HIV envelope antigen valency on peptide nanofibers modulates antibody magnitude and binding breadth

Chelsea N Fries,Jui-Lin Chen,Joshua Eudailey,Derek W Cain,Cliburn Chan,Barton F Haynes,M Anthony Moody,Genevieve G Fouda,Joel H Collier,Maria L Dennis,Sallie R Permar,Kelly M Hainline,Richard Barfield,Kevin O Saunders,Brian E Watts,Nicole L Votaw

doi:10.1038/s41598-021-93702-x

Chelsea N Fries, Jui-Lin Chen + Show 14 more

Open Access

https://doi.org/10.1038/s41598-021-93702-x

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Abstract

A major challenge in developing an effective vaccine against HIV-1 is the genetic diversity of its viral envelope. Because of the broad range of sequences exhibited by HIV-1 strains, protective antibodies must be able to bind and neutralize a widely mutated viral envelope protein. No vaccine has yet been designed which induces broadly neutralizing or protective immune responses against HIV in humans. Nanomaterial-based vaccines have shown the ability to generate antibody and cellular immune responses of increased breadth and neutralization potency. Thus, we have developed supramolecular nanofiber-based immunogens bearing the HIV gp120 envelope glycoprotein. These immunogens generated antibody responses that had increased magnitude and binding breadth compared to soluble gp120. By varying gp120 density on nanofibers, we determined that increased antigen valency was associated with increased antibody magnitude and germinal center responses. This study presents a proof-of-concept for a nanofiber vaccine platform generating broad, high binding antibody responses against the HIV-1 envelope glycoprotein.

Highlights

A major challenge in developing an effective vaccine against HIV-1 is the genetic diversity of its viral envelope
The clade C HIV envelope glycoprotein (1086.C gp120) used in this study has been shown to induce strong antibody responses in mice when administered with Alum or AS01B adjuvant[49] and in non-human primates when adjuvanted with 3M-052-SE or STS/R84850
We demonstrate that conjugation of 1086.C gp[120] antigens to Q11 nanofibers is associated with improved immune responses toward this antigen by increasing the magnitude of antibody responses in adjuvanted formulations, and by improving the heterologous binding breadth of antibodies in both adjuvanted and unadjuvanted formulations

Summary

Introduction

A major challenge in developing an effective vaccine against HIV-1 is the genetic diversity of its viral envelope. We have developed supramolecular nanofiber-based immunogens bearing the HIV gp[120] envelope glycoprotein These immunogens generated antibody responses that had increased magnitude and binding breadth compared to soluble gp[120]. Nanoparticle vaccines have demonstrated several benefits over immunization with soluble proteins, existing approaches have not yet been able to consistently generate broad antibody responses. Peptide nanofibers have demonstrated unique immunogenicity in contexts where very few, and likely low-affinity B cell clones, exist These include tolerized epitopes such as those from autologous proteins such as TNF19 or IL-1720. Nanofiber vaccines can be administered mucosally[21,22] and do not require additional adjuvants to raise high-titer antibody responses[23], features which may be advantageous for a vaccine to be used in low-resource settings For these reasons, we have constructed proof-of-concept nanofiber vaccines displaying the HIV envelope antigen gp[120]. These effects were associated with the density of antigens on nanofibers, where increased antigen density was associated with increased antibody titers and induction of T follicular helper ( TFH) cells

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