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. 2019 Jul 5;8(10):4938–4953. doi: 10.1002/cam4.1879

Risk of newly detected infections and cervical abnormalities in adult women seropositive or seronegative for naturally acquired HPV‐16/18 antibodies

Dominique Rosillon 1,✉, Laurence Baril 1, Maria Rowena Del Rosario‐Raymundo 2, Cosette Marie Wheeler 3, Susan Rachel Skinner 4,5, Suzanne Marie Garland 6, Jorge Salmeron 7, Eduardo Lazcano‐Ponce 8, Carlos Santiago Vallejos 9, Tanya Stoney 10, Bram ter Harmsel 11, Timothy Yong Kuei Lim 12, Swee Chong Quek 13, Galina Minkina 14, Shelly Ann McNeil 15, Celine Bouchard 16, Kah Leng Fong 17, Deborah Money 18, Arunachalam Ilancheran 19, Alevtina Savicheva 20, Margaret Cruickshank 21, Archana Chatterjee 22, Alison Fiander 23, Mark Martens 24, Marie Cecile Bozonnat 25, Frank Struyf 1, Gary Dubin 26, Xavier Castellsagué 27
PMCID: PMC6712465  PMID: 31273942

Abstract

Background

Infections with human papillomavirus (HPV) types 16 and 18 account for ~70% of invasive cervical cancers but the degree of protection from naturally acquired anti‐HPV antibodies is uncertain. We examined the risk of HPV infections as defined by HPV DNA detection and cervical abnormalities among women >25 years in the Human Papilloma VIrus Vaccine Immunogenicity ANd Efficacy trial's (VIVIANE, NCT00294047) control arm.

Methods

Serum anti‐HPV‐16/18 antibodies were determined at baseline and every 12 months in baseline DNA‐negative women (N = 2687 for HPV‐16 and 2705 for HPV‐18) by enzyme‐linked immunosorbent assay (ELISA) from blood samples. HPV infections were identified by polymerase chain reaction (PCR) every 6‐months, and cervical abnormalities were confirmed by cytology every 12 months. Data were collected over a 7‐year period. The association between the risk of type‐specific infection and cervical abnormalities and serostatus was assessed using Cox proportional hazard models.

Results

Risk of newly detected HPV‐16‐associated 6‐month persistent infections (PI) (hazard ratio [HR] = 0.56 [95%CI:0.32; 0.99]) and atypical squamous cells of undetermined significance (ASC‐US+) (HR = 0.28 [0.12; 0.67]) were significantly lower in baseline seropositive vs baseline seronegative women. HPV‐16‐associated incident infections (HR = 0.81 [0.56; 1.16]) and 12‐month PI (HR = 0.53 [0.24; 1.16]) showed the same trend. A similar trend of lower risk was observed in HPV‐18‐seropositive vs ‐seronegative women (HR = 0.95 [0.59; 1.51] for IIs, HR = 0.43 [0.16; 1.13] for 6‐month PIs, HR = 0.31 [0.07; 1.36] for 12‐month PIs, and HR = 0.61 [0.23; 1.61] for ASC‐US+).

Conclusions

Naturally acquired anti‐HPV‐16 antibodies were associated with a decreased risk of subsequent infection and cervical abnormalities in women >25 years. This possible protection was lower than that previously reported in 15‐ to 25‐year‐old women.

Keywords: human papillomavirus infection, naturally acquired antibodies, redetection or reactivation of HPV infection, cervical abnormality, risk reduction

1. BACKGROUND

Infections with human papillomavirus (HPV) types 16 and 18 are responsible for approximately 70% of invasive cervical cancers.1 While most infections clear on their own, some develop into precancerous lesions and cervical cancer.

Previous studies have shown that many women with incident HPV‐16 or HPV‐18 infections develop serum antibodies of the corresponding type of HPV.2, 3, 4, 5, 6, 7, 8 These naturally acquired antibodies can remain detectable for at least 4‐5 years after the initial infection.9 Whether or not these naturally acquired antibodies protect against future infection remains debatable.10, 11, 12, 13, 14, 15, 16, 17, 18

Risk of incident HPV infections in adult women is positively associated with new sexual partners and with the lifetime number of sexual partners.19, 20 In older women, both new viral acquisition and intermittent detections of HPV from past HPV exposures are likely to account for what has been classified as apparent new HPV infections. In women 30‐50 years of age, factors associated with repeat HPV detection have been shown to be comparable in short‐term and longer‐term studies, suggesting association between short‐term repeat detection and long‐term persistence.21 As incident HPV detection is negatively associated with viral load as well as with repeat detection, this suggests that actual new acquisition of HPV is less common than reactivation or intermittent persistence.

The role of naturally acquired antibodies in the prevention of new infections and cervical abnormalities can be explored in the control arms of large HPV vaccine trials. A correlation between naturally acquired antibodies to HPV‐16 (and to a lesser extent HPV‐18) and reduced risk of newly detected infection was demonstrated in younger women (15‐25 years) in the control arm of the PApilloma TRIal against Cancer In young Adults (PATRICIA; NCT00122681).12 Here, we examined the risk of “newly” detected HPV infections and cervical abnormalities among women >25 years in relation to naturally acquired HPV‐16/18 antibodies in the control arm of the VIVIANE during a 7‐year follow‐up period.22, 23

Our aim was to assess whether the risk factors for HPV infection differed between seropositive and seronegative women. We also analyzed risk factors stratified by baseline serostatus to mitigate the limitations in differentiating between new and reactivated infections.

2. METHODS

2.1. Study participants and procedures

Women aged >25 years were included in the control arm of the multinational, VIVIANE trial and were followed up for seven years. VIVIANE is the Human Papilloma Virus: Vaccine Immunogenicity and Efficacy trial. This is a phase 3 double‐blind, controlled vaccine trial based on age, cytology, region, and serostatus.23 The methodology of VIVIANE has been presented in detail elsewhere.24

Our analysis included women DNA‐negative for HPV‐16 and −18 at Month 0, with normal or low‐grade cytology (ie, negative or atypical squamous cells of undetermined significance [ASC‐US] or low‐grade squamous intraepithelial lesion [LSIL]) at Month 0, who had received at least one control vaccine dose (Al[OH]3) and who had sexual intercourse before or during the follow‐up (Figure 1).

Figure 1.

Figure 1

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Flowcharts. HPV, human papillomavirus; TVC, total vaccinated cohort; N, number of women; Sero+, women seropositive for HPV‐16/18; Sero −, women seronegative for HPV‐16/18

Serum anti‐HPV‐16/18 antibodies were determined by enzyme‐linked immunosorbent assay (ELISA) from blood samples collected at baseline and every 12 months thereafter. Seropositivity was defined as an antibody level greater than or equal to the assay cutoff which was 8 ELISA units (EU)/mL for HPV‐16 and 7 EU/mL for HPV‐18.25

Liquid‐based cytology samples were tested for HPV using DNA typing PCR‐based assays every six months and cytopathological examinations every12 months.25 Information on known risk factors that predispose women to HPV cervical infection or recognized cofactors for cervical carcinogenesis was also collected through questionnaires. These data were collected at study entry and included demographic information, smoking habits, past and current sexual history, and reproductive status. In addition, data on participants' sexual behavior and use of contraception were collected every six months up to month 48.

Written informed consent was obtained from each woman before any study‐specific procedures were implemented. The protocol and other materials were approved by a national, regional, or investigational center Independent Ethics Committee or Institutional Review Board. The trial was conducted based on the Code of Ethics of the World Medical Association (Declaration of Helsinki).

The endpoints included in these analyses were (a) newly detected HPV‐16 and HPV‐18 incident infections, (b) 6‐ and 12‐month persistent infection (PI), ASC‐US+, and (c) histopathologically confirmed cervical intraepithelial neoplasia grade 1 or greater (CIN1+ and CIN2+). HPV‐16 and HPV‐18 serostatus were the main exposure variables.

2.2. Statistics

The analyses were performed on the total vaccinated cohort (TVC) of the control arm of the VIVIANE trial and included all women who received at least one control vaccine dose, who were DNA‐negative for HPV‐16 and HPV‐18 at Month 0, and who also had a normal or low‐grade cytology (ie, negative or ASC‐US or LSIL) at Month 0. All analyses were performed on women who had ever had sexual intercourse before study entry or during the follow‐up period.

Analyses were performed using SAS version 9.2. The incidence rate (IR) was calculated as the number of incident events divided by the total person‐time. Person‐years were calculated as the sum of the follow‐up for each participant expressed in years. The follow‐up period started on the day after first vaccination (control vaccine) and ended on the first occurrence of the endpoint or the last visit (whichever occurred first). The relationship between the exposure variables and the risk of newly detected infections or cervical abnormalities was assessed using Cox proportional hazard models. Univariate analyses were done to obtain unadjusted hazard ratios of the determinants of interest (not shown). For each endpoint, the following multivariable Cox models were performed including:

  1. the type‐specific serostatus at baseline as a binary variable;

  2. the type‐specific serostatus as a binary time‐dependent variable;

  3. the antibody level as a time‐dependent continuous variable;

  4. log‐transformed antibody level as a time‐dependent continuous variable.

For each endpoint, we included nine covariates in these models: region, age at inclusion, age at first sexual intercourse, marital status, smoking status at baseline, number of sexual partners during the past year, previous pregnancy, history of Chlamydia trachomatis infection, history of HPV infection/treatment or nonintact cervix. HPV‐associated infection or treatment was defined as two or more abnormal smears in sequence, an abnormal colposcopy or biopsy, or treatment of the cervix after abnormal smear or colposcopy findings. The histories of HPV infection/treatment were collected at baseline using medical history.

For ASC‐US+ only, previous type‐specific HPV infection was included as a time‐dependent variable since the presence of these cells indicates an active infection at a specific point in time. For CIN1+ and CIN2+ endpoints, no inferential analyses were performed due to the low number of cases. Also, analyses of determinants of interest were performed separately for the baseline seronegative and seropositive subjects to help determine whether newly detected infections were new or had been reactivated. The analysis is based on two assumptions: (a) An association between a latent reactivated infection and a known risk factor should be weaker than an association between a new infection and a known risk factor. (b) The reactivation of a PI should be more frequent in the baseline seropositive (representing presumed prior HPV infection exposure) subjects than in the baseline seronegative (representing presumed naïve, absent prior HPV infection exposure) subjects.

3. RESULTS

3.1. Study population

In total, 2687 and 2705 participants were included in the analysis of HPV‐16 and HPV‐18 endpoints, respectively (Figure 1). There was a difference of 3% between HPV‐16/18 by serostatus at baseline. Seroprevalence at enrollment was 31% (828/2687 seropositive women) for HPV‐16 and 28% (756/2705 seropositive women) for HPV‐18 (Table 1). This difference is entirely in agreement with the well‐known higher prevalence of 16 than 18 in HPV infections.

Table 1.

Frequency distributions of exposure variables and risk factors at study entry ‐ TVC‐Control arm‐excluding high grade or missing cytology at Month 0 – Ever had sexual intercourse

Overall (N = 2785) Baseline HPV‐16 serostatus (N = 2687) Baseline HPV‐18 serostatus (N = 2705)
Sero− (N = 1859) Sero+ (N = 828) Sero− (N = 1949) Sero+ (N = 756)
Exposure variables and Risk factors Category n % n % n % n % n %
Marital status Living or Lived with partner 2354 84.52 1629 87.63 659 79.59 1677 86.04 618 81.75
Single 430 15.44 230 12.37 169 20.41 271 13.90 138 18.25
Missing 1 0.04 1 0.05
Number of pack years [0; 0.5] 2016 72.39 1415 76.12 549 66.30 1451 74.45 514 67.99
≥0.5 757 27.18 439 23.61 273 32.97 493 25.30 237 31.35
Missing 12 0.43 5 0.27 6 0.72 5 0.26 5 0.66
Smoking status at baseline No 2398 86.10 1639 88.17 688 83.09 1702 87.33 631 83.47
Yes 386 13.86 220 11.83 140 16.91 246 12.62 125 16.53
Missing 1 0.04 . . 1 0.05 .
Sexual history at study entry No 5 0.18 4 0.22 1 0.12 4 0.21 1 0.13
Yes 2779 99.78 1855 99.78 827 99.88 1944 99.74 755 99.87
Missing 1 0.04 . . 1 0.05 .
History of HPV – Infection/treatment or not intact cervix No 2431 87.29 1674 90.05 685 82.73 1725 88.51 636 84.13
Yes 354 12.71 185 9.95 143 17.27 224 11.49 120 15.87
Age at first sexual intercourse (years) <15 141 5.06 66 3.55 67 8.09 73 3.75 59 7.80
15–17 899 32.28 507 27.27 354 42.75 557 28.58 309 40.87
18–25 1561 56.05 1137 61.16 377 45.53 1173 60.18 354 46.83
>26 177 6.36 146 7.85 27 3.26 141 7.23 32 4.23
Missing 7 0.25 3 0.16 3 0.36 5 0.26 2 0.26
Number of lifetime sexual partners 0 5 0.18 4 0.22 1 0.12 4 0.21 1 0.13
1 1068 38.35 876 47.12 174 21.01 864 44.33 183 24.21
2–5 1017 36.52 666 35.83 310 37.44 703 36.07 286 37.83
6–10 361 12.96 177 9.52 167 20.17 214 10.98 130 17.20
11–15 146 5.24 68 3.66 69 8.33 79 4.05 60 7.94
16–20 67 2.41 23 1.24 41 4.95 30 1.54 35 4.63
>20 120 4.31 45 2.42 66 7.97 54 2.77 61 8.07
Missing 1 0.04 . . 1 0.05 .
Number of sexual partners during the last year 0 301 10.81 195 10.49 96 11.59 214 10.98 85 11.24
1 2219 79.68 1533 82.46 623 75.24 1585 81.32 574 75.93
2‐3 230 8.26 115 6.19 95 11.47 132 6.77 83 10.98
≥4 34 1.22 16 0.86 14 1.69 17 0.87 14 1.85
Missing 1 0.04 1 0.05
At least one previous pregnancy No 439 15.76 277 14.90 138 16.67 299 15.34 119 15.74
Yes 2345 84.20 1582 85.10 690 83.33 1649 84.61 637 84.26
Missing 1 0.04 1 0.05
Chlamydia trachomatis No 2626 94.29 1794 96.50 741 89.49 1862 95.54 693 91.67
Yes 133 4.78 56 3.01 72 8.70 70 3.59 55 7.28
Missing 26 0.93 9 0.48 15 1.81 17 0.87 8 1.06
Contraception during lifetimea No contraception 413 14.83 298 16.03 102 12.32 297 15.24 110 14.55
Hormonal use for contraception or another indication 1802 24.85 1139 61.27 596 71.98 1220 62.60 515 68.12
Intra‐Uterine Device 692 25.96 477 25.66 193 23.31 501 25.71 172 22.75
Sterilized 723 35.30 498 26.79 204 24.64 522 26.78 183 24.21
Menopausal Status Premenopausal 2448 87.90 1636 88.00 721 87.08 1717 88.10 657 86.90
Perimenopausal 180 6.46 116 6.24 60 7.25 117 6.00 59 7.80
Postmenopausal 142 5.10 93 5.00 46 5.56 101 5.18 39 5.16
Missing 15 0.54 14 0.75 1 0.12 14 0.72 1 0.13
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N = total Number of subjects with a given group.

a

A subject can be included in more than one category.

Among those seropositive at enrollment, the geometric mean antibody concentration was 38.3 EU/mL (range: 8‐2527) and 23.3 EU/mL (range: 7‐725) for HPV‐16 and HPV‐18, respectively.

At enrollment, 45% of women were 26‐35 years old, 44% were 36‐45 years old, and 11% were ≥46 years old. Nearly all participants had been previously sexually active at the start of the study, except five who had their first sexual intercourse during the follow‐up. 56% had started sexual activity between 18 and 25 years (32% between 15 and 17), 80% had had one sexual partner during the previous year, and 84% had had a previous pregnancy. Moreover, 14% of women were current smokers, 5% were C trachomatis‐positive, and 87.8% were classified as pre‐menopausal, 6.5% as peri‐menopausal, 5.1% as post‐menopausal, while the status for the remaining 0.5% was missing.

3.2. Incidence rates of the endpoints

The IR per 100 person‐years of newly detected infections was 1.07 (95% confidence interval [CI]: 0.91‐1.25) for HPV‐16 and 0.64 (0.52‐0.78) for HPV‐18. For 6‐month PI, the IRs were 0.56 (0.44‐0.69) for HPV‐16 and 0.23 (0.16‐0.32) for HPV‐18. For 12‐month PI, these were 0.30 (0.22‐0.40) for HPV‐16 and 0.13 (0.08‐0.20) for HPV‐18.

The IRs for ASC‐US+ were 0.34 (0.26‐0.45) for HPV‐16 and 0.21 (0.14‐0.30) for HPV‐18.

During the seven years of follow‐up, 13 new HPV‐16 CIN1+ cases, 14 HPV‐18 CIN1+ cases, 8 HPV‐16 CIN2+ cases, and 9 HPV‐18 CIN2+ cases were detected.

3.3. Multivariable models

The multivariable Cox proportional hazard model, including the serostatus at baseline as a binary variable, showed that the risk of newly detected HPV‐16, 6‐month PI and ASC‐US+ was statistically significantly lower in seropositive vs seronegative women (hazard ratio [HR] = 0.56 [0.32‐0.99; P = 0.04] and 0.28 [0.12‐0.67; P = 0.004], respectively; Table 2). Analysis for HPV‐16 incident infections and 12‐month PI also showed a somewhat lower risk in seropositive than seronegative women although the difference was not statistically significant (HR = 0.81 [0.56‐1.16; P = 0.26] and 0.53 [0.24‐1.16; P = 0.11], respectively). With regard to HPV‐18, we found the risk of newly detected infections and cervical abnormalities was lower in seropositive vs seronegative women, but not statistically significant (HR = 0.95 [0.59‐1.51; P = 0.82] for incident infections, 0.43 [0.16‐1.13; P = 0.09] for 6‐month PI, 0.31 [0.07‐1.36; P = 0.12] for 12‐month PI, and 0.61 [0.23‐1.61; P = 0.32] for ASC‐US+; Table 3). Other determinants (Tables 2 and 3, and Supplementary Tables) associated with a higher risk of new infections were ≥2 sexual partners during the past year (for incident HPV‐16 and HPV‐18 infections, and 6‐month and 12‐month HPV‐16 and HPV‐18 PI), being single (for incident HPV‐18 infections), a history of HPV infection/treatment, or having a nonintact cervix (for incident HPV‐16 and HPV‐18 infections). Women older than 35 years at enrollment had a lower risk of incident HPV‐16 infections as well as HPV‐18 incident infections, 6‐month PI, and ASC‐US+. The risk of infections varied significantly among geographical regions. The risk factors associated with ASC‐US+ were a history of HPV infection/treatment, a nonintact cervix (for HPV‐18), and a previous type‐specific HPV infection (for HPV‐16 and HPV‐18).

Table 2.

Multivariable Cox model for HPV‐16 newly detected infections and cervical abnormalities including serostatus at baseline

Risk factor Category Enrollment serostatus (binary)
Incident infection 6‐mo PI 12‐mo PI ASC‐US+
N n Hazard ratio (95% CI) P‐value N n Hazard ratio (95% CI) P‐value N n Hazard ratio (95% CI) P‐value N n Hazard ratio (95% CI) P‐value
HPV‐16 serostatus Negative 1814 114 1 ‐ 1779 67 1 ‐ 1755 38 1 ‐ 1787 43 1 ‐
Positive 790 45 0.81 (0.56‐1.16) 0.2559 767 17 0.56 (0.32‐0.99) 0.0446 753 8 0.53 (0.24‐1.16) 0.1123 774 9 0.28 (0.12‐0.67) 0.0043
Age at inclusion 26‐35 1157 94 1 ‐ 1134 45 1 ‐ 1109 21 1 ‐ 1139 33 1 ‐
≥36 1157 65 0.58 (0.42‐0.82) 0.0016 1412 39 0.78 (0.50‐1.24) 0.2946 1399 25 0.99 (0.54‐1.82) 0.9817 1423 19 0.57 (0.31‐1.03) 0.0640
Region Europe 505 22 1 ‐ 495 6 1 ‐ 491 5 1 ‐ 500 8 1 ‐
Asia Pacific 779 38 1.19 (0.68‐2.08) 0.5445 772 23 2.57 (1.01‐6.52) 0.0476 765 15 1.75 (0.61‐5.05) 0.3004 772 10 0.77 (0.28‐2.10) 0.6065
Latin America 679 43 1.56 (0.90‐2.71) 0.1142 663 29 3.86 (1.54‐9.70) 0.0040 658 16 2.26 (0.79‐6.48) 0.1308 666 18 1.66 (0.65‐4.21) 0.2862
North America 641 56 2.38 (1.42‐3.97) 0.0009 616 26 4.28 (1.74‐10.54) 0.0015 594 10 1.89 (0.63‐5.66) 0.2575 623 16 1.32 (0.50‐3.46) 0.5716
Age at first sexual intercourse grouped ≥18 1654 98 1 ‐ 1621 57 1 ‐ 1600 33 1 ‐ 1630 32 1 ‐
15‐17 817 50 0.85 (0.58‐1.23) 0.3775 799 57 0.62 (0.36‐1.09) 0.0967 784 9 0.56 (0.26‐1.22) 0.1473 804 14 1.05 (0.53‐2.08) 0.8832
<15 127 11 1.08 (0.56‐2.07) 0.8271 120 8 1.48 (0.67‐3.27) 0.3329 118 4 1.30 (0.43‐3.95) 0.6433 121 6 2.20 (0.79‐6.16) 0.1322
Marital status at baseline Living or lived with partner 2227 129 1 ‐ 2177 69 1 ‐ 2151 41 1 ‐ 2190 44 1 ‐
Single 377 30 0.79 (0.49‐1.29) 0.3493 369 15 0.89 (0.46‐1.75) 0.7434 357 5 0.70 (0.24‐2.04) 0.5116 371 8 0.67 (0.27‐1.67) 0.3878
Smoking status at baseline No 2264 131 1 ‐ 2221 72 1 ‐ 2192 40 1 ‐ 2229 40 1 ‐
Yes 340 28 1.35 (0.88‐2.06) 0.1701 325 12 1.15 (0.61‐2.17) 0.6678 316 6 1.10 (0.45‐2.70) 0.8278 332 12 1.78 (0.89‐3.59) 0.1049
Number of sexual partners during the last year 0 283 16 1 ‐ 277 8 1 ‐ 272 2 1 ‐ 279 5 1 ‐
1 2096 112 0.88 (0.52‐1.52) 0.6563 2052 59 1.02 (0.48‐2.18) 0.9634 2026 35 2.26 (0.54‐9.57) 0.2663 2064 36 0.89 (0.33‐2.35) 0.8105
≥2 225 31 2.36 (1.26‐4.44) 0.0074 217 17 3.53 (1.47‐8.48) 0.0048 210 9 8.20 (1.70‐39.49) 0.0087 218 11 1.72 (0.56‐5.28) 0.3399
Pregnancy No 401 35 1 ‐ 393 19 1 ‐ 384 7 1 ‐ 394 11 1 ‐
Yes 2203 124 0.74 (0.47‐1.14) 0.1732 2153 65 0.57 (0.31‐1.05) 0.0696 2124 39 0.82 (0.33‐2.06) 0.6793 2167 41 0.91 (0.40‐2.06) 0.8211
Chlamydia infection at baseline No 2458 150 1 ‐ 2407 81 1 ‐ 2371 44 1 ‐ 2420 48 1 ‐
Yes 122 7 0.59 (0.27‐1.29) 0.1848 115 2 0.36 (0.08‐1.51) 0.1618 113 2 0.95 (0.21‐4.32) 0.9486 117 3 2.57 (0.71‐9.27) 0.1483
History of HPV infection/treatment or not intact cervix No 2285 128 1 ‐ 2234 72 1 ‐ 2202 39 1 ‐ 2246 3 1 ‐
Yes 319 31 1.56 (1.03‐2.35) 0.0348 312 12 1.17 (0.62‐2.18) 0.6316 306 7 1.31 (0.57‐3.02) 0.5240 315 8 1.03 (0.45‐2.36) 0.9416
Previous HPV‐16 infection No ‐ ‐ ‐ ‐ ‐ ‐ 2561 24 1 ‐
Yes ‐ ‐ ‐ ‐ ‐ ‐ 128 28 122.89 (67.91‐222.37) <.0001
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HPV = human papillomavirus; PI = persistent infection; CI = confidence interval; ACS‐US+ = atypical squamous cell of undetermined significance or greater; N = total number of subjects; n = number of cases reported. Bold: P‐values <0.05

Table 3.

Multivariable Cox model for HPV‐18 newly detected infections and cervical abnormalities including serostatus at baseline

Risk factor Category Enrollment serostatus (binary)
Incident infection 6‐mo PI 12‐mo PI ASC‐US+
N n Hazard ratio (95% CI) P‐value N n Hazard ratio (95% CI) P‐value N n Hazard ratio (95% CI) P‐value N n Hazard ratio (95% CI) P‐value
HPV‐18 serostatus Negative 1907 97 1 ‐ 1874 31 1 ‐ 1840 18 1 ‐ 1882 26 1 ‐
Positive 713 25 0.95 (0.59‐1.51) 0.8165 689 5 0.43 (0.16‐1.13) 0.0883 681 2 0.31 (0.07‐1.36) 0.1198 696 6 0.61 (0.23‐1.61) 0.3176
Age at inclusion 26‐35 1156 70 1 ‐ 1133 28 1 ‐ 1108 15 1 ‐ 1137 25 1 ‐
≥36 1464 27 0.35 (0.22‐0.56) <.0001 1430 8 0.29 (0.13‐0.65) 0.0029 1413 5 0.39 (0.13‐1.15) 0.0863 1441 7 0.32 (0.13‐0.77) 0.0115
Region Europe 518 19 1 ‐ 508 6 1 ‐ 502 7 1 ‐ 513 5 1 ‐
Asia Pacific 775 28 1.22 (0.65‐2.32) 0.5361 768 9 1.32 (0.41‐4.24) 0.6364 761 6 1.70 (0.38‐7.60) 0.4907 768 7 1.16 (0.31‐4.36) 0.8207
Latin America 688 23 1.14 (0.58‐2.21) 0.7049 672 8 1.35 (0.41‐4.45) 0.6178 666 3 0.98 (0.18‐5.43) 0.9834 675 11 3.04 (0.82‐11.25) 0.0964
North America 639 27 1.12 (0.60‐2.09) 0.7281 615 13 2.06 (0.71‐5.98) 0.1837 592 7 1.99 (0.49‐8.13) 0.3378 622 9 2.70 (0.73‐9.97) 0.1371
Age at first sexual intercourse grouped ≥18 1666 67 1 ‐ 1633 23 1 ‐ 1610 14 1 ‐ 1642 23 1 ‐
15‐17 821 31 0.96 (0.59‐1.55) 0.8591 804 12 0.81 (0.37‐1.78) 0.6062 787 6 0.71 (0.24‐2.09) 0.5349 809 6 0.41 (0.15‐1.12) 0.0818
<15 126 9 1.57 (0.74‐3.34) 0.2430 119 1 0.37 (0.05‐2.91) 0.3439 117 0 Not estimated ‐ 120 3 1.82 (0.46‐7.24) 0.3945
Marital status at baseline Living or lived with partner 2234 67 1 ‐ 2185 24 1 ‐ 2156 12 1 ‐ 2198 22 1 ‐
Single 385 30 2.13 (1.22‐3.71) 0.0076 377 12 1.96 (0.79‐4.86) 0.1452 364 8 2.79 (0.82‐9.48) 0.1010 379 10 1.66 (0.58‐4.71) 0.3426
Smoking status at baseline No 2270 82 1 ‐ 2228 29 1 ‐ 2196 16 1 ‐ 2236 28 1 ‐
Yes 349 15 0.88 (0.49‐1.58) 0.6754 334 7 1.33 (0.56‐3.14) 0.5190 324 4 1.43 (0.45‐4.51) 0.5416 341 4 0.78 (0.26‐2.35) 0.6547
Number of sexual partners during the last year 0 291 7 1 ‐ 285 2 1 ‐ 280 2 1 ‐ 287 3 1 ‐
1 2097 68 1.46 (0.65‐3.26) 0.3565 2054 25 1.85 (0.42‐8.16) 0.4151 2026 13 1.09 (0.22‐5.27) 0.9169 2066 23 1.23 (0.34‐4.36) 0.7530
≥2 231 22 3.28 (1.36‐7.88) 0.0080 223 9 4.69 (0.97‐22.56) 0.0540 214 5 2.92 (0.53‐16.23) 0.2197 224 6 1.57 (0.35‐7.15) 0.5589
Pregnancy No 404 21 1 ‐ 396 9 1 ‐ 386 6 1 ‐ 397 8 1 ‐
Yes 2215 76 1.17 (0.66‐2.06) 0.5931 2166 27 1.14 (0.46‐2.83) 0.7715 2134 14 1.03 (0.32‐3.35) 0.9621 2180 24 0.96 (0.32‐2.87) 0.9462
Chlamydia infection at baseline No 2477 89 1 ‐ 2427 33 1 ‐ 2388 18 1 ‐ 2440 30 1 ‐
Yes 118 6 0.82 (0.34‐1.96) 0.6579 111 2 0.80 (0.18‐3.52) 0.7643 109 1 0.73 (0.09‐5.82) 0.7666 113 1 0.27 (0.03‐2.53) 0.2534
History of HPV infection/treatment or not intact cervix No 2285 75 1 ‐ 2236 27 1 ‐ 2203 1 1 ‐ 2248 22 1 ‐
Yes 335 22 1.72 (1.03‐2.86) 0.0373 327 9 1.79 (0.79‐4.09) 0.1658 318 5 1.64 (0.52‐5.20) 0.3980 330 10 2.57 (1.10‐6.01) 0.0288
Previous cervical HPV‐18 infection No ‐ ‐ ‐ ‐ ‐ ‐ 2578 20 1 ‐
Yes ‐ ‐ ‐ ‐ ‐ ‐ 68 12 122.93 (54.69‐276.33) <.0001
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HPV = human papillomavirus; PI = persistent infection; CI = confidence interval; ACS‐US+ = atypical squamous cell of undetermined significance or greater; N = total number of subjects; n = number of cases reported. Bold: P‐values <0.05

The other multivariable Cox proportional hazard models (including the serostatus as a time‐dependent variable, antibody level as a time‐dependent variable, and log‐transformed level as a time‐dependent variable) showed similar results (Figure 2 and Supplementary Tables).

Figure 2.

Figure 2

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Risk ratio of incident, 6‐mo persistent, and 12‐mo persistent infection and atypical squamous cell of undetermined significance or greater in HPV‐16/HPV‐18 type‐specific seropositive vs seronegative women. Error bars represent 95% confidence intervals; #95% confidence intervals are narrow and not visible; HPV, human papillomavirus; PI, persistent infection; bin, binary; ab, antibody; ACS‐US+, atypical squamous cell of undetermined significance or greater

The analyses stratified by baseline serostatus showed that these risk factors (number of sexual partners in the last 12 months, living single and smoking) were more marked in seronegative than in seropositive women (Table 4).

Table 4.

Multivariable Cox model for HPV‐16 and HPV‐18 6‐mo persistent infection and incident infection according to different serostatus at baseline

Risk factor HPV‐16 6‐mo PI HPV‐18 6‐mo PI HPV‐16 incident infection HPV‐18 incident infection
Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive Seronegative Seropositive
N = 1767 event=67 N = 749 event=16 N = 1852 event=30 N = 679 event=5 N = 1802 event=114 N = 772 event=43 N = 1885 event =70 N = 703 event=25
Hazard ratio (95% CI) P‐value Hazard ratio (95% CI) P‐value Hazard ratio (95% CI) P‐value Hazard ratio (95% CI) P‐value Hazard ratio (95% CI) P‐value Hazard ratio (95% CI) P‐value Hazard ratio (95% CI) P‐value Hazard ratio (95% CI) P‐value
Age at inclusion
26‐35 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐
≥36 0.73 (0.44‐1.22) 0.2306 1.27 (0.43‐3.74) 0.6625 0.33 (0.14‐0.77) 0.0103 Not estimated ‐ 0.62 (0.42‐0.92) 0.0177 0.51 (0.27‐0.97) 0.0409 0.33 (0.19‐0.57) <0.001 0.41 (0.17‐1.01) 0.0527
Region
Europe 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐
Asia Pacific 2.70 (0.88‐8.29) 0.0825 2.79 (0.50‐15.71) 0.2447 1.16 (0.35‐3.81) 0.8069 Not estimated ‐ 1.13 (0.59‐2.13) 0.7172 1.25 (0.37‐4.21) 0.7169 1.06 (0.48‐2.31) 0.8893 1.85 (0.57‐5.95) 0.3033
Latin America 5.00 (1.66‐15.02) 0.0042 1.33 (0.18‐10.04) 0.7804 0.83 (0.23‐2.95) 0.7750 Not estimated ‐ 1.46 (0.77‐2.76) 0.2433 2.03 (0.65‐6.36) 0.2225 1.07 (0.49‐2.33) 0.8717 1.41 (0.38‐5.25) 0.6131
North America 5.27 (1.77‐15.73) 0.0029 2.80 (0.58‐13.52) 0.2002 1.74 (0.57‐5.28) 0.3319 Not estimated ‐ 2.27 (1.24‐4.17) 0.0081 2.76 (1.03‐7.43) 0.0445 1.44 (0.69‐3.00) 0.3268 0.59 (0.18‐2.01) 0.4022
Age at first sexual intercourse grouped
≥18 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐
15‐17 0.58 (0.30‐1.09) 0.0915 0.67 (0.20‐2.29) 0.5274 0.67 (0.28‐1.60) 0.3669 5.52 (0.37‐81.42) 0.2133 0.81 (0.52‐1.26) 0.3457 0.88 (0.43‐1.81) 0.7343 0.97 (0.56‐1.68) 0.9072 0.79 (0.29‐2.15) 0.6378
<15 0.86 (0.29‐2.55) 0.7829 4.04 (1.06‐15.47) 0.0413 Not estimated ‐ 29.71 (0.70‐1263.78) 0.0763 0.58 (0.20‐1.64) 0.3042 1.77 (0.69‐4.54) 0.2372 0.78 (0.23‐2.63) 0.6868 3.58 (1.19‐10.83) 0.0237
Marital status at baseline
Living or lived with partner 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐
Single 0.97 (0.45‐2.11) 0.9381 0.87 (0.22‐3.46) 0.8395 1.93 (0.70‐5.36) 0.2039 2.73 (0.20‐36.42) 0.4484 0.75 (0.42‐1.37) 0.3537 1.02 (0.45‐2.30) 0.9587 1.93 (1.00‐3.73) 0.0514 2.64 (0.93‐7.44) 0.0672
Smoking status at baseline
No 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐
Yes 1.36 (0.68‐2.74) 0.3825 0.68 (0.15‐3.17) 0.6283 1.40 (0.55‐3.58) 0.4801 0.84 (0.07‐9.42) 0.8874 1.75 (1.07‐2.86) 0.0247 0.72 (0.29‐1.74) 0.4633 1.03 (0.59‐3.92) 0.9385 0.57 (0.16‐1.98) 0.3747
Number of sexual partners during the last year
0 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐
1 1.08 (0.45‐2.59) 0.8652 0.72 (0.15‐3.52) 0.6853 1.58 (0.35‐7.15) 0.5522 Not estimated ‐ 0.84 (0.45‐1.57) 0.5839 0.99 (0.34‐2.92) 0.9919 1.52 (0.59‐3.92) 0.3916 1.33 (0.28‐6.22) 0.7199
≥2 4.49 (1.62‐12.49) 0.0039 2.04 (0.33‐12.59) 0.4428 4.51 (0.90‐22.75) 0.0679 Not estimated ‐ 2.60 (1.23‐5.50) 0.0127 1.98 (0.59‐6.69) 0.2704 3.36 (1.18‐9.63) 0.0238 3.36 (0.67‐16.91) 0.1419
Pregnancy
No 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐
Yes 0.59 (0.30‐1.19) 0.1396 0.57 (0.15‐2.22) 0.4207 1.74 (0.60‐5.01) 0.3044 0.10 (0.01‐1.72) 0.1119 0.60 (0.36‐1.01) 0.0127 1.44 (0.57‐3.63) 0.4343 1.40 (0.70‐2.79) 0.3415 0.70 (0.25‐1.97) 0.4954
Chlamydia infection at baseline
No 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐
Yes Not estimated ‐ 0.85 (0.18‐4.06) 0.8404 0.59 (0.08‐4.55) 0.6120 1.97 (0.15‐26.31) 0.6071 0.17 (0.02‐1.22) 0.0777 1.09 (0.44‐2.72) 0.8547 0.73 (0.22‐2.45) 0.6094 1.03 (0.26‐4.12) 0.9658
History of HPV infection/treatment or not intact cervix
No 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐ 1 ‐
Yes 0.87 (0.39‐1.94) 0.7329 1.74 (0.58‐5.22) 0.3202 2.10 (0.86‐5.13) 0.1024 0.76 (0.07‐8.56) 0.8229 1.36 (0.80‐2.32) 0.2582 1.89 (0.96‐3.71) 0.0648 1.82 (0.99‐3.35) 0.0530 1.19 (0.43‐3.30) 0.7309
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HPV = human papillomavirus N = number of subjects used in the model; event = number of HPV‐type‐specific 6‐mo persistent cervical infection; PI = persistent infection; CI = confidence interval. Bold: P‐values <0.05

4. DISCUSSION

In this study, HPV‐16‐seropositive women of 25 years and older had a moderate decrease in risk of developing a new type‐specific HPV, PI, and ASC‐US+ compared to seronegative women. This result agrees with the hypothesis that naturally acquired HPV antibodies probably provide only partial protection against subsequent infection with the same HPV type. However, HPV‐18‐seropositive women had deficient levels of protection. Any naturally acquired protection afforded by either antibody is unlikely to be better than the benefits acquired by vaccination. Another study has found that women aged between 30 and 50 who were seropositive for high risk (HR) HPV at baseline had a higher incidence of new type‐specific HPV infection than women who were seronegative.26

The association between seropositivity and the reduced risk of new infection was less in our study of 26+‐year‐old women than demonstrated in our study of younger women aged 15‐25 years in PATRICIA and in the Costa Rica Vaccine Trial.12, 15 This low protective effect or even absence of protective effect in >25‐year‐old women could suggest waning of the natural immunity but it could also reflect reactivation of prior infection.26

In the present study, we were not able to determine an accurate antibody threshold value for a defined reduction rate in infection. In the PATRICIA trial, HPV‐16 antibody levels comprised between 200 and 500 EU/mL were associated with a 90% reduction of incident infection, of 6‐month PI and of ASC‐US+.12 For HPV‐18, seropositivity was associated with a lower risk of ASC‐US+ and CIN1+ but no association was found between naturally acquired antibodies and new infection.12

The current study also attempted to consider the change in serostatus during the follow‐up period. Including the serostatus as a time‐dependent variable and as a continuous variable in the Cox models is original. In a recent meta‐analysis, assessing the naturally acquired immunity against HPV infection, none of the 14 included studies considered the possible change of serostatus during the follow‐up period.27 Overall, our various models gave consistent results. However, the interpretation of the time‐dependent serostatus models can be challenging because of the interaction between the change in antibody titers and the incidence of new HPV infections. Because the serology was collected every 12 months and the cervical sample every six months, new, but undetected, infection could have boosted the antibody titer.

In another analysis of the control cohort of the VIVIANE trial, the risk of detecting CIN after natural HPV infection in women aged >25 years was similar to that observed in women aged 15‐25 years from the PATRICIA trial.24 This observation suggests that there are little to no age‐related differences in the detection of natural HPV infection and their associated CIN lesions.

Our analysis of determinants when considered separately for the baseline seronegative and seropositive subjects partially supports the hypothesis suggested by other studies that most of the newly detected HPV infections in seropositive women would be a reactivation of prior HPV infections.19, 20

The strengths of this study included the large cohort size of approximately 2700 women, and the relatively extended follow‐up period of seven years, which allowed for a thorough evaluation of an unvaccinated cohort. This study also had several limitations. A cervical sample test was performed only every six months, which could have meant that some incident HPV infections were not detected. In addition, it was not possible to determine whether an infection was quiescent, persistent at undetectable levels or was a new infection. Evidence exists that type‐specific HPV infection can present after a period of nondetection.28 Based on this assumption, some infections considered as new could indeed be a PI. This scenario could also bias the assessment of the relationship between natural antibodies and risk of new infection. Furthermore, the number of CIN1+ and CIN2+ cases was too low to allow for inferential analyses. Since we were unable to define which HPV type caused the abnormal cytology, ASC‐US+ lesions could ensue from non‐HPV‐16/18 types.

Further research is needed to better understand the natural history of HPV infection and the link between seropositivity and subsequent protection in women of different age groups.

In conclusion, multivariable Cox analyses showed evidence of lower risk of newly detected incident and persistent HPV infections and ASC‐US+ in women with naturally acquired antibodies against HPV‐16. The results for HPV‐18 are not conclusive since only a limited and nonsignificant decrease in risk was observed. These findings are consistent with a partial protective role of naturally acquired HPV antibodies against future infection with the corresponding HPV type. However, no threshold of antibody levels necessary for protection could be defined.

CONFLICT OF INTEREST

D Rosillon and F Struyf are employed by the GSK group of companies and received GSK shares. L Baril was employed by the GSK group of companies at the time of the study and received GSK shares. G Dubin is currently a full‐time employee of Takeda Pharmaceuticals, Deerfield, Illinois, and receives salary and stock shares. MR Del Rosario‐Raymundo reports payment of honorarium as principal investigator and support for travel to meetings for the study from the GSK group of companies during the conduct of the study; payment for lectures including service on speakers' bureaus from the GSK group of companies. M Martens reports grants from the GSK group of companies, during the conduct of the study. C Bouchard reports grants from the GSK group of companies, during the conduct of the study. She reports grants and honorarium from Merck. KL Fong reports grant from the GSK group of companies via her institution for the conduct of the study. MC Bozonnat is a consultant outsourced from 4Clinics to the GSK group of companies. A Chatterjee received grant funding for clinical trials, and served on the speakers' bureau and advisory boards for the GSK group of companies and Merck. SM Garland has received advisory board fees and grants from CSL and the GSK group of companies, and lectures fees from Merck, the GSK group of companies, and Sanofi Pasteur. In addition, she received funding through her institution to conduct HPV vaccines studies for MSD and the GSK group of companies. She is a member of the Merck Global Advisory Board as well as the Merck Scientific Advisory Committee for HPV. E Lazcano‐Ponce received fees to conduct HPV vaccines studies from the GSK group of companies and Merck. SA McNeil has received research grants from the GSK group of companies and Sanofi Pasteur and speaker honoraria from Merck. B Romanowski received research grants, travel support, and speaker honoraria from the GSK group of companies. SR Skinner received funds through her institution from the GSK group of companies to cover expenses involved in the collection of data for this study. The GSK group of companies provided funds to reimburse expenses incurred with travel to conference to present data from other studies and paid honoraria to her institution for work conducted in the context of Advisory Board and educational meetings. CM Wheeler's institution received a contract from the GSK group of companies to act as a clinical trial site for this study, and reimbursements for travel related to publication activities and for HPV vaccine studies. Her institution also received funding from Merck to conduct HPV vaccine trials, and from Roche Molecular Systems equipment and reagents for HPV genotyping studies, outside the submitted work. X Castellsagué received research funding through his institution (ICO) from Merck & Co, SPMSD, the GSK group of companies, and Genticel. He also received honoraria for conferences from Vianex and SPMSD. G Minkina, as an investigator at a study clinical site, received fees from the GSK group of companies through her institution. She also received funding from Merck Sharp & Dohme to participate as principal investigator in efficacy trials. She received travel support to attend scientific meetings, honoraria for speaking engagements and participation in advisory board meetings, and consulting fees from the GSK group of companies and Merck Sharp & Dohme. T Stoney received honoraria from the GSK group of companies for study committee membership (Asia Pacific study follow‐up committee for Zoster studies), for conference attendance, and travel support. Her institution also received additional funding from a bioCSL grant for a project in which she is an investigator, funded by National Health and Medical Research Council. She also received travel support for participation in study investigator meetings from Novartis Vaccine and Diagnostics, Sanofi Pasteur, Alios BioPharma, and Pfizer. SC Quek received honoraria and travel expenses from the GSK group of companies for speaking at various symposia. A Savicheva received grants and fees from the GSK group of companies to participate in an epidemiological study (HERACLES). J Salmeron received grants from the GSK group of companies, Qiagen, and Merck Inc. D Money has received grants from Merck, the GSK group of companies, Novartis, and Sanofi for studies conduct. CS Vallejos, TYK Lim, B ter Harmsel, M Cruickshank, A Fiander, and A Ilancheran have nothing to disclose.

Supporting information

 

Click here for additional data file. (80KB, docx)

ACKNOWLEDGMENTS

The authors thank all study participants and their families, all clinical study site personnel who contributed to the conduct of this trial, and Dr. N Chakhtoura and Dr. L Myron as investigators. Writing support services were provided by John Bean (Bean Medical Writing), Kristel Vercauteren, and Claire Verbelen (XPE Pharma & Science, Belgium) on behalf of GSK, Wavre, Belgium. The authors would also like to thank Business & Decision Life Sciences platform for editorial assistance and manuscript coordination, on behalf of GSK. Thibaud André coordinated manuscript development and editorial support.

Rosillon D, Baril L, Del Rosario‐Raymundo MR, et al. Risk of newly detected infections and cervical abnormalities in adult women seropositive or seronegative for naturally acquired HPV‐16/18 antibodies. Cancer Med. 2019;8:4938–4953. 10.1002/cam4.1879

†Deceased 12 June 2016.

Trademark: Cervarix is a trademark of the GSK group of companies.

Funding information

GlaxoSmithKline Biologicals SA was the funding source and was involved in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals SA also funded costs associated with the development and the publishing of the present manuscript.

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