Structure-based design of a quadrivalent fusion glycoprotein vaccine for human parainfluenza virus types 1-4.

Published

Journal Article

Parainfluenza virus types 1-4 (PIV1-4) are highly infectious human pathogens, of which PIV3 is most commonly responsible for severe respiratory illness in newborns, elderly, and immunocompromised individuals. To obtain a vaccine effective against all four PIV types, we engineered mutations in each of the four PIV fusion (F) glycoproteins to stabilize their metastable prefusion states, as such stabilization had previously enabled the elicitation of high-titer neutralizing antibodies against the related respiratory syncytial virus. A cryoelectron microscopy structure of an engineered PIV3 F prefusion-stabilized trimer, bound to the prefusion-specific antibody PIA174, revealed atomic-level details for how introduced mutations improved stability as well as how a single PIA174 antibody recognized the trimeric apex of prefusion PIV3 F. Nine combinations of six newly identified disulfides and two cavity-filling mutations stabilized the prefusion PIV3 F immunogens and induced 200- to 500-fold higher neutralizing titers in mice than were elicited by PIV3 F in the postfusion conformation. For PIV1, PIV2, and PIV4, we also obtained stabilized prefusion Fs, for which prefusion versus postfusion titers were 2- to 20-fold higher. Elicited murine responses were PIV type-specific, with little cross-neutralization of other PIVs. In nonhuman primates (NHPs), quadrivalent immunization with prefusion-stabilized Fs from PIV1-4 consistently induced potent neutralizing responses against all four PIVs. For PIV3, the average elicited NHP titer from the quadrivalent immunization was more than fivefold higher than any titer observed in a cohort of over 100 human adults, highlighting the ability of a prefusion-stabilized immunogen to elicit especially potent neutralization.

Full Text

Duke Authors

Cited Authors

  • Stewart-Jones, GBE; Chuang, G-Y; Xu, K; Zhou, T; Acharya, P; Tsybovsky, Y; Ou, L; Zhang, B; Fernandez-Rodriguez, B; Gilardi, V; Silacci-Fregni, C; Beltramello, M; Baxa, U; Druz, A; Kong, W-P; Thomas, PV; Yang, Y; Foulds, KE; Todd, J-P; Wei, H; Salazar, AM; Scorpio, DG; Carragher, B; Potter, CS; Corti, D; Mascola, JR; Lanzavecchia, A; Kwong, PD

Published Date

  • November 27, 2018

Published In

Volume / Issue

  • 115 / 48

Start / End Page

  • 12265 - 12270

PubMed ID

  • 30420505

Pubmed Central ID

  • 30420505

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1811980115

Language

  • eng

Conference Location

  • United States