A Comprehensive Monograph on the Tick-Borne Encephalitis Vaccine (Whole Virus, Inactivated) - TicoVac™ (DB16611)

Executive Summary

This report provides a comprehensive monograph on the Tick-borne encephalitis vaccine (whole virus, inactivated), identified by DrugBank ID DB16611, a biotech product marketed principally as TicoVac™ and FSME-Immun®. This vaccine represents the single most effective public health tool for the primary prevention of Tick-Borne Encephalitis (TBE), a potentially severe and life-threatening neuroinvasive disease for which no specific antiviral treatment exists. The vaccine is a formalin-inactivated, whole-virus preparation derived from the Tick-Borne Encephalitis Virus (TBEV) propagated in cell culture and adjuvanted with aluminum hydroxide.

The vaccine's mechanism of action is the induction of a robust humoral immune response, characterized by the production of TBEV-neutralizing antibodies. These antibodies are the primary correlate of protection and have been shown to provide cross-protective immunity against all three major TBEV subtypes (European, Siberian, and Far Eastern). The clinical development program, comprising extensive trials in both adult and pediatric populations, has consistently demonstrated high immunogenicity, with seropositivity rates exceeding 98% after the completion of a three-dose primary immunization series.[1]

Furthermore, the vaccine's efficacy is powerfully substantiated by decades of real-world use in national immunization programs, particularly in Austria, where field effectiveness in preventing hospitalized TBE has been estimated at over 96%.[1] The safety profile of the vaccine is well-characterized and favorable, with the most common adverse events being mild and transient local or systemic reactions. Its long history of use, with hundreds of millions of doses administered in Europe, provides an exceptionally high degree of confidence in its safety.[3]

International public health bodies, including the World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC), recommend the vaccine for at-risk populations, including residents of and travelers to TBE-endemic regions who are likely to have occupational or recreational exposure to ticks.[4] The availability of flexible standard and rapid dosing schedules enhances its utility, particularly for international travelers. This monograph synthesizes the virological, manufacturing, clinical, and public health data to serve as an authoritative reference on this critical vaccine.

Section 1: The Target Pathogen and Disease: Tick-Borne Encephalitis (TBE)

To fully appreciate the role and value of the TBE vaccine, it is essential to first understand the pathogen it targets and the disease it prevents. Tick-Borne Encephalitis is a significant cause of viral neurological disease across Eurasia, presenting a substantial public health challenge due to its potential for severe morbidity, long-term sequelae, and mortality, compounded by the absence of a specific curative therapy.

1.1 Virology and Pathogenesis of the TBE Virus (TBEV)

The causative agent of TBE is the Tick-Borne Encephalitis Virus (TBEV), an enveloped, single-stranded RNA virus. It is a member of the family Flaviviridae and the genus Flavivirus, placing it in the same family as other significant human pathogens such as West Nile virus, dengue virus, yellow fever virus, and Zika virus.[6] The viral particle, or virion, is a smooth sphere approximately 50 nanometers in diameter. Its genome encodes three structural proteins—Capsid (C), pre-Membrane/Membrane (prM/M), and Envelope (E)—and seven non-structural (NS) proteins that are essential for viral replication.[7] The E protein, which covers the surface of the virion, is the most critical component for pathogenesis and immunity, as it mediates the virus's attachment to and entry into host cells. It is also the primary target for the host's neutralizing antibody response.[7]

TBEV is categorized into three principal subtypes, which are distinguished by their genetic makeup, geographic distribution, and associated clinical severity:

• European subtype (TBEV-Eu): Predominant in western, central, and northern Europe.
• Siberian subtype (TBEV-Sib): Found primarily in the Asian parts of Russia.
• Far Eastern subtype (TBEV-Fe): Circulates in eastern Russia, northern China, and Japan.[4]

The existence of these distinct subtypes presents a fundamental challenge for disease prevention, as any effective vaccine must be capable of inducing an immune response that is broadly protective against all three variants.

1.2 Epidemiology, Transmission, and Global Distribution

TBE is endemic across a vast geographical belt stretching from western and northern Europe to northern and eastern Asia.[10] While official reports document approximately 10,000 to 12,000 clinical cases annually, this figure is widely believed to be a significant underestimation of the true disease burden due to variations in surveillance and reporting systems.[4]

The virus is maintained in a natural cycle involving tick vectors and vertebrate hosts. Ticks serve as both the primary vector and the reservoir for the virus. The main vectors responsible for transmission to humans are Ixodes ricinus in Europe (transmitting TBEV-Eu) and Ixodes persulcatus in Asia (transmitting TBEV-Sib and TBEV-Fe).[8] Small rodents are the primary amplifying hosts, while larger mammals can support tick populations.[6]

The primary mode of transmission to humans is through the bite of an infected tick, which can occur during any of its life stages (larva, nymph, or adult).[8] A less common but documented route of infection is the alimentary route, through the consumption of unpasteurized milk or dairy products from infected goats, sheep, or cows.[9] Humans are considered incidental or dead-end hosts, as they do not typically develop a high enough level of virus in their blood to transmit it to other feeding ticks. Consequently, direct person-to-person transmission does not occur, with the rare exception of vertical transmission from an infected mother to her fetus.[6]

The geographic distribution of TBE is not uniform but is characterized by its occurrence in distinct natural foci. These are typically woodland habitats, such as deciduous forests and the transitional zones between forests and grasslands, at altitudes up to about 2,000 meters.[6] The risk of transmission is highly seasonal, coinciding with the peak activity of ticks during the warmer months, generally from April through November in the Northern Hemisphere.[11]

1.3 Clinical Presentation, Sequelae, and Disease Burden

Infection with TBEV does not always result in clinical illness; approximately two-thirds of infections are asymptomatic.[6] When symptoms do occur, the disease often manifests in a characteristic biphasic course.[6]

• Phase 1 (Viremic Phase): Following an incubation period of about 7 to 14 days, the first phase begins. It is characterized by non-specific, flu-like symptoms, including fever, fatigue, headache, muscle pain (myalgia), and nausea.[6] This phase typically lasts for 2 to 10 days and corresponds to the presence of the virus in the bloodstream.
• Asymptomatic Interval: The first phase is followed by an asymptomatic period lasting from 1 to 33 days (commonly about one week), during which the patient feels better.[6] This interval can create a false sense of recovery, which is a particularly insidious feature of the disease. The initial non-specific symptoms are easily dismissed or misdiagnosed as a common viral illness. By the time the patient appears to have recovered, the virus may be invading the central nervous system, setting the stage for a much more severe and untreatable phase of the disease. This clinical progression underscores the critical importance of pre-exposure prophylaxis, as there is no effective intervention once the neurological stage begins.
• Phase 2 (Neurological Phase): In up to 30% of symptomatic patients, the disease progresses to a second phase, marked by the involvement of the central nervous system (CNS).[6] This phase can manifest as meningitis (inflammation of the membranes surrounding the brain and spinal cord), encephalitis (inflammation of the brain itself), or meningoencephalitis (inflammation of both). Symptoms include high fever (often exceeding 40°C), severe headache, neck stiffness, confusion, sensory disturbances, loss of coordination, and in severe cases, paralysis or seizures.[9]

The severity and outcome of TBE are highly dependent on the viral subtype and the age of the patient.

Table 1: Comparison of TBE Virus Subtypes (Clinical and Epidemiological Features)
Subtype	Primary Vector	Geographic Region	Typical Mortality Rate	Rate/Nature of Neurological Sequelae
European (TBEV-Eu)	Ixodes ricinus	Western, Central, Northern Europe	0.5% - 2%	Up to 10% of patients suffer long-term or permanent neurological problems.6
Siberian (TBEV-Sib)	Ixodes persulcatus	Siberia, Asian parts of Russia	1% - 3%	Patients tend to develop chronic or long-term disease.9
Far Eastern (TBEV-Fe)	Ixodes persulcatus	Eastern Russia, China, Japan	Up to 35%	Higher rate of severe, permanent neurological problems.9

Severity also increases significantly with age. Children often experience a milder course, typically limited to meningitis, whereas adults over 40 are at a higher risk of developing severe encephalitis. The highest rates of mortality and long-lasting sequelae are observed in individuals over the age of 60.[6] There is no specific antiviral treatment for TBE. Management is purely supportive, often requiring hospitalization for hydration, respiratory support, and reduction of brain swelling.[9]

1.4 Risk Factors and Non-Vaccine Prevention Strategies

The risk of acquiring TBE is not uniformly distributed but is concentrated among individuals whose activities bring them into contact with tick-infested environments. The risk is less a function of mere presence in an endemic country and more intricately linked to specific human behaviors that intersect with tick ecology. This makes TBE a disease of behavior as much as geography. A person's itinerary and lifestyle are more predictive of risk than their nationality. This understanding is fundamental to public health messaging and clinical risk assessment, explaining why vaccination recommendations are activity-based rather than based on broad geography.[5]

High-risk groups include people with occupational or recreational exposure in endemic forested areas, such as:

• Forestry workers, farmers, and military personnel.[6]
• Individuals engaging in outdoor activities like hiking, camping, fishing, hunting, birdwatching, or collecting mushrooms and berries.[6]

Non-vaccine prevention strategies are important but have limitations. These measures focus on avoiding tick bites and include:

• Using tick repellents on skin and clothing.
• Wearing protective clothing, such as long trousers tucked into socks.[6]
• Performing thorough body checks for ticks after outdoor activities and promptly removing any attached ticks.[6]
• Avoiding the consumption of unpasteurized dairy products in endemic areas.[6]

While these measures reduce risk, they are behavior-dependent and not completely effective; tick bites can go unnoticed in a significant number of cases.[8] This reality elevates vaccination to the status of the single most effective means of preventing TBE, a position supported by major public health organizations like the WHO and CDC.[6]

Section 2: Vaccine Profile: TicoVac™ (Tick-Borne Encephalitis Vaccine, Whole Virus, Inactivated)

The vaccine identified by DrugBank ID DB16611 is a well-established biotech product designed for the active immunization against TBE. It has a long history of use and a well-defined regulatory and compositional profile.

2.1 Product Overview and Regulatory Status

The vaccine is a whole virus, inactivated preparation. It is manufactured by Pfizer and marketed under several brand names globally. In the United States, it is known as TicoVac™, while in Europe and other regions, it is commonly known as FSME-Immun®.[3] A similar inactivated TBE vaccine,

Encepur®, is manufactured by Bavarian Nordic and is also widely used in Europe.[15]

TicoVac™ has a long and successful history, having been used in Europe for over 45 years.[2] This extensive period of post-marketing use provided a vast repository of safety and effectiveness data that supported its more recent regulatory approvals elsewhere. On August 13, 2021, the U.S. Food and Drug Administration (FDA) approved TicoVac™ for active immunization to prevent TBE in individuals one year of age and older.[3] In Europe, the vaccine holds marketing authorization in numerous countries, with regulatory oversight provided by national agencies such as the Paul-Ehrlich-Institut in Germany.[18]

The existence of multiple brands based on similar technology, such as TicoVac/FSME-Immun and Encepur, which may utilize different virus strains and have slightly different approved age ranges in some jurisdictions, creates a complex regulatory and clinical landscape.[15] While the vaccines are often discussed collectively in terms of their public health impact, clinicians must adhere to the specific guidelines and Summary of Product Characteristics (SmPC) for the particular product being administered. This has also prompted research into the interchangeability of these vaccines in immunization schedules.[1]

2.2 Composition and Formulation

TicoVac™ is a sterile, off-white, homogenous, opalescent suspension for intramuscular injection.[16] Its design is based on a classic and well-understood technological platform: the whole inactivated virus. This approach involves using the entire, intact TBE virus particle, which has been rendered non-infectious.

The manufacturing process begins with the propagation of a specific TBEV strain (e.g., the Neudoerfl strain) in chick embryo fibroblast (CEF) cells.[7] The harvested virus is then chemically inactivated with formaldehyde, a process that kills the virus, making it incapable of replicating or causing disease.[3] This inherent inability to replicate is a key safety feature, allowing the vaccine to be administered to individuals with weakened immune systems, a significant advantage over live-attenuated vaccines.[20] However, because an inactivated virus typically elicits a less robust immune response than a live virus, the vaccine formulation includes an adjuvant to enhance its immunogenicity.

The final formulation is precisely defined and contains several key components:

Table 2: TicoVac™ Product Characteristics and Formulation
Product Name	TicoVac™ (FSME-Immun®)
DrugBank ID	DB16611
Vaccine Type	Whole Virus, Inactivated
Manufacturer	Pfizer Inc.
Active Ingredient	Inactivated Tick-Borne Encephalitis Virus (TBEV)
Antigen Content	Adult Dose (0.5 mL): 2.4 micrograms (µg) Pediatric Dose (0.25 mL): 1.2 micrograms (µg)
Adjuvant	Aluminum hydroxide (0.35 mg in adult dose)
Key Excipients	Human Serum Albumin (stabilizer), sodium chloride, dibasic sodium phosphate, monobasic potassium phosphate
Presentation	Sterile suspension for intramuscular (IM) injection
Residuals	May contain trace amounts of formaldehyde, sucrose, protamine sulfate, chick proteins, neomycin, and gentamicin

Data sourced from.[7]

The use of aluminum hydroxide as an adjuvant is a standard practice for many inactivated vaccines; it works by stimulating local immune cells and keeping the antigen at the injection site for a longer period, thereby improving the overall immune response.[21] Human serum albumin acts as a stabilizer to maintain the vaccine's integrity. The presence of trace residual amounts of substances from the manufacturing process, such as chick proteins and antibiotics, are important considerations for individuals with known severe allergies and are disclosed in all regulatory filings.[19] The vaccine is formulated without preservatives.[19]

Section 3: Mechanism of Action and Pharmacodynamics

The TBE vaccine confers protection by actively stimulating the host's immune system to develop a targeted and durable defense against the TBE virus. The process relies on the principles of adaptive immunity, specifically the generation of neutralizing antibodies.

3.1 Induction of Humoral Immunity

The vaccine works by introducing inactivated, non-infectious TBE virions into the body, thereby causing the production of protective antibodies.[16] When administered via intramuscular injection, the viral antigens are taken up by specialized immune cells known as antigen-presenting cells (APCs). These APCs process the viral proteins and present fragments of them on their surface to other immune cells, primarily T-helper cells. The activated T-helper cells then orchestrate a broader immune response, which includes stimulating B-cells to mature and differentiate into plasma cells. These plasma cells are responsible for producing large quantities of TBEV-specific antibodies.[20] A subset of these activated B-cells also become long-lived memory B-cells, which provide the basis for long-term immunity.

3.2 Role of Neutralizing Antibodies and Correlates of Protection

The primary mechanism by which the vaccine-induced antibodies protect against TBE is through viral neutralization.[3] The most effective of these are neutralizing antibodies, which bind to critical sites on the virus's surface, particularly on the Envelope (E) protein. By binding to the E protein, these antibodies can physically block the virus from attaching to and entering host cells, effectively preventing infection from taking hold.[7]

The entire clinical development and regulatory approval pathway for this vaccine is built upon the acceptance of neutralizing antibody titers as a valid surrogate for clinical protection. Conducting traditional, large-scale, placebo-controlled efficacy trials for a disease with a relatively low incidence like TBE would be logistically and ethically infeasible.[5] In response to this challenge, regulatory bodies have accepted a strong immunogenicity endpoint as sufficient evidence for licensure. Based on extensive animal and human data, a consensus has formed that the presence of neutralizing antibodies is a reliable indicator of protection. While a formal, absolute correlate of protection has not been established, a neutralizing antibody (NT) titer of

≥10 is generally accepted and used as the threshold to define a seropositive, and likely protected, state.[4] This pragmatic approach, which relies on a surrogate endpoint, is powerfully validated by the decades of real-world effectiveness data confirming that high antibody levels translate directly to a dramatic reduction in clinical disease.

3.3 Cross-Protective Immunity Across TBEV Subtypes

A critical feature of the TBE vaccine is its ability to induce immunity that is effective against all three major TBEV subtypes. TicoVac™ is developed using a strain of the European subtype (TBEV-Eu).[3] Despite the genetic and pathogenic differences between the European, Siberian, and Far Eastern subtypes, their surface E proteins are antigenically similar enough that the immune response generated against one provides protection against the others. Studies have confirmed that vaccination with a TBEV-Eu-derived vaccine induces broadly reactive, cross-neutralizing antibodies that are effective against the more virulent Siberian and Far Eastern subtypes.[2]

This antigenic conservatism of the TBE virus is a major public health advantage. It greatly simplifies vaccination logistics and travel medicine recommendations. A traveler planning to visit multiple regions within the TBE-endemic zone does not need to worry about which specific viral subtype they might encounter. A single primary immunization series provides broad protection, making pre-travel counseling straightforward and ensuring that individuals are protected regardless of the specific viral lineage prevalent at their destination. This stands in stark contrast to other viruses, like influenza, where significant antigenic drift necessitates frequent reformulation of vaccines.

Section 4: Manufacturing and Quality Control

The production of the TBE vaccine is a complex bioprocess that requires rigorous control at every stage to ensure the final product is safe, pure, and potent. The safety profile of an inactivated vaccine is fundamentally determined by the quality and validation of its manufacturing process.

4.1 Cell-Based Virus Propagation and Harvest

The manufacturing process begins with the large-scale propagation of the TBE virus. TicoVac™ is produced using a cell-based platform where the virus is grown in chick embryo fibroblast (CEF) cells.[19] This method allows for the generation of large quantities of virus under highly controlled and reproducible conditions in bioreactors.[22] The upstream process is carefully optimized, including the formulation of cell culture media and the control of environmental parameters, to maximize the viral yield. Once the virus has replicated to a sufficient titer, the culture is harvested. The first step in downstream processing is clarification, which involves separating the virus-containing fluid from the host cells and cellular debris, often using filtration.[23] The use of a well-characterized cell line like CEF is a modern standard that enhances vaccine safety and consistency compared to older methods that used primary animal tissues.[22]

4.2 Purification and Inactivation Process

Following harvest, the virus undergoes purification and concentration to remove host cell proteins and other impurities. The TicoVac™ process utilizes sucrose gradient centrifugation for this purpose.[19] The most critical step in the entire manufacturing process is viral inactivation. This step renders the virus non-infectious while preserving the integrity of its surface antigens, which are necessary to provoke an immune response. For TicoVac™, inactivation is achieved through chemical treatment with formaldehyde.[3]

The inactivation process is the single most important safety control point. Incomplete inactivation could result in the administration of live, pathogenic virus. Therefore, the kinetics of the inactivation process must be meticulously studied and validated to demonstrate that the method reliably and completely kills the virus under all conditions.[22] While specific parameters are proprietary, a proposed process for TBEV involves treatment with 0.05% formaldehyde for 5 days at 22°C.[22] Each manufacturer must validate its own process with regulatory authorities. As a final quality control measure, samples from every batch of inactivated virus undergo a test for completeness of inactivation. This typically involves inoculating multiple vaccine doses' worth of the material onto a susceptible cell culture and monitoring for any sign of viral replication, ensuring no infectious virus remains.[22] The rigor of this step means that a substantial portion of the regulatory review for the vaccine focuses on the Chemistry, Manufacturing, and Controls (CMC) data package to guarantee a consistently safe and non-infectious product.

4.3 Formulation, Adjuvant Integration, and Final Product Specifications

In the final stages of production, the purified, inactivated viral antigen is formulated into the final vaccine product. This involves several key steps:

1. Adjuvant Integration: The viral antigen is adsorbed onto an aluminum hydroxide adjuvant. This step is crucial for enhancing the vaccine's immunogenicity.[19]
2. Excipient Addition: Other ingredients, or excipients, are added. These include stabilizers like human serum albumin to prevent degradation and maintain potency, and buffering salts to maintain the correct pH.[19]
3. Sterile Filtration and Filling: The final formulated bulk vaccine is passed through a 0.22 micrometer (µm) filter to ensure sterility. It is then aseptically filled into its final containers, such as single-dose syringes or vials.[23]

Every final lot of the vaccine must undergo a battery of quality control tests to ensure it meets the pre-defined release specifications approved by regulatory agencies. These tests confirm the vaccine's identity, purity, potency, and sterility before it can be released for public use.[1]

Section 5: Clinical Development and Efficacy Assessment

The clinical evidence supporting the licensure and use of the TBE vaccine is exceptionally robust, built upon a unique and powerful synergy between controlled immunogenicity data from a comprehensive clinical trial program and decades of compelling real-world effectiveness data from large-scale public health use.

5.1 Overview of the Clinical Trial Program

The FDA's approval of TicoVac™ was supported by a substantial data package that included 21 non-IND clinical studies. This extensive program was designed to thoroughly evaluate the vaccine's safety and immunogenicity across all indicated age groups, from children as young as one year to older adults.[1] The trials encompassed various designs, including:

• Dose-finding studies to determine the optimal antigen content for pediatric and adult formulations.
• Lot-to-lot consistency studies to ensure manufacturing reproducibility.
• Comparative studies evaluating different immunization schedules (both standard and rapid).
• Long-term follow-up studies to assess the persistence of the antibody response (seropersistence) and the effectiveness of booster doses, with some cohorts followed for up to 10 years.[1]

This comprehensive program was not only about achieving initial licensure but also serves as a strategic tool for life-cycle management. The long-term seropersistence and booster studies, in particular, provide the evidence needed for public health bodies to continuously refine and optimize vaccination recommendations over time, ensuring the vaccine's use provides maximum, cost-effective benefit long after its initial approval.

5.2 Immunogenicity in Adult Populations (≥16 Years)

Clinical trials in adults consistently demonstrated that the three-dose primary immunization series elicits a potent and reliable immune response. In pivotal studies, the seropositivity rates, as measured by the highly specific neutralization test (NT), were excellent.

• In Study 213, which evaluated the standard immunization schedule in subjects aged 16 to 64, the NT seropositivity rate was 98.8% (411 out of 416 participants) 21 to 28 days after the third dose.[1]
• In Study 690601, the NT seropositivity rate after the third dose was 100% in subjects aged 16 to 49 and 98.7% in subjects aged 50 and older.[1]
• Studies also confirmed the effectiveness of a rapid immunization schedule, which is crucial for travelers. In Study 690501, this schedule resulted in a 100% NT seropositivity rate.[1]

These data confirm a highly effective immune response across the adult age spectrum, including in older individuals who are at the greatest risk for severe TBE.

5.3 Immunogenicity in Pediatric Populations (1 to <16 Years)

The pediatric clinical program was equally robust, establishing the safety and immunogenicity of the 1.2 µg antigen dose (in a 0.25 mL volume) for individuals from 1 to 15 years of age.[1] The pivotal pediatric trial,

Study 209, showed outstanding results 35 to 42 days after the third vaccination:

• The overall NT seropositivity rate was 99.5% (365 out of 367 children).
• The response was consistent across age sub-groups: 99.2% in children aged 1 to 5 years and 99.6% in those aged 6 to 15 years.[1]

These results demonstrate that the vaccine is highly immunogenic in children, providing a reliable means of protecting this population in endemic regions or during travel.

Table 3: Summary of Key Immunogenicity Studies (Adult and Pediatric)
Study ID	Population (Age Range)	N	Dosing Schedule	Primary Endpoint	Key Result (%)
Pediatric Studies
Study 209	1 - 15 years	367	Standard	NT Seropositivity after Dose 3	99.5
Study 700801	1 - <12 years	129	Standard	NT Seropositivity after Dose 3	100
Adult Studies
Study 213	16 - 64 years	416	Standard	NT Seropositivity after Dose 3	98.8
Study 690601	≥16 years	297	Standard	NT Seropositivity after Dose 3	99.3
Study 690501	16 - <66 years	56	Rapid	NT Seropositivity after Dose 3	100

Data sourced from FDA Summary Basis for Regulatory Action.[1] NT = Neutralization Test.

5.4 Long-Term Seropersistence and Booster Response

A key question for any vaccine is the duration of protection. Long-term follow-up studies have shown that the TBE vaccine induces durable immunity.

• Three years after completion of the primary series, NT seropositivity remained high, at 94.2% in adults and over 97% in children.[1]
• Even 10 years after the first booster dose, seropositivity rates were still robust, at 84.9% in adults and over 86.2% in children.[1]
• When a booster dose was administered three years after the primary series, it reliably restored seropositivity rates to 100% in study participants.[1]

This strong evidence on the longevity of the immune response provides the scientific basis for the recommended booster intervals, which are designed to maintain protective antibody levels in individuals with ongoing risk.

5.5 Real-World Vaccine Effectiveness (VE): Evidence from National Programs

The ultimate validation of a vaccine's value comes from its performance in the real world. While the clinical trials provide the mechanistic evidence of how the vaccine works (by generating antibodies), real-world data shows that it works to prevent disease. For the TBE vaccine, this evidence is overwhelmingly positive.

Observational data from Austria, a country with a long-standing TBE vaccination program and high vaccine coverage, provides the most powerful evidence. An analysis of data from 2000 to 2011 on individuals who had received at least three doses of a TBE vaccine found that:

• The vaccine effectiveness (VE) for preventing hospitalized TBE was estimated to be between 96.3% (worst-case analysis) and 98.7% (best-case analysis).[1]
• Other studies and real-world data confirm a high VE, ranging from 90.1% to over 98%.[2]

This real-world data is crucial. It bridges the gap between the surrogate endpoint of immunogenicity measured in trials and the true clinical endpoint of disease prevention. It confirms that the high antibody levels observed in clinical trials translate directly and powerfully into a dramatic reduction in severe disease at the population level, providing the ultimate validation of the vaccine's public health utility.

Section 6: Safety and Tolerability Profile

The safety and tolerability of the TBE vaccine have been extensively evaluated in numerous clinical trials and confirmed by over four decades of widespread post-marketing use. The confidence in its safety is exceptionally high, hardened not just by controlled studies but by the administration of hundreds of millions of doses in diverse real-world populations over a long period.

6.1 Analysis of Adverse Reactions from Pivotal Clinical Trials

The clinical trial safety database is substantial, including data from 4,427 adults and 3,240 children who received at least one dose of TicoVac™.[1] The adverse reaction profile is consistent with that of other inactivated, adjuvanted vaccines and is characterized by predictable, generally mild, and transient events.

• In Adults (16-65 years): The most frequently reported adverse reactions were local injection site reactions, such as tenderness (29.9%) and pain (13.2%). Common systemic reactions included fatigue (6.6%), headache (6.3%), and muscle pain (5.1%).[1]
• In Children (1-15 years): Local reactions were also common, including tenderness (18.1%) and pain (11.2%). The most frequent systemic reactions were headache (11.1%), fever (9.6%), and restlessness (9.1%).[1] Notably, fever ( ≥38°C) was observed in approximately 36% of the youngest children (aged 1-2 years) within four days of the first dose, an important point for parental counseling.[1]

Table 4: Incidence of Common Adverse Reactions from Pivotal Trials
Adverse Reaction	Pediatric Population (1-15 years) Incidence (%)	Adult Population (16-65 years) Incidence (%)
Local Reactions
Injection Site Tenderness	18.1	29.9
Injection Site Pain	11.2	13.2
Systemic Reactions
Headache	11.1	6.3
Fever (≥38°C)	9.6	N/A
Restlessness	9.1	N/A
Fatigue	N/A	6.6
Muscle Pain (Myalgia)	N/A	5.1

Data sourced from FDA Summary Basis for Regulatory Action [1] and TicoVac™ official information.[19]

6.2 Serious Adverse Events (SAEs) and Post-Marketing Surveillance

In the extensive clinical trial database, Serious Adverse Events (SAEs) were rare. Of the 62 SAEs reported in children and 54 in adults, all but one were considered unrelated to the vaccine by the study investigators. The single event deemed possibly related was a case of febrile convulsion in a 12-month-old child two days after vaccination, an event known to be associated with fever in this age group.[1]

The vast post-marketing experience from Europe, where the vaccine has been in use since the 1970s, provides the strongest evidence of its safety. Severe adverse reactions are described as rarely occurring.[4] The FDA's comprehensive review of this extensive post-marketing data did not identify any new or unexpected safety signals.[1]

6.3 Contraindications, Warnings, and Precautions

The vaccine's use is guided by standard contraindications and precautions:

• Contraindication: The vaccine is contraindicated in anyone with a known history of a severe allergic reaction (e.g., anaphylaxis) to a previous dose of the vaccine or to any of its components, including chick protein.[13]
• Warnings: As with any vaccine, TicoVac™ may not protect 100% of individuals who receive it.[16] Although rare, serious allergic reactions, including anaphylaxis, can occur following administration and appropriate medical treatment should be available.[16]
• Precautions:
• Immunocompromised Individuals: Patients with a weakened immune system, either due to an underlying medical condition or treatment with immunosuppressive drugs, may have a diminished immune response to the vaccine.[16]
• Human Albumin: The vaccine contains human serum albumin, a derivative of human blood. Based on effective donor screening and manufacturing processes, the risk of transmission of viral diseases or variant Creutzfeldt-Jakob disease (vCJD) is considered extremely remote.[7]

6.4 Use in Special Populations

Guidance for specific populations is based on available data and clinical considerations:

• Geriatric Use: Clinical studies have not identified specific safety problems in the elderly. However, the immune response may be less robust and wane more quickly with age, reinforcing the importance of adhering to recommended booster schedules.[15]
• Pediatric Use: The vaccine is approved for use in children aged one year and older. Safety and efficacy have not been established in infants below one year of age, and the FDA granted a waiver for studies in this age group due to ethical and logistical challenges.[1]
• Pregnancy and Lactation: There are no adequate and well-controlled studies of TicoVac™ in pregnant or breastfeeding women. Its use should be based on a careful risk-benefit assessment, weighing the potential risk of TBE infection against the theoretical risks of the vaccine.[16] The WHO notes that pregnant women who are at high risk of infection can be vaccinated.[4]
• Immunocompromised Patients: The vaccine is not contraindicated, but the immune response may be suboptimal. Clinical trials have specifically investigated the vaccine's immunogenicity in patients with rheumatoid arthritis receiving immunosuppressive therapy, demonstrating a proactive approach to understanding its performance in this important population.[24]

Section 7: Dosing, Administration, and Public Health Recommendations

The translation of clinical data into practical guidance is essential for the effective use of the TBE vaccine. Dosing schedules are designed to be both immunologically effective and logistically feasible, and recommendations from major public health bodies provide a framework for its targeted implementation.

7.1 Primary Immunization Schedules (Standard and Rapid)

TicoVac™ is administered as a three-dose primary immunization series by intramuscular (IM) injection, typically into the deltoid muscle of the upper arm.[14] The vaccine should be shaken well before use to ensure a homogenous suspension.[19]

Two primary schedules are available to accommodate different needs:

• Standard Immunization Schedule:
• For individuals 1 through 15 years of age (0.25 mL dose):
• Dose 1: At a selected date (Day 0).
• Dose 2: 1 to 3 months after the first dose.
• Dose 3: 5 to 12 months after the second dose.[3]
• For individuals 16 years of age and older (0.5 mL dose):
• Dose 1: At a selected date (Day 0).
• Dose 2: 14 days to 3 months after the first dose.
• Dose 3: 5 to 12 months after the second dose.[13]
• Rapid Immunization Schedule: The flexibility in the interval between the first two doses for adults allows for an accelerated schedule, which is particularly valuable for travelers with imminent departure dates. This availability of both standard and rapid schedules represents a sophisticated public health strategy that balances an ideal immunological response with the practical realities of travel planning. While a longer interval may be immunologically optimal for developing a mature response, the rapid schedule provides a high level of protection quickly, making it a crucial tool for last-minute travelers and maximizing vaccine uptake in this key population.

For optimal protection, the primary immunization series should be completed at least one week prior to potential exposure to the TBE virus.[3]

7.2 Booster Dose Recommendations

The immune protection induced by the primary series is long-lasting but not lifelong. To maintain protective antibody levels in individuals with a continued or renewed risk of exposure, booster doses are recommended.

• A first booster dose (the fourth dose overall) may be given at least 3 years after the completion of the primary immunization series.[3]
• Subsequent booster doses are generally recommended every 3 to 5 years. These recommendations are derived directly from the long-term seropersistence studies. Some guidelines provide more nuanced, age-stratified advice, suggesting longer intervals (e.g., every 5 years) for individuals under 60 and shorter intervals (e.g., every 3 years) for those aged 60 and over, to account for the more rapid waning of immunity in older adults.[4]

7.3 International Guidelines for Use (WHO, CDC/ACIP)

There is a strong international consensus on the indications for TBE vaccination. The recommendations are not for universal immunization but are highly targeted to individuals whose risk of exposure is elevated due to their location, occupation, or activities.

• World Health Organization (WHO): The WHO recommends that TBE vaccination be offered to people of all age groups, including children, in areas where TBE is highly endemic. A highly endemic area is generally defined as one with an average annual incidence of ≥5 clinical cases per 100,000 population.[4] The WHO considers vaccination to be the most effective protective measure against the disease.[10]
• U.S. Centers for Disease Control and Prevention (CDC) and the Advisory Committee on Immunization Practices (ACIP): The ACIP recommends the TBE vaccine for U.S. persons who are at risk of exposure, which includes certain travelers and laboratory workers.[5]
• Vaccination is recommended for persons who are moving or traveling to a TBE-endemic area and will have extensive exposure to ticks based on their planned outdoor activities and itinerary.[5]
• Vaccination may be considered for persons traveling to an endemic area who might engage in outdoor activities in areas where ticks are likely to be found (e.g., forests, fields). The decision to vaccinate should be based on a personalized risk assessment that considers the specific locations to be visited, the types and duration of planned activities, individual risk factors for a poor medical outcome (e.g., older age), and the traveler's personal risk tolerance.[5]

Table 5: Recommended Dosing and Administration Schedules by Age Group
Age Group	Dose Number	Recommended Interval	Antigen/Volume per Dose
1 through 15 years	Dose 1	Day 0	1.2 µg / 0.25 mL
	Dose 2	1 to 3 months after Dose 1	1.2 µg / 0.25 mL
	Dose 3	5 to 12 months after Dose 2	1.2 µg / 0.25 mL
	Booster	≥3 years after Dose 3	1.2 µg / 0.25 mL
≥16 years	Dose 1	Day 0	2.4 µg / 0.5 mL
	Dose 2	14 days to 3 months after Dose 1	2.4 µg / 0.5 mL
	Dose 3	5 to 12 months after Dose 2	2.4 µg / 0.5 mL
	Booster	≥3 years after Dose 3	2.4 µg / 0.5 mL

Data compiled from.[3]

Section 8: Analysis and Recommendations for Stakeholders

8.1 Synthesis of Evidence: Strengths and Limitations

The Tick-borne encephalitis vaccine (whole virus, inactivated) (DB16611) is a highly effective and safe public health intervention with a robust evidence base.

Strengths:

• High Efficacy and Effectiveness: The vaccine demonstrates exceptionally high immunogenicity in clinical trials across all age groups and this translates to outstanding real-world vaccine effectiveness of over 96% in preventing severe, hospitalized disease.
• Extensive Safety Record: A favorable safety profile established in large clinical trials is further solidified by over four decades of post-marketing surveillance involving hundreds of millions of doses, providing an unparalleled level of confidence.
• Broad Cross-Protection: The vaccine induces neutralizing antibodies that are effective against all three major TBEV subtypes, making it a globally useful tool for travelers and residents in any endemic region.
• Flexible Dosing: The availability of both standard and rapid immunization schedules accommodates the needs of diverse populations, including last-minute travelers.
• Well-Understood Technology: The vaccine is based on a classic inactivated virus platform, whose manufacturing process, mechanism of action, and safety profile are well-understood.

Limitations:

• Lack of Traditional Efficacy Trials: The evidence base does not include traditional, large-scale, placebo-controlled efficacy trials. This is an accepted and necessary limitation due to the low incidence of the disease, and it is effectively overcome by the combination of strong immunogenicity data and compelling real-world effectiveness data.
• Limited Data in Specific Populations: As with many vaccines, robust clinical data in pregnant women and infants under one year of age are lacking, requiring careful risk-benefit assessments for these groups.
• Reduced Response in Immunocompromised: While safe for use, the vaccine may elicit a suboptimal immune response in individuals with weakened immune systems, and protection cannot be guaranteed.

8.2 Implications for Clinical Practice and Travel Medicine

For clinicians, the primary implication is the need for proactive, personalized risk assessment. The decision to recommend TBE vaccination should be based on a thorough travel and activity history, not just the destination country. Key questions should focus on the season of travel, the duration of time spent outdoors, and the specific nature of planned activities (e.g., hiking, camping, forestry work). Clinicians should use the well-defined safety and dosing information to counsel patients effectively, reassuring them about the predictable and mild nature of most side effects while emphasizing the critical importance of completing the full three-dose primary series for durable protection. The availability of the rapid schedule for adults should be highlighted for travelers with limited time before departure.

8.3 Considerations for Public Health Immunization Policy

The successful TBE vaccination program in Austria serves as a powerful case study for public health authorities in other endemic regions. It demonstrates that achieving high vaccination coverage in at-risk populations can dramatically reduce the incidence of a severe neurological disease, leading to significant public health and economic benefits by preventing hospitalizations and long-term disability. The targeted vaccination strategies recommended by the WHO and CDC, which focus on high-risk geographical areas and populations, provide a sound, evidence-based framework for developing or refining national immunization policies.

8.4 Future Research Directions

While the current TBE vaccine is highly effective, several areas warrant further research to optimize its use:

• Optimization of Booster Schedules: Continued long-term seropersistence studies could help to further refine booster intervals, potentially allowing for longer, evidence-based intervals in certain age groups, which could improve adherence and cost-effectiveness.
• Studies in Special Populations: If ethically and logistically feasible, prospective studies in pregnant women could provide much-needed data to guide recommendations in this group. Further research into strategies to enhance the immune response in older adults and various immunocompromised populations (e.g., using different adjuvants or higher antigen doses) would be valuable.
• Correlates of Protection: While neutralizing antibody titers are a reliable surrogate, further research to define a precise, standardized correlate of protection could help to more accurately assess individual immune status and guide personalized booster decisions.

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