Abstract
Human papillomavirus (HPV) is the causative agent of cervical and other cancers and represents a significant global health burden. HPV vaccines demonstrate excellent efficacy in clinical trials and effectiveness in national immunization programmes against the most prevalent genotype, HPV16. It is unclear whether the greater protection conferred by vaccine-induced antibodies, compared to natural infection antibodies, is due to differences in antibody magnitude and/or specificity. We explore the contribution of the surface-exposed loops of the major capsid protein to antigenic domains recognized by vaccine and natural infection neutralizing antibodies. Chimeric pseudoviruses incorporating individual (BC, DE, EF, FG, HI) or combined (All: BC/DE/EF/FG/HI) loop swaps between the target (HPV16) and control (HPV35) genotypes were generated, purified by ultracentrifugation and characterized by SDS-PAGE and electron microscopy. Neutralizing antibody data were subjected to hierarchical clustering and outcomes modeled on the HPV16 capsomer crystal model. Vaccine antibodies exhibited an FG loop preference followed by the EF and HI loops while natural infection antibodies displayed a more diverse pattern, most frequently against the EF loop followed by BC and FG. Both vaccine and natural infection antibodies demonstrated a clear requirement for multiple loops. Crystal modeling of these neutralizing antibody patterns suggested natural infection antibodies typically target the outer rim of the capsomer while vaccine antibodies target the central ring around the capsomer lumen. Chimeric pseudoviruses are useful tools for probing vaccine and natural infection antibody specificity. These data add to the evidence base for the effectiveness of an important public health intervention. IMPORTANCE The human papillomavirus type 16 (HPV16) major virus coat (capsid) protein is a target for antibodies induced by both natural infection and vaccination. Vaccine-induced immunity is highly protective against HPV16-related infection and disease while natural infection associated immunity significantly less so. For this study, we created chimeric functional pseudoviruses based upon an antigenically distant HPV genotype (HPV35) resistant to HPV16-specific antibodies with inserted capsid surface fragments (external loops) from HPV16. By using these chimeric pseudoviruses in functional neutralization assays we were able to highlight specific and distinct areas on the capsid surface recognized by both natural infection and vaccine induced antibodies. These data improve our understanding of the difference between natural infection and vaccine induced HPV16-specific immunity.
Original language | English |
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Journal | Microbiology Spectrum |
Volume | 10 |
Issue number | 3 |
DOIs | |
Publication status | Published - Jun 2022 |
Bibliographical note
Funding Information:This work was supported by UK Health Security Agency (UKHSA). This publication is independent research part funded by the National Institute for Health Research Policy Research Program (“Vaccine Evaluation Consortium Phase II,” 039/0031). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. We have no conflicts of interest to declare.
Funding Information:
We are indebted to John T. Schiller and Christopher Buck (National Cancer Institute, Bethesda, MD, USA) for access to the psheLL backbone used for the pseudovirus clones. We thank Sara L. Bissett previously from UK Health Security Agency (UKHSA) (formerly Public Health England) for creation of some of the clones used in this study. This work was supported by UK Health Security Agency (UKHSA). This publication is independent research part funded by the National Institute for Health Research Policy Research Program (“Vaccine Evaluation Consortium Phase II,” 039/0031). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. We have no conflicts of interest to declare.
Publisher Copyright:
© Crown copyright 2022.
Keywords
- human papillomavirus
- neutralizing antibodies
- pseudovirus
- surface-exposed loops