Characterization of HIV-1 Nucleoside-Modified mRNA Vaccines in Rabbits and Rhesus Macaques

Norbert Pardi,Celia C Labranche,Guido Ferrari,Derek W Cain,István Tombácz,Robert J Parks,Hiromi Muramatsu,Barbara L Mui,Ying K Tam,Katalin Karikó,Patricia Polacino,Christopher J Barbosa,Thomas D Madden,Michael J Hope,Barton F Haynes,David C Montefiori,Shiu-Lok Hu,Drew Weissman

doi:10.1016/j.omtn.2019.03.003

Abstract

Despite the enormous effort in the development of effective vaccines against HIV-1, no vaccine candidate has elicited broadly neutralizing antibodies in humans. Thus, generation of more effective anti-HIV vaccines is critically needed. Here we characterize the immune responses induced by nucleoside-modified and purified mRNA-lipid nanoparticle (mRNA-LNP) vaccines encoding the clade C transmitted/founder HIV-1 envelope (Env) 1086C. Intradermal vaccination with nucleoside-modified 1086C Env mRNA-LNPs elicited high levels of gp120-specific antibodies in rabbits and rhesus macaques. Antibodies generated in rabbits neutralized a tier 1 virus, but no tier 2 neutralization activity could be measured. Importantly, three of six non-human primates developed antibodies that neutralized the autologous tier 2 strain. Despite stable anti-gp120 immunoglobulin G (IgG) levels, tier 2 neutralization titers started to drop 4 weeks after booster immunizations. Serum from both immunized rabbits and non-human primates demonstrated antibody-dependent cellular cytotoxicity activity. Collectively, these results are supportive of continued development of nucleoside-modified and purified mRNA-LNP vaccines for HIV. Optimization of Env immunogens and vaccination protocols are needed to increase antibody neutralization breadth and durability.

Highlights

There has been great progress in understanding the biology of human immunodeficiency virus type 1 (HIV-1) infection, but no effective vaccine has advanced to clinical development
The ability of selected HIV-1 anti-Env antibodies to bind to 1086C Env protein expressed on the surface of transfected 293F cells was determined by flow cytometry. 1086C Env gp[160] binding to antibodies CH58,14 CH106,15 and 17b16 was observed (Figure S2)
Immunization with Nucleoside-Modified 1086C Env mRNA-Lipid nanoparticle (LNP) Elicits High Levels of Antigen-Specific Antibodies with antibody-dependent cellular cytotoxicity (ADCC) and Tier 1 Virus Neutralization Activity in Rabbits New Zealand white rabbits were intradermally immunized with 50 mg ($0.025 mg/kg) 1086C B2 ecto Env, influenza virus A/California/07/ 2009 hemagglutinin (HA)-encoding[8] purified, nucleoside-modified mRNA-LNPs, or poly(C) RNA-LNPs at weeks 0, 6, 18, and 30 (Figure 1A), and 1086C anti-gp[120] immunoglobulin G (IgG) titers were determined at weeks 0, 6, 18, 30, 34, and 38 sera by ELISA

Summary

Introduction

There has been great progress in understanding the biology of human immunodeficiency virus type 1 (HIV-1) infection, but no effective vaccine has advanced to clinical development. Generation of broadly neutralizing antibodies (bnAbs) that recognize a wide range of HIV-1 isolates has been difficult due to the large number of host glycans that are linked to the HIV-1 envelope (Env), the rapid mutability of viral immunogens, and the ability of the virus to hide neutralization epitopes.[1] Interestingly, some HIV-infected individuals develop bnAbs years after natural infection, which suggests that generation of antibody-based protective vaccines may be possible. Recent studies have demonstrated that this vaccine type has the ability to efficiently activate T follicular helper (Tfh) cells[6,10] that drive germinal center (GC) reactions, leading to durable, highaffinity neutralizing antibody responses.[11] Generation of HIV bnAbs in infected patients can take 2–4 years due to their complexity (multiple somatic hypermutations, long complementarity determining regions [CDRs]); it has been widely accepted that strong and sustained GC reactions are prerequisites for the production of such antibodies.[12]

Methods

Results

Conclusion