Long-term Antibody Response to Human Papillomavirus Vaccines: Up to 12 Years of Follow-up in the Finnish Maternity Cohort.

Background: Most cervical cancers are caused by vaccine-preventable infections with human papillomaviruses (HPV). The HPV prophylactic vaccines Gardasil and Cervarix have been widely used for >10 years and are reported to induce high antibody levels. A head-to-head comparison of the antibody responses induced by the 2 vaccines has been performed only up to 5 years. Methods: Among 3300 Finnish females aged 16-17 years who got 1 of the 2 HPV vaccines in phase 3 licensure trials, virtually all consented to registry-based long-term follow-up. Linkage with the Finnish Maternity Cohort found that they donated >2500 serum samples up to 12 years later. Sera of 337 (38.6%) Gardasil and 730 (30.3%) Cervarix vaccine recipients were retrieved from the Finnish Maternity Cohort biobank and type-specific anti-HPV antibody levels were determined using in-house multiplexed heparin-HPV pseudovirion Luminex assay. Results: Anti-HPV-16 and anti-HPV-18 antibody levels remained stable and above natural infection-related antibody levels for up to 12 years for most vaccine recipients. The median antibody levels were higher among Cervarix recipients 7-12 years post vaccination (P < .0001). Conclusions: The stability of vaccine-induced antibody levels is in accordance with the high long-term protection reported previously. The differences in antibody levels induced by the 2 vaccines imply that continued follow-up to identify possible breakthrough cases and estimation of the minimal protective levels of serum antibodies is a research priority.

Seropositivity to Multiple Anogenital Human Papillomavirus (HPV) Types Is Associated With Current Anogenital HPV Infection, Abnormal Cytology, and Seropositivity for Nongenital HPVs.

Background: Antibodies against human papillomaviruses (HPVs) are biomarkers for current or past infections. We assessed whether antibodies against multiple HPV types were determinants of current multiple anogenital HPV infections, abnormal cytology, and seropositivity for cutaneous HPVs. Methods: A total of 1848 Slovenian women attended 2 rounds of cervical cancer screening 3 years apart and provided data on HPV antibodies and HPV DNA at both visits. Antibodies against 15 anogenital HPV types and 6 cutaneous HPVs were determined using pseudovirion-Luminex serology and anogenital HPV DNA using Linear Array. Antibodies to polyomaviruses were evaluated as a control. Women were grouped as either HPV seronegative or having antibodies to 1-2 HPV types or to ≥3 HPV types. Results: Presence of antibodies to multiple anogenital HPV types at baseline was associated strongly with (i) presence of HPV DNA at the cervix (χ2 = 68.8; P < .0001), (ii) multiple types of HPV DNA at baseline (χ2 = 58.6; P < .0001), (iii) HPV DNA at follow-up (χ2 = 22.9; P < .0001), (iv) abnormal cytology (χ2 = 9.8; P = .0017), and (v) concomitant presence of antibodies to any of 6 nongenital HPV types (χ2 = 40.1; P < .0001). Presence of antibodies to ≥3 anogenital HPV types tended to persist over time. Conclusions: Seropositivity against at least 3 anogenital HPV types is associated with current multiple anogenital HPV infections, abnormal cytology, and seropositivity to nongenital HPVs.

Seroprevalences of Antibodies to 11 Human Papillomavirus (HPV) Types Mark Cumulative HPV Exposure.

Background: The antibody responses against human papillomavirus type 16 (HPV-16) and HPV-18 are well known, but many genital HPV types are oncogenic. We assessed the correlation between detection of type-specific HPV DNA and antibodies for 11 HPV types. Methods: A total of 2024 women attending the organized national cervical cancer screening program in Slovenia were tested for cervical high-risk HPV DNA (HPV-16, -18, -31, -33, -35, -39, -45, -52, -56, -58, -59, and -68) and serum anti-HPV antibodies. Of these, 1848 women were tested with the same methods 3 years earlier. Results: Type-specific antibodies against 10 of 11 HPV types (HPV-16, -18, -31, -33, -35, -39, -45, -52, -56, and -58) were associated with concomitant presence of type-specific DNA (median odds ratio [OR], 7.5; 95% confidence interval [CI], 2.2-26.1). When the concomitant presence of type-specific HPV DNA at the 3-year visit was combined with the presence of the same HPV DNA type 3 years earlier, the statistical precision was greatly improved, and antibodies against all 11 types (HPV-16, -18, -31, -33, -35, -39, -45, -52, -56, -58, and -59) were associated with the presence of DNA of the same HPV type (median OR, 7.4; 95% CI, 4.2-12.8). Sensitivity had a slight tendency to increase (from 47% to 52%) when DNA positivity at the earlier time point was included, whereas specificity was the same (88%). Seroconversion was associated with previous HPV DNA positivity. Seropositivity mostly remained stable during the observation period. Conclusions: For 11 HPV types, type-specific seropositivity was associated with the presence of DNA of the same HPV type (either concomitantly or previously). Antibodies to these HPV types mark cumulative HPV exposure.

Effect of naturally acquired type-specific serum antibodies against human papillomavirus type 16 infection.

BACKGROUND: While vaccine-induced antibodies are known to confer protection against incident human papillomavirus (HPV) infection, there is inconsistent data regarding the protective effect of naturally acquired anti-HPV antibodies. OBJECTIVES: To estimate the protective effect of naturally acquired anti-HPV16 serum antibodies against incident anogenital infection with HPV16 in females aged 20-64 years and to assess whether antibodies influence the persistence/clearance of anogenital HPV16 infection. STUDY DESIGN: 4432 women attending the organized national cervical cancer screening program in Slovenia were initially enrolled. 2199 and 1848 women had valid HPV DNA results obtained using PCR-based assays and HPV antibody serotyping results obtained using pseudovirion-based serological assay, at baseline and at three-year follow-up, respectively. RESULTS: Baseline HPV16 seroprevalence was 2.4-fold higher among HPV16 DNA-positive women (55.7% vs. 23.2%; p<0.01). Baseline HPV16 DNA-positive/seronegative women frequently acquired anti-HPV16 antibodies during follow-up (OR=8.2; 95% CI: 3.8-17.8). Baseline anti-HPV16 antibodies persisted at follow-up, irrespective of baseline HPV16 DNA status (OR=40.6; 95% CI: 30.3-54.5). Baseline HPV16 DNA-negative/seropositive women were less likely to acquire HPV16 infection at follow-up (unadjusted OR=0.2; 0.1-0.9). However, the age-adjusted association was non-significant (adjusted OR=0.3; 0.1-1.2). The tendency for protective effect was stronger among women older than 25 years (OR=0.2; 0.03-1.8). Baseline anti-HPV16 antibodies were not associated with persistence/clearance of HPV16 infection at follow-up (OR=0.8; 0.3-1.9). CONCLUSIONS: Naturally acquired anti-HPV16 serum antibodies appeared to protect against anogenital HPV16 infection, but this association was at least partially confounded by age. Baseline anti-HPV16 serum antibodies did not influence persistence/clearance of HPV16 infection at follow-up.