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<body><p class="default_Text"><b>Environmental Assessment for Field Testing </b></p>
<p class="default_Text"><b>Foot and Mouth Disease Virus Vaccine, </b></p>
<p class="default_Text"><b>Live Adenovirus Vector</b></p>
<p class="default_Text"><b>I</b>.
<b>Proposed Action</b></p>
<p class="default_Text">APHIS is considering granting authorization to ship an unlicensed Foot and Mouth Disease Virus Vaccine, Live Adenovirus Vector, for field safety testing.  PerOs USA Inc., under contract with GenVec, Inc., has requested authorization to conduct field tests under conditions of husbandry that are typical of the commercial cattle industry in the United States.
</p>
<p class="default_Text">Under the provisions of the Virus-Serum-Toxin Act of 1913, as amended in 1985, the USDA must ensure that veterinary biologics are pure, safe, potent, and efficacious and not worthless, contaminated, dangerous, or harmful.  Accordingly, APHIS has conducted a risk analysis and has concluded that the safety risks to animals, public health, and the environment are low.  A copy of the risk analysis with confidential business information removed is made available to the public, along with this environmental assessment, following the publication of the <i>Federal Register </i>Notice regarding pending field trials.
</p>
<p class="default_Text"><b>II.
Background
</b></p>
<p class="default_Text">GenVec, Inc. has developed a live recombinant foot and mouth disease virus (FMDV) vaccine for intramuscular (IM) administration in healthy cattle at 12 weeks of age or older.  This vaccine is intended as an aid in the prevention of clinical signs of disease caused by FMDV which is an aphthovirus of the family Picornaviridae.  The recombinant vaccine construct consists of a live recombinant replication-deficient human adenovirus C, serotype 5 (Ad5) vector expressing the capsid and protease genes of FMDV, and is adjuvant-free.  </p>
<p class="default_Text">Adenoviruses infect various vertebrate species, including humans.  Human adenoviruses cause cold-like symptoms in people but are not considered to be pathogenic for cattle or other animals.  The adenovirus vector used here has been attenuated by complete or partial deletions of certain genes, rendering the virus replication-deficient.  The Ad5 vector is sufficiently attenuated by its gene deletions to render it nonpathogenic in humans.  </p>
<p class="default_Text">The proposed field safety test will be conducted in at least three different geographical locations according to instructions on the product circular.  The potential for escape and dispersal of the experimental vaccine from the proposed release sites is low.  The personnel who will conduct the study are experienced in bovine health management.
</p>
<p class="default_Text"><b>III.
Need for the Proposed Action</b></p>
<p class="default_Text">FMDV causes a highly contagious vesicular disease of cloven-hoofed animals, including domesticated species of cattle, pigs, sheep, goats, and buffalo.  Also, many species of cloven-hoofed wildlife are susceptible, e.g. deer, antelope and feral pigs.   FMDV is endemic in southeast Asia, the Middle East, portions of the former Soviet Union, India, Iran, Egypt, Eritrea, Ethiopia, and most of sub-Saharan Africa.  It occurs sporadically in various areas throughout the rest the world.  Central and North America are considered free of FMDV, but there is the possibility it could be introduced into these areas at any time.  If introduced, FMDV could cause severe animal disease and economic loss to our nation. (1, 2)</p>
<p class="default_Text">This recombinant vaccine represents efforts by GenVec, Inc. and PerOs USA, Inc. to produce an efficacious and safe vaccine that protects cattle against FMDV with one vaccination in the event of an outbreak.  An additional advantage of this vaccine is that vaccinated animals can potentially be differentiated from infected animals, given that only key genes of the FMDV genome are present. (3)  Testing for other parts of the virus using an appropriate validated assay will yield negative results from an uninfected animal. </p>
<p class="default_Text"><b>IV.
Areas of Concerns
</b></p>
<p class="default_Text">The three areas of concern to APHIS are:  1) animal safety, 2) public health, and </p>
<p class="default_Text">3) environmental safety.  APHIS has conducted a risk analysis to assess the risks associated with the proposal to field test this experimental vaccine.  The safety characteristics of this vaccine have been thoroughly evaluated.  The conclusions derived from the risk analysis for each of the areas of concern are summarized below.
</p>
<p class="default_Text">
<b>A.
Animal Safety</b></p>
<p>The risk to animals is low. </p>
<p>1. Adenoviruses are considered to be host-specific and a human adenovirus should have little to no infectivity for cattle, mice, or mammals other than humans.  Further, genetic manipulation has rendered the adenovirus vector replication-deficient in normally permissive cell lines and in its preferred human host.</p>
<p>2. In the backpassage/reversion-to-virulence study conducted by the firm, the recombinant was unable to establish itself in 10 intranasally inoculated cattle.  Following high titer intranasal inoculation, the inoculum containing the adenovirus vector could be isolated by nasal swabs from 4 of the 10 animals.  However, at 48 hours no virus could be isolated from inoculated cattle.</p>
<p>3. Shed/spread studies show that the virus vector cannot be isolated from cattle or pigs after administration of vaccine by the intramuscular route.</p>
<p>4. Host animal safety testing has shown that the vaccine candidate is safe in cattle following a single immunization given intramuscularly.  Intramuscular administration to cattle of the vaccine vector seed stock used to produce the master seed, at doses up to ten times the proposed serial release titer, did not cause any fever, site reactions, systemic reactions, clinical disease, or mortality.</p>
<p>5. The master seed was safety tested in mice and calves per Title 9, Code of Federal Regulations (9CFR) Parts 113.33 and 113.41, respectively (4), with satisfactory results.</p>
<p>6. Results of PCR, sequencing, and Western blot testing on the Master Seed (MS) and on the MS following its 5th passage in cell culture (the highest pass to be used in vaccine production), were consistent with expected genetic identity, with genomic stability of the recombinant vector and the inserted FMDV genes, and with adequate expression of the FMDV proteins.  Testing of the MS for purity, sterility, and extraneous agents was satisfactory.  Sequences of vector and foreign gene inserts were evaluated for unwanted open reading frames (ORF) using Blast searches and no known unwanted ORF were detected.</p>
<p>7. The master seed is not virulent for domestic cloven-hoofed livestock nor anticipated to be virulent for non-target animals such as wildlife, domestic companion animals, and birds, based on testing in cattle, swine, mouse, and calf, and on reports in the literature of testing similar attenuated adenovirus vectors in animals and on human and other cell lines, as cited in the risk analysis for this vaccine candidate.</p>
<p class="default_Text">
<b>B.
Public Health
</b></p>
<p class="default_Text">The risk to public health is low.  </p>
<p class="default_Text">1. There are no indications that special safety measures should be taken to conduct this study.  Human exposure will be limited to the qualified personnel administering the vaccine and handling the animals during vaccination.</p>
<p class="default_Text">2. According to the National Institutes of Health (NIH) Guidelines for Research Involving Recombinant DNA Molecules (Section II-A-1), “Risk Group 2 (RG2) agents are associated with human disease which is rarely serious and for which preventive or therapeutic interventions are <i>often</i> available.”(5)  Adenoviruses are classified as RG2 agents (Appendix B-II-D).  The genetic attenuations introduced into the Ad5 viral vector render it replication-deficient and thus at very low risk for causing human disease.  Previous safe use of replication-deficient adenovirus vectors in humans includes clinical trial evaluations of several candidate vaccines.</p>
<p class="default_Text">3. Picornaviruses are also considered RG2 agents.  Here, only key genes of FMDV, neither associated with virulence when separated from the rest of the virus, are present in the construct.  Although not specifically addressed by the Guidelines, FMDV is not associated with disease in healthy adult humans.  The likelihood of recombination occurring in the field with an undetected live FMDV virus is very low.  Even if it did happen, only another FMDV would be generated without any additional potential to be a human pathogen.  The likelihood of a hypothetical recombination across genera, e.g. with a bovine or human picornavirus, is extremely low.  It has not been detected in any combination of genera in picornaviruses where it has been examined.     </p>
<p class="default_Text">4. Accidental human injection is not expected to cause adverse effects.  Replication-deficient human adenovirus vectors have been tested and used extensively.  Although the safety of this specific experimental vaccine in humans has not been evaluated and is therefore unknown, no safety hazards to the public health are expected.     </p>
<p class="default_Text">C. <b>Environmental Safety</b></p>
<p class="default_Text">The risks to the environment are low.  </p>
<p>1. The potential for escape and dispersal of this recombinant vaccine is low.  The shed and spread capabilities of the vaccine used in cattle, if any, are undetectable even under direct contact exposure and serologic examination of in-contact controls.</p>
<p>2. Virulence and survivability of the vaccine virus in any host requires an ability to achieve a certain level of replication <i>in vivo</i>.  Given the deletions present in the construct, generation of a replication-competent adenovirus requires two independent recombination events, one of them an infrequent nonhomologous event, in a single adenoviral vector genome.  The likelihood of this happening is negligible.  Also, the firm has conducted numerous serial assays to detect revertants and has found no revertants throughout their testing.</p>
<p>3. Even if recombination should occur, the likely result would be a virus lacking the FMDV genes, excised by the recombination event.  Because the Ad5 portion of the construct is avirulent, recombination with wild-type Ad5 would not be expected to generate a more virulent virus.  </p>
<p>4. FMDV is a single-stranded positive sense RNA virus (picornavirus), and the recombinant vector is a double-stranded DNA virus (adenovirus) with double-stranded inserts, thus making it unlikely an exchange of genetic material with wildtype FMDV would occur.</p>
<p>There are no apparent substantial issues with adverse environmental impacts concerning this agent.  Peer review of the firm’s risk assessment by adenovirus and picornavirus subject matter experts has reinforced the CVB’s estimation of the safety of this construct to animal and public health and the environment.  As there are no expected adverse effects in animal, human, or environmental safety associated with the proposal to conduct field testing with this experimental vaccine, this is a finding of no significant impact (FONSI) for conducting the proposed field trials.  
</p>
<p class="default_Text"><b>V.
Alternatives</b></p>
<p class="default_Text">Two alternatives were considered.  The only alternative considered, other than the preferred action alternative, is not to approve the proposed field tests, the “no action” alternative.  We have considered the applicants’ goals in light of the agency’s public interest and responsibilities and any potential environmental impact.  Based upon the results of our risk analysis and the potential applications for this vaccine in disease control, APHIS adopts the alternative that the proposed field tests be approved.
</p>
<p class="default_Text"><b>VI.
Conclusion</b></p>
<p class="default_Text">Based upon the risk analysis documented in this environmental assessment, APHIS has determined that implementation of the proposal would not significantly affect the quality of the human environment and that the preparation of an Environmental Impact Statement is not required (Finding of No Significant Impact).</p>
<p class="default_Text"><b>References
</b></p>
<p class="default_Text">1. Kitching, R.P. 2005. Foot-and-mouth Disease: Introduction. In: The Merck Veterinary Manual, Ninth Edition. C.M. Kahn, (Ed), Merck & Co., Inc., Whitehouse Station, N.J. Available online: <a href="http://www.merckvetmanual.com"><u>http://www.merckvetmanual.com</u></a></p>
<p class="default_Text">2. Kitching, R.P., Barnett, P. V., Paton, D., Mackay, D<i>. </i>2008. Foot and Mouth Disease. In: Manual of Diagnostic Tests and Vaccines for Terrestrial Animals, Sixth Edition. OIE, Paris, France.</p>
<p class="default_Text">3. Foley, P.L., Hill, R.E. 2005. Regulatory considerations for marker vaccines and diagnostic tests in the U.S. Biologicals 33:253-256.</p>
<p class="default_Text">4. Code of Federal Regulations, Washington, DC. Available online: <a href="http://www.gpoaccess.gov/cfr/index.html"><u>http://www.gpoaccess.gov/cfr/index.html</u></a></p>
<p class="default_Text">5. National Institutes of Health Guidelines for Research Involving Recombinant DNA Molecules, Washington, DC. Available online: <a href="http://oba.od.nih.gov/rdna/nih_guidelines_oba.html"><u>http://oba.od.nih.gov/rdna/nih_guidelines_oba.html</u></a></p>
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