Potent Immune Responses in Rhesus Macaques Induced by Nonviral Delivery of a Self-amplifying RNA Vaccine Expressing HIV Type 1 Envelope With a Cationic Nanoemulsion

Abstract

Self-amplifying messenger RNA (mRNA) of positive-strand RNA viruses are effective vectors for in situ expression of vaccine antigens and have potential as a new vaccine technology platform well suited for global health applications. The SAM vaccine platform is based on a synthetic, self-amplifying mRNA delivered by a nonviral delivery system. The safety and immunogenicity of an HIV SAM vaccine encoding a clade C envelope glycoprotein formulated with a cationic nanoemulsion (CNE) delivery system was evaluated in rhesus macaques. The HIV SAM vaccine induced potent cellular immune responses that were greater in magnitude than those induced by self-amplifying mRNA packaged in a viral replicon particle (VRP) or by a recombinant HIV envelope protein formulated with MF59 adjuvant, anti-envelope binding (including anti-V1V2), and neutralizing antibody responses that exceeded those induced by the VRP vaccine. These studies provide the first evidence in nonhuman primates that HIV vaccination with a relatively low dose (50 µg) of formulated self-amplifying mRNA is safe and immunogenic.

Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose

“…Immunogenicity and/or toxicity of delivery compounds that could be used to deploy the vaccine by more amenable routes poses an additional complication. Cationic lipids, efficacious in some applications (29,84), can be toxic when used at higher doses and if incompletely complexed (85)(86)(87). Furthermore, cationic lipids can be immunogenic, which can limit transgene expression and raise safety concerns (88).…”

“…However, to our knowledge, only two nonviral in vivo delivery methods have been reported. These methods include a cationic nanoemulsion, comprising cationic lipid 1,2-Dioleoyl-3-trimethylammonium propane emulsified with the constituents of the MF59 adjuvant (26,28), and a 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA)-centric lipid nanoparticle (27,29), both of which are five-component systems. Although these methods have been used as a synthetic delivery method for a chimeric SIN/VEEV replicon vaccine in vivo, they have yet to show protection against lethal pathogen challenges (27-29).…”

“…Nonretroviral RNA vaccines are attractive due to their inherent transience and absence of recombination or integration into the patient's genome. However, RNA-based vaccines require intracellular delivery methods to function (24)(25)(26)(27)(28)(29).…”

Induction of Broad-Based Immunity and Protective Efficacy by Self-amplifying mRNA Vaccines Encoding Influenza Virus Hemagglutinin

“…Furthermore, in the process of amplification of their genomes, RNA replicons engage pattern recognition receptors in the host cell, adjuvanting the responses to the encoded immunogen (45)(46)(47). Although both mRNA-and replicon RNA-based vaccines were shown to elicit antigen-specific antibody and cellular immune responses against several pathogens (44,(48)(49)(50)(51), the self-amplifying nature of replicon-based vaccines is likely to result in higher levels of antigen expression and in a more effective engagement of innate immune responses than mRNA-based vaccine candidates.…”

Dendritic Cell Targets for Self-Replicating RNA Vaccines

“…Considering that the unformulated Alphavirus RNA was already a functional vaccine, albeit relatively inefficient, the employed lipid formulations may not be delivering the RNA, but acting more as an adjuvant. Indeed, this replicon RNA was co-formulated with pre-formed squalene-based nanoemulsions [54], employing the squalene-based MF59 adjuvant [55]. Nonetheless, cell delivery of replicon RNA by nanoparticulate delivery vehicles [40] has clearly been demonstrated [2,45,51], leading to translation and replication in DCs and the induction of immune responses in vivo.…”