The COVID-19 pandemic demonstrated the utility of RNA vaccines as a flexible platform that can be rapidly deployed to control emerging infections. RNA vaccines have huge potential for use against a wide range of pathogens. One of the challenges with their broader rollout is systemic inflammation and adverse side effects. However, certain types of inflammation are necessary for the induction of an adaptive immune response to an RNA vaccine.1 Approaches that focus inflammation where it is needed and reduce systemic responses could be extremely beneficial. In the August issue of Molecular Therapy, Kimura et al. investigated how RNA vaccine formulations can alter this inflammation profile.2
The authors looked at a specific RNA delivery platform: cationic nanocarrier formulation, which they call LION. The LION particles are subtly different from the lipid nanoparticles (LNPs) used in the licensed COVID mRNA vaccines because the RNA is located on the outside. LION-formulated RNA leads to significantly greater transgene expression and less systemic inflammation. Importantly, the dampening of systemic inflammation is not associated with a reduction in adaptive immunity. This is potentially because the LION formulation still leads to the activation of a localized immune response in the injected tissue, based on the transcriptomic response. A similar approach of localizing inflammation to the injection site has been used for protein adjuvants, such as a small molecule TLR7 agonist.3
The present study used self-amplifying replicon RNA (repRNA, also called saRNA) rather than mRNA. repRNA is derived from alphaviruses and encodes a replicase complex as well as the vaccine antigen, allowing the repRNA to make copies of itself. The first ever human clinical trials using the repRNA platform were formulated with LNP and had mixed results, with 13% of vaccinated individuals not responding to saRNA.4 Despite this limitation, the authors of the current study argue that the LION formulation may provide some benefit in human immunization. Additionally, a LION-formulated repRNA vaccine has received emergency licensure in India based on a phase II/III clinical trial (clinical trial: CTRI/2021/09/036379); some data are available in the package insert but have not been peer reviewed at the time of writing.5 Interestingly, in the clinical trial, the authors report that not everyone responded, with 94.1% seroconversion, so further optimization may be needed. The authors also suggest that changing the formulation may increase the amount of repRNA that can be used, therefore potentially enabling the delivery of multiple antigens. This approach has been suggested as a way to develop a universal influenza vaccine—by including a “sledgehammer” array of flu antigens to improve coverage.6 While the technology to deliver multiple antigens is possible, it does not necessarily overcome other immunological issues such as original antigen sin and potentially antigen dominance.7
Overall, this paper offers insight on how to balance inflammation and immunogenicity through focusing the response to the site of immunization and reducing systemic effects. In the future, it would be interesting to see the effects of this approach in the context of mRNA.
References
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