(ORDO NEWS) — The new technology is designed to stop the spread of Ebola, rabies and other viruses in wildlife. It could prevent the next pandemic by preventing pathogens from passing from animals to humans.
Imagine a drug that is as contagious as the disease it fights – a vaccine that can replicate in the host and spread to other people nearby, quickly and easily protecting the entire population from microbial attacks.
This is the goal of several groups of specialists around the world who are resurrecting controversial research on the development of self-propagating vaccines.
They hope to reduce the transmission of infectious diseases in wildlife, thereby reducing the risk that dangerous viruses and bacteria can pass from wildlife to humans, as many experts believe happened with the SARS-CoV-2 virus that caused the COVID pandemic. -19.
The US Centers for Disease Control and Prevention estimates that 60 percent of all known infectious diseases and 75 percent of new or emerging infectious diseases are zoonotic.
Scientists cannot predict why, when, or how new zoonotic diseases will emerge. But when they appear, these diseases are often deadly, and the fight against them is costly. Moreover, many researchers predict that climate change, biodiversity loss and population growth will accelerate their spread.
Vaccines are a key tool to prevent the spread of disease, but wild animals are difficult to vaccinate because each one must be found, captured, vaccinated and released into the wild. Self-propagating vaccines offer a solution to this problem.
Advances in genomic technology and virology, as well as a better understanding of disease transmission, has accelerated work that began in the 1980s to create genetically engineered viruses that spread from one animal to another, conferring immunity to disease rather than infection.
Researchers are currently developing self-propagating vaccines against Ebola, bovine tuberculosis and Lassa fever, a viral disease spread by rats that causes up to 300,000 infections each year in parts of West Africa. This approach could be extended to control other zoonotic diseases, including rabies, West Nile virus, Lyme disease and distemper.
Proponents of self-propagating vaccines say they could revolutionize public health by interrupting the spread of infectious diseases in animals before zoonotic spread occurs – potentially preventing the next pandemic.
However, others argue that the viruses used in these vaccines can themselves mutate, change into another species, or cause a chain reaction with devastating consequences for entire ecosystems.
“Once you release something engineered and self-transmitting into nature, you don’t know what will happen to it or where it will go,” says Jonas Sandbrink, a biosecurity researcher at Oxford University’s Future of Humanity Institute. “Even if you just start spreading it in animal populations, some of the genetic elements can get back into the human body.”
First and only field trial of a self-propagating vaccine
In 1999, veterinarian José Manuel Sanchez-Viscaino led a team of researchers to Isla del Aire, off the east coast of Spain, to test a self-propagating vaccine against two viral diseases: rabbit haemorrhagic disease and myxomatosis.
Although neither of these diseases infects humans, at that time both of them had been decimating the populations of domestic and wild rabbits in China and Europe for several decades.
Traditional vaccines for both diseases were used for domestic rabbits, but capturing and vaccinating wild rabbits, which are known to breed rapidly, was an insurmountable task, Sanchez-Viscaino explains. He saw great potential in self-propagating vaccines.
In the lab, Sanchez-Viscaino, then director of the Center for Animal Health Research in Spain, and his team cut out a gene from the rabbit hemorrhagic disease virus and inserted it into the genome of a weak strain of the myxoma virus that causes myxomatosis.
The result was a hybrid viral vaccine that protected both rabbit haemorrhagic disease and myxomatosis. Sanchez-Viscaino suggested that because the vaccine was similar enough to the original myxoma virus that caused the disease, it would still spread to wild rabbits.
On the island, a team of researchers captured 147 rabbits, placed microchips on their necks, vaccinated about half of them, and released them back into the wild. During the next 32 days, vaccinated and unvaccinated rabbits lived as usual.
When the researchers took microchipped rabbits that had not been vaccinated initially, they found that 56 percent of them had antibodies to both viruses, indicating that the vaccine had successfully spread from vaccinated to unvaccinated animals.
This experiment was the first field test of the concept of self-propagating vaccines and is still the only one in history.
In 2000, the research team submitted laboratory and field data to the European Medicines Agency, or EMA, for evaluation and approval for real-world use. The EMA noted technical problems with evaluating the safety of the vaccine and required the team to decipher the myxoma genome, which had not been done before.
Although the group was given two years to meet this requirement, the funding body did not provide support for further work, recalls Juan Barcena, then a graduate student working under Sanchez-Viscaino.
Barcena no longer advocates self-propagating vaccine technology, but he says data from laboratory and field trials showed the vaccine was safe and was limited to distribution to the rabbit population.
However, Barcena doubts the EMA would ever approve their vaccine, given the hesitancy and controversy surrounding genetically modified organisms.
Scott Nuismer, a professor at the University of Idaho who is now doing research on mathematical modeling of self-propagating vaccines, noted that the Sanchez-Viscaino vaccine may have posed a greater risk than existing technologies because the team used the myxoma virus, which is itself deadly, as a vaccine carrier. .
Since the field trials at Isla del Aire, research into self-propagating vaccines has largely died down. According to Sanchez-Viscaino, pharmaceutical companies were not interested in investing in research and development of technology that was supposed to lower their own profit margins.
Vaccines under development
Renewed interest and funding for the technology occurred around 2016, and today several research groups are developing self-propagating animal vaccines.
Each of these new vaccines are so-called recombinant viruses. First, the researchers identify a target microbe protein that serves as an antigen, a substance that triggers an immune response in vaccinated people or animals.
The researchers then select a virus that will carry the vaccine and distribute it. To do this, the researchers capture several animals from the target population – Ebola test animals, Lassa rats – and isolate a virus that naturally infects these animals. They then add genetic material from the target population to create a vaccine.
Each of these vaccines uses cytomegalovirus, or CMVs, which belongs to the herpes family.
DEMs help researchers overcome several technical challenges. For example, CMVs have large double-stranded DNA genomes, which means their genetic code is more stable and can accommodate additional target microbe genes, says Alec Redwood, chief scientist at the University of Western Australia. He did research on self-propagating vaccines in the early 2000s and is now a member of a team developing a CMV-based Lassa vaccine.
CMV also infects the host for life, elicits a strong immune response, and does not often cause severe disease. Perhaps most importantly, CMVs are uniquely species-specific; for example, CMV that spreads among Mastomys natalensis, a species of rat that spreads Lassa fever, cannot infect animals other than M. natalensis.
Several small studies have shown that CMV-based Ebola and bovine TB vaccines are effective when traditionally injected. In two trials involving about 50 monkeys, the CMV-based TB vaccine reduced the incidence by 68 percent, according to the researchers. In a separate study, three out of four monkeys vaccinated with the Ebola vaccine survived direct exposure to Ebola.
Similar experiments with a Lassa virus vaccine are scheduled to begin within a year, Redwood said. This vaccine will also use proprietary genetic protection that will allow researchers to control the number of times the vaccine is replicated, thereby limiting its duration, Redwood explains.
So far, no field or laboratory studies have been conducted evaluating the impact and safety of these vaccines delivered by a self-propagating mechanism. However, a recent mathematical modeling study reported that if everything works as expected, a Lassa fever vaccine release could reduce disease transmission in rodents by 95% in less than a year.
“You really see how powerful this idea can be,” says Nuismer, who was senior author on the modeling study.
Risks of self-propagating vaccines
Despite the potential benefits, many experts warn that too little is known about zoonotic disease transmission and virus evolution to accurately predict what might happen if a self-propagating vaccine were released into the wild.
“Our understanding of the dynamics of infectious diseases in the wild for the most part remains too simple to reliably predict the outcome of such an intervention,” says Andrew Peters, associate professor of wildlife health and pathology at Charles Sturt University in Australia and president of the Wildlife Diseases Association. .
Barchena’s view of self-spreading diseases changed after he saw how previous animal control strategies involving the deliberate release of viruses led to unintended consequences.
For example, the myxoma virus, which has become such a devastating problem in Europe, arose because a man in France deliberately released the virus in 1952 to keep rabbits out of his home garden.
In 2018, Spanish researchers began noticing that the myxoma virus was killing wild hares, a rabbit-like species. Scientists sequenced its genome and concluded that the myxoma virus mixed with the poxvirus, which allowed it to pass into another species.
“I don’t know if the mathematical model could say that something like this could happen 70 years later,” says Barcena, who is now a senior fellow at the Center for Animal Health Research in Spain.
Philippa Lenzos, an expert on science and international security at King’s College London, notes that viruses are genetically unstable and prone to frequent mutations; therefore, a self-propagating vaccine virus can evolve into a different species or cause other unknown effects in wild and domestic animal populations, and possibly even in humans.
Nuismer and Redwood say that, given the biology of the virus, it is extremely unlikely that a CMV-based vaccine will ever be able to crossover.
Although the evolutionary factors underlying the species specificity of CMV are not fully known, neither in the wild nor in the laboratory has a single case of successful cross-species infection of CMV been documented.
Another potential risk of self-resorbable vaccines is that ridding wild animals of infectious diseases could disrupt natural population control.
Rodents that spread the Lassa virus are pests that destroy crops and homes, contaminate stored food and drinking water, and create unsanitary living conditions. If the virus no longer affects them, their numbers can increase dramatically.
“Let’s say we cure these rodents of the Lassa virus, and that’s good, that’s great for humanity. But what if this virus controls their population or something like that? And then we get a wild expansion of reservoir rodents,” Nuismer says. “I think it’s a much safer place where we can go wrong…because we can flip the ecology in a way that’s very unfortunate,” he says.
In addition, there is an emerging understanding that viruses and bacteria exist in complex microbial ecosystems, possibly keeping each other’s populations in check. Exposure to a self-propagating vaccine that kills one specific virus may have unknown consequences.
“Dramatically rebalancing by trying to eradicate or reduce an endemic virus in nature could lead to the risk of other pathogens emerging that will affect wild animals themselves, as well as humans and our pets,” says Peters.
To mitigate these risks, Nuismemer and Redwood envision a gradual transition from laboratory testing to large-scale enclosures, possibly on an island, as Sanchez-Viscaino and his team did more than 20 years ago.
Long way ahead
Most researchers agree that self-propagating vaccines can never be used in human populations because universal informed consent will never be reached.
“We can’t even get people to take the vaccine during a global pandemic. The idea that you can covertly vaccinate the population with the virus without causing unrest is just fantasy. It will never be used on humans,” says Redwood.
But even the use of a self-propagating vaccine in animals faces regulatory and social hurdles.
“What are the political consequences of such interventions that do not recognize and cannot be contained by state or national boundaries?” Peters asks. Peters asks.
Sandbrink also notes that self-propagating vaccine research poses a biosecurity risk. Developing them and preventing some of their potential consequences involves fine-tuning transmissibility and changing genetic stability – techniques that “in a unique way advance certain capabilities applicable to the creation of viruses for pandemics and as biological weapons,” he says.
The scientific community and global health, as well as funding bodies, should consider alternative solutions that provide the same benefit with less risk, Sandbrink urges.
For example, educating people about how to safely interact with wild animals can reduce the chances of spreading viruses. Improving disease surveillance in high-risk areas and scaling up research and development of traditional vaccines and therapeutics for humans and livestock are also key strategies.
Given the extremely high risk and international nature of this work, and that the effects are “potentially irreversible”, Lentsos believes that stakeholders should engage in dialogue on how this research is regulated, and Nuismemer and Redwood agree that there is more to come. long haul.
“You don’t have to be a Rhodes scientist to understand that people will be nervous about a spreading viral vector. It’s a concept that will scare people,” says Redwood.
“I like to think of it like this: maybe it will never be used, but it’s better to have something in the closet that can be used and will mature if needed. And to say:” Let’s just not do this research, because it too dangerous” – in my opinion, pointless.
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