Lipid nanoparticle encapsulated nucleoside-modified mRNA vaccines elicit polyfunctional HIV-1 antibodies comparable to proteins in nonhuman primates

Kevin O Saunders,Michael J Hogan,Robert Parks,Maggie Barr,Mark G Lewis,Laura L Sutherland ,Zekun Mu,David Gordon ,Richard M Scearce ,Drew Weissman,Theodore C Pierson,Yunfei Wang,Chris Barbosa,Sampa Santra,Amanda Eaton,Ying K Tam ,Norbert Pardi,Derrick Goodman,Guido Ferrari,István Tombácz ,Georgia D Tomaras,David C Montefiori,Giovanna Hernandéz ,Xiaoying Shen,R Wes Rountree,Barton F Haynes

doi:10.1038/s41541-021-00307-6

Abstract

The development of an effective AIDS vaccine remains a challenge. Nucleoside-modified mRNAs formulated in lipid nanoparticles (mRNA-LNP) have proved to be a potent mode of immunization against infectious diseases in preclinical studies, and are being tested for SARS-CoV-2 in humans. A critical question is how mRNA-LNP vaccine immunogenicity compares to that of traditional adjuvanted protein vaccines in primates. Here, we show that mRNA-LNP immunization compared to protein immunization elicits either the same or superior magnitude and breadth of HIV-1 Env-specific polyfunctional antibodies. Immunization with mRNA-LNP encoding Zika premembrane and envelope or HIV-1 Env gp160 induces durable neutralizing antibodies for at least 41 weeks. Doses of mRNA-LNP as low as 5 μg are immunogenic in macaques. Thus, mRNA-LNP can be used to rapidly generate single or multi-component vaccines, such as sequential vaccines needed to protect against HIV-1 infection. Such vaccines would be as or more immunogenic than adjuvanted recombinant protein vaccines in primates.

Highlights

Messenger ribonucleic acid-based vaccines have been shown to elicit protective immunity against Zika virus (ZIKV)infection after a single immunization of rhesus macaques[1], and have been designed for many other pathogens including Ebola, influenza, Hepatitis C, Cytomegalovirus, and respiratory syncytial virus[2,3,4,5,6,7].The recent development of mRNA vaccines has overcome initial roadblocks to their use. mRNA vaccines were initially hindered by innate immune sensing of mRNA7–9
We demonstrate in 28 rhesus macaques that immunization with nucleoside-modified mRNA-lipid nanoparticles (LNP) (n = 16) was equal to or superior to the immunogenicity of adjuvanted Env protein
MRNA is delivered by LNP to dendritic cells and likely other immune cells that are able to activate naive T cells to respond to the vaccine immunogen[59,60,61]

Summary

Introduction

Messenger ribonucleic acid (mRNA)-based vaccines have been shown to elicit protective immunity against Zika virus (ZIKV)infection after a single immunization of rhesus macaques[1], and have been designed for many other pathogens including Ebola, influenza, Hepatitis C, Cytomegalovirus, and respiratory syncytial virus[2,3,4,5,6,7].The recent development of mRNA vaccines has overcome initial roadblocks to their use. mRNA vaccines were initially hindered by innate immune sensing of mRNA7–9. Messenger ribonucleic acid (mRNA)-based vaccines have been shown to elicit protective immunity against Zika virus (ZIKV). The recent development of mRNA vaccines has overcome initial roadblocks to their use. MRNA vaccines were initially hindered by innate immune sensing of mRNA7–9. Advances in modifying mRNA nucleosides have improved mRNA translation, while eliminating recognition by innate pattern recognition receptors[7,8,10]. The incorporation of pseudouridine and 1-methyl-pseudouridine prevents recognition of mRNA by. Toll-like receptor 7 and 8 and other nucleic acid sensing pattern recognition receptors[7]. One method for protecting the mRNA from degradation has been its encapsulation in lipid nanoparticles (LNP)[7,8,13]. Advances in encapsulation and preventing mRNA immune sensing have made mRNA vaccines a feasible vaccine platform

Methods

Results

Conclusion