An In-Depth Monograph on the Yellow Fever 17D Vaccine (DB10805): From Molecular Biology to Global Public Health

Executive Summary

The Yellow Fever 17D vaccine (DrugBank ID: DB10805) stands as a monumental achievement in the history of vaccinology and a cornerstone of global public health. Developed in the 1930s through the empirical attenuation of a wild-type virus, it remains one of the most effective live-attenuated vaccines ever created.[1] Its remarkable success is predicated on its ability to induce a robust, polyvalent, and, in most individuals, lifelong immune response that closely mimics natural infection. This monograph provides a comprehensive analysis of the vaccine, synthesizing information from its historical development and molecular biology to its clinical application, safety profile, and global regulatory status.

A single 0.5 mL subcutaneous dose of the vaccine confers durable protection in the vast majority of healthy individuals, a conclusion supported by decades of extensive use and formally endorsed by the World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC), which have largely eliminated the need for routine 10-year boosters.[3] The vaccine's profound efficacy is rooted in its sophisticated mechanism of action. The live, attenuated 17D virus replicates systemically, engaging multiple arms of the immune system. This process begins with a potent innate immune response mediated through the activation of a broad array of Toll-Like Receptors (TLRs) on dendritic cells, which in turn orchestrates a durable adaptive response. This response is characterized by the rapid development of high-titer neutralizing antibodies—the primary correlate of protection—and the generation of a unique, long-lasting, stem-cell-like memory T-cell population that contributes to its lifelong efficacy.[7]

The primary indication for the vaccine is the active immunization of individuals aged 9 months and older who are living in or traveling to yellow fever-endemic regions of Africa and South America. It is also recommended for laboratory personnel who may be exposed to the virus and is a mandatory requirement for entry into certain countries, enforced through the International Certificate of Vaccination or Prophylaxis (ICVP).[10]

While the vaccine is generally safe and well-tolerated, with most side effects being mild and transient, it is associated with rare but severe adverse events. These include Yellow Fever Vaccine-Associated Neurotropic Disease (YEL-AND) and Yellow Fever Vaccine-Associated Viscerotropic Disease (YEL-AVD), a life-threatening condition that mimics severe wild-type disease. The risks for these events are significantly elevated in specific, well-defined populations, including infants under 9 months of age, adults over 60, individuals with thymus disorders, and the severely immunocompromised. This distinct risk profile necessitates a careful and individualized risk-benefit assessment prior to administration, which is why the vaccine is exclusively administered at designated vaccination centers by trained professionals.[11]

Globally, the yellow fever vaccine is an indispensable tool for public health. It is central to international travel regulations and is the foundation of large-scale prevention initiatives, such as the WHO's "Eliminate Yellow Fever Epidemics (EYE)" strategy, which aims to protect at-risk populations through routine immunization and emergency stockpiles.[4] The vaccine's history, efficacy, and safety profile provide a compelling case study in the development, deployment, and management of a highly successful biologic agent that has saved countless lives and continues to prevent the international spread of a deadly disease.

Historical Context and Development of the 17D Strain

The development of the yellow fever vaccine is a landmark narrative in medical history, a story of scientific perseverance, serendipitous discovery, and iterative refinement in the face of a devastating disease. The journey from identifying the viral agent to creating a safe and effective vaccine was fraught with challenges and shaped the principles of modern vaccinology.

The Scourge of Yellow Fever

From the colonial era through the early 20th century, yellow fever was one of the most feared infectious diseases, known colloquially as "Yellow Jack" or the "saffron scourge." Caused by a mosquito-borne flavivirus, the disease presents with a spectrum of illness ranging from mild febrile symptoms to a severe, toxic phase characterized by jaundice, hemorrhagic fever, and multi-organ failure, with case-fatality rates for severe disease often exceeding 20% and sometimes reaching as high as 47%.[1] Devastating epidemics swept through port cities in the Americas, Africa, and Europe, disrupting trade, halting major engineering projects like the Panama Canal, and instilling widespread public terror, which created an urgent and compelling need for an effective prophylactic measure.[1]

Pioneering Research and the Asibi Strain

The modern era of yellow fever research began in 1927, when a team of researchers from the Rockefeller Foundation—Adrian Stokes, J. H. Bauer, and N. P. Hudson—successfully isolated the yellow fever virus in Ghana. They transmitted the virus from a 28-year-old West African man named Asibi, who had a mild case of the disease, into rhesus monkeys (Macacus rhesus), which proved to be a suitable animal model for studying the infection.[17] This wild-type "Asibi strain" became the invaluable, albeit highly virulent, progenitor of the vaccine virus used today.[18]

A subsequent critical advance was made by Max Theiler, a South African-born microbiologist. While early research relied on the expensive and difficult-to-manage rhesus monkeys, Theiler demonstrated in 1930 that the virus could be propagated by intracerebral injection into mice.[17] This discovery provided a cheaper, more accessible, and safer animal model that dramatically accelerated the pace of research and laid the groundwork for attenuation studies.[20]

The Nobel Prize-Winning Work of Max Theiler

Working at the Rockefeller Foundation in the 1930s, Theiler embarked on a systematic effort to attenuate, or weaken, the virulent Asibi strain to render it safe for human use.[20] The primary method for this was serial passage—the process of repeatedly growing the virus in a series of non-native hosts or tissue cultures to force it to adapt and, in doing so, lose its virulence in the original host. Theiler's initial work involved passaging the virus through mouse brains, which successfully reduced its viscerotropism (the tendency to attack visceral organs like the liver) but unfortunately enhanced its neurotropism (the tendency to attack the central nervous system).[17]

The decisive breakthrough came from shifting the culture substrate. Theiler and his colleague Hugh Smith began passaging the Asibi strain in minced chicken embryo tissue cultures from which the brain and spinal cord had been meticulously removed, a deliberate strategy to select against neurotropic variants.[7] During this laborious process, a "fortunate chance mutation" occurred. At the 176th passage, a variant emerged that was found to be remarkably attenuated; it no longer caused fatal viscerotropic or neurologic disease when injected into monkeys but was still highly immunogenic, inducing a robust protective antibody response.[19] This attenuated strain was designated "17D".[19] For this monumental achievement, which led directly to one of the safest and most effective vaccines in history, Max Theiler was awarded the Nobel Prize in Physiology or Medicine in 1951—the first and only Nobel Prize ever awarded for the development of a virus vaccine.[2]

Evolution of Substrains and the Seed Lot System

The original 17D culture gave rise to the two primary substrains that are still used for vaccine production worldwide: 17D-204 and 17DD, which were derived from the 204th and 195th passages, respectively.[7] A third substrain, 17D-213, is also used in some vaccines and is derived from the 17D-204 lineage.[18]

The early years of vaccine production highlighted the inherent instability of live viruses and the risks of uncontrolled passaging. An incident of post-vaccinal encephalitis was traced back to a particular substrain that had undergone further, unwanted genetic modifications during additional passages.[2] This event underscored the critical need for consistency and control in the manufacturing process. In response, the "seed lot system" was established, a foundational principle of modern vaccine manufacturing. This system mandates that all vaccine production must originate from a single, well-characterized master seed virus lot, with a limited number of subsequent passages allowed to create working seed lots for production. This practice minimizes the risk of genetic drift and ensures the safety and immunogenicity of the final product remain stable and predictable over time.[2]

Early Manufacturing Challenges and Refinements

The path to a globally deployable vaccine was not without significant setbacks that provided crucial lessons in vaccine safety. In the early 1940s, a major crisis emerged when large numbers of vaccinated U.S. soldiers developed post-vaccination jaundice.[2] Investigations revealed that the cause was contamination of the vaccine with what was later identified as hepatitis B virus. The source of the contamination was the human serum that was being used as a stabilizer in the vaccine formulation.[2]

This episode also highlighted a fascinating dynamic in international scientific collaboration. Researchers in Brazil, who were also producing the 17D vaccine, independently identified the link between human serum and jaundice and had already developed and implemented a serum-free vaccine formulation, effectively solving the problem.[2] They repeatedly warned their U.S. colleagues of the danger, but these warnings were initially met with skepticism. This delay in adopting the serum-free method contributed to the scale of the hepatitis outbreak among U.S. troops, serving as a powerful historical lesson on the importance of global surveillance and open scientific exchange, regardless of a finding's country of origin.[27]

Further refinements to the manufacturing process occurred over the following decades. In the 1960s, avian leukosis virus, a potential oncogenic agent, was discovered as a contaminant in the chicken embryo cultures used for vaccine production. This led to the development of methods to eliminate the contaminant virus and the establishment of standards requiring the use of specific pathogen-free eggs, further enhancing the vaccine's safety profile.[16] The developmental history of the 17D vaccine is therefore a testament not only to the initial scientific breakthrough but also to a continuous process of rigorous quality control and safety improvement in response to real-world challenges.

Vaccine Composition, Manufacturing, and Characteristics

The Yellow Fever Vaccine is a biotech product, specifically a live, attenuated viral vaccine. Its formulation, manufacturing process, and physical characteristics are highly standardized to ensure consistent potency, stability, and safety. The most widely used brand, YF-VAX®, serves as a representative example of the vaccine's technical specifications.

Biological Classification

The vaccine is derived from the yellow fever virus, the prototype virus of the genus Flavivirus within the family Flaviviridae. Yellow fever virus is a small, enveloped virion containing a genome composed of a single-stranded, positive-sense RNA molecule.[7] The vaccine itself is classified as a live, attenuated biologic, meaning it contains a weakened form of the virus that can replicate in the host but does not cause disease in immunocompetent individuals.[10]

Composition of YF-VAX®

The composition of the YF-VAX® vaccine is precisely defined to ensure its efficacy and stability.

• Active Ingredient: The vaccine contains live, attenuated yellow fever virus of the 17D-204 strain.[10]
• Potency: Each 0.5 mL dose is formulated to contain a minimum potency of 4.74 log10 plaque-forming units (PFU) throughout the product's entire shelf life.[11] A plaque-forming unit is a measure of the number of infectious virus particles. This potency standard is consistent with the requirements set by the World Health Organization for yellow fever vaccines.[11]
• Excipients and Stabilizers: To maintain the viability of the live virus during the manufacturing and storage process, the vaccine contains sorbitol and gelatin as stabilizers. These compounds protect the viral particles during lyophilization (freeze-drying) and help preserve potency. The formulation contains no preservatives.[15]
• Diluent: The lyophilized vaccine powder is supplied with a separate vial containing a sterile diluent, which is Sodium Chloride Injection USP (0.9% NaCl). This diluent is also preservative-free and is the only liquid that should be used for reconstitution.[15]

Manufacturing Process

The production of the yellow fever vaccine follows a well-established, though technologically traditional, process.

• Substrate: The 17D-204 virus strain is propagated in living, embryonated chicken eggs. A critical safety measure is the exclusive use of eggs from flocks that are certified as avian leukosis virus-free (ALV-free) to prevent contamination of the vaccine with this extraneous agent.[11]
• Processing: After the virus has replicated sufficiently within the chicken embryos, the viral material is harvested. It is then combined with the sorbitol and gelatin stabilizers, dispensed into vials, and subjected to lyophilization. This freeze-drying process removes water from the preparation, rendering the virus dormant and stable for long-term storage. Finally, the vials are hermetically sealed under nitrogen gas to protect the contents from oxygen and moisture, further ensuring stability.[15]
• Modern Challenges and Future Directions: The reliance on embryonated chicken eggs is a significant logistical constraint. This "legacy" manufacturing method is slow, resource-intensive, and difficult to scale up rapidly in response to sudden increases in demand, such as during a major outbreak. This dependency has contributed to occasional global vaccine shortages.[34] Consequently, there is active research and development into next-generation manufacturing platforms using cell culture-based systems, such as Vero, BHK21, or EB66 cells. These modern platforms offer the potential for a more reliable, scalable, and straightforward manufacturing process that could secure the global vaccine supply.[34] The 17D virus is also being explored as a versatile vector for developing new chimeric vaccines against other diseases like Zika, Ebola, and SARS-CoV-2, which provides additional impetus for modernizing its production technology.[1]

Physical Characteristics

The vaccine has distinct physical properties before and after it is prepared for administration.

• Before Reconstitution: In its lyophilized state, the vaccine is a pinkish-colored powder or cake within the vial.[15]
• After Reconstitution: Once the sterile saline diluent is added, the powder dissolves to form a slight pink-brown suspension.[15]
• Vial Stopper Composition: There is a critical and concerning contradiction in the available product information regarding the composition of the vial stopper. Some official documentation states that the vial stoppers for both the vaccine and diluent are not made with natural rubber latex.[15] However, multiple other sources, including package inserts and medical references, explicitly warn that the stopper does contain dry natural rubber (a derivative of latex) and may cause allergic reactions in latex-sensitive individuals.[16] This discrepancy represents a significant patient safety issue. It suggests that materials may vary between manufacturers, production lots, or regional products. Therefore, clinicians cannot assume the vaccine is latex-free and must verify the specific product being administered, exercising extreme caution for any patient with a history of latex allergy.

The lyophilized formulation is a crucial design feature that enhances the vaccine's stability, which is essential for distribution and storage, particularly within the cold-chain infrastructure required in the tropical regions where yellow fever is endemic.[16]

Table 1: Vaccine Profile Summary

Parameter	Details
DrugBank ID	DB10805
Generic Name	Yellow fever vaccine
Brand Name	YF-VAX®
Manufacturer	Sanofi Pasteur, Inc.
Type	Biotech, Live-attenuated virus vaccine
Active Strains	17D-204, 17DD (YF-VAX® uses 17D-204)
Substrate	Avian leukosis virus-free (ALV-free) chicken embryos
Key Excipients	Sorbitol, Gelatin
Potency Standard	≥4.74log10​ PFU / 0.5 mL dose

Mechanism of Action and Pharmacodynamics: The Immunological Basis of Lifelong Protection

The exceptional and durable efficacy of the Yellow Fever 17D vaccine is a direct result of its sophisticated interaction with the human immune system. As a live-attenuated vaccine, its fundamental mechanism is to simulate a natural infection, thereby engaging a full spectrum of innate and adaptive immune responses that lead to the formation of robust, long-term immunological memory. This process is far more comprehensive than that induced by inactivated or subunit vaccines, which often require multiple doses and boosters to achieve and maintain protection.[7]

Simulating Natural Infection

Upon subcutaneous injection, the attenuated 17D vaccine virus begins to replicate in vivo. This replication is not uncontrolled but is sufficient to cause a transient, systemic viral infection.[7] The immune system has evolved to respond powerfully to microbial multiplication, and it is this limited replication that serves as the critical signal to mount a comprehensive defense. The virus is initially taken up by professional antigen-presenting cells (APCs), most notably dendritic cells (DCs), located in the dermis and subcutaneous tissues near the injection site.[7] These cells act as sentinels, initiating the cascade of events that culminates in protective immunity.

Innate Immune Activation: The First Line of Defense

The activation of the innate immune system is the crucial first step that shapes the quality and magnitude of the subsequent adaptive response. The Yellow Fever vaccine is a uniquely potent activator of this system.

• Toll-Like Receptor (TLR) Engagement: A key feature of the 17D vaccine's immunogenicity is its ability to activate multiple subsets of DCs through a broad array of Toll-Like Receptors (TLRs). Research has shown that the vaccine virus and its components engage TLR2, TLR7, TLR8, and TLR9.[7] This is highly significant because these receptors are located in different cellular compartments and recognize distinct viral patterns (e.g., surface proteins, single-stranded RNA). This simultaneous, multi-pronged activation creates a powerful synergistic effect, leading to a more diverse and robust immune stimulation than could be achieved by triggering a single pathway. This capacity for polyvalent activation is a primary reason the yellow fever vaccine is often used as a "gold standard" model for studying effective human antiviral immunity.[7]
• Cytokine Production: The engagement of these TLRs triggers a powerful signaling cascade within the DCs, leading to the production and secretion of a variety of crucial immune-signaling molecules. These include proinflammatory cytokines such as interleukin-6 (IL-6) and IL-12, as well as Type I interferons (e.g., IFN-α). These cytokines are essential for recruiting other immune cells to the site of infection and for instructing the developing adaptive immune response.[7]

Adaptive Immune Response: Building Specific, Long-Term Memory

The innate immune response sets the stage for the highly specific and long-lasting adaptive immune response, which is composed of both humoral (antibody-mediated) and cellular (T-cell-mediated) components.

• Humoral Immunity (B-cells and Antibodies):
• Activated DCs migrate to nearby lymph nodes, where they process viral proteins and present the resulting antigens to B-cells. This interaction, with help from CD4+ T-cells, stimulates the B-cells to proliferate and differentiate into plasmablasts, which are factories for producing antibodies.[7]
• The most critical product of this humoral response is the generation of high titers of neutralizing antibodies (nAbs). These antibodies are the primary correlate of protection against yellow fever. They function by binding to the surface of the virus, physically blocking it from entering and infecting host cells, thus neutralizing its infectivity.[7]
• The production of these nAbs is both rapid and efficient. Protective levels of antibodies are detectable in over 90% of vaccinated individuals within 10 days of vaccination, and in more than 99% by day 30.[6] In most healthy individuals, these neutralizing antibodies persist at protective levels for decades, and likely for life.[6]
• Cellular Immunity (T-cells):
• The yellow fever vaccine is remarkable for its ability to induce a strong and broad T-cell response that closely resembles the response seen during an acute viral infection, a feature not shared by most other vaccines.[7]
• CD8+ Cytotoxic T-cells: The vaccine triggers a massive expansion of virus-specific effector CD8+ T-cells, which peaks approximately two weeks after vaccination. These cytotoxic T-lymphocytes (CTLs) are essential for identifying and eliminating host cells that have already been infected with the virus, thereby halting further viral replication.[7]
• Unique Memory Formation: A particularly striking feature of the immune response to the 17D vaccine is the formation of a stable, self-renewing population of stem cell-like memory CD8+ T-cells. These cells have been shown to persist for at least 25 years post-vaccination.[7] This long-lived cellular reservoir provides a powerful layer of secondary protection. Even if antibody levels were to wane over many decades, this T-cell population can rapidly expand upon re-exposure to the virus, mounting a swift and effective defense. This dual-layered protection, provided by both long-lasting antibodies and a persistent cellular memory, is the likely immunological basis for the vaccine's lifelong durability.
• CD4+ T-helper cells: The vaccine also elicits a balanced Th1/Th2 CD4+ T-cell response. These "helper" T-cells play a crucial coordinating role in the immune response. They provide essential signals to B-cells to promote the production of high-affinity antibodies and also support the activation and function of the CD8+ cytotoxic T-cells.[7]

In summary, the pharmacodynamic effect of the yellow fever vaccine is a masterfully orchestrated immune response. By acting as a polyvalent agonist for the innate immune system, it initiates a powerful cascade that results in a highly effective, multi-layered, and exceptionally durable adaptive immune memory.

Pharmacokinetics

For a live, replicating vaccine, traditional pharmacokinetic parameters such as absorption, distribution, metabolism, and excretion (ADME) are not directly applicable in the way they are for small-molecule drugs. Instead, the key pharmacokinetic concept is the behavior of the live virus within the host, specifically the kinetics of its replication and presence in the bloodstream, a phenomenon known as viremia. This period of viremia is central to the vaccine's mechanism of action but also underlies some of its most significant safety considerations.

Vaccine-Associated Viremia

Following subcutaneous administration, the attenuated 17D vaccine virus does not remain localized. It undergoes an initial phase of replication at the injection site and in regional lymph nodes, after which it disseminates systemically, leading to a measurable presence of infectious virus in the bloodstream.

• Kinetics: Vaccine-associated viremia typically becomes detectable 4 to 10 days after primary vaccination and generally persists for a short duration, lasting for up to 5 days in most individuals.[39] The timing of this viremia coincides with the onset of the innate immune response and the initial priming of the adaptive immune system.
• Clinical Significance and Role in Immunogenicity: The period of viremia is not an unwanted side effect but rather an essential biological process for inducing a protective immune response. The level of viral replication and the magnitude of the resulting viremia have been shown to correlate directly with the strength of the subsequent immune reaction, particularly the expansion of the critical CD8+ T-cell response.[7] This indicates that the systemic presence of the virus provides the necessary antigenic stimulus to drive the development of robust and durable immunity. During this period of high viremia, a vaccinated individual is theoretically infectious to biting mosquitoes, which could then transmit the vaccine-strain virus, although sustained transmission is not possible in non-endemic areas lacking the appropriate mosquito vectors.[39]

Implications for Transmission

The systemic circulation of live vaccine virus during the viremic phase has important implications for person-to-person transmission through biological products and fluids.

• Blood Products and Organ Transplantation: The presence of infectious virus in the blood creates a well-established risk of transmitting the vaccine strain through the transfusion of blood products (e.g., whole blood, plasma) or via solid organ transplantation from a recently vaccinated donor.[12] To mitigate this risk, public health authorities, including the CDC, recommend that individuals defer blood donation for at least two weeks (14 days) after receiving the yellow fever vaccine.[12]
• Breastfeeding: There have been several documented cases of probable transmission of the vaccine-strain virus from a lactating mother to her nursing infant through breast milk.[11] In these rare instances, the infants, who were too young to be vaccinated themselves, developed vaccine-associated neurotropic disease (encephalitis). This risk of transmission is the basis for the strong precaution against vaccinating breastfeeding mothers whose infants are younger than 9 months of age, as this age group is particularly vulnerable to the neurological complications of the vaccine.[11]

The viremia induced by the yellow fever vaccine can be viewed as a double-edged sword. It is the necessary engine driving the development of powerful, long-lasting immunity. At the same time, it is the primary source of the vaccine's potential for iatrogenic transmission and is the underlying mechanism for the rare but severe viscerotropic adverse events, where uncontrolled viral replication leads to multi-organ damage.[2] The entire risk-benefit calculus of the vaccine, therefore, hinges on the host's ability to mount a timely and effective immune response that controls this viremia before it can cause harm—a delicate balance that can be disrupted in immunologically vulnerable individuals.

Clinical Efficacy and Long-Term Immunogenicity

The clinical utility of the yellow fever vaccine is defined by its exceptional efficacy and the remarkable duration of the protection it confers. Decades of real-world use and numerous immunological studies have established its high rate of initial success and its ability to provide long-term immunity, although this protection may be less robust in certain specific populations.

Primary Immunogenicity and Effectiveness

While the 17D vaccine was developed before the advent of modern, large-scale, placebo-controlled Phase III efficacy trials, its effectiveness has been overwhelmingly demonstrated through decades of use in preventing disease.[40]

• Seroconversion Rates: The vaccine is highly immunogenic, reliably inducing a protective immune response in the vast majority of healthy recipients. Controlled clinical studies consistently demonstrate that approximately 90% of vaccinees develop protective levels of neutralizing antibodies within 10 days of vaccination, and virtually all (>99%) achieve seroprotection within 28 to 30 days.[6] This rapid onset of immunity is critical for travelers, as the International Certificate of Vaccination or Prophylaxis becomes valid 10 days after administration.[11]
• Real-World Effectiveness and Vaccine Failures: The vaccine's effectiveness in preventing clinical disease is extremely high. After the administration of more than 600 million doses globally, documented cases of vaccine failure—where a vaccinated individual contracts yellow fever—are exceedingly rare.[19] Between 1970 and 2015, only one of eleven reported yellow fever cases in unvaccinated U.S. and European travelers had a documented history of vaccination, and that individual survived.[30] This attests to the vaccine's profound protective effect in real-world settings.

Duration of Immunity and the Lifelong Protection Paradigm

For many years, international health regulations recommended a booster dose of the yellow fever vaccine every 10 years. However, a growing body of evidence on the long-term persistence of immunity led to a major shift in global policy.

• Policy Shift: In 2013, the World Health Organization's Strategic Advisory Group of Experts on Immunization (SAGE) reviewed the available data and concluded that a single primary dose of the yellow fever vaccine is sufficient to confer lifelong protection in most individuals.[5] Consequently, in 2016, the 10-year booster requirement was officially removed from the International Health Regulations.[5] The CDC's Advisory Committee on Immunization Practices (ACIP) had issued a similar recommendation for most travelers in 2015.[5]
• Supporting Evidence: This landmark policy change was underpinned by numerous studies demonstrating the extraordinary durability of the immune response. Evidence suggests that protective antibody levels persist for at least 30-35 years and likely for the life of the individual.[14] A comprehensive systematic review and meta-analysis published in 2023 found a pooled seroprotection rate of 94% among healthy adult travelers who had been vaccinated 10 to 60 years prior.[49] Furthermore, a 10-year follow-up study of travelers who received their primary vaccination at age 60 or older found that 100% of participants remained seropositive, providing strong evidence for long-term protection even when the vaccine is first administered at an advanced age.[47]

Waning Immunity in Specific Populations

While the "lifelong protection" paradigm holds true for the general healthy population, it is a nuanced policy that does not apply universally. There are well-defined subgroups in whom the immune response may be less robust or may wane more quickly, necessitating consideration of additional or booster doses.

• Infants and Young Children: There is substantial evidence that children vaccinated before the age of two have a less durable immune response. The immature immune system of a young child may be less capable of establishing long-term immunological memory. A meta-analysis found that the seroprotection rate in children vaccinated before age two dropped to just 52% within five years of vaccination.[50] Another analysis reported a rate of 47% at 10 or more years post-vaccination.[49] These findings suggest that a booster dose should be considered for this population if they continue to be at risk of exposure.
• Immunocompromised Individuals: As expected, individuals with compromised immune systems mount a weaker and less durable response to the vaccine. Persons with HIV, for example, have been shown to have lower seroprotection rates (a pooled rate of 61% at ≥10 years) and a faster decline in antibody titers, particularly if their HIV viral load is not well-controlled.[5]
• Pregnancy: The complex immunological shifts that occur during pregnancy can dampen the response to vaccination. Studies have shown that seroconversion rates can be significantly lower in pregnant women, particularly when the vaccine is administered during the third trimester (as low as 39% seroconversion in one study).[5] In contrast, vaccination during the first trimester appears to be much more immunogenic (98% seroconversion).[5] This variability is the basis for the recommendation that women who were vaccinated during pregnancy receive an additional dose before their next potential exposure.[5]
• Residents of Endemic Areas: An intriguing and not fully understood finding is the observation of lower long-term seroprotection rates in some studies of residents in endemic areas (pooled rate of 76%) compared to travelers from non-endemic areas (94%).[49] This discrepancy may be partly attributable to methodological differences, such as the use of a higher antibody titer cutoff to define seroprotection in some Brazilian studies.[49] However, it also raises the possibility that other factors, such as host genetics or frequent exposure to other cross-reacting flaviviruses like dengue, could modulate the long-term immune response to the yellow fever vaccine.[2] This remains a critical area for further research.

The public health message, therefore, must be carefully communicated: a single dose provides lifelong protection for most healthy people, but targeted booster strategies remain essential for specific, vulnerable populations to ensure they are not left under-protected by an oversimplified application of the general guideline.

Approved Indications, Dosage, and Administration

The administration of the yellow fever vaccine is governed by specific guidelines regarding indications for use, dosage, administration route, and coadministration with other vaccines. These guidelines are designed to maximize efficacy while minimizing risks, particularly for vulnerable populations.

Primary Indications for Use

The yellow fever vaccine is indicated for active immunization to prevent yellow fever in persons aged 9 months and older who fall into one of the following categories [4]:

• Travelers and Residents in Endemic Areas: This is the largest group and includes individuals who live in or are traveling to regions with a recognized risk of yellow fever virus transmission. These areas are primarily located in sub-Saharan Africa and tropical South America.[10]
• Country Entry Requirements: Many countries, particularly those with competent mosquito vectors but no active transmission, require travelers arriving from endemic regions to present a valid International Certificate of Vaccination or Prophylaxis (ICVP) as a condition of entry. This measure is designed to prevent the importation and subsequent spread of the virus.[14]
• Occupational Risk: Vaccination is strongly recommended for laboratory personnel who may be exposed to virulent, wild-type yellow fever virus or to concentrated preparations of the 17D vaccine virus strains through their work.[5]

Dosage and Route of Administration

• Standard Dose: A single 0.5 mL dose of the reconstituted vaccine is the standard for all eligible individuals, including children (aged 9 months and older) and adults.[30]
• Route of Administration: The vaccine must be administered via the subcutaneous (SC) route.[11] Administration by intravascular, intramuscular, or intradermal routes is explicitly not recommended and may affect the vaccine's safety and immunogenicity profile.[11]
• Fractional Dosing: In the specific context of a large outbreak where vaccine supplies are limited, the WHO may recommend the use of a fractional dose (e.g., one-fifth of the standard dose) as a dose-sparing strategy to extend the available supply. This practice has been shown to be immunogenic in adults but is not intended for routine immunization and is generally not recommended for specific groups such as young children or pregnant women.[4]

Booster Dose Recommendations for Specific High-Risk Groups

While a single dose is considered sufficient for lifelong protection for most people, the evidence of waning immunity in certain populations has led to specific recommendations for additional or booster doses for individuals who remain at high risk of exposure [5]:

• Individuals Vaccinated During Pregnancy: Should receive one additional dose before their next travel to an at-risk area.
• Hematopoietic Stem Cell Transplant (HSCT) Recipients: Those who received an HSCT after their last yellow fever vaccination should be revaccinated before their next potential exposure, provided they are deemed sufficiently immunocompetent to receive a live vaccine safely.
• Persons with HIV: Individuals who were HIV-infected at the time of their last vaccination should receive a booster dose every 10 years if they continue to be at risk.
• High-Risk Laboratory Workers: Personnel who routinely handle wild-type yellow fever virus should either have their neutralizing antibody titers measured at least every 10 years to confirm ongoing protection or receive a booster dose every 10 years.
• Travelers to High-Risk Settings: A booster dose may be considered for travelers who were vaccinated 10 or more years previously and are planning to travel to a higher-risk setting, such as an area with an ongoing outbreak or for prolonged periods in a highly endemic region.

Coadministration with Other Vaccines

• Inactivated and Oral Live Vaccines: Inactivated vaccines (e.g., inactivated polio, tetanus toxoid) and oral live vaccines (e.g., oral typhoid, oral cholera) do not interfere with the immune response to the yellow fever vaccine. They can be administered simultaneously or at any interval before or after yellow fever vaccination.[12]
• Injectable Live-Attenuated Vaccines (e.g., Measles-Mumps-Rubella, Varicella):
• Simultaneous Administration: The preferred approach, if multiple live vaccines are needed, is to administer them on the same day at different anatomical sites.[12]
• Separated Administration: If the vaccines are not given on the same day, a minimum interval of 30 days should be maintained between the administration of the yellow fever vaccine and other injectable live vaccines like MMR.[12] This is a specific recommendation that differs from the standard 28-day interval for other live vaccines.
• Rationale: The 30-day interval is recommended because some studies have demonstrated a potential for immune interference when the YF and MMR vaccines are coadministered. This can result in a blunted antibody response (lower antibody concentrations or seroconversion rates) to the rubella and yellow fever components compared to when the vaccines are administered at least 30 days apart.[12] While simultaneous administration is acceptable if travel is imminent and there is not enough time to observe the interval, separating the doses is the preferred strategy to ensure an optimal immune response to all vaccine components.

Table 2: Dosing and Booster Recommendations for Special Populations

Population Group	Primary Dose Recommendation	Booster Dose Consideration
General Healthy Population (≥9 months)	0.5 mL SC once	Single dose provides lifelong protection; no routine booster needed.
Children Vaccinated <2 Years of Age	0.5 mL SC once	Consider one booster dose if ongoing risk, due to evidence of more rapid waning of immunity.
Women Vaccinated During Pregnancy	0.5 mL SC once	Receive one additional dose before next at-risk travel.
Persons with HIV	0.5 mL SC once	Revaccinate every 10 years if ongoing risk of exposure.
HSCT Recipients	0.5 mL SC once	Revaccinate post-transplant if sufficiently immunocompetent and at risk of exposure.
High-Risk Laboratory Workers	0.5 mL SC once	Receive a booster dose or have neutralizing antibody titers measured every 10 years.

Comprehensive Safety Profile and Risk Management

The yellow fever vaccine has a well-established safety profile, characterized by a high degree of tolerability for the vast majority of recipients. However, its status as a live-attenuated virus means it carries a low but significant risk of rare, severe adverse events, particularly in specific, identifiable subpopulations. Effective risk management, therefore, depends on a thorough understanding of this safety dichotomy and meticulous pre-vaccination screening.

Common Adverse Events

Reactions following yellow fever vaccination are typically mild, self-limited, and occur in a small percentage of recipients.

• Incidence and Timing: Approximately 2% to 5% of vaccinees experience mild systemic reactions that begin 5 to 10 days after vaccination, coinciding with the period of viral replication.[3]
• Symptoms: The most commonly reported symptoms include mild headache, myalgia (muscle aches), low-grade fever, and soreness or redness at the injection site.[3] These symptoms are generally not severe, with fewer than 0.2% of recipients reporting that they needed to curtail their regular activities.[14]

Rare and Serious Adverse Events (SAEs)

While extremely uncommon, the vaccine is associated with three main categories of serious adverse events.

• Hypersensitivity and Anaphylaxis: Immediate hypersensitivity reactions, including life-threatening anaphylaxis, are exceedingly rare, with an estimated incidence of less than 1 per million doses.[12] These reactions are primarily linked to severe, pre-existing allergies to vaccine components, most notably eggs (due to the chicken embryo substrate) or gelatin (used as a stabilizer).[16]
• Yellow Fever Vaccine-Associated Neurotropic Disease (YEL-AND):
• Clinical Presentation: YEL-AND is a collective term for a range of neurological complications that can occur following vaccination. These include meningoencephalitis (inflammation of the brain and its surrounding membranes), Guillain-Barré syndrome (an autoimmune disorder affecting the peripheral nerves), and acute disseminated encephalomyelitis (ADEM).[2]
• Incidence and Risk Factors: The overall risk is very low, estimated at approximately 0.8 cases per 100,000 doses distributed.[57] However, the risk is not uniform across all age groups. It is significantly elevated in infants under 9 months of age, which is the primary reason the vaccine is contraindicated in this group.[11] The risk also increases with advanced age, rising to approximately 2.2 cases per 100,000 doses for individuals aged 60 years and older.[44]
• Yellow Fever Vaccine-Associated Viscerotropic Disease (YEL-AVD):
• Clinical Presentation: YEL-AVD is the most severe adverse event associated with the vaccine. It is a life-threatening illness caused by the uncontrolled replication and dissemination of the vaccine virus throughout the body. This leads to a clinical syndrome of multi-organ system failure, including hepatitis, renal failure, and shock, which closely mimics severe, wild-type yellow fever infection.[1]
• Case-Fatality Rate: The mortality rate for YEL-AVD is extremely high, with reports of 60% or more of affected individuals succumbing to the illness.[2]
• Incidence and Risk Factors: YEL-AVD is very rare, with global incidence estimates ranging from 0.04 to 3 per million doses.[13] However, the risk is concentrated in specific, identifiable populations:

1. Advanced Age (≥60 years): This is the most significant and well-established risk factor. The incidence rises to approximately 1.2 cases per 100,000 doses for those aged 60 and older, and is even higher for those over 70.[11]
2. History of Thymus Disorder: A history of diseases affecting the thymus gland (such as myasthenia gravis or thymoma) or prior surgical removal of the thymus (thymectomy) for any reason is a strong, independent risk factor for YEL-AVD.[13] The thymus is essential for the proper development and regulation of T-cells, and its dysfunction likely impairs the immune system's ability to control the replication of the live vaccine virus.
3. First-time Vaccination: To date, all confirmed cases of YEL-AVD have occurred in individuals receiving their primary (first-ever) dose of the yellow fever vaccine. No cases have been reported following a booster dose.[2]

The distinct safety profile of the yellow fever vaccine, with its predictable concentration of severe risks in specific subpopulations, makes pre-vaccination screening and risk assessment the single most critical safety measure. A simple but thorough patient history focusing on age, immune status, and any history of thymus disorders can effectively identify individuals at the highest risk for severe complications. This knowledge allows clinicians to make an informed risk-benefit decision, potentially opting for a medical waiver instead of vaccination for high-risk individuals whose travel itineraries involve low exposure risk. The existence of these rare but catastrophic events is also the primary justification for the controlled administration of the vaccine exclusively at designated vaccination centers, ensuring that providers are specially trained in this nuanced risk assessment process.[12]

Table 3: Risk Profile of Serious Adverse Events (SAEs)

Parameter	YEL-AND (Neurotropic Disease)	YEL-AVD (Viscerotropic Disease)
Clinical Presentation	Meningoencephalitis, Guillain-Barré syndrome, Acute Disseminated Encephalomyelitis	Multi-organ failure mimicking severe wild-type yellow fever
Estimated Incidence (Overall)	~0.8 per 100,000 doses	~0.3 per 100,000 doses
Estimated Incidence (Age ≥60)	~2.2 per 100,000 doses	~1.2 per 100,000 doses
Key Risk Factors	Infancy (<9 months), Advanced Age (≥60 years)	Advanced Age (≥60 years), Thymus Disorder/Thymectomy, Primary (first-time) Vaccination

Contraindications, Warnings, and Drug Interactions

The safe administration of the yellow fever vaccine hinges on the careful identification of individuals for whom the vaccine is contraindicated or for whom the risks may outweigh the benefits. Additionally, awareness of potential drug interactions is essential to ensure both safety and efficacy.

Absolute Contraindications

The yellow fever vaccine, being a live virus, should not be administered under any circumstances to individuals with the following conditions, as the risk of severe adverse events is unacceptably high:

• Age: Infants less than 6 months of age are strictly contraindicated due to the high risk of vaccine-associated encephalitis.[30] The U.S. FDA extends this contraindication to infants less than 9 months of age.[11]
• Hypersensitivity: A history of a severe, life-threatening allergic reaction (i.e., anaphylaxis) to a previous dose of the yellow fever vaccine or to any of its components, which include eggs, egg products, chicken proteins, or gelatin, is an absolute contraindication.[11]
• Immunosuppression: The vaccine is contraindicated in individuals with severe immunosuppression, whether congenital (e.g., DiGeorge syndrome) or acquired. This includes, but is not limited to:
• Symptomatic HIV infection or Acquired Immunodeficiency Syndrome (AIDS).[11]
• Individuals with an asymptomatic HIV infection but with evidence of severe immunosuppression (e.g., CD4+ T-cell counts <200 cells/mm³).[3]
• Leukemia, lymphoma, or other generalized malignancies.[11]
• Individuals undergoing immunosuppressive therapies such as high-dose corticosteroids, chemotherapy, or radiation therapy.[33]
• Thymus Disorder: A history of any thymus disorder, including myasthenia gravis, thymoma, or DiGeorge syndrome, or a history of thymectomy (surgical removal of the thymus), is an absolute contraindication due to the strong association with an increased risk of fatal YEL-AVD.[13]

Precautions

For certain individuals, the risk of serious adverse events is increased, but vaccination may still be considered if the risk of acquiring yellow fever during travel is deemed to be high and unavoidable. This requires a careful, individualized risk-benefit analysis by the clinician. These situations include:

• Age: Infants aged 6 to 8 months and adults aged 60 years or older.[3]
• Pregnancy and Breastfeeding: The vaccine is generally not recommended for pregnant women. However, if travel to a high-risk endemic area cannot be postponed, vaccination may be offered after a thorough discussion of the risks.[3] For breastfeeding mothers, vaccination is a precaution due to the potential for transmitting the vaccine virus to the infant via breast milk, a risk of particular concern if the infant is less than 9 months old.[3]
• Asymptomatic HIV Infection with Moderate Immunosuppression: Individuals with asymptomatic HIV infection and CD4+ T-cell counts between 200 and 499 cells/mm³ fall into this category.[3]

Clinically Significant Drug Interactions

Drug interactions with the yellow fever vaccine are primarily pharmacodynamic and can be broadly categorized into two main types:

• Drugs that Increase Risk of Infection (Immunosuppressants): The most significant interactions involve medications that suppress the immune system. Coadministration of the live yellow fever vaccine with these drugs can impair the host's ability to control viral replication, potentially leading to a disseminated and severe vaccine-related infection. This is a major interaction class, and concurrent use should be avoided. Examples of such drugs include:
• Biologic agents: Adalimumab, Belimumab, Anakinra.[10]
• Systemic corticosteroids: Betamethasone, Prednisone (high-dose, long-term use).[10]
• Conventional immunosuppressants: Methotrexate, Azathioprine.[10]
• Cancer chemotherapies: Bendamustine, Amsacrine, and many others.[10]
• Drugs that Decrease Vaccine Efficacy (Antivirals): Concurrent administration of antiviral medications with activity against flaviviruses could theoretically inhibit the replication of the 17D vaccine virus. Since viral replication is essential for stimulating a robust immune response, this could lead to reduced immunogenicity and potential vaccine failure. Examples of drugs with potential for this interaction include:
• Acyclovir, Amantadine, Amprenavir, Baloxavir marboxil, and Oseltamivir (Tamiflu).[10]

It is also important to note that underlying disease states, particularly any condition causing immunodeficiency or an active febrile illness, represent significant interactions that may serve as contraindications or reasons to postpone vaccination.[35]

Table 4: Summary of Key Contraindications and Precautions

Absolute Contraindications (Vaccine Should Not Be Given)	Precautions (Careful Risk-Benefit Assessment Required)
* Age <6-9 months	* Age 6-8 months
* Severe Hypersensitivity (to eggs, chicken, gelatin, or previous dose)	* Age ≥60 years
* Severe Immunosuppression (e.g., symptomatic HIV/AIDS, malignancy, high-dose immunosuppressive therapy)	* Pregnancy
* History of Thymus Disorder or Thymectomy	* Breastfeeding (especially if infant is <9 months old)
	* Asymptomatic HIV infection (CD4+ count 200-499/mm³)

Global Regulatory Status and Public Health Implications

The yellow fever vaccine is not merely a therapeutic agent but also a critical instrument of international public health policy. Its regulatory status with major global health organizations and its role in international travel regulations underscore its importance in preventing the spread of a dangerous disease across borders.

Regulatory Approvals and Standards

The vaccine is licensed and standardized by major national and international regulatory bodies, ensuring its quality and consistent application worldwide.

• U.S. Food and Drug Administration (FDA): In the United States, the YF-VAX® vaccine, manufactured by Sanofi Pasteur, is licensed (STN: BL 103915) for active immunization against yellow fever in individuals aged 9 months and older.[52] The U.S. has a single licensed manufacturer, which has highlighted the vulnerability of the national supply chain. During a period when YF-VAX® production was being transitioned to a new facility, the FDA implemented an Expanded Access Program (EAP) to allow for the temporary importation of Stamaril®, Sanofi Pasteur's French-manufactured yellow fever vaccine, to ensure an uninterrupted supply for the U.S. population.[64]
• World Health Organization (WHO): The yellow fever vaccine is included on the WHO's List of Essential Medicines, signifying its critical importance for global health.[19] The WHO runs a stringent prequalification program for vaccines, including those for yellow fever, from various global manufacturers. This prequalification ensures that any vaccine procured by United Nations agencies for large-scale immunization campaigns meets international standards of quality, safety, and efficacy.[4] The formulation and potency standards of widely used vaccines like YF-VAX® are in compliance with these WHO requirements.[11]

International Health Regulations (IHR) and Travel

The vaccine is a central component of the legal framework designed to prevent the international spread of infectious diseases.

• International Certificate of Vaccination or Prophylaxis (ICVP): The ICVP, colloquially known as the "yellow card," serves as official, internationally recognized proof of vaccination.[11] Under the IHR, countries are permitted to require travelers to present a valid ICVP as a condition of entry, particularly if they are arriving from countries with a risk of yellow fever transmission. This is a biosecurity measure to prevent the importation of the virus into areas that have competent mosquito vectors but are currently free of the disease.[14]
• Validity: The ICVP becomes legally valid 10 days after primary vaccination.[11] A pivotal change to the IHR occurred in 2016, when the validity of the certificate was extended from 10 years to the lifetime of the vaccinee.[5] This policy change was a direct result of the overwhelming scientific evidence demonstrating that a single dose of the vaccine provides lifelong protection in the majority of individuals. This shift has had significant logistical benefits, simplifying travel requirements for millions of people and reducing the burden on healthcare systems to provide unnecessary booster doses.

Global Public Health Strategies

Vaccination is universally recognized as the single most important and effective measure for preventing yellow fever.[4]

• The "Eliminate Yellow Fever Epidemics (EYE)" Strategy: This is a comprehensive global initiative launched in 2017 and led by the WHO, Gavi, the Vaccine Alliance, and UNICEF. The EYE strategy has three primary objectives: protecting at-risk populations through vaccination, preventing international spread, and containing outbreaks rapidly when they occur.[4] The strategy is implemented through a combination of routine infant immunization programs in endemic countries, large-scale preventive mass vaccination campaigns, and the maintenance of a global emergency vaccine stockpile of 6 million doses per year to respond to outbreaks.[4]
• Herd Immunity: The success of these public health efforts relies on achieving a high level of population immunity, or herd immunity. The WHO recommends that vaccination coverage should be at least 80% in all high-risk and endemic areas. Maintaining this level of coverage disrupts the virus's transmission cycle between mosquitoes and humans, thereby protecting the entire community, including those who cannot be vaccinated.[4]

The central role of the yellow fever vaccine in international law and global health security highlights a powerful synergy between scientific advancement and public policy. The legal framework of the IHR and the mandatory ICVP would not be feasible without a vaccine that is both highly effective and provides exceptionally long-lasting protection. However, the recurring theme of vaccine shortages, often stemming from the "legacy" egg-based manufacturing process, reveals a critical vulnerability in the global response. The reliance on a complex and difficult-to-scale production method means that the supply chain is fragile. Without continued investment in modern, scalable manufacturing technologies, the world remains at risk of large-scale outbreaks that could rapidly deplete existing stockpiles and undermine the ambitious goals of initiatives like the EYE strategy.

Conclusion

The Yellow Fever 17D vaccine (DB10805) is a triumph of 20th-century medical science, a live-attenuated vaccine whose enduring efficacy and complex immunological profile continue to inform the field of vaccinology. Its development, a story of empirical discovery and refinement, provided a tool that has successfully controlled a once-feared hemorrhagic fever, saving countless lives and enabling safe travel and commerce in vast regions of the world.

The vaccine's profound success lies in its ability to orchestrate a comprehensive and durable immune response that closely mimics natural infection. By engaging multiple innate immune pathways via Toll-Like Receptors, it triggers a powerful cascade that results in the rapid production of high-titer neutralizing antibodies and the establishment of a unique, self-renewing population of memory T-cells. This multi-layered defense is the immunological basis for the lifelong protection conferred by a single dose in the majority of healthy individuals.

However, the vaccine's potency is intrinsically linked to its safety profile. As a live, replicating virus, it carries rare but severe risks of neurotropic and viscerotropic disease. Decades of surveillance have revealed that these risks are not random but are concentrated in specific, identifiable populations: the very young, the elderly, and the immunocompromised, particularly those with thymus disorders. This knowledge transforms risk management from a matter of chance to one of clinical diligence. Meticulous pre-vaccination screening based on age, immune status, and medical history is the most critical tool for ensuring the vaccine's safe use. This distinct risk-benefit profile justifies its controlled administration in designated centers by trained professionals capable of performing the necessary nuanced assessment.

As an instrument of international law and a pillar of global health security, the vaccine's role extends beyond individual protection. It is the foundation of the International Health Regulations governing travel and the centerpiece of global strategies aimed at eliminating yellow fever epidemics. Yet, the reliance on a technologically dated and difficult-to-scale manufacturing process represents a persistent vulnerability in the global supply chain, a challenge that must be addressed through investment in modern cell-based production platforms.

In conclusion, the Yellow Fever 17D vaccine is a paradigm of successful immunization. It serves as a gold standard for inducing protective immunity, a case study in the evolution of vaccine safety, and an essential tool for global public health. Its continued success will depend on vigilant safety monitoring, targeted vaccination strategies that account for vulnerable populations, and a modernized manufacturing infrastructure capable of meeting the challenges of a changing world.

Works cited

1. Current Status and Future Prospects of Yellow Fever Vaccines - PMC - PubMed Central, accessed September 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5563254/
2. Serious adverse events associated with yellow fever vaccine - PMC, accessed September 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4635904/
3. Yellow Fever Vaccine - CDC, accessed September 17, 2025, https://www.cdc.gov/yellow-fever/vaccine/index.html
4. Yellow Fever Vaccines - Immunization, Vaccines and Biologicals, accessed September 17, 2025, https://www.who.int/teams/immunization-vaccines-and-biologicals/diseases/yellow-fever
5. Yellow Fever Vaccine Booster Doses: Recommendations of the Advisory Committee on Immunization Practices, 2015 - PMC, accessed September 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4584737/
6. Yellow fever - World Health Organization (WHO), accessed September 17, 2025, https://www.who.int/news-room/fact-sheets/detail/yellow-fever
7. Yellow fever virus vaccination: an emblematic model to elucidate robust human immune responses - PMC - PubMed Central, accessed September 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8475614/
8. pmc.ncbi.nlm.nih.gov, accessed September 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8475614/#:~:text=YF%20vaccination%20causes%20a%20systemic,contrast%20to%20most%20other%20vaccines.
9. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets ..., accessed September 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2118210/
10. Yellow fever vaccine: Uses, Interactions, Mechanism of Action, accessed September 17, 2025, https://go.drugbank.com/drugs/DB10805
11. Yellow Fever Vaccine - YF-Vax - FDA, accessed September 17, 2025, https://www.fda.gov/media/76015/download
12. Yellow Fever Vaccine Information for Healthcare Providers - CDC, accessed September 17, 2025, https://www.cdc.gov/yellow-fever/hcp/vaccine/index.html
13. Safety - World Health Organization (WHO), accessed September 17, 2025, https://www.who.int/groups/global-advisory-committee-on-vaccine-safety/topics/yellow-fever-vaccines/safety
14. Yellow Fever Vaccine Recommendations of the Immunization Practices Advisory Committee (ACIP) - CDC, accessed September 17, 2025, https://www.cdc.gov/mmwr/preview/mmwrhtml/00001620.htm
15. Yellow Fever Vaccine YF-VAX DESCRIPTION CLINICAL PHARMACOLOGY - Amazon S3, accessed September 17, 2025, https://s3-us-west-2.amazonaws.com/drugbank/fda_labels/DB10805.pdf?1508443552
16. YF-VAX, Yellow Fever Vaccine - IN.gov, accessed September 17, 2025, https://www.in.gov/health/idepd/files/Yellow_Fever_Vaccine_Package_Insert.pdf
17. Advances and controversies in yellow fever vaccination - PMC, accessed September 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3991151/
18. Yellow Fever - World Health Organization (WHO), accessed September 17, 2025, https://www.who.int/teams/health-product-policy-and-standards/standards-and-specifications/norms-and-standards/vaccine-standardization/yellow-fever
19. Yellow fever vaccine - Wikipedia, accessed September 17, 2025, https://en.wikipedia.org/wiki/Yellow_fever_vaccine
20. Developing a Novel Vaccine Against Yellow Fever That Remains Important Seventy Years Later - The Rockefeller University » Hospital Centennial, accessed September 17, 2025, https://centennial.rucares.org/index.php?page=Yellow_Fever
21. Theiler, Max - Science Heroes, accessed September 17, 2025, https://www.scienceheroes.com/theiler-yellowfever
22. A Brief History of Vaccination - World Health Organization (WHO), accessed September 17, 2025, https://www.who.int/news-room/spotlight/history-of-vaccination/a-brief-history-of-vaccination
23. Yellow fever and Max Theiler: the only Nobel Prize for a virus ..., accessed September 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2118520/
24. The early use of yellow fever virus strain 17D for vaccine production in Brazil - a review, accessed September 17, 2025, https://www.scielo.br/j/mioc/a/Mk9HP3HbF8qgPN4KTxysFTS/?lang=en
25. The yellow fever 17D virus as a platform for new live attenuated vaccines - PMC, accessed September 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4896586/
26. www.who.int, accessed September 17, 2025, https://www.who.int/teams/health-product-policy-and-standards/standards-and-specifications/norms-and-standards/vaccine-standardization/yellow-fever#:~:text=Yellow%20Fever%20Vaccines&text=Two%20substrains%20of%20the%2017D,204%20(17D%2D213).
27. The 1942 Massive Contamination of Yellow Fever Vaccine: A Public Health Consequence of Scientific Arrogance - PMC, accessed September 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8589052/
28. YF-VAX, accessed September 17, 2025, https://pdf.hres.ca/dpd_pm/00050691.PDF
29. The Yellow Fever Vaccine: A History - PMC, accessed September 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2892770/
30. Yellow Fever | Yellow Book - CDC, accessed September 17, 2025, https://www.cdc.gov/yellow-book/hcp/travel-associated-infections-diseases/yellow-fever.html
31. Vaccine Types - HHS.gov, accessed September 17, 2025, https://www.hhs.gov/immunization/basics/types/index.html
32. READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR ... - Sanofi, accessed September 17, 2025, https://www.sanofi.com/assets/countries/canada/docs/products/vaccines/yf-vax-pmi-en.pdf
33. YF-VAX® - Sanofi, accessed September 17, 2025, https://www.sanofi.com/assets/countries/canada/docs/products/vaccines/yf-vax-en.pdf
34. Yellow Fever Vaccine Production - Institut Magdeburg, accessed September 17, 2025, https://www.mpi-magdeburg.mpg.de/4420869/Yellow_Fever_Vaccine_Production
35. Yellow fever vaccine (subcutaneous route) - Side effects & uses - Mayo Clinic, accessed September 17, 2025, https://www.mayoclinic.org/drugs-supplements/yellow-fever-vaccine-subcutaneous-route/description/drg-20066731
36. Yellow Fever Vaccine: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed September 17, 2025, https://www.rxlist.com/yellow_fever_vaccine/generic-drug.htm
37. Study Details | Yellow Fever Vaccine on Statin/ Non Statin Subjects | ClinicalTrials.gov, accessed September 17, 2025, https://clinicaltrials.gov/study/NCT03116802?term=AREA%5BConditionSearch%5D(%22Yellow%20Fever%22)&rank=3
38. Study Details | Human Immune Responses to Yellow Fever Vaccination | ClinicalTrials.gov, accessed September 17, 2025, https://www.clinicaltrials.gov/study/NCT00694655
39. Yellow fever vaccine: Canadian Immunization Guide - Canada.ca, accessed September 17, 2025, https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-25-yellow-fever-vaccine.html
40. 1 EFFICACY AND DURATION OF IMMUNITY FOLLOWING ..., accessed September 17, 2025, https://terrance.who.int/mediacentre/data/sage/SAGE_Docs_Ppt_Apr2013/5_session_yellow_fever/Apr2013_session5_YF_efficacy.pdf
41. Yellow Fever Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP) - CDC, accessed September 17, 2025, https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5907a1.htm
42. Yellow Fever Vaccine - What You Need To Know - CDC, accessed September 17, 2025, https://www.cdc.gov/yellow-fever/media/pdfs/yf.pdf
43. Protocol for Yellow Fever Vaccine (YF-VAX®) - Oregon.gov, accessed September 17, 2025, https://www.oregon.gov/pharmacy/Documents/PrevCare_Yellow_Fever_v.10.2023.pdf
44. contraindications and precautions - Yellow fever vaccine, accessed September 17, 2025, https://nathnacyfzone.org.uk/media_lib/mlib-uploads/full/yellow-fever-vaccine-contraindications-and-precautions.pdf
45. A comprehensive review of yellow fever vaccine breakthrough infection across 8 decades, accessed September 17, 2025, https://pubmed.ncbi.nlm.nih.gov/39577331/
46. Yellow fever | The Australian Immunisation Handbook, accessed September 17, 2025, https://immunisationhandbook.health.gov.au/contents/vaccine-preventable-diseases/yellow-fever
47. Long-term immunity after a single yellow fever vaccination in travelers vaccinated at 60 years or older: A 10-year follow-up study | Journal of Travel Medicine | Oxford Academic, accessed September 17, 2025, https://academic.oup.com/jtm/article/28/8/taab126/6353012
48. The Present and Future of Yellow Fever Vaccines - MDPI, accessed September 17, 2025, https://www.mdpi.com/1424-8247/14/9/891
49. Long-term immunity following yellow fever vaccination: a systematic review and meta-analysis - PubMed, accessed September 17, 2025, https://pubmed.ncbi.nlm.nih.gov/38272044/
50. Duration of Protection After Vaccination Against Yellow Fever: A ..., accessed September 17, 2025, https://academic.oup.com/cid/article/75/12/2266/6646957
51. YF Vax (yellow fever vaccine) dosing, indications, interactions, adverse effects, and more, accessed September 17, 2025, https://reference.medscape.com/drug/y-f-vax-yellow-fever-vaccine-343179
52. YF-VAX - FDA, accessed September 17, 2025, https://www.fda.gov/vaccines-blood-biologics/vaccines/yf-vax
53. Travel Vaccine Recommendations for Infants and Children | Yellow Book | CDC, accessed September 17, 2025, https://www.cdc.gov/yellow-book/hcp/family-travel/travel-vaccine-recommendations-for-infants-and-children.html
54. YELLOW FEVER VACCINE - MSF Medical Guidelines, accessed September 17, 2025, https://medicalguidelines.msf.org/en/viewport/EssDr/english/yellow-fever-vaccine-16687834.html
55. Vaccination and Immunoprophylaxis—General Principles | Yellow Book - CDC, accessed September 17, 2025, https://www.cdc.gov/yellow-book/hcp/preparing-international-travelers/vaccination-and-immunoprophylaxis-general-principles.html
56. Yellow Fever: The Disease & Vaccines | Children's Hospital of Philadelphia, accessed September 17, 2025, https://www.chop.edu/vaccine-education-center/vaccine-details/yellow-fever-vaccine
57. Yellow Fever Vaccine - Fit for Travel, accessed September 17, 2025, https://www.fitfortravel.nhs.uk/advice/disease-prevention-advice/yellow-fever-vaccine
58. Real-world evidence of yellow Fever vaccination data-driven study - PubMed, accessed September 17, 2025, https://pubmed.ncbi.nlm.nih.gov/39848130/
59. Travel health - yellow fever immunisation, accessed September 17, 2025, https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/travel-health-yellow-fever-immunisation
60. Yellow Fever Vaccine: Benefits & Side Effects - Cleveland Clinic, accessed September 17, 2025, https://my.clevelandclinic.org/health/drugs/18844-yellow-fever-vaccine-live-suspension-for-injection
61. Study Details | VAC-SIP-YF (Vaccination- Safety & Immunogenicity During Pregnancy- Yellow Fever) | ClinicalTrials.gov, accessed September 17, 2025, https://www.clinicaltrials.gov/study/NCT06694766?cond=Yellow%20fever%20OR%20%22bronze%20John%22%20OR%20%22%20jungle%20yellow%20fever%22%20OR%20%22%20sylvatic%20yellow%20fever%22%20OR%20%22%20urban%20yellow%20fever%22%20OR%20%22%20Yellow%20fever%20virus%20caused%20disease%20or%20disorder%22%20OR%20%22%20Yellow%20fever%20virus%20disease%20or%20disorder%22%20OR%20%22%20Yellow%20fever%20Virus%20infection%22%20OR%20%22%20Yellow%20fever%20virus%20infectious%20disease%22%20OR%20%22%20Yellow%20fever,%20sylvan%22%20OR%20%22%20Yellow%20Jack%22%20OR%20%22%20YF%22&aggFilters=status:not%20rec&viewType=Table&rank=1
62. Yellow fever vaccine Interactions - Drugs.com, accessed September 17, 2025, https://www.drugs.com/drug-interactions/yellow-fever-vaccine.html
63. YF-VAX Yellow Fever Vaccine — Vax-Before-Travel, accessed September 17, 2025, https://www.vax-before-travel.com/vaccines/yf-vax-yellow-fever-vaccine
64. Yellow Fever Vaccine Administration at Global TravEpiNet (GTEN) Clinics during a Period of Limited Vaccine Availability in the United States, 2017–2018 - PMC, accessed September 17, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7941836/