Thursday, June 7, 2012
An oral polio vaccine strain that cannot revert to virulence is needed Wouldn't it be nice to have a better sort of oral polio vaccine? Widespread use of the oral vaccine has brought the eradication of polio tantalisingly within reach. Since 1988 when the world embarked on an effort to wipe out the disease entirely, the number of cases has fallen by 99.8 per cent. Developed by an American scientist, Albert Sabin, the oral polio vaccine (OPV) uses weakened strains of the virus. The vaccine is easy to administer — simply put a couple of drops of it in a child's mouth. The viruses in the vaccine replicate in cells in the gut and evoke an immune response that protects the child when a wild virus comes along. Nevertheless, the oral vaccine has a major drawback, one that could stand in the way of the total eradication of all polioviruses. As it multiplies in the gut, the mutations that weaken the virus can get reversed, giving rise sporadically to vaccine-derived strains that are as virulent as wild forms and spread as easily. In India, although no child has so far fallen victim to the wild virus this year, one has already been paralysed by a vaccine-derived strain. Consequently, the endgame for polio eradication could well involve introducing inactivated polio vaccines (IPV), which use ‘killed' viruses that cannot replicate and therefore carry no risk of turning virulent again. But IPV has its own problems, including higher cost and the fact that it has to be injected. An oral polio vaccine strain that has been further crippled so that it cannot revert to virulence is therefore an attractive proposition. Recently, Hyderabad-based Ella Foundation received a grant from the ‘Grand Challenges Explorations' initiative of the Bill & Melinda Gates Foundation to develop just such a vaccine strain. The Ella Foundation is an independent scientific and industrial research organisation with a focus on research in infectious diseases. It was established by Krishna Ella and his wife, Suchitra Ella, who started the biotechnology company, Bharat Biotech International, which makes a variety of vaccines and biotherapeutics. Scientists of the Foundation would, according to information given on the Grand Challenges Explorations web site, “develop and test for use in a vaccine a live single-cycle poliovirus that has been modified to eliminate the gene essential for replication. This highly disabled virus will be tested for its immunogenicity and its inability to re-emerge as vaccine-derived poliovirus.” NO REPLICATION In a review paper published in 2006, U.S. scientists Tim Dudek and David Knipe, outline how it might be possible to create replication-defective viruses that could be used in vaccines. Such mutant viruses would possess the advantages of both classical types of viral vaccines, i.e. those using inactivated viruses and ones based on attenuated strains, they noted. The paper notes that by manipulating the viral genome, mutant versions could be made that lack a key protein needed for successfully completing its replication cycle in a cell. The mutants are then propagated in cell lines that supply the missing protein. If such mutated strain could be successfully created for polio, the idea is that, given as an oral vaccine, the viruses would infect intestinal cells and go through its replication cycle just once. But without the crucial protein, these viruses would not be able to produce viable progeny that could go on to infect other cells. According to information provided by the Ella Foundation's public relations agency, more experiments were needed before deciding which poliovirus gene (or genes) would be deleted. “The idea is full of holes,” exclaimed Vincent Racaniello, Higgins Professor of Microbiology and Immunology at Columbia University in the U.S., who has worked a great deal on the poliovirus. “First and foremost, if you are delivering a polio vaccine orally, I suspect that it has to replicate,” he pointed out in an email. THE BIG QUESTION It would be straightforward to delete a poliovirus gene and make a stock of the mutant virus. The question was what sort of immune response it would elicit after being given orally. Even if the mutant strain was taken up by gut cells, without viral replication and in the absence of immune-boosting chemicals known as adjuvants, “it would not make a robust immune response.” Although many replication-defective viral vaccines are being tested, particularly against HIV, none have yet been licensed for use in humans, said Dr. Racaniello in his email.