Hildesheim, Allan

Lowy, Douglas R.

Nardelli-Haefliger, Denise

Schiller, John T.

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Re: Specific Antibody Levels atthe Cervix During theMenstrual Cycle of WomenVaccinated With HumanPapillomavirus 16 Virus-LikeParticlesWe read with interest the article byNardelli-Haefliger et al. (1) in which theauthors reported an approximate nine-fold reduction in cervical anti-humanpapillomavirus 16 (HPV16) immuno-globulin (Ig; specific IgG and total IgGand IgA) levels at the time of ovulationin 11 women who received aluminum-free (i.e., adjuvant-free) HPV16 L1virus-like particle (VLP) vaccine syn-thesized in a baculovirus system (1).The authors hypothesized that the effi-cacy of prophylactic HPV16 L1 VLPvaccines may be reduced during theperi-ovulatory phase in women who arenot using hormonal contraception.We recently reported (2) the primaryefficacy results of a multicenter,placebo-controlled trial of a prophylac-tic HPV16 L1 VLP vaccine in 2392women aged between 16 and 23 years.The HPV16 L1 VLPs were synthesizedin yeast and formulated on aluminumadjuvant. In the primary efficacy cohort,the vaccine was found to be 100% ef-412 CORRESPONDENCE Journal of the National Cancer Institute, Vol. 96, No. 5, March 3, 2004fective in preventing persistent cervico-vaginal HPV16 infection and relatedcervical intraepithelial neoplasia for amedian of 17.4 months following thecompletion of vaccination.In our study (2), information on con-traceptive use was collected at each visitand contraceptive methods were dividedinto ovulation-suppressing contracep-tives (i.e., oral or parenteral hormonecontraceptives) or non-suppressing con-traceptives (i.e., barrier, abstinence,rhythm). The extent of use of these cat-egories of contraceptives was assessedin two ways: 1) the number of individ-uals who reported use of an ovulation-suppressing contraceptive on at least onestudy visit and 2) the overall duration ofexposure to ovulation-suppressing con-traceptives, measured in woman-years atrisk. In the primary efficacy cohort, 77%of women reported use of an ovulation-suppressing contraceptive on at leastone study visit. However, many womenused these products for only short periodsof time or intermittently. Thus, ovulation-suppressing contraceptives were used inonly 54% of the woman-years at risk inthis cohort. Hence, because vaccine ef-ficacy was observed to be 100%, ovula-tion and potential fluctuations in cervicalanti-HPV16 IgG levels did not appear toaffect vaccine efficacy in our study.In light of our study (2), the findingsof Nardelli-Haefliger et al. (1) can leadto one of three alternate hypotheses.First, although vaccine-induced anti-HPV16 levels in cervicovaginal secre-tions may fluctuate during the ovulatorycycle, they remain sufficiently high toprevent HPV16 infection. Second, theefficacy of HPV16 L1 VLP vaccines isnot affected by anti-HPV16 levels incervical secretions—that is, because theHPV16 infectious cycle depends criti-cally on infection of the basal cell layerof the cervical epithelium, the deliveryof anti-HPV16 IgG by extravasatedblood may be a more important deter-minant of vaccine efficacy. Third, theimpact of ovulation-induced fluctuationsin cervical anti-HPV16 IgG levels onHPV vaccine efficacy may be subtle;therefore, a larger study with longerfollow-up would be required to detectsuch an effect.Assuming that vaccine-induced anti-HPV16 in cervicovaginal secretions isan important mechanism for the vac-cine’s protective effect, cervical IgGlevels in the peri-ovulatory periodwould have to drop below the level re-quired for maintenance of the vaccine’sprotective efficacy to result in a clinicalimpact. Although such a level has notbeen defined, it stands to reason thatvaccines that induce high levels of anti-HPV16 IgG are less likely than less im-munogenic vaccines to be affected byperi-ovulatory fluctuations in cervicalanti-HPV16 Ig levels. The vaccine for-mulation used in the study by Nardelli-Haefliger et al. (1) contained no adju-vant. In our experience, the use ofaluminum adjuvant in the formulation ofHPV16 L1 VLP vaccines increases se-rum anti-HPV16 IgG levels more than10-fold compared with an adjuvant-freeformulation. If our vaccine inducedhigher anti-HPV16 levels than those in-duced by the vaccine used by Nardelli-Haefliger et al., then our vaccine may beless prone to clinically meaningful de-creases in cervical IgG levels than theformulation used by Nardelli-Haefligeret al. (1).We have reported that vaccine-induced anti-HPV16 responses declineover time (2). Women in our study werefollowed for a median of 17.4 monthsafter completing the vaccination. How-ever, women remain at risk for HPVinfection for several years. To fully ad-dress the impact in peri-ovulatory anti-HPV16 IgG levels on vaccine efficacy,it will be important to assess the dura-tion of HPV16 L1 VLP vaccine efficacyover a longer period of follow-up.ELIAV BARRLAURA A. KOUTSKYREFERENCES(1) Nardelli-Haefliger D, Wirthner D, Schiller JT,Lowy DR, Hildesheim A, Ponci F, et al. Spe-cific antibody levels at the cervix during themenstrual cycle of women vaccinated withhuman papillomavirus 16 virus-like particles.J Natl Cancer Inst 2003;95:1128–37.(2) Koutsky LA, Ault KA, Wheeler CM, BrownDR, Barr E, Alvarez FB, et al. A controlledtrial of a human papillomavirus type 16 vac-cine. N Engl J Med 2002;347:1645–51.NOTESEditor’s note: E. Barr is an employee of MerckResearch Laboratories, which is developing aquadrivalent human papillomavirus vaccine. L. A.Koutsky is currently conducting research that issponsored by Merck Research Laboratories.Affiliations of authors: Biologics Clinical Re-search, Merck Research Laboratories, West Point,PA (EB); HPV Research Group, Department ofEpidemiology, University of Washington, Seattle(LAK).Correspondence to: Eliav Barr, MD, BiologicsClinical Research, Merck Research Laboratories,West Point, PA 19486-0004 (e-mail: eliav_barr@merck.com).DOI: 10.1093/jnci/djh071RESPONSEWe thank Drs. Barr and Koutsky fortheir comments related to our recentlypublished article, in which we reportedthat human papillomavirus 16 (HPV16)antibody levels at the cervix, followingsystemic immunization with an HPV16virus-like particle (VLP) vaccine, varysubstantially during the course of themenstrual cycle (1). We agree that long-term studies of vaccinees are needed todetermine whether, and to what degree,these variations in HPV16 antibody lev-els may influence vaccine efficacy sev-eral years after vaccination. As noted byDrs. Barr and Koutsky and by ourselves(2), such efficacy results should help toclarify whether serum antibody or cer-vical antibody levels are the primarycorrelate of vaccine efficacy. In ongoinglong-term efficacy studies, it may beuseful to distinguish between the groupof women who, after the vaccinationperiod, do not use hormonal contracep-tives at all and the group of women whouse hormonal contraceptives intermit-tently, because it may be difficult toinfer, with the latter group of women,whether their risk of HPV exposure willbe similar during intervals on and offhormonal contraceptives.In addition, we would also like topoint out that the magnitude of the fluc-tuation we observed in HPV16 antibodylevels at the cervix during the menstrualcycle was also seen for total immuno-globulin G levels at the cervix (1).Therefore, we believe that the observedmenstrual cycle–dependent changes inHPV16 antibody levels at the cervixhave nothing to do with our HPV16VLP vaccine having been formulatedwithout adjuvant, and we would expectthat analogous fluctuations in antibodylevels would be seen following systemicimmunization with any VLP-based vac-cine. We also note that, in apparent con-trast to the observations of Drs. Barr andKoutsky, we did not find increased im-munogenicity from the addition of alu-minum adjuvant to the 50-g dose ofVLPs used in our study (1), although wehave observed an adjuvant effect fromJournal of the National Cancer Institute, Vol. 96, No. 5, March 3, 2004 CORRESPONDENCE 413aluminum when given with a 10-gdose of VLPs (3).DOUGLAS R. LOWYDENISE NARDELLI-HAEFLIGERALLAN HILDESHEIMJOHN T. SCHILLERREFERENCES(1) Nardelli-Haefliger D, Wirthner D, Schiller JT,Lowy DR, Hildesheim A, Ponci F, et al. Spe-cific antibody levels at the cervix during themenstrual cycle of women vaccinated withhuman papillomavirus 16 virus-like particles.J Natl Cancer Inst 2003;95:1128–37.(2) Lowy DR, Schiller JT. Papillomaviruses: pro-phylactic vaccine prospects. Biochim BiophysActa 1999;1423:M1–8.(3) Harro CD, Pang YY, Roden RB, HildesheimA, Wang Z, Reynolds MJ, et al. Safety andimmunogenicity trial in adult volunteers of ahuman papillomavirus 16 L1 virus-like particlevaccine. J Natl Cancer Inst 2001;93: 284–92.NOTESAffiliations of authors: Laboratory of CellularOncology, Center for Cancer Research (DRL,JTS), Environmental Epidemiology Branch, Divi-sion of Cancer Epidemiology and Genetics (AH),National Cancer Institute, National Institutes ofHealth, Bethesda, MD; Department of Gynecol-ogy, Centre Hospitalier Universitaire Vaudois,Lausanne, Switzerland (DNH).Correspondence to: Douglas R. Lowy, MD,Laboratory of Cellular Oncology, Bldg. 37, Rm.4106, National Cancer Institute, National Insti-tutes of Health, Bethesda, MD 20892 (e-mail:drl@helix.nih.gov).DOI: 10.1093.jnci/djh072414 CORRESPONDENCE Journal of the National Cancer Institute, Vol. 96, No. 5, March 3, 2004

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

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