Rational design of a triple-type human papillomavirus vaccine by compromising viral-type specificity

Abstract

Sequence variability in surface-antigenic sites of pathogenic proteins is an important obstacle in vaccine development. Over 200 distinct genomic sequences have been identified for human papillomavirus (HPV), of which more than 18 are associated with cervical cancer. Here, based on the high structural similarity of L1 surface loops within a group of phylogenetically close HPV types, we design a triple-type chimera of HPV33/58/52 using loop swapping. The chimeric VLPs elicit neutralization titers comparable with a mix of the three wild-type VLPs both in mice and non-human primates. This engineered region of the chimeric protein recapitulates the conformational contours of the antigenic surfaces of the parental-type proteins, offering a basis for this high immunity. Our stratagem is equally successful in developing other triplet-type chimeras (HPV16/35/31, HPV56/66/53, HPV39/68/70, HPV18/45/59), paving the way for the development of an improved HPV prophylactic vaccine against all carcinogenic HPV strains. This technique may also be extrapolated to other microbes.

SARS-CoV-2 spike produced in insect cells elicits high neutralization titres in non-human primates

“…It is worthy noted that the neutralization titres elicited by 10 μg and 100 μg aluminium adjuvanted RBD were comparable in mice, which might be due to a two-fold reason, (1) immunization programme of 0, 2, 4w may facilitate the antibody response in 10 μg group ( Figure 5(H)) rather than 0, 1, 4w in 100 μg dose, which might be associated with a longer B cell maturation timer [44] in 0, 2, 4w regiment; (2) The dose dependency of RBD immunization with 3-dose administration may reach saturated at about 10 μg, demonstrating comparable neutralization titres at 10 μg and 100 μg, but significantly lower at 1 μg. We have found this phenomenon in immunogenicity data for the chimeric HPV33/52/58 VLPs, where 10 μg and 1 μg induced comparable neutralization titres but significantly lower for 0.1 μg [45]. A recently reported inactivated vaccine candidate (PiCoVacc) was able to induce SARS-CoV-2 neutralization titres in rhesus macaques that were comparable with the convalescent sera from recovered COVID-19 patients, but still conferred efficacious protection against SARS-CoV-2 challenge [19].…”

Identification and Analysis of Unstructured, Linear B-Cell Epitopes in SARS-CoV-2 Virion Proteins for Vaccine Development

“…The 437 residues in our epitope dataset permit a reduction of at least 4.5-fold of the virion proteome, thus facilitating the construction of chimeric proteins including only highly antigenic sequences. Antigen engineering involving the incorporation of protein loops into chimeric proteins to improve protection has already been applied in other viruses such as papillomavirus [ 58 ] and Zika [ 54 ].…”

Emerging Concepts and Technologies in Vaccine Development

“…A computationally designed antigen found to be protective in animal models was first reported for the respiratory syncytial virus (RSV) F antigen in 2013 ( 79 ). Many challenging vaccine targets have since been developed rationally for HIV ( 80 – 82 ), hepatitis C ( 83 , 84 ), herpes ( 85 ), Zika ( 86 , 87 ), RSV ( 82 ), HPV ( 88 ), as well as for bacteria ( 82 , 89 ), fungi ( 90 ), and cancers ( 91 ). Rational vaccine design has also been utilized to improve VLP and NP vaccines by selecting a repetitive and predictive protein backbone structure for enhanced antigen presentation ( 92 ).…”