Helen Trottier

Little is known about natural humoral immunity against recurrent HPV DNA detection. The objective of this study was to asses the risk of cervical HPV16 DNA detection in unvaccinated women according to HPV16 IgG and IgM seroreactivity status. We analyzed data from 618 women (mean age of 32 years) participating in the Ludwig–McGill cohort. Women were classified into three HPV16 exposure groups based on IgG and IgM seroreactivity measured by enzyme‐linked immunosorbent assay (ELISA): likely unexposed, recently exposed, and past exposed. HPV DNA was tested by PCR every 4–6 months. Associations between presumed HPV16 exposure and HPV16 DNA detection were measured using Cox regressions. Past exposed women had significantly higher risk of having HPV16 DNA detection (adjusted hazard ratio (aHR) [95% confidence interval (CI)] = 5.03 [2.00–12.63]) and recurrent detections (6.33 [2.38–16.82]) during the first year, compared to unexposed women. Recently exposed women showed similar patterns with HRs of lower magnitude. Naturally developed HPV16 IgG and IgM antibodies were positively associated with primary and recurrent HPV16 DNA detection. HPV antibodies may serve as serological markers for past and latent infections, enabling risk stratification in resource‐limited settings. Testing for specific IgM antibodies could help identify women at risk of recurrent HPV16 DNA detection.

Little is known about the factors associated with the natural humoral immune response against human papillomavirus (HPV) infection. The association between HLA‐DRB1 and ‐DQB1 polymorphism and (1) HPV16 DNA detection, (2) naturally developed humoral immune response (IgG and IgM) against HPV16 L1 and L2 capsid proteins, and (3) type of HPV16 infection (transient or persistent) was investigated. Data from 943 women participating in the Ludwig‐McGill cohort study was analyzed. HLA‐DRB1 and HLA‐DQB1 genotyping was done by PCR‐based methods. HPV DNA was assessed every 4 months during the first year of follow‐up, and HPV16 IgG and IgM antibody measurements were performed by ELISA in serum samples from the first and/or second visits. Associations were estimated by adjusted logistic regression models. HLA‐DRB1*03:02 was associated with HPV16 DNA positivity (OR = 2.49, 95% CI: 1.11–5.60). HLA‐DRB1*13:01 and HLA‐DQB1*04:02 were associated with low levels of HPV16 IgG antibodies (OR = 0.44, 95% CI:0.23–0.87; OR = 0.10, 95% CI: 0.02–0.55, respectively). Neither IgM HPV16 antibodies nor the type of HPV16 infection (transient or persistent) were associated with HLA‐DRB1 or ‐DQB1 variants. HLA‐DRB1 and ‐DQB1 polymorphism might be associated with different levels of IgG against HPV16 infection, but IgM production and the type of infection seem to occur independently of these variants.

Background: Little is known on the vertical transmission of human papillomavirus (HPV) and on the dynamics of HPV among children. Our objective was to determine the risk of HPV recurrence, persistence, and incidence over 2 years of age among children born to HPV-positive mothers. Methods: We conducted the HERITAGE study among pregnant women recruited between 2010 and 2016 in Canada. HPV DNA testing was done on vaginal samples collected during the first and third trimesters of pregnancy, and on conjunctival, oral, pharyngeal, and genital samples collected in children from birth and at every 3–6 months up to 2 years. We estimated the probability of HPV vertical transmission, and of HPV recurrence, persistence, and incidence among children during follow-up. Time to clear HPV among children was estimated using Kaplan-Meier technique. Results: Among the 422 women with HPV during pregnancy, 390 carried pregnancy to term, and 395 children were born alive including twins/triplets. HPV vertical transmission was estimated at 7.3% (95% confidence interval [CI], 5.0%–10.4%) with a genotype concordance of 85.2%. During the entire follow-up, we observed 91 HPV detections (among 51 children) including 2 recurrent and 1 persistent. Incident genotypes occurred in 26 of the 270 (9.6%) children with valid HPV testing during follow-up. Most HPV infections detected in children cleared with a mean time of 3.9 months (95% CI, 3.6–4.2 months). Conclusions: HPV vertical transmission and incident HPV occasionally occur during infancy, but the risk of persistence or recurrence is overall very low.

Little is known on the dynamics of human papillomavirus (HPV) viral load during pregnancy and on the impact of viral load on HPV vertical transmission. We described viral loads for several genotypes during pregnancy and analyse its association with vertical transmission. Data were analysed from the HERITAGE study, a cohort of pregnant women recruited between 2010 and 2016 in three centres in Canada. Vaginal samples were collected at the first and third trimesters of pregnancy, placental samples were collected at birth, and conjunctival, oral, pharyngeal, and genital samples were collected in children at birth and 3 months were tested for HPV DNA and viral load by Linear Array essay. The association between viral load and vertical transmission was measured using logistic regression. Odd ratios (ORs) and their 95% Confidence intervals (CI) were adjusted for age of the mother. We included women in the cohort infected with the 13 most common genotypes during pregnancy ( n = 287). A decrease in HPV viral load was observed during pregnancy (median difference between the third and first trimester of pregnancy = −0.005 copies/cell [ p < 0.05]). Women with more than 2 HPV copies/cell (compared to those with ≤ 2 copies) at first trimester had a statistically significant higher risk of vertical transmission (adjusted OR = 6.41; 95% CI: 1.10–37.34 for any genotypes and OR = 17.17; 95% CI: 1.18–250.28 for HPV‐16). Viral load values analysed continuously or categorized with different cut‐offs showed comparable results. HPV viral load varied during pregnancy and was strongly associated with HPV vertical transmission. The results provide a better understanding of risk factors associated with vertical transmission.

Background: It is unclear whether recurrent cervical human papillomavirus type 16 (HPV16) infections can be prevented by naturally induced HPV16 antibodies in unvaccinated healthy women.Methods: We systematically searched the literature for studies that prospectively evaluated the association between HPV16 naturally induced IgG, IgM, and neutralising antibodies and newly detected cervical HPV16 infection in unvaccinated women. Data were quantitatively summarised by random effect meta-analysis.Results: Naturally induced HPV16 IgG and neutralising antibodies were negatively associated with newly detected HPV16 infection (relative risk (RR) (95% confidence interval (CI))=0.71 (0.63 to 0.80) and 0.54 (0.36 to 0.73), respectively). HPV16 antibodies tend to offer protection against subsequent HPV16 DNA detection in young women (RR (95% CI)=0.65 (0.55 to 0.74)), but not in women aged over 25 years (RR (95% CI)=0.88 (0.73 to 1.04)). HPV16 IgG antibodies were also negatively associated with persistent HPV16 infection (adjusted RR=0.67 (0.56 to 0.78)). There was high heterogeneity between studies (I²statistic=63.9%; p=0.007), and most had low risk of bias. We did not find studies evaluating IgM antibodies.Conclusion: Seroreactivity to HPV16 infection seems to provide moderate protection against newly detected cervical HPV16 infection outcomes in unvaccinated women. However, protection seems to be affected by age. These findings should be considered when evaluating public health interventions against HPV.PROSPERO registration number: CRD42022339579.

Little is known about the protection conferred by antibodies from natural human papillomavirus (HPV) infection. Our objective was to evaluate the association between HPV16 seroreactivity and HPV16 redetection, newly detected HPV infections, and loss of HPV DNA detection during follow‐up. We analyzed data from 2462 unvaccinated Brazilian women. HPV16 IgG and neutralizing antibodies at baseline were assessed by enzyme‐linked immunosorbent assay (n = 1975) and by the pseudovirus‐based papillomavirus neutralization assay (n = 487). HPV detection, genotyping, and viral load were assessed by PCR‐based methods. The associations were analyzed by Cox proportional hazards models. We observed a positive association between HPV16 IgG seroreactivity and redetection of HPV16 infections. Age‐adjusted hazard ratios (HR) with 95% confidence intervals (CI) ranged from 2.45 (1.04–5.74) to 5.10 (1.37–19.00). Positive associations were also observed between HPV16 IgG antibodies and (1) newly detected HPV infections by genotypes unrelated to HPV16 (age‐adjusted HR [95% CI] = 1.32 [1.08–1.2]) and (2) loss of detection of HPV infections by genotypes unrelated to HPV16 (age‐adjusted HR [95% CI] = 1.24 [1.03–1.50]). Naturally developed HPV16 antibodies do not prevent recurrent HPV infections. Overall HPV16 IgG and neutralizing antibodies seem to be serological markers for latent or past infections.

Human papillomavirus (HPV) can be vertically transmitted. Our objective was to measure the association between the mode of delivery and the detection of HPV in infants. We used data collected from pregnant women during the HERITAGE study. Self-collected vaginal samples from the first and third trimester were obtained for HPV testing. Specimens from oral, pharyngeal, conjunctival and anogenital mucosa were collected from infants 36–48 h after delivery and at 3 months of age. All samples were tested for HPV DNA by the Linear Array assay. Adjusted odd ratios (aOR) and 95% confidence interval (CI) were estimated using multivariate logistic regressions. From the 282 women revealed to be HPV-positive in both the first and third trimesters, 25 infants were born HPV-positive. The overall probability of transmission was 8.9% (25/282); 3.7% (3/81) in participants with a caesarean section and 10.9% (22/201) for those who delivered vaginally. Vaginal delivery increased the risk of HPV in infants compared to caesarean (aOR: 3.63, 95%CI: 1.03–12.82). Infants born after a caesarean with ruptured membranes were not at increased risk of HPV compared to infants born after an elective caesarean section with intact membranes (aOR: 1.31, 95%CI: 0.10–17.76). Our results support the hypothesis that transmission occurs mostly during the passage in the vaginal canal.

Recent evidence shows increased preterm birth risk with human papillomavirus-16 (HPV16) infection during pregnancy. This study aimed to measure the association between HPV16 viral load during pregnancy and preterm birth. We used data from participants in the HERITAGE study. The Linear Array assay was used for HPV DNA testing on vaginal samples collected during the first and third trimesters of pregnancy. The HPV16 viral load was measured with a real-time polymerase chain reaction. We used logistic regression to measure the associations between HPV16 viral load during pregnancy and preterm birth (defined as birth before 37 weeks of gestation). The adjusted odd ratios (aORs) and the 95% confidence intervals [CIs] were estimated with inverse probability treatment weighting of the propensity score. This study included 48 participants who tested positive for HPV16 during the first trimester of pregnancy. The aOR for the association between first-trimester HPV16 viral load (higher viral load categorized with a cutoff of 0.5 copy/cell) was 13.04 [95% CI: 1.58–107.57]). Similar associations were found using different cutoffs for the categorization of viral load during the first and third trimesters. Our findings suggest a strong association between a high HPV16 viral load during pregnancy and preterm birth, demonstrating a biological gradient that reinforces the biological plausibility of a causal association.

Objective: To estimate the association between several risk factors and high-grade squamous intraepithelial lesions (HSIL) treatment failure in order to identify predictors. Methods: The study population included 1,548 Canadian women treated for HSIL who participated in a randomized control trial. HSIL treatment failure was the presence of histologically confirmed HSIL or worse during the two-year follow-up period. This nested-case control study included all 101 cases of treatment failure and controls that were matched 1:1 on treatment center and date of failure. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between each potential predictor and HSIL treatment failure. Independent variables that were examined included age, parity, smoking status, number of sexual partners, condom use, method of contraception, margins, number of passes, diagnosis on conisation, genotype, and number of infecting types. Interactions between smoking and margins and genotype were evaluated. Results: Having positive vs. negative margins (adjusted OR=4.05, 95% CI 1.57-10.48) and being positive for Human Papillomavirus (HPV)16 and/or HPV18 vs. any other type (adjusted OR=2.69, 95% CI 1.32-5.49) were predictors of HSIL treatment failure in multivariable models. ORs suggested that older age, more severe lesions, and single-type infections may be at a higher risk of treatment failure but were not statistically significant. The ORs for smoking status, number of sexual partners, condom use, contraception, parity, and number of passes were near the null value. We did not observe any evidence of interaction between smoking and genotype, nor between margins and genotype. Conclusion: Only positive margins and HPV16/18 positivity were predictors for being diagnosed with HSIL or worse within two years of treatment. However, we do not recommend automatic retreatment of those with positive margins because over 90% of those with positive margins did not fail treatment. The predictive value of HPV16 and HPV18 for HSIL treatment failure suggests that high coverage vaccination programs should contribute to a significant reduction in residual/recurrent disease.