Can a biotechnology company afford to feel and act altruistic? Is itpossible to participate in the international Children's Vaccine Initiative,led by worldwide organizations to produce a supervaccine? Can acompany help children and those devastated by diseases such asmalaria and shigellosis by designing a clever biotech vaccine? Whathurdles lie in a firm's path to get that vaccine to market?Elegant design ideas for the perfect supervaccine _ one that canprotect against a variety of contagion from a single shot _ abound,Jerald Sadoff told attendees at the 21st International Symposium on theControlled Release of Bioactive Materials recently in Nice, France."There is a great need for a special usable vaccine but the regulatoryobstacles and the lack of return on a company's investment remain asproblems in vaccine development," said Sadoff, director of theDivision of Communicable Diseases and Immunology at Walter ReedArmy Institute of Research in Washington, D.C.Sadoff challenged the innovation and creativity of biotechnologycompanies to design the "ideal vaccine," one that:y is efficacious for everyone;y can be given as soon as possible after birth;y requires just one dose;y is easy to deliver (preferably oral);y is thermostable _ at 37 degrees Celsius (refrigeration can bedifficult).The Search For 'Milkmaids'"We're looking for milkmaids," said Sadoff, referring to thedevelopment of vaccines based on epidemiological data. Vaccinepioneer Edward Jenner noted that young milkmaids seemed protectedagainst smallpox. He later discovered that the secretions of cowpoxlesions prevented smallpox.Epidemiological correlations and animal models are primitive ways todiscover correlations between disease and immunity. Lots ofempiricism continues in the design of vaccines today. Researchers needto know how a vaccine protects _ its immunological mechanism ofaction also. Current dogma, or debate, contends that most vaccinesproduce antibodies against a pathogen or by cellular destruction. Thevaccine against meningococcus seems to have a bacterial action whileopsonic or engulfing methods destroy various toxic bacteria. Thediptheria, pertussis and tetanus vaccine acts by neutralizing toxin. Withthe cholera vaccine, the motility of the infectious organism is inhibited.How a vaccine protects is a moot point if you cannot get the vaccineinto people or animals. According to P.H. Lambert of the GlobalProgramme for Vaccines at the World Health Organization in Geneva,Switzerland, more than 10 million deaths occur each year frominfectious diseases worldwide. But all the design tricks cannotovercome the insufficient health systems in many areas of the world.Predicting that polio would follow smallpox as an eradicated disease bythe year 2000, Lambert noted vaccine production is up overall.Vaccines prevent 3 million deaths in children each year.Most vaccine development has focused on disease prevention amongpopulations in industrialized countries. These vaccines are not alwaysadaptable to situations in developing areas that generally lack adequatehealth care systems.Technical factors to overcome to better immunize developing countriesinclude:y age specificity _ ideally vaccines could be given for all diseasesduring the first six months of life;y complete vaccination of the population at risk;y repeated administration _ only about 30 percent receive thenecessary second or booster doses;y injection is a problem _ people would comply more with avaccination program if oral administration were available;y refrigeration _ a thermostable vaccine that did not require a stringentcold chain would help in the bush or rural areas."New technologies have allowed the conception of vaccines based onrecombinant proteins or polysaccharides known to be the immuneresponse target of the parent pathogen," noted Nathalie Garcon,manager of the Vaccine Formulation Science Division of SmithKlineBeecham in Belgium. "But a real need for a one dose vaccine hasemerged."Sustained ReleaseGarcon outlined how novel compositions of microspheres could beused to modulate their degradation rates and release of antigen. Bymixing microspheres with various degradation profiles, scientists couldmimic the vaccination effects of several consecutive injections. Inaddition, sustained release mechanisms could be used to administermultiple vaccines at once.What's needed for a sustained released vaccine? According to Garcon,it must be biodegradable, tissue compatible and nonimmunogenic(particularly when antigen is present). It also must be processed easilyas well as retain the optimum conformation and the epitope must bepreserved. Microsomes, nanoparticles and liposomes have worked inanimal studies and remain contenders in the formulation in a controlledrelease vaccine.Another question related to immunity is how to formulate the polymerstructure of the vesicle for antigen release. Will pulse release or slowrelease produce the optimum vaccination immunity? Burst effect andantigen dispersion from the polymer core come into play in pulserelease. Sustained release of a vaccine might require more of amicrocapsule formulation.What should a scientist consider when designing a controlled releaseformulation for a vaccine? Garcon suggests starting with the polymer'ssolubility in water.Next, is the polymer biocompatible with people and the antigen? Theantigen's integrity depends on its molecular nature. Linear peptidesusually do well with polymers, but whole viruses and recombinantproteins are highly sensitive to the environment. Sometimes placing theantigen in a matrix aids its immunogenicity. Old standard materials,such as polymethylmethacrylate (PMMA), and new ones, such aspolyphosphazene, allow the scientist to optimize the system.Mixing various types of microspheres may lead to the goal of a one-shot vaccine. But oral administration may be possible via the buccal ormucosal route rather than through the gastrointestinal tract."Sustained release of vaccine is complex, but evidence from animalstudies shows it is a reachable goal," said Garcon. She did not venturehow costly a goal, however.The vaccine section ended the recent International Symposium on theControlled Release of Bioactive Materials. "Overwhelmed" woulddescribe the feeling that settled over the attendees. But the directors ofvarious groups supporting the worldwide Children's Vaccine Initiativeadmitted the global picture can be discouraging.The speakers challenged the business and science participants toexplore ways to make vaccinating the world easier, cheaper and moresuccessful. They even discussed the problem of the lack of anyfinancial return for all the effort that goes into devising and making avaccine.As one attendee put it, how can you convince a company to developany vaccine when the total worldwide income from all vaccinesreaches only $1 billion annually? Compared to the $3 billion yearlysales for a drug such as erythropoietin (EPO), vaccines are not thatattractive an investment.Another example of the problematic pricing for vaccines is the hepatitisB vaccine. Developed for an "at risk" population, the U.S. Centers forDisease Control and Prevention in Atlanta recently came out in favorof all children receiving this vaccine. The initial pricing for the three-dose hepatitis B vaccine was $60, but now all three doses sell for $2 to$6. Of course, the physician/practitioner's markup will dissuade manyfamilies from inoculating their offspring against hepatitis B. Althoughonly a few dollars buys the total vaccination, doctors routinely charge$40 to $50 for each injection ($150 for all three doses)."Imagine having to administer the vaccine to my whole hospital staffwho [are] at risk for hepatitis B because they work with bloodproducts," said Robert Gurny of the University of Geneva, one of theorganizers of the vaccine section at the international symposium.Governments have emerged as the obvious source of research budgetfunds for vaccine research. Alternatively, governments need to deviseways for biotech and pharmaceutical companies to avoid the liabilitiesof vaccines. But industry has not welcomed this suggestion with openarms. While agencies and industry look for solutions, the pathogenscausing malaria, AIDS and tuberculosis continue to trick the humanimmune system. n
-- Mary Jean Pramik Special To BioWorld Today
(c) 1997 American Health Consultants. All rights reserved.