RESUMEN
In 2022, mpox virus (MPXV) spread worldwide, causing 99,581 mpox cases in 121 countries. Modified vaccinia Ankara (MVA) vaccine use reduced disease in at-risk populations but failed to deliver complete protection. Lag in manufacturing and distribution of MVA resulted in additional MPXV spread, with 12,000 reported cases in 2023 and an additional outbreak in Central Africa of clade I virus. These outbreaks highlight the threat of zoonotic spillover by Orthopoxviruses. mRNA-1769, an mRNA-lipid nanoparticle (LNP) vaccine expressing MPXV surface proteins, was tested in a lethal MPXV primate model. Similar to MVA, mRNA-1769 conferred protection against challenge and further mitigated symptoms and disease duration. Antibody profiling revealed a collaborative role between neutralizing and Fc-functional extracellular virion (EV)-specific antibodies in viral restriction and ospinophagocytic and cytotoxic antibody functions in protection against lesions. mRNA-1769 enhanced viral control and disease attenuation compared with MVA, highlighting the potential for mRNA vaccines to mitigate future pandemic threats.
RESUMEN
Mpox virus (MPXV) caused a global outbreak in 2022. Although smallpox vaccines were rapidly deployed to curb spread and disease among those at highest risk, breakthrough disease was noted after complete immunization. Given the threat of additional zoonotic events and the virus's evolving ability to drive human-to-human transmission, there is an urgent need for an MPXV-specific vaccine that confers protection against evolving MPXV 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 with modified vaccinia virus Ankara (MVA), which forms the basis for the current MPXV vaccine, immunization with an mRNA-based MPXV vaccine generated superior neutralizing activity against MPXV and VACV and more efficiently inhibited spread between cells. We also observed greater Fc effector TH1-biased humoral immunity to the four MPXV antigens encoded by the vaccine, as well as to the four VACV homologs. Single MPXV antigen-encoding mRNA vaccines provided partial protection against VACV challenge, whereas multivalent vaccines combining mRNAs encoding two, three, or four MPXV antigens protected against disease-related weight loss and death equal or superior to MVA vaccination. These data demonstrate that an mRNA-based MPXV vaccine confers robust protection against VACV.
Asunto(s)
Vacuna contra Viruela , Vacunas Virales , Humanos , Monkeypox virus/genética , Virus Vaccinia/genética , Vacuna contra Viruela/genética , Antígenos Virales , ARN Mensajero/genéticaRESUMEN
Many bacteria require ATP binding cassette (ABC) transporters for the import of the essential metal zinc from limited environments. These systems rely on a periplasmic or cell-surface solute binding protein (SBP) to bind zinc with high affinity and specificity. AztABCD is one such zinc transport system recently identified in a large group of diverse bacterial species. In addition to a classical SBP (AztC), the operon also includes a periplasmic metallochaperone (AztD) shown to transfer zinc directly to AztC. Crystal structures of both proteins from Paracoccus denitrificans have been solved and suggest several structural features on each that may be important for zinc binding and transfer. Here we determine zinc binding affinity, dissociation kinetics, and transfer kinetics for several deletion mutants as well as a crystal structure for one of them. The results indicate specific roles for loop structures on AztC and an N-terminal motif on AztD in zinc binding and transfer. These data are consistent with a structural transfer model proposed previously and provide further mechanistic insight into the processes of zinc binding and transfer.