The Calicivirus – Part 1

U.S. navy initiated research Dr Smith’s involvement with the calicivirus began in 1972 when he was given the task of exploring the possibility of diseases in the ocean which might be transmittable to people working in the ocean with marine mammals and in other areas. The US navy was interested in the answer to this question.

Dr Al Smith Photo source – Dr Neil Cherry

Research into sea lions To address this question Al began going to where there were manifestations of illness in marine mammals. The community he studied first was sea lions off the California coast who had suffered what was described as “an abortion storm with high instances of premature birth”. He was to investigate the pathology, the pesticide levels in the blubber, try to do bacteriology and virology. This was a broad-based investigation into why these animals were having problems.

Isolation of the caliciviruses Out of this work came the very first viruses that were isolated from seals. These turned out to be the caliciviruses which have proved to be very important to the livestock industries of the United States and have already been shown to be important in human health.

A twenty six year project In the past twenty six years Dr Smith has conducted what he believes to be the only continuous project over that time looking specifically at caliciviruses. At Oregon State University in Corvallis he runs the laboratory for calicivirus studies.

Tremendous livestock problems in the United States Disease attacking swine in California A disease was introduced from unknown origins into the swine in California – a disease similar to the rabbit haemorrhagic disease in China in 1984 which was also a disease appearing from nowhere. The swine developed blistering which looked like foot and mouth disease which causes great concern to livestock people and even more to regulatory people. This meant that they eradicated the disease by killing over 19,000 head of exposed livestock and buried them, thinking it was an outbreak of foot and mouth disease.

Repeated outbreaks The outbreak was contained, but recurred again one year later 100 miles away. That in turn was contained but there was an outbreak the following year 500 miles away on the California coast. This occurrence, eradication and recurrence of a disease which was affecting only swine, continued for some twenty years in California.

Spread over the entire country Then raw pork from a passenger train was put into the garbage in Cheyenne, Wyoming. The pork scraps were fed to pigs, the pigs were sold through a saleyard and the disease within fourteen months blanketed the United States. It was eventually controlled by the simple measure of ensuring that all garbage was cooked before it was fed to pigs and so the disease was said to have been eradicated.

Reappearance of the disease in ocean reservoirs and mammals Some twenty years after it was said to have been eradicated it is found in the ocean reservoirs and in the ocean mammals. If pigs were exposed to the viruses from ocean animals including fish, they would develop this disease which was supposedly eradicated. Thus the ocean has become a reservoir for a disease that in the United States and worldwide is called “foreign animal disease”. This term means that if an outbreak occurs it must be eradicated, as happens with foot and mouth disease and as happened in Mexico when rabbit haemorrhagic disease occurred.

Safety and species specificity Dr Smith’s main concern Safety for non-target species and possible human health risk have been the focus of Dr Smith’s discussion.

Caliciviruses adaptable and not species specific The reason that this becomes important is that in the beginning it was said that swine were the only naturally infected host. Subsequently this has been shown to be untrue. If there is one thing that can be said for sure about the caliciviruses it is that they have a propensity for moving between species. They are not species-specific. In fact they are extremely adaptable and able to move into a very broad array of host species. They have built-in genetic mechanisms for doing that. Using that as a modelling system Dr Smith says, “Be very careful of caliciviruses and don’t make the mistake that was made in the United States for forty years in saying that they are species specific.”

Five groups of the virus Caliciviruses can be divided into five groups. Four groups are known to infect people and cause disease, and three, or possibly four, are known not to be species-specific.

Rabbit haemorrhagic disease The only one where the proof is lacking on human disease and on host specificity is the rabbit haemorrhagic disease. It appears to be the exception to the rule, but it has only a very short history having only occurred for a little over ten years, and already there is a great deal of evidence to tell us that it is not species specific.

The disease emerged suddenly in China. It would kill 95% of the rabbits within 24 to 48 hours. Dr Smith’s says, “No virus treats it natural host that way, because it is counter productive. A virus can’t survive in nature if it does that. Any virologist would tell you that it is the classic sign of a new introduction into a species.”

No one knows the origin of the virus that attacked the rabbits. A shipment of rabbits arrived from Germany and within seventy two hours they were dead. The disease then was transmitted from those rabbits to other rabbits in China and in Germany. The natural reservoir is not the rabbit species, but elsewhere.

Research on rabbit haemorrhagic disease in Australia Researchers looked at the impact of the disease on different species. Their mandate was to show that this virus would not infect any other animals, so they set up experiments to give this answer. The desired outcome was pre-determined and the experiments were designed to give that outcome rather than to answer the question.

How were the experiments done? Thirty four species were tested but only four animals per species were used – a very small group. The range of species included the kiwi and the short-tailed bat for New Zealand.

The doses of virus that were given those animals are stated in terms that startle the public, but they actually are not large in terms of infectious diseases. Researchers say that they gave each animal sufficient virus to kill a thousand rabbits. It sounds like a very large dose, but in actual fact a single fox eating the liver of one infected rabbit will get thirty thousand times more virus than the dose to which they exposed the fox in their experimental protocol. Under terms of natural exposure the amount of virus used in the experiments is a pittance.

The doses were very small and were calculated to be small in terms of actual virus particles. The usual infectious dose for a virus might be in the neighbourhood of a million viruses, whereas these researchers were giving a thousand.

Why were the researchers giving such a low dose and setting a short testing period? The reason for the low dose is that animals have an immune response if enough foreign protein enters their system so that they recognise it as foreign. If an animal becomes infected then the viruses begin to multiply and the number of viruses can get to a level that triggers an immune response. The doses given the experimental animals were purposefully held low so that they would not trigger an immune response. Lack of antibody production was going to be used as a measure of non-infection.

The protocol then said that each animal should be killed on day fourteen and fully examined. That seems reasonable except that even rabbits would not produce antibodies that would react in the test they used within fourteen days. Many other reasons were given for choosing fourteen days, but for the most part the fourteen days took them out of the window for expected production of antibodies by terminating the experiment early.

Results Eleven of the thirty four species showed increases in antibodies after exposure, and with some of the little animals the increase was quite profound – a tenfold increase in antibody levels. Using rabbit data the researchers had set the cut off for positive and negative tests at 30%, so no matter how much increase there was in antibodies for these little animals that were infected if they could not get up to the 30% then they were called negative. Rabbits do not even get up to 30% in fourteen days.

Tests orchestrated for the desired outcome Thus it was a series of tests fairly carefully orchestrated to provide a desirable outcome, and that outcome was to be able to say that the virus would not affect any species but rabbits.

Read Part 2 of the calicivirus interview.