DNA and mRNA vaccination against allergies

Abstract

Allergen-specific immunotherapy, which is performed by subcutaneous injection or sublingual application of allergen extracts, represents an effective treatment against type I allergic diseases. However, due to the long duration and adverse reactions, only a minority of patients decides to undergo this treatment. Alternatively, early prophylactic intervention in young children has been proposed to stop the increase in patient numbers. Plasmid DNA and mRNA vaccines encoding allergens have been shown to induce T helper 1 as well as T regulatory responses, which modulate or counteract allergic T helper 2-biased reactions. With regard to prophylactic immunization, additional safety measurements are required. In contrast to crude extracts, genetic vaccines provide the allergen at high purity. Moreover, by targeting the encoded allergen to subcellular compartments for degradation, release of native allergen can be avoided. Due to inherent safety features, mRNA vaccines could be the candidates of choice for preventive allergy immunizations. The subtle priming of T helper 1 immunity induced by this vaccine type closely resembles responses of non-allergic individuals and-by boosting via natural allergen exposure-could suffice for long-term protection from type I allergy.

Keywords: DNA vaccines; allergy; genetic vaccines; healthy responses; mRNA vaccines; natural protection; prevention; therapy.

Figure 1

Optimization strategies for genetic vaccines. Modifications of the genetic sequence encoding the antigen of interest include (A) recoding in order to adapt the codon usage, adjust the GC content, and remove sequences that inhibit efficient translation (B) optimization of 5′ and 3′ UTRs to enhance mRNA stability and translation (C) usage of targeting sequences that shuttle the translated protein into specific cellular compartments (D) use of self‐replicating RNAs by incorporating alphavirus replicases and (E) mutations of the antigen itself to influence its immunogenicity and/or allergenicity. Such optimized sequences can be used directly as mRNA vaccines, or expressed from a plasmid DNA vector (pDNA). By choosing different promoters, expression strength and cell specificity can be adjusted. Using minicircle plasmids, unwanted bacterial sequences or antibiotic resistance genes needed for production can be removed from the plasmid backbone. Immunostimulatory CpG‐ODN can be covalently linked to an antigen of interest or incorporated in liposomal formulations or viruslike particles (VLP) to enhance their efficacy. Genetic vaccines can be injected intramuscularly (i.m.), intradermally (i.d., also using injection devices like the Biojector^™ 2000) or even applied intranodal. Alternatively, (epi)cutaneous vaccination can be achieved with biolistic devices (gene gun) or using microneedles, with or without additional in vivo electroporation