[Background]Structural vaccinology represents the natural progression from reverse vaccinology,leveraging genome-based methodologies and structural biology techniques to selectively design antigens using protective determinants.These antigens are further refined and simplified for vaccine formulation integration.The primary aim of this approach is to engineer innovative vaccines that offer broad-spectrum protection against infectious diseases,addressing the current lack of vaccines for pathogens such as human immunodeficiency virus(HIV),Zika virus,tuberculosis,and multiple antibiotic-resistant bacteria,all of which pose severe threats to public health.Moreover,structural vaccinology harnesses a genomic approach that merges information from diverse disciplines,including immunology,biochemistry,molecular biology,and structural biology,to guide vaccine development through the analysis of three-dimensional structures of pathogens'surface proteins or components.Leveraging advanced structural biology techniques such as X-ray crystallography,nuclear magnetic resonance(NMR)spectroscopy,and cryo-electron microscopy(Cryo-EM),scientists can elucidate the intricate molecular structures of pathogen antigens.This understanding facilitates a deeper insight into the interaction mechanisms between pathogens and the host immune system.[Progress]The variability of antigenic epitopes in pathogens constitutes a significant hurdle in vaccine development for infectious diseases.However,the early successes in applying structural biology to vaccine design underscore the immense potential of structural vaccinology,particularly in challenging scenarios of vaccine development.The elucidation of antibody-antigen complex structures for critical pathogens,including HIV,COVID-19,and influenza,has yielded a wealth of potentially viable epitopes.Several representative examples underscore the structure-based vaccine molecular designs.The discovery of the respiratory syncytial virus(RSV)F protein's pre-fusion(pre-F)conformation has emerged as a primary target for neutralizing antibodies,heralding novel vaccine development pathways.Last year,we witnessed the market approval of two RSV vaccines employing the pre-F design.Despite the current absence of an HIV vaccine,HIV Env trimer proteins designed around a stable conformation have advanced to clinical trials.Moreover,innovative vaccine design strategies,including the deglycosylation of proteins to target specific epitopes,are unfolding.Influenza vaccines featuring headless hemagglutinin(HA)designs and nanoparticle molecular presentations have demonstrated significant cross-protection efficacy and have entered clinical evaluation.The identification of broadly neutralizing epitopes through structural vaccinology has opened up possibilities for a universal influenza vaccine.COVID-19 vaccine research has benefitted from integrating disulfide bond and proline mutations into the S protein to stabilize its conformation,a strategy employed in several marketed mRNA and recombinant protein vaccines.Additionally,structure-based receptor binding domain(RBD)dimer vaccines have proven highly effective in generating neutralizing antibodies.Overcoming human papilloma virus(HPV)type-specificity through chimeric epitope transplantation represents a milestone in developing the next generation of HPV vaccines.Similarly,fusion protein molecules combining various epitopes present promising candidates for future meningococcal group B(MenB)vaccines.Lastly,Epstein-Barr virus(EBV)nanoparticle vaccines and epitope peptide combination vaccines are showing promising results in preclinical studies.[Perspective]The subsequent challenge,incorporating these epitopes into antigen redesign to generate targeted protective immunogens or vaccines,remains a key forthcoming objective in structural vaccinology.The integration of modern technologies,including artificial intelligence and de novo design,offers transformative potential in vaccine development.Using structural data as templates to envisage the construction of vaccine antigen molecules de novo represents a groundbreaking advancement.David Baker's research group in protein design has demonstrated that it is feasible to de novo design protein inhibitors with exceptionally high affinities capable of preventing viral entry into cells.This breakthrough paves the way for new avenues in protein drug discovery and exerts a constructive influence on vaccine research,illustrating the immense possibilities inherent in employing de novo design strategies for the meticulous and logical creation of vaccine immunogens.Structural vaccinology,combined with the application of modern computing and artificial intelligence technologies,can provide unprecedented solutions to the medical and scientific challenges of the 21st century.The field of vaccine development is poised achieve a major leap forward.This review delineates the structural underpinnings of vaccine design and elucidates the process of structurally based molecular design.
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