Saturday, June 29, 2019

It's Been Called 'Pig Ebola': "Scientists Race to Build Vaccine for African Swine Fever"

From The Scientist, June 24:

The devastating outbreak of the disease that has led to millions of pig deaths in East Asia has intensified efforts to develop a vaccine quickly, but the virus presents several challenges that are yet to be overcome.
African swine fever, a fatal disease of pigs, has been around for decades. Believed to have originated in sub-Saharan Africa, it’s made several visits to other continents, with outbreaks surfacing in Russia, Brazil, and various parts of Europe—where it still maintains a stronghold in wild boar populations.
But it only escalated to what Dirk Pfeiffer calls “the biggest animal disease outbreak ever” when it reached China last August, spreading like wildfire across the world’s largest pig congregations. “There’s so many pigs in China, it was just a matter of time,” says Pfeiffer, a veterinary epidemiologist at the City University of Hong Kong and the UK’s Royal Veterinary College.
The disease not only threatens the world’s largest pork industry, but also the global supply of the blood thinner heparin, most of which is produced by Chinese pigs.

Alarmed, Chinese officials have reportedly culled more than 1.2 million pigs to date in an attempt to prevent new infections, but the disease is spreading and has jumped to Vietnam and Cambodia in recent months. Pfeiffer reckons that anywhere between 10 percent and 40 percent of Chinese pigs could have been infected with the virus so far, although official statistics have not yet been released.
Desperate for a vaccine, China has put around $15 million towards research on the virus, according to Nature News, spurring researchers to find one quickly. There are several routes researchers are taking to do so, but this is proving challenging—in part because of the very nature of the virus.

Early failures of an ASFV vaccine
The sheer complexity of African swine fever virus (ASFV) is one reason why it’s so hard to tackle. Its double-stranded DNA genome can span an impressive 190 kilobases and codes for almost 170 proteins, dwarfing many other viruses, such as Ebola (some strains have only 7 proteins).
ASFV infects and replicates in macrophages, but also induces cell death in uninfected B and T lymphocytes. “It effectively wipes out the immune system so there’s not an effective response,” explains Linda Dixon, a virologist at the UK’s Pirbright Institute, part of the government’s Biotechnology and Biological Sciences Research Council. Ultimately, ASFV kills pigs by causing extreme hemorrhagic fever and massive destruction of lymphocytes in lymph tissues.

Both early studies in 1967 and more recent ones have shown that the classical and most obvious strategy of developing a vaccine doesn’t work for ASFV: killing or inactivating the virus and injecting it into healthy animals to prompt their immune system to generate antibodies that protect against future infections was attempted, but it failed. The protective antibodies produced just weren’t enough to ward off ASFV infection.

Scientists have instead learned that one of the most effective ways to produce immunity against ASFV is to expose animals to a less virulent strain of the virus. This can be produced through passaging the virus in culture until it loses its virulence, a strategy that has been successful in containing the spread of a different virus that causes similar symptoms in pigs, classical swine fever. Alternatively, attenuated viruses can be isolated from animals: in wild boar populations across Europe, for instance, many ASFV strains have naturally lost their potency to kill over time.

Some groups have shown that injecting a weaker ASFV strain isolated in 2017 from a wild boar in Latvia can protect domestic pigs against a virulent form of the virus, explains José Manuel Sánchez-Vizcaíno, a virologist at the World Organization for Animal Health’s reference laboratory for ASF in Madrid. He and his colleagues recently demonstrated that the same strain could also protect wild boars, an approach he thinks may be helpful in preventing spillovers of the disease to domestic pigs.

However, the main concern with live attenuated vaccine candidates is safety. Researchers realized this as early as the 1960s, when they tried to vaccinate large numbers of pigs in Portugal and Spain with a naturally attenuated form of ASFV. Although the animals didn’t die, many of them developed a debilitating, chronic form of the disease. “This is the biggest problem: it’s good protection, but not very safe,” explains Sánchez-Vizcaíno. He and his colleagues are currently evaluating the safety of their attenuated virus.

Genetically modified viruses
As researchers have amassed more knowledge about ASFV’s biology and its genome, they have adopted a more targeted approach to attenuate ASFV: genetically modifying the virus by deleting genes that make it so virulent and then vaccinated animals with it. “It’s a case of trying to disarm the virus so that the host has a chance to respond and control replication and induce an adaptive immune response that will be a memory response,” explains Dixon....