1. Abstract
2. Background
3. Matters to be considered for
decision making
4. Other General Issues
5. Comments on specific submissions
6. Conclusion
3 March, 1997
Barry O' Neil
Chief Veterinary Officer
MAF Regulatory Authority PH20-23-2
Ministry of Agriculture g:cd/nac/rcdfin
P O Box 2526
WELLINGTON
Dear Barry
APPLICATION TO IMPORT RABBIT CALICIVIRUS DISEASE INTO NEW ZEALAND: ISSUES REPORT
Further to the Ministry of Health comments dated 17 January 1997, I am writing to
provide the Ministry of Health final report of issues related to human health and other
issues related to our area of expertise that should be considered as part of the decision
making process with regard to the Application to Import Rabbit Calicivirus Disease into New Zealand.
In submissions the Ministry of Health has reviewed the major issues identified by MAF that have been raised in submissions by the submitters in relation to the application to import RCD into New Zealand. The topics of primary concern from the Ministry of Health viewpoint as identified in the "Matters" to be considered for decision making are:
5. Host range of the virus
6. Risk of human infection
The virological issues are as much centred on risk analysis and economics as on human health concerns. While the Taylor Baines and Associates report is comprehensive in its general analysis, it is superficial in technical areas. There remain unresolved issues regarding the application to import rabbit calicivirus into New Zealand. There is a lack of confidence in the quality of the scientific data.
The best parallel for the introduction of calicivirus would be between a new vaccine or drug and a similar standard of proof of non toxicity for humans ought to be established. This has not been done and the burden of proof should remain on those who wish to release the virus to provide the positive evidence rather than purely negative evidence before approval is determined.
The Ministry of Health has consulted the three New Zealand virologists who provided expert comment on earlier phases of this process.
One of the virologists consulted by the Ministry of Health was not able to provide comments due to overseas commitments within the preliminary report timeframe to enable us to include these in the preliminary report we provided on 17 January 1997. This assessment provided to the Ministry indicated the following issues which the reviewer considered significant in the analysis of submissions prepared by Taylor Baines and Associates:
(a) There is inadequate demonstration of the purity of RCD virus inoculum to be used by the applicant
(b) The mechanism of transmission of the virus requires further investigation prior to release being contemplated.
(c) There is the need to monitor the proposed release programme, but this issue is not adequately address in the application.
(d) Detailed analysis of the progress of the epidemic in Australia should be required prior to any release of the virus in New Zealand.
(e) There is the need for better documentation of the efficacy of the RCD vaccines currently available.
These have been included in this final report.
The virological issues are as much centred on risk analysis and economics as on human health concerns. We have categorised the other issues we wish to comment on further under the "matters to be considered for decision making" MAF identified as being priority issues.
3. Matters to be considered for decision making
(As identified in MAF instructions 23 December 1996)
5.2 assessment of current control measures
Does the magnitude of the rabbit problem in New Zealand justify the quantified risks and expense involved?
While this is outside the brief of the Ministry of Health to comment in an informed manner, we would note that the magnitude and extent of the problem is disputed in the documents provided, and no financial analysis of the overall cost of the rabbit problem is provided.
Undertaking an economic cost benefit analysis appears justified and there are standard techniques available for this type of work. Such an analysis could weigh, for example, the cost of retiring the affected properties from production (or adopting other different, or modified, land uses) against the costs that will be involved in acquiring a much better knowledge of the biology, transmissibility and host range for the virus. The cost of vaccination of laboratory and domestic rabbits and the monitoring of the human cohort likely to be exposed should be able to be readily quantified. Cost benefit analyses of this type are now commonplace for many other areas of human endeavour. The pastoral based agriculture sector might benefit from the application of this approach, because it would quantify, in a transparent fashion, the total costs and benefits involved in any release of RCD that is considered for approval in New Zealand.
5.4 the intended programme in which RCD virus is proposed to be used
· the technical and financial underpinning of the programme
Issues with respect to the application itself.
There is uncertainty expressed about the composition of the "expert committees" and which committee actually was recommending what. The specific membership of the expert committees and the specific recommendations coming from that committee should be clearly documented.
There is uncertainty about conflict of interest in that the proposer and the assessor seem to overlap.
Issues with respect to the epidemic in Australia.
Comments to the Ministry of Health questioned "Is there ongoing research and evaluation of the spread and behaviour of the virus in Australia?" Has New Zealand got an active programme along these lines monitoring developments in Australia? If not why not? What data precisely is being sought and by whom?
This would seem important to predict the behaviour of the virus in New Zealand and the likelihood that any programme would achieve it's aim.
The seeming haste of the decision maker
There are concerns expressed about the perceived haste. The proposal and application to introduce RCV into NZ has been brought forward because of the Australian escape of the virus.
This is not scientifically logical and is explained on the basis that the likelihood of inadvertent/ mischievous importation into NZ is increased. The converse view would be that this is an argument for delaying importation, because
a) the escape emphasises the uncertainty about this viruses' behaviour
b) the epidemic in Australia provides unexpected opportunity for extensive "field study" of the virus If there were a genuine desire to establish as much information and safety data as possible the Australian epidemic should be energetically exploited for this purpose.
Detailed analysis of the progress of the epidemic in Australia should be required prior to any release of the virus in New Zealand
There are few details provided of the progress of the epidemic in Australia. Australia is a very large continental land mass with a wide range of climatic and environmental conditions that span many of those found in New Zealand. The Australian experience should provide a reasonable basis for assessing whether the release of virus in New Zealand is likely to be effective. The accidental release in Australia also provides the opportunity for many of the contentious points raised in the public submissions to be investigated - and in most cases resolved.
(Neither the application itself, nor the summary of submissions recognises this important point.)
There is the need to monitor the proposed release programme, but this issue is not adequately addressed in the application.
RCD is a relatively newly discovered virus and our knowledge of its biology and replicative mechanisms is fragmented at best. It is therefore important that measures be put in place to monitor any effects exposure might create should a release be contemplated. The application is seriously deficient in this area in that Table 5.3 at page 98 does not propose any monitoring of those exposed occupationally and provides only a very vague outline of the monitoring that would be carried out on the spread, mutation and transmissibility of RCD in rabbits.
Given what appears to be widespread concern amongst the public, at a minimum it is necessary to identify a cohort of humans who can be effectively monitored prior to and after exposure. There would also be the need to monitor livestock and other indigenous and native animals and to monitor the spread of the virus in the rabbit population itself. The absence of details of such a programme is a major deficiency of the application and such a monitoring programme should be a requirement of any approval given for release.
Details of the reagents to be used for the virus or antibody detection are required and details of the sensitivities of the assays employed should be provided so that a proper scientific assessment can be made of the protocols developed.
Informing the public of any programme
The Ministry of Health in the earlier reviews stressed the importance of informing the public about the details of any release programme. This includes information on the location and timing of any release with information for the public. The locations need to be clearly identified, the public need to know what they should do about rabbit carcases, hunting and consuming rabbits in the area and other areas.
This information is essential and its demand is clear from the TBK spraying programme in Auckland, as MAF will well be aware.
Liability
The matter of potential liability of the Crown is raised by some submitters. It would be a wise precaution for the Crown to have prior knowledge of the extent of the cross reactivity (if any) between antibodies raised against RCD and those primed by those human caliciviruses that are currently known to be in circulation in New Zealand. In the absence of this type of knowledge, it would be difficult to identify clearly any replication of RCD that might occur in humans.
5.5 the effects, positive and negative, of RCD virus on:
Effects on non target species
There is a lack of confidence in the quality of the scientific investigation into the susceptibility of other species to infection with RCV. Various concerns regarding this data have not been resolved, including how much virus (in terms of virus particles and therefore virus protein load ) was present in the challenge doses; what determined the duration of the observations of the challenged animals, the quality of the antibody testing (no dilution series, no controls ie no animals which had been deliberately "immunised" to check capability for response); the apparent response in kiwis occurred predominantly after the observation time for which other species were scrutinised, raising the possibility that there might have been response in other species if the observation time had been similarly extended.
The post mortem results on the kiwi are inconclusive. Although the researchers did not demonstrate RCV in any tissue they did not explain the likely cause of the abnormal pathology and histology. This suggests further investigation is needed.
The health and social well being of people
What is the magnitude of the risk to human health ? The risk is likely to be very low, but the risk is unable to be quantified at present given the lack of knowledge of the biology of transmission (even for the rabbit) and the absence of any controlled epidemiological study of an exposed human cohort.
Our reviewers asked: Is this information currently being gathered in Australia ? If not, why not ?
(Submission #376) questions the validity of the Australian epidemiological study, the history of human illness and the validity of their serology. The Australian investigators have advised the Ministry of Health they consider the negative results from all the human sera tested by both the direct and competitive RCV EIA assays were valid, although they do agree that they had no positive human serum control.
The concern is whether or not the rabbit calicivirus could infect humans and, more particularly, whether there are particular groups of humans who are at increased risk. From reading the information provided there has been some study done to examine the possibility of infection to humans.
This shows:
Humans who have been working closely with rabbits do not show seroconversion.
There has not been any documented clinical illness in humans associated with outbreaks in rabbits or use of the virus, although there have been some anecdotal reports, particularly from the UK, of humans being infected with the virus. These have not been verified medically with fairly extensive testing.
There has been the study in Australia of people exposed occupationally to the rabbit virus. 259 people were tested and did not show any seroconversion or increase in clinical illness. However it is important to note the clinical history was gathered retrospectively.
See later comments on this study.
There has been one challenge study with humans eating cooked rabbits which have been infected with the rabbit calicivirus. Some staff were tested serologically and one person who slept in the same location infected rabbits responded serologically. The antibody level was low and disappeared very quickly. It is unclear from this whether or not this person was infected or whether antigen alone produced some serological response.
This evidence is reassuring; however it is not conclusive.
It is important to note there is a broad range of human hosts with a whole spectrum of immune competence. This ranges from neonates and children, through patients who are immunosuppressed from HIV and chemotherapy for malignancies. Many of these patients may be much more susceptible to infection than immunologically competent workers exposed to the virus.
Special risks to the foetus and neonate
There is no information either in the application or literature provided to confirm the safety of the virus in these special groups. This is important both regarding the risk of teratogenicity and of foetal or perinatal infection.
Domestic rabbits
There is the need for better documentation of the efficacy of the RCD vaccines currently available
Mention is made in the application of the fact that there are a number of RCD vaccines available that are licensed for use in animals. There is a need for full details to be made available of the efficacy of the vaccines available for rabbits.
The biomedical research community depends heavily on the use of rabbits for raising antibodies and there are important areas of human clinical diagnostics that are dependent on the ability to raise antisera in rabbits. The development of the in-bred laboratory white rabbit is, in fact, a very important contribution that this country has made to international medical research. The safety of the colonies currently established needs to be assessed. Yet there is no data in the application that enables the economic affect to be met and the only information presented is anecdotal.
Vaccine issues - safety
There are a number of RCV vaccines available which are solely for the immunisation of rabbits. Two vaccines, "Cylap-HVD'-Cyanamid, Spain and one other are registered in New Zealand. The RCV vaccine and its accidental use in humans was not considered by the Australian group.
In the report of the Australian epidemiological study, a letter was sent to laboratories world-wide, although seeking anecdotal evidence, they did not specifically enquire of any human needlestick injuries with the RCD vaccine nor consider this line of inquiry. They received one response from a RCD vaccine manufacturer in Spain regarding virus exposure (Australian Report Attachment 4 ).
5.7 characteristics of the virus itself and its method of production and dispersion
Host range/ RCD Species switching
The following raise concerns over the future behaviour of the virus:
· Unknown/ unknowable natural history of rabbit calicivirus. Available evidence suggests that in time this virus can and will mutate.
· The rapid emergence of RCD approximately 12 years ago implies that there was a change in this virus giving rise to its dramatically lethal capabilities in rabbits.
· The known propensity for mutation of RNA viruses.
It is not possible to forecast the evolution of this virus. Any prediction must be based on imperfect data and analysis of probabilities using other viruses as models. Almost any conceivable change will be detrimental, ranging from a negative change in virulence ie the virus may cease to kill rabbits; to increases in virulence such that it may infect /damage or kill other species of animals; it may infect humans, it may infect a susceptible subset of humans viz immunocompromised.
Caliciviruses are RNA viruses and as such are likely to show considerable mutability. In addition, of the five recognised calicivirus groups, the rabbit calicivirus group is the only group to date which has a limited host range. It makes sense to accept that there is a potential risk of cross species infection occurring with RCD.
It is now apparent that variants of RCD virus are being identified. An Italian group (Cappuci, Fusi, Lavazza et al. 1996 J Virol, 70:12) - has identified a "new rabbit calicivirus" which shows 90% amino acid homology in the VP60 gene of RHDV and may be the progenitor of RHDV and EBHSV. This variant causes seroconversion of infected rabbits but not disease. Certainly Donald Burke, while at the ANZMS Meeting in Christchurch last October, when reviewing RNA virus mutability, pointed out that little was known about the Caliciviruses. I believe he will present a reasoned evaluation of all available data on RCD their mutability and the possibility of infection of humans or other species in his submission.
There is inadequate demonstration of the purity of RCD virus inoculum to be used by the applicant group
The virus inoculum was obtained as a series of ampoules from an institute in Czechoslovakia. The applicant's document ( at page 184) states that some of these ampoules were pooled and that this material was then amplified in a rabbit derived from a barrier- maintained (but not SPF) colony. Presumably subsequent passages took place in additional rabbits. As far as can be determined from the application, there was no attempt made to prepare a stock derived from a single (or very few) virus particle(s). It is standard virological practice to do this when preparing an infectious stock. This presents difficulty for RHVD because the virus cannot yet be plaque purified. However, terminal dilution is an alternative approach that would be feasible in this situation, particularly should a cell line be available. This could be coupled with RT/PCR to provide a sensitive assay for virus replication.
One of our reviewers stated that it is not acceptable to release a virus stock that is merely a pool of infectious material derived from high multiplicity passage because there is too greater level of uncertainty concerning the initial inoculum and the possible presence of contaminants.
Better evidence of the use of standard virological procedures needs to be provided by the applicant and the source of the rabbits that the applicant proposes to use for amplification (and the SPF status of these animals) needs to be better documented.
RCD Inoculin purity: comments in submissions;
(Submission #1000) discusses this issue in some depth, and several other submissions identified inoculum purity as an issue.
The arguments are logical and of course can't be discounted as the RCD virus cannot yet be cultured in cell cultures, however the Australians' laboratory experience provides evidence suggestive that they are dealing with a single agent. The name change by the Australians from RHDV to RCV could possibly be challenged legally.
The mechanism of transmission of the virus requires further investigation prior to release being contemplated
An ability to assess any risks that might be involved in release of the virus requires prior knowledge of the mechanisms of transmission of the virus and whether any vector might be involved. Reference is made in the applicant's document to a lack of knowledge in this area. Comment is made that the AAHL researchers have achieved transmission with rabbit fleas and mosquitos. It is not possible to assess adequately the likelihood of a potential to human health in the absence of a much better knowledge of the natural method of transmission of RCD. Given the availability of the rabbit as the target species and the experimental model, these experiments should be relatively straight forward and should be undertaken without delay.
We note that there is reference in the application to recorded instances of the transmission of the virus for long distances over water. Given this prior knowledge, it seems questionable that a "quarantine" release was undertaken in Australia on Wardang Island so close to the mainland.
If a contained field trial was considered to be necessary in Australia, why is it not considered to be necessary in New Zealand ? If such a study is considered unnecessary because equivalent data can be gathered from the epidemic in Australia, should it not be a requirement that this data be gathered and submitted as part of the application ?
There is a lack of scientific data. Specifically the virus escaped at least twice whilst being studied under supposedly secure scientific conditions. The precise mechanism of spread is still not known. It is not known how the epidemic is maintained. The basis for non-lethality in young rabbits is not known.
Other mechanisms of transmission of RCD
The only new information our reviewers commented on relates to the experimental feeding of foxes with RCD infected rabbit livers and the demonstration of subsequent virus transmission to rabbits via fox faeces.
It is clear from the application and from the summary of submissions that there is widespread interest and concern relating to the release of RCD. It is therefore important that the scientific data available on which the decision is based be as comprehensive as possible. Compelling evidence on the inadequacy of information concerning transmission is provided by the fact that a "contained field trial" went badly wrong and the virus escaped.
The question whether or not the virus could jump hosts is obviously a complex one. Recent experience with CJD (mad cow disease) and the likelihood that some leptospiral strains are changing hosts, suggests that we should be cautious before assuming that viruses or other pathogens cannot infect new species.
It therefore becomes a question of what standard of proof is required to justify introducing a new species into New Zealand. A reviewer stated that his view would be that there has been inadequate experimentation done to justify this. If a parallel is drawn with the introduction of a new drug, it would require animal challenge studies, possibly primate studies, and human volunteer studies to be conducted in a prospective manner with well researched techniques. There is no evidence of this having been done here.
It is also important to realise that there is a difference in disease between a foetus, neonate and a mature adult. It may well be there are expressions of disease which are not contemplated at this stage. Indeed neonates and adults often respond quite differently to viruses. This includes not only the expression of the disease but occasionally susceptibility as well. Further, there are a very significant number of adults who are immunoocompromised including patients with AIDS and chemotherapy for cancer. It is not clear what effect it would have if same humans are susceptible.
In short, my own feeling is that the best parallel for introduction of this would be between a new vaccine or drug and a similar standard of proof of non toxicity for humans ought to be established. This has not been done and the burden of proof is an those who wish to release the virus to provide the positive evidence rather than purely negative evidence.
The Australian Report of the Rabbit Calicivirus Human Health Report Group - Rabbit Calicivirus (RCV) serological Data
We wish to make the following comments on the Australian report:
It is unusual that none of the assay data for the 1013 baseline sera and 259 test sera are included in the report. The Ministry of Health therefore sought details of the serological results from the Australian researchers. This was sent to the reviewers for comment.
It was noted that the assay data for the 259 test sera had not been grouped in any way for analysis, suggesting that the authors underlying hypothesis was that no antibody would be detected, hence there was no need to analyse the data more extensively. Grouping of the data into RCD exposure risk categories and inclusion into the report would seem logical.
Competitive EIA assay for RCV antibody in humans
The design of this assay appears standard - antigen coated plate, incubated first with test serum and subsequently challenged with monoclonal antibody, subsequently monoclonal antibody attachment measured by enzyme tagged antisera and substrate. The absence of a control positive human serum is unfortunate but perhaps unavoidable at the moment. Certainly positive and negative rabbit antisera were used as controls so that the assay was broadened beyond the mouse. However, it has to be conceded that the assay is not at this point able to be controlled for ability to detect human reactivitiy - absence of detectable "false positive" reactivity does not prove ability to detect true positive reactivity.
The competitive EIA assay was carried out first on the 259 test sera in duplicate as a screening assay and the results presented as percentage inhibition. The cut off level used was 50% although 30% was used for rabbit (Collins et al, 1995) and other species testing, and no explanation is given for the choice of this cut off level. The baseline sera data should have been presented so that the logic of the choice of cut off levels could be followed.
The competitive EIA results ranged from -5 to 28% suggesting that the competitive EIA is a sensitive test, however, 15 samples have been repeatedly tested, the results of which vary greatly, casting doubts on the accuracy of any value using this assay.
The indirect EIA was performed as a supplementary assay. The negative cut off for the assay was 0.3 and positive cut off 0.5 which was not stated in the Materials and Methods of the report and no baseline data was included. Results ranged from OD readings of 0.01 to 0.16 suggesting that this test is of lower sensitivity than the competitive EIA.
No positive serum is included in the assays. The report states that "No positive human sera were available for testing and therefore the sensitivity of the assay in humans could not be assessed". Without the presence of adequate controls we cannot be certain what both EIA assays are measuring.
5. Comments on specific submissions
Both submissions 376 and 1000 both identify serious flaws with the human survey and question the reliability of the results. They also question the design of and the results of the human illness survey.
Submission 376 - Professor Alvin Smith
Submission 376 questions the validity of the Australian human illness and the validity of their serology. The Australian investigators have advised the Ministry of Health they consider the negative results from all the human sera tested by both the direct and competitive RCY EIA assays were valid, although they do agree that they had no positive human serum control.
Submission 1000 - Dr Neil Cherry
The Ministry of Health was asked by the Ministry of Agriculture to comment specifically on the comments in submission 1000 on the Australian study. Our reviewers commented:
Submission 1000 discusses the validity of the study in some depth. The arguments are logical and of course can't be discounted as the RCD virus cannot yet be cultured in cell cultures, however the Australians' laboratory explained provides evidence suggesting that they are dealing with a single agent. The name change by the Australians from RHDV to RCV could possibly be challenged legally.
Submission 1000 has carried out an analysis which "shows significant increase in Diarrhoea/gastrointestinal illness and fever/flu-like symptoms, neurological symptoms and overall bouts of illness". This is in contrast to the Australian report concluding that "no significant association between exposure to RCV and subsequent bouts of illness could be demonstrated".
This submission on the Application to Import Rabbit Haemorrhagic Disease (RHD) Virus, questions the proof relating to rabbit calicivirus being the causal agent of RHD. The virus is central to the application and by bringing its causual role into question, it also brings into the question the validity of many of the claims made in the application.
Submission 1000 is a social epidemiologist and although is not a biological scientist, is skilled in the evaluation of scientific reason. The attention to detail is well illustrated by researching the literature leading to the claim that "although rabbit haemorrhagic disease (RHDV) was initially characterised as a picornavirus or as a parvovirus, it is now proved to be a calicivirus" (Beringer and Hosue, 1995) and showing that it is an unjustified claim.
Koch's Postulates are yet to be fulfilled with RCV as this virus has not been grown as pure culture outside the rabbit, so the theoretical possibility that another infectious agent is also present in RHD must exist. To elucidate this possibility and at least clear up the parvovirus debate, either rabbit inoculum limiting dilution experiments or experiments to detect parovirus DNA could be attempted. These or similar test have not been attempted to our knowledge during the Australian investigations. It also suggests that the term which should still be used to describe the agent of RHD is RHDV, which is the name of the organ material (VIR-CAPM V351 strain of rabbit haemorrhagic disease virus) initially imported into Australia from Czechoslovakia.
Following this line of argument, all viral rabbit inocula used in the Australian experiments as well as viral antigen used for the competitive EIA and indirect EIA serological assays could theoretically contain RCV plus additional antigens form one or more agents. Hence Dr Cherry's claim that "the failure of the AAHL to properly carry out the non target species testing by allowing for the complex nature of RHVD, places the whole credibility of that programme in doubt and invalidates many of the claims made in The Application." (#1000, page 20).
Submission 1000 also addresses the Australian Rabbit Calicivirus Human Health Study Group 1996(RCHHSG) report. He questions the validity of the human serological data by:
1. Pointing out that no serological test results were presented other than a statement.
2. Suggested that the arbitrary raising of the competitive EIA threshold to 50% would exclude positive results.
3. Noted that no positive (human) sera were available for assay standardisation.
Analysis of the clinical signs section of the RCHHSG report is also questioned. His case/control presentation of symptom incidence in the non exposed and exposed groups, taking onto account the different exposure periods simply represents the data in table 3 (Page 21), demonstrating statistically significant increases in Diarrhoea/gastrointestinal illness and Fever/flu-like symptoms, Neurological symptoms, and Total Bouts of Illness. He then questions the statement made on page 29 in the conclusions report that "no significant association between exposure to RCV and subsequent bouts of illness could be demonstrated." (See Ministry of Health statistician comments below).
The reviewing virologist noted that in the final analysis, the clinical data must be treated with caution as the study was designed and carried out with extremely tight time restraints and no laboratory diagnosis of illness episodes was attempted other than the collection of single sera from some of the study subjects for the serosurvey.
Another of the virologists consulted by the Ministry of Health commented on submission 1000:
It is agreed/conceded that the calicivirus cannot at this stage be plaque purified in tissue culture and therefore the purity of the liver derived material remains debatable. However, submission 1000 protests that the antibody assays were specifically designed to detect response to calicivirus and would miss other components. However, the assays used liver-derived material as antigen, so in fact any contaminant virus could/would indeed have been present also in the coating antigen and could therefore contribute to detection of reactivity. So, although this consideration does not clarify whether the reactivity measured (in eg rabbits) was to calicivirus, to parvovirus or a mixture of the two, nevertheless it measures reactivity (or lack of) to the liver derived material before inoculation (pre-bleed) as compared to reactivity to liver derived material after inoculation (of liver-derived material).
The prolonged discussion on the possible parvovirus contribution refers apparently to earlier Chinese work. It is not too unusual for initial evaluation of a virus to be revised in light of subsequent data and further characterisation.
The challenge dose of infectious is virus indeed a cause for concern. It does not appear to be known how many virus particles are required to infect a rabbit. With a highly susceptible species, this may be a low number of particles and therefore the LD50 may be not be a significant challenge to a less susceptible species. Nor was the timing and extent of the possible antibody response in the challenged species established before live virus challenge (By eg deliberate immunisation of representative individuals). So the submission 1000 concerns that possible infection of other species is not excluded, is probably valid.
As with other submissions, submission 1000 registers concern about possible future evaluation of the virus/viruses. This is unknowable, however could undoubtedly be better predicted after careful study of the Australian experience over the next few years.
The Ministry of Health asked a statistician in the Public Health Group for comment on the reanalysis by submission 1000. He commented:
"My understanding of the study is:
· A sample of potentially exposed and unexposed was chosen
· Exposure to the virus was estimated, including time of first exposure
· Symptons over the previous year were recorded
The report states "The findings may be affected by the periods for which the groups were under observation. While the data for the unexposed group covers the full 13 month period, for the exposed group the average period of observation after first exposure to RCV was only 6.6 months."
This is used by submission 1000, but his revised analysis may be in error. Submission 1000 suggests that we consider person-years of exposure based on time since first exposure (equivalent to a cohort analysis), or total time for unexposed. However the outcomes (illness) are reported for the previous year for all individuals, rather than time since first exposure. In essence, submission 1000 has assumed that all illnesses for exposed are since exposure, so that it is not surprising he found significant results. Ideally, an analysis of illness since exposure would be the preferred analysis.
The design of the study is such that a null result would be expected given the number of biases. Retrospective recall of illness is difficult to collect and subject to error apart from other limitations of carrying out such a study in a short timeframe."
The Ministry of Health has identified that there remain unresolved issues regarding the application to import rabbit calicivirus into New Zealand. We consider these should be addressed by the decision maker before any contemplation of the release of rabbit calicivirus can be given any serious consideration.
While the introduction of the rabbit calicivirus appears to pose a low risk to human health, it is unable to be quantified at present given the lack of knowledge of the biology of transmission. There is a lack of confidence in the quality of the scientific data.
Caliciviruses are RNA viruses and as such are likely to show considerable mutability. In addition to the five recognised calicivirus groups, the rabbit calicivirus group is the only group to date which has a limited host range. There remains a possibility that there is a potential risk of cross species infection occurring with RCD.
The decision maker needs to address the following issues of concern:
1. There is inconclusive evidence due to the unknown /unknowable history of the characteristics of the rabbit calicivirus and its method of production and dispersion to suggest that the host range will not be limited to the rabbit and that in time the virus will not cross species.
2. There is inadequate demonstration of the purity of RCD virus inoculum to be used by the applicant group.
3. The mechanisms of transmission of the virus requires further investigation prior to release being contemplated.
4. A detailed analysis of the progress of the epidemic in Australia should be required prior to the release of the virus in New Zealand.
5. The public needs to be informed about the details of any release programme that may eventuate.
6. There is the need to monitor the proposed release of the proposed programme that may eventuate. Proposed evaluation needs to be explained before release.
Contact for Enquiries
Manager, Strategic Science Team
MAF Biosecurity New Zealand
PO Box 2526
Wellington
NEW ZEALAND
Phone: +64 4 894 0115
Fax: +64 4 894 0731
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