Development of Self-Replicating Propagation-Defective RNAs as Next Generation Vaccine Candidates Against Human Coronaviruses

Self-amplifying RNA replicons are promising candidates for next generation vaccines against human coronaviruses with pandemic potential. Self-amplification of RNAs in host cells generates more potent immune
responses with significantly reduced amounts of RNA delivered. Their defects in essential functions for viral dissemination make them highly safe as vaccines. We have shown that the deletion of the envelope (E) gene from Middle East respiratory syndrome coronavirus (MERS-CoV) led to a replication-competent propagation-defective RNA replicon (MERS-CoV-ΔE) that does not produce infectious progeny and behaves as a safe single-cycle virus in cell cultures and in vivo. The combined deletion of E gene with accessory proteins 3, 4a, 4b and 5, which are involved in the interference with the innate immune response, further attenuated the propagation-defective RNA replicon in vivo, in a mouse model of infection. 

Inside the cells, in the absence of E protein, MERS RNA replicons formed highly immunogenic polymeric structures. Intranasal administration of MERS-CoV RNA replicons to mice provided 100% protection after challenge with a lethal dose of virulent MERS-CoV. Interestingly, they induced sterilizing immunity, as no infectious virus was detected in the lungs of challenged mice. These results represent a proof of concept for the development of safe and effective RNA replicon vaccines against deadly human CoVs. We are currently developing replication-competent propagation-defective RNA replicons derived from SARS-CoV-2 as safe and more efficient vaccine candidates, since they simultaneously express multiple viral antigens.

LEARNING OBJECTIVES

1.    Define the potential of self-amplifying RNA replicons derived from coronaviruses as vaccine candidates.
2.    Explain current approaches to the development of RNA-replicon vaccine candidates against SARS-CoV-2.