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With the success of messenger RNA (mRNA) vaccines against coronavirus disease 2019, strategies can now focus on improving vaccine potency, breadth, and stability. We designed and evaluated domain-based mRNA vaccines encoding the wild-type spike protein receptor binding domain (RBD) or N-terminal domain (NTD) alone or in combination. An NTD-RBD–linked candidate vaccine, mRNA-1283, showed improved antigen expression, antibody responses, and stability at refrigerated temperatures (2° to 8°C) compared with the clinically available mRNA-1273, which encodes the full-length spike protein. In BALB/c mice administered mRNA-1283 as a primary series, booster, or variant-specific booster, similar or greater immune responses from viral challenge were observed against wild-type, beta, delta, or omicron (BA.1) viruses compared with mRNA-1273–immunized mice, especially at lower vaccine dosages. K18-hACE2 mice immunized with mRNA-1283 or mRNA-1273 as a primary series demonstrated similar degrees of protection from challenge with SARS-CoV-2 Delta and Omicron variants at all vaccine dosages. These results support clinical assessment of mRNA-1283, which has now entered clinical trials (NCT05137236). Editor's summary: The initial SARS-CoV-2 mRNA vaccines changed the course of the coronavirus disease 2019 (COVID-19) pandemic. Because these first-generation vaccines were successful, there is now the opportunity to improve upon them. To do this, Stewart-Jones et al. generated domain-based mRNA vaccines that expressed only the N-terminal domain (NTD) and receptor binding domain (RBD) of the SARS-CoV-2 spike protein rather than the full-length spike protein. This NTD-RBD–based mRNA vaccine generated similar or superior immune responses to the original full-length spike protein-encoding vaccine when given as a primary vaccine or as a booster, translating into similar degrees of protection against SARS-CoV-2 challenge in mice. Importantly, the domain-based vaccine was also more stable at refrigerated temperatures than the full-length vaccine, an important feature for global distribution. —Courtney Malo [ABSTRACT FROM AUTHOR]

Influencing influenza immunity: Humans are exposed to influenza virus throughout their lifetimes through a combination of infections and vaccinations. Yet, it remains unclear whether infection and vaccination induce distinct influenza-specific immunological memory. To address this question, Dugan et al. compared antibodies produced by individuals after influenza infection or vaccination. The authors found that infection-induced antibodies reacted to non-neutralizing epitopes of influenza virus, whereas vaccination-induced antibodies reacted to neutralizing epitopes. In addition, infection-induced antibodies preferentially responded to influenza strains present during an individual's childhood. Last, passive transfer of vaccination-induced antibodies, but not infection-induced antibodies, protected mice in a model of influenza infection. These findings demonstrate that existing influenza-specific memory and route of exposure influence influenza immunity. Humans are repeatedly exposed to variants of influenza virus throughout their lifetime. As a result, preexisting influenza-specific memory B cells can dominate the response after infection or vaccination. Memory B cells recalled by adulthood exposure are largely reactive to conserved viral epitopes present in childhood strains, posing unclear consequences on the ability of B cells to adapt to and neutralize newly emerged strains. We sought to investigate the impact of preexisting immunity on generation of protective antibody responses to conserved viral epitopes upon influenza virus infection and vaccination in humans. We accomplished this by characterizing monoclonal antibodies (mAbs) from plasmablasts, which are predominantly derived from preexisting memory B cells. We found that, whereas some influenza infection–induced mAbs bound conserved and neutralizing epitopes on the hemagglutinin (HA) stalk domain or neuraminidase, most of the mAbs elicited by infection targeted non-neutralizing epitopes on nucleoprotein and other unknown antigens. Furthermore, most infection-induced mAbs had equal or stronger affinity to childhood strains, indicating recall of memory B cells from childhood exposures. Vaccination-induced mAbs were similarly induced from past exposures and exhibited substantial breadth of viral binding, although, in contrast to infection-induced mAbs, they targeted neutralizing HA head epitopes. Last, cocktails of infection-induced mAbs displayed reduced protective ability in mice compared to vaccination-induced mAbs. These findings reveal that both preexisting immunity and exposure type shape protective antibody responses to conserved influenza virus epitopes in humans. Natural infection largely recalls cross-reactive memory B cells against non-neutralizing epitopes, whereas vaccination harnesses preexisting immunity to target protective HA epitopes. [ABSTRACT FROM AUTHOR]

In this study, we report that antigen-specific CD19 + CD27 + CD21 lo (CD21 lo ) B cells are transiently induced 14 to 28 days after immunization, at the time germinal centers (GCs) peak. Although clonally related to memory B cells and plasmablasts, CD21 lo cells form distinct clades within phylogenetic trees based on accumulated variable gene mutations, supporting exit from active GCs. CD21 lo cells express a transcriptional program, suggesting that they are primed for plasma cell differentiation and are refractory to GC differentiation, although they do not spontaneously secrete antibody. In addition, CD21 lo cells differentially express multiple cell surface markers and have elevated intracellular levels of Blimp-1 and T-bet protein compared with memory B cells. Together, these data support a model in which CD21 lo cells are recent GC graduates that represent a distinct population from CD27 + classical memory cells, are refractory to GC reentry, and are predisposed to differentiate into long-lived plasma cells., (Copyright © 2017, American Association for the Advancement of Science.)