A randomized, observer-blinded immunogenicity trial of Cervarix(®) and Gardasil(®) Human Papillomavirus vaccines in 12-15 year old girls

Abstract

Background: The current generation of Human Papillomavirus (HPV) vaccines, Cervarix® and Gardasil®, exhibit a high degree of efficacy in clinical trials against the two high-risk (HR) genotypes represented in the vaccines (HPV16 and HPV18). High levels of neutralizing antibodies are elicited against the vaccine types, consistent with preclinical data showing that neutralizing antibodies can mediate type-specific protection in the absence of other immune effectors. The vaccines also confer protection against some closely related non-vaccine HR HPV types, although the vaccines appear to differ in their degree of cross-protection. The mechanism of vaccine-induced cross-protection is unknown. This study sought to compare the breadth and magnitudes of neutralizing antibodies against non-vaccine types elicited by both vaccines and establish whether such antibodies could be detected in the genital secretions of vaccinated individuals.

Methods and findings: Serum and genital samples were collected from 12-15 year old girls following vaccination with either Cervarix® (n = 96) or Gardasil® (n = 102) HPV vaccine. Serum-neutralizing antibody responses against non-vaccine HPV types were broader and of higher magnitude in the Cervarix®, compared to the Gardasil®, vaccinated individuals. Levels of neutralizing and binding antibodies in genital secretions were closely associated with those found in the serum (r = 0.869), with Cervarix® having a median 2.5 (inter-quartile range, 1.7-3.5) fold higher geometric mean HPV-specific IgG ratio in serum and genital samples than Gardasil® (p = 0.0047). There was a strong positive association between cross-neutralizing antibody seropositivity and available HPV vaccine trial efficacy data against non-vaccine types.

Conclusions: These data demonstrate for the first time that cross-neutralizing antibodies can be detected at the genital site of infection and support the possibility that cross-neutralizing antibodies play a role in the cross-protection against HPV infection and disease that has been reported for the current HPV vaccines.

Trial registration: ClinicalTrials.gov NCT00956553.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. CONSORT diagram.

Allocations, interventions, follow up and analysis of 198 subjects recruited into the comparative HPV vaccine immunogenicity study.

Figure 2. Neutralizing antibody responses over time course of study.

Percentage of vaccinees with neutralization titers of ≥20 (left panels) and GMT (right panels) against indicated vaccine (HPV16, HPV18) and non-vaccine (HPV31, HPV45) types. Error bars, ±95% CI. * p<0.05; ** p<0.01; *** p<0.001. Denominators for each measure were as follows: Cervarix® (blue) M0 (n = 94), M2 (n = 91), M7 (n = 91), M12 (n = 92); Gardasil® (red) M0 (n = 93), M2 (n = 98), M7 (n = 97), M12 (n = 96).

Figure 3. Breadth of neutralizing antibody responses elicited by HPV vaccines.

Percentage of serum samples neutralizing indicated number of A9 (top panel) or A7 (bottom panel) non-vaccine types within each of the low (T1), middle (T2) or high (T3) vaccine-type tertiles (dark to light gradient shading) for indicated vaccine (blue, Cervarix®; red, Gardasil®).

Figure 4. Relationship between HPV-specific vaccine antibodies in sera and genital samples.

(A) Neutralization titers were normalized to IgG levels in serum and genital samples for HPV16 (left panel; Cervarix® n = 21, Gardasil® n = 28) and HPV18 (right panel; Cervarix® n = 21, Gardasil® n = 26). (B) VLP binding titers were normalized to IgG levels in serum and genital samples for HPV16 (top left panel; Cervarix® n = 20, Gardasil® n = 21), HPV18 (top right panel; Cervarix® n = 19, Gardasil® n = 21), HPV31 (bottom left panel; Cervarix® n = 14, Gardasil® n = 21) and HPV45 (bottom right panel; Cervarix® n = 17, Gardasil® n = 24). Geometric mean ratios of the HPV specific IgG/total IgG for each sample type presented for Cervarix® (blue lines) and Gardasil® (red lines). (C) Relationship between serum and genital samples using normalized neutralizing and binding antibody for all tests. Overall Pearson's (r) coefficients are given. PsV, HPV pseudovirus. VLP, HPV virus-like particle.

Figure 5. Type-specific neutralizing antibody seroprevalence in study participants against reported vaccine efficacy.

Seroprevalence data are plotted against (A) efficacy against persistent infection and (B) efficacy against CIN2+ reported from trials of Cervarix® (blue points) and Gardasil® (red points) vaccinees for each non-vaccine HPV type (HPV31, HPV33, HPV45, HPV52 and HPV58). Vertical error bars represent exact 95% confidence intervals for the efficacy data, while horizontal error bars represent exact 95% confidence intervals for the neutralization seroprevalence data. The best fitting linear relationship between the two variables (black line) and the 95% range of bootstrap estimates for this relationship (dotted lines) is also shown. Exact 95% confidence intervals for data points were calculated using the Fisher's exact method for vaccine efficacy (1-odds ratio) and Clopper-Pearson for seroprevalence.