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Structure-based design of glycoprotein subunit vaccines for mumps
Rebecca J Loomis1, Yen-Ting Lai1, Sun B Sowers2
1Vaccine Research Center, NIH, Bethesda, MD 20892.
Abstract:
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 neutralizing titers to genotypes A, G, and H mumps. A crystal structure of mumps Pre-F at 2.16 Å 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.
Insights
New mumps subunit vaccines using prefusion F glycoproteins show promise. These engineered immunogens elicit potent neutralizing antibodies against diverse mumps virus genotypes, potentially boosting immunity or serving as next-generation vaccines.
Area of Science:
- Virology and Immunology
- Vaccine Development
- Structural Biology
Background:
- Mumps virus (MuV) remains a global public health concern, causing outbreaks despite high vaccination rates.
- Waning immunity and antigenic drift between vaccine strains and circulating wild-type mumps viruses contribute to vaccine ineffectiveness.
- Current measles, mumps, and rubella (MMR) vaccines may require boosting or next-generation alternatives.
Purpose of the Study:
- To engineer novel mumps virus subunit vaccine candidates based on structure-based design.
- To evaluate the immunogenicity and cross-neutralizing potential of stabilized prefusion F (Pre-F) and chimeric Pre-F/HN immunogens.
- To characterize the neutralizing antibody responses elicited by these novel immunogens.
Main Methods:
- Structure-based design was employed to engineer mumps fusion (F) glycoprotein stabilized in its prefusion conformation (Pre-F).
- A chimeric immunogen comprising Pre-F linked to mumps hemagglutinin neuraminidase (HN) was created.
- Crystal structure of mumps Pre-F was determined; monoclonal antibodies were generated and characterized for neutralizing activity against different mumps virus genotypes.
Main Results:
- Both Pre-F antigen and the chimeric Pre-F/HN immunogen elicited potent cross-reactive neutralizing antibody titers against mumps virus genotypes A, G, and H in mice.
- The crystal structure confirmed the stabilization of the mumps Pre-F.
- Isolated antibodies demonstrated neutralization of various mumps virus genotypes, targeting distinct antigenic sites on Pre-F and HN glycoproteins.
Conclusions:
- Engineered mumps Pre-F and chimeric Pre-F/HN immunogens are effective in eliciting broad cross-neutralizing antibody responses.
- These novel immunogens represent promising candidates for boosting existing MMR-induced immunity or as next-generation mumps vaccines.
- Further development could lead to improved control of mumps outbreaks in highly immunized populations.
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