Recombinant DMA Advisory Committee - 3/3-4/94 
IX. REPORT FROM THE RAC WORKING GROUP ON VACCINES-AMENDMENTS TO 
FOOTNOTE 21 OF THE NIH GUIDELINES REGARDING THE DEFINITION OF 
RECOMBINANT DNA VACCINES/DR. POST 
Dr. Walters called on Dr. Post, Chair of the RAC Working Group on Vaccines, to 
provide background information regarding the proposed amendment to Footnote 21 of 
the NIH Guidelines. Dr. Post explained that the current Footnote 21, which defines 
experiments involving the administration of recombinant DNA to human subjects that 
are exempt from the NIH Guidelines, was adopted in 1986. The original definition of 
Footnote 21 is outdated due to the scientific advances in recombinant DNA technology. 
The Working Group on Vaccines (Drs. Post, Parkman, and Straus) was established to 
formulate a revised definition of Footnote 21. The amended version of Footnote 21 
(Version A) reads: 
Version A: "Experiments where the induction or enhancement of an immune 
response to a vector-encoded immunogen is the major therapeutic goal, and such 
an immune response has been demonstrated in model systems, are not covered 
under Section III-A-4 of the Guidelines. Such experiments can occur without 
RAC review if a Federal regulatory agency has approved the experiments." 
The proposed definition emphasizes the immune response to a "vector-encoded 
immunogen;" therefore, other cellular immunogens would be excluded, e.g., genetically 
modified cells expressing 11^2 and cells modified to express a histocompatibility antigen. 
The proposed definition is intended to include immunogens encoded by vectors derived 
from vaccinia viruses, adenoviruses, and retroviruses. 
Drs. Parkman and Straus proposed an alternative definition (Version B) for Footnote 21. 
Version B: "Human studies in which the induction or enhancement of an immune 
response to a vector-encoded microbial immunogen is the major goal, such an 
immune response has been demonstrated in a model system, and the persistence 
of the vector-encoded immunogen is not expected, are not covered under Section 
III-A-4 of the NIH Guidelines. Such studies can be initiated without RAC review 
if approved by another Federal regulatory agency." 
Dr. Post suggested that the term "persistence" should be removed from Version B since 
persistence is difficult to define, e.g., adenovirus and retrovirus vectors have been shown 
to persist to some extent in humans. 
Dr. Parkman explained that for the purposes of Footnote 21, "persistence" is defined as 
whether the construct is intended to be expressed for a significant period of time in 
order to achieve prolonged stimulation that elicits an immune response. The 
investigator's intent regarding persistent expression supersedes any residual biochemical 
persistence. One example of an exempt vaccine covered by Version B would be a 
retrovirus construct encoding an HIV antigen that is not intended to persist. Although 
there may be biochemical persistence, the experiment is considered exempt from the 
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Recombinant DNA Research, Volume 19 
