Nudity, say those who practice it on secluded beaches, is a form ofself-expression.

Expression of naked DNA in a laboratory mouse, say itspractitioners, is a promising form of vaccination.

Three research papers in the August issue of Nature Medicine,released Thursday, report "encouraging" results in immunizinganimals with the genes encoding antigens rather than injecting theimmunogenic protein products of the stripped-down DNA.

Two of the three articles describe preclinical nucleic acid-vaccinesagainst tuberculosis; the third, against an animal model of multiplesclerosis.

The two initial reports of anti-TB vaccines using naked DNA _ fromMerck Research Laboratories in West Point, Pa. and Britain'sNational Institute for Medical Research (NIMR) in London _ setforth experiments and results that are strikingly, though not entirely,similar and symmetrical.

"We find it encouraging," physician and immunologist Margaret Liutold BioWorld Today, "that in both cases, simply using a constructencoding a single protein is able to give good protection in ouranimals, at least as good as the existing BCG vaccine against TB."

Liu is senior author of the Nature Medicine paper titled:"Immunogenicity and protective efficacy of a tuberculosis DNAvaccine."

The companion report, by mycobacterial immunologist DouglasLowrie at Britain's NIMR, bears the title: "Vaccination againsttuberculosis by DNA injection."

Lowrie told BioWorld Today, "It's very simple to produce a DNAvaccine. You just grow up a load of E. coli, extract the DNA in whatis essentially a one-step process, and you've got your vaccine. It's aprocess that could be applied to any target infectious disease that youwant a vaccine for."

Tuberculosis, more than any other disease on earth, cries out for aneffective vaccine.

Lowrie cites its toll of "three million deaths a year worldwide, withAIDS compounding the problem."

BCG, which stands for "Bacillus Calmet-Gurin," is a weakenedlive-bacterial vaccine derived from Mycobacterium bovis, whichcauses TB in cows. For the past 70 years or more, it's been the onlyform of immunization against M. tuberculosis, and it's not clearlysafe and effective. (See BioWorld Today, March 3, 1995, p. 1.)

BCG: Only TB Vaccine Game Around

Lowrie counts the ways in which BCG vaccine is wanting: It fails toprotect in some of the populations that need it most; BCG vaccineestest false-positive in diagnostic tests; in immunodeficiencies such asAIDS, "live vaccines threaten to become less safe."

But M. tuberculosis is too smart to roll over for killed vaccines, oreven those based on subunit antigenic proteins. These prove lessprotective even than BCG.

"The naked DNA approach," Lowrie said, "causes the antigen to besynthesized within the cells of the immune system. That is a keydistinction from preparing the protein in other subunit vaccines, andinjecting it."

He and his NIMR co-authors injected mice with naked DNA thatexpressed a heat-shock protein from M. leprae, a somewhat lessferocious mycobacterial cousin to M. tuberculosis, with which itshares 95 percent identical genes.

"The animals," he reported, "made specific cellular [i.e., T-cell] andhumoral [antibody] responses to the protein, and became immune tosubsequent challenges with M. tuberculosis." This protection "wasequivalent to that obtained by vaccinating with live BCG, whereasimmunizing with the protein was ineffective."

Lowrie said, "We now hope to optimize that preliminary data, andget something that's better than BCG." The NIMR group, hecontinued, has now switched from M. leprae antigens to M.tuberculosis or M. bovis genes, and "obtained positive results fromanother, recently discovered, antigen, ESAT-6."

He expects to present this new data at an International BusinessCommunications meeting in Bethesda, Md., Oct. 23 and 24 ongenetic vaccines. A member of Liu's immunology group at Merckhelped to organize that event.

Liu, whom Lowrie called "a friendly rival," reports similar resultswith much the same strategy but different antigens.

"We did not target that particular heat-shock protein," Liu said,"because of an association with autoimmune responses." She added,"Lowrie agrees with that potential concern."

Merck's current anti-TB protein is called Antigen85. "Itssignificance," she explained, "is that it's actually secreted by theorganism. Since it's an intracellular pathogen, which resides insidethe cells it infects, the fact that it secretes the antigen presumablymakes it accessible to the intracellular processes of that target cell."

Wanted: More Antigens For Multivalent Vaccines

Liu sees as key to her work and Lowrie's that the naked DNAapproach "generates the particular types of immunity that are criticalfor preventing tuberculosis. This is in addition to its parity with BCGvaccine as a protective model. Therefore, we now are trying to makea vaccine that's better than BCG, by adding DNA encodingadditional antigens."

Right now, she observed, with support from the Wellcome Trust inLondon, a worldwide effort is well under way to sequence the wholeM. tuberculosis genome. When that becomes available, it will "allowthe relatively facile naked DNA technology to take genes, put theminto DNA constructs, then immunize animals, and screen for otherantigens without even having the protein."

Merck is applying the DNA vaccine approach to other pathogens,including influenza. It began Phase I clinical trials in April, at TheJohns Hopkins University. "Besides its focus on safety," Liu pointedout, "we also will get immunogenicity data as a spin-off."

Nature Medicine's third paper on a naked-DNA vaccine reports that"Suppressive vaccination with DNA encoding a variable region geneof the T-cell receptor prevents autoimmune encephalomyelitis andactivates Th2 immunity."

Its co-authors, an international research team, at the WeizmannInstitute in Rehovot, Israel, Stanford University in Palo Alto, Calif.,and the University of California at San Francisco, were able to"switch" the autoimmune response, with prospects for use againstdiseases such as multiple sclerosis, juvenile diabetes and rheumatoidarthritis. n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.