Federal Register / Vol. 45, No. 12 / Thursday, January 17, 1980 / Notices 
3553 
By law. “no live virus of foot-and- 
mouth disease may be introduced for 
any purpose into any part of the 
mainland of the United States except 
coastal islands ..." (21 U.S.C. 113a). 
The only research on foot-and-mouth 
disease virus in the United States is 
carried out at the Plum Island Animal 
Disease Center of the U.S. Department 
of Agriculture, located on Plum Island, 
about 1.5 miles from the eastern tip of 
Long Island in the State of New York. 
The Plum Island Animal Disease Center, 
which occupies essentially all of Plum 
Island, was established in 1954 for the 
study of exotic diseases of domestic 
animals. 
Foot-and-mouth disease is a highly 
contagious viral disease of cattle, swine, 
sheep, and other cloven hoofed animals. 
There were 9 outbreaks of this disease 
in the United States between 1870 and 
1929. Since that time stringent 
quarantine measures and inspection at 
ports of entry have kept this country 
free of the disease. 
Foot-and-mouth disease is 
characterized by the formation of 
vesicles on the mucous membranes of 
the mouth, on the nose, and on the skin 
between and adjacent to the claws of 
the feet. Transmission is primarily from 
the infected animal itself, especially 
during the early febrile stage when virus 
is present in the blood and all organs, 
tissues, secretions and excretions. The 
spread of FMD among animals in close 
proximity probably occurs chiefly 
through virus in saliva and foot lesions. 
Excreted virus, and virus in dried blood, 
in carcasses, and on hay. soil. wood, 
clothing, and other objects, persist for 
long intervals, serving as a reservoir of 
infection. 
Foot-and-mouth disease virus is a 
member of the rhinovirus genus of the 
picomavirus group of single-stranded 
RNA viruses. The single-stranded RNA 
(molecular weight = 2.8 X 10* daltons) 
acts in vivo as a template for both viral 
RNA replication and for translation. 
There are 33 or more-natural hosts (all 
cloven-footed) for FMD. Immunological 
complexity in FMD is characterized by 
seven types of virus and by 
approximately 85 subtypes. Animals 
immune to One type are susceptible to 
the other six types. 
Foot-and-mouth disease virus 
contains primarily four capsid 
proteins — VP,. VPi, VP, and VP« 
(molecular weights approximately 
33.000. 30.000. 27.000. and 8.000). An 
experimental vaccine containing 
punfied VP, has been shown to protect 
swine against foot-and-mouth disease. 
Prior to the December 6-7, 1979. RAC 
meeting, the Committee members had 
been sent copies of a Memorandum of 
Understanding and Agreement (MUA) 
entitled “Cloning and Expression in E. 
coli of the VP, protein of Foot and 
Mouth Disease Virus," as well as 
numerous other background documents 
dealing with foot-and-mouth disease. 
As noted in the MUA, "Genentech 
Inc.. South San Francisco, California, 
and the Plum Island Animal Disease 
Center, Greenport. New York, are 
joining in a research effort with the goal 
of the eventual production of a viral 
subunit vaccine for this disease." Stage I 
of the scientific plan involves "the 
production of double stranded cDNA 
from intact 37S viral RNA isolated from 
FMD virions. Using reverse 
transcriptase. E. coli polymerase I and 
various DNA oligonucleotide primers, 
we will produce a double stranded 
cDNA that contains the entire genome in 
subgenomic fragments. With these 
fragments a gene bank can be 
constructed of FMD virus sequences 
attached to the plasmid pBR322 . . . 
This plasmid preparation will be 
transformed into E. coli K-12 and 
plasmid containing bacteria selected on 
suitable agar plates. The colonies 
obtained will be transferred to filters 
and screened for the presence of FMD 
sequences using hybridization 
techniques against radiolabelled FMD 
virus cDNA. . . . Colonies containing 
FMD virus sequences will then be grown 
up and analyzed. Plasmids 
demonstrated to contain subgenomic 
FMD virus sequences of interest will be 
prepared. This preparation will be 
tested for the lack of infectious material 
by Plum Island researchers. ... All of 
the cloning experiments with cDNA will 
be done in the foreign animal disease 
control laboratories on Plum Island. 
These are maintained at greater than the 
P3 requirements of the NIH Guidelines." 
The MUA also describes Stage II to be 
"carried out at Genentech Inc., South 
San Francisco. California. Various 
plasmid DNA's, demonstrated to contain 
only subgenomic fragments, will be 
transferred to Genentech. . . Stages 
III and IV are also described. The MUA, 
signed by the principal investigators at 
Plum Island Animal Disease Center and 
Genentech. Inc., includes certification 
from the Institutional Biosafety 
Committees at both Plum Island and 
Genentech. The proposed work was 
endorsed in an October 23. 1979 
memorandum from the office of the 
Deputy Administrator. Veterinary 
Services, Animal and Plant Health 
Inspection Service. U.S. Department of 
Agriculture which states that "the 
proposed work plan as presented has 
been reviewed and considered by 
Veterinary Services and the Parent 
Committee on Foreign Pathogens and 
Vectors. Taking into account the safety 
procedures that are to be followed to 
assure that cultures of the organism E. 
coli containing the specific protein VP, 
are free of any infectious material that 
could originate from the FMD virus, or 
from any other exotic pathogens, we 
have no objections to this work being 
conducted, or to the transfer of the 
specified noninfectious protein of the 
FMD virus to Genentech Laboratories, 
South San Francisco, California." 
At the December 6-7, 1979, RAC 
meeting. Dr. ). J. Callis, Director, and 
Howard Bachrach of Plum Island 
Animal Disease Center (PIADC). and Dr 
Michael Ross of Genentech. Inc., 
answered questions from the RAC about 
the proposal. Dr. Callis said that 
currently 800 million doses of foot-and- 
mouth virus vaccine are used annually 
throughout the world. 
During the extensive discussion of this 
proposal at the meeting, RAC members 
endorsed the enormous benefits to the 
world that could accrue from this 
project. It was stated that the plan 
seems safe as long as no potentially 
infectious foot-and-mouth virus leaves 
Plum Island. A concern was expressed 
that it would be theoretically possible 
for separate subgenomic pieces of foot- 
and-mouth virus cDNA. after they left 
Plum Island spliced to pBR322, to 
recombine with each other to regenerate 
a complete cDNA copy of foot-and- 
mouth disease virus. While it was 
agreed that the probability of this 
occurrence was exceedingly low. it was 
also agreed that the probability would 
be zero if a condition were placed on the 
work that the clones to be approved for 
removal from Plum Island shall not 
contain among them, collectively or 
individually, the full genome of the foot- 
and-mouth disease virus. 
A motion was passed by a vote of 17 
to zero, with one abstention, that the 
RAC "approve the formation of 
recombinants between foot-and-mouth 
disease virus and plasmid pBR322 as 
outlined in Stage I of the scientific plan 
of Document #763, to take place at Plum 
Island." 
A motion was passed by a vote of 13 
in favor, 4 opposed, with 1 abstention 
[ 431 ] 
