Understanding Immune Responses to Build a Better Vaccine

Left to right: Mark Peeples, PhD; Asuncion Mejias, MD, PhD; and Octavio Ramilo, MD

Mark Peeples, PhD, is a principal investigator and member of the Center for Vaccines and Immunity at The Research Institute at Nationwide Children's Hospital. Asuncion Mejias, MD, PhD, is a principal investigator in the Center for Vaccines and Immunity at The Research Institute at Nationwide Children's Hospital and Octavio Ramilo, MD is the Chief of Infectious Diseases at Nationwide Children’s Hospital.

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In 2015, a team of six researchers received a $6.75 million program project grant from the National Institutes of Health to study immune responses to RSV with the ultimate goal of developing a vaccine candidate.

The team spans multiple areas of expertise and three research institutions: Nationwide Children’s Hospital, The Ohio State University and the University of South Florida. Its principal investigators include Octavio Ramilo, MD, Asuncion Mejias, MD, PhD, Mark Peeples, PhD, Jianrong Li, DVM, PhD, Stefan Niewiesk, DVM, PhD, and Michael Teng, PhD.

The team has published more than 46 peer-reviewed articles based on grant-funded research. And even more importantly, they’ve achieved their initial goal of developing a vaccine candidate for RSV.

 

Research by the team, including their 2020 publication in Science Translational Medicine, profiled immune responses in children with mild and severe RSV and led to an insight in clinical outcomes and a recommendation that for children with severe RSV, steroids should be avoided.

“By defining what a protective immune profile looks like, we can design the vaccine candidates that should stimulate that response,” says Dr. Mejias. “For example, we know based on in vivo and in vitro studies that higher levels of IL-6 indicate a more severe illness. But higher levels of IP-10 are protective. Understanding a ‘good’ immune response is critical to our success in developing an effective vaccine.”

The team’s novel vaccine candidate, described in the Journal of Virology, uses recombinant RSV carrying mutations in two viral proteins, one in the RSV G protein that attaches the virus to the ciliated cells lining the airways, and one in the RSV polymerase protein that replicates the virus genome.

“We learned several years ago that the G protein is cut when RSV is produced in cultured cells, making the virus less able to infect the cells lining the nose. We located the site of the cut and mutated it to prevent this cleavage. As a result, we increased the amount of vaccine produced by 5 times,” says Dr. Peeples.

The vaccine candidate was evaluated in the cotton rat model for in vivo immunogenicity and protection. Intranasal delivery of a small dose of the RSV vaccine candidate provided complete protection of both the upper and lower respiratory tracts.

REFERENCES:
Jenkin T, Wang R, Harder O, Xue M, Chen P, Corry J, Walker C, Teng M, Mejias A, Ramilo O, Niewiesk S, Li J, Peeples ME. A novel live attenuated RSV vaccine candidate with mutations in the L protein SAM binding site and the G protein cleavage site is protective in cotton rats and a rhesus macaque. Journal of Virology. 2021 Jan;95(3):e01568-20.
Xue M, Wang R, Harder O, Chen P, Lu M, Cai H, Li A, Liang X, Jennings R, La Perle K, Niewiesk S, Peeples ME, Li J. Stable attenuation of human respiratory syncytial virus for live vaccines by deletion and insertion of amino acids in the hinge region between the mRNA capping and methyltransferase domains of the large polymerase protein. Journal of Virology. 2020 Nov 23;94(24):e01831-20.
Heinonen S, Velazquez VM, Ye F, Mertz S, Acero-Bedoya S, Smith B, Bunsow E, Garcia-Maurino C, Olivia S, Cohen DM, Moore-Clingenpeel M, Peeples ME, Ramilo O, Mejias A. Immune profiles provide insights into respiratory syncytial virus disease severity in young children. Science Translational Medicine. 22 Apr 2020;12(540):eaaw0268.
Binjawadagi B, Ma Y, Binjawadagi R, Brakel K, Harder O, Peeples M, Li J, Niewiesk S. Mucosal delivery of recombinant VSV vectors expressing envelope proteins of RSV induces protective immunity in cotton rats. Journal of Virology. Feb 2021;95(6):e02345-20.