However, other aspects of vaccine-induced immunity must account for severe disease prevention. access and principal target for infection-blocking (i.e., neutralizing) antibodies, worried scientists that vaccine immunity would be significantly weakened. In this issue of shed some light around the breadth issue. Vaccination with the original parent SARS-CoV-2 spike provided strong neutralizing antibody activity to the parent Rabbit Polyclonal to Doublecortin SARS-CoV-2 strain but extremely poor activity against the Omicron variant. However, boosting with a third dose of the same vaccine several months later dramatically increased (20C30) neutralizing antibodies to Omicron but only increased neutralization activity to the original parent strain modestly (1C4) compared to the two-dose vaccine regimen Pexmetinib (ARRY-614) (Garcia-Beltran et?al., 2021; Dejnirattisai et?al., 2022; Hoffmann et?al., 2021). In other words, a third jab tended to equalize neutralization protection of the highly mutated Omicron variant and the original parent strain. How do these new findings help us understand associations between vaccination and clinical disease? Omicron spreads like wildfirewith seemingly little deference to whether individuals have been vaccinated with a two-dose mRNA vaccine regimen (considered today as fully vaccinated) or not. In contrast, the same vaccine regimen is still 70% successful at preventing hospital admission from the disease (Collie et?al., 2021). In this light, the insufficiency of two-dose mRNA vaccination to induce anti-Omicron neutralizing antibodies correlates well with Omicron breakthrough infections, consistent with the crucial role neutralizing antibodies play in working upstream to prevent viral invasion into cells. However, other aspects of vaccine-induced immunity must account for severe disease prevention. Neutralizing antibodies are a a part of a complex adaptive immune response that works collaboratively to protect against infectious disease. Other parts of adaptive immunity include other (non-neutralizing) antibody functions and T?cell responses, which are in general more resistant to immune escape by evolving variants and are likely jointly responsible for vaccine-induced protection from severe disease. With this in mind, to what degree can prevention of severe disease alone (the possible prospect without neutralizing antibodies) be sufficient to stem the tide of a pandemic in todays world? Regardless of the answer to this question, a solution Pexmetinib (ARRY-614) to this and future pandemics would likely be much more feasible if it is possible to innovate improved vaccine strategies to induce broadly neutralizing antibodies. In this context, perhaps the most impactful revelation of the triptych published in this issue of is the view of how a third dose of a homologous vaccine works much better to induce neutralizing activity to the very non-homologous Omicron variant. Its a noteworthy demonstration of the reach of flexible antibody memory, and a better understanding of mechanisms responsible for this will help inform future Pexmetinib (ARRY-614) vaccine strategy. To understand possible underlying mechanisms of how a homologous booster vaccine stretches antibody memory toward variants, we need to take a Pexmetinib (ARRY-614) deeper look under the hood of the immune system. As a balance to viral development, the mammalian antibody system is equipped with its own quick evolution-based system to resist viral immune escape by expanding the functional breadth of its immune memory banks. Antibodies are expressed from a vast diversity of immunoglobulin (Ig) gene segments put together during B cell ontogeny. Ig variable region exons encoding antibodies that in the beginning participate antigen during an immune response, clonally expand and contribute to the memory B cell pool. They can also differentiate into antibody-secreting plasma cells. Some activated B cells enter germinal centers where their Ig genes undergo somatic hypermutation (SHM) over time. Mutated antibody variants that bind with higher affinity are selected to expand further and can also contribute to the memory B cell pool and become plasma cells. The frequency of broadly neutralizing antibodies in an antibody response can vary. Because not all antibodies that bind a pathogen can neutralize it, an important factor that influences neutralization capability is usually where around the antigen the binding occurs. In this light, the most potent neutralizing antibodies recognize the RBD roughly in the same region recognized by ACE2 (epitopic region RBD-2) (Tong et?al., 2021), the receptor used by SARS-CoV-2 for cell access. A likely contributing factor to early vaccine success was that the baseline (pre-SHM) human antibody repertoire tends to harbor very potent neutralizing antibodies to this region, which are available without the need for considerable maturation in germinal center reactions. This is also the region targeted by most FDA-approved monoclonal therapeutic antibodies. The downside is usually that many of Omicrons spike mutations are concentrated on or near this.