- RABBIT CALICIVIRUS (RCV) CLASSIFICATION, HISTORY AND ORIGINS
- EPIDEMIOLOGY OF RCV
- HOST RANGE OF THE VIRUS
- RISK OF HUMAN INFECTION
- PROBABILITY OF RCV TO MUTATE AND CONSEQUENCES OF MUTATION OF RCV
INTRODUCTION OF RABBIT CALICIVIRUS INTO NEW ZEALAND
ISSUES REPORT
Submitted by:
Robert E Shope, MD
Professor of Pathology
Department of Pathology
University of Texas Medical Branch
301 University Blvd
Galveston, TX 77555-0609, USA
Phone: 409 747-2430
facsimile: 409 747-2429
e-mail: rshope@mspo6.med.utmb.edu
RABBIT CALICIVIRUS (RCV) CLASSIFICATION, HISTORY AND ORIGINS
RCV was first recognised in China in 1984 as the cause of a lethal disease of rabbits. Any statement of its prior history is speculation. Speculation includes: a) that it existed as a lethal disease of rabbits, but in a focus where its activity went unreported; b) that it existed as a non-lethal disease or inapparent infection of rabbits; and that a successful mutation occurred so that it evolved into a lethal disease; and c) that it existed as an infection of another species, and that a successful mutation occurred so that it became infectious for rabbits and was lethal.
Reports of antibodies to RCV in sera of rabbits collected as long ago as 1975 may be correct, but should be viewed with skepticism in the absence of an isolate of a non-virulent form of RCV. Serological tests of any virus can detect non-specific reactions unless carefully
The classification of RCV is correctly described in the Import Impact Assessment (IIA) of the RCD Applicant Group. RCV is Aa single stranded positive sense RNA virus@ and its nucleotide sequence is completely established by sequences derived in several laboratories. The evolutionary trees or dendrograms of the caliciviruses have been carefully delineated and are documented in the application. One can conclude that RCV did not recently evolve from any of the other caliciviruses, with the possible exception of the virus of European brown hare syndrome (EBHS), and this latter is an unlikely source. There is a paucity of information about RCV pathogenesis (why does it attack the liver? Why does it cause haemorrhage?), mode of transmission (is it airborne? Is it carried by insects or other arthropods? Does it infect by the oral route?). The evidence that it might be contaminated with a parvovirus is weak and I believe should be discounted. The name of the virus and the name of the disease of rabbits it causes is not critical, and in my opinion unimportant to the present application.
The issue of importing and eventually releasing a strain of RCV that contains contaminating agents is valid, but can be addressed by submitting the imported material to careful laboratory analysis. The techniques are the same as apply to a vaccine virus for veterinary or human use. Such a vaccine virus is rigidly tested for adventitious agents by the manufacturer and the government control authorities before being released. The same can be done with RCV.
The IIA reports unpublished studies done at CSIRO-AAHL of mosquito and flea transmission in which these insects transmitted RCV mechanically. The virus has also been transmitted by inoculation intramuscularly, and by inhalation. I was unable to find other reports of controlled experiments on spread of RCV. There is ample anecdotal evidence, however, that the virus can spread rapidly and over long distances. Therefore, for release of virus in New Zealand, this information may not be essential prior to field use, but should certainly be studied during field use.
The European rabbit (Oryctolagus cuniculus) is the only known host of RCV. It is entirely possible that other hosts exist. Only 7 out of 48 species of rabbits and hares have been tested for susceptibility. Tests at CSIRO-AAHL were carried out by intramuscular inoculation of some 30 different animal species. In spite of considerable public criticism of the methodology of these tests, there was not convincing evidence that any of these animals were infected. The critics held: that virus might have been present early on after inoculation and was not tested for at that time, that antibody studies by competitive ELISA were imperfectly standardised, and that the route of infection was not a natural route. Each of these points has some merit, but in my opinion the laboratory inoculation studies should be interpreted within the limits of what was one, not what was not done. The conclusion holds. The experiments did not demonstrate infection of any of the animals tested. Similar experiments under different laboratory conditions, outside of Australia, also failed to show infection of non-target species. Antibody was raised in some of the exposed Australian and New Zealand animals, notably kiwi birds, but this should not be taken as proof that the animals were infected. Antibody may variably be induced by a sufficient antigenic mass without infection (ie replication of virus) occurring. I do not know the numbers of non-target species in Australia and New Zealand, but there must be at least thousands. Since it is impractical ever to test all non-target species in the laboratory, one is left with observations in nature, ie in Australia where the natural experiment is now going on. In my opinion, it would be an excellent investment to mount a systematic study in cooperation with Australian scientists of the naturally occurring vertebrate animals in selected areas where RCV is established, to search for virus and antibody. Perhaps this is already underway. Such a study could be a precondition to RCV importation.
With the information currently available to me, I conclude that upon importation of RCV, the risk of transmission of RCV to New Zealand non-target native species, including birds, is minimal.
The point has been made by scientists in the USA that caliciviruses other than RCV have a broad host range, and that the host range was established only after 20 or more years of research. This point is valid and should be considered by the decision makers. On the other hand, there are examples of RNA viruses, measles for instance, in other virus families that have an extremely restricted host range. The host range of measles (humans and higher primates) has been studied intensively for over 50 years and has not changed.
Human beings in Asia, Europe, Australia, and North America have been exposed to RCV. Some of these exposures have been of a very high level including farmers and workers who have handled sick and dead rabbits. No convincing evidence of human infection has been presented. Serological tests were done on 259 humans in a survey of potentially exposed people in Australia; an additional 6 workers at CSIRO-AAHL were seronegative. I interpret this evidence and the negative anecdotal evidence from Europe, Asia, and Mexico, to mean that the likelihood that humans have been infected is minimal.
The issue of possible contamination of food and water supply by rabbit carcasses is as much an aesthetic and public perception problem as a scientific problem. The data quoted above indicate that there is minimal risk to human health from RCV, but because of bacterial agents in putrefying carcasses, a short term effort to dispose of dead rabbits should be considered in any distribution plan for RCV.
PROBABILITY OF RCV TO MUTATE AND CONSEQUENCES OF MUTATION OF RCV
RCV is a RNA virus. RNA viruses mutate at a high frequency. These mutations may be successful or unsuccessful. Those that are successful may lead to a change in the biological properties of the virus. For instance a mutation may lead to an increase or decrease in the virus= ability to make an animal or person sick. A mutation may also lead to a change in the virus= ability to infect a given host. An unsuccessful mutation results in the virus being unable to replicate itself, it becomes a crippled virus. Although a given RNA virus mutates at a high frequency, this does not necessarily mean that the virus will evolve (change) rapidly. This only happens when the mutations are successful.
The concern expressed by expert viral evolutionists is the potential for adverse evolution. This potential is present for RCV as it is for any other RNA virus (including influenza, rabies, the common cold, and dengue). In controlled laboratory experiments, scientists can select for a change in virulence, and also for a change in host range. It is more difficult for conditions to be appropriate to select for these changes in nature. In my opinion it is not possible to assess numerically the risk of an adverse mutation of RCV. Scientists who have determined the sequence of RCV report a 1-4% change in the nucleotides over a 10 year period. Many of these changes are silent in that they do not modify the make-up of the proteins of the virus. Those nucleotide changes that resulted in changes in the protein over this period have not modified the virulence or switched the host range of RCV as far as we know. Therefore, although we cannot assign a numerical risk value, we can say on a historical basis that such a mutation is highly unlikely. It is no more or less likely than that a change will occur in any one of the hundreds of other RNA viruses that infect animals and humans in New Zealand.
I find very little scientific evidence for or against a possible effect on the human fetus and neonate. Such evidence will be difficult to accrue. I do not know how you would identify, for instance, pregnant females with high exposure levels to RCV. It would be practical, however, to expose pregnant non-human primates and look for adverse effects. Such experiments should be considered by New Zealand.
The effect of mutation on virulence of RCV for the European rabbit needs to be considered in the planning of a control programme. Natural selection of less virulent virus by repeated passage is a well described phenomenon, and can be expected with RCV. Similarly, the rabbit can be expected to undergo natural selection to resist disease caused by RCV. In addition, infection of young rabbits will lead to protective antibody rather than death, and these survivors will need to be controlled by other means. Although control of rabbits is not my field of expertise, I would agree that if RCV is to be used, integrated control including proper land management, and perhaps regular reseeding of virulent RCV, is important to counter potential changes in RCV and its target host.
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
Contact this person
