A study led by Australian researchers at the University of Queensland (UQ) has shown that a newly developed antibody targets the flavivirus nonstructural protein 1 (NS1) and was shown to reduce viremia and improve survival in mouse models of dengue, Zika and West Nile infections.
"We initially identified NS1 as a potential new target for flavivirus treatments in 2015, after the Zika outbreak," said study leader Daniel Watterson, an associate professor in the School of Chemistry and Molecular Biosciences at UQ in Brisbane.
"Now we have shown for the first time that a single NS1 antibody, 1G5.3, can be protective against multiple flaviviruses, with no other antibody having shown such a broad range of protection."
Study first author Naphak Modhiran, a research fellow in the School of Chemistry and Molecular Biosciences at UQ, said the antibody could also provide the first line of defense in future viral outbreaks across the world.
"The antibody can bind NS1 from a very wide range of mosquito-borne flaviviruses that have already caused local outbreaks in the past and have the potential to be the next Zika," said Modhiran.
"These include the dengue, Zika, West Nile, Saint Louis and Japanese encephalitis, yellow fever, Spondweni, Ilheus, Rocio and Usutu viruses," she told BioWorld Science.
"Although it is hard to predict pandemic emergence, the Usutu, Ilheus, Rocio and Spondweni viruses all have the potential for sudden emergence [as happened with] Zika."
Reported in the January 8, 2021, edition of Science, the new study could lead to the development of broad-spectrum vaccines or therapies to reduce global mortality due to flaviviruses, in particular that due to the dengue virus.
For example, an estimated 390 million people are infected with the dengue virus each year, approximately half a million of whom will develop potentially fatal dengue hemorrhagic fever.
However, at present there are no effective flavivirus treatments available and their development may be limited by antibody-dependent enhancement (ADE), whereby antibodies that target the main viral envelope protein can also enhance disease.
"Creating flavivirus vaccines and therapies has been greatly hindered by ADE, which has also contributed to the complications arising from large-scale roll-out of the first licensed dengue vaccine," said Watterson.
When that vaccine, Dengvaxia (Sanofi Pasteur), was used in the Philippines, "there was indirect evidence of vaccine-induced ADE in the roll-out, with vaccinated seronegative children having a higher rate of dengue hospitalization than controls," Watterson told BioWorld Science.
"These results led to restricted use of the vaccine, which was a major blow for dengue vaccine development, as this was the first licensed vaccine," he said.
"But because NS1 antibodies don't drive ADE, our [current study's] findings provide the blueprint for new and safe broad-spectrum vaccines against multiple flaviviruses, including dengue."
In the new Science study, the UQ researchers collaborated with scientists at the Institute of Microbiology of the Chinese Academy of Sciences in Beijing to provide the structural basis of NS1 cross-reactivity through co-crystallization of the 1G5.3 antibody with dengue and Zika NS1 proteins.
"Co-crystallization of both the NS1 antigen and 1G5.3 antibody fragment allowed us to elicit the structure of the complex by X-ray diffraction to see how 1G5.3 binds to NS1 from both dengue and Zika viruses," explained Watterson. "This will allow the rational design of improved broad-spectrum antibodies and small-molecule antivirals that target the same site... Most importantly, it will allow the development of targeted vaccines that aim to elicit 1G5.3-like antibodies upon vaccination."
The antibody blocked flavivirus NS1-mediated cell permeability in disease-relevant cell lines, which "establishes the mechanism of protection for 1G5.3 and shows that it can block disease-specific pathological functions of NS1 from multiple viruses," said Modhiran.
Importantly, therapeutic administration of 1G5.3 was shown to reduce viremia and improve survival in mouse models of dengue, Zika and West Nile infections.
"Antibody treatment showed the highest potency in mice challenged with dengue, in which it provided 90% protection, followed by 50% protection in mouse models of Zika," said Modhiran.
Moreover, "1G5.3 antibody treatment prolonged survival time in mice infected with the West Nile virus and reduced the viral load by approximately 5-fold in all mouse models tested."
While no safety issues were observed in mice, "testing in humans will be critical, as some NS1 antibodies have been reported to have cross-reactivity against human proteins," said Watterson.
"Nevertheless, we have demonstrated that 1G5.3 does not react with human plasminogen, which is a previously identified auto-antigen for NS1 antibodies, which is good news for the potential for 1G5.3 to be used in humans."
However, "because 1G5.3 is a murine antibody that was developed using immunized mice, it would be best to make a fully humanized equivalent antibody, in order to improve pharmacokinetics and reduce any anti-murine response in human use," said Watterson.
"This work is currently underway and is expected to take 1-2 years before a lead humanized antibody might be ready for clinical phase testing, which will represent the first NS1-targeting therapeutic with the potential for broad-spectrum protection."