In brief

Viruses that are alive but minimally infectious make for good vaccines, but impairing virus infectivity remains a tricky problem.

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How to maim a virus without killing it

7 Nov 2019

Targeted mutagenesis is being used to create live-attenuated vaccines against the chikungunya virus.

In the 1950s, humanity scored a victory against one of the most debilitating diseases at that time—polio. The disease, caused by the poliomyelitis virus, was widely regarded as a death sentence until American virologist Jonas Salk developed a vaccine to prime the human immune system to detect and destroy the virus.

While the vaccine that Salk developed was based on viruses that had been killed or inactivated, another type of vaccine exists, consisting of living viruses that have been weakened so that they are unable to cause the full extent of infection. These are known as live-attenuated vaccines.

Creating a live-attenuated vaccine requires deep knowledge of how to maim a virus while keeping it alive. In the present study, researchers led by Lisa F. P. Ng at the Singapore Immunology Network (SIgN) developed a live-attenuated vaccine candidate against the chikungunya (CHIKV) virus, which causes fever and joint pain in its human host, using targeted mutagenesis.

“We introduced missense mutations into the CHIKV genome that were based on naturally occurring mutations in the Semliki Forest virus,” said Ng. Because the Semliki Forest virus belongs to the same family of alphaviruses as CHIKV, her team hypothesized that mutations resulting in less virulent Semliki Forest virus strains would similarly impair the ability of CHIKV to cause infections.

Mutations in the genes encoding non-structural proteins in CHIKV caused the virus to become less infectious. In the study, mice infected with mutant CHIKV had an acute viral load that was between ten to a thousand times lower compared to a control group infected with unmutated, or wild type CHIKV (WT-CHIKV). Despite the lower infection level, mutant CHIKV induced a stronger antiviral response in host mice than WT-CHIKV.

Additionally, the researchers noted a general reduction in immune cell infiltration into the joints of mice that were infected with mutant CHIKV strains as compared to WT-CHIKV, suggesting milder symptoms from the infection.

“In mice, vaccination with mutant CHIKV strains also induced a long-lasting protective antibody response which was slightly weaker than vaccination with WT-CHIKV, but it was sufficient to confer vaccinated mice with protection against subsequent WT-CHIKV challenge,” Ng explained.

She noted that the antibody response to the mutant CHIKV strains was also cross-protective against another closely related virus, the O’nyong-nyong virus.

“Our mutagenesis approach could be adopted to develop live attenuated vaccines specific for other alphaviruses as well,” she said.

The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN) and the Institute of Molecular and Cell Biology (IMCB).

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Chan, Y. H., Teo, T. H., Utt, A., Tan, J. J., Amrun, S. N. et al. Mutating chikungunya virus non-structural protein produces potent live-attenuated vaccine candidate. EMBO Molecular Medicine 11(6), e10092 (2019) | article

About the Researcher

Lisa F.P. Ng obtained her PhD in molecular virology in coronaviruses from the National University of Singapore (NUS) in 2002. After joining A*STAR’s Genome Institute of Singapore (GIS) in 2002 as a Postdoctoral Fellow, she worked on viral diseases such as hepatitis, severe acute respiratory syndrome and influenza. Ng is currently the Executive Director at A*STAR Infectious Diseases Labs (ID Labs) where she focuses on the immune responses to arthritic arboviruses that are epidemic or highly endemic in the tropical region. Ng has won numerous accolades for her research, including the ASEAN ‘International Young Scientist and Technologist Award’ in 2008 and A*STAR’s ‘Most Inspiring Mentor Award’ in March 2013.

This article was made for A*STAR Research by Wildtype Media Group