A monkeypox mRNA-lipid nanoparticle vaccine targeting virus binding, entry, and transmission drives protection against lethal orthopoxviral challenge

Abstract

Monkeypox virus (MPXV) caused a global outbreak in 2022, fueled by behaviorally-altered and enhanced human-to-human transmission. While smallpox vaccines were rapidly deployed to curb spread and disease among those at highest risk, breakthrough disease was noted after complete immunization. Given the imminent threat of additional zoonotic events as well as the viruses evolving ability to drive human-to-human transmission, there is an urgent need for the development of a MPXV-specific vaccine that is able to also confer broad protection against evolving strains and related orthopoxviruses. Here, we demonstrate that an mRNA-lipid nanoparticle vaccine encoding a set of four highly conserved MPXV surface proteins involved in virus attachment, entry and transmission can induce MPXV-specific immunity and heterologous protection against a lethal vaccinia virus (VACV) challenge. Compared to Modified Vaccinia Virus Ankara (MVA), which forms the basis for the current MPXV vaccine, mRNA-vaccination generated superior neutralizing and cellular spread-inhibitory activities against MPXV and VACV as well as greater Fc-effector Th1-biased humoral immunity to the four MPXV antigens and the four VACV homologs. Single MPXV antigen mRNA vaccines provided partial protection against VACV challenge, while combinations of two, three or four MPXV antigen expressing mRNAs protected against disease-related weight loss and death. Remarkably, the cross-protection by multivalent MPXV mRNAs was superior to the homologous protection by MVA, associated with a combination of neutralizing and non-neutralizing antibody functions. These data reveal robust protection against VACV using an mRNA-based vaccine targeting four highly conserved viral surface antigens, linked to the induction of highly functional antibodies able to rapidly control viral infection.

SPR Sensor-Based Analysis of the Inhibition of Marine Sulfated Glycans on Interactions between Monkeypox Virus Proteins and Glycosaminoglycans

“…The MPXV has a set of highly conserved Orthopoxvirus surface proteins, which can be targeted to block the viral infection [ 6 ]. Among these surface proteins, MPXV A29 and M1 are involved in the cellular entry into the intracellular mature virion, while proteins B6 and A35 play important roles in the transmission on the surface of extracellular enveloped virion [ 10 ]. The poxvirus A35 protein is reported to be an important virulence factor of poxviruses.…”

A Quadrivalent mRNA Immunization Elicits Potent Immune Responses against Multiple Orthopoxviral Antigens and Neutralization of Monkeypox Virus in Rodent Models

“…Each has its own limitations such as severe skin side effects of live attenuated vaccine [14], weak immunogenicity of replication-deficient virus vaccines [24] and DNA vaccines [43], and long development cycle of recombinant protein technology [44]. Encouraged by the two new COVID-19 mRNA vaccines, some researchers have also tried to use mRNA technology to develop monkeypox vaccines, through the designing of multiple mRNAs that express a single or fused monkeypox antigen [45][46][47][48][49][50]. Some of those designs elicit potent immunogenicity but will face challenges in delivering multiple mRNAs during process development and manufacturing.…”

Nanomedicine as a Potential Tool against Monkeypox

“…The reaction briefly works by conducting an isothermal MCDA reaction for the DNA templates followed by the lateral flow biosensor detection of the preamplification target sequences, with the optimal reaction temperature and time being 64 °C for 30 min. The detection tool developed in this study was shown to be effective and rapid [ 68 ]. Moreover, the efficient inhibition of cell-pathogen interactions to prevent infections is an urgent yet unsolved problem.…”