Strong immune responses and protection of PcrV and OprF-I mRNA vaccine candidates against Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa (PA) is a leading cause of hospital-acquired and ventilator-associated pneumonia. The multidrug-resistance (MDR) rate of PA is increasing making the management of PA a global challenge. Messenger RNA (mRNA) vaccines represent the most promising alternative to conventional vaccines and are widely studied for viral infection and cancer immunotherapy while rarely studied for bacterial infections. In this study, two mRNA vaccines encoding PcrV– the key component of the type III secretion system in Pseudomonas and the fusion protein OprF-I comprising outer membrane proteins OprF and OprI were constructed. The mice were immunized with either one of these mRNA vaccines or with the combination of both. Additionally, mice were vaccinated with PcrV, OprF, or the combination of these two proteins. Immunization with either mRNA-PcrV or mRNA-OprF-I elicited a Th1/Th2 mixed or slighted Th1-biased immune response, conferred broad protection, and reduced bacterial burden and inflammation in burn and systemic infection models. mRNA-PcrV induced significantly stronger antigen-specific humoral and cellular immune responses and higher survival rate compared with the OprF-I after challenging with all the PA strains tested. The combined mRNA vaccine demonstrated the best survival rate. Moreover, the mRNA vaccines showed the superiority over protein vaccines. These results suggest that mRNA-PcrV as well as the mixture of mRNA-PcrV and mRNA-OprF-I are promising vaccine candidates for the prevention of PA infection.

In silico designed novel multi-epitope mRNA vaccines against Brucella by targeting extracellular protein BtuB and LptD

“…Kozak sequence is recognized by ribosomes as translation initiation site 42 . TPA 43 is a sequence located before the coding region in a structural gene, which can be transcribed but not translated. The open reading frame is the translation area of mRNA, and replacing rare codons with common codons is beneficial to the efficiency of subsequent translation 44 .…”

Advances in Development of Novel Therapeutic Strategies against Multi-Drug Resistant Pseudomonas aeruginosa

“…Notably, both PcrV and OprF-I mRNA vaccines could induce immunity; the PcrV vaccination elicited a higher level of humoral and cellular immune responses and significantly reduced the colonization of P. aeruginosa in the skin, lung, liver, spleen, and kidney, providing a broad protective effect against P. aeruginosa. Furthermore, the immune response and protection elicited by a single mRNA vaccine and combined ones showed the superiority of mRNA vaccines over PcrV and OprF protein vaccines, respectively [97]. Many Gram-negative bacteria share highly homologous TTSS.…”

Evolution of Vaccines Formulation to Tackle the Challenge of Anti-Microbial Resistant Pathogens

“…Moreover, the immune response obtained from the administration of mixed mRNA-PcrV-LNP and mRNA-OprF-I-LNP was higher than that obtained from protein vaccines. Notably, both the mRNA against P. aeruginosa was demonstrated to be protective against PA infection [85].…”