Status: approved; marketed; no longer manufactured; product being sold from stockpiled supplies

Organizations involved:

Research Foundation for Microbial Diseases – Manuf.; R&D; Tech.; Asia mark.

Sanofi Pasteur Inc. – USA mark.

Sanofi Pasteur Ltd. – Manuf. other

Sanofi Pasteur S.A. – Parent

Sanofi Pasteur MSD – Europe mark.

Cross ref.: See also Japanese Encephalitis Vaccine/Intercell (#490) and a Chimerivax-JE, a recombinant vaccine (#224), which will be marketed internationally by Sanofi Pasteur and replace JE-VAX as the companies JE vaccine.

Description: Japanese Encephalitis Virus Vaccine Inactivated or JE-VAX is a lyophilized (freeze-dried) formulation of formaldehyde-inactivated Japanese en-cephalitis virus (Nakayama-NIH strain) cultured in vivo in infected mouse brains.  This is currently the only FDA-approved Japanese encephalitis virus vaccine.

The vaccine is packaged in single dose vials (3 or 10 per package) along with vials of Sterile Water for Injection diluent (containing no preservative) for reconstitution and subcutaneous injection.  Each 1.0 mL dose contains approximately 500 µg of gelatin (bovine source), less than 100 µg of formaldehyde, less than 0.0007% v/v Polysorbate 80 (Tween 80), and less than 50 ng of mouse serum protein.  Thimerosal (mercury derivative) is added as a preservative at a final concentration of 0.007%.  No murine myelin basic protein (from brain tissue) can be detected at the detection threshold of the assay used (< 2 ng/mL).  Prior to reconstitution, the vaccine is a white caked powder, and after reconstitution the vaccine is a colorless transparent liquid.

The potency of Japanese encephalitis vaccine is determined by immunizing mice with the test vaccine and a reference vaccine.  Neutralizing antibodies are measured in a plaque neutralization assay performed on sera from the immunized mice.  The potency of the test vaccine must be no less than that of the reference vaccine.

Nomenclature: Japanese Encephalitis Vaccine/Sanofi [BIO]; JE-VAX [TR]; Japanese Encephalitis Virus Vaccine Inactivated [FDA]; NDC 49281-680-30; NDC 49281-680-20 [NDC]

Biology: The Nakayama-NIH strain of Japanese encephalitis virus was originally isolated from spinal fluid of a human case in 1935 and maintained by continuous mouse brain passage.  This strain has been the principal virus strain used in mouse brain-derived Japanese encephalitis (JE) virus vaccines worldwide.  The strain was chosen because of good propagation characteristics, and because it provided cross-protection against other JE viral strains in mice.  Note, the ‘NIH’ portion of Nakayama-NIH refers to the National Institute of Health of Japan, not the U.S. National Institutes of Health.

Companies: JE-VAX was developed and is manufactured by the Research Foundation for Microbial Diseases, Osaka University (BIKEN; Osaka, Japan), FDA CBER est. no. 1156.  It is manufactured exclusively for final manufacture by Sanofi Pasteur Ltd. (Toronto, Ontario, Canada), the Canadian subsidiary of Sanofi Pasteur S.A.  Aventis merged into Sanofi Aventis S.A. in laste 2004. 

The vaccine is exclusively marketed in the U.S. by Sanofi Pasteur Inc.  It is marketed in Japan, Korea, Taiwan, India and other Asian countries by BIKEN.  The vaccine is marketed in some European countries by Sanofi Pasteur MSD (joint venture of Aventis Pasteur/Sanofi Aventis and Merck & Co.). 

BIKEN has been developing its own next-generation cell-cultured vaccine, and stopped production of JE-VAX in 2005.  At the time, Sanofi-Pasteur was estimated to have stockpiled about 5 million doses. 

Manufacture: The vaccine is prepared by inoculating mice intra-cerebrally with Japanese encephalitis (JE) virus, Naka-yama-NIH strain.  Infected brains are harvested and homogenized in phosphate buffered saline, pH 8.0.  The homogenate is centrifuged and the virus-rich supernatant inactivated with formaldehyde, then processed to yield a partially purified, inactivated virus suspension.  This is further purified by ultracentrifugation through 40% w/v sucrose.  Thimerosal (mercury derivative) is added as a preservative to a final concentration of 0.007%.  The suspension is lyophilized in final containers and sealed under dry nitrogen atmosphere. 

Vaccine potency is tested in mice against a reference vaccine, and neutralizing antibodies are measured by plaque assay using sera from immunized mice.  Vaccine production lots must be at least as potent (protective) as the reference vaccine.

The vaccine’s murine neural tissue culture substrate has raised concerns about the possibility of postvaccination-neurologic side effects.  The manufacturing process purifies the infected mouse brain suspension extensively and myelin basic protein (MBP; a surrogate marker for nerve cells) content is controlled below 2 ng/mL, well below the dose considered to have an encephali-togenic effect in the guinea pig test system.  Experimental immunization of guinea pigs and cynomolgus monkeys with adjuvant and 50 times the normal dose of vaccine did not result in clinical or histopathological evidence of encephalomyelitis.

FDA class: Biologic PLA

Approvals: Date = 19921210; first approval, PLA

Indications: [full text of “INDICATIONS AND USAGE” section from product insert/label]:

JE-VAX is indicated for active immunization against JE [Japanese encephalitis virus] for persons one year of age and older. For recommended primary immunization series see DOSAGE AND ADMINISTRATION section.  JE-VAX should be considered for use in persons who plan to reside in or travel to areas where JE is endemic or epidemic during a transmission season. JE-VAX is NOT recommended for all persons traveling to or residing in Asia. The incidence of JE in the location of intended stay, the conditions of housing, nature of activities, duration of stay, and the possibility of unexpected travel to high-risk areas are factors that should be considered in the decision to administer vaccine. In general, vaccine should be considered for use in persons spending a month or longer in epidemic or endemic areas during the transmission season, especially if travel will include rural areas. Depending on the epidemic circumstances, vaccine should be considered for persons spending less than 30 days whose activities, such as extensive outdoor activities in rural areas, place them at particularly high risk for exposure.

Status: The Research Foundation for Microbial Diseases (BIKEN) originally filed its PLA in 1990 at the request of the U.S. Department of Defense (DOD), which required the vaccine for military personnel in Pacific Rim countries.  The vaccine had long been marketed by BIKEN in Japan, China, Taiwan, India, and other parts of Asia.  Subsequently, after an American student in Beijing, China, died of Japanese encephalitis, the CDC sponsored the BIKEN vaccine in the U.S., obtaining an IND exemption from FDA, and made its available to American travelers and the military.  More than 17,000 doses were distributed in the U.S. through travel clinics between 1984-1987.  After 1987 and until FDA approval, the vaccine was distributed in the U.S. exclusively by the DOD (i.e., CDC halted distribution), because of liability concerns. 

The Vaccines and Related Biologics Advisory Committee, FDA, twice reviewed and recommended approval for JE-VAX, requesting further adverse effects data after the first review.  Adverse reactions data were subsequently presented from vaccination experience with over 35,000 U.S. military personnel and dependents in Okinawa. 

JE VAX has a high-perceived level of reactogenicity, mainly due to residual matter left over from its manufacturing method; and JEV vaccinees are recommended to remain within access of healthcare personnel around 10 days after vaccination (package insert).  In 2005, Japanese authorities withdrew JE mandatory vaccination after noting adverse events in the pediatric population.

Trials: Efficacy of the vaccine has been evaluated in two masked randomized placebo (tetanus toxoid) controlled field trials.  In the first study, a less-refined prototype of the current vaccine was field tested in 1965 in Taiwan.  Two doses yielded 80% efficacy in the first year after immunization.  The efficacy of BIKEN’s current monovalent Nakayama-NIH vaccine (and a bivalent vaccine also containing Beijing-1 antigen) was demonstrated in a placebo-controlled, 3-arm, randomized clinical trial in over 60,000 children ages 1-14 in Thailand sponsored by the U.S. Army.  During the trial, only one case of Japanese encephalitis (a rate of 5 cases/100,000) occurred in children receiving the vaccine, the same rate as those receiving the bivalent vaccine, compared to 11 cases (51/100,000) in the placebo group.  The observed efficacy was 91% (95% confidence interval, 54-98%).  Side effects were reported in less than 1%, about the same as placebo (tetanus toxoid).

Medical: For persons 3 years of age and older, a single dose is 1.0 mL by subcutaneous injection.  For children 1 year to 3 years of age, a single dose is 0.5 mL.  A three-dose vaccination schedule is recommended for U.S. travelers and military personnel, with the vaccine administered to those over 3 years old as a series of three subcutaneous doses on days 0, 7 and 30.  An accelerated schedule (days 0, 7 and 14) may be used in urgent situations, but this provides lower antibody titers and has a slightly higher incidence of adverse effects.  Booster may be administered after two years.

Disease: Japanese encephalitis (JE), a mosquito-borne arbo-viral Flavivirus infection, is the leading cause of viral encephalitis in Asia.  JE virus is transmitted seasonally in most areas of Asia, although transmission may occur year-round.  The seasonal patterns of viral transmission are correlated with the abundance of vector mosquitoes and vertebrate amplifying hosts, and factors including rainfall (rainy season) and irrigation practices.  Viral infection leads to overt encephalitis in 1 of 20 to 1,000 cases.  However, encephalitis usually is severe, resulting in a fatal outcome in 25% of cases and residual neuropsychiatric sequelae in 50% of cases. 

The virus is transmitted in an enzootic cycle among mosquitoes and vertebrate amplifying hosts, chiefly domestic pigs and, in some areas, wild Ardeid (wading) birds.  Viral infection rates in mosquitoes in affected areas range from < 1% to 3%.  Infected mosquito species are prolific in rural areas of Asia where their larvae breed in ground pools and flooded rice fields.  In areas where JE is endemic, annual incidence ranges from 1 to 10 per 10,000 people.  Cases occur primarily in children under 10 years of age.  Seroprevalence studies in these endemic areas indicate nearly universal exposure (and natural vaccination) by adulthood (with about 10% of the susceptible population infected per year).

Market: BIKEN had been reported to export about 2 million doses annually. 

Although JE VAX is effective, its three-dose profile is not optimum for compliance, neither in the travellers market nor in emergency campaigns during outbreak situations.

The major U.S. market for JE-VAX has been the Department of Defense (DOD), which presumably pays a substantially discounted price.  For those not in the military, a course of vaccination (3 doses) costs about $300 or more.

In the U.S., an estimated 120,000 doses of JE VAX are administered annually, with the majority of doses (~75%) involving the U.S. military.  Presuming that 30,000 doses are sold at the Sanofi-Pasteur list price of about $270 for a pack of three doses (see below), this means about 10,000 packs were sold in the U.S. private sector, with a market of $2,700,000.  Presuming the DOD pays a discounted price of about $200/pack (pure guess on the part of the author) and uses 30,000 packs/year, this provides a market of $6 million.  Thus, the author’s guess for the U.S. market for JE-VAX is on the order of $9 million/year.  The DOD price, likely involving 10-dose vials, could be much less than estimated, so the U.S. market could be even smaller.

The 2007 Average Wholesale Price (AWP) is $336.59/3 single-dose vials, with a Direct Price (manufacturer’s discount price) cost of $280.49 (Red Book, 2007). 

The Sanofi Pasteur list price (Jan. 2006) is $272.32/package of 3 one-dose vials ($256.68 in 2004). 

In its March 22, 2006 price list, FFF Enterprises, a major biologics distributor, reported $287.91/package of 3 one-dose vials (same in 2005; $285.75 in 2004); and $769.27/10-dose vial (same in 2004).

The market potential for JE vaccines is difficult to project.  An estimated that 1 billion people living in endemic countries are below the age of 15 years; and each year around 14 million visits are made to JE endemic areas.  Travelers from developed to endemic countries are expected to increase, e.g., to 25 million in 2017).With the inevitable withdrawal (expiration or running out of stock) of JE VAX, it is widely assumed that a new JE vaccine is not a blockbuster opportunity.  VacZine Analytics projects future markets in the range of $100-300 million (for newer, cell-cultured vaccines).  Many, if not most. travellers meeting the CDC “at-risk” criteria for staying in rural areas longer than one-month are “budget conscious back-packers who might preferentially reserve funds for other vaccines such as Hepatitis A and Hepatitis B.” Further complicating market estimates, in many lesser-developed countries where JE is endemic, public health programs are reported to typically pay about $1/dose (with developed countries obviously subsidizing these prices).  Chimerivax-JE, which requires just a single dose, may have a significant market advantage as JE-VAX leaves the market.

Competition: Worldwide, three types of JE vaccines are in large-scale production.  Inactivated mouse brain-derived vaccines using the Nakayama-NIH or Beijing-1 (Pl) strains are also manufactured by Chiba, Denka, Katetsuken, Kitasato, Saika-ken, and Takeda in Japan; Green Cross in Korea; National Institute of Preventive Medicine in Taiwan; Government Phar-maceutical Organization in Thailand; and the National Institute of Hygiene in Vietnam.  Inactivated primary hamster kidney (PHK) cell cultured vaccines using the P3 virus strain are manufactured by the Bejiing, Shanghai, Wuhan, and Chang--chun Institutes of Biological Products in China (PRC).  Live, attenuated SA14-14-2 virus strain cultured in primary hamster kidney cells is manufactured by the Chengdu Institute of Biological Products in China.  The manufacturers in Japan produce about 11 million doses annually for use in Japan.  More than 75 million doses of inactivated PHK vaccine and 25 million doses of live attenuated vaccine are produced and distributed annually within China. 

Mouse brain-derived, inactivated JE vaccine, e.g., JE-VAX, is manufactured and distributed internationally by BIKEN and the Green Cross (Korea).  However, other vaccines are used in most countries of Europe, North America (other than the U.S.), and Australia. 

In July 2006, Technip (Paris, France) was awarded a contract by the Chengdu Institute of Biological Products (CDIBP; PRC/China) for the design, construction and qualification of a new facility for manufacture of a Japanese encephalitis vaccine.  The is partially financed by PATH, an international non-profit organization, through its Japanese Encephalitis Project, which is supported by the Bill & Melinda Gates Foundation.  The objective is to give CDIBP, with support from PATH, the ability to furnish the World Health Organization (WHO) with vaccines for use in the Asia Pacific region.  CDIBP currently manufactures a two-dose Japanese encephalitis virus vaccine, which has been used in China for childhood immunization for over 17 years.  The company is sponsoring trials to obtain recognition for the vaccine from WHO (allowing marketing in many lesser-developed countries)

R&D: See the entry for a recombinant Japanese ence-phalitis virus vaccine in the Recombinant DNA Products section.

OctoPlus Technologies BV (the Netherlands) and SingVax Pte Ltd. (Singapore) are co-developing a single-dose Japanese encephalitis vaccine using OctoPlus’ controlled- release delivery technology.  OctoPlus is responsible for formulation and manufacturing of formulated product. SingVax is responsible for developing assays, producing viral particles and manufacturing virus. The partners share costs and profits.