Abstract
BackgroundThe 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 FindingsSerum 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.ConclusionsThese 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 RegistrationClinicalTrials.gov NCT00956553
Highlights
Cancer of the cervix is the third most common cancer of women and accounts for an estimated 530,000 cervical cancer cases and 275,000 deaths per annum worldwide [1,2]
The current generation of virus-like particle (VLP)-based vaccines (CervarixH and GardasilH) target HPV16 and HPV18 and have been shown in clinical trials to be highly efficacious at reducing persistent infections and cervical lesions associated with these types [6,7]
High levels of serum neutralizing antibodies against pseudovirions representing these two types and antibodies capable of blocking murine monoclonal antibodies targeting putative neutralizing domains on immobilized VLP can be detected [8,9,10,11,12,13,14]. These observations corroborate findings from animal models in which passive transfusion of immune sera or purified IgG protected animals from subsequent papillomavirus challenge [15,16]. Taken together these data suggest that neutralizing antibodies against the vaccine types, HPV16 and HPV18, play a significant role in mediating vaccineinduced protection from infection and disease associated with these two Human Papillomavirus (HPV) types [17,18,19]
Summary
Cancer of the cervix is the third most common cancer of women and accounts for an estimated 530,000 cervical cancer cases and 275,000 deaths per annum worldwide [1,2]. High levels of serum neutralizing antibodies against pseudovirions representing these two types and antibodies capable of blocking murine monoclonal antibodies targeting putative neutralizing domains on immobilized VLP can be detected [8,9,10,11,12,13,14]. These observations corroborate findings from animal models in which passive transfusion of immune sera or purified IgG protected animals from subsequent papillomavirus challenge [15,16]. 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
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