AsianScientist (Apr. 16, 2015) – In September 2012, the results of an efficacy trial of the most advanced dengue vaccine candidate in development—Sanofi Pasteur’s live, attenuated, tetravalent formulation—were published in The Lancet. The results were highly anticipated, yet disappointing: the mosquito-borne disease is caused by four related viruses, or serotypes, and while the trial vaccine protected Thai children against three of these, it surprisingly gave no protection against the dengue 2 serotype.
While a handful of infectious diseases such as measles, polio and diphtheria have largely been eliminated thanks to highly effective vaccines, the complex biology and transmission cycles of other pathogens continue to pose a number of unique challenges.
In the case of dengue, vaccine development is complicated by the fact that immunity against one serotype does not protect against the others. In fact, through a phenomenon known as antibody-dependent enhancement, existing immunity can actually lead to more severe disease if a patient is infected a second time with a different serotype. Candidate vaccines must be therefore elicit potent immune responses to all four serotypes—a tall order, as evidenced by the outcome of the clinical trial.
The results nevertheless establish that a safe dengue vaccine is possible and an important milestone in the fight against the virus quartet, which causes 390 million infections annually, of which Asia is thought to account for 70 percent.
“The complexity of dengue virus infection has hampered vaccine research for decades. This is the first time in 50 years of dengue research that I have seen a vaccine that protected a large group of children from clinical disease caused by dengue viruses. Best yet, the vaccine met the highest safety expectations,” said Dr. Scott Halstead of the International Vaccine Institute in South Korea.
Other potential vaccine candidates are in various stages of development. In work published in PLoS Pathogens in August 2013, researchers at the Singapore Immunology Network and the Novartis Institute for Tropical Diseases generated a weakened strain of the dengue virus by mutating a gene coding for the enzyme 2’-O-methlytransferase. The enzyme normally modifies viral RNA, allowing it to fly under the radar of the host immune response. In animal models, immunization with the weakened virus provided full protection against infection with wild type virus.
“Wild type dengue virus escapes the human immune response efficiently and is therefore able to infect many cells in the body. Our vaccine is the first in the dengue field that contains targeted mutations to weaken the virus by blocking one of the virus’ strategies to escape the immune response,” as Dr. Katja Fink of SIgN, senior author of the study, explained to Asian Scientist Magazine.
“The targeted mutation strategy means that we can also make these mutations in new virus strains that will be relevant in maybe ten years from now. The dengue virus evolves constantly, so the vaccine which protects now might not protect so well in 10 or 20 years.”
Researchers are also developing drugs against the dengue virus (none have yet been approved for use). Earlier this year, researchers at the Singapore-MIT Alliance for Research and Technology engineered a monoclonal antibody that targets the dengue envelope protein and efficiently neutralizes all four virus serotypes; meanwhile, Celgosivir, a candidate anti-dengue compound derived from the seeds of the Moreton Bay chestnut tree, is currently undergoing clinical trials in Singapore.
Pandemic at the gate
While vector-borne diseases pose their own set of challenges, influenza perhaps typifies the kind of emerging disease that keeps public health experts awake at night. Its segmented genome and ability to replicate asymptomatically in non-human hosts such as birds and pigs give it enormous potential to recombine into strains that can be extremely virulent in humans.
As a case in point, Chinese scientists reporting in The Lancet in May 2013 found that the H7N9 outbreak strain that crossed the species barrier from birds to humans earlier in 2013 is actually a mish-mash of genes from four different bird influenza viruses: one from ducks, another from migratory birds, and two from chickens.
Because of the presence of multiple virus subtypes and their potential to mutate and recombine, influenza is the only disease against which we produce a new vaccine annually. The viruses incorporated into each vaccine are based on our best predictions of which influenza strains will cause the most disease that year. And we are not always right. In addition, although cell-based production is becoming more widely used, most vaccine production is still carried out by growing the virus in chicken eggs, a slower process that can significantly delay responses to outbreaks of novel strains.
Therefore, the ultimate goal would be to develop a universal influenza vaccine that protects against all virus strains. This could potentially be done by targeting highly conserved regions of the influenza hemagglutinin (HA) protein, a surface protein that the virus uses for docking onto cells it infects, or by making HA more accessible to the immune system.
In one such study, researchers at the US National Institute of Allergy and Infectious Diseases designed an experimental vaccine by fusing HA to a protein called ferritin, which has the ability to self-assemble into spherical nanoparticles. The resulting nanospheres present eight protruding HA spikes to the immune system, stimulating more potent and broader responses in rodent models than traditional vaccines, the researchers reported in Nature in May 2013. Importantly, the vaccine also protected against virus strains that it had not been designed against, representing a small step towards a pan-influenza vaccine.
Developing vaccines that can be produced efficiently is another key strategy. Singapore’s Agency for Science, Technology and Research (A*STAR) has partnered with Swiss company Cytos Biotechnology AG to carry out a clinical trial on a bacteriophage-derived virus-like particle (VLP) H1N1 vaccine candidate, which induces a potent immune response and can be easily produced on a large scale in bacterial cells. The agreement, which gives A*STAR the right to develop and commercialize the vaccine for Singapore and other ASEAN countries, will increase pandemic preparedness in the region.
“If this VLP vaccine strategy proves to be effective, it can accelerate the production of vaccines against new emerging strains of flu. This will greatly aid Singapore’s preparedness to produce vaccines quickly, safely and economically in the event of a flu epidemic. This could potentially open doors for faster production of vaccines to a range of viral diseases as well,” said Professor Alex Matter, CEO of the D3 (Drug, Discovery and Development) program and A*STAR’s Experimental Therapeutics Center.
The infectious disease challenges that remain for us to overcome are especially tricky, and addressing them will require a detailed and fundamental understanding of host-pathogen interactions, coordinated vaccine, drug and surveillance efforts, and a healthy dose of ingenuity. It remains to be seen whether we are up to the task.
This article was first published in the print version of Asian Scientist Magazine, Jan 2014.
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