KHV Vaccine Development World Wide
A status report by the Project KHV team
November 2006
Seven groups (world wide) are reported to be working on KHV vaccines: Hebrew-University-Hadassah Medical School in Israel,
Henderson Morley of Brittan, North Carolina State University-College of Veterinary Medicine, University of Georgia, the Mie
University and the Tokyo University of Marine Science and Technology in Japan, and Novartis in Canada.
The techniques being pursued include killed virus, attenuated live virus and DNA, and delivery methods range from oral
preparations to immersion and injection. Hopefully, some of these projects will be successful and we will have several usable
vaccines in the not too distant future. Even one would be nice.
The problems that face the vaccine developers are many. The two biggies are technical and regulatory. The challenge of
developing and producing an effective vaccine is only the beginning. Once developed, there are government approvals to be
reckoned with and these can be every bit as challenging as the development. Typically, government regulations have two important
aspects: safety and effectiveness.
A killed virus vaccine is typically the least expensive and quickest to develop. And with regard to safety, a killed vaccine
must prove that the virus is, in fact, killed/inactivated and therefore not capable of infecting fish as well as demonstrate
the vaccine and/or its adjuvant (stuff that enhances the desired reaction to the vaccine) does not precipitate an unfavorable
immune response. Its drawbacks are that killed virus vaccines don’t usually produce as strong an immune response nor
do they provide protection for as long as modified live virus vaccines and they are usually relatively expensive to produce.
A modified live virus is generally the next least expensive to develop and typically takes the next longest time to develop.
It is, however, frequently the most effective in producing a strong, long lasting effect. The rub with modified live virus
vaccines comes in proving they are safe, i.e., proving that the modified virus will not revert to the pathogenic wild type.
Proving safety is reported to be a real bear on this type! Additionally, keeping the vaccine "alive" until it’s administered
adds another layer of complexity and expense to a final product.
DNA vaccines are generally considered to be the vaccines of the future. A portion of the viral DNA (gene) is incorporated
into plasmids and introduced into the host, in this case our koi or food carp. Once in the host the viral DNA is incorporated
into the host genome. The theory is the host (carp) then manufactures the antigenic proteins of the viral coat resulting in
a protective antibody response to the virus. Since only the viral gene(s) are injected rather than the whole virus, there
is safety regarding potential spread of disease. Unfortunately, not all DNA vaccines work to protect the host from viral disease.
There is an ongoing debate regarding the safety of DNA vaccines. Major concerns with regards to safety are the integration
of the viral DNA from the plasmid to the host genome. These might include immunopathological effects (messing up the immune
system), the formation of anti-DNA antibodies resulting in autoimmune diseases and the use of molecular adjuvants. In regards
to food animals there are safety concerns regarding potential transformation of environmental microflora by complete or fragmented
plasmids. Debate and controversy regarding regulation and licensing of DNA based immunization continues.
However, once developed it is typically the least expensive to produce. Most DNA vaccines do not use the entire genome
sequence, so they are also likely the safest. That said, the regulatory process is essentially uncharted waters at this point
as there are currently precious few DNA vaccines and that makes this part of the equation a large unknown.
Information reported about the specific groups working on KHV vaccine development is as follows:
Israel:
Kovax has been testing a modified live vaccine (developed by Perelberg, Kotler and others at the Hebrew-University-Hadassah
Medical School) for two years and now has it approved for use within Israel. They report having vaccinated about 7 million
carp within Israel in the year 2005 with very acceptable protection rates for both immersion and injection vaccinations. There
are also reports that they are trying to obtain approval to sell the vaccine outside Israel. We suspect the Israeli effort
is ahead of the others contenders.
United Kingdom:
In October of this year Henderson Morley PLC, a UK pharmaceutical company, announced it has been working on a vaccine against
Koi Carp Herpes virus for the past 10 months and is now ready to start field trials of a candidate vaccine in a collaboration
with Hagerman Aquaculture Research Institute in Idaho under the supervision of the Institute Director, Professor Ron Hardy.
The report did not mention the type of vaccine or the method of delivery.
United States:
A University of North Carolina State University, College of Veterinary Medicine team lead by Drs. Levine and Shivappa report
they have two candidate DNA vaccines ready for initial efficacy testing. In 2005 Project KHV agreed to fund this vaccine research.
After sending a first payment they received money from a federal grant that also covered their work on KHV vaccine. They returned
the money. So the work goes on and the money is back in the fund, a good/good result.
In 2004 a funding effort by NAWGS and Dr. Erik Johnson reportedly raised over $50,000 for Dr. Branson Ritchie’s KHV
vaccine efforts at the University of GA. We have no information on what the status of that work is. We do know that a year
or so ago the group inadvertently developed a strain of KHV that would not reliably infect and kill fish, i.e., an attenuated
virus.
Japan:
In May of 2005 a press release reported that Tetsuro Yoshimura and Teruo Miyazaki at Mie University in Japan had developed
an oral vaccine for KHV. The team gave koi feed incorporating a KHV liposome vaccine. The oral administration of vaccine resulted
in antibodies 5 to 25 times greater than the usual levels. Compared with conventional methods of injecting vaccines the newly
developed method requires less time and work. The research team plans to mass-produce the oral vaccine and conduct a large-scale
experiment to obtain authorization from the Ministry of Agriculture, Forestry and Fisheries and other related ministries.
We have no specific information on the vaccine development reportedly underway at the Tokyo University of Marine Science
and Technology and associated with Dr. T. Aoki. It was this group that was the first to completely sequenced the KHV genome.
Canada:
In a March 2006 press release the government of Canada announced that:
Novartis is developing an immunization strategy for the prevention of koi herpes virus. While preventing KHV in koi carp
is a priority for hobbyists and sellers to protect the breeding, export, wholesale and retail markets, the control of the
disease will reduce the risk of infection in the food carp industry which is of great importance in developing nations. This
project, with total estimated costs of $2.5 million, will receive up to $1.8 million from the Atlantic Innovation Fund over
a five-year period.
Additionally, Novartis has acquired rights to a patent covering the use of DNA vaccines in fish and also to another patent
covering a unique delivery methodology.
Project KHV sees all the work in KHV vaccines as extremely encouraging and believes the "push" in the vaccine area is logical
for two major reasons: a) it is almost undoubtedly the best hope for effective control and possible eradication of the disease
and b) it is the area most likely to produce good profits for any group that develops a successful vaccine.
Therefore, we at Project KHV have concluded that while we will certainly continue tracking the progress of the various
vaccine developments and will try to be helpful when and where we can, we will now concentrate our efforts elsewhere. We will
pursue projects in areas that are also very important to the prevention and control of the disease but which are not nearly
so likely to produce the return on investment that vaccines promise. These other areas include:
● Education - prevention and control
● Epidemiology (studying how the disease spreads)
● Etiology (or aetiology in the U.K. <grin>) – studying how the virus causes the disease
● Testing – better, safer, easier, cheaper and less invasive
We see progress in these areas as critical to our stated goals of near-term prevention and control and the longer-term
eradication of the disease.
Toward this end we have funded a Phase 1 project that focuses on the education of koi dealers and hobbyists. It intends
to prepare and deliver educational materials on prevention and control of the disease. This will be done in several ways (see:
http://www.akcaprojectkhv.org/updatejune06.htm) :
Regional presentations
Presentations at technical and trade meetings
Web-based information
Free printed and electronic information
The Phase 1 grant group is scheduled to start its public education efforts in March of 2007. Watch the Project KHV web
site for a schedule. See: http://www.akcaprojectkhv.org/ .
Recently we released an updated fact sheet on KHV that was primarily the result of a literature survey and provides what
is currently known, what is unknown and a brief but current best practices for preventing the disease. See: http://www.akcaprojectkhv.org/KHVfactsheet-final.pdf
Additionally, we are soliciting and otherwise seeking projects that enhance our educational efforts, e.g., a Best Health
Practices Certification program for koi retailers (see: http://www.akcaprojectkhv.org/RFP-BHPC-KoiRetailers.pdf
). We are also seeking proposals in the other areas, e.g., the study of where the virus persists when it’s not causing
disease (latency and/or environmental persistence).
It’s not easy to find good, targeted programs to support. To date we have funded two requests but have turned down
several others. We have our eyes on the goals and are working hard to make sure we get a reasonable bang for the buck. We
are making progress but it’s certainly not time to let up. We need to build our fund so when we find projects that meet
our criteria we’ll have the money to pursue them.
You know the drill. If you leave it up to someone else, it won’t get done. So please send us a check today. We will
thank you in advance and we’ll keep working hard to make it happen and to keep you updated.
Make checks payable to AKCA Project KHV.
Send contributions to:
AKCA Project KHV
P.O. Box 4045
Oakhurst, CA 93644
