Publication - Abstract
Nov 29, 2018
The swine influenza pandemic of 2009 and more recent zoonotic transmissions of several avian influenza subtypes to human populations punctuates the threat posed by new pathogens for which we have no pre-existing immunity. Traditional vaccines require 5-6 months to develop and produce sufficient quantities to protect a significant portion of a population. Given how rapidly outbreaks can spread, a more rapid response is necessary to mitigate the consequences. Messenger RNA (mRNA) vaccines offer more suitable production speed and scale to respond to pandemic outbreaks. Having recently published successful results with mRNA vaccines against Zika virus in mouse models, Moderna therapeutics’ vaccine spin-off, Valera, is blazing a trail in the clinic with a first-in-human trial of an mRNA vaccine for avian influenza subtype H10N8. With the Phase 1 trial ongoing, Valera has reported promising early results along with animal model studies in mice, ferrets, and non-human primates in the journal Molecular Therapy. The paper is available online now, and will feature in the June edition for print.
Although nucleic acid vaccines address some challenges in traditional vaccine development and production, there are several challenges to realizing mRNA vaccines. mRNA requires chemical modifications of the nucleotides to enhance stability. Encapsulation within a lipid nanoparticle (LNP) will further enhance stability and provide a vehicle for intracellular delivery. To produce LNPs of appropriate size, and sufficient size-homogeneity and efficacy for in vivo use, Valera have used the NanoAssemblrTM technology to formulate their mRNA LNP vaccines.
For their animal studies, two mRNA-LNP vaccines were formulated using modified mRNAs encoding the hemagglutinin (HA) protein from either the H10N8 or H7N9 avian influenza subtypes. LNPs were administered intramuscularly (IM) or intradermally (ID) where they drain into nearby lymph nodes. LNPs promote cellular uptake into host cells and are designed to release mRNA into the cytoplasm. This leads to authentic viral antigen expression and presentation to the host immune system. Both formulations produced potent neutralizing antibody titers in all three animal models. The choice of administration route had no discernable effect on outcomes. The H7 mRNA-LNP formulation was also assessed in challenged mouse and ferret models and a significant increase in survival rate and decrease in viral titers were observed in the groups that received the vaccine. Both formulations were also tested in cynomolgus monkey and generated high levels of neutralizing antibodies.
At the time of publication, human phase 1 trials were still ongoing to evaluate the safety and immunogenicity of the H10 mRNA vaccine. Results from randomized, double-blinded, placebo-controlled and dose-escalating trials were reported at day 43 post-vaccination. Of the 31 subjects, 23 were administered the vaccine via IM injection while 8 were given a placebo. 87% of vaccinated and none of the placebo subjects had hemagglutination inhibition titers of 40 or greater, a measure that indicates a 50% reduction in risk of contracting influenza compared to persons with undetectable titer. Importantly, reports of adverse events were similar to existing H1N1 vaccines in terms of their nature, severity, and frequency. Though full results and analyses will be necessary to evaluate the success of the trial, these interim results are encouraging.
In all, Valera’s mRNA vaccines encoding avian influenza antigens were efficacious in animal models. Though additional results are still forthcoming, this phase 1 study represents not only a first-in-human study for mRNA vaccines, but also the first time any nucleic acid vaccine was used in humans without electroporation. Hence, this study is not only an important data-point for LNP formulations in the clinic, but also a leap forward in realizing the potential for rapid on-demand development of vaccines. Because mRNA LNPs represent a vaccine platform that can induce host presentation of virtually any peptide antigen with minimal reformulation, a successful trial will precipitate rapid advancement of numerous future vaccines.
Recently, the World Health Organization confirmed 120 new human cases of avian H7N9 influenza in China resulting in 37 deaths, highlighting the concern for a potential pandemic and the need for an effective, safe, and high-speed vaccine production platform. Production speed and scale of mRNA-based vaccines make them ideally suited to impede potential pandemic threats. Here we show that lipid nanoparticle (LNP)-formulated, modified mRNA vaccines, encoding hemagglutinin (HA) proteins of H10N8 (A/Jiangxi-Donghu/346/2013) or H7N9 (A/Anhui/1/2013), generated rapid and robust immune responses in mice, ferrets, and nonhuman primates, as measured by hemagglutination inhibition (HAI) and microneutralization (MN) assays. A single dose of H7N9 mRNA protected mice from a lethal challenge and reduced lung viral titers in ferrets. Interim results from a first-in-human, escalating-dose, phase 1 H10N8 study show very high seroconversion rates, demonstrating robust prophylactic immunity in humans. Adverse events (AEs) were mild or moderate with only a few severe and no serious events. These data show that LNP-formulated, modified mRNA vaccines can induce protective immunogenicity with acceptable tolerability profiles.
Publication - Abstract
Nov 29, 2018
Publication - Abstract
Jan 14, 2018
The Journal of Physical Chemistry
Here, we show how dynamic nuclear polarization (DNP) NMR spectroscopy experiments permit the atomic level structural characterization of loaded and empty lipid nanoparticles (LNPs). The LNPs used here were synthesized by the microfluidic mixing tec...
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