ABSTRACT
My areas of expertise
Comment on the Process
General Comments
Summary of
new (recently emerged) virus diseases around the world
Terminology and technology limitations
Summary of the
"evolvability" and emergence of RNA viruses
Comment
on: The effectiveness and suitability of RCD virus as a biocontrol agent in New Zealand
Comment on: Details of
how RCD virus will be deployed
Comment
on: The effects, positive and negative, of RCD virus on non-target species and human
health
Comment
on: The likely success and costs of measures which can be employed to ameliorate negative
impacts on domestic and laboratory rabbits.
Comment
on: Characteristics of the virus itself including host range and epidemiology.
Concluding comments
RECENT VIRAL
PANDEMICS (Ro>>1) IN HUMAN POPULATIONS
RECENT
LOCALLIZED (Ro<1) NEW VIRAL EPIDEMICS IN HUMAN POPULATIONS
SOME IMPORTANT
RECENT VIRAL EPIDEMICS IN ANIMAL POPULATIONS*
RNA
VIRUSES OF VERTEBRATES: NATURAL OR IN VIVO GENERATION OF NOVEL RECOMBINANTS
REFERENCES
ISSUES REPORT on the APPLICATION TO IMPORT RABBIT CALICIVIRUS DISEASE VIRUS INTO NEW ZEALAND
Donald S. Burke, M.D., Washington D.C., 28 February 1997
In the past 30 years at least seven new viruses have caused world-wideepidemics among humans, six new viruses have caused localizedoutbreaks among humans, and seven new viruses have caused localized orglobal epidemics among various animal species. Nineteen of these 20"new" epidemic viruses are RNA viruses that are thought to have arisenthrough inter-species transmission into a new host species or by mutationor recombination / reassortment of the genome of a previously relativelybenign virus. RNA viruses are inherently highly "evolvable" due to theirhigh mutation rate. Although there is no evidence that the RabbitCalicivirus Disease Virus - an RNA virus - can replicate in any host otherthan the European rabbit Oryctolagus cuniculus, understanding of howRCD virus is transmitted in nature is still incomplete. The risk of anadverse epidemiological consequence of the intentional release of RCDvirus is low but it is not zero.
ISSUES REPORT:
APPLICATION TO IMPORT RCD INTO NEW ZEALAND
Donald S. Burke, M.D.
28 February 1997
Dr. Barry O'Neil
Chief Veterinary Officer
Ministry of Agriculture of New Zealand
MAF Regulatory Authority
ASB Bank House
101-103 The Terrace
PO Box 2526
Wellington, New Zealand
Phone (64-4) 894 0100
Fax (64-4) 474 4133
Dear Dr. O'Neil,
I have completed my review of the materials provided by your offices on theapplication to import RCD into New Zealand, and offer the following
My professional interests center on the epidemiology, pathogenesis, and vaccinedevelopment for RNA viruses, especially the flaviviruses and HIV. I do not have expertise specifically in caliciviruses, but I instead bring a more general expertise inRNA virus molecular epidemiology. I have served as an expert consultant to the WHOon flaviviruses, HIV, and other RNA viruses on numerous occasions, and I am theimmediate past-president of the American Society of Tropical Medicine and Hygiene.
Dr. Lance Jennings, Director of Virology at the Christchurch Public Health Laboratory,heard my plenary lecture on the global molecular epidemiology of HIV at the AmericanSociety of Virology meeting in the USA in 1995 and invited me to deliver a similarplenary lecture at the Australia/New Zealand Society of Microbiology meting inChristchurch this past fall. At this meeting I also presented a review of the currentstate of knowledge of the relationship between viral evolution and emergence of newdiseases. Dr. Jennings thought that the information I presented in this review mightbe useful in your deliberations on RCD and recommended me as a consultant.
I received and reviewed the following items in preparing this report:
The Import Impact Assessment and Application, with 18 accompanying appendices
The Disease Risk Assessment for Rabbit Calicivirus
The Proposal for the importation of the rabbit calicivirus diseases virus (RCD virus) as a biocontrol agent
The Processing an RCD Application - Summary
Copies of reports from two rounds of internal NZ governmental review
Copies of all of submitted comments from the public, categorized as dealing with "virus" issues ( N approx 400) or "health" issues (N approx 100).
An Analysis of Submissions on the Importation Impact Assessment for the RCD Virus: A report by Taylor Baines & Associates prepared for the Chief Veterinary Officer, MAF.
I am impressed with your efforts to provide all available information, both supportiveand opposed, for my review. Included in the public submissions you provided to mewere several which are highly critical of your offices. Regardless of your final decision, Iam satisfied that you have made a genuine effort to solicit and evaluate all possibleperspectives.
You have requested that I comment on issues related to the biology and epidemiology of RCD, including (a) the effectiveness and suitability of RCD virus as a biocontrol agent in New Zealand and the details of the intended program; (b) the effects, positive and negative of RCD virus; (c) measures which can be employed to ameliorate negative impacts; and (d) characteristics of the virus itself and its method of production and dispersion.
I do not think that is possible for a scientist to take an absolutist position on whether RCD virus should be imported into New Zealand and deployed as a biocontrol agent. There are simply too many variables to allow either a projection of unqualified success or a prediction of certain calamity. The benefits may be great but they are uncertain, and the risks may be small but they are finite. Value judgements will be important in arriving at a decision. I understand that my appropriate role is to provide advice that will help you weigh the data.
Summary of new (recently emerged) virus diseases around the world
Recent viral major epidemics (pandemics) in human populations: In the past 30 years there have been at least seven "new" viruses that have caused global epidemics involving millions of humans. These are shown in Table I (seleted references are also provided for this and other tables). All of these recent global pandemics have been of RNA viruses with an ability to recombine or reassort genetic material between viruses. For the influenza A viruses (H3N2 and H1NI) there is solid evidence that the new epidemic strains arise through mixing of genes from animal influenza viruses with genes from pre-existent human influenza virus. For the retroviruses (HIV and HTLV) there is suggestive evidence that these viruses crossed the species barrier from non- human primates into humans. The recent pandemic picornaviridae (enterovirus 70, enterovirus 71, and Coxsackie A24/variant) probably derived directly from pre- existent human viruses, but a genetic contribution from an animal picornavirus gene pool can not be ruled out.
Recent localized new viral epidemics in human populations: Outbreaks and epidemics of new viruses in humans are continually being observed around the world. Some very recent examples are shown in Table II; all are RNA viruses. As compared to the viruses causing global pandemics (above), these viruses show no or only a limited capacity for human to human transmission. For four of the six viruses shown in Table II, humans are known to become infected directly with a virus that is native to animals. In one case (Borna) an animal reservoir is suspected, and one (Ebola) the reservoir is unknown.
Recent new viral epidemics in animal populations: New viral epidemics are also continually being observed around the world in animal populations. Table III shows some very recent examples. All but one of these recent epidemic viruses are RNA viruses; the canine parvovirus is the only example of a new epidemic animal DNA virus. Four of these viruses are thought to have arisen through inter-species transfer (canine parvovirus, lion paramyxovirus, dolphin paramyxovirus, equine paramyxovirus) while the other two are thought to have arisen through mutation of a virus already endemic in the species (pig coronavirus, chicken influenza virus).
Collectively these new epidemics demonstrate the ability of viruses in many RNA virus families to cross species barriers where they can cause disease and become serially transmitted within the new host species.
Published observations on the close genetic relationship of swine and sea lion caliciviruses, and successful transmission of these viruses to several other vertebrate species, demonstrates that at least some caliciviruses have the property of cross- species transmissibility.
Terminology and technology limitations
For a virus to cross from one species to cause an epidemic in another, two thresholds must be crossed:
Infection: the virus infects one individual of the new host species
Transmission: the virus is transmitted from one individual of the new host species to infect another individual.
Neither of these crucial thresholds is an easily defined, all-or-nothing event. Simple variables such as dose and route of inoculation and host age can have a huge effect on whether a virus inoculum will cause infection in the new host species. Furthermore, the method used to detect infection may not be sufficiently sensitive to measure infections that are abortive or low-level but nonetheless genuine "infections." The term "productive infection" is sometimes used in an attempt to differentiate between low- level and high-level infections, but this term simply reflects the technology employed to detect "infection". It follows logically that if the definition of "infection" is imprecise and technology dependent, then the definition of "transmission" - infection of one individual by another - is also imprecise.
It is my impression that there are no known RNA viruses for which there is proven to be a true single host species specificity. Even for relatively host species-specific viruses, low level infections occur when the virus is inoculated at high levels into a different but related host species. Virtually all human RNA virus pathogens can infect chimpanzees and other primates. Most known positive strand RNA viruses like the picornaviridae, flaviviridae, alphaviridae, and coronaviridae can even be passed successively through mice by serial tissue homogenate transfers.
Just as RNA virus infection is not usually species specific, RNA virus transmission can and probably does occur under epidemiologic circumstances where virus from one species comes into contact with the tissues of another related host species. Data are lacking on the frequency with which incidental inter-species contact leads to virus transmission. However, given the number of epidemics and outbreaks listed in Tables I, II, and III above, it seems that such transmission are not rare events.
Summary of the "evolvability" and emergence of RNA viruses
It is widely appreciated that RNA viruses in general have a high replication error rate, about 1 in 104 nucleotides, or since most RNA viruses like caliciviruses are about 104 nucleotides long, on the order of one misincorporation per genome. Restated, like snowflakes, every new RNA virus genome is unique. This high mutability confers a high "evolvability" and adaptability.
RNA viruses also can evolve by exchange of genetic material between related virus types through reassortment (for segmented genomes) or recombination (for unsegmented genomes). While in vitro RNA viral reassortment and recombination have been well described in laboratory studies for some time, it is only recently that these phenomenon have been recognized to occur in vivo in dually-infected animals. Table IV presents a summary of publications documenting natural or in vivo generation of new reassortant / recombinant viruses between two parental strains. For unsegmented plus strand RNA viruses recombination is thought to occur as a strand "copy-choice" switch during negative strand synthesis.
It can be difficult to prove that a given virus isolated from nature is a genetic recombinant. To do so requires that both parent viruses must already have been isolated and sequenced, so that the putative recombinant can be shown to be constructed from sequences strings unique to each parent. The virus families that have been most dangerous in causing global pandemics among humans (the picornaviridae, retroviridae, and myxoviridae) all show ready reassortment or recombination in vitro and in vivo, suggesting that recombination/reassortment is an "evolvability" feature that facilitates the emergence of new virus epidemics.
I have not aware of any published studies that address recombination between caliciviruses.
Comment on: The effectiveness and suitability of RCD virus as a biocontrol agent in New Zealand
I do have any expertise in pest control using biological microbial agents. However, I suggest that any models developed for the release of RCD should address three kinds of rabbit resistance to the lethal effects of RCD:
Resistance factor #1: age insusceptibility
Resistance factor #2: acquired immunity [eg antibodies]
Resistance factor #3: genetic immunity
Based on the information provided regarding the inherent insusceptibility (factor #1) and subsequent life-long immunity of these infected young rabbits to RCD virus (factor #2), it is possible that the effects of RCD release on rabbit populations may be only very transient. Annual releases may be necessary to achieve a sustained effect to overcome the combined effects of factor #1 and factor #2.
Resistance factor #3, genetic immunity, may not be a dominant effect early in a RCD virus release program, but over a few years it is likely that genetically resistant rabbits will arise through natural selection. This pattern (emergence of genetically resistant rabbits) was observed in the Australian myxomatosis biocontrol program.
Comment on: Details of how RCD virus will be deployed
My major comment on the plans for RCD virus release deals with the uncertainty about how the virus is spread in nature. The observations that fleas and mosquitoes can transmit RCD virus under laboratory conditions raises a whole host of unanswered questions about the natural epidemiology of RCD virus. The rapid skip spreading pattern of RCD virus in southeastern along prevailing wind patterns supports the hypothesis that RCD may be vector-borne. What are these arthropod vectors of RCD virus in Australia and New Zealand? What is the host range (feeding preference) of these biting arthropods? Is it certain that the RCD virus does not replicate and amplify in the tissues of these arthropod vectors? This question may not be as far-fetched as it sounds: although there are no known arthropod-borne caliciviruses, at least one insect virus is reported to have a genome structure typical of caliciviruses [ Koonin EV, Gorbalenya A. An insect picornavirus may have a genome organization similar to that of caliciviruses. FEBS Lett 1992; 297:81-6].
Comment on: The effects, positive and negative, of RCD virus on non-target species and human health
I am impressed that a substantial effort has been made to determine if RCD virus can replicate in vertebrate hosts other than European rabbits, and that results have been uniformly negative in the tests as performed. However, as I commented above ("Terminology and technology limitations") proof of lack of replication - proof of a negative - can be very difficult. Based on my own experience with other RNA virus families, and based on reports of broad host ranges for other caliciviruses, I would be surprised if RCD virus did not replicate - at least to some extent - in species other than Oryctolagus cuniculus. I would expect that RCD virus replication could be most easily demonstrated in other related lagomorphs, and I am not ready to dismiss the published data suggesting RCD virus replication in hares and EBHS virus replication in rabbits.
I have read and considered the critiques of the antibody test results offered in some of the public submitted comments, and I must agree that I find it impossible to be sure if the weak positive serologic responses in some challenged vertebrate species resulted simply from antigenic stimulation (from RCD virus antigens in the challenge inoculum) or if they represent an immune response to a replicating virus. The vertebrates showing such responses included mice and kiwis. I am impressed that PCR assays and rabbit bioassays failed to detect direct evidence of RCD virus, which is reasonable evidence that infection was either transient, very low level, or completely absent. However, even these more rigorous assays do not constitute proof of lack of replication.
Given this absent or very low replication in other species, it is unlikely that RCD virus would successfully jump species, replicate, and cause disease in a species other than Oryctolagus cuniculus., except perhaps to another lagomorph. It is even less likely that RCD virus would then be serially transmitted to cause an epidemic in another species. I am somewhat more uncertain about the possibility that RCD virus might recombine with another indigenous calicivirus, with subsequent spread of the progeny chimeric virus. There is almost no data with which to address this concern. I am only aware of transmission of Norwalk-like viruses in humans as the only autochthonous (within country) calicivirus transmission in New Zealand. However, it seems likely that other as yet undetected caliciviruses of other groups may also be present and transmitted within country, so the hypothetical possibility of dual infection and recombination can not be ruled out.
Given the current multi-continent geographic distribution of wild RCD virus (Europe and Australia), release of RCD virus in New Zealand is unlikely to add appreciably to the very low risk that RCD virus might - somewhere in the world - jump species barrier to cause a new disease. However, the continual occurrence of "low-probability" emergences of new RNA virus diseases around the world, as shown in Tables I, II, and III should impress the reader that this probability is not zero.
I do not have direct knowledge of the safety and efficacy, and cost-benefit of the existing RCD vaccines, but it does seem that use of these vaccines could obviate this problem.
Comment on: Characteristics of the virus itself including host range and epidemiology.
I believe I have adequately addressed this issue in my above comment on "The effects, positive and negative, of RCD virus on non-target species and human health" above.
After reviewing the specific available data on RCD virus and considering these data in light of more general principals of viral evolution, emergence, and epidemiology, it is my conclusion that the risk of a significant adverse epidemiological event consequent from intentional release of RCD virus in New Zealand is very low, but it is not zero. While I consider it very unlikely that a significant adverse epidemiological event will result from this particular release of this particular virus, I am concerned that if this general biocontrol strategy (with this level of uncertainty) is repeated 10 or 100 times around the world using other RNA viruses for control of other pests, that the probabilities will not always be in our favor.
If you do decide to proceed with release of RCD virus in New Zealand, I would recommend that some fixed percentage, perhaps 20%, of the anticipated annual economic gains from the program should be budgeted ahead of time specifically to fund monitoring and evaluation of the virologic, epidemiologic, and ecologic effects. Since there are so many unknowns that can only be resolved through field studies, a good case can be made that the release of RCD virus should be thought of as a large field experiment, with an appropriate level of political and financial support to insure that sound conclusions can drawn from the experiment.
RECENT VIRAL PANDEMICS (Ro>>1) IN HUMAN POPULATIONS
| HOST | DISEASE | YEAR | LOCATION | FAMILY | VIRUS |
| Human | Hem conjunc'itis | 1969 | Ghana | Picorna | EV70 |
| Human | Meningitis | 1969 | USA | Picorna | EV71 |
| Human | Hem conjunc'itis | 1970 | Singapore | Picorna | CoxA24v |
| Human | AIDS | 1981 | USA, Zaire | Retro | HIV-1 |
| Human | Leuk/lymphoma | 1982 | Japan | Retro | HTLV |
| Human | Influenza | 1968 | Hong Kong | Orthomyxo | Influ A / H3N2 |
| Human | Influenza | 1977 | Russia | Orthomyxo | Influ A / H1N1 |
RECENT LOCALLIZED (Ro<1) NEW VIRAL EPIDEMICS IN HUMAN POPULATIONS
| HOST | DISEASE | YEAR | LOCATION | FAMILY | VIRUS |
| Human | Neuropsych | 1985 | Germany | Paramyxo | Borna |
| Human | AIDS-like | 1986 | West Africa | Retro | HIV-2 |
| Human | Hemorrhagic Fev | 1989 | Venezuela | Arena | Guanarito |
| Human | Influenza | 1993 | Netherlands | Orthomyxo | Influ A H3N2/avian |
| Human | Pulmonary Synd | 1993 | West USA | Bunya | Sin Nombre |
| Human | Hemorrhagic Fev | 1995 | Zaire | Filo | Ebola |
SOME IMPORTANT RECENT VIRAL EPIDEMICS IN ANIMAL POPULATIONS*
| HOST | DISEASE | YEAR | LOCATION | FAMILY | VIRUS |
| Pig | Respiratory | 1984 | Europe | Corona Porc Resp | Corona |
| Dog | Enteritis | 1978 | World-wide | Parvo | Canine Parvo |
| Chicken | Influenza | 1983 | USA | Orthomyxo | Influ A H5N2 |
| Lion | Enceph | 1994 | Tanzania | Paramyxo | Canine Distemper |
| Dolphin | Respiratory | 1988 | USA | Paramyxo | Dolph & Porp Morb |
| Horse | Respiratory | 1994 | Australia | Paramyxo | Equ Morbilli |
* Table does not include emergence of rabbit calilcivirus disease in China in 1984.
RNA VIRUSES OF VERTEBRATES: NATURAL OR IN VIVO GENERATION OF NOVEL RECOMBINANTS
| FAMILY | VIRUS | EVIDENCE | REFERENCE |
| Arteri Equine | Art Field isolate M, N | phylogenies non-congruent | Chirnside 1994 |
| Corona | Inf Bronch | Experimental egg inoculation | Kottier 1995 |
| Corona | Inf Bronch | Field isolates had vaccine S1 gene | Wang 1993 |
| Corona | Inf Bronch | Field isolate had vaccine S2 gene | Jia 1995 |
| Corona | Mouse Hep | Mouse brain isolates recombined | Keck 1988 |
| Picorna | Polio 1 | Field isolates had vaccine non-capsid gene | Zheng 1993 |
| Picorna | Polio 1 | Vaccine associated cases = vac/vac recombinants | King 1988 |
| Picorna | Polio 1 | Field isolates had vaccine genes | Rico-Hesse 1987 |
| Toga | WEE | Chimera: env = Sindbis, rest = EEE | Weaver 1993 |
REFERENCES FOR TABLE I
Hayashida H. Evolution of influenza virus genes. Mol Biol Evol 1985; 2:289.
Young JF. Evolution of human influenza A viruses in nature: recombination contributes to genetic variation of H1N1 strains. Proc Natl Acad Sci 1979; 76:6547.
Cox NJ. Pathways of evolution of influenza A (H1N1) viruses from 1977 to 1986 as determined by oligonucleotide mapping and sequencing studies. J Gen Virol 1989; 70:299.
Guo Y. Human influenza A (H1N1) viruses isolated from China. J Gen Virol 1992; 73:383.
Takeda N. Molecular evolution of the major capsid protein VP1 of enterovirus 70. J Virol 1994; 68:854.
Kono R. Apollo 11 disease or acute hemorrhagic conjunctivitis: a pandemic of a new enterovirus infection of the eye. Am J Epidemiol 1975; 101:383.
Lin K-H. Molecular epidemiology of variant Coxsackie A24 in Taiwan: two epidemics caused by phylogenetically distinct viruses from 1985 to 1989. J Clin Micro 1993; 31:1160.
Koralnik IJ. Phylogenetic associations of human and simian T-cell leukemia/lymphtropic virus type 1 strains: evidence for interspecies transmission. J Virol 1994; 68:2693.
Burke DS, McCutchan FM. Global distribution of Human Immunodeficiency Virus-1 clades. Chapter 7 in AIDS, Biology, Diagnosis, Treatment and Prevention, fourth edition, ed. VT DeVita, S Hellman, SA Rosenberg. Lippincott-Raven Publishers, 1996.
Liu H-F. New retroviruses in human and simian T-lymphotropic viruses. Lancet 1994; 344:265.
REFERENCES FOR TABLE II
Gonzalez J-P. Molecular phylogeny of Guanarito virus, an emerging arenavirus affecting humans. Amer J Trop Med Hyg 1995; 53:1.
Bode L. Borna disease virus genome transcribed and expressed in psychiatric patients. Nature Med 1995; 1:232.
Class ECJ. Infection of children with avian-human reassortant influenza viruses from pigs in Europe. Virology 1994; 204:453.
Chen Z. Genetic characterization of new West African SIVsm: Geographic clustering of household derived SIV strains with HIV type 2 subtypes and genetically diverse viruses from a single feral Sooty Mangabey troop. J Virol 1996; 70:3617.
Sanchez A. Reemergence of Ebola virus in Africa. Emerg Inf Dis 1995; 1: 96
Khan AS. Hantavirus pulmonary syndrome. The first 100 US cases. J Infect Dis 1996; 173:1297
REFERENCES FOR TABLE III
Sanchez CM. Genetic evolution and tropism of transmissible gastroenteritis coronaviruses. Virology 1992; 190:92.
Bean WJ. Characterization of virulent and avirulent A/Chicken/Pennsylvania/83 influenza A viruses: potential role of defective interfering RNAs in nature. J Virol 1985; 54:151.
Roelke-Parker ME. A canine distemper virus epidemic in Serengeti lions. Nature 1996; 379:441.
Taubenberger JK. Two morbilliviruses implicated in bottlenose dolphin epizootics. Emerg Inf Dis 1996; 2:213.
Parrish C. Evolution of Canine Parvovirus involved loss and gain of feline host range. Virology 1996; 215:186.
Murray K. A morbillivirus that caused fatal disease in horses and humans. Science 1995; 268:94.
REFERENCES FOR TABLE IV
Chirnside ED. Comparison of M and N gene sequences distinguishes variation amongst equine arteritis virus isolates. J Gen Virol 1994; 75:1491.
Kottier SA. Experimental evidence of recombination in Coronavirus Infectious Bronchitis Virus (of chickens). Virology 1995; 213:569.
Wang L. Evidence of natural recombination within the S1 gene of infectious bronchitis virus. Virology 1993; 192:710.
Jia W. A novel variant of avian infectious bronchitis virus resulting from recombination among three different strains. Arch Virol 1995; 140:259.
Keck JG In vivo RNA-RNA recombination of coronavirus in mouse brain. J Virol 1988; 62:1810.
Zheng D-P. Distribution of wild-type 1 poliovirus in China. J Infect Dis 1993; 168:1361.
King AMQ. Genetic recombination in positive strand RNA viruses. In: Domingo E, ed. RNA Genetics, Volume 2. Retroviruses, Viroids and RNA Recombination. 1988, pp. 149-165.
Rico-Hesse R. Genographic distribution of wild poliovirus type 1 genotypes. Virology 1987; 160:311.
Weaver SC. A comparison of the nucleotide sequences of Eastern and Western Equine Encephalomyelitis viruses with those of other alphavirus and related RNA viruses. Virology 1993; 197:375.
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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