Immunizations with diverse sarbecovirus receptor-binding domains elicit SARS-CoV-2 neutralizing antibodies against a conserved site of vulnerability.
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ABSTRACT:
SUBMITTER: Burnett DL
PROVIDER: S-EPMC8554075 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern pose a challenge to the effectiveness of current vaccines. A vaccine that could prevent infection caused by known and future variants of concern as well as infection with pre-emergent sarbecoviruses (i.e., those with potential to cause disease in humans in the future) would be ideal. Here we provide data showing that potent cross-clade pan-sarbecovirus neutralizing antibodies are induced in survivors of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) infection who have been immunized with the BNT162b2 messenger RNA (mRNA) vaccine. The antibodies are high-level and broad-spectrum, capable of neutralizing not only known variants of concern but also sarbecoviruses that have been identified in bats and pangolins and that have the potential to cause human infection. These findings show the feasibility of a pan-sarbecovirus vaccine strategy. (Funded by the Singapore National Research Foundation and National Medical Research Council.).
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Project description:Natural infections and vaccination with a pathogen typically stimulate the production of potent antibodies specific for the pathogen through a Darwinian evolutionary process known as affinity maturation. Such antibodies provide protection against reinfection by the same strain of a pathogen. A highly mutable virus, like HIV or influenza, evades recognition by these strain-specific antibodies via the emergence of new mutant strains. A vaccine that elicits antibodies that can bind to many diverse strains of the virus-known as broadly neutralizing antibodies (bnAbs)-could protect against highly mutable pathogens. Despite much work, the mechanisms by which bnAbs emerge remain uncertain. Using a computational model of affinity maturation, we studied a wide variety of vaccination strategies. Our results suggest that an effective strategy to maximize bnAb evolution is through a sequential immunization protocol, wherein each new immunization optimally increases the pressure on the immune system to target conserved antigenic sites, thus conferring breadth. We describe the mechanisms underlying why sequentially driving the immune system increasingly further from steady state, in an optimal fashion, is effective. The optimal protocol allows many evolving B cells to become bnAbs via diverse evolutionary paths.
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Project description:Vaccination will likely be a key component of strategies to curtail or prevent future sarbecovirus pandemics and to reduce the prevalence of infection and disease by future SARS-CoV-2 variants. A "pan-sarbecovirus" vaccine, that provides maximum possible mitigation of human disease, should elicit neutralizing antibodies with maximum possible breadth. By positioning multiple different receptor binding domain (RBD) antigens in close proximity on a single immunogen, it is postulated that cross-reactive B cell receptors might be selectively engaged. Heteromultimeric vaccines could therefore elicit individual antibodies that neutralize a broad range of viral species. Here, we use model systems to investigate the ability of multimeric sarbecovirus RBD immunogens to expand cross-reactive B cells and elicit broadly reactive antibodies. Homomultimeric RBD immunogens generated higher serum neutralizing antibody titers than the equivalent monomeric immunogens, while heteromultimeric RBD immunogens generated neutralizing antibodies recognizing each RBD component. Moreover, RBD heterodimers elicited a greater fraction of cross-reactive germinal center B cells and cross-reactive RBD binding antibodies than did homodimers. However, when serum antibodies from RBD heterodimer-immunized mice were depleted using one RBD component, neutralization activity against the homologous viral pseudotype was removed, but neutralization activity against pseudotypes corresponding to the other RBD component was unaffected. Overall, simply combining divergent RBDs in a single immunogen generates largely separate sets of individual RBD-specific neutralizing serum antibodies that are mostly incapable of neutralizing viruses that diverge from the immunogen components.
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