1
EPA staff assessment report on application APP202371
To import and release a genetically modified live-attenuated vaccine (IMOJEV®) to protect humans against Japanese encephalitis.
10 April 2019
ADVICE TO THE DECISION MAKER
Executive summary and recommendation
On 3 April 2019, EPA formally received an application from Sanofi-Aventis New Zealand Limited (the applicant) to import for release a genetically modified organism. The organism, a live-attenuated vaccine (IMOJEV®) to protect humans against Japanese encephalitis, was lodged pursuant to section 34 of the Hazardous Substances and New Organisms (HSNO) Act 1996 (the “HSNO Act”).
Section 38I of the HSNO Act provides for a rapid assessment of applications received under section 34, if the application seeks the release of a qualifying organism. A qualifying organism is, in part, a new organism (including a genetically modified organism) that is a medicine or is contained in a medicine.
Based on the information in the application and from other published sources, we found, based on its well-established safety record, that it is highly improbable that IMOJEV® could form a self-sustaining population and have significant adverse effects on the health of the public, any valued species, natural habitats, or the environment.
Therefore, we recommend that the application is approved without controls.
Table of Contents
Executive summary and recommendation ... 2
Table of Contents ... 3
Purpose of this document ... 4
Application summary ... 4
Flaviviruses ... 4
Japanese encephalitis virus ... 8
Japanese encephalitis virus vaccines ... 11
The organism: IMOJEV® ... 12
Māori considerations ... 21
Summary of information from other agencies ... 22
Legislative criteria to be considered ... 23
International obligations ... 25
Conclusion and recommendation ... 25
References ... 26
Appendix 1: Medsafe comments ... 31
Appendix 2: MPI comments... 32
Appendix 3: Letters in support of application APP202371 ... 34
Purpose of this document
1. This Staff Assessment Report has been prepared by EPA staff to assist the decision-maker in considering application APP202371. It contains information from the applicant and other readily available sources, and it sets out the statutory criteria applicable to the consideration of this application under the HSNO Act.
Application summary
2. On 3 April 2019, Sanofi formally lodged an application under section 34 of the HSNO Act seeking approval to import for release a genetically modified live-attenuated vaccine with the trade name IMOJEV® that protects people from Japanese encephalitis. Prior to its commercial sale, IMOJEV was also known as JE-CV, or ChimeriVax-JE.
3. The applicant intends to market and distribute IMOJEV to healthcare providers in New Zealand for the immunisation of travellers, including military personnel and emergency aid workers dispatched on short notice to regions where Japanese encephalitis virus (JEV) is endemic, and thus will potentially be exposed to the virus (see section 2.3 of the application).
Flaviviruses
4. Flaviviruses are responsible for a number of different zoonotic (transmissible amongst animals and humans) diseases that have varying pathogenicities and effects in human hosts. These viruses are often transmitted to humans via the bites of infected arthropods (specifically,
mosquitoes or ticks). Therefore, flaviviruses are also referred to as arboviruses (arthropod-borne viruses), together with many unrelated viruses that also have arthropod vectors. Flavivirus diseases include yellow fever, dengue fever, west Nile fever, Japanese encephalitis, St Louis encephalitis, and zika fever.
Figure 1: Generic structure of Flaviviruses (Excerpted from ExPASy 2016). E dimer: Envelope protein dimer; C protein: Viral Core protein; M protein: Membrane protein.
5. Flavivirus particles approach a spherical shape (Fig. 1), with the outer surface of the virus comprising two structural proteins, the envelope (E) glycoprotein and the membrane (M) protein.
The E protein functions as a dimer, and their arrangement on the viral surface displays two-fold, three-fold and five-fold axes of symmetry. The E protein mediates cell binding and fusion during virus infection, and it is the major antigenic determinant of the virion. The M protein is the mature form of the precursor membrane (prM) protein, produced via proteolytic processing during viral maturation within the endoplasmic reticulum to facilitate its sequestration from RNases and its secretion from the cell (Pierson & Diamond 2013).
6. A third structural protein, the core (C) protein, constitutes the icosahedral viral capsid, which encloses the viral genome, a single-stranded RNA molecule, within the outer surface layer made up of the E and M proteins.
7. When a host cell becomes infected, the flavivirus genome (Fig. 1) serves directly as a messenger RNA molecule, and it is translated directly as a single polyprotein molecule that is post-
translationally processed into the various viral proteins in infected cells. Viruses that use this mode of replication are collectively classified as positive strand RNA viruses.
8. In addition to their three structural proteins, there are five non-structural proteins (NS1-NS5) encoded in the viral genome. These include a protease to initiate the post-translational processing of the viral polyprotein, as well as a high-fidelity RNA-dependent RNA polymerase for the
replication of the viral genome in the later stages of infection.
9. Flavivirus is the type genus of the family Flaviviridae (type species: Yellow fever virus), and thus are related to three other genera in the family:
Hepacivirus (type species: Hepacivirus C; formerly hepatitis C virus)
Pestivirus (type species: Pestivirus A; formerly bovine viral diarrhoea virus)
Pegivirus (type species: Pegivirus A) – this is a genus of several non-pathogenic
human/primate/animal flaviviruses split into a new genus by virtue of nucleic acid sequence data (ICTV 2017).
10. Flavivirus replication involves the production of a single polyprotein molecule from the viral genomic positive-stranded RNA, using the infected host cell’s own translational machinery (Chin
& Torresi 2013; Lindenbach et al, 2013). The polyprotein is then post-translationally processed using both host and viral proteases into the various structural and non-structural proteins, the latter of which eventually accumulate to sufficient quantities to allow the replication of the genomic RNA itself.
11. Unlike many other RNA viruses, including HIV, flaviviruses do not replicate via a DNA
intermediate form. Rather, all flaviviruses replicate using an RNA-dependent RNA polymerase (Lindenbach et al, 2013). This involves the production of the negative-stranded form of the RNA, from which additional positive strands are produced, using specialised membrane-bound
replicative complexes in the endoplasmic reticulum comprising both viral and host cell proteins and membranes (Lindenbach et al, 2013).
12. Mosquito and tick vectors become infected with flaviviruses via the blood of viraemic1 animals, often birds and mammals, but also reptiles (Marschang 2011). The viruses replicate in the guts
1The terms “viraemic” and “viraemia” refer to the presence of virus particles in the bloodstream
and salivary glands of the arthropods, whereby they transmit flaviviruses to uninfected animals, including humans, via their bites.
13. There are three major groups of flaviviruses that are categorised in accordance with their mode of transmission: tick-borne, mosquito-borne, and no known vector. Amongst the mosquito-borne viruses, a further subgrouping is made based on whether the vectors belong to either the Aedes or Culex genera. Phylogenetic analysis strongly supports these divisions, with tick-borne and mosquito-borne species grouping into distinct phylogenetic clades (Pierson & Diamond 2013).
The Aedes-borne flaviviruses are paraphyletic (two separate origins), and the Culex-borne flaviviruses are thought to have been derived from one branch of the Aedes-borne tree. The phylogeny of “no known vector” flaviviruses has two distinct clades, one that clusters most closely with the tick-borne viruses, the other with Aedes-borne viruses (Pierson & Diamond 2013), which may indicate potential, as yet undiscovered, vectors for these viruses.
14. The majority of flavivirus infections in humans are asymptomatic, but in cases in which disease develops, mortality rates can be high, particularly for yellow fever, St Louis encephalitis, and Japanese encephalitis, ranging from 20-50%, 5-20%, and 10-20%, respectively. In the case of Japanese encephalitis, only about 44% of patients go on to make a full recovery, with 30% of survivors showing symptoms such as seizures, mental retardation, and psychiatric disorders (Pierson & Diamond 2013).
15. Flaviviruses are relatively sensitive to heat, desiccation, UV light, household disinfectants and detergents. These viruses cannot survive for extended periods of time outside the host or vector organism (World Organisation for Animal Health 2013; Monath et al, 2015).
Flavivirus vaccines
16. Since the development of the yellow fever vaccine in 1937, a number of other flavivirus vaccines have been developed, mostly for Tick-borne encephalitis virus and Japanese encephalitis virus (Heinz & Stiasny 2012; Pierson & Diamond 2013; Ishikawa et al, 2014; Collins & Metz 2017). A useful vaccine against Dengue virus has remained elusive, mainly because of the difficulty involved in making it effective against the four major strains of Dengue virus in various regions where it is endemic (Heinz & Stiasny 2012; Collins & Metz 2017). Depending on the specific vaccine, they are either live-attenuated or inactivated whole virus varieties (Heinz & Stiasny 2012).
17. The development of the yellow fever vaccine has served as a model for the development of vaccines against other flaviviruses. In recent times, genetic modification techniques have come into use, taking advantage of the yellow fever vaccine’s limited replicative ability, with the substitution of the E and M proteins of other flaviviruses for those of Yellow fever virus (YFV) to create live-attenuated chimaeric vaccines, which have been reported to have good clinical effect (Guirakhoo et al, 1999; Arroyo et al, 2004; Johnson et al, 2004; Pugachev et al, 2004). In the case of JEV, this work has culminated in the licensing of IMOJEV as a single-dose JEV vaccine in Australia and much of southeast Asia (Chotpitayasunondh et al, 2017). To understand the
IMOJEV vaccine and its effectiveness, it is necessary to understand the yellow fever vaccine from which it is partially derived.
Yellow fever virus
18. Yellow fever virus is endemic in a band in the central latitudes of Africa, as well as in the northern latitudes of South America. However, sporadic infections in humans are reported outside these
regions of the two continents (CDC 2019). YFV is transmitted to humans via the bites of infected Aedes mosquito species, with A. aegypti as its primary mosquito vector (Pierson & Diamond 2013). The host range of YFV includes non-human primates, primarily monkeys, and a sylvatic (forest/jungle) transmission cycle amongst monkey species, which may in part explain the limited success of vaccination programmes. Viraemia in humans is sufficiently high that an urban transmission cycle (mosquito-human-mosquito, etc.) now exists, and is a growing problem with increasing urbanisation in parts of the world where YFV is endemic (Pierson & Diamond 2013).
Yellow fever viral vaccine strain 17D-204
19. The original yellow fever vaccine was created in 1937, and named YF17D. This vaccine was created by 176 serial passages of the so-called “Asibi” West African strain of YFV through mouse and chicken embryonic tissue, until it demonstrated substantially reduced neurotropic (attacking nerve cells, including the brain) and viscerotropic (attacking internal organs) activity (Pierson &
Diamond 2013). The vaccine proved to be highly effective, and is still in use today over 80 years later, albeit in slightly modified forms (Pierson & Diamond 2013).
20. There are two derivatives of the original YF17D vaccine that are in common use today. Both of these substrains were created by additional serial passaging of YF-17D. Strain YF-17DD is derived from passages 287-289, and is used in vaccines in South America. Vaccine strain YF17D-204 is derived from passages 235-240, and is used in other parts of the world (Pierson &
Diamond 2013). In New Zealand and Australia, strain YF17D-204 is the live-attenuated viral component of the licensed Stamaril® vaccine (Medsafe 2017) that has been used for more than 70 years to protect against YFV. More than 500 million doses of Stamaril have been administered worldwide, including in New Zealand, with an outstanding safety record (Guy et al, 2010; Pierson
& Diamond 2013). However, given the sheer number of vaccine recipients, it is unsurprising that rare adverse events have been observed.
21. In extremely rare cases (2-4 per million vaccinations), YF17D yellow fever vaccines (including the YF17D-204 vaccine Stamaril upon which the recombinant IMOJEV vaccine is based), cause a severe adverse reaction known as yellow fever vaccine-associated viscerotropic disease (YEL- AVD; Monath et al, 2005; CDC 2018a). Additionally, the less severe yellow fever vaccine- associated neurotropic disease (YEL-AND) also occurs at a rate of approximately 8 per million vaccinations (CDC 2018b). Both of these reactions are due to host factors, particularly age, with children under six months and adults over 60 years of age at greater risk than the general population (Medsafe 2017).
Japanese encephalitis virus
22. Japanese encephalitis is one of the most prevalent viral encephalitides in Asia – but it also occurs sporadically in northern Australia and parts of the Western Pacific (Campbell et al, 2011; CDC 2015a). Twenty-four countries are endemic for Japanese encephalitis (Figure 2, Campbell et al, 2011; CDC 2015a).
Japanese encephalitis is the leading cause of vaccine-preventable encephalitis in Asia and the Western Pacific. Among the reasons for transmission in many of these regions is the juxtaposition of pigs (the amplifying host species for the virus), rice fields (breeding grounds for the mosquito vectors as well as waterfowl hosts with no obvious signs of disease) and humans on farms in Asia (Fig. 3). Specifically, JEV is usually transmitted to humans via the bites of infected Culex
mosquitoes, although some Aedes and Anopheles mosquitoes are also minor vectors (Sucharit et al, 1989; Mackenzie et al, 2002; Impoinvil et al, 2012), and is sustained in the environment by so- called commensal hosts such as aquatic birds (Misra & Kalita 2010; Campbell et al, 2011; Dutta et al, 2011; Desai et al, 2012; Impoinvil et al, 2012).
Figure 2. Geographic distribution of Japanese encephalitis virus. JEV is found in the following countries (highlighted in red): Australia, Bangladesh, Brunei, Burma, Cambodia, China, India, Indonesia, Japan, Laos, Malaysia, Nepal, North Korea, Pakistan, Papua New Guinea, Philippines, Russia, Singapore, South Korea, Sri Lanka, Taiwan, Thailand, Timor-Leste, Vietnam, and the US territories of Guam and the Mariana Islands (Saipan Island only). Excerpted from CDC (2015a).
23. Japanese encephalitis virus is highly viraemic in pigs, and this species is therefore described as an amplifying host (Mackenzie et al, 2002; Dutta et al, 2011; Impoinvil et al, 2012). Mosquitoes that feed on infected viraemic pigs can carry a sufficiently high amount of virus to cause a symptomatic infection in humans. However, viraemia in humans is not sufficient to allow further amplification of the virus, and they, along with horses, are thus considered to be ‘dead end’ hosts (Mackenzie et al, 2002; Misra & Kalita 2010; Dutta et al, 2011; Desai et al, 2012; Impoinvil et al, 2012).
24. Cattle and other ruminants do not manifest signs of infection, and are thus also considered to be
“dead end” hosts. However, because JEV vector mosquito species preferentially feed on cattle rather than swine, cattle may either serve as “zooprophylactic” hosts, diverting the mosquitoes away from feeding on pigs, or zoopotentiating hosts, causing a “spillover” of JEV-carrying mosquitoes from the cattle population into the swine population (Mackenzie et al, 2002; Impoinvil et al, 2012). The interrelationship between zooprophylaxis and zoopotentiation is thought to be dependent on the geographical location of the cattle relative to human hosts and larval development sites (Impoinvil et al, 2012).
25. In humans, between 96% and 99.999% of JEV infections are asymptomatic (Guy et al, 2010;
Misra & Kalita 2010). Symptomatic cases start with mild symptoms (fever and/or headache), and approximately 20% of these cases resolve at this stage. The remaining 80% of symptomatic cases then progress to viral (aseptic) meningitis with stiffness, nausea, and vomiting, and five to 10% percent of cases resolve at this stage. The remaining 65 to 70% of cases progress to
Figure 3: Transmission life cycle of Japanese encephalitis virus. Culex mosquito eggs are laid in irrigated rice fields, where they mature to adulthood. Adult females are thought to contract the virus from the blood of infected, but non-diseased, waterfowl hosts. The mosquitoes in turn transmit the virus to pigs, where it is viraemic and highly amplified. Generally, JEV is only transmitted to so-called
“dead end” (viraemia too low to be a source of further transmission of the virus) hosts, that either develop clinical neurological signs (humans, horses) or are unaffected (cattle). Excerpted from Dutta et al, (2011).
inflammation of the brain (encephalitis), with accompanying severe symptoms including polio-like flaccid paralysis, Parkinson’s disease-like symptoms, seizures, coma, and death (Ghosh & Basu 2009; Misra & Kalita 2010; Halstead & Thomas 2011; Chin & Torresi 2013).
26. Between 20 and 30% of patients who develop Japanese encephalitis eventually die (Campbell et al, 2011; Desai et al, 2012). Among survivors, the disease leads to long-term cognitive, linguistic and psychological impairment in 30-50% of patients (Ghosh & Basu 2009). Campbell et al, (2011) estimate that approximately 68,000 Japanese encephalitis cases typically occur annually across the current geographic range of JEV. In unvaccinated populations in endemic areas, JE is largely a paediatric disease, with approximately 75% of cases occurring in children aged 0-15 years (Campbell et al, 2011; Lopez et al, 2015). Regional incidences range from 0.003 – 10.6 people per 100,000 population. Conversely, in regions with childhood vaccination programmes, ie, Japan, South Korea, Taiwan and Thailand, Japanese encephalitis is usually a rare disease of non- immune adults, particularly the elderly (Campbell et al, 2011; Desai et al, 2012).
27. There is no cure or treatment for Japanese encephalitis, other than pain medications and hydration, so personal protective measures to prevent mosquito bites, eg, insect repellent and mosquito nets, are recommended in areas where JEV is endemic. However, vaccination is considered to be the best defence against this disease (CDC 2015b).
Japanese encephalitis virus vectors
28. The primary vector for JEV is the mosquito Culex tritaeniorhynchus, the geographical distribution of which correlates nearly perfectly with the distribution of JEV (Longbottom et al, 2017; Fig. 1).
JEV has been spreading over the last 100 years (Mackenzie et al, 2002; Ghosh & Basu 2009;
Misra & Kalita 2010), and the disease arrived in Australia relatively recently. The first detection of JEV was in the Torres Strait Islands in the mid-1990s (Mackenzie et al, 2002), and the disease is now known to be present in North Queensland (CDC 2015a). Culex tritaeniorhynchus is not a species that is known to be present in Australia, and investigations revealed that C. annulirostris appears to be the main vector of JEV in Australia (Mackenzie et al, 2002). Culex annulirostris is a vector for other flaviviruses, including Murray Valley encephalitis virus, the most common
encephalitide in Australia (Mackenzie et al, 2002). Despite the presence of JEV in Northern Queensland, its incidence in Australia is classified as extremely low (Campbell et al, 2011).
29. Many other Culex species are also known to be JEV vectors. Among these, C. quinquefasciatus is of particular interest from a New Zealand perspective, as this species has established a self- sustaining population in the country (Landcare 2018). Some Ochlerotatus species, of which New Zealand has both native and introduced species (Landcare 2018), are also known to be JEV vectors (Mackenzie et al, 2002).
30. As discussed in paragraph 22, like other flaviviruses, JEV is transmitted amongst animals,
including humans, via arthropod vectors. However, a recent study reported evidence that JEV can be directly transmitted between pigs (Ricklin et al, 2016). These authors reported high viral loads in the tonsils of infected pigs, and they observed viral shedding as late as 10 days after infection, well after the viraemic (and clinically apparent) stage of the infection (Ricklin et al, 2016). To date, direct pig-to-pig transmission of JEV has neither been independently replicated, nor demonstrated in field conditions. However, a study by Park et al, (2018) also noted high viral titres in tonsils and oronasal shedding in pigs that were intravenously inoculated with JEV. These authors suggested that the oronasal shedding of JEV may be sufficient for pig-to-pig transmission amongst an entire herd from a single infected animal.
31. Transmission to humans via any vector other than mosquitoes has never been observed. Park et al (2018) noted that that rhesus monkeys, macaques and mice can be experimentally infected with JEV via intranasal administration. However, the viral titres required to achieve infection in rhesus monkeys, for example, were six to seven orders of magnitude higher than those observed in the oronasal secretions of infected pigs (Raengsakulrach et al, 1999).
Japanese encephalitis virus vaccines
32. Unlike the yellow fever vaccine, there have been several different licensed JEV vaccines. These vaccines were created using different production methods, from which either live-attenuated or inactivated viruses were used. These vaccines are discussed below in the chronological order of their development.
Inactivated BIKEN vaccine (JE-VAX™)
33. The first JEV vaccine, a killed, whole-virus vaccine extracted from infected mouse brains was developed by Osaka University’s Research Foundation for Microbial Diseases (BIKEN). The vaccine was marketed as JE-VAX™, and was used in Japan, Korea, and several other countries from South and Southeast Asia From 1954 to 2005 (Pierson & Diamond 2013). While the vaccine is effective, it requires a two-dose regime, plus a booster vaccination one to two years later.
Travellers require a 3-dose regime at 0, 7 and 30 days before sufficient protective immunity is acquired. Patient safety concerns led to JE-VAX being phased out in favour of newer vaccines with better allergenicity and safety profiles (Pierson & Diamond 2013).
Live-attenuated SA14-14-2 vaccine
34. The SA14-14-2 vaccine is derived from a JEV strain that was isolated from Culex pipiens larvae in China in 1954. Like the Stamaril yellow fever vaccine, SA14-14-2 was derived via serial passage of an infectious virus in cell culture, as well as in hamsters and suckling mice (Pierson & Diamond 2013). At least five mutations in the attenuated virus are in genes encoding the membrane and envelope proteins, which are collectively responsible for decreased affinity of the vaccine for neural (ie, brain) cells. Thus, these mutations result in what is described as a “neuroattenuation”
phenotype (Guy et al, 2010).
35. Like the YF17DD and YF17D-204 vaccines (paragraphs 19-21), SA14-14-2 resulted from additional serial passages from earlier vaccines, and was found to have low virulence, while conferring good protective immunity (85-100% after a single dose). The vaccine is licenced in China, Nepal, South Korea, Sri Lanka, and India (Pierson & Diamond 2013).
Inactivated SA14-14-2 vaccine IC51 (JEspect™, IXIARO™)
36. An inactivated version of the SA-14-14-2 vaccine known as IC51, and which is marketed under the trade names IXIARO™ in the United States and JEspect™ in Australia and New Zealand has been available since 2009 (Pierson & Diamond 2013). The vaccine is formalin2-inactivated and contains an aluminium hydroxide adjuvant. The vaccine requires a two dose injection schedule 28 days apart for neutralising immunity to be acquired. JEspect is currently the only JE vaccine
237% (w/v) formaldehyde in water.
available in New Zealand, and it is approved for use in people 18 years of age and older (Medsafe 2019).
The organism: IMOJEV®
37. The organism IMOJEV® is a genetically modified chimaeric derivative of both the live-attenuated yellow fever viral vaccine strain 17D-204 (paragraphs 19-21), and the live-attenuated JE vaccine strain 14-14-2 (paragraphs 34-35). The vaccine takes advantage of the common genomic constitution of all flaviviruses by substituting the yellow fever 17D-204 viral vaccine coat prM and E genes, (Figs. 4 and 5) with the orthologous genes from the SA14-14-2 live-attenuated JE viral
vaccine strain (Chambers et al, 1999; Guirakhoo et al, 1999). Thus, the chimaeric virus replicates using the non-structural (NS) YF17D genes, but displays the neuroattenuated M and E proteins from the attenuated SA14-14-2 JEV vaccine strain on its surface (Fig. 5). Thus, the chimaeric vaccine is doubly attenuated, first (based on the YF-17D-204 non-structural proteins) in its ability to replicate, and second (based on the 14-14-2 M and E proteins) in its affinity for neural cells.
The JEV 14-14-2 E protein constitutes the major antigenic determinant of the chimaeric virus (Pierson & Diamond 2013), and the vaccine recipient’s immune response to this protein forms the basis of immunity to potential infections by JEV in the environment.
38. Currently, IMOJEV is licensed for use in 14 different countries/jurisdictions, including Australia (Sanofi 2016), the Philippines (Capeding et al, 2018), South Korea (ClinicalTrials.gov 2018), Figure 4. Schematic diagrams of the genomic organization of the live-attenuated viral vaccines YF17D (yellow fever), SA14-14-2 (Japanese encephalitis), and IMOJEV (“Chimaeric JE Virus”; Japanese encephalitis).
Yellow colour depicts yellow fever virus genes, Blue colour represents Japanese encephalitis virus genes.
C: core protein gene, preM: pre-membrane protein gene, E: envelope protein gene, NS1-NS5: non-structural protein genes 1–5. Excerpted from (Chin & Torresi 2013).
Thailand (TGA 2014; ClinicalTrials.gov 2016; Chotpitayasunondh et al, 2017), Malaysia, Myanmar, and Singapore (MIMS 2019).
Comparison of Japanese Encephalitis Virus vaccines licensed in Australasia
39. Currently two JEV vaccines, JEspect™, and IMOJEV™ are licensed in Australia (Australian Technical Advisory Group on Immunisation 2018). The characteristics of these vaccines are compared in Table 1. If IMOJEV is approved for use in New Zealand, this would mirror the situation in Australia, so it is useful to compare the recommendations for the two vaccines there as an indication of their potential use in New Zealand.
Figure 5. Schematic diagram of the virion structures of JE virus vaccine SA14-14-2, YF virus vaccine 17D-204, and IMOJEV. The chimaeric vaccine has the M (membrane) and E (envelope) proteins of SA14-14-2 (blue), and the C (core) protein of 17D (brown). Excerpted from the application.
40. It is important to note that, despite the Australian indications above, JEspect is not approved for use in New Zealand for any person under the age of 18 (Medsafe 2019). If the present application is approved, age restrictions (if any) will be imposed by Medsafe, if any subsequent application for the use of IMOJEV as a medicine is approved by Medsafe.
Intended use and benefits of IMOJEV®
41. As stated in Section 2.3 of the application, the intended use of IMOJEV is for people expecting to travel to regions where JEV is endemic, and for researchers and laboratory workers that may potentially be exposed to JEV in the course of their work. This proposed use has potential benefits not provided by the JEspect vaccine, which is currently the only JEV vaccine available in New Zealand. A potential benefit of IMOJEV, if approved in New Zealand, is its ability to rapidly confer strong, and long-lasting immunity after a single dose, as detailed in the remainder of this section.
42. As discussed in paragraphs 32-36, aside from IMOJEV, there are two other JEV vaccines that are available in different parts of the world. Comparison of available clinical trial and post-vaccination follow-up studies amongst the three vaccines shows that the two live-attenuated vaccines (SA14-
Vaccine JEspect™ IMOJEV™
Formulation Inactivated SA14-14-2 strain;
known as IXIARO outside of Australia/New Zealand with aluminium hydroxide adjuvant
Live-attenuated chimaeric virus strain; YF-17D non-structural proteins, JEV SA14-14-2 coat proteins, no adjuvant
Route of administration Intramuscular injection Subcutaneous injection Dosage Neonates under two months:
Contraindicated
Infants & children aged two months to three years: Two doses (0.25 ml) 28 days apart
All others: 2 doses 0.5 ml 28 days apart
Neonates under nine months:
Contraindicated
All others: single dose 0.5 ml
Booster Infants & children: No data – consider a booster after one-two years if ongoing protection needed All others: one-two years after primary dose if ongoing risk of JEV exposure
Children nine months to 18 years:
booster one-two years after primary dose if ongoing protection needed All others: Not required
Seroconversion/immunity Immunity is established in 98% of vaccine recipients 3 days after the second dose, 28 days after the first.
Immunity is established in 93% of vaccinees 14 days after a single dose, and 99.1% of vaccinees by 30 days after the single dose.
Table 1: Japanese Encephalitis Virus vaccines approved for use in Australia (Australian Technical Advisory Group on Immunisation 2018)
14-2 and IMOJEV) appear to be more immunogenic than the JEspect/IXIARO killed vaccine (Appaiahgari & Vrati 2010; Torresi et al, 2010; Chin & Torresi 2013), and unlike other JEV
vaccines, IMOJEV appears to stimulate T cell-mediated immunity, in addition to humoral immunity (immunity that is mediated by macromolecules found in extracellular fluids eg, secreted
antibodies), which may provide additional protection, and potentially, longer-lasting immunity (Guy et al, 2010).
43. Although the data sets are incomplete, there is a clear difference between the killed vaccine and IMOJEV in 1-year post-vaccination follow-up studies, with 69% seropositivity after a 2-dose regime for the killed vaccine, versus 95% seropositivity for IMOJEV recipients after a single dose (Chin & Torresi 2013).
44. In children, it appears that IMOJEV is approximately equivalent to the SA-14-14-2 vaccine in providing protective immunity to children. Two-year follow-up data from children 36 to 42 months old show 80% seropositivity with IMOJEV, and four-year follow-up data in children aged 1-15 years at vaccination showed 90% seroposivity with SA14-14-2 (Chin & Torresi 2013). No data from children were available for JEspect. As noted earlier, JEspect is not approved for use in New Zealand in any person under 18 years of age (Medsafe 2019), although it is approved for use in children in Australia (Table 1).
45. Statistical modelling to predict the persistence of neutralising antibodies in adults vaccinated with IMOJEV was carried out using seroprotection data in adults at six months (97% seropositive) and five years (87% seropositive) post-vaccination. A number of different statistical models were used in the study, and the best-fitting model predicted a short, rapid post-vaccination decline in
antibody levels, followed by a far slower decline starting at approximately 3 months post-
vaccination. The model predicted a seroprotection rate of 85.5% at 10 years post-vaccination of a single dose of IMOJEV. The estimated median duration of seroprotection was 21.4 years
(Campbell et al, 2011; Desai et al, 2012).
46. In support of the proposed use for pre-travel immunisation of New Zealanders, the applicant has provided two letters of support from medical doctors who specialise in travel medicine
(Appendix 3). In the first, Dr Jenny Visser, University of Otago, Wellington, notes that IMOJEV requires only a single dose to confer protective immunity to a vaccine recipient, and that New Zealand does not have a JEV vaccine that is approved for use in children, but that IMOJEV is licenced in Australia for use in children as young as nine months of age. The second letter, from Dr Marc Shaw, the Medical director of Worldwise Travellers’ Health Centres New Zealand, noted IMOJEV’s single dose and rapid acquisition of protective immunity, good patient acceptability, and longer post-vaccination immunity before a booster shot is required. Doctor Shaw also mentioned delays in a humanitarian aid response from New Zealand to the Philippines in 2014, due to the two injection requirement of the available JEV vaccine.
47. According to Statistics New Zealand, an average of 470,000 New Zealand residents travelled to JEV-endemic countries in South, East, and South-East Asia3 (Stats NZ 2018), in each of the years 2016-2018 (Fig. 2). Holiday or business travellers often do not seek travel health advice in the time required for vaccinations to be effective ahead of trips. Moreover, many travellers, such as medical response teams, charity workers, or military personnel, are often called from New Zealand to these regions on an emergency basis, and therefore often do not have enough time to
3Cambodia, China, Hong Kong, India, Indonesia, Japan, South Korea, Malaysia, Philippines, Singapore, Sri Lanka, Taiwan, Thailand, Viet Nam.
receive multiple doses of JEspect before they need to travel to these regions where the virus is endemic. This poses a potentially serious health issue for New Zealanders who are called upon for such activities. Therefore, such personnel often travel without protection against the virus.
These points are reflected in the two supporting letters (Appendix 3) discussed above.
Potential adverse effects from IMOJEV® use
48. The most common systemic reactions after IMOJEV administration are headache, fatigue, malaise and myalgia (Torresi et al, 2010; Feroldi et al, 2012; WHO 2016). These symptoms are similar to those caused by other JEV vaccines, and they occur at similar rates observed for those vaccines (WHO 2016).
49. As described in paragraph 21, the Stamaril YF17D yellow fever vaccine causes the severe adverse reactions YEL-AVD and YEL-AND at rates of 0.0002-0.0004% (2-4 events per million vaccinations), and 0.0008% (8 per million vaccinations), respectively. Although IMOJEV is derived from Stamaril, such symptoms have not been reported to date in persons vaccinated with
IMOJEV, including young children (Chokephaibulkit et al, 2010; Feroldi et al, 2012; WHO 2016).
50. Under section 38I(4) of the Act, no consideration is to be given to any potential adverse effects upon the recipient of a qualifying medicine assessed under this pathway. However, such adverse effects may be considered when examining the possibility of people who might be inadvertently exposed to the medicine.
51. As discussed below, the likelihood that IMOJEV will spread from the recipient after vaccination is highly improbable. Therefore, the likelihood of these potential adverse effects eventuating in a non-vaccinated host are themselves highly improbable. However, if by some circumstance a non-vaccinated person were to be exposed to IMOJEV, the expected adverse effects would be expected to be no worse than those described in paragraph 48. Such adverse effects may not eventuate at all, given that any potential dose received by an unintended recipient would be several orders of magnitude less than that received via vaccination.
Capacity of IMOJEV® to spread from vaccinated individuals
52. Under section 38I(4)(a) of the HSNO Act, in determining whether a qualifying organism is or is contained in a qualifying medicine, the effects on the individual receiving it are not to be taken into account. Therefore, an environmental risk assessment carried out under s38I must only take potential adverse environmental effects, including the health and safety of the public, into account.
53. In order for any potential adverse environmental effects from the use of IMOJEV to take place, the virus would first need to be transmitted in some way from the recipient to the environment. There are a number of ways in which such an event might occur. These include:
transmission via blood donation after vaccination
transmission to a foetus during pregnancy
direct shedding by vaccine recipients
transmission via mosquito vectors
transmission via an amplifying host
reversion to virulence via recombination
infection by IMOJEV via improper handling of the vaccine Each of these potential pathways is discussed in turn below.
Transmission of IMOJEV via blood donation after vaccination
54. As expected for a live-attenuated viral vaccine, IMOJEV was seen to replicate to very low levels for a transient period in clinical trials, with detection of the virus in blood samples taken from one to eight days post-inoculation in vaccine recipients (Monath et al, 2002; Monath et al, 2003). Thus, IMOJEV, like other live-attenuated vaccines such as yellow fever, influenza, diphtheria, pertussis, and tetanus vaccines, among others, could potentially be transmitted from a vaccine recipient to another person via a transfusion of blood donated by vaccine recipients while they are still viraemic.
55. Clinical trials comparing viraemia induced by IMOJEV4 to a YF-17D vaccine (which contains the YF-17D non-structural genes) found that viraemia induced by the two vaccines was comparable, approximately 25-40 plaque-forming units per millilitre of blood (Monath et al, 2003). The only known case of transmission of the YF-17D yellow fever vaccine in its 80 year history of use was documented by Lederman et al, (2010) when, due to a breakdown in reporting, US military recruits donated blood shortly after receiving the yellow fever vaccine. Despite this accident, there were no adverse effects reported. Therefore, given similar levels of post-inoculation viraemia, such a route of transmission is at least theoretically possible for IMOJEV as well.
56. The New Zealand Blood Service has published, long-standing eligibility criteria, and pre-donation screening procedures for blood donation in New Zealand (NZBlood 2019a, b), including the completion of a donor health questionnaire which includes vaccination history within six months of donation (NZBlood 2019b). While recipients of most killed vaccines can donate whole blood immediately after vaccination, the Blood Service requires a four week stand-down period from whole blood donation from recipients of live-attenuated vaccines, although donations for blood plasma only are still allowed from such individuals (NZBlood 2019a). Therefore, the likelihood that IMOJEV could be transmitted to another person via a blood transfusion is highly improbable.
Transmission of IMOJEV to a foetus during pregnancy
57. In addition to blood donation by viraemic vaccine recipients, another potential route of
transmission of IMOJEV is to a foetus by vaccination of a pregnant woman. The Ministry of Health has published guidelines, in its Immunisation Handbook (Ministry of Health 2018), regarding the administration of live-attenuated vaccines to pregnant women, as well as to women who intend to become pregnant after receiving such vaccines. These guidelines advise medical professionals to advise women not to become pregnant within 4 weeks of receiving any live-attenuated viral vaccine. The Immunisation Handbook also advised medical professionals that “live vaccines should be avoided until after the delivery”.
58. For obvious ethical reasons, the only data available regarding the effects of any live-attenuated vaccine are from infants born to mothers who were inadvertently vaccinated during pregnancy.
The Immunisation Handbook notes this point by stating: "Deferring administration of live vaccines until after delivery is a precautionary safety measure. Studies of women who inadvertently received a live vaccine during pregnancy and their infants have not identified any adverse effects.”
59. Given the relatively recent registrations of IMOJEV by Australian and other regulatory authorities, there are no data available regarding inadvertent administration of IMOJEV to pregnant women.
However, in its 2014 public assessment report of IMOJEV, the Australian Therapeutic Goods
4Known at the time as ChimeriVax™-JE.
Administration noted that Sanofi had submitted two studies it had conducted on the administration of IMOJEV to pregnant and nursing rabbits with young kittens (TGA 2014). Full human doses (approximately a 20X human dose on a per-weight basis) were administered to pregnant and nursing does, and adverse effects were not observed in foetuses or newborn kittens from mothers that demonstrated seroconversion (development of neutralising antibodies). Therefore, the
likelihood that IMOJEV could have adverse effects on a foetus via vaccination during pregnancy is highly improbable.
Direct shedding of IMOJEV by vaccine recipients
60. Although flaviviruses are generally known as arboviruses (arthropod-borne viruses), there are reports of flavivirus infection via other routes as well as oronasal shedding. Oronasal West Nile virus infections have been reported in several animal species, as well as transmission to suckling humans and hamsters (Ricklin et al, 2016). Both West Nile virus and YFV RNA have been detected in the urine of infected patients (Zhao et al, 2013). Zika virus has been reported to be shed from humans in the semen of infected men (Mead et al, 2018), and in the stools of mice (Li et al, 2018).
61. As discussed earlier, JEV is reported to be shed from infected pigs (Ricklin et al, 2016; Park et al, 2018). There was also a single report of JEV shedding in infected mice (Zhao et al, 2013).
Therefore, the consideration of the potential for IMOJEV shedding from vaccinated humans must be taken into account in this context.
62. As discussed earlier, JEV viraemia in humans is generally very low. This is true for essentially all of the pathogenic flaviviruses in humans (Solomon 2004), and viraemia is usually undetectable in infected patients using standard diagnostic laboratory tests. For this reason, diagnostic testing for flaviviruses in humans usually involves the detection of antiviral immunoglobulin M (IgM)
antibodies in the cerebrospinal fluid (a clear body fluid in the brain and spinal cord) of infected patients (Solomon 2004).
63. The shedding of some flaviviruses in the urine of infected patients led Zhao et al, (2013) to test for JEV RNA in the urine of JEV-infected patients to evaluate its potential as a diagnostic test for the virus. However, this group was unable to detect JEV in urine samples from 52 infected patients (Zhao et al, 2013). Conversely, a recent report described the detection of JEV RNA in the urine of a 69 year-old Australian man who contracted JEV while on holiday in Thailand (Huang et al, 2017). Similarly, Mai et al, (2017) discuss the diagnosis of JEV in a 16 year-old Vietnamese boy through its detection in his urine by a deep-sequencing metagenomics approach. These are the only two known cases of JEV shedding of any kind from humans. The basis for the difference in the findings of Zhao et al, (2013), versus those of Huang et al, (2017), and Mai et al, (2017) is unclear, especially as there appears to be no correlation regarding the timing of the urine sample relative to disease progression and viraemia and detection of JEV in urine samples.
64. In clinical trials in humans, IMOJEV viraemia was found to be very low, approximately 25-40 plaque-forming units per millilitre of blood, with a mean viraemic period of 1 to 3 days, comparable to that of the YF17D vaccine (Monath et al, 2003). Subsequent work performed on other
chimaeric flavivirus vaccines has shown that the potential for shedding is very low (Monath et al, 2015). Although this finding might appear contradictory to the statements above regarding the general inability to detect wild-type JEV in blood samples, it should be noted that the methods used for the non-specific diagnostic detection of the cause of an unidentified febrile infection, versus the direct and specific detection of JEV in clinical trial work are substantially different from one another.
65. Given that infectious, wild-type JEV is only extremely rarely shed from infected humans, and that vaccine recipients have extremely low virus titres and short-duration viraemia after vaccination, we conclude that any adverse effects of transmission of IMOJEV to an unvaccinated person via direct shedding is highly improbable.
Transmission of IMOJEV via mosquito vectors
66. Another potential route of transmission of IMOJEV to individuals is through mosquito bites of viraemic vaccine recipients, which could then be transmitted to a different person by the mosquito vector. To test this hypothesis, the mosquito flavivirus vector species Culex tritaeniorhynchus, Aedes albopictus, or A. aegypti were fed blood meals of IMOJEV containing 8 million plaque- forming units/ml (Bhatt et al, 2000), a titre approximately 200,000 times higher than the maximum titres observed for IMOJEV viraemia in clinical trials with human vaccine recipients (Monath et al, 2002; Monath et al, 2003). Vaccine replication was not detected in any of these species, but controls fed wild-type JEV or other live-attenuated JEV vaccines developed replicative viral infections. In another set of experiments, IMOJEV was administered to these mosquito species by intrathoracic injection. In these experiments, vaccine replication was not detected in the primary JEV vector C. tritaeniorhynchus, but low titres were detected in both of the Aedes species (Bhatt et al, 2000). Positive controls injected with either wild-type JEV or other JEV vaccines were seen to develop replicative viral infections.
67. Later experiments carried out in the Australian mosquito species Culex annulirostris, C. gelidus, and Aedes vigilax that were fed blood meals containing 5 million plaque-forming units of IMOJEV (approximately 125,000 times higher than the maximum peak viraemia in IMOJEV vaccine recipients) demonstrated that IMOJEV did not replicate in these species either (Reid et al, 2006).
Based on these data, the likelihood that vector mosquitoes could become infected with IMOJEV after feeding on an IMOJEV vaccine recipient is highly improbable.
Transmission of IMOJEV by an amplifying host
68. Regardless of the fact that IMOJEV does not replicate in mosquitoes when taken as a blood meal, and IMOJEV is not administered to animals, tests were carried out on the replicative ability of IMOJEV in pigs. Swine inoculated with IMOJEV do not have detectable viraemia (Guy et al, 2010). Thus, the likelihood that IMOJEV might spread from an inoculated individual to mosquitoes to create secondary infections in other people or JEV-amplifying hosts is highly improbable.
Reversion of IMOJEV to virulence via reversion mutations or recombination
69. Regardless of whether or not it is a genetically modified organism, a theoretical concern regarding any live-attenuated vaccine is the potential for reversion mutations or recombination(s) with a wild-type virus to restore it to virulence. IMOJEV is a genetically modified chimeric virus vaccine derived from two live-attenuated parental viruses: YF17D-204, and the JEV SA14-14-2 (Figure 4).
IMOJEV’s replicative ability is dependent on the 17D-204 RNA-dependent RNA polymerase.
70. The YF17D-204 yellow fever viral vaccine strain is genetically stable due to its high-fidelity RNA- dependent RNA polymerase (Guy et al, 2010), making reversion mutations highly unlikely. This observation is substantiated by a retrospective analysis performed on 12 bulk lots of Stamaril manufactured over 12 years, which found no changes to the vaccine’s genome sequence (Barban et al, 2007). Moreover, through 70 years of usage and 500 million doses, no reversion to wild type has ever been reported (Guy et al, 2010). Finally, multiple reversion mutations in the viral RNA would be required to increase its virulence (Guy et al, 2010).
71. Two separate “recombination trap” studies with 17D virus strains concluded that the propensity for recombination amongst flaviviruses is extremely low (Taucher et al, 2010; McGee et al, 2011).
Moreover, most of the data regarding recombination suggests that recombined viruses are generally attenuated relative to the parental viruses (Monath et al, 2005; Taucher et al, 2010;
McGee et al, 2011). Furthermore, several studies have shown that when recombination has been achieved under experimental conditions, the recombinant vaccines are not more virulent than the vaccine, nor do they become more likely to be transmitted by mosquitoes (Monath et al, 2015).
72. For a live-attenuated virus such as IMOJEV to revert to a neurovirulent virus, either through reversion mutations, six independent mutations would need to occur to restore neurovirulence, based on systematic experimental reversion mutations tested in mice (Arroyo et al, 2001). Given the high fidelity of IMOJEV’s RNA polymerase, the likelihood of six independent reversion mutations occurring is highly improbable.
73. Restoration of neurovirulence to IMOJEV via recombination with wild-type JEV or another flavivirus would require extremely high virus titres in vivo. It is estimated that co-infections of approximately 1030 cells would be required, based on experimentally determined recombination rates between flaviviruses (McGee et al, 2011). For reference, there are estimated to be 3.72×1013 cells in an average human body (Bianconi et al, 2013). Therefore, the likelihood of recombination events of IMOJEV with wild-type flaviviruses resulting in a virulent virus is highly improbable.
Infection by IMOJEV via improper handling of the vaccine
74. As with any injectable vaccine, there is a possibility that IMOJEV could accidentally be introduced into a person other than the intended recipient through mishandling (eg, a needle stick from a syringe used to administer IMOJEV). Such an event is rendered unlikely by the fact that IMOJEV will only be available as a physician-administered prescription medicine. This means that IMOJEV can only be used by medical professionals who are trained in the handling and administration of vaccines by injection, as well as the proper disposal and destruction of medical waste, including needles. Even in the highly improbable event of such an occurrence, an adverse effect on the health and safety of an unintended recipient is highly improbable, based on the known characteristics of IMOJEV, as described in this document.
75. Another possible means by which IMOJEV could find its way into the environment is via improper disposal of the vaccine, either before or after its intended use. The likelihood of such an event is again mitigated by the fact that IMOJEV can only be administered by medical professionals, who are trained in the proper disposal of medicines and medical waste products. Regardless of this, were IMOJEV to find its way into the environment, the virus would not survive long outside a host, as noted in paragraph 15. Therefore, the likelihood of an adverse effect on the health and safety of the public or the environment occurring, or an undesirable self-sustaining population
establishing is highly improbable.
Māori considerations
76. As specified in Part 2 of the HSNO Act (Purpose of Act), the EPA must recognise and account for (among other things) several principles and matters of relevance to Māori, particularly as they relate to:
the maintenance and enhancement of the capacity of people and communities to provide for their own economic, social, and cultural well-being and for the reasonably foreseeable needs of future generations (section 5(b))
the relationship of Māori and their culture and traditions with the ancestral lands, water, sites, wāhi tapu, valued flora and fauna, and other taonga (section 6(d))
the principles of the Treaty of Waitangi (Te Tiriti o Waitangi) (section 8)
77. The assessment of these principles and matters of relevance to Māori was undertaken by the EPA’s Māori advisory unit, Kaupapa Kura Taiao. The full text of this assessment is reproduced below.
Kupu arataki (Context)
This application is for approval to allow Sanofi to import and distribute a vaccine called ‘Imojev’ to protect people against a viral disease known as Japanese encephalitis.
The potential effects of this proposal on the relationship of Māori to the environment have been assessed in accordance with sections 5(b), 6(d) and 8 of the Act. Under these sections all persons exercising functions, powers and duties under this Act shall: Recognise and provide for the maintenance and enhancement of people and communities to provide for their cultural well-being, and; take into account the relationship of Māori and their culture and traditions with their ancestral lands, water, taonga, and the principles of the Te Tiriti o Waitangi.
Taha hauora (Human health and well-being)
Implications for taha hauora (human health and well-being) are vitally important to Māori. It is noted that significant numbers of Māori travel to places in South-East Asia and Western Pacific where the Culex species of mosquito (vector of JE) and JE exist. The Imojev proposal would protect the taha hauora (health and well-being) of Māori and other New Zealanders undertaking such travels, in particular the dimensions of taha tinana (physical health and well-being) and taha wairua (spiritual health and well- being obtained through the maintenance of a balance with nature and the protection of mauri).
A particularly beneficial aspect of Imojev is its preventative nature – much preferable to treating un- inoculated patients after they have contracted JE and dealing with associated impacts on their whānau members. That is, whānau suffer too supporting loved ones infected with JE. In this respect, the Imojev proposal would support taha whanaunga – caring for, and sharing, in the collective including relationships and whānau contexts, and being connected to people and things that foster a sense of belonging, enjoyment, well-being and safety.
Ngā kōrero tukipū (General comments)
This proposal does not raise any major concerns from a Māori perspective. We are satisfied that Imojev is not likely to adversely affect Māori interests including potential impacts on the environment. This includes potential effects on Māori communities, culturally significant species and materials, and cultural values and practices associated with these.
It is assumed this proposal will be considered by District Health Boards and Māori representatives within those entities, if they have not already done so. We are comfortable that such consideration would likely pick up any key issues potentially of concern to Māori.
Individuals have the choice of whether or not to be vaccinated with Imojev, and it will not be used on persons of Māori descent unless their express consent has been obtained. As such, use of Imojev will respect the mana of individuals.
This proposal is consistent with the practice of manaakitanga i.e. valuing people, acting with goodwill and beneficial purpose, showing respect, caring for and protecting the well-being of people – which can manifest in dimensions of taha hauora (human health).
Ngā hua (Benefits)
Any reservations Māori might have about Imojev are outweighed by its benefits in terms of:
Enhancing oranga pai me te toiora - quality of life and enjoyment of healthy life styles.
Enhancing mauri (vital essence) and manawaroa (resilience) of individuals.
Preventing hauātanga - impairment of functions and potential to participate fully at work, play, home or in society.
Protecting against ngā whakakino i ngā pūnaha ā tinana - adverse effects on body organs and/or systems.
Kupu Whakatepe (Conclusion)
This proposal is not likely to put cultural well-being of Māori at risk by infringing on Māori cultural beliefs and frameworks.
Summary of information from other agencies
78. The Department of Conservation (DOC), the Ministry for Primary Industries (MPI) and Medsafe were given the opportunity to comment on the application.
79. Medsafe stated that it had no concerns regarding IMOJEV, and (assuming its approval by EPA as a qualifying organism), that it was ‘highly likely’ IMOJEV would be subject to regulation as a prescription medicine (Appendix 1).
80. DOC replied that they had no objections to the application.
81. MPI stated that the importation of IMOJEV is not foreseen to be an issue, noting the attenuated nature of the vaccine, and its parental vaccine strains. The MPI comments noted the low titres and short duration of viraemia in humans. They also questioned how the tracking of disposal of IMOJEV would occur (Appendix 2).
82. MPI further commented that, assuming approval of this application from EPA, the MPI Animal Imports team would need to undertake a Chief Technical Officer (CTO) direction to allow the importation of IMOJEV under a general import permit, because the Microorganisms Import Health Standard (MICROIC.ALL) requires new organisms to be directed to a containment facility
(Appendix 2).
Response to information and comments from MPI
83. We considered the MPI query about the tracking of the disposal of IMOJEV, as well as the Chief Technical Officer direction in the context of this risk/benefit assessment. We note that the MPI
comments are only pertinent if IMOJEV is regulated as a new organism released with controls. As noted extensively in this document, the likelihood of IMOJEV causing adverse effects on the health of the public or any valued species, as well as the likelihood of establishing an undesirable self-sustaining population, including via a pathway of improper disposal, is highly improbable. If IMOJEV is released without controls, we do not consider that there is any need for tracking of the disposal of IMOJEV to be necessary, beyond what may be required for the disposal of live- attenuated vaccines under the Medicines Act 1981, or in the Ministry of Health’s Immunisation Handbook. Similarly, if IMOJEV is released without controls, it will not be considered a new organism for the purpose of the HSNO Act, and the CTO direction will not be required.
Legislative criteria to be considered
84. Section 38I of the HSNO Act provides for the rapid assessment of applications that seek to release qualifying organisms. A qualifying organism is, in part, a new organism that is or is contained in a medicine (as defined in section 3 of the Medicines Act 1981).
85. IMOJEV® is a medicine as it is “for administering to 1 or more human beings for a therapeutic purpose” (in accordance with section 3 of the Medicines Act 1981).
86. In order to be approved for release as a qualifying organism, section 38I(3) of the HSNO Act requires that the decision-maker be satisfied that, taking into account all the controls that will be imposed (if any), it is highly improbable that:
a) the dose and routes of administration of the medicine would have significant adverse effects on-
i) the health of the public; or ii) any valued species; and
b) the qualifying organism could form an undesirable self-sustaining population and would have significant adverse effects on-
i) the health and safety of the public; or ii) any valued species; or
iii) natural habitats; or iv) the environment.
87. In doing so, the effects of the medicine or qualifying organism in the person who receives the medicine are not to be taken into account as per section 38I(4) of the HSNO Act.
88. In the first instance, we have assessed the organism against these criteria, as set out in the following section of this report.
89. If the organism is not considered to meet these criteria, the applicant may request that the application be considered under section 38, or section 38A.
Assessment of the risk of IMOJEV® conditional release against legislative criteria
90. It is highly improbable that the dose and administration of IMOJEV® will have significant adverse effects on the health of the public or any valued species, given that:
blood service screening procedures prevent blood donations for a period of four weeks after receiving any live-attenuated vaccine
IMOJEV is not directly shed by vaccine recipients
IMOJEV does not replicate to a detectable degree in either vector animal species (ie, mosquitoes), or in known JEV-amplifying hosts (ie, swine)
reversion of IMOJEV to virulence via mutation or recombination with wild-type flaviviruses is highly unlikely, due to a high-fidelity RNA-dependent RNA polymerase, and low
recombination frequencies amongst flaviviruses in general
IMOJEV will be handled and disposed of in accordance with accepted medical practices as a prescription-only medicine administered by trained medical personnel
the known reactions to IMOJEV in humans are very mild, and severe adverse effects resulting from vaccination with IMOJEV have never been reported
The use of IMOJEV as a vaccine in New Zealand is not likely to put the cultural well-being of Māori at risk by infringing on Māori cultural beliefs and frameworks.
91. Moreover, it is highly improbable that IMOJEV® could form an undesirable self-sustaining population that would have significant adverse effects on the health and safety of the public, any valued species, natural habitats or the environment, given that:
flaviviruses cannot survive for extended periods of time outside a host/vector organism, they are not found as free virus particles in the environment, and they are sensitive to heat, desiccation, ultraviolet light, household disinfectants, and detergents.
IMOJEV does not replicate to a detectable degree in either vector animal species (ie, mosquitoes), or in known JEV-amplifying hosts (ie, swine), and thus cannot be transmitted amongst animals or humans
92. As noted by the applicant in section 6A of the application form, if the applicant receives approval from EPA for the release of IMOJEV, they intend to submit IMOJEV to Medsafe for approval and eventual sale to healthcare professionals in New Zealand. However, pending registration by Medsafe, IMOJEV could potentially be sold and distributed in New Zealand in accordance with section 29 of the Medicines Act 1981, which allows the use of a medicine prior to its registration by Medsafe at the request of a medical practitioner for the treatment of a particular patient.
93. Any medical practitioner administering IMOJEV prior to its registration by Medsafe must report the sale or supply of the medicine to the Director-General of the Ministry of Health “naming the practitioner and patient, describing the medicine, and identifying the occasion when and the place where the medicine was so sold or supplied.”5 This effectively requires the medical practitioner to treat IMOJEV as a prescription-only medicine, with an additional reporting requirement to the Ministry of Health when it is used.
94. We acknowledge that all medical practitioners administering vaccines in New Zealand are expected to do so in accordance with the standards set out in the Ministry of Health’s
Immunisation Handbook (Ministry of Health 2018), which includes requirements for the proper handling, and disposal of vaccines.
5Medicines Act 1981, section 29(2).
International obligations
95. Should this application be approved, the approval for the release of IMOJEV must be reported to the UN Convention on Biological Diversity’s Biosafety Clearing House6, as required by Article 20 of the Cartagena Protocol for Biosafety, to which New Zealand is a Party. This risk assessment, as well as the decision document, must also be provided to the. Biosafety Clearing House
Conclusion and recommendation
96. Based on the intrinsic properties of both IMOJEV, the two live-attenuated parental vaccine strains from which it is derived, as well as the general biological characteristics of flaviviruses, we consider it highly improbable that IMOJEV will establish a self-sustaining population, or have any significant adverse effects on the health and safety of the public, any valued species, natural habitats or the environment.
97. We recommend that this application to import and release IMOJEV® be approved for release from containment as a qualifying organism without controls.
98. We note, and Sanofi recognises, that an approval for a qualifying medicine granted under section 38I of the HSNO Act is not an approval to use that medicine until it has been lawfully supplied for use under the Medicines Act 1981.
6http://bch.cbd.int/
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