Over the past 60 years, some six million people _nearly half theworld's present population _ have had live tuberculosis bacteriainjected into their skin to ward off tuberculosis. The vaccine theyreceived, universally known as BCG, consists of weakenedMycobacterium bovis, the strain that infects cows.
The acronym stands for Bacille Calmette-Guerin, named after twoFrench scientists who developed BCG in the early 1900s.
Just as the cowpox virus immunized humans against smallpox,BCG's cow microbe prevents infection by the virulent M.tuberculosis, which is now staging a comeback in the world.
The U.S. eschews BCG immunization, because a person vaccinatedwith BCG converts to BCG-positive, so that the patch-test screeningfor exposure to tuberculosis is lost. With the current reemergence oftuberculosis, that policy may be changing.
BCG vaccination against tuberculosis is mandatory in 64 countries,and recommended in another 118, as mucosal immunologistSolomon Langermann, who directs mucosal immunity and vaccinesat MedImmune Inc., in Gaithersburg, Md., will report tomorrow to aNational Institutes of Health seminar in Bethesda on "Vaccines: newapproaches and concepts."
Recombinant BCG Delivers Lyme Antigen
He will tell the seminar of a recently completed preclinical trial ofrecombinant BCG as a vector for intranasal delivery of an antigenfrom a totally unrelated microbe, Borrella burgdorferi _ the tick-borne pathogen of Lyme disease.
In today's issue of Nature (Dec. 8), the MedImmune researcher setsout the full story of how seven mice that inhaled the BCG-Borrellaantigen developed strong immunity to Lyme disease. The paper, ofwhich he is first author, reports: "Systemic and mucosal immunityinduced by BCG vector expressing outer-surface protein A ofBorrella burgdorferi."
Snuffling the vaccine into the respiratory tract by nasal spray, insteadof by needle into the bloodstream, exposes the pathogenic antigen tothe far-flung immune defenses of the body's mucosal surfaces. Theseantibody-generating mucous membranes, Langermann explained,extend from nose and mouth down through the airways and lungs,and from the esophagus and stomach on through the gastrointestinal,urinary and genital tracts.
In humans, Langermann pointed out, "the mucosal surfaces representthe largest area of exposure to infectious pathogens, and thereforethe first line of defense against many diseases."
A single snort of the vaccine conferred on the mice, as Naturereported, "a prolonged [more than one year] protective systemic [i.e.,total-body] IgG [antibody] response and a highly sustained secretoryIgA response, which is disseminated throughout the mucosalimmune system."
Injectable Version Poised For Phase I Trial
MedImmune had previously developed a vaccine against Lymedisease based on its conversion of BCG into a multi-purposerecombinant vector. A Phase I clinical trial of this formulation,injected intradermally, (like BCG TB vaccine) will begin "withinweeks," the company's investor relations manager, Mark Kaufmann,told BioWorld Today. The controlled study, in adult volunteers, willtake place at the University of Maryland-Baltimore's Center forVaccine Development. Results, Kaufmann said, "may be expectedwithin a year."
Lyme disease surfaced in 1975 as an exotic ailment, named for theConnecticut town of Lyme. It's now reported from all 48 continentalstates, where 10,000 new cases a year arise.
"A number of groups would be interested in looking at human trialsof intranasal immunization against Lyme disease," Langermann said,"We don't have any immediate plans to do that, but we'd certainlylike to explore the possibility."
Before trying a mucosal vaccine on people, he says "the next stepwould be to look at a more human-like animal than the mouse _ aprimate _ to see if we get similar mucosal immune responses."
Beyond B. burgdorferi, he and his co-workers have expressed, asBCG surface antigens, foreign proteins from bacteria that cause anumber of other mucous-membrane, diseases, such as pneumonia,urinary tract infection, and respiratory and gastrointestinal diseases.
"In many cases," Langermann said, "we express them as surfacelipoproteins, which makes them highly immunogenic." In fact, thismonth's Journal of Experimental Medicine reports such alipoprotein-armed (though non-mucosal) vaccine againststreptococcal pneumonia infection, with BCG expressing the S.pneumoniae surface protein antigen.
"To get expression of these foreign antigens in BCG," Langermannexplained, "we use mycobacterial shuttle vectors, where we canclone antigens in E. coli on vehicles that replicate in both that hostcell and in the mycobacterium. Then, we transform these plasmids,and electroporate them into BCG."
Summing up, Langermann said, "Recombinant BCG may be avaluable vaccine delivery method for introducing primary protectionagainst respiratory, gastrointestinal and sexually transmittedorganisms, which gain entry via mucosal surfaces, while at the sametime providing a long-lasting systemic response." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.