Recombinant DMA Advisory Committee - 06/7-8/93 
FDA or any other federal agency, the RAC is the only review body for this particular 
proposal. Dr. Krogstad provided a clinical overview of SFV infection. In Tubingen, 
Germany, 1978, a laboratory worker death was reported in association with SFV 
infection. Although the cause of death was not clearly established, the containment 
classification of SFV was raised from BL2 to BL3. In 1990, there was an outbreak of 
SFV infection among a group of French soldiers in Africa. Clinical manifestations 
included fever and other mild symptoms of systemic infection. Other instances of 
infection in laboratory workers have been reported who demonstrated seroconversion 
and developed antibodies against SFV. Dr. Krogstad stated that the RAC must exercise 
extreme caution in their consideration of this proposal since a judgement must be 
rendered without adequate clinical information. 
Review-Dr. Miller 
Dr. Miller outlined the issues that remained at the time this proposal was last reviewed 
by the RAC. Little information was known about the frequency of recombination 
yielding replication-competent SFV under conditions for using the cloning vector system. 
In addition, the incidence of seropositivity of laboratory workers exposed to this virus 
had not been determined. On this resubmission, the applicants have determined the 
frequency of helper virus production in the system. The results indicate that helper virus 
will be readily detectable. Two strategies were employed to reduce the possibility of 
generating helper virus. One involves the separation of helper function on different 
RNA molecules. The frequency of generating helper virus is 10" 3 per vector infectious 
unit. The other strategy involves mutation of the spike protease region to prevent virus 
activation, and the maximum rate of helper production with this mutation is 2 x 10 4 . 
These rates are much higher than the 10 -6 that was originally proposed by the Pis. These 
results indicate the real potential for generating SFV helper virus in the gene expression 
vector product. Regarding the risk to laboratory workers from using this system, the 
risks are very real and must be considered. Seroconversion rates are still too low to 
evaluate the potential for disease following infection. The RAC must consider that a 
fatal infection was previously reported. Given that one can expect helper virus 
production at some rate, the risk to laboratory workers cannot be ignored. 
Dr. Miller said that he recommends reclassification of this cloning vector from BL3 to 
BL2 provided that potential customers are adequately informed of the potential risks 
associated with the system. The investigators must provide customers with: (1) an 
information sheet that describes the potential health risks, (2) appropriate methods to be 
used for virus inactivation, (3) a simple helper virus assay to detect replication competent 
SFV, (4) a description of the symptoms that would be expected in the event of SFV 
infection, and (5) a warning indicating the potential for SFV recombination. 
Dr. Miller said that the investigators' response to the RACs initial concerns appeared to 
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Recombinant DNA Research, Volume 17 
