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Polymeric and lipid nanoparticles in self-amplifying RNA vaccines result in higher protein expression and immunogenicity

Self-amplifying RNA (saRNA) is an advanced platform for nucleic acid vaccine development. The backbone is typically derived from an alphaviral genome and encodes a gene of interest (GOI) and a viral replicase that can amplify the genomic and subgenomic RNA. Thanks to its self-amplification properties, much lower doses (typically 100-fold lower) of saRNA are sufficient for vaccine production compared to messenger RNA (mRNA). saRNA, being a versatile platform, can be used to generate vaccines against any pathogen with a known protein target, including influenza, chlamydia, HIV-1, Ebola, and RSV.

Polymeric and lipid nanoparticle delivery platforms for saRNAs

saRNAs, similar to all nucleic acid vaccines and therapies, need a delivery vehicle to encourage cellular uptake and inhibit RNA degradation. To date, delivery platforms for saRNAs have included lipid nanoparticles (LNP), cationic nanoemulsions, and polyplexes, with LNPs being the most advanced of these. While the impact of RNA on vaccine immunogenicity has been well studied, the role of biomaterials in the effectiveness of saRNA vaccine has not been sufficiently investigated.

First-in-human clinical trial against SARS-CoV-2 to test the potency and scalability of the saRNA technology

The potential of saRNA was recently tested for the first time in humans in a combined Phase I/II clinical trial against SARS-CoV-2. The study demonstrated the potency and scalability of the saRNA technology. The trial was a head-to-head comparison of saRNA formulated with a bioreducible polymer, LNP or pABOL, that has been shown to be an effective delivery vehicle for saRNA vaccines.

“Here, we performed a head-to-head comparison of saRNA formulated with LNP or pABOL, a bioreducible polymer that was previously shown to be an efficient delivery vehicle for saRNA vaccines.”

The researchers first compared the in vivo protein expression of saRNA formulated with pABOL and several LNP formulations. They then compared the matching formulations with saRNA encoding the influenza hemagglutinin (HA) glycoprotein as a model antigen to assess differences in immunogenicity. They also investigated the dose-response curve for LNP against the SARS-CoV-2 spike glycoprotein protein antigen and compared intramuscular (IM) and intranasal (IN) routes of administration. This study is published in the open-access journal, Journal of Controlled Release.

pABOL-formulated saRNA resulted in higher protein expression, while LNP formulations improved immunogenicity

The researchers observed that pABOL-formulated saRNA led to higher protein expression, but the LNP formulations were more immunogenic. They also observed that both the helper phospholipid and IM vs. IN administration of LNP affected vaccine immunogenicity of 2 model antigens – HA and SARS-CoV-2 spike protein.

“Interestingly, pABOL resulted in higher protein expression, whereas LNP resulted in higher humoral and cellular immunity.”

The results also showed that LNP administered intramuscularly, but not LNP or pABOL administered intranasally, led to increased acute interleukin-6 expression post-vaccination. This indicates that intramuscular antigen expression is not the only factor that impacts vaccine immunogenicity and also that protein expression alone is a poor predictor of the effectiveness of vaccines.

“To our knowledge, this is the first head-to-head comparison of leading saRNA formulations (polyplex and LNP) to characterize both the protein expression and immunogenicity.”

Delivery systems and routes of administration fulfill different delivery niches in saRNA genetic medicines

Overall, these findings indicate that delivery systems and administration routes may satisfy different delivery niches within the field of saRNA genetic medicines. To summarize, the authors compared pABOL and LNP delivery systems for saRNA vaccines. pABOL formulations led to 100-fold higher intramuscular protein expression compared to LNP. LNPs led to higher antibody and cellular responses to flu as well as SARS-CoV-2 antigens compared to pABOL. Compared to pABOL, LNPs induced higher levels of systemic cytokines such as IL-6 about 4 hours after injection.

“In addition, these comparative studies highlight the importance of considering the effects of immune sensing of biomaterials, in addition to saRNA, on formulation efficacy.”

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