antidepressants (not FDA-approved)
  • Other sleep aids
• Compounded medications

Appendix D. Compounded Medications and Supplements in Use for PTLDS

• Low-dose naltrexone
• Dimercaptosuccinic acid (better known as DMSA) and other heavy metal chelators
• Glutathione
• Liposomal formulations (artemisia extracts, oregano oil, curcumin)
• Compounded hormones: thyroid, sex hormone
• Dye- and/or excipient-free compounded antibiotics for patients with environmental illness or chemical sensitivity
• Other compounded medications, such as methylene blue

[1] Patients experiencing pain associated with PTLDS may have co-existing depression, which may be treated with either selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors.

[2] Patients experiencing fatigue associated with PTLDS may benefit from identification and treatment of co-existing conditions, such as sleep apnea, restless leg syndrome, postural orthostatic tachycardia syndrome, and depression.

[3] Patients experiencing cognitive symptoms associated with PTLDS may benefit from identification and treatment of co-existing conditions, such as pain, fatigue, and depression.

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Content last reviewed on May 9, 2018Link Here- https://www.hhs.gov/ash/advisory-committees/tickbornedisease/reports/vaccines-and-therapeutics-2018-5-9/index.html