Field-Testing a DNA Canine Melanoma Vaccine

[Guest guest]

Field-Testing a DNA Canine Melanoma Vaccine

press-release

Tue, 13 Dec 2005 13:23:28 +0000

 

 

The Institute of Science in Society Science Society

Sustainability http://www.i-sis.org.uk

 

General Enquiries sam Website/Mailing List

press-release ISIS Director m.w.ho

 

This article can be found on the I-SIS website at

http://www.i-sis.org.uk/FTADNACMC.php

========================================================

 

 

ISIS Press Release 13/12/05

 

Field-Testing a DNA Canine Melanoma Vaccine

**************************************

 

A proposal that uses " confidential business information " to

conceal the most critical aspects with regard to safety

while dismissing genuine safety concerns. Prof. Joe Cummins

 

This report has been submitted to US Department of

Agriculture-Animal and Plant Inspection Service on behalf of

the Independent Science Panel

 

The United States Department of Agriculture-Animal and Plant

Health Inspection Service (APHIS) is considering granting

authorization to ship an unlicensed DNA canine melanoma

vaccine for field-testing, as requested by Merial, Inc.,

Athens, Georgia.

 

The company wants to conduct clinical studies that will

provide efficacy and safety data in dogs administered this

vaccine. Efficacy will be measured by the sparing effect of

the vaccine in dogs diagnosed with melanoma; and the safety

of the vaccine will be evaluated in all animals

participating in the studies. The Assessment for Field

Testing Canine Melanoma Vaccine, DNA 11/15/2005 is open for

public comment before 15 December 2005 at:

http://www.regulations.gov/fdmspublic-bld61/component/main

 

The environmental assessment dealt with the novel features

of DNA vaccines. But with large sections of the assessment

blacked out as " confidential business information " (CBI),

full evaluation of the assessment is impossible; and this is

not in the public interest. Nevertheless, the use of DNA

vaccines to treat canine melanoma has been discussed in the

scientific literature.

 

DNA vaccines are normally delivered by intramuscular

injection or a biolistic device, or orally administered. The

vaccines are normally bacterial plasmids into which are

spliced a promoter active in mammals, such as the

cytomegalovirus promoter, driving the coding sequence for an

antigen. The plasmid is taken up by the mammalian cells and

reaches the nucleus of some of those cells. There it is

transcribed into RNA, which is translocated to the cytoplasm

and translated into antigen protein. The bacterial plasmid

sequences are rich in CpG sequences which act as adjuvant to

enhance the immune response. The DNA vaccines induce the

full spectrum of immune responses including antibodies, T

helper cells and cytotoxic T lymphocytes [1]; but concerns

have been expressed over the induction of autoimmunity and

anti-DNA antibodies, which were observed in rabbits

immunized with plasmids bearing a HIV reverse transcriptase

gene [2].

 

A phase one clinical trial of a DNA vaccine using a plasmid

modified with two peptides from human tyrosinase - an enzyme

on the path to melanin formation that is greatly elevated in

melanoma cancer cells - was undertaken on human subjects

with stage IV melanoma, in which the melanoma has spread

from its site of origin. Plasmid DNA was injected into the

groin lymph nodes; and 16 of 24 patients survived for 12

months [3].

 

Metastatic (spreading) canine malignant melanoma is common

and resistant to chemotherapy. A clinical study of dogs

with malignant melanoma involved treatment with plasmids

containing peptides from human or mouse tyrosinase. The

study showed that the inoculations were safe and resulted in

anti-tyrosinase antibodies [4]. Dogs with advanced malignant

melanoma survived for more than a year when inoculated with

a plasmid containing a gene for a peptide from human

tyrosinase. The trial supported the use of the vaccine in

both dogs and humans with advanced melanoma [5].

 

The report " Nucleic Acid-Mediated (Genetic) Vaccines Risk

Analysis for Melanoma DNA Vaccine (Product Code 9240.D0,

Unlicensed) " [6] indicated that the DNA vaccine was derived

from a bacterial plasmid, but all of the pertinent

information about the antigen sequence and antibiotic

selection markers was blacked out presumably deemed

confidential business information (CBI). The only

information on the plasmid not blacked out was that it was

an E coli plasmid.

 

Among the issues considered in the review was the chance

that the vaccine antigen would recombine with genes in the

dog chromosomes causing mutations. No effort was made to

measure integration of the vaccine DNA, the proponents and

APHIS argued that the chance of integration was low based on

studies of antigen integration from the malaria parasite [7]

or influenza virus or HIV virus [8]. But the dog melanoma

vaccines have all been based on genes present in the

mammalian genomes with high levels of DNA homology, allowing

legitimate recombination at a much higher frequency than the

antigen genes from parasites or viruses that have little or

no homology with the mammalian genome, and must depend on

illegitimate recombination. It is surprising that APHIS and

the proponent failed to mention this important point.

 

The proponent and APHIS argue that immuno-modulator

sequences such as the CpG motif are not known to be present

in something blacked out related to the plasmid vaccine DNA.

This point is clearly in error, for the CpG motif is present

in E. coli plasmids, and is certainly active in dogs and

cats [9].

 

The problem of auto-immunity and anti-DNA antibodies was

dealt with in a cursory manner; and so was the handling and

escape of plasmid bearing bacteria, with no data provided to

support conclusions. The dissemination of the vaccine

plasmid in the environment was also considered in the

absence of experimental data. The conclusion that the

plasmid ingested by animals would be of no consequence was

similarly based on no experimental data, as was the

dismissal of horizontal gene transfer.

 

The report claims that there is little or no chance of

problems arising from accidental spills of solutions

containing the plasmid, because the plasmid is not

infectious and is unstable in the environment. Again, no

data were supplied to support that conclusion, which would

appear at odds with what we now know about the stability of

DNA in all environment. The report maintains that plasmid

shed or released from test animals posed no concern because

the levels of plasmid released by those animals would be

low. But no data were provided to support that conclusion;

and there was no indication that feces, urine or vomited

materials would be handled in any special way to prevent

dispersal of the plasmid in the environment. The antibiotic

resistance markers associated with the plasmid were

designated CBI, and hence unavailable to any member of the

public exposed to the plasmid from surface or groundwater,

in air associated with dust particles or in bacteria. Many

bacteria are capable of taking up DNA molecules and

integrating them into the bacterial chromosome; there are at

least 87 species of naturally transformable bacteria in the

soil alone [10].

 

In conclusion, the proposal for a field trial of a DNA

vaccine to treat canine melanoma suffers from serious

defects, chief among which, using CBI to conceal the most

critical aspects of the proposal with regard to safety while

dismissing genuine safety concerns with no empirical

evidence. This proposal must be rejected and given no

further consideration unless and until those defects are

made good.

 

References

 

Kowalczyk D and Ertl H. Immune response to DNA vaccines.

CMLS Cell. Mol. Life Sci. 1999, 55, 751-70.

 

Isaguliants MG, Iakimtchouk K, Petrakova NV, Yermalovich MA,

Zuber AK, Kashuba VI, Belikov SV, Andersson S,

Kochetkov SN, Klinman DM and Wahren B. Gene immunization

may induce secondary antibodies reacting with DNA. Vaccine

2004, 22(11-12),1576-85.

 

Tagawa ST, Lee P, Snively J, Boswell W, Ounpraseuth S, Lee

S, Hickingbottom B, Smith J, Johnson D and Weber JS. Phase

I study of intranodal delivery of a plasmid DNA vaccine for

patients with Stage IV melanoma. Cancer 2003, 98,144-54.

 

Bergman PJ, Camps-Palau MA, McKnight JA, Leibman NF, Craft

DM, Leung C, Liao J, Riviere I, Sadelain M, Hohenhaus AE,

Gregor P, Houghton AN, Perales MA and Wolchok JD.

Development of a xenogeneic DNA vaccine program for canine

malignant melanoma at the Animal Medical Center. Vaccine

2005 Sep 23; [Epub ahead of print]

 

Bergman PJ, McKnight J, Novosad A, Charney S, Farrelly J,

Craft D, Wulderk M, Jeffers Y, Sadelain M, Hohenhaus AE,

Segal N, Gregor P, Engelhorn M, Riviere I, Houghton AN and

Wolchok JD. Long-term survival of dogs with advanced

malignant melanoma after DNA vaccination with xenogeneic

human tyrosinase: a phase I trial. Clin Cancer Res. 2003,

9(4), 1284-90.

 

Merial, Inc. Environmental Assessment for Field Testing

Canine Melanoma Vaccine, DNA 2005 Nucleic Acid-Mediated

(Genetic) Vaccines Risk Analysis for Melanoma DNA Vaccine

(Product Code 9240.D0, Unlicensed) "

http://www.regulations.gov/fdmspublic-bld61/component/main

 

Martin T, Parker SE, Hedstrom R, Le T, Hoffman SL, Norman J,

Hobart P and Lew D. Plasmid DNA malaria vaccine: the

potential for genomic integration after intramuscular

injection. Hum Gene Ther. 1999, 10(5), 759-68.

 

Ledwith BJ, Manam S, Troilo PJ, Barnum AB, Pauley CJ,

Griffiths TG 2nd, Harper LB, Beare CM, Bagdon WJ and Nichols

WW. Plasmid DNA vaccines: Investigation of integration into

host cellular DNA following intramuscular lnjection in mice.

Intervirology 2000, 43(4-6), 258-72.

 

Krieg A. CpG Motifs in bacterial DNA and their immune

effect. Ann Rev. Immunol. 2002, 20, 709-60.

 

de Vries J, Meier P and Wackernagel W. Microbial horizontal

gene transfer and the DNA release from transgenic crop

plants. Plant and Soil 2004, 266, 91-104.

 

 

========================================================

This article can be found on the I-SIS website at

http://www.i-sis.org.uk/FTADNACMC.php

 

If you like this original article from the Institute of

Science in Society, and would like to continue receiving

articles of this calibre, please consider making a donation

or purchase on our website

 

http://www.i-sis.org.uk/donations.

 

ISIS is an independent, not-for-profit organisation

dedicated to providing critical public information on

cutting edge science, and to promoting social accountability

and ecological sustainability in science.

 

 

 

 

========================================================

CONTACT DETAILS

 

The Institute of Science in Society, PO Box 32097, London

NW1 OXR

 

telephone: [44 1994 231623] [44 20 8452 2729] [44 20

7272 5636]

 

General Enquiries sam Website/Mailing List

press-release ISIS Director m.w.ho

 

MATERIAL ON THIS SITE MAY NOT BE REPRODUCED IN ANY FORM

WITHOUT EXPLICIT PERMISSION.

FOR PERMISSION, PLEASE CONTACT enquiries