The rise and fall of Japanese Encephalitis vaccination in the ADF – Where to now?

Abstract

The currently licenced Japanese encephalitis (JE) vaccine in Australia is now out of production. A live attenuated vaccine (SA14-14-2) currently used in Asia is not being licenced in Australia. Two new vaccines are in development in Australia, though not yet licensed. Researchers in the ADF have participated in both development programs. A program of research undertaken at the Army Malaria Institute offers an interim solution using intradermal administration of the currently licensed vaccine to reduce the rate of usage of the remaining stockpile. However, given the apparent risk to non-immune military populations, reassessment of actual risk on deployments to endemic areas may be another valid means of extending the life of the existing stockpile.

Introduction

The Australian licenced Japanese Encephalitis (JE) vaccine (JE-VAX^®) was founded in unparalleled research.It entered the marketplace in unusual circumstances with a stuttering beginning in Australia.Eventually the vaccine became part of the routine vaccination schedule for Australian Defence Force (ADF) personnel with a short (one month or less) notice to deploy.It is no longer in production at a time when the virus is emerging in the area of influence of the ADF, yet no replacement for the vaccine is licenced.

This raises the question of where to now, or at least for now?This paper will examine the risk to ADF personnel, the existing vaccine, future alternatives and, as we wait for the future, the interim solutions.

Epidemiology

An infection with JE virus may vary from being sub-clinical to causing death from encephalitis in ratios between 1:25 among naïve US military personnel serving in Korea1and 1:1000², though it is commonly quoted at around 1:300³.

The endemic areas for JE are pictured below, stretching from the subcontinent to Papua New Guinea in the areas immediately north of Australia.The military significance of JE has been outlined elsewhere, but these are clearly areas of influence for the ADF⁴.

Figure 1.Distribution of Japanese Encephalitis in Asia, 1970-1998

(from www.cdc.gov, last accessed 26 Dec 07)

Japanese encephalitis was recognised as a health risk of military operations in Vietnam including on redeployment.^5,6Fifty-seven cases were recorded in 1969 from approximately 10,000 deployed troops with varying individual exposures^7.

Deployment of the Sixth Battalion, Royal Australian Regiment (6RAR) into Phuoc Tuy Province of Vietnam from April 1966 was studied with a febrile illnesssurvey including samples taken to determine infectious disease exposures⁸. During this deployment no cases of JE were reported, though 20.9% of the soldiers of 6RAR had become seropositive to JE.The ratio of cases was estimated to be less than 1:420.

Later a case of Japanese encephalitis was described in a soldier returned from Vietnam but it was concluded that even though the disease was a serious hazard for non-immune soldiers deployed, it would be unlikely to become a problem in Australia^9.

The clinical risk of JE for non-immune military populations appears to be very low from the pre-vaccination experience.

The most recent experience of Australians with JE infection is during the emergence of the virus in the Torres Strait.Of the 215 Badu Island residents tested in the initial report¹⁰, 21 had serological evidence of JE infection and there were three confirmed human cases.This suggests a clinical:subclinical ratio of 1 in 7.Overall, 55 people had presumptive serological evidence of JE infection, suggesting cases represent approximately 1 in 18 infections.Defence personnel are based and exercise in this area,butwere not involved.The population of the Torres  Strait outbreak is not directly comparable to the ADF.

The rise of JE-VAX^®

The Japanese encephalitis vaccine currently available in Australia (JE-VAX^®) has an interesting development that perhaps explains why it is no longer in production and Australia is employing a dwindling stockpile of this vaccine.

JE-VAX^® is derived from the Nakayama strain of the virus first isolated in 1935.The strain was grown in mouse brain, inactivated and purified to produce the vaccine^11, which was found to be safe and immunogenic in non-endemic areas¹².The massive randomised field study demonstrating the efficacy of the prototype vaccine was conducted over four JE-endemic counties of Taiwan¹³.Only four serologically confirmed cases were recorded among the 111,749 children vaccinated twice while 24 cases were recorded among the 110,166 children in the placebo group suggesting 80% efficacy.The vaccine was then licenced and used from 1966.Records have been kept since the following year.A review of these records until 2000 found efficacy was in fact greater than 85% in an endemic area¹⁴.

In 1981 and 1982, two US citizens died from Japanese encephalitis after travelling to China.This prompted new research efforts into JE vaccines by US agencies.In Thailand, the US Armed Forces Research Institute of Medical Science (AFRIMS) project of monitoring students in the Kampangphet Province was newly instigated in 1984 providing a base for recruitment of 65,224 children from 458 villages in a mammoth study of the efficacy of monovalent Nakayama-NIH strain mouse brain inactivated JE vaccine and the bivalent vaccine of Nakayama strain with Beijing-1 strain against a placebo of tetanus toxoid¹⁵.The study rested on 13 cases (one in each vaccine group and 11 in the placebo group), barely enough to demonstrate the efficacy of either form of the vaccine, at 91% (CI: 70%-97% combined vaccine groups).

The CDC was prompted to begin an evaluation of the Nakayama strain vaccine available in Japan¹⁶ for the Food and Drug Administration.Two doses of the vaccine were given to 126 volunteers producing only modest responses measured by antibody titres.This was considered unsatisfactory, so the protocol was modified to include a third dose one to two weeks after the second and another 83 recruits were vaccinated and successfully immunized.

At around the same time, the US Department of Defense extended the information derived in the Thai study¹⁵ due to the effect of endemic flavi-virus exposure.From 1987 to 1989, 4,034 soldiers were vaccinated with two doses of the mouse brain inactivated Nakayama strain vaccine one week apart¹⁷.The sample size is impressive, however only 27 volunteers were bled forserum samples.Seven weeks after two vaccinations, 16 of 20 were considered adequately immunized, dropping to 9 of 27 at six months when a booster was given.Four weeks later 25 tested had responded.The conclusion drawn was the two doses provided adequate immunity “between eight and 12 weeks after (onset of) immunisation”.

The vaccine was released for use in the United States in December 1992 with the recommendation for three doses over one month for those exposed to JE endemic areas for one month or more^18.

On an opportunity basis, a small cohort of the original US soldiers vaccinated to determine an appropriate schedule were reviewed when they had contributed sera to a HIV study¹⁹.Only 17 soldiers were directly contacted for review and several confounders such as accurate flavi-virus and flavi-vaccine exposure were not controlled.Conclusions were that as 16 retained immunity three years after vaccination, this was a suitable time for boosting, and all were offered another vaccination.

These formed the basis for the NH&MRC Guidelines for the newly licenced vaccine in Australia.After an unusual history and entry to the Australian market as the only licenced JE vaccine, JE-VAX was broadly available for use when the wild virus appeared in the Torres Strait in 1995²⁰.The vaccine rose to play a central part in the initial and on-going outbreak management.

An initial fall

Initial studies of the mouse brain inactivated Nakayama strain vaccine in Taiwan suggested the vaccine was of low reactogenicity and was well accepted.With the Thai efficacy trial major adverse events such as anaphylaxis and post-vaccine encephalitis were anticipated and observedclosely in all recipients.Mild adverse events were no more frequent than for tetanus toxoid or with the second vaccination.Despite the scrutiny, no anaphylaxis or post-vaccine encephalitis was identified.

With the trials for registration of the vaccine in the United States, a higher incidence of adverse events than that reported by Asian children began to be evident.More than a fifth of soldiers reported arm pain, though no severe adverse events were recorded.Similarly, with the CDC study 20% of vaccinees reported arm pain and in the three-dose arm, two anaphylactic reactions occurred,one of which was exercise-induced.

The US Navy responded to an outbreak of JE on Okinawa in 1991 by offering to vaccinate the 20,000 Marines stationed there²¹.They recruited 14,249 Marines to conduct the definitive military study of adverse events from the vaccine in the process.Marines received 36,850 doses of the vaccine after which 38 hypersensitivity reactions were reported, which totalled ten times the number of cases of JE prompting the program.

In April of 1991, a Danish series of 18 cases derived from the national notification system for vaccine side effects was published in the Lancet²².The reports began to appear after September 1989, despite no reports from in excess of 40,000 doses of JE vaccine being administered in the country since 1988.After the 35,000-dose batch of vaccine, EJN 016, was exhausted in November 1990, only two urticarial cases were reported from the next batch, EJN 032, of 15,000 doses.

Later, in October 1991, Lancet published another case collection by eminent travel medicine consultants in Australia reporting 1,606 doses administered to 601 patients in 1990/91, citing similarity to the Danish experience and a high probability of adverse events being casually related to JE vaccines²³.The collection of three cases included two patients having reacted with allergic reactions after a second dose of batch EJN017 and a third after EJN042.All three cases developed reactions two or three days after vaccination.

At this stage, Australians accessed the JE vaccine by individual patient use (IPU) authorisations.In a short statement two days prior to the paper in the Lancet, IPU authorisations were suspended in Australia citing delayed hypersensitivity reactions after the second dose as the reason²⁴.Australia-wide, from 1987 to this time, approximately 4,000 doses were administered for only seven reports of patients with adverse reactions, including the three cases described above^25.

Three years later the call came for reconsideration of the restriction of vaccine availability and was supported by the series during the interim from Fairfield Hospital and the suspension was lifted for wider use^26,27.

Some evidence arose that reactions may be related to the gelatin used to stabilize the vaccine in Japan^28. Three children having had immediate systemic reactions following the vaccine, were found the have developed anti-gelatin IgE and two of the children had a history of allergic reactions to gelatin-containing foods prior to vaccination.Other children thought to have allergic reactions to the gelatin, manifesting only cardiovascular symptoms without urticaria and wheezing, did not have demonstrable IgE^29.Gelatin has since been removed from the vaccine in Japan and other countries.

The alternatives

Table 1: Alternative JE vaccines

SA14-14-2

As with the isolation and use of a wild (Nakayama) strain in Japan for development towards the currently available vaccine, the SA14 JE strain collected in China was attenuated and adapted for growth in a canine cell line for production as another vaccine.This vaccine was demonstrated to be safe and immunogenic in children and entered the Chinese schedule of vaccinations in 1988³⁰,³¹.Efficacy in China ranged from 80% with one dose to 97% with two doses³².This vaccine has also been tested and licenced in Korea^33, and by the Health Departments in Thailand and Nepal³⁴.In Nepal it was demonstrated to have protective efficacy in excess of 95% over a 5 year period.This is considered to be an international vaccine now, although it has not been submitted for licensure in Australia.

Intercell / CSL

Addressing some of the issues of a live vaccine produced in cell lines of uncertain provenance, the US Walter Reed Army Institute of Research (WRAIR) has inactivated the SA14-14-2 strain for development and licensing.Despite inactivation, this vaccine was demonstrated to maintain immunogenicity after two doses in Phase II studies³⁵.Further recent commercial development into Phase III including 867 adults confirmed the two dose schedule (0 & 28 days) produces better immunogenicity than JE-VAX^® (98% v 95%) and was well tolerated³⁶.The vaccine is presently under development towards licensure in Australia in collaboration with CSL. Final Therapeutic Goods Administration (TGA) approval is likely to be several years away as further phase III research will be necessary.

Acambis / Sanofi Pasteur

Homer described a beast referred to as the “chimera” which had the head of a lion, body of a goat and tail of a snake³⁷.Using the genome of the well established 17D yellow fever live attenuated vaccine (17DYF) and the original Chinese SA14-14-2 live attenuated vaccine a chimeric virus has been produced.This replicates with a viral core of 17D YF and antigenic surface of SA14-14-2.The live chimeric virus is attenuated however, immunogenic (producing JE antibodies, not YF) and well tolerated in early phase studies^38.

Concerns with using the yellow fever core have been regarding the recently identified serious adverse events associated with yellow fever vaccines (viscerotropic and neurotropic events) which have limited the recommendations for their use, though these events have been found to be rare³⁹.Other chimeric vaccines using the 17D YF for arboviral diseases such as for dengue and West Nile virus have been immunogenic and well tolerated^40.

With this information, a program of development towards approval by the Australian TGA began in 2003.Phase II studies of this vaccine in Australia were reported at the Asia Pacific Military Medicine Conference in Brisbane in 2004⁴¹.A recent Phase III study comparing a single dose of the vaccine to JE-VAX^® (full 3 dose schedule), including subjects recruited in Australia was recently reported⁴².Notably, the single dose satisfactorily immunized 93% of recipients within 14 days.JE-VAX^® in this study only seroconverted 75% of recipients compared to 99% following ChimeriVax-JE.Acambis has partnered with Sanofi-Pasteur for the licensing of this vaccine in Australia.Since this is the only one phase III study with fewer than 1,000 subjects,TGA approval of the vaccine is also several years away.

An interim solution

Following the key role JE-VAX^® played in the management of the emergence of the wild virus in Australia in 1995 and 1998, the vaccine entered regular use by the ADF for deployment to the near north of Australia.The vaccine grew to consume almost half the ADF vaccine budget by FY98/99⁴³.The cost of the vaccine and the potential for adverse events lead to a program of research at the Army Malaria Institute to mitigate these issues.

The first study in this program was based on the previous success of intradermal vaccination with hepatitis B and rabies vaccines.The licenced JE vaccine in Australia was administered to three groups using the recommended schedule (0, 1 & 4 weeks).The first group received the recommended route (subcutaneous) which was compared to the vaccine delivered intradermal at 1/10 volume into the deltoid skin of volunteers on either one or both sides (single and dual intradermal groups)⁴⁴.The findings were that the dual intradermal approach was as immunogenic as the conventional subcutaneous approach, produced fewer adverse events and was 1/5 of the cost.The single intradermal method was only suitably immunogenic when recipients had previously been vaccinated or infected with related arboviruses (dengue, yellow fever, Murray  Valley encephalitis).In the second study of this program, a Battalion was vaccinated using dual intradermal administration confirming the immunogenicity of the method.

That the single intradermal vaccination was effective in “boosting” those previously infected with related viruses was employed in a further study to demonstrate this as a suitable means of boosting JE vaccination⁴⁵.

These two pieces of information developed in the ADF provide the opportunity to extend the existing stockpile of JE-VAX^® significantly.

Conclusions

The only licenced vaccine against JE in Australia has been JE-VAX^® which began with a questionable safety profile before being employed to respond to the emergence of JE in Australia.Ironically, both CSL and Sanofi-Pasteur have marketed JE-VAX^® in Australia and now are looking to replacements though consistent supply is not ensured.Production of the existing vaccine licenced in Australia has ceased.Other vaccines available elsewhere will not be licenced for use in Australia.Replacement vaccines are being developed including in Australian based studies. They are not currently licensed nor will be in the immediate future.An interim vaccine solution to extend the existing stockpile of licenced vaccine has been tested in the ADF. Given the apparent risk to non-immune military populations, reassessment of actual risk on deployments to endemic areas may be another valid means of extending the life of the existing stockpile.

Declaration of conflicts of interest:

Dr. Kitchener was involved in placing studies of ChimeriVax-JE in Australia when employed by Acambis Research and in advising CSL regarding collaboration with Intercell JE-PIV.