Structure- based design of glycoprotein subunit vaccines for mumps

• 成果类型: Article
• 署名作者: Loomis, Rebecca J.; Lai, Yen-Ting; Sowers, Sun B.; Fisher, Brian; Derrien-Colemyn, Alexandrine; Ambrozak, David R.; Tsybovsky, Yaroslav; Crooke, Stephen N.; Latner, Donald R.; Kong, Wing-Pui; Ruckwardt, Tracy J.; Plotkin, Stanley A.; Kwong, Peter D.; Mascola, John R.; Graham, Barney S.; Hickman, Carole J.; Stewart-Jones, Guillaume B. E.
• 署名单位: National Institutes of Health (NIH) - USA; Centers for Disease Control & Prevention - USA; CDC National Center for Immunization & Respiratory Diseases (NCIRD); National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; University of Pennsylvania
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13418
• DOI: 10.1073/pnas.2404053121
• 发表日期: 2024-11-19
• 关键词: prefusion form; virus vaccine; OUTBREAK; immunization; efficacy; students; iowa

摘要

Mumps virus (MuV) is a highly contagious paramyxovirus that is endemic in most regions of the world and continues to cause outbreaks even in highly immunized populations. Outbreaks of mumps in countries with high measles, mumps, and rubella vaccination coverage have been attributed to waning immunity and antigenic differences between the Jeryl Lynn vaccine strain (genotype A) and circulating wild- type viruses. To obtain a subunit vaccine, we used structure- based design to engineer the mumps fusion (F) glycoprotein stabilized in its prefusion conformation (Pre- F) as well as a chimeric immunogen comprising Pre- F linked to mumps hemagglutinin neuraminidase (HN); in mice, both Pre- F antigen and the chimeric antigen elicited potent cross- reactive plaque reducing neutralizingtiters to genotypes A, G, and H mumps. A crystal structure of mumps Pre- F at 2.16 & Aring; resolution validated the stabilization strategy, while a post- fusion form of F was engineered as a comparator. Monoclonal antibodies to mumps Pre- F and HN were isolated from immunized mice; 7 of 14 Pre- F- specific antibodies and 9 of 15 HN- specific antibodies were capable of neutralizing genotype G MuV with a range of potencies. Additionally, 7 of 14 Pre- F- specific antibodies neutralized genotype A mumps. Structural and binding analyses of Pre- F- specific antibodies revealed binding to four discrete neutralizing antigenic sites and binding analyses of HN- specific antibodies revealed binding to five discrete neutralizing antigenic sites. Overall, the PreF and the chimeric Pre-F/HN immunogens are promising candidates to boost MMR- elicited immunity to mumps or as a next- generation vaccine.