Japanese Encephalitis Virus Strain SA 14-14-2 Antigen (Formaldehyde Inactivated): A Comprehensive Review

1. Introduction to Japanese Encephalitis Virus Strain SA 14-14-2 Antigen (formaldehyde inactivated)

Overview of Japanese Encephalitis (JE) and Its Public Health Significance

Japanese Encephalitis (JE) is a severe mosquito-borne viral illness and a leading cause of viral encephalitis in Asia, particularly Southeast Asia.[1] The disease is caused by the Japanese Encephalitis Virus (JEV), a member of the Flaviviridae family.[3] JEV transmission follows a zoonotic cycle involving mosquitoes (primarily Culex species) as vectors, with water birds serving as natural reservoirs and pigs acting as significant amplifying hosts.[3] Humans are generally considered incidental or dead-end hosts because the level of viremia in infected individuals is typically insufficient to infect mosquitoes.[3]

While a large proportion of JEV infections are subclinical or result in mild, undifferentiated febrile illness, the development of clinical JE can have devastating consequences.[3] The incubation period in humans is estimated to be 5 to 15 days, often followed by the sudden onset of fever.[3] If the virus invades the central nervous system, it can manifest as meningitis, encephalitis, or myelitis.[3] Children are particularly vulnerable, often presenting with altered sensorium, seizures, and other severe neurological symptoms.[3] Approximately 1 in 250 JEV infections results in clinical disease.[3] Among those who develop encephalitis, the case-fatality rate can be as high as 30%, and around 30-50% of survivors experience significant long-term neurological or psychiatric sequelae, leading to lifelong disability.[3]

Given the severity of the disease and the absence of specific antiviral treatments, vaccination stands as the most effective public health intervention for preventing JE.[3] The JEV envelope (E) protein is a crucial viral component as it mediates viral entry into host cells and is the primary target for virus-neutralizing antibodies, making it a central focus for vaccine development efforts.[3]

The SA 14-14-2 Strain as a Vaccine Antigen

The SA 14-14-2 virus strain is an attenuated strain of JEV, which was originally developed and is used for live attenuated JE vaccines.[6] However, the specific antigen identified by DrugBank ID DB10769 is derived from this same SA 14-14-2 strain but is formaldehyde inactivated.[3] This inactivation process, coupled with its production in Vero cell culture (a continuous line of cells derived from the kidney of an African green monkey), distinguishes this antigen from its live attenuated counterpart and forms the basis of several modern, widely used inactivated JE vaccines.[3] These vaccines represent a significant improvement in terms of safety and manufacturing consistency compared to earlier-generation mouse brain-derived JE vaccines, which were associated with safety concerns.[3]

The development and adoption of Vero cell-derived, inactivated vaccines utilizing the SA 14-14-2 antigen signify a crucial advancement in JE vaccine technology. Historically, mouse brain-derived JE vaccines (such as JE-VAX) raised concerns regarding neurological adverse events, potentially linked to residual myelin basic protein or other neural tissue components from the manufacturing substrate.[3] The use of a well-characterized and controlled Vero cell line for antigen production minimizes the risk of such contaminants, thereby enhancing the overall safety profile of the vaccine.[19] Furthermore, formaldehyde inactivation ensures that the virus cannot replicate and cause disease, while its antigenicity, particularly of the crucial E protein, is preserved to effectively stimulate a protective immune response. This technological progression directly addresses the safety limitations of earlier vaccines and is a primary driver for the development and widespread adoption of vaccines based on the SA 14-14-2 inactivated antigen.

DrugBank ID

The antigen "Japanese encephalitis virus strain sa 14-14-2 antigen (formaldehyde inactivated)" is cataloged under the DrugBank Accession Number DB10769 and is classified as a biotech-type drug.

2. Vaccine Characteristics and Formulation

Vaccines utilizing the Japanese encephalitis virus strain SA 14-14-2 antigen (formaldehyde inactivated) share core characteristics related to their antigen source and manufacturing principles, though specific formulations may vary between products.

Antigen Source

• Virus Strain: The antigen is derived from the Japanese Encephalitis Virus (JEV) SA 14-14-2 strain. This strain was originally attenuated for use in live vaccines but is employed in its inactivated form for this vaccine type.[3]
• Cell Substrate: The SA 14-14-2 virus is propagated in Vero cells, a continuous cell line derived from African Green Monkey kidney cells. Vero cells are widely accepted and utilized in the production of various human vaccines due to their well-characterized nature and ability to support viral growth to high titers.[3]

Manufacturing Process

• Inactivation: After viral propagation in Vero cells, the JEV SA 14-14-2 strain is inactivated using formaldehyde. This chemical inactivation process renders the virus non-infectious, eliminating its ability to replicate and cause disease, while critically preserving the immunogenicity of its key antigenic components, particularly the envelope (E) protein.[3]
• Purification: The inactivated virus preparation typically undergoes purification processes, often involving chromatographic techniques, to remove impurities, cellular debris from the Vero cell substrate, and residual manufacturing components. This ensures a higher degree of purity for the final vaccine product.[19]

Formulation Components

• Adjuvant: These vaccines are typically formulated with an aluminium hydroxide adjuvant. Aluminium salts are widely used in inactivated vaccines to enhance the immune response. They are thought to work by creating a depot effect at the injection site, allowing for a slower, more sustained release of the antigen, and by stimulating the innate immune system, which in turn promotes a more robust adaptive immune response, including antibody production.[7]
• For IXIARO®, the formulation contains approximately 0.25 milligrams of Al3+ (as aluminium hydroxide, hydrated) per 0.5 mL dose.[10]
• For JEEV®, the formulation contains 0.1% w/v Aluminium as Aluminium Hydroxide.[9]
• Excipients:
• IXIARO® typically includes Phosphate Buffered Saline (containing sodium chloride, potassium dihydrogen phosphate, and disodium hydrogen phosphate). Residuals from the manufacturing process may include trace amounts of protamine sulphate, formaldehyde, bovine serum albumin, host cell DNA, sodium metabisulphite, and host cell protein.[10] The vaccine is essentially 'potassium-free' and 'sodium-free' per dose, referring to the low levels of these ions.[13]
• JEEV® also includes Phosphate Buffer Saline. Some multi-dose vial presentations of JEEV® may contain Thiomersal (e.g., 0.005% w/v) as a preservative.[9] However, it is noted that Biological E. Limited also produces thiomersal-free formulations of their SA 14-14-2 based vaccine, reflecting a global trend towards reducing or eliminating thiomersal in vaccines where feasible, particularly for single-dose presentations and pediatric use.[6]

Presentation and Appearance

• IXIARO®: Generally supplied as a suspension for injection in a 0.5 mL pre-filled syringe. The vaccine appears as a clear liquid containing a white precipitate.[10]
• JEEV®: Typically supplied as a suspension for injection in vials (e.g., 1-dose, 5-dose). It appears as a white, clear non-uniform suspension that becomes homogenous upon shaking.[9]

The standardization of the core antigen (SA 14-14-2, Vero-derived, inactivated) and the use of an aluminum-based adjuvant are consistent features across the major vaccine brands like IXIARO® and JEEV®. This consistency in the active immunizing component is fundamental to achieving comparable protective efficacy. However, minor variations in the reported quantity of adjuvant (though likely practically equivalent), the presence or absence of preservatives such as thiomersal (often dictated by single-dose versus multi-dose vial presentations), and the specific list of other excipients highlight that final product formulations can differ between manufacturers or even between different presentations from the same manufacturer. These differences, while generally not expected to significantly impact the core immunogenicity or safety profile attributed to the SA 14-14-2 antigen itself, can have practical implications. For instance, the choice of preservative can influence storage requirements, multi-dose vial policies (crucial for mass vaccination campaigns), and suitability for individuals with known sensitivities to specific components like thiomersal. The development of thiomersal-free formulations, as noted for a Biological E. product [6], aligns with a broader global public health preference, particularly for pediatric vaccines, to minimize exposure to mercury-containing compounds, even though the levels in vaccines have been deemed safe by major health authorities.

3. Mechanism of Action

The Japanese encephalitis virus strain SA 14-14-2 antigen (formaldehyde inactivated) vaccine functions by inducing active immunity in the recipient, preparing the body to effectively combat a future infection with the live Japanese Encephalitis Virus (JEV).

Principle of Active Immunization

The vaccine introduces inactivated JEV antigens to the host's immune system. This exposure allows the immune system to recognize these antigens as foreign and mount a specific immune response without causing the disease itself. This process "trains" the immune system, so that upon subsequent exposure to the live virus, a more rapid and robust protective response can be initiated.[9]

Induction of Neutralizing Antibodies

The cornerstone of the vaccine's protective mechanism is the generation of JEV-specific neutralizing antibodies.[1] The JEV envelope (E) protein, a major structural protein on the surface of the virus, is the primary target for these neutralizing antibodies.[3] These antibodies are believed to bind to the E protein, thereby interfering with critical steps in the viral life cycle, such as attachment to host cells or fusion of the viral and cellular membranes, ultimately preventing the virus from successfully infecting cells and replicating.

Correlate of Protection (CoP)

A significant body of evidence supports a serum neutralizing antibody titer of ≥1:10, as measured by a 50% Plaque Reduction Neutralization Test (PRNT$_{50}$), as an immunological correlate of protection against clinical JE disease.[1] This PRNT$_{50}$ ≥1:10 threshold is recognized by the World Health Organization (WHO) and is widely used in clinical trials to assess vaccine immunogenicity. Animal challenge studies, particularly in mice, have demonstrated that animals achieving this antibody titer are largely protected from lethal JEV challenge, providing experimental validation for this surrogate marker of protection.[11]

The establishment and consistent use of the PRNT$_{50}$ ≥1:10 titer as a CoP has been pivotal in the development and licensure of JE vaccines, including those based on the SA 14-14-2 inactivated antigen. This immunologic benchmark allows for robust immunogenicity bridging studies, enabling comparisons of new vaccine candidates or regimens against existing ones, and facilitating regulatory approvals. This is particularly valuable for diseases like JE, where the relatively low incidence of clinical disease in some populations or during specific trial periods can make large-scale clinical efficacy trials (designed to directly measure prevention of disease) logistically complex, time-consuming, and ethically challenging if an effective vaccine already exists. The ability to rely on a validated surrogate endpoint like PRNT$_{50}$ titers streamlines the vaccine development process, allowing potentially life-saving vaccines to reach at-risk populations more efficiently.

Role of Adjuvant

The vaccine formulations typically include aluminium hydroxide as an adjuvant.[7] Adjuvants are substances that enhance the body's immune response to an antigen. Aluminium hydroxide is thought to work by creating a depot effect at the injection site, leading to a slower, more sustained release of the viral antigens. Additionally, it stimulates local innate immune cells, which in turn help to shape and augment the subsequent adaptive immune response, leading to higher and more durable antibody production.

Inactivated Nature

Being an inactivated vaccine, the viral particles have been treated with formaldehyde, which cross-links viral proteins and nucleic acids, rendering the virus incapable of replication and therefore unable to cause JE.[9] This inactivation process is carefully controlled to ensure that the critical antigenic structures, especially on the E protein, remain sufficiently intact to elicit a protective immune response.

Specificity

The immune response generated by the vaccine is specific to the Japanese Encephalitis Virus. It does not confer protection against encephalitis caused by other viral or bacterial pathogens, nor does it protect against other diseases transmitted by mosquitoes.[9]

4. Marketed Vaccines Utilizing SA 14-14-2 Inactivated Antigen

The formaldehyde-inactivated Japanese encephalitis virus strain SA 14-14-2 antigen (DrugBank ID: DB10769) is the active immunizing component in several commercially available JE vaccines. The most prominent among these are IXIARO® (also marketed as JESPECT®) and JEEV®.

IXIARO® / JESPECT® (Valneva, formerly Intercell)

• Developer/Manufacturer History: The vaccine IC51, which later became IXIARO®, was originally developed by Intercell AG, a biotechnology company based in Vienna, Austria.[1] In 2012, Intercell AG merged with Vivalis SE to form Valneva SE.[30] Consequently, Valneva became the successor company responsible for IXIARO®. Valneva Austria GmbH is typically listed as the marketing authorization holder in Europe [5], and Valneva Scotland Ltd. has also been cited as a manufacturer.[33] Intercell USA, Inc., acquired by Valneva in May 2013, was subsequently renamed Valneva USA, Inc..[35] This corporate evolution is important for tracing the vaccine's development and regulatory history.
• Trade Names: The vaccine is marketed under the trade name IXIARO® in many regions, including the United States, Europe, Canada, Hong Kong, Singapore, and Israel.[1] In Australia and New Zealand, it is marketed as JESPECT®.[6]
• Antigen Content: Each 0.5 mL dose of IXIARO®/JESPECT® contains 6 micrograms (μg) of the inactivated JEV SA14-14-2 antigen.[10]

JEEV® (Biological E. Limited)

• Developer/Manufacturer: JEEV® is manufactured by Biological E. Limited, a pharmaceutical company based in Hyderabad, India.[6] The development of JEEV® involved a technology transfer agreement with Intercell AG.[6] This collaboration facilitated the local production of a modern JE vaccine in an endemic country.
• Trade Name: The vaccine is marketed under the trade name JEEV®.[6]
• Antigen Content: JEEV® is available in two different strengths, tailored for different age groups:
• A 0.5 mL dose containing 6 μg of the inactivated JEV SA14-14-2 antigen, primarily for adults and older children.[9]
• A 0.5 mL dose containing 3 μg of the inactivated JEV SA14-14-2 antigen, specifically for younger children.[14] Note that some pediatric formulations of IXIARO® for the youngest age groups (2 months to <3 years) also use a 0.25 mL volume which would correspond to a 3 μg antigen content if derived from the standard 6 μg/0.5 mL concentration.[13]

The presence of multiple manufacturers for vaccines based on the SA 14-14-2 inactivated antigen, such as Valneva (originating from Intercell) and Biological E. Limited, has significant implications for the global supply and accessibility of JE vaccines. Valneva's IXIARO®/JESPECT® primarily targets traveler markets in developed nations like the USA, Europe, and Australia.[5] In contrast, Biological E. Limited's JEEV® is manufactured in India and its distribution is largely focused on endemic regions, including India and other Asian countries, with a strong emphasis on pediatric populations.[6]

A critical factor in the global public health impact of JEEV® is its WHO prequalification.[6] WHO prequalification signifies that the vaccine meets international standards of quality, safety, and efficacy, making it eligible for procurement by United Nations agencies like UNICEF and for inclusion in national immunization programs in many low- and middle-income countries, often with support from organizations like Gavi, the Vaccine Alliance. The technology transfer from Intercell to Biological E. [6] facilitated local production in India, an endemic country. This strategy is often pursued to enhance vaccine affordability, ensure a more secure supply chain for regions most affected by the disease, and build local manufacturing capacity. This dual-manufacturer landscape, therefore, contributes significantly to broader JE vaccine availability and supports global efforts to control Japanese encephalitis.

5. Regulatory Landscape and Global Approvals

Vaccines based on the Japanese encephalitis virus strain SA 14-14-2 antigen (formaldehyde inactivated) have received approvals from major regulatory authorities worldwide, although specific indications, approved age groups, and dosing schedules can vary.

FDA (USA) - Primarily IXIARO®

• Initial Approval: IXIARO®, developed by Intercell AG (now Valneva), received its initial FDA approval on March 30, 2009. This approval was for active immunization against JE in individuals aged 17 years and older.[42] The Biologics License Application (BLA) number is 125280.[31]
• Pediatric Age Expansion: On May 17, 2013, the FDA expanded the approval of IXIARO® to include children aged 2 months to <17 years.[43]
• Orphan Drug Designation (Pediatric): Prior to the pediatric age expansion, IXIARO® was granted Orphan Drug Designation by the FDA on September 25, 2012, for use in individuals 2 months to <17 years. This designation was based on the anticipated use in fewer than 200,000 individuals within this age group in the U.S. annually.[8]
• Booster Dose: A booster dose for IXIARO® was approved on October 14, 2010, for individuals aged 17 years and older. Information regarding pediatric booster doses was subsequently updated based on further studies, such as IC51-325.[21]
• Accelerated Dosing Schedule: An accelerated 2-dose primary immunization schedule (Day 0 and Day 7) for adults aged 18-65 years was approved on October 5, 2018.[38]
• Concomitant Use with Rabies Vaccine: On October 4, 2018, the FDA approved labeling to support the concomitant administration of the IXIARO® primary immunization series with U.S.-licensed rabies vaccines (e.g., RabAvert) for pre-exposure prophylaxis.[31]
• Current Approved Indication (IXIARO®): IXIARO® is indicated for the prevention of disease caused by the Japanese encephalitis virus in individuals 2 months of age and older.[29]

EMA (Europe) - Primarily IXIARO®

• Initial Marketing Authorisation: IXIARO® received its marketing authorisation valid throughout the European Union on March 31, 2009.[5]
• Current Approved Indication (IXIARO®): The vaccine is indicated for active immunisation against Japanese encephalitis in adults, adolescents, children, and infants aged 2 months and older.[5]
• Dosing Schedules: The standard primary immunization series consists of two doses administered 28 days apart. For adults aged 18 to 65 years, an accelerated schedule (two doses 7 days apart) is also approved. Booster dose recommendations are in place and vary depending on age and ongoing risk of exposure.[5]
• Assessment History: The European Medicines Agency (EMA) has documented numerous post-authorisation variations and updates for IXIARO®, reflecting ongoing safety surveillance and refinements to the product information. Pivotal studies such as IC51-301 (non-inferiority in adults) and IC51-302 (safety in adults) supported the initial licensure. Pediatric approval was supported by studies including IC51-221, IC51-322, and IC51-323, with booster dose recommendations informed by studies like IC51-325.[5]

TGA (Australia) - JESPECT® (IXIARO®)

• Initial Approval (JESPECT®): JESPECT®, the brand name for the SA14-14-2 inactivated vaccine in Australia and New Zealand, was first registered by the Therapeutic Goods Administration (TGA) on January 30, 2009 (AUST R 150602). The initial approval was for individuals 18 years of age and older.[54]
• Current Status: While [54] (dated March 2023) indicates that a specific approval for JESPECT® had lapsed, IXIARO® (Valneva) is currently available and approved in Australia with broader age indications, including for children from 2 months of age, similar to other major regulatory regions.

CDSCO (India) - Primarily JEEV®

• Licensure (JEEV®): JEEV®, manufactured by Biological E. Limited, was licensed in India by the Central Drugs Standard Control Organisation (CDSCO) on September 29, 2011.[58] The Summary of Product Characteristics (SmPC) for the 6mcg/0.5mL presentation indicates its first authorization date as September 1, 2017, under License Number: 01/RR/AP/2006/V/R.[9]
• Approved Indications & Age Groups (JEEV®):
• 6 mcg/0.5 mL dose: Indicated for active immunization against JE in children and adults aged ≥ 3 years to ≤ 49 years.[9]
• 3 mcg/0.5 mL dose: Indicated for active immunization against JE in children aged ≥ 1 year to < 3 years.[14]

WHO Prequalification Status

• General: The World Health Organization (WHO) plays a crucial role in assessing vaccines for safety, efficacy, and manufacturing quality, particularly for vaccines intended for use in global public health programs and procurement by UN agencies.
• JEEV® (Biological E. Limited): Both the 6µg and 3µg formulations of JEEV® have achieved WHO prequalification status.
• JEEV® (6µg/dose): Prequalified on July 12, 2013 (single-dose vial). The 5-dose vial presentation was prequalified on October 2, 2018.[24]
• JEEV® (3µg/dose, Pediatric): Prequalified on August 3, 2016 (single-dose vial). The 5-dose vial presentation was prequalified on October 2, 2018.[24]
• IXIARO®/IC51: While IXIARO® itself is primarily marketed in developed countries, its underlying technology and antigen (SA14-14-2 inactivated, Vero-derived) are closely related to WHO-prequalified products like JEEV®. The WHO often refers to IC51 in its assessments of this vaccine type.[6]

A notable aspect of the global regulatory landscape for JE vaccines based on the SA 14-14-2 inactivated antigen is the variation in approved age indications and specific dosing schedules across different regions and products. For instance, IXIARO® has approvals for use from 2 months of age in the USA and Europe.[5] In contrast, JEEV® in India has distinct formulations and age brackets: the 3mcg dose is for children aged 1 to <3 years, while the 6mcg dose is for individuals aged 3 to 49 years.[9] The TGA's initial approval for JESPECT® in Australia was for adults (≥18 years) [54], although current availability of IXIARO® in Australia reflects the broader pediatric indications seen elsewhere. These differences arise from a combination of factors, including the specific epidemiological context of JE in a region (e.g., higher burden in children in endemic areas like India), the particular clinical trial data submitted to and reviewed by national regulatory authorities (NRAs), and the distinct risk-benefit assessments undertaken by these agencies. This underscores the importance for healthcare providers to adhere strictly to the locally approved prescribing information for the specific vaccine product being used, as approvals and recommendations are not universally interchangeable despite the common antigenic origin.

The following table summarizes the approved indications, age groups, and primary dosing schedules for prominent vaccines utilizing the SA 14-14-2 inactivated antigen, based on available information from key regulatory authorities.

Table 1: Approved Indications, Age Groups, and Primary Dosing Schedules for Key Japanese Encephalitis Virus SA 14-14-2 Inactivated Antigen Vaccines

Vaccine Brand Name(s)	Manufacturer(s)	Regulatory Authority	Approved Indication	Approved Age Group(s)	Primary Dosing Schedule (Conventional)	Notes on Accelerated/Booster Schedules
IXIARO®	Valneva Austria GmbH (formerly Intercell AG)	FDA (USA)	Prevention of Japanese Encephalitis	2 months and older	2 doses (0.5 mL each for ≥3 yrs; 0.25 mL each for 2 mo to <3 yrs), 28 days apart 29	Accelerated (Days 0, 7) for adults 18-65 yrs. Booster recommended ≥1 year after primary series for ongoing risk.37
IXIARO®	Valneva Austria GmbH	EMA (Europe)	Active immunisation against Japanese Encephalitis	2 months and older	2 doses (0.5 mL each for ≥3 yrs; 0.25 mL each for 2 mo to <3 yrs), 28 days apart 5	Accelerated (Days 0, 7) for adults 18-65 yrs. Booster recommended 12-24 months after primary series; second booster after 10 years for adults.5
JESPECT® (IXIARO®)	Valneva Scotland Ltd. / Seqirus Pty Ltd (Distributor in Australia)	TGA (Australia)	Active immunisation against Japanese Encephalitis	Originally ≥18 years 54; IXIARO now available with broader pediatric indications similar to FDA/EMA.	2 doses (0.5 mL each), 28 days apart 26	Booster information generally aligns with IXIARO.
JEEV®	Biological E. Limited	CDSCO (India)	Active immunization against Japanese Encephalitis	3mcg/0.5mL dose: Children ≥1 year to <3 years.14 6mcg/0.5mL dose: Children and Adults ≥3 years to ≤49 years.9	2 doses, 28 days apart 9
JEEV®	Biological E. Limited	WHO Prequalification	Active immunization against Japanese Encephalitis	3mcg/0.5mL dose: Children ≥1 year to <3 years. 6mcg/0.5mL dose: Individuals ≥3 years to ≤49 years 24	2 doses, 28 days apart 58

Note: Dosing volumes for pediatric populations can vary (e.g., 0.25 mL vs. 0.5 mL) depending on age and specific product labeling. Always refer to the local prescribing information.

6. Clinical Development Program

The clinical development of vaccines based on the Japanese encephalitis virus strain SA 14-14-2 (formaldehyde inactivated) antigen has been extensive, encompassing preclinical studies, multiple phases of clinical trials in diverse populations and regions, and post-marketing surveillance.

Preclinical Studies

• Immunogenicity in Animal Models: Preclinical research consistently demonstrated the immunogenicity of the SA 14-14-2 inactivated antigen. Studies with IXIARO® (IC51) showed that it induced high titers of JEV-specific neutralizing antibodies in mice, rats, and rabbits in a dose-dependent manner after two injections, with PRNT$_{50}$ titers ranging from 1280 to 7781 in the highest dose groups (800ng).[18] Even at a low dose of 32 ng, the vaccine elicited neutralizing antibodies in 100% of vaccinated mice, with Geometric Mean Titers (GMTs) of 113.[18] Another study involving an Advax-adjuvanted Vero cell candidate vaccine using the SA14-14-2 strain showed that a two-dose, low-antigen (50 ng) regimen in mice produced robust neutralizing immunity comparable to that of the live attenuated ChimeriVax-JE vaccine and superior to higher doses of a traditional non-adjuvanted JE vaccine.[22] This highlights the importance of adjuvants, such as the aluminum hydroxide used in the final vaccine formulations, in enhancing the immune response to inactivated viral antigens. This enhancement allows for potentially dose-sparing formulations while still achieving strong immunogenicity, a key principle in modern vaccinology.
• Protective Efficacy: Crucially, these preclinical studies also demonstrated protective efficacy. Mice vaccinated with the SA14-14-2 inactivated antigen (both IXIARO® and the Advax-adjuvanted candidate) were protected against morbidity and mortality following challenge with live, virulent JEV strains, including homologous (genotype III, e.g., SA14) and heterologous (genotype I, e.g., KE-093) viruses.[18] This protection was shown to correlate strongly with the achieved anti-JEV neutralizing antibody titers, with a PRNT$_{50}$ titer of ≥1:10 being established as a protective threshold.[18]
• Safety in Animals: Preclinical safety evaluations were also conducted. For instance, JENVAC®, a vaccine from Biological E. based on an Indian JEV strain but relevant to the technology, was found to be safe and immunogenic in a 28-day repeat-dose toxicity study in Wistar rats.[11] The Advax-adjuvanted SA14-14-2 vaccine candidate was reported to be well tolerated with minimal reactogenicity and no systemic toxicity in animal models.[22] Formal Good Laboratory Practice (GLP) developmental and reproductive toxicity studies were also part of the preclinical data package for IXIARO®.[18]

Phase I & II Clinical Trials (IXIARO®/IC51)

• Early Phase I (IC51): Initial Phase I trials with IC51 indicated its safety in human subjects. Immunogenicity was observed in approximately 50% of vaccinees, which was attributed to the low antigen doses (0.5 µg and 2.0 µg) used in these very early studies.[18]
• Phase II (IC51, adults, non-endemic): A Phase II randomized, open-label, single-center trial compared three different dose regimens of JE-PIV (IC51) – 6 µg/dose on Days 0 and 28; 6 µg/dose on Days 0, 14, and 28; and 12 µg/dose on Days 0 and 28 – against the licensed mouse-brain derived vaccine JE-VAX®. All IC51 regimens were found to be tolerable and induced robust and durable immune responses, with high seroconversion rates (SCR) at Day 56. These responses appeared superior to those elicited by JE-VAX® and were sustained with high GMTs for at least 2 years.[18]
• Phase II (IC51, Indian children 1-3 years): A comparative study in 60 healthy Indian children (1-3 years old) evaluated the immunogenicity and safety of 3 µg and 6 µg doses of IXIARO® against JenceVac (a mouse-brain derived vaccine). At Day 56 post-vaccination, SCRs were high and comparable across groups: 95.7% for 3 µg IXIARO®, 95.2% for 6 µg IXIARO®, and 90.9% for JenceVac. GMTs were also similar (201, 218, and 230, respectively). The safety profiles were comparable, and these findings supported the use of the 3 µg dose (administered as 0.25 mL of the 6 µg/0.5 mL formulation) for further development in children younger than 3 years.[18]

Phase III Pivotal Trials (IXIARO®/IC51 - Valneva/Intercell)

The clinical development of IXIARO® (IC51) was underpinned by a series of robust Phase III trials that established its immunogenicity, safety, and interchangeability, leading to its widespread regulatory approval. A key regulatory strategy employed in these trials was the demonstration of non-inferiority to existing licensed vaccines based on immunogenicity endpoints, primarily seroconversion rates (SCR) to a PRNT$_{50}$ titer of ≥1:10. This approach is common in vaccine development when a correlate of protection is well-established and conducting large-scale efficacy trials against clinical disease is challenging.

• IC51-301 (Non-inferiority vs. JE-VAX®, adults, non-endemic, EudraCT 2004-002474-36): This pivotal multinational trial enrolled 867 adults who received either IC51 (two 6 µg doses on Days 0 and 28) or the comparator JE-VAX® (three doses on Days 0, 7, and 28). IC51 demonstrated non-inferiority, with a Day 56 SCR of 98% versus 95% for JE-VAX®. Notably, the GMT for IC51 recipients was significantly higher (244 vs. 102). IC51 also showed a more favorable local tolerability profile.[2]
• IC51-302 (Safety vs. Placebo, adults, non-endemic, NCT00605058): This large-scale safety trial randomized 2,675 adults (3:1) to receive either IC51 (n=2012) or placebo (n=663) in two doses 28 days apart. The study found that the safety profile of IC51 was similar to placebo, with comparable rates of severe adverse events following immunization (AEFI) (0.5% for IC51 vs. 0.9% for placebo) and overall AEFI. No acute allergic reactions were noted, confirming the favorable safety of the vaccine.[1]
• Pediatric Trials (IC51-322, IC51-323, IC51-324, IC51-325): A comprehensive pediatric development program was crucial for IXIARO®'s approval in children.
• IC51-322 (Non-endemic children): Conducted in children aged >2 months to <18 years in non-endemic regions, this study confirmed the tolerability and immunogenicity of a two-dose schedule (age-appropriate dosing: 0.25 mL for 2 months to <3 years, 0.5 mL for ≥3 years). High SCRs (100% in a subset) were observed.[18] Data from this study contributed to FDA and EMA pediatric approvals.[21]
• IC51-323 (Endemic children - Philippines): This large Phase III trial enrolled 1,869 children (2 months to <18 years) in a JE-endemic region. IXIARO® was well-tolerated and highly immunogenic, with SCRs >99% four weeks after the second dose. The safety profile was comparable to age-specific control vaccines (Havrix® or Prevnar®).[18]
• IC51-325 (Long-term immunity and booster in endemic children, NCT01246479): This follow-up to IC51-323 in 300 children assessed long-term immunity (up to 36 months) and the response to a booster dose given 12 months after the primary series. The booster dose resulted in 100% SCR and markedly increased GMTs. Even without a booster, a substantial proportion of children (81-100%) maintained seroprotective titers at 24 months. These data were crucial for establishing booster dose recommendations in pediatric populations.[18] Study IC51-324 also contributed long-term pediatric data.[21]
• Concomitant Use Studies:
• IC51-308 (with Hepatitis A vaccine): Demonstrated that IXIARO® could be co-administered with HAVRIX® (hepatitis A vaccine) without compromising the immunogenicity or safety of either vaccine.[18]
• IC51-315 (with Rabies and MenACWY vaccines): Showed that IXIARO® can be co-administered with Rabipur® (rabies vaccine) and Menveo® (MenACWY-CRM conjugate vaccine) without negatively impacting antibody responses or safety profiles.[18]
• Accelerated Schedule Trial (Adults 18-65 years): A Phase III study (likely NCT01943464, though not explicitly linked in all snippets for this specific outcome) compared an accelerated JE vaccination regimen (Days 0, 7) administered concomitantly with a rabies vaccine to the standard 4-week JE regimen alone. The accelerated regimen demonstrated non-inferior immunogenicity (99% vs. 100% PRNT$_{50}$ ≥1:10 at 28 days post-last active vaccine) with a satisfactory safety profile, supporting its use for travelers needing rapid protection.[41]

The extensive pediatric clinical trial program for IXIARO®, covering diverse age groups from 2 months upwards, in both endemic and non-endemic settings, and including long-term follow-up and specific booster dose evaluations, was a cornerstone for its broad pediatric approvals by regulatory agencies like the FDA and EMA. This comprehensive data package addressed the specific needs and immune responses in children, a key target population for JE prevention.

Clinical Trials (JEEV® - Biological E. Limited)

• Phase I (Adults, India): Initial safety of JEEV® was established in 20 healthy adult volunteers.[12]
• Phase II/III (Adults 18-49 years, India, vs. IXIARO®): This open-label, randomized study (n=162) compared the immunogenicity and safety of JEEV® (6µg/0.5mL IM, 2 doses Days 0, 28) with IXIARO®. JEEV® demonstrated non-inferiority to IXIARO®, with Day 56 seroprotection rates of 99.07% for JEEV® and 98.15% for IXIARO®. Both vaccines were well-tolerated, with similar adverse event profiles. Injection site pain was reported in 44.7% of JEEV® recipients versus 54.2% for IXIARO®, and fever in 23.7% versus 29.2%, respectively.[12]
• Phase II/III (JENVAC - another Biological E. inactivated JE vaccine, Children 1-50 years, India, vs. SA 14-14-2 live vaccine): While JENVAC uses an Indian JEV strain (Kolar-821564XY) and not SA14-14-2, this study is relevant as it's from Biological E. and compares an inactivated vaccine to the live SA 14-14-2. A 2-dose regimen of JENVAC was well-tolerated and immunogenic. After a single dose, JENVAC showed an SPR of 98.7% at 28 days, compared to 79.6% for a single dose of the SA 14-14-2 live vaccine. Two doses of JENVAC demonstrated a significantly higher immune response than the SA 14-14-2 live vaccine at other time points.[64]
• Phase IV (JENVAC, Children, India, Interchangeability): This study, also with JENVAC, showed that a single dose induced protective titers for up to 1 year and demonstrated appreciable interchangeability with the SA 14-14-2 live vaccine, with a JENVAC/JENVAC combination yielding the highest immune response.[64]
• Phase IV (JEEV®, Adults 18-49 years, India): A post-marketing safety study (n=432) was conducted.[12]

The use of a non-inferiority design was a key regulatory strategy in the pivotal Phase III trials for both IXIARO® (against JE-VAX®) [2] and JEEV® (against IXIARO®).[12] This approach, based on achieving comparable immunogenicity (seroconversion rates and GMTs using the PRNT$_{50}$ ≥1:10 correlate of protection), is a standard pathway for new vaccines, especially when placebo-controlled efficacy trials are ethically or logistically difficult. It allows for the introduction of improved (e.g., better tolerated, more consistently manufactured) vaccines by demonstrating they are at least as good as an existing standard in terms of inducing a protective immune response.

Table 2: Summary of Key Phase III Clinical Trials for IXIARO®/JESPECT® (IC51)

Trial ID / Name (if available) & NCT (if available)	Phase	Population	Regimen(s) Studied	Comparator	Primary Endpoints	Key Immunogenicity & Safety Outcomes	Reference(s)
IC51-301 (EudraCT 2004-002474-36)	III	Adults (non-endemic)	IC51 (2 doses, 6µg, Days 0, 28)	JE-VAX® (3 doses, Days 0, 7, 28)	Immunogenicity (SCR, GMT at Day 56), Safety	SCR: IC51 98% vs. JE-VAX 95%. GMT: IC51 244 vs. JE-VAX 102. IC51 better local tolerability.	2
IC51-302 (NCT00605058)	III	Adults (non-endemic)	IC51 (2 doses, 6µg, Days 0, 28)	Placebo	Safety (AEFI rates)	AEFI rates similar to placebo. Severe AEFI: IC51 0.5%, Placebo 0.9%. No acute allergic reactions.	1
IC51-323	III	Children (2 mo - <18 yrs, endemic)	IXIARO® (age-appropriate 2 doses, Days 0, 28)	Havrix® or Prevnar® (age-specific controls)	Safety, Immunogenicity (SCR at 4 wks post-dose 2)	Well-tolerated. SCR >99%.	18
IC51-325 (NCT01246479)	III (Follow-up)	Children (previously in IC51-323, endemic)	IXIARO® booster at 12 mo vs. no booster	No booster	Long-term immunogenicity, Booster response (SCR, GMT)	Booster: 100% SCR, high GMTs. Without booster: 81-100% SPR at 24 mo.	18
Accelerated Schedule Trial (e.g., NCT01943464 context)	III	Adults (18-65 yrs)	IXIARO® (Days 0, 7) + Rabies vaccine	IXIARO® (Days 0, 28) alone	Non-inferiority of immune response (JE PRNT$_{50}$ ≥1:10)	Accelerated JE+Rabies non-inferior to standard JE alone (SCR 99% vs 100%). Satisfactory safety.	41

Table 3: Summary of Key Clinical Trials for JEEV® (Biological E. Limited)

Trial Phase	Population	Regimen(s) Studied	Comparator	Primary Endpoints	Key Immunogenicity & Safety Outcomes	Reference(s)
Phase II/III	Adults (18-49 yrs, India)	JEEV® (2 doses, 6µg, Days 0, 28)	IXIARO® (2 doses, 6µg, Days 0, 28)	Non-inferiority (SCR at Day 56), Safety	SCR: JEEV 99.07% vs. IXIARO 98.15%. Similar safety profiles.	12
Phase I	Adults (India)	JEEV®	N/A (Safety focus)	Safety	Established initial safety.	12
Phase IV (Post-marketing)	Adults (18-49 yrs, India)	JEEV®	N/A (Safety focus)	Safety	Further safety data collected.	12

Long-Term Immunogenicity and Booster Dosing

• IXIARO®: Studies have shown that protection with IXIARO® can last for at least 2-3 years in most vaccinated individuals.[53] A booster dose is generally recommended 12-24 months after the primary series for individuals with ongoing or renewed risk of exposure to JEV.[5] For adults (18-65 years), a second booster dose may be considered 10 years after the first booster.[23] Clinical trials like IC51-305 and IC51-325 specifically investigated booster responses, confirming that a booster dose effectively elicits high seroprotective antibody titers.[18]
• JEEV®: While specific long-term immunogenicity and booster data for JEEV® are less detailed in the provided snippets, such considerations are standard for national immunization programs using JE vaccines.

Special Populations and Considerations

• Pediatric Use: IXIARO® is approved for use in infants from 2 months of age in the US and Europe, with specific 0.25 mL dosing for children aged 2 months to <3 years.[5] JEEV® has specific formulations and approvals for children in India, with the 3mcg/0.5mL dose for children aged 1 to <3 years, and the 6mcg/0.5mL dose for those ≥3 years.[9]
• Pregnancy and Lactation: For both IXIARO® and JEEV®, use during pregnancy or lactation is generally advised against as a precautionary measure due to limited data. Healthcare providers are encouraged to report inadvertent use during pregnancy.[9]
• Immunocompromised Individuals: Individuals with weakened immune systems may have a diminished immune response to IXIARO®.[29]
• Bleeding Disorders: For individuals with thrombocytopenia, haemophilia, or other bleeding disorders where intramuscular injection is contraindicated, IXIARO® can be administered subcutaneously, although this may lead to a suboptimal response.[9] JEEV® SmPCs advise against IM administration in such individuals.[9]

7. Safety and Tolerability Profile

Vaccines containing the Japanese encephalitis virus strain SA 14-14-2 antigen (formaldehyde inactivated) have demonstrated a generally favorable safety and tolerability profile across numerous clinical trials and post-marketing surveillance.

General Profile

Both IXIARO®/JESPECT® and JEEV® are generally well-tolerated. The majority of adverse events reported are mild to moderate in severity and transient, typically resolving within a few days of vaccination.[1]

IXIARO®/JESPECT® (IC51)

• Common Local Reactions (Adults): The most frequently reported local adverse reactions in adults (≥18 years) are injection site pain and tenderness, often occurring in >25% of recipients.[29] Other local reactions include redness, hardening, swelling, and itching at the injection site.[23]
• Common Systemic Reactions (Adults): Headache (reported in >20%) and myalgia (muscle pain, reported in >10%) are the most common systemic side effects in adults.[29] Other reported systemic reactions include nausea, fatigue, flu-like illness, fever, irritability, and loss of appetite.[23]
• Common Reactions (Children 2 months to <12 years): In this age group, commonly reported adverse events include fever, irritability, diarrhea, vomiting, loss of appetite, and injection site pain or redness.[29] Specifically, fever was reported in >20% of infants 2 months to <1 year and children 1 to <3 years, and in >10% of children 3 to <12 years.[36]
• Common Reactions (Adolescents 12 to <18 years): Injection site pain (15%) and tenderness (10%) were the most common solicited injection site reactions in adolescents.[29]
• Serious Adverse Events: Serious adverse events (SAEs) have been rare in clinical trials. The pivotal safety trial (IC51-302) comparing IXIARO® to placebo showed similar rates of severe AEFI and overall AEFI, with no acute allergic reactions noted.[1] Post-marketing surveillance initially reported a few SAEs (neuritis, meningism, oropharyngeal spasm, iritis), but these were subsequently considered unrelated to vaccination upon further review.[7] No increased risk of neurological events has been reported with IXIARO® compared to background rates.[7]

JEEV® (Biological E. Limited)

• Common Local Reactions: Injection site pain is frequently reported (ranging from 8.5% to 44.7% in different studies/contexts), along with tenderness (4.6%), swelling (3.29% to 7.41%), and erythema/redness (2.63% to 7.41%).[9]
• Common Systemic Reactions: Pyrexia (fever) is a common systemic reaction (4.63% to 23.7%). Other reported systemic effects include myalgia (12.04%), headache (4.63%), decreased appetite, somnolence, and rash.[9]
• Serious Adverse Events: No serious adverse events were reported in some comparative studies of JEEV®.[9]

The safety profiles of IXIARO® and JEEV® appear broadly comparable, which is expected given their shared antigen origin (SA 14-14-2 inactivated) and use of aluminum adjuvant. Both vaccines are predominantly associated with mild to moderate, transient local and systemic reactions. A direct comparative study between JEEV® and IXIARO® in adults found similar adverse event profiles, with minor numerical differences in the frequencies of specific common reactions like injection site pain and fever, but no statistically significant differences in overall safety were highlighted.[9] This consistency across products from different manufacturers reinforces the general safety and tolerability of the Vero cell-derived, inactivated SA 14-14-2 JE vaccine platform.

Contraindications

• Hypersensitivity: Known hypersensitivity to the active substance (JEV SA14-14-2 antigen), any of the excipients, or to any residuals from the manufacturing process (e.g., protamine sulphate for IXIARO® and JEEV®; formaldehyde, bovine serum albumin, host cell DNA, sodium metabisulphite for IXIARO®) is a contraindication.[9]
• Previous Allergic Reaction: A history of a severe allergic reaction (e.g., anaphylaxis) to a previous dose of the same JE vaccine or any other JE vaccine is a contraindication.[9]
• Acute Severe Febrile Illness: Vaccination should be postponed in individuals suffering from an acute severe febrile illness.[9]

Precautions

• Anaphylaxis Management: As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available to manage rare anaphylactic reactions following administration.[9]
• Route of Administration: The vaccine is for intramuscular injection and must not be administered intravascularly.[9] Subcutaneous administration may be considered for IXIARO® in individuals with bleeding disorders, though it may lead to a suboptimal response.[10] JEEV® SmPCs advise against IM administration in those with thrombocytopenia or other bleeding disorders.[9]
• Protection: Vaccination may not result in protection in all vaccinees. Completion of the primary immunization series is necessary, and it should be completed at least one week prior to potential exposure to JEV.[9]

Table 4: Summary of Common Adverse Events (Reported in >10% of subjects where specified for IXIARO®; common AEs for JEEV®)

Vaccine Brand	Age Group	Adverse Event Type	Specific Adverse Event	Frequency (IXIARO®) / Note (JEEV®)	Reference(s)
IXIARO®	Adults (≥18 yrs)	Local	Injection site pain, Tenderness	>25% each	29
IXIARO®	Adults (≥18 yrs)	Systemic	Headache	>20%	29
IXIARO®	Adults (≥18 yrs)	Systemic	Myalgia	>10%	29
IXIARO®	Infants (2 mo to <1 yr)	Local	Injection site redness	>15%	29
IXIARO®	Infants (2 mo to <1 yr)	Systemic	Fever	>20%	29
IXIARO®	Infants (2 mo to <1 yr)	Systemic	Irritability	>15%	29
IXIARO®	Infants (2 mo to <1 yr)	Systemic	Diarrhea	>10%	29
IXIARO®	Children (1 yr to <3 yrs)	Systemic	Fever	>20%	29
IXIARO®	Children (3 yrs to <12 yrs)	Systemic	Fever	>10%	29
IXIARO®	Adolescents (12 yrs to <18 yrs)	Local	Injection site pain	15%	29
IXIARO®	Adolescents (12 yrs to <18 yrs)	Local	Injection site tenderness	10%	29
JEEV®	Adults & Children	Local	Injection site pain	Common (8.5%-44.7%)	9
JEEV®	Adults & Children	Systemic	Pyrexia (Fever)	Common (4.63%-23.7%)	9
JEEV®	Adults & Children	Systemic	Myalgia	Common (12.04%)	9

8. WHO Recommendations and Public Health Implications

The World Health Organization (WHO) plays a pivotal role in guiding global strategies for Japanese Encephalitis (JE) prevention and control, including recommendations for vaccine use.

WHO Position on JE Vaccines

The WHO recommends that JE vaccination be integrated into national immunization schedules in all areas where JE disease is recognized as a significant public health issue.[4] This recommendation underscores the importance of routine immunization as a primary strategy for disease prevention. WHO advises that strong JE prevention and control activities, including robust immunization programs, should be prioritized in regions where JEV transmission is suitable and the disease poses a public health threat, even if the number of laboratory-confirmed JE cases is low due to surveillance limitations.[4] The introduction of JE vaccine into a national program should ideally be accompanied by a one-time catch-up vaccination campaign targeting older age groups to rapidly increase population immunity.[4]

Vaccine Types

WHO recognizes three main types of JE vaccines currently in use globally:

1. Inactivated Vero cell-derived vaccines: This category includes vaccines based on the SA14-14-2 strain (such as IXIARO® and JEEV®) as well as others.[4]
2. Live attenuated vaccines: The most widely used is the SA 14-14-2 live attenuated vaccine (e.g., CD.JEVAX).[6]
3. Live recombinant (chimeric) vaccines: An example is a vaccine using the yellow fever 17D vaccine strain as a vector for JE antigens (e.g., IMOJEV).[6]

Target Populations

The WHO emphasizes that the majority of JE cases occur in children under 15 years of age, making them a primary target for vaccination programs in endemic areas.[4] While most adults in endemic countries may have acquired natural immunity through subclinical childhood infections, individuals of any age can be affected if non-immune.[4] For travelers, vaccination is recommended for those planning to spend extensive time in JE-endemic areas, particularly if their travel involves rural areas or activities that increase mosquito exposure.[4] WHO prioritizes human vaccination over interventions like pig vaccination or mosquito control measures for reducing the JE disease burden, citing limited evidence for the latter's impact on human disease incidence.[4]

SA 14-14-2 Based Inactivated Vaccines

• Vaccines like IXIARO® (IC51) and JEEV® are specifically identified as Vero cell-derived inactivated vaccines utilizing the SA14-14-2 strain.[6]
• The WHO prequalification of JEEV®, manufactured by Biological E. Limited, is a significant endorsement, indicating that the vaccine meets international standards of quality, safety, and efficacy.[6] This prequalification is crucial for procurement by UN agencies (like UNICEF) and for use in Gavi-supported national immunization programs, particularly in resource-limited endemic countries. The availability of a WHO-prequalified JE vaccine based on the SA 14-14-2 inactivated antigen significantly contributes to global JE control efforts by ensuring access to a safe and effective vaccine for vulnerable populations.
• The WHO recognizes a PRNT$_{50}$ titer of ≥1:10 as a reasonable correlate of protection against JE, a benchmark used in the evaluation of these vaccines.[7]

Safety (WHO Global Advisory Committee on Vaccine Safety - GACVS Review)

The GACVS has reviewed JE vaccines, including those based on the SA-14-14-2 strain (both live attenuated and inactivated). The committee has noted that both the live attenuated and the inactivated vaccines derived from the SA-14-14-2 strain appear to have excellent safety profiles.[66] For inactivated Vero cell-derived SA14-14-2 vaccines, clinical trial data indicated that the most frequent systemic adverse events were headache, myalgia, flu-like symptoms, and fatigue, mostly mild to moderate. Post-marketing surveillance data, while initially flagging some serious events, found them to be unrelated to vaccination upon further review, and no increased risk of neurological events has been reported with these vaccines.[7]

9. Conclusion

The Japanese encephalitis virus strain SA 14-14-2, when formaldehyde inactivated and produced in Vero cell culture (DrugBank ID: DB10769), serves as a critical antigenic component in several modern, highly effective, and well-tolerated Japanese Encephalitis vaccines. Prominent examples include IXIARO® (JESPECT®) manufactured by Valneva and JEEV® manufactured by Biological E. Limited. These vaccines represent a significant advancement over older, mouse brain-derived JE vaccines, primarily due to their improved safety profiles and consistent manufacturing standards.

The mechanism of action for these inactivated vaccines relies on the induction of JEV-specific neutralizing antibodies, with a PRNT$_{50}$ titer of ≥1:10 widely accepted as a correlate of protection. Extensive clinical development programs, including numerous Phase I, II, and III trials across diverse age groups (from infants as young as 2 months to adults) and geographical regions (both endemic and non-endemic), have robustly demonstrated the immunogenicity and safety of these vaccines. Both IXIARO® and JEEV® have achieved high seroconversion rates and have shown favorable safety profiles, characterized mainly by mild to moderate local and systemic reactions.

Regulatory approvals for these vaccines are widespread, with agencies such as the FDA, EMA, TGA, and CDSCO granting marketing authorizations. These approvals often include specific indications for various age groups and dosing schedules, including primary series and booster doses, tailored to regional needs and epidemiological contexts. The WHO prequalification of JEEV® further underscores the global public health importance of this vaccine type, facilitating its use in national immunization programs in JE-endemic countries.

In summary, the formaldehyde-inactivated JEV SA 14-14-2 antigen has enabled the development of safe and immunogenic vaccines that play a vital role in the global strategy to prevent and control Japanese encephalitis, a severe and often debilitating disease. The consistent performance of vaccines based on this antigen, despite minor formulation differences and manufacturing by different entities, highlights the robustness and reliability of this vaccine platform.

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