Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2011 Dec;7(12):1359-73.
doi: 10.4161/hv.7.12.18282. Epub 2011 Dec 1.

Comparison of the immunogenicity of the human papillomavirus (HPV)-16/18 vaccine and the HPV-6/11/16/18 vaccine for oncogenic non-vaccine types HPV-31 and HPV-45 in healthy women aged 18-45 years

Mark H Einstein  1 , Mira Baron, Myron J Levin, Archana Chatterjee, Bradley Fox, Sofia Scholar, Jeffrey Rosen, Nahida Chakhtoura, Marie Lebacq, Robbert van der Most, Philippe Moris, Sandra L Giannini, Anne Schuind, Sanjoy K Datta, Dominique Descamps; HPV-010 Study Group
Collaborators, Affiliations
Clinical Trial

Comparison of the immunogenicity of the human papillomavirus (HPV)-16/18 vaccine and the HPV-6/11/16/18 vaccine for oncogenic non-vaccine types HPV-31 and HPV-45 in healthy women aged 18-45 years

Mark H Einstein et al. Hum Vaccin. 2011 Dec.

Abstract

Protection against oncogenic non-vaccine types (cross-protection) offered by human papillomavirus (HPV) vaccines may provide a significant medical benefit. Available clinical efficacy data suggest the two licensed vaccines (HPV-16/18 vaccine, GlaxoSmithKline Biologicals (GSK), and HPV-6/11/16/18 vaccine, Merck & Co., Inc.) differ in terms of protection against oncogenic non-vaccine HPV types -31/45. The immune responses induced by the two vaccines against these two non-vaccine HPV types (cross-reactivity) was compared in an observer-blind study up to Month 24 (18 mo post-vaccination), in women HPV DNA-negative and seronegative prior to vaccination for the HPV type analyzed (HPV-010 [NCT00423046]). Geometric mean antibody titers (GMTs) measured by pseudovirion-based neutralization assay (PBNA) and enzyme-linked immunosorbent assay (ELISA) were similar between vaccines for HPV-31/45. Seropositivity rates for HPV-31 were also similar between vaccines; however, there was a trend for higher seropositivity with the HPV-16/18 vaccine (13.0-16.7%) versus the HPV-6/11/16/18 vaccine (0.0-5.0%) for HPV-45 with PBNA, but not ELISA. HPV-31/45 cross-reactive memory B-cell responses were comparable between vaccines. Circulating antigen-specific CD4+ T-cell frequencies were higher for the HPV-16/18 vaccine than the HPV-6/11/16/18 vaccine (HPV-31 [geometric mean ratio [GMR] =2.0; p=0.0002] and HPV-45 [GMR=2.6; p=0.0092]), as were the proportion of T-cell responders (HPV-31, p=0.0009; HPV-45, p=0.0793). In conclusion, immune response to oncogenic non-vaccine HPV types -31/45 was generally similar for both vaccines with the exception of T-cell response which was higher with the HPV-16/18 vaccine. Considering the differences in cross-protective efficacy between the two vaccines, the results might provide insights into the underlying mechanism(s) of protection.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Seropositivity rates for anti-HPV-31 and anti-HPV-45 serum neutralizing antibodies measured by pseudovirion-based neutralization assay at Months 7 and 24 (ATP cohort for immunogenicity, seronegative and DNA-negative at baseline for HPV type analyzed). N, number of evaluable subjects; n, number of seropositive subjects, per vaccine, per timepoint. Percentages indicate seropositivity rates at each timepoint [seropositivity defined as neutralizing antibody titer ≥40 ED50 (the PBNA limit of quantification)]. Black bars, Human Papillomavirus Bivalent (Types 16 and 18) Vaccine (Recombinant, adjuvanted, adsorbed) (Cervarix®); white bars, Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant (Gardasil®). The ATP cohort for immunogenicity included all evaluable subjects who received three vaccine doses (i.e., those meeting all eligibility criteria and complying with the procedures defined in the protocol) for whom data concerning immunogenicity endpoint measures were available.
Figure 2
Figure 2
Geometric mean titers (GMTs) for anti-HPV-31 and anti-HPV-45 serum neutralizing antibodies measured by pseudovirion-based neutralization assay at Months 7, 12, 18 and 24 (ATP cohort for immunogenicity, seronegative and DNA-negative at baseline for HPV type analyzed). ED50, effective dose producing 50% response; GMT, geometric mean titer. Black square line, Human Papillomavirus Bivalent (Types 16 and 18) Vaccine (Recombinant, adjuvanted, adsorbed) (Cervarix®); white square line, Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant (Gardasil®). Error bars denote 95% confidence intervals (CIs) of GMTs; dashed line, PBNA limit of detection (40 ED50). N, number of evaluable subjects. The ATP cohort for immunogenicity included all evaluable subjects who received three vaccine doses (i.e., those meeting all eligibility criteria and complying with the procedures defined in the protocol) for whom data concerning immunogenicity endpoint measures were available.
Figure 3
Figure 3
Seropositivity rates for anti-HPV-31 and anti-HPV-45 IgG antibodies measured by enzyme-linked immunosorbent assay at Months 7 and 24 (ATP cohort for immunogenicity, seronegative and DNA-negative at baseline for HPV type analyzed). N, number of evaluable subjects; n, number of seropositive subjects, per vaccine, per timepoint. Percentages indicate seropositivity rates at each timepoint (seropositivity defined as IgG titer ≥59 ELISA units/mL [the ELISA limit of quantification]). Black bars, Human Papillomavirus Bivalent (Types 16 and 18) Vaccine (Recombinant, adjuvanted, adsorbed) (Cervarix®); white bars, Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant (Gardasil®). The ATP cohort for immunogenicity included all evaluable subjects who received three vaccine doses (i.e., those meeting all eligibility criteria and complying with the procedures defined in the protocol) for whom data concerning immunogenicity endpoint measures were available.
Figure 4
Figure 4
Geometric mean titers (GMTs) for anti-HPV-31 and anti-HPV-45 IgG antibodies measured by enzyme-linked immunosorbent assay at Months 7, 12, 18 and 24 (ATP cohort for immunogenicity, seronegative and DNA-negative at baseline for HPV type analyzed). GMT, geometric mean titer; IgG, immunoglobulin G. Black square line, Human Papillomavirus Bivalent (Types 16 and 18) Vaccine (Recombinant, adjuvanted, adsorbed) (Cervarix®); white square line, Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant (Gardasil®). Errors bars denote 95% confidence intervals (CIs) of GMTs. Dashed line, ELISA limit of detection (59 ELISA units/mL). Dotted line, GMTs for natural infection antibody levels (183.5 ELISA units/mL for HPV-31 and 139.0 ELISA units/mL for HPV-45). N, number of evaluable subjects. The ATP cohort for immunogenicity included all evaluable subjects who received three vaccine doses (i.e., those meeting all eligibility criteria and complying with the procedures defined in the protocol) for whom data concerning immunogenicity endpoint measures were available.
Figure 5
Figure 5
Proportion of responders for (A) HPV-31- and (B) HPV-45-specific memory B-cell responses at Months 7, 12, 18 and 24 (ATP cohort for immunogenicity; seronegative, DNA-negative and with no detectable HPV cross-reactive B-cells prior to vaccination). N, number of subjects with available results; n, number of responders, per vaccine, per timepoint; %, percentage of responders, per vaccine, per timepoint. Black bars, Human Papillomavirus Bivalent (Types 16 and 18) Vaccine (Recombinant, adjuvanted, adsorbed) (Cervarix®); white bars, Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant (Gardasil®). Responders defined as subjects with detectable HPV cross-reactive memory B cells (≥1 cell/million cells). p-values were calculated using Fisher's exact test to compare proportion of responders.
Figure 6
Figure 6
Geometric means (GM) and GM ratios (GMR) in responders only for (A) HPV-31- and (B) HPV-45-specific memory B-cells at Months 7, 12, 18 and 24 (ATP cohort for immunogenicity; seronegative, DNA-negative and with no detectable HPV cross-reactive B cells prior to vaccination). GMR, geometric mean ratio; N, number of responders [i.e., subjects with detectable HPV cross-reactive memory B cells (≥1 cell/million cells)]. Black square line, Human Papillomavirus Bivalent (Types 16 and 18) Vaccine (Recombinant, adjuvanted, adsorbed) (Cervarix®); white square line, Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant (Gardasil®). Error bars denote 95% confidence intervals of geometric means. Statistical comparison (GMR ANOVA p-value) was performed on B-cell responders because data for all subjects in the subset did not follow a normal distribution.
Figure 7
Figure 7
Proportion of responders for (A) HPV-31- and (B) HPV-45-specific CD4+ T-cell response at Months 7, 12, 18 and 24 (ATP cohort for immunogenicity; seronegative, DNA-negative and with a HPV-specific CD4+ T-cell response below 500 cells per million cells prior to vaccination). N, number of subjects with available results; n, number of responders, per vaccine, per timepoint; %, percentage of responders, per vaccine, per timepoint. *p < 0.05. Black bars, Human Papillomavirus Bivalent (Types 16 and 18) Vaccine (Recombinant, adjuvanted, adsorbed) (Cervarix®); white bars, Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant (Gardasil®). Responders defined as subjects with ≥500 HPV cross-reactive memory CD4+ T-cells expressing at least two of four immune markers (CD40L, IL-2, TNFα, IFNγ) per million cells. p-values were calculated using Fisher's exact test to compare proportion of responders.
Figure 8
Figure 8
Geometric means (GM) and GM ratios (GMR) for (A) HPV-31- and (B) HPV-45-specific CD4+ T-cell response at Months 7, 12, 18 and 24 in all subjects in the subset (ATP cohort for immunogenicity; seronegative, DNA-negative and with a HPV cross-reactive CD4+ T-cell response below 500 cells per million cells prior to vaccination). *p < 0.05. GMR, geometric mean ratio; N, number of subjects with available results. Black square line, Human Papillomavirus Bivalent (Types 16 and 18) Vaccine (Recombinant, adjuvanted, adsorbed) (Cervarix®); white square line, Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant (Gardasil®). Error bars denote 95% confidence intervals of geometric means. Statistical comparison (GMR ANOVA p-value) was performed on all subjects.
Figure 9
Figure 9
Phylogenetic tree of anogenital human papillomavirus types (adapted from Schiffman and Wentzensen 2010 and Schiffman et al. 2005)., This phylogenetic tree is based on the alignment of concatenated early and late open reading frames. The carcinogenicity of HPV types reflects viral evolution. The clade presented in detail in the figure above (α5, 6, 7, 9, 11) reflects the HPV types associated with cervical cancers and their precursors.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–2917. doi: 10.1002/ijc.25516. - DOI - PubMed
    1. Muñoz N, Bosch FX, de Sanjosé S, Herrero R, Castellsagué X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518–527. doi: 10.1056/NEJMoa021641. - DOI - PubMed
    1. Smith JS, Lindsay L, Hoots B, Keys J, Franceschi S, Winer R, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: A meta-analysis update. Int J Cancer. 2007;121:621–632. doi: 10.1002/ijc.22527. - DOI - PubMed
    1. de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010;11:1048–1056. doi: 10.1016/S1470-2045(10)70230-8. - DOI - PubMed
    1. Barr E, Tamms G. Quadrivalent human papillomavirus vaccine. Clin Infect Dis. 2007;45:609–617. doi: 10.1086/520654. - DOI - PubMed

Publication types

MeSH terms

Substances

Associated data

  NODES
admin 1
chat 7
Note 4
twitter 2