The success of the World Health Organization smallpox eradication program three decades ago resulted in termination of routine vaccination and consequent decline in population immunity. Despite concerns regarding the reintroduction of smallpox, there is little enthusiasm for large-scale redeployment of licensed live vaccinia virus vaccines because of medical contraindications and anticipated serious side effects. Therefore, highly attenuated strains such as modified vaccinia virus Ankara (MVA) are under evaluation in humans and animal models. Previous studies showed that priming and boosting with MVA provided protection for >2 years in a monkeypox virus challenge model. If variola virus were used as a biological weapon, however, the ability of a vaccine to quickly induce immunity would be essential. Here, we demonstrate more rapid immune responses after a single vaccination with MVA compared to the licensed Dryvax vaccine. To determine the kinetics of protection of the two vaccines, macaques were challenged intravenously with monkeypox virus at 4, 6, 10, and 30 days after immunization. At 6 or more days after vaccination with MVA or Dryvax, the monkeys were clinically protected (except for 1 of 16 animals vaccinated with MVA), although viral loads and number of skin lesions were generally higher in the MVA vaccinated group. With only 4 days between immunization and intravenous challenge, however, MVA still protected whereas Dryvax failed. Protection correlated with the more rapid immune response to MVA compared to Dryvax, which may be related to the higher dose of MVA that can be tolerated safely.biodefense ͉ modified vaccinia virus Ankara ͉ poxvirus ͉ smallpox vaccine ͉ neutralizing antibody

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The metabotropic glutamate receptors (mGlus) are involved in modulation of synaptic transmission and neuronal excitability in the central nervous system 1 . These receptors likely exist as both homo-and heterodimers with unique pharmacological and functional properties 2-4 . Here we report four cryo-electron microscopy structures of the human mGlus, including inactive mGlu2 and mGlu7 homodimers, agonist/PAM-bound mGlu2 homodimer, and inactive mGlu2-7 heterodimer. A subtype-dependent dimerization mode of mGlus was observed, as a unique dimer interface mediated by helix IV important to limit receptor activity exists in the inactive mGlu2 structure only. The structures provide molecular details of inter-and intrasubunit conformational changes that are required for receptor activation, which distinguish class C G-proteincoupled receptors (GPCRs) from classes A and B receptors. Furthermore, the mGlu2-7 heterodimer structure and functional studies suggest that the mGlu7 subunit plays a dominant role in controlling dimeric association and G protein activation in the heterodimer. These insights into mGlu homo-and heterodimers highlight the complex landscape of mGlu dimerization and activation.The mGlus contain a large extracellular domain (ECD) composed of the Venus flytrap (VFT) domain that binds agonist and a cysteine-rich domain (CRD) connected to a seven-helical transmembrane domain (TMD) responsible for G protein coupling 4 . It has been acknowledged that homodimerization is mandatory for the function of the mGlus, making them complex allosteric proteins with two subunits influencing each other 3 . In addition, there is increasing evidence suggesting that different mGlu subunits can associate to form multiple types of heterodimers, adding complexity of function modulation in this receptor family 2,4 . However, conformational difference between the mGlu homo-and heterodimerization and how these dimers control mGlu function remain unclear. Thus, we performed single-particle