Background A vaccine is available to prevent human papillomavirus (HPV) 6, 11, 16 and 18; in the prevaccine era, seropositivity to vaccine types is a measure of natural exposure.
Methods We describe HPV seropositivity in the USA among 14–59-year-olds using the 2003–2006 National Health and Nutrition Examination Surveys.
Results Seropositivity to HPV 6, 11, 16 and 18 was 17.5%, 6.8%, 15.1% and 5.9%, respectively, among women, and 7.0%, 2.4%, 5.2% and 1.5%, respectively, among men. Overall in both sexes, seropositivity was 22.5% for any vaccine type (31.8% in women and 12.9% in men), but substantially lower for three or more types (1.7% overall, 2.8% in women and 0.6% in men).
Conclusions Almost a quarter of the participants were seropositive to any HPV vaccine type but few were seropositive to at least three vaccine HPV types in the prevaccine era. Further study is needed to assess if seropositivity would be useful as a biological marker of vaccination.
- Epidemiology (General)
- Virology Clinical
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More than 150 types of human papillomavirus (HPV) have been described, and several of these types commonly infect the genital skin and mucosa of people worldwide.1 ,2 In the USA, HPV is the most prevalent and frequently occurring sexually transmitted infection.3 Most HPV infections are transient and asymptomatic; however, some types of HPV can lead to disease. Low-risk HPV types (eg, types 6 and 11) are usually associated with benign papillomatous overgrowths of the epithelium, which are known as anogenital warts when they occur on the anogenital skin or mucosa.2 High-risk HPV types (eg, types 16 and 18) can cause intraepithelial neoplasias and invasive malignancies, including cervical, vulvar, vaginal, penile, anal and oropharyngeal cancers.2
Seropositivity in the prevaccine era represents natural exposure to HPV, however not all persons develop antibody to infection after exposure.3 One study found that 67% of women seroconverted after HPV 16 infection,4 and fewer young men than young women seroconvert after infection.5 Seroconversion after natural infection likely depends on interactions between host factors, such as sex, immune status, site of infection and concurrent infections; and viral factors, particularly HPV type and persistence of infection.5 ,6 A previous analysis of National Health and Nutrition Examination Surveys (NHANES) 2003–2004 data estimated overall seroprevalences of 17.0%, 7.1%, 15.6% and 6.5% for HPV types 6, 11, 16 and 18, respectively, among women, with lower seroprevalences of 6.3%, 2.0%, 5.1% and 1.5%, respectively, among men.7
Seropositivity in the vaccine era will reflect vaccination as well as natural exposure to HPV. In the USA, a quadrivalent vaccine against HPV types 6 and 11, which cause 90% of anogenital warts, and types 16 and 18, which cause 70% of cervical cancers was licensed in 2006, and a bivalent vaccine against HPV types 16 and 18 was licensed in 2009.8 Vaccination results in high seroconversion to all vaccine types and geometric mean titres that are higher than those after natural infection.9 However, one study found that up to 35% of female vaccinees lose detectable antibody to HPV 18 using one assay by month 36,10 so seropositivity to ≥three vaccine types may be a better long-term measure of vaccination. Seropositivity to one or two HPV types would be a less specific indicator of vaccination because of the frequency of natural exposure.
This study provides updated prevaccine era data on HPV vaccine type seroprevalence using the 2003–2006 NHANES. We also evaluate seropositivity to three or more HPV types as a potential marker of vaccination status.
Survey design and population
NHANES is an ongoing series of cross-sectional surveys conducted by the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention designed to collect health-related data from a nationally representative sample of the non-institutionalised US population.11 The complex survey design includes oversampling of some populations; during the period of this analysis, adolescents, non-Hispanic African-Americans, and Mexican Americans were oversampled. Participants complete a household interview followed by physical examination in a mobile examination centre (MEC). From 2003 to 2006, participants aged 14–59 years who were examined in the MECs had blood samples taken for HPV serological analysis. Serum antibodies to HPV types 6, 11, 16 and 18 were measured using a multiplexed, competitive Luminex Immunoassay (cLIA) that measures antibody to a type-specific neutralising epitope on the L1 protein of each type (HPV 6, 11, 16 and 18).7 ,12 The NHANES data collection was approved by the NCHS Ethics Review Board and informed consent was obtained from all participants.
Participants aged 14–59 years who submitted an adequate sample for HPV serological examination were included in this analysis. Serum specimens and questionnaire data for 8767 participants (4531 women and 4236 men) were analysed. Statistical analyses were conducted using SAS, V.9.3 (SAS Institute) and SAS callable SUDAAN, V.11 (RTI). Estimates were weighted using 2-year weights constructed from the MEC weights provided by NCHS to account for the complex survey design and non-response. Seropositivity estimates are reported as weighted percentages and 95% CIs. Bivariate associations with select demographic characteristics were examined using the Wald F-test adjusted for survey design. Differences with p values less than 0.05 were considered statistically significant. Prevalence estimates with a relative standard error (RSE) of ≥30% were considered unstable and noted in the results.
Seropositivity to HPV 6, 11, 16 and 18 was 17.5%, 6.8%, 15.1% and 5.9%, respectively, among women and 7.0%, 2.4%, 5.2% and 1.5%, respectively, among men (table 1). The differences in seropositivity between female and male participants were statistically significant for each HPV type (p<0.001). Seropositivity to any HPV vaccine type was 22.8%; 31.8% among women and 12.9% among men (p<0.001).
Statistically significant differences in seropositivity were found by age group and racial/ethnic group. Among women, seropositivity to HPV types 6, 16 and 18, and any HPV vaccine type increased with age to 22.8%, 21.6%, 9.7% and 43.5%, respectively, among those aged 30–39 years and then decreased (table 1). For HPV type 11, seropositivity increased to 9.3% through age 40–49 years and then decreased. Among women, seropositivity to any vaccine type was higher among non-Hispanic African-Americans (46.9%) compared with non-Hispanic Caucasians (30.8%) and Mexican Americans (24.9%) (p<0.001). This pattern of seropositivity among racial/ethnic groups was seen for each individual type as well (table 1). Among men, seropositivity to any HPV vaccine type increased with age through age 40–49 years to 18.5% (p<0.001). The seropositivity to any HPV vaccine type was higher among non-Hispanic African-Americans (18.1%) compared with non-Hispanic Caucasians (12.4%) and Mexican Americans (11.7%) (p<0.001).
Overall, seropositivity to only one type was 16.0%, only two types was 4.8%, only three types was 1.5% and to all four types was less than 1%; seropositivity to HPV16 and HPV18 was 1.3% (data not shown). Seropositivity to at least three vaccine types was 1.7% overall (2.8% in women and 0.6% in men). We further examined seropositivity to at least three vaccine types by sex, age group and race/ethnicity (table 1). Among women, seropositivity to at least three types increased with age, peaked among those aged 30–39 years (4.0%), and then decreased (p<0.001). Non-Hispanic African-American women had higher seropositivity to at least three types (7.1%) compared with non-Hispanic Caucasians (2.3%) and Mexican Americans (1.5%) (p<0.001). Among non-Hispanic African-Americans women seropositivity was 2.4% among those aged 14–19 years, and increased to 8.2% among those aged 20–24 years. Among men, seropositivity to at least three types was low among all demographic groups (table 1).
Our data from NHANES 2003–2006 demonstrate that in the prevaccine era, almost a quarter of 14–59 year-olds were seropositive to at least one HPV vaccine type. Seropositivity to three or more vaccine types was substantially lower (1.7%) and in the vaccine era it might be useful as a specific marker of vaccination.
Seropositivity to HPV vaccine types from NHANES 2003–2006 in this analysis are similar to previously reported estimates from NHANES 2003–2004 data.7 The 4 year data we describe are robust and are the last nationally representative estimates of seropositivity due to natural exposure to HPV. As observed in earlier analyses, there are significant differences in seropositivity by sex and other demographic characteristics. HPV vaccine type seropositivity was common, with 31.8% of women and 12.9% of men being seropositive to any HPV vaccine type. The highest seropositivity to any HPV vaccine type occurred in women aged 30–39 years (43.5%) and in men aged 40–49 years (18.5%).
A biological marker of HPV vaccination, such as seropositivity to vaccine types, could be useful as it does not rely on provider or patient report; a marker that is specific to vaccination (rather than natural exposure) would be advantageous. In our study, because seropositivity to any HPV type was high due to natural exposure, in the vaccine era this measure would not be specific for vaccination. However, seropositivity to at least three HPV types and all four types was much lower, especially among younger persons. Vaccination results in high seroconversion to all three vaccine types, but up to 35% of female vaccinees lose detectable HPV 18 antibody within 5 years by the cLIA, so seropositivity to at least three HPV vaccine types might be a better long-term marker for vaccination than all four HPV types.10 It is important to note that our study found that some groups (eg, older non-Hispanic African-Americans women) have higher seropositivity to at least three vaccine types resulting in possible limitations of this measure in certain demographic groups. Also, seropositivity to at least three HPV vaccine types could only be used as a marker of vaccination in a setting implementing quadrivalent vaccine; in the USA most vaccine being administered is quadrivalent vaccine.13 A future assessment comparing HPV serology with vaccination self-report in NHANES, as well as provider verified report, would be useful to assess serology as a measure of vaccination.
Our study is subject to several limitations. First, as previously mentioned, not all people develop a measurable serological response to HPV upon infection, so seropositivity is an imperfect measure of HPV exposure, particularly among men. Second, there are limitations to serological assays, including some evidence to suggest the cLIA might be less sensitive for HPV type 18 antibody than other assays.14 Because serological assays differ, our results cannot be compared with other serological assays and platforms.9 We assessed seropositivity to at least three HPV types using cLIA as a measure of quadrivalent HPV vaccine as this vaccine is being used most frequently in the USA. In settings where the bivalent vaccine is in use, seropositivity to two types could be examined, although the distinction between natural exposure and vaccination may not be sufficient. Finally, it would be important to assess if this would be the most cost-effective approach to assessing vaccination coverage.
Assessing HPV vaccination uptake is useful for vaccine programme evaluation and monitoring; seropositivity to at least three HPV vaccine types might be a biological marker of vaccination in settings that are using the quadrivalent HPV vaccine. Future evaluations of serology in different populations and compared with vaccination measures will be useful.
Handling editor Jackie A Cassell
Contributors All authors have met authorship contribution requirements.
Funding Centers for Disease Control and Prevention.
Disclaimer The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention (CDC). Mention of company names or products does not imply endorsement by CDC.
Competing interests None.
Ethics approval Centers for Disease Control and Prevention.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The NCHS NHANES data is a public data use file and is posted online.
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