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Comparative Study
. 2016 Sep 7;34(39):4724-4731.
doi: 10.1016/j.vaccine.2016.07.051. Epub 2016 Aug 11.

Immunogenicity of next-generation HPV vaccines in non-human primates: Measles-vectored HPV vaccine versus Pichia pastoris recombinant protein vaccine

Gaurav Gupta  1 , Viviana Giannino  2 , Narayan Rishi  3 , Reinhard Glueck  4
Affiliations
Comparative Study

Immunogenicity of next-generation HPV vaccines in non-human primates: Measles-vectored HPV vaccine versus Pichia pastoris recombinant protein vaccine

Gaurav Gupta et al. Vaccine. .

Abstract

Human papillomavirus (HPV) infection is the most common sexually transmitted disease worldwide. HPVs are oncogenic small double-stranded DNA viruses that are the primary causal agent of cervical cancer and other types of cancers, including in the anus, oropharynx, vagina, vulva, and penis. Prophylactic vaccination against HPV is an attractive strategy for preventing cervical cancer and some other types of cancers. However, there are few safe and effective vaccines against HPV infections. Current first-generation commercial HPV vaccines are expensive to produce and deliver. The goal of this study was to develop an alternate potent HPV recombinant L1-based vaccines by producing HPV virus-like particles into a vaccine that is currently used worldwide. Live attenuated measles virus (MV) vaccines have a well-established safety and efficacy record, and recombinant MV (rMV) produced by reverse genetics may be useful for generating candidate HPV vaccines to meet the needs of the developing world. We studied in non-human primate rMV-vectored HPV vaccine in parallel with a classical alum adjuvant recombinant HPV16L1 and 18L1 protein vaccine produced in Pichia pastoris. A combined prime-boost approach using both vaccines was evaluated, as well as immune interference due to pre-existing immunity against the MV. The humoral immune response induced by the MV, Pichia-expressed vaccine, and their combination as priming and boosting approaches was found to elicit HPV16L1 and 18L1 specific total IgG and neutralizing antibody titres. Pre-existing antibodies against measles did not prevent the immune response against HPV16L1 and 18L1.

Keywords: HPV16L1; HPV18L1; Pichia expressed; Prophylactic vaccine; Recombinant measles.

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Figures

Fig. 1
Fig. 1
Schematic representation of rMVEZ antigenome. N: nucleocapsid protein, P: phosphoprotein, M: matrix protein, F: fusion protein, H: attachment protein, L: large RNA-dependent RNA polymerase protein, C and V represents nonstructural proteins encoded in the P transcription unit. P2 represents position in measles vector to insert HPV16L1 or HPV18L1 genes as additional transcription unit.
Fig. 2
Fig. 2
Positive p(+)MVEZHPV18L1 clone selection by restriction analysis. M: size marker, Lambda/HindIII; 1: p(+)MVEZHPV18L1; 2: p(+)MVEZHPV18L1 BssHII-AatII digested. White arrow: HPV18L1 transgene.
Fig. 3
Fig. 3
rMVEZHPV18L1 clone characterisation by western blot analysis. M: size marker, SeeBlue Plus2 standard; 1. Negative control, MVEZ; 2. Positive control, PsV18; 3. rMVEZHPV18L1 (∼58 kDa); 4. Negative control, rMVEZ-malaria. Used 1:4000 diluted specific anti-18L1 monoclonal antibody, Abcam.
Fig. 4
Fig. 4
Anti-HPV16L1 and anti-HPV18L1 antibody response. (A). Anti-HPV16L1 total IgG titres measured by ELISA; (B). Anti-HPV18L1 total IgG titres measured by ELISA. These figures represents anti-HPV 16 L1 and anti-HPV18 L1 IgG antibody titres elicited in monkey groups immunized with our test vaccines at different time intervals. Statistical significance of the difference in titre between groups was determined by one-way non-parametric analysis of variance. P < 0.001 was considered statistically significant. Significance was calculated with respect to PBS negative control group.
Fig. 5
Fig. 5
Anti-HPV16L1 and Anti-HPV18L1 neutralizing antibody determination. (A). Anti-HPV16L1 neutralizing antibodies measured by 16PBNA; (B). Anti-HPV18L1 neutralizing antibodies measured by 18PBNA. These figures represents anti-HPV 16 L1 and anti-HPV18 L1 neutralizing antibody titres elicited in monkey groups immunized with our test vaccines at different time intervals. Statistical significance of the difference in titre between groups was determined by one-way non-parametric analysis of variance. P < 0.001 was considered statistically significant. Significance was calculated with respect to PBS negative control group, Note- sera were tested as pool for anti HPV18 L1 neutralization therefore no statistical significance calculated.
Fig. 6
Fig. 6
Anti-measles neutralizing antibody response. Figure represents anti-measles neutralizing antibody titres elicited in monkey groups immunized with our test vaccines at different time intervals. Statistical significance of the difference in titre between groups was determined by one-way non-parametric analysis of variance. P < 0.001 was considered statistically significant. Significance was calculated with respect to measles alone group.
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