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The first crude mouse brain derived inactivated
Japanese Encephalitis (JE) vaccines were produced in the 1930s by the Japanese
and Russians, and similar vaccines were used for the U.S. armies during the
world war II (1). The first Nakayama strain based inactivated mouse brain-derived (IMB)
JE vaccine was licensed in Japan in 1954 (2) and in the United States in 1992 (3). It then became the most
widely used JE vaccine internationally and was also a part of the routine
immunization programs in some Asian countries (4). However, concerns appeared
regarding temporal association of rare, but severe,
neurological adverse events with this vaccine, despite the lack of causal association (5,6). In 2006, WHO recommended this vaccine
to be eventually replaced by non-mouse brain vaccines considering advantageous safety profile (7). Marketed
as BIKEN® or JE-VAX® it’s production ceased in 2006 while
the last lot expired in February 2011 (8).

Currently three types of WHO prequalified non-mouse brain
vaccines are available.

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Inactivated Vero cell-derived vaccines: Licensed in china
in 1998 (8) the alum-adjuvanted vaccine based on SA14–14–2 virus strain marketed as IXIARO or JESPECT (9), is the only JE vaccine used in
the U.S. and other developed countries (8). Administered in 2 doses at 4-week intervals, the primary
dose starts at ?6 months of age in endemic settings (10),  and a booster is recommended after 1 year for the alum-adjuvanted vaccine SA 14-
14-2 strain and every
3 years for the Beijing-1
strain (11).

Live attenuated vaccines: Primary hamster kidney
(PHK) cell-derived, live attenuated vaccine based on the SA 14-14-2 strain of
the JEV has been used in China since 1988 and is being increasingly used in
other Asian countries (12). Single dose of vaccine is
administered at  ?8 months of age (10) and some places recommend boosters at 6–7 years of age (5).

recombinant vaccine: First licensed in Australia in 2010, this recombinant vaccine is prepared by replacing Pre-membrane
(prM) and envelope (E) coding sequences of the YF live attenuated 17D vaccine
virus with analogous sequences from the SA 14-14-12 live attenuated JE vaccine
virus (12) (Image in Appendix 1). A single dose is administered at ?9 months of age (10) while the booster dose
recommendation have not yet been determined(5).

Immunological basis
for vaccine efficacy and protection duration

Protection from all the vaccine is based on sufficient
neutralizing antibodies (10).  There are no concerns about a deficiency for cross-protection
across the five genotypes so far (7). JE vaccine doesn’t induce herd immunity (10).

Vero cell-derived vaccines: Seroprotection rates as high as 99% has been observed
in non-endemic settings (7). Whereas, a seroprotection rate of 95.7%
to >99% have been reported among children in endemic settings (10). Sustained seroprotection (90%)
were noted even after three years in endemic-(6) and after two years in non-endemic (13) pediatric population. The
seroprotection seems to wane over time but a booster dose has proven to be
effective for protective seroconversion (14).

attenuated vaccines:

Several safety studies from
China have shown that this vaccine is safe (15) with no indication of
viral reversion to a neurovirulent phenotype (8). Sustained
seroprotection has been observed; 98% by the end of 1 year (16) and 96% by the end of 5 years (17) after the initial vaccination with
a  single dose in endemic setting.

recombinant vaccine:

A recent study showed that there
were no safety concerns in children and adults aged 9 months to 60 years in
Vietnam (18). Clinical trials result have 99.3% seroprotection
rates in children of 9-18 months old in endemic settings (19) and 95.0% in children aged 12–18 months in non-endemic settings (20). High seroprotection rates 99.1% sero protected (95%)
were  observed among adults 18-65 years
in non-endemic settings (21). Seroprotection rates have been
observed to decline over time (7) and a very recent study found that seroprotection
after a JE-CV primary immunization dropped from 88.5%, to 68.6% in 5 years (22). There is recent evidence
that a booster dose can elicit anamnestic response
and lead to 100% seroconversion (23) even after 5 years of primary
immunization (22).

Natural boosting and ambiguity

Implications for
booster doses is of concern. For newer vaccines with limited follow up time in
endemic areas, it is unclear how long protective level of antibodies will last,
and whether natural boosting contributes to maintaining protective antibody level

effects profile

GAVCS conclude that the
live attenuated and the inactivated vaccines based on SA-14-14-2 have excellent
safety profiles in 2103(24). Further evidence of safety has been subsequently added
by a recently
published study of the inactivated Vero cell vaccine, IXIARO with the control
vaccines, Prevnar and HAVRIX 720, where the safety profile of IXIARO was
comparable to the control vaccines in a large pediatric population in endemic
setting(25).  A year after that a post marketing
surveillance from 2007 through 2012 in Guangdong, China that covered 23.29 million doses of the JEV-L vaccine  was published which concluded that the JEV-L
has a reasonable safety profile, with most adverse events being relatively
mild, and events related to neurologic damage being relatively rare (26). Another study in Korea where the vaccine has been used for
a long time most adverse events following immunization were self-limited, and
no serious adverse events were reported until 42 days after each dose. The
2-dose administration of LAJEV in the primary immunization schedule appeared to
be highly immunogenic and safe.(27). GACVS concluded that the
novel live recombinant (IMOJEV) is safe in 2104 based on the pre-licensure and post-licensure
safety and immunogenicity data. Considering the short duration of viremia post vaccination and
the limited potential for virus vaccine replication and dissemination within
the mosquito the probability of viral reversion has been regarded as remote (28). Subsequently, there recent studies from endemic
settings showed no safety concerns in children and adults (18,22,29). Safety of the Inactivated Japanese
Encephalitis Virus Vaccine IXIARO in Children: An Open-label, Randomized,
Active-controlled, Phase 3 Study (25).


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