INFORMATION SHEET

OBSERVED RATE OF VACCINE REACTIONS Global Vaccine Safety Essential Medicines & Health Products JAPANESE ENCEPHALITIS VACCINE

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The Vaccines

Japanese encephalitis (JE) vaccines are either inactivated or live attenuated.

Inactivated vaccines

Inactivated vaccines are either mouse brain-derived or cell culture-derived:

Mouse brain-derived vaccines - The only internationally approved vaccine is produced from infected adult mouse brain tissue in several Asian countries, where millions of doses have been administered since 1930s (Shlim et al., 2002; WHO, 1998). The countries using this vaccine include India, Japan, Malaysia, South Korea, Sri Lanka, Taiwan, Thailand, and Vietnam The most widely used vaccine comes from the Research Institute of Osaka University (Biken) in Japan. Other manufacturers are found in South Korea, Taiwan, Thailand, and Vietnam. Major manufacturers have recently discontinued production of this vaccine (Cochrane review 2007 ref PATH). Increasing supply problems are expected in the coming years as manufacturers scale back production with the availability of new and improved JE vaccines;

Cell culture-derived vaccines - The cell culture-derived inactivated vaccine is manufactured exclusively in the People´s Republic of China and has been in use since the late 1960s where more than 70 million doses are administered annually. Due to its limited efficacy and the need for numerous doses, the vaccine is gradually being replaced by the SA 14-14-2 live attenuated vaccine. New, inactivated vaccines manufactured in Vero cells are currently in use in several countries.

Live attenuated vaccine

The only currently available live attenuated vaccine, the SA 14-14-2 vaccine is based on a stable neuro-attenuated strain of the JE virus. The SA 14-14-2 vaccine strain was obtained from its wild-type SA 14 parent by serial passages in cell cultures (primary hamster kidney cells) and in animals (mice, hamsters) with successive plaque purifications in primary chick embryo cells. The vaccine was licensed in the PR China in 1988. The countries primarily using this vaccine include China (since 1988); Nepal (since 1999); South Korea (since 2001); India (since 2006) and Thailand (since 2007). A genetically engineered JE vaccine that combines the attenuated SA14-14-2 strain and yellow fever vaccine strain 17D (YF 17D) virus as a vector for genes encoding the protective antigenic determinants, has been tested in several clinical trials and is under continued assessment (Cochrane 2007).

Type of vaccines

Route Vaccine antigens Excipients

Inactivated Mouse brain-derived Gelatin is used as a stabiliser and thiomersal as a Most manufacturers produce vaccine from the preservative prototype Nakayama strain of JE virus, whereas in Japan the vaccine for the domestic market is prepared from the Beijing-I strain

Cell culture-derived The P3 strain of the JE virus is grown in primary Serum albumin is used as a stabiliser. hamster kidney cells. The vaccine is formalin inactivated. Vero cell-derived Inactivated SA14-14-2 is Aluminium hydroxide as adjuvant prepared using tissue culture

Live attenuated The SA 14-14-2 vaccine is based on a stable Gelatin and sucrose used as a stabiliser neuro-attenuated strain of the JE virus with a Yellow Fever vaccine acting as a viral vector.

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Adverse events

Mild adverse events

Local adverse events:

With inactivated vaccines local reactions at the injection site including erythema, oedema and tenderness have been seen in about 20% of vaccine recipients of the mouse brain-derived vaccine and 4% with the cell culture vaccine. With the live attenuated SA-14-14-2 vaccine in a study in Korea, redness and swelling at the site of injection was reported in <1% of vaccinees.

Systemic adverse events:

Inactivated mouse brain-derived vaccine mild to moderate systemic reactions include headache, malaise, myalgia, low-grade fever, nausea, vomiting, abdominal pain, rash, chills and dizziness occurred in 5 to 30% of vaccinees (Monath 2002, Takahashi et al., 2000, DeFraites et al., 1999, Tsai et al., 1999, Poland 1990). Inactivated cell culture vaccines mild systemic symptoms, such as headache and dizziness were reported in less than 1% of vaccinees. Febrile reactions (temperature >38°C) were seen in 12% of vaccinees; their frequency was markedly reduced after a reduction in the bovine serum content of the vaccine (Monath, 2002; Tsai et al., 1999). Several clusters of adverse reactions after vaccine administration in Chinese schoolchildren were thought to be psychogenic in origin (Ahmad, 2002). The live attenuated vaccine SA-14-14-2 vaccine has been evaluated in several trials conducted in the PR China. Mild adverse events such as fever, irritability, skin rash, nausea and dizziness were very rarely reported (Yu et al., 1988). In an uncontrolled trial with almost 600,000 vaccinees, a very low incidence of adverse events including fever (5/10,000), skin-rash (1/10,000), nausea and dizziness (3 per million) was observed (Ma et al., 1993). In a subset of 266 vaccinated children from another trial, fever (5%) and irritability (4%) were the most frequently reported events in the first week after vaccination (Liu et al., 1997). In a small study involving Korean children, elevated temperature (7%), vomiting (1%), skin rash (1%), loss of appetite (1%) and irritability (1%) were observed during the first month after immunisation (Sohn et al., 1999). Vero cell-derived Inactivated SA14-14-2: The most frequent adverse events were skin and subcutaneous tissue disorders (24%, mainly rash), general disorders and administration site conditions (20%, mainly fever), nervous system disorders (20%, mainly headache) and gastrointestinal disorders (16%).

Severe adverse events

Allergic adverse events:

Inactivated mouse brain-derived vaccine - hypersensitivity reactions, such as serious generalized urticaria, facial angio-oedema or respiratory distress, have been reported (18–64 per 10,000 vaccinees), principally in vaccine recipients from non-endemic areas: most have been described among adult travellers from Europe, Australia and North America and consisted of urticaria and/or pruritus (often generalised), angioedema (of the extremities, face, oropharynx and lips) and very rarely of respiratory distress (Monath, 2002; Shlim et al., 2002; Takahashi et al., 2000; Tsai et al., 1999, Plesner et al., 1997). A unique feature is that such reactions may occur as late as 12–72 hours following immunization (WHO, 2006). The median interval between immunization and onset was 18 to 24 hours after the first dose, with 74% of reactions occurring within 48 hours; however reactions may be delayed up to 10 days following vaccination (Berg SW et al 1997). In addition, 70% of these reactions developed after the second or a later dose with a median onset of 3 days. They have been described as late type III allergic reactions (Monath 2002, Shlim et al., 2002; Leder et al., 2001; Tsai, 2000; CDC, 1993).

In Japanese children systemic immediate-type reactions occurred with a frequency of 1 to 2 per million doses (Sakaguchi et al., 2001, Sakaguchi et al., 1998). These have been described as anaphylaxis with cutaneous and respiratory symptoms, possibly related to the presence of IgE antibodies to the gelatin component of the vaccine, as well as cardio-vascular symptoms such as hypotension and cyanosis. Up to two cases of anaphylactic shock per 1 million doses of JE vaccine have been reported from passive surveillance in Japan. Two deaths from acute anaphylaxis in Korea have been attributed to the vaccine (Sohn, 2000; Tsai, 2000).

Risk factors for such serious reactions included a history of allergies or asthma, young adult age and female gender. The pathogenesis of the hypersensitivity reactions is unclear but a gelatin allergy should be excluded.

Inactivated cell culture vaccine - following inactivated primary hamster kidney cell-derived JE vaccine, few serious adverse events have been reported. In a survey of vaccines, an urticaria has been observed in 6.6 per 100,000 (Tsai et al., 1999).

4 serious cases (neuritis, meningism, oropharyngeal spasm and iritis) from 10 phase III trials were reported from a study on the safety profile of the Vero cell-derived Japanese encephalitis virus vaccine prepared by propagating JEV strain SA 14-14-2 in Vero cells. This corresponds to a rate of 1.6 per 100,000 doses distributed in the first 12 months of post-marketing use. (Elisabeth Schuller et al 2011).

Live attenuated cell culture vaccine - an increased risk of allergic reactions has not been reported with this vaccine.

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Neurological adverse events:

Inactivated mouse brain-derived cell culture vaccine - The nerve tissue content of the vaccine raised concerns about possible neurological adverse reactions. Up to one case of acute disseminated encephalomyelitis (ADEM) per million vaccinees has been reported in Japan (Monath, 2002; Tsai et al., 1999). In Denmark, between 1983 and 1995, this rate temporarily reached 1 per 50,000 – 75,000 vaccinees for reasons not yet fully understood (Plesner et al., 1996). Only one fatal case (8-year old boy with a complex congenital heart condition), however, was noted during surveillance of more than 10 million doses administered in Japan and the US (Takahashi et al., 2000). Neurological complications including encephalitis, encephalopathy, convulsions, peripheral neuropathy, transverse myelitis and aseptic meningitis have been reported in Japanese children with an incidence of 1 to 2.3 per million vaccinees (Ohtaki E et al., 1995).

Inactivated cell culture vaccine - an increased risk of neurological events has not been reported with this vaccine.

Live attenuated cell culture vaccine - in a randomized trial of the safety of Japanese encephalitis vaccine (SA14-14-2) in 26,239 children prospectively followed for 30 days for severe adverse events such as encephalitis, meningitis and ‘‘all-cause’’ hospitalization, no cases of encephalitis or meningitis or severe reaction consistent with anaphylaxis occurred in either group. In the same study, adverse events observed in a convenience sample of 266 vaccinated subjects examined at days 1, 2, 3, and 7 after JE immunization included Fever >37.5C (4.9%), Irritability (3.8%), Rash (2,2%) and vomiting (1.1%) (Zheng-Le Liu et al 1997)

Vaccine-associated JE

No cases of vaccine-associated disease were reported in a review of data covering a 20 year period that was presented to the GACVS in 2005 (WHO 2005).

Other safety issues

Use of JE vaccine in Indian mass campaign - The safety of the live attenuated vaccine (SA 14-14-2) was reviewed following its use in a mass campaign in India when >9.3 million children aged 1 to 15 years were vaccinated. There were initial reports of serious adverse events, including fatal events, however reviews by experts including the Global Advisory Committee on Vaccine Safety (GACVS) concluded that these events, which included 2 clusters of cases of encephalopathy and encephalitis were unlikely to have been caused by the vaccine (WHO 2007).

Summary of mild and severe adverse events

Nature of adverse event Description Rate/doses

Inactivated Injection site reactions 20 per 100 Mouse brain Headache, malaise, myalgia, low-grade fever, 5-30 per 100 nausea, vomiting, abdominal pain, rash, chills and dizziness.

Allergic reactions 17 per 106 Anaphylaxis 1-2 per 106 Neurological complications including encephalitis, encephalopathy, convulsions, 1-2.3 per 106 peripheral neuropathy, transverse myelitis

Inactivated Injection site reaction 4 per 100 Cell culture Headache and dizziness < 1 per 100 High Fever >38°C 12 per 100 Urticarial skin rash 6.6 per 105

Live attenuated High Fever 5-7 per 100-104 SA-14-14-2 Skin-rash 1 per 104

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References

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Andersen MM, Ronne T. Side-effects with Japanese encephalitis vaccine. Lancet 1991; 337:1044.

Berg SW, Mitchell BS, Hanson RK, et al. Systemic reactions in U.S. Marine Corps personnel who received Japanese encephalitis vaccine. Clin Infect Dis 24:265–266, 1997.

CDC. Inactivated Japanese encephalitis virus vaccine. Recommendations of the advisory committee on immunisation practices. MMWR 1993; 42(RR-01):1-15.

DeFraites RF, Gambel JM, Hoke CH, Sanchez JL, Withers BG, Karabatsos N, Shope RE, Tirrell S, Yoshida I, Takagi M, Meschievitz CK, Tasi TF. Japanese encephalitis vaccine (inactivated, BIKEN) in US soldiers: immunogenicity and safety of vaccines administered in two dosing regimens. Am J Trop Med Hyg 1999; 61(2):288-93.

Elisabeth Schuller∗, Anton Klingler, Katrin Dubischar-Kastner, Shailesh Dewasthaly, Zsuzsanna Müller Safety profile of the Vero cell-derived Japanese encephalitis virus (JEV) vaccine IXIARO®_ Vaccine 29 (2011) 8669– 8676.

Leder K, Weller PF, Wilson ME: Travel vaccines and elderly persons: review of vaccines available in the United States. Clin Infect Dis 2001; 33(9):1553-66.

Liu ZL, Hennessy S, Strom BL, Tsai TF, Wan CM, Tang SC, Xiang CF, Bilker WB, Pan XP, Yao YJ, Xu ZW, Halstead SB. Short-term safety of live attenuated Japanese encephalitis vaccine (SA 14-14-2): results of a randomized trial with 26,239 subjects. J Infect Dis 1997; 176(5):1366-9.

Marcus LC. Liability for vaccine-related injuries. NEJM. 318:191, 1988.

Ma X, Yu YX, Wang SG. Observations on safety and serological efficacy from a large-scale field trial of Japanese encephalitis vaccine. Chin J Biol 1993; 6:188-91.

Monath TP: Japanese encephalitis vaccines: current vaccines and future prospects. Curr Top Microbiol Immunol 2002; 267:105-38.

Ohtaki E, Matsuishi T, Hirano Y, Maekawa K. Acute disseminated encephalomyelitis after treatment with Japanese B encephalitis vaccine (Nakayama-Yoken and Beijing strains). J Neurol Neurosurg Psychiatry 1995; 59(3):316-7.

Plesner AM, Ronne T, Wachmann H. Case-control study of allergic reactions to Japanese encephalitis vaccine. Vaccine 2000; 18:1830-6.

Plesner AM, Ronne T: Allergic mucocutaneous reactions to Japanese encephalitis vaccine. Vaccine 1997; 15:1239-43.

Plesner AM, Arlien-Soborg P, Herning M. Neurological complications and Japanese encephalitis vaccination. Lancet 1996; 348:202-3.

Poland JD, Cropp CB, Craven RB, et al. (1960). Evaluation of the potency and safety of inactivated Japanese encephalitis vaccine in US inhabitants. Journal of Infectious Diseases, 161:878–82.

Robinson P, Ruff TA, Kass R. Australian case-control study of adverse reations to Japanese encephalitis vaccine. J Travel Med 1995; 2:159-64.

Sakaguchi M, Inouye S. Two patterns of systemic immediate-type reactions to Japanese encephalitis vaccines. Vaccine 1998; 16:68-9.

Sakaguchi M, Miyazawa H, Inouye S. Specific IgE and IgG to gelatin in children with systemic cutaneous reactions to Japanese encephalitis vaccines. Allergy 2001; 56:536-9.

Shlim DR, Solomon T. Japanese encephalitis vaccine for travellers: exploring the limits of risk. Clin Infect Dis 2002; 35(2):183-8.

Sohn YM. Japanese encephalitis immunization in South Korea: past, present and future. Emerg Infect Dis 2000; 6(1):17-24.

Sohn YM, Park MS, Rho HO, Chandler LJ, Shope RE, Tsai TF. Primary and booster immune response to SA 14-14-2 Japanese encephalitis vaccine in Korean infants. Vaccine 1999; 17: 2259-64.

Schiøler K, Samuel M, Wai K. Vaccines for preventing Japanese encephalitis Cochrane Database Syst Rev. 2007 Jul 18;(3):CD004263.

Takahashi H, Pool V, Tsail TF, Chen RT. Adverse events after Japanese encephalitis vaccination: review of post-marketing surveillance data from Japan and the United States. The VAERS Working Group. Vaccine 2000; 18:2963-9.

Tsai TF. New initiatives for the control of Japanese encephalitis by vaccination: minutes of a WHO/CVI meeting, Bangkok, Thailand, 13-15. October 1998. Vaccine 2000; 18(Suppl 2):1-25.

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Tsai TF, Chang J, Yu YX: Japanese encephalitis vaccine. In: Plotkin SA, Orenstein WA, eds. Vaccines, 3rd ed. Philadelphia, PA: Saunders 1999:672-710.

WHO. Japanese encephalitis vaccines - WHO position paper. WER 1998; 73:337-44.

WHO. Global Advisory Committee on Vaccine Safety WER 2005; 80(28):242-43.

WHO. Global Advisory Committee on Vaccine Safety 29-30 November 2006. WER 2007; 82: 23-24.

Yu YX, Ming ZG, Peng GY, Jian AO. Safety of live attenuated Japanese encephalitis virus vaccine (SA 14-14-2) for children. Am J Trop Med Hyg 1988;39:214-7.

This information sheet has been developed in close collaboration with the Global Advisory Committee on Vaccine Safety (GACVS). GACVS experts are independent and have declared no interests related to the expertise displayed in this product. Information displayed has been developed using primary sources such (Plotkin et al 2008, Institute of Medicine of the National Academies 2011) and from data derived from a literature search on Pubmed in 2008 using key words “vaccine antigen”, “Safety” and “adverse events”. An independent expert provided a first draft which was reviewed by nominated experts and the GACVS. Data of different vaccines that may be found in this product should only be compared if there is indication that a comparative randomised controlled trial has been undertaken. The information sheets will be updated as new information may become available at the following web link: http://www.who.int/vaccine_safety/vaccrates/en/index.html

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