Specific Antibody Levels at the Cervix During the Menstrual Cycle of Women Vaccinated With Human Papillomavirus 16 Virus-Like Particles

Nardelli-Haefliger, Denise; Wirthner, D.; Schiller, John T.; Lowy, Douglas R.; Hildesheim, Allan; Ponci, Françoise; Grandi, P. De

doi:10.1093/jnci/djg018

Cited by 205 publications

(163 citation statements)

References 37 publications

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“…This suggests the importance of future studies to better understand the effects of the menstrual cycle phase on antibody measurements in the periphery and cervix. We observed that OC use was not an important modifier of the degree of correlation observed between serum and cervical secretion measures, which appears to contrast with previous data from Nardelli-Haefliger et al [25]. This contradiction may be due to variations in sample size and study design, such as in the Nardelli-Haefliger et al study participants were sampled multiple times during a two month period following immunization while our correlations are only based on month 12 samples for serum and cervical secretions.…”

Section: Discussioncontrasting

confidence: 99%

“…A study performed by Nardelli-Haefliger et al examined levels of anti-HPV16 antibody at the cervix following vaccination and found that cervical HPV16 type-specific antibodies range from 0.5-50% of systemic levels [25]. It is currently unclear whether systemic measures of post-vaccination immunity can serve as a good surrogate for local levels of immune protection at the cervix.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of systemic and mucosal anti-HPV16 and anti-HPV18 antibody responses from vaccinated women

Kemp¹,

Garcı́a-Piñeres²,

Falk³

et al. 2008

Vaccine

106

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Ideal methods to monitor HPV neutralizing antibodies induced by vaccination have not been established yet. Here, we evaluated systemic and cervical antibody levels induced by HPV16/18 AS04-adjuvanted vaccine (GlaxoSmithKline Biologicals) using a secreted alkaline phosphatase neutralization assay (SEAP) and ELISA. Serum and cervical secretions from 50 vaccinated women were used to assess 1) overall assay reproducibility, 2) inter-assay and inter-specimen correlation; 3) correlations between month 1 and month 12 titers. Strong correlations between SEAP-NA and ELISA were observed (serum anti-HPV16/18, ρ=0.91/0.85; cervix anti-HPV16/18, ρ=0.84/0.89). Systemic and cervical antibody measures also correlated well (ρ range: 0.64 -0.75); except at mid-cycle (ρ range: 0.28 -0.65). Correlations between antibody levels at one and twelve months following the start of vaccination were poor (ρ range: 0.16 -0.38). In conclusion, HPV16/18 VLP-based ELISA is a reliable and valid method to monitor anti-HPV16/18 neutralizing potential for the first year following vaccination; however, additional studies will be Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Conflict of Interest: Troy J. Kemp, no conflict; Alfonso García-Piñeres, no conflict; Roni T. Falk, no conflict; Sylviane Poncelet is employed by GSK Biologicals, the manufacturer of the vaccine used in this trial; Francis Dessy is employed by GSK Biologicals, the manufacturer of the vaccine used in this trial; Sandra L. Giannini is employed by GSK Biologicals, the manufacturer of the vaccine used in this trial; Ana Cecilia Rodriguez, no conflict; Carolina Porras, no conflict; Rolando Herrero, no conflict; Allan Hildesheim, no conflict; Ligia A. Pinto, no conflict. Merocel is a trademark of Medtronic Ophthalmics, a division of Medtronic Xomed, Inc., Jacksonville, FL, and Hemastix is a trademark of Bayer Corporation, Elkhart, IN. NIH Public Access Author ManuscriptVaccine. Author manuscript; available in PMC 2014 August 13.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evaluation of systemic and mucosal anti-HPV16 and anti-HPV18 antibody responses from vaccinated women

Kemp¹,

Garcı́a-Piñeres²,

Falk³

et al. 2008

Vaccine

106

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“…In cell cultures, oestrogen interacts with adhesion molecules, producing increased deformability and contraction, which theoretically could facilitate cellular exfoliation (Gorodeski, 1998). Finally, levels of immunoglobulins in cervical secretions reach their nadir at mid-cycle, which may favour HPV replication and accumulation to high viral loads (Franklin and Kutteh, 1999;Nardelli-Haefliger et al, 2003). The explanation for the observed, more minor spike in viral load around the time of menses is also unexplained, although apoptosis secondary to oestrogen withdrawal represents a possible explanation (Wang et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Performance of cytology and human papillomavirus testing in relation to the menstrual cycle

2006

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Cervical smears prepared around the time of menses have been linked to unsatisfactory specimens and false negative results; however, it is unclear whether liquid-based cytology is similarly affected and data relating date of last menstrual period (LMP) to human papillomavirus (HPV) DNA testing are conflicting. Accordingly, we evaluated liquid-based cytology and HPV test results using Hybrid Capture 2 and PCR by LMP (days 0 -10; 11 -21; 22 -28). We studied 5060 participants in ALTS, the Atypical Squamous Cells of Undetermined Significance (ASCUS) Low Grade Squamous Intraepithelial Lesion (LSIL) Triage Study. On average, women had 3.4 examinations (median 4, range 1 -5) during a 2-year period of observation permitting an examination of intra-individual variation in cytology and HPV by LMP. Although uncommon, unsatisfactory cytology specimens were most likely on days 0 -10. For satisfactory specimens, the frequency with which cytologic categories were reported varied by time since LMP, although differences were modest and did not affect the chance of abnormal cytology or its severity among women diagnosed with CIN2 þ . The frequency of positive HC2 tests did not vary with date of LMP. Among HPV infected women, independent of eventual diagnosis and the number of viral genotypes present, mid-cycle specimens yielded the highest frequency of LSIL cytologic interpretations and the highest HPV load; however, the magnitude of these effects were small. Intraindividual correlations of cytology or HPV by LMP were generally weak. We conclude that mid-cycle specimens yield slightly higher HPV DNA loads and slightly increased LSIL interpretations, but the clinical impact is marginal. Standardizing collection times would slightly improve interpretation of trends in HPV load. Finally, these data are consistent with the view that the biological properties of the HPV-infected cervix vary with the date of the LMP. Historically, clinicians have recognized that cytologic samples collected on days of active menstruation are typically bloody and often yield smears that are hypocellular, obscured, and lack endocervical cells (Vooijs et al, 1987). Furthermore, data demonstrating that unsatisfactory cytology specimens are associated with a higher than expected frequency of cervical intraepithelial neoplasia (CIN) and carcinoma (Ransdell et al, 1997;Nygard et al, 2004) in later follow-up, suggest that that these specimens may be linked to false negative results. However, efforts to coordinate return visits to re-screen women with unsatisfactory cytology often fail (McGarahan and Smith-McCune, 2005), and presumably, deferring screening for women who present near the time of menses would present similar problems. Given this dilemma, it is important to determine whether the advantages of liquid-based cytology methods, such as increased cellular recovery and reduction of obscuring by blood (Bernstein et al, 2001), eliminate the association between the performance of cytology and LMP that has been demonstrated for smears.Similarly, the implement...

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“…2). In addition to the IgG antibodies that are transudating through mucosal membranes, and, thus are found at the uterine cervix 25 also IgA are expected to be beneficial for HPV-specific protection. Although antibody titers may fall during ovulation, clinical studies with VLP have shown efficient and continuous protection.…”

Section: Discussionmentioning

confidence: 99%

Vaccination trial with HPV16 L1E7 chimeric virus‐like particles in women suffering from high grade cervical intraepithelial neoplasia (CIN 2/3)

Kaufmann

Nieland

Jochmus

et al. 2007

Intl Journal of Cancer

115

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Persistent infection with human papillomaviruses (HPV) is a prerequisite for the development of cervical cancer. Vaccination with virus-like particles (VLP) has demonstrated efficacy in prophylaxis but lacks therapeutic potential. HPV16 L1E7 chimeric viruslike particles (CVLP) consist of a carboxy-terminally truncated HPV16L1 protein fused to the amino-terminal part of the HPV16 E7 protein and self-assemble by recombinant expression of the fusion protein. The CVLP are able to induce L1-and E7-specific cytotoxic T lymphocytes. We have performed a first clinical trial to gain information about the safety and to generate preliminary data on the therapeutic potential of the CVLP in humans. A randomized, double blind, placebo-controlled clinical trial has been conducted in 39 HPV16 mono-infected high grade cervical intraepithelial neoplasia (CIN) patients (CIN 2/3). Two doses (75 lg or 250 lg) of CVLP were applied. The duration of the study was 24 weeks with 2 optional visits after another 12 and 24 weeks. The vaccine showed a very good safety profile with only minor adverse events attributable to the immunization. Antibodies with high titers against HPV16 L1 and low titers against HPV16 E7 as well as cellular immune responses against both proteins were induced. Responses were equivalent for both vaccine concentrations. A trend for histological improvement to CIN 1 or normal was seen in 39% of the patients receiving the vaccine and only 25% of the placebo recipients. Fifty-six percent of the responders were also HPV16 DNA-negative by the end of the study. Therefore, we demonstrated evidence for safety and a nonsignificant trend for the clinical efficacy of the HPV16 L1E7 CVLP vaccine. ' 2007 Wiley-Liss, Inc.Key words: cervical cancer; clinical trial; immunization; antibody; T cell Genital infection with human papillomavirus (HPV) is one of the most common sexually transmitted diseases. Various molecular and epidemiological studies have documented a correlation between infection with ''high risk'' HPV types and premalignant or malignant tumors of the anogenital tract. 1,2 It is widely acknowledged that a causal relationship exists between persistent HPV infection and development of cervical intraepithelial neoplasia (CIN) and cervical cancer. 3,4 There are over 100 known papillomavirus types that are stratified into low and high risk, based on their association with malignant and invasive lesions. More than 95% of invasive cervical cancers are positive for HPV-DNA, mainly from HPV types 16 (50%) and 18 (20%). Moreover, HPV16 can be detected in 30270% of all HPV-positive high grade CIN patients. 5,6 The prevalence of HPV16 in other intraepithelial neoplasias is even higher, e.g., 70280% in high grade vulvar intraepithelial neoplasia. 7 Whereas for low grade CIN a high spontaneous recovery rate is observed 6,8 high grade CIN regress less often particular at higher age when lesions are more persistent. 9 Because of the potential progression of high grade CIN to invasive cancer, 10 a thorough evaluation consisting of colp...

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Specific Antibody Levels at the Cervix During the Menstrual Cycle of Women Vaccinated With Human Papillomavirus 16 Virus-Like Particles

Abstract: The relatively high titer of anti-HPV16 antibodies at the cervix is promising in terms of vaccine efficacy; however, the decrease in antibody titer around ovulation raises the possibility that the HPV16 VLP vaccine might be less effective during the peri-ovulatory phase.

Cited by 205 publications

References 37 publications

Evaluation of systemic and mucosal anti-HPV16 and anti-HPV18 antibody responses from vaccinated women

Evaluation of systemic and mucosal anti-HPV16 and anti-HPV18 antibody responses from vaccinated women

Performance of cytology and human papillomavirus testing in relation to the menstrual cycle

Vaccination trial with HPV16 L1E7 chimeric virus‐like particles in women suffering from high grade cervical intraepithelial neoplasia (CIN 2/3)

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