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Clinical and epidemiological research
Extended report
Immunogenicity and safety of a quadrivalent human papillomavirus vaccine in patients with systemic lupus erythematosus: a case–control study
  1. Chi Chiu Mok,
  2. Ling Yin Ho,
  3. Lai Shan Fong,
  4. Chi Hung To
  1. Department of Medicine, Tuen Mun Hospital, Hong Kong
  1. Correspondence to Dr Chi Chiu Mok, Department of Medicine, Tuen Mun and Pok Oi Hospital, New Territories, Hong Kong, SAR China; ccmok2005{at}yahoo.com

Abstract

Objectives To evaluate the immunogenicity and safety of GARDASIL, a quadrivalent human papillomavirus (HPV) vaccine, in patients with systemic lupus erythematosus (SLE).

Methods Women with SLE aged 18–35 years who had stable disease were recruited to receive GARDASIL vaccination and an equal number of age-matched healthy women were also vaccinated. Seroconversion rates of antibodies to HPV serotypes 6, 11, 16 and 18 at months 7 and 12 and adverse events (AEs) were compared between patients and controls. The rate of disease flares in SLE participants was compared with matched SLE controls.

Results 50 patients with SLE and 50 healthy controls were studied. The mean age and disease duration of the patients was 25.8±3.9 years and 6.6±4.5 years, respectively. At month 12 the seroconversion rates of anti-HPV serotypes 6, 11, 16 and 18 in patients and controls were 82%, 89%, 95%, 76% and 98%, 98%, 98%, 80%, respectively. In patients with SLE there were no significant changes in the titres of anti-dsDNA, complements, anti-C1q and SLE Disease Activity Index scores from baseline to months 2, 7 and 12. There was one mild/moderate SLE flare at months 0–2, two mild/moderate flares at months 3–6 and six mild/moderate and two severe flares at months 7–12. Disease flares in patients with SLE occurred at a similar frequency to that of 50 matched SLE controls (0.22/patient/year vs 0.20/patient/year, p=0.81). Injection site reaction was the commonest AE (5%), and the incidence of AEs was comparable between patients with SLE and controls.

Conclusions The quadrivalent HPV vaccine is well tolerated and reasonably effective in patients with stable SLE and does not induce an increase in lupus activity or flares.

https://doi.org/10.1136/annrheumdis-2012-201393

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    Introduction

    Genital infection with human papillomavirus (HPV) is one of the commonest sexually transmitted infections worldwide.1 HPV infections are often asymptomatic or transient. However, in some individuals, especially those with impaired immunity, HPV infection may persist and result in genital warts, cervical smear abnormalities, cervical intraepithelial neoplasia (CIN) and cervical cancer.

    Systemic lupus erythematosus (SLE) predominantly affects women of childbearing age. Patients with SLE are immunocompromised because of the intrinsic immunological aberrations and immunosuppressive treatment. A cross-sectional study of 85 patients with SLE (mean age 42 years) revealed a 16.5% prevalence of abnormal cervical smears and 12% prevalence of CIN on screening, which was significantly higher than that of age-matched healthy women.2 Cervical HPV infection was more common in patients with SLE than in controls (11.8% vs 7.8%). Moreover, multiple HPV infection occurred at a higher frequency in patients with SLE (4.7% vs 1.1% in controls). Longitudinal follow-up of 144 patients with SLE (mean age 41 years) for up to 3 years revealed a significant increase in the rates of HPV (12.5% to 25%) and multiple HPV infections (6.9% to 16.7%).3 Up to 48.5% of the incident HPV infection persisted for more than 6 months. These data show that patients with SLE are at risk of cervical HPV infection and its persistence, which contributes to the observed higher prevalence of CIN.

    The recombinant quadrivalent HPV vaccine GARDASIL has been shown in randomised controlled trials to be efficacious in reducing the occurrence of high-grade CIN lesions and anogenital disease related to HPV infection in women.4 ,5 Vaccination of young women aged 16–23 years resulted in very high seroconversion rates for HPV serotypes 6, 11, 16 and 18 and was well tolerated.6 A more recent study in older women aged 24–45 years also showed the efficacy of the vaccine in reducing HPV-related disease or infection.7

    There is little information regarding the quadrivalent HPV vaccine in immunocompromised hosts other than patients with HIV.8 The objectives of the current study are to evaluate the immunogenicity and safety of the quadrivalent HPV vaccine in patients with SLE in terms of HPV antibody conversion, adverse events (AE) and rate of disease flares.

    Methods

    Study design and population

    A 12-month prospective case–control study of the immunogenicity and safety of a quadrivalent HPV vaccine was performed in a cohort of women with SLE. Consecutive women who fulfilled ≥4 American College of Rheumatology criteria for SLE9 were recruited and an equal number of age-matched healthy subjects (female doctors, nurses and clerical staff working in our hospital and their friends) were also recruited for the same vaccination protocol. The inclusion criteria for patients with SLE were age 18–35 years and receiving a stable dose of immunosuppressive agents within 3 months of entry. The inclusion criteria for female controls were age 18–35 years (matching that of recruited patients), absence of any chronic medical illness and not receiving any long-term medications including non-prescription drugs and herbs. Exclusion criteria for patients and controls were previous HPV vaccination, a history of allergy to HPV vaccines and a history of documented HPV-related genital infections.

    Study protocol

    Eligible patients and controls were given the HPV vaccine (GARDASIL) by intramuscular injection at baseline, month 2 and month 6. All participants were followed at baseline and months 2, 6 and 12 for disease activity assessment (SLE patients) and AE (patients and controls). Serum neutralising antibodies to HPV serotypes 6, 11, 16 and 18 were measured at baseline and at months 7 and 12 after vaccine administration. For patients with SLE, disease activity score, physician's global assessment (PGA) of disease activity, anti-dsDNA, anti-C1q and complement levels were assessed at baseline and at months 2, 6 and 12. Flares of SLE at any time within the first 12 months of vaccination were also assessed.

    Outcomes of interest

    The primary outcome of this study was the seroconversion rates of anti-HPV serotypes after vaccination in patients and controls. Secondary outcomes included: (1) AEs; (2) serial changes in anti-dsDNA, anti-C1q antibodies, complements C3 and C4, SLE Disease Activity Index (SLEDAI) and PGA scores in patients with SLE; and (3) rate of disease flares within 12 months of vaccination in patients with SLE, which was compared with an equal number of female controls matched for age and disease duration but not participating in the study within the same period.

    Withdrawal criteria

    For safety reasons, subjects who developed significant AEs thought to be related to vaccination (eg, severe hypersensitivity reactions) were discontinued from the study. These subjects would receive usual treatment according to the nature of the AEs and followed until the events had resolved. All serious AEs were reported to the Research and Ethics Committee.

    Measurement of anti-HPV antibodies

    Epitope-specific neutralising immunoglobulin G anti-HPV antibodies were assayed by a competitive Luminex-based immunoassay developed by Merck Research Laboratories using technology from the Luminex Corporation as described previously.10 Positive results were defined by anti-HPV titres ≥20 milli Merck Units (mMU; arbitrary value for measuring HPV antibody responses in serum), 16 mMU, 20 mMU and 24 mMU/ml for anti-HPV 6, 11, 16 and 18, respectively.

    Assessment of disease activity and flares of SLE

    Disease activity of SLE was assessed by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI, a validated instrument employed in the SELENA trials.11 The PGA of disease activity (score 0–3) was also performed by the attending rheumatologists to grade their impression of the disease activity of the patients.12 Flares of SLE were assessed by the SELENA flare instrument as described elsewhere,11 according to the clinical status of the patients with reference to that of the preceding clinic visit. Essentially, mild to moderate or severe flares were defined by different degrees of increase in the SLEDAI score, PGA score, severity of new manifestations or the intensity of new immunosuppressive treatment.

    Sample size calculation and recruitment of study subjects

    There is little information regarding the seroconversion rate of anti-HPV after vaccination with GARDASIL in immunocompromised individuals. Assuming the seroconversion rate is 80% in patients with SLE but 97% in the controls, 42 subjects in each group would be required to detect the difference with an α error of 5% and a study power of 80%.

    Statistical analyses

    Values in this study were expressed as mean±SD. Median (IQR) values were used for the anti-HPV titres because they did not follow a normal distribution. The demographic characteristics of patients and controls were compared by the independent sample Student t test and the seroconversion rates of the anti-HPV serotypes of patients and controls were compared by the χ2 test. The Fisher exact test was used when the frequency of any cell was <5. Comparison of the anti-dsDNA, anti-C1q, SLEDAI and PGA scores between baseline and months 2, 7 and 12 in patients with SLE was performed by the paired Student t test. The anti-HPV titres at months 7 and 12 were compared with baseline by the non-parametric Wilcoxon matched pair test. Spearman rank correlation was used to study the relationship between doses of immunosuppressive medications and anti-HPV titres at months 7 and 12 in patients with SLE. Finally, the anti-HPV titres and seroconversion rates at months 7 and 12 in patients with SLE were compared by the Mann–Whitney U test and χ2 test, respectively, between those with and without concomitant immunosuppressive medications.

    Statistical significance was defined as a two-tailed p value of <0.05. All statistical analyses were performed using the SPSS program Version 11.5 (SPSS, Chicago, Illinois, USA) for Windows Vista.

    Results

    Participants and clinical characteristics

    Fifty women with SLE and 50 healthy controls were recruited. The mean age of the patients and controls was similar (25.8±3.9 years and 25.8±3.9 years, respectively; p=0.90). The mean disease duration in patients with SLE was 6.6±4.5 years and the median SLEDAI score at study entry was 4 (IQR 2–4). None of the patients had SELENA flares at baseline. The cumulative clinical manifestations of the patients with SLE are shown in table 1. The proportions of patients who were receiving immunosuppressive medications at baseline were: prednisolone (70%), hydroxychloroquine (HCQ) (66%), azathioprine (AZA) (48%), mycophenolate mofetil (MMF) (18%), ciclosporin A (CSA) (4%), tacrolimus (Tac) (10%) and methotrexate (MTX) (6%). The mean doses of these drugs were: prednisolone (4.8±2.0 mg/day), HCQ (249±71 mg/day), AZA (68.8±24 mg/day), MMF (1.11±0.33 g/day), CSA (113±53 mg/day), Tac (2.4±0.9 mg/day) and MTX (12.5±4.3 mg/week). The percentages of patients receiving different daily doses of prednisolone at entry were: 0 mg (30%), >0–2.5 mg (16%), >2.5–5 mg (40%) and >5–10 mg (14%). No patients were receiving a daily prednisolone dose of >10 mg.

    View this table:
    Table 1

    Cumulative clinical manifestations in patients with systemic lupus erythematosus (N=50)

    All the participants completed the study protocol except for one control subject who withdrew from the study after signing the contract (no vaccination given).

    Seroconversion rates of antibodies to HPV

    Table 2 shows the seroconversion rates of antibodies to HPV serotypes 6, 11, 16 and 18 at months 7 and 12 in patients with SLE and normal controls who were tested negative for these antibodies at baseline. At month 7 the seroconversion rates of anti-HPV types 6, 11, 16 and 18 in patients with SLE and controls were 74%, 76%, 92%, 76% and 96%, 95%, 98%, 93%, respectively. At month 12 the seroconversion rates of anti-HPV types 6, 11, 16 and 18 in patients with SLE and controls were 82%, 89%, 95%, 76% and 98%, 98%, 98%, 80%, respectively.

    View this table:
    Table 2

    Seroconversion of IgG anti- human papillomavirus (HPV) serotypes 6, 11, 16 and 18 at months 7 and 12 after vaccination

    Figure 1A–D shows the titres of these four anti-HPV antibodies in patients and controls at different time points. Significant increase in titres of anti-HPV to all the four serotypes was demonstrated in both the patients with SLE and healthy controls from baseline to month 7 and month 12 (p<0.001 in all).

    Figure 1
    Figure 1

    Antibody titres to human papillomavirus (HPV) serotypes 6, 11, 16 and 18 at baseline, month 7 and month 12 in patients with systemic lupus erythematosus (SLE) and normal controls of (A) anti-HPV type 6, (B) anti-HPV type 11, (C) anti-HPV type 16 and (D) anti-HPV type 18.

    Adverse events

    Table 3 shows the AEs reported by patients and controls within 12 months of the first dose of vaccination. The most common AE was erythema and pain at the injection site (5%) which was exclusively mild and subsided spontaneously after 1–2 days. Non-specific symptoms such as rash, nausea, headache, menstrual disturbance and upper respiratory tract infection were reported in a few participants. No significant difference in the frequency of AEs was observed between patients and controls. None of the participants had serious AEs that led to study withdrawal.

    View this table:
    Table 3

    Adverse events reported by study participants

    Changes in disease activity of patients with SLE and comparison with controls

    There were no significant changes in the titres of anti-dsDNA, anti-C1q, C3, C4, SLEDAI and PGA scores from baseline to months 2, 6 and 12 (table 4). There was one mild/moderate lupus flare at months 0–2, two mild/moderate lupus flares at months 3–6 and six mild/moderate lupus flares at months 7–12. Two patients with SLE had severe disease flares at months 7–12. All flares were treated with usual regimens. The causal relationship between the vaccination and the flares of SLE was unclear, but there were no withdrawals because of flares.

    View this table:
    Table 4

    Changes in C3, C4, anti-dsDNA, anti-C1q, SLEDAI and PGA in patients with SLE after GARDASIL vaccination

    The overall rate of disease flares of the patients with SLE was 0.22/patient/year. Fifty SLE controls matched for age and disease duration who did not participate in the study but were followed up in our clinics within the same study period were retrieved from our database for comparison. The mean age of these SLE controls was 26.6±4.4 years (p=0.31 vs patients with SLE participating in this study) and their disease duration was 7.5±3.5 years (p=0.26). There were 10 SLE flares (five mild/moderate and five severe) within the 12-month period. The rate of flare in these SLE controls was 0.20/patient/year, which was not significantly different from that of the SLE participants (p=0.81).

    Factors affecting the seroconversion rates and titres of anti-HPV

    Table 5 shows the seroconversion rates and anti-HPV titres at months 7 and 12 according to the use of immunosuppressive agents at baseline. No significant differences in the seroconversion rates between users and non-users of different medications were observed except for MMF (used in combination with low-dose prednisolone in all patients) which was associated with significantly lower seroconversion rates of HPV 6 and 18 at month 12. The anti-HPV titres achieved after vaccination were generally lower in users of immunosuppressive medications. In particular, the anti-HPV 16 titres at month 7 were significantly lower in users of prednisolone (p=0.04) and MMF (p=0.02) than in non-users. At month 12 the anti-HPV 6 and 18 titres were significantly lower in users of MMF (p=0.001 and p=0.04, respectively).

    View this table:
    Table 5

    Seroconversion rates and anti-HPV titres in patients with SLE at months 7 and 12 according to baseline immunosuppressive medications

    The antibody titres of HPV at months 7 and 12 did not correlate significantly with age at vaccination, SLE disease duration or daily doses of prednisolone, HCQ, AZA, CSA and Tac (data not shown). However, the baseline daily dose of MMF was inversely correlated with the anti-HPV 16 titre at month 7 (ρ=−0.37, p=0.02), the anti-HPV 6 titre at month 12 (ρ=−0.49, p=0.002) and the anti-HPV 18 titre at month 12 (ρ=−0.33, p=0.04).

    Discussion

    HPV is a major cause of cervical cancer.13 Up to 46% of women develop cervical HPV infection 3 years after initiation of sexual activity.14 HPV serotypes 6 and 11 are the commonest causes of anogenital warts while HPV serotypes 16 and 18 are associated with cervical and anogenital cancers as well as precancerous lesions.15 The quadrivalent HPV vaccine GARDASIL has been proved to be effective in reducing the incidence of HPV-related high-grade cervical lesions and anogenital disease in women aged 15–26 years.4 ,5 Extended observation up to 42 months showed that the efficacy of the vaccine in protecting against low-grade HPV-related lesions is sustained.16

    One concern of HPV vaccination in SLE is the lower potential of patients to generate protective anti-HPV antibodies because of concomitant immunosuppressive treatment. Case–control studies of influenza and pneumococcal vaccination have shown a similar or lower immunogenic potential of these vaccines in terms of rise in antibody titres or seroconversion rates in patients with SLE.17 This is in line with our finding that the seroconversion rates of anti-HPV in patients with SLE were lower than those of healthy controls but exceeded 79%. These rates were regarded as satisfactory, given the fact that a substantial proportion of patients were receiving immunosuppression at enrolment. We also showed that patients receiving immunosuppressive drugs, especially MMF combined with low-dose prednisolone, had lower anti-HPV titres after vaccination than those not receiving these drugs. However, as the intensity of immunosuppressive treatment correlated closely with SLE activity, the latter was not adjusted when the anti-HPV titres were compared between users and non-users of immunosuppressive agents. Moreover, the dosage of prednisolone received by patients was rather low and therefore a negative correlation could not be demonstrated between prednisolone dosage and anti-HPV titres after vaccination. Although there is still no evidence to show that a higher antibody titre would confer better protection against HPV infection, our results indicated that the optimal timing of vaccination for patients with SLE should not be during the stage of active disease that requires high doses of immunosuppressive medications for disease control.

    Another concern of vaccination in patients with SLE is disease reactivation that may be triggered by viral antigens or adjuvants contained in the vaccine. Isolated case reports of SLE onset or flares after influenza or hepatitis B vaccination have been found in the literature.18 However, case–control studies of influenza and pneumococcal vaccination in patients with SLE did not reveal an increase in clinical activity or flares after vaccination.17

    GARDASIL consists of L1 virus-like particle adjuvanted with amorphous aluminium hydroxyphosphate sulphate, which has been shown to be more immunogenic than other adjuvants such as aluminium hydroxide and aluminium phosphate (alum).19 Alum enhances antigen uptake and formation of inflammasomes by the dendritic cells, leading to increased production of proinflammatory cytokines.20 However, a postmarketing survey of 189 629 women who received GARDASIL vaccination did not report a significant increase in the incidence of 16 autoimmune diseases except Hashimoto's disease.21 Our study did not show a significant change in disease activity of patients with SLE up to 12 months after vaccination. The rate of disease flare was also no different from a group of SLE controls matched for age and disease duration who did not receive HPV vaccination. Our results are reassuring that GARDASIL is not associated with flares in patients with stable SLE.

    In clinical trials, solicited AEs and serious AEs following GARDASIL vaccination were similar in the vaccine and placebo groups of subjects.22 Headache was the most commonly reported AE in both groups (28.2% in the vaccine group vs 28.4% in the placebo group). Fever (13.0% vs 11.2%), nausea (6.7% vs 6.5%) and severe injection site reactions (2.2% vs 0.9%) were slightly more frequent in the vaccine recipients. The safety of GARDASIL has recently been summarised according to data reported to the voluntary national Vaccine Adverse Event Reporting System in the USA.23 Serious AEs comprised 6.2% of all reports. The six most frequently reported AEs were syncope, local site reaction, dizziness, nausea, headache and hypersensitivity reactions. Syncope and venous thromboembolism (90% of patients with known risk factors) was disproportionally reported. In our study, the commonest reported AE was injection site reaction which occurred in 5% of the participants. The reaction was mild, self-limiting and did not lead to study withdrawal. Headache and nausea were reported in 3% of participants. None of the studied subjects developed syncope, dizziness or venous thromboembolism after vaccination. Although direct comparison of the incidence of AEs across studies may not be appropriate, the data from our study suggest that GARDASIL vaccination was well tolerated in our local Chinese participants with SLE and healthy subjects.

    In summary, this is the first prospective study to test the immunogenicity and safety of a quadrivalent HPV vaccine in SLE. Our results indicate that the seroconversion rates of the antibodies to HPV exceed 93% in healthy controls and 76% in patients with SLE. The HPV vaccine did not lead to an increase in SLE disease activity or flares up to 12 months after vaccination. In patients with SLE the use of immunosuppressive agents, particularly low-dose prednisolone and MMF, was associated with lower immunogenicity of the vaccine. We conclude that the quadrivalent HPV vaccine is safe and reasonably efficacious in patients with stable SLE and controls. Further studies with a larger sample size are necessary to confirm our findings.

    References

    1. ↵
      1. Carter JR,
      2. Ding Z,
      3. Rose BR
      . HPV infection and cervical disease: a review. Aust N Z J Obstet Gynaecol 2011;51:103–8.
      OpenUrlCrossRefPubMed
    2. ↵
      1. Tam LS,
      2. Chan AY,
      3. Chan PK,
      4. et al
      . Increased prevalence of squamous intraepithelial lesions in systemic lupus erythematosus: association with human papillomavirus infection. Arthritis Rheum 2004;50:3619–25.
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      1. Tam LS,
      2. Chan PK,
      3. Ho SC,
      4. et al
      . Natural history of cervical papilloma virus infection in systemic lupus erythematosus: a prospective cohort study. J Rheumatol 2010;37:330–40.
      OpenUrlAbstract/FREE Full Text
    4. ↵
      1. Garland SM,
      2. Hernandez-Avila M,
      3. Wheeler CM,
      4. et al
      .; Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007;356:1928–43.
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915–27.
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      1. Block SL,
      2. Nolan T,
      3. Sattler C,
      4. et al
      .; Protocol 016 Study Group. Comparison of the immunogenicity and reactogenicity of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in male and female adolescents and young adult women. Pediatrics 2006;118:2135–45.
      OpenUrlAbstract/FREE Full Text
    7. ↵
      1. Muñoz N,
      2. Manalastas R Jr.,
      3. Pitisuttithum P,
      4. et al
      . Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24-45 years: a randomised, double-blind trial. Lancet 2009;373:1949–57.
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      1. Levin MJ,
      2. Moscicki AB,
      3. Song LY,
      4. et al
      .; IMPAACT P1047 Protocol Team. Safety and immunogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine in HIV-infected children 7 to 12 years old. J Acquir Immune Defic Syndr 2010;55:197–204.
      OpenUrlCrossRefPubMed
    9. ↵
      1. Tan EM,
      2. Cohen AS,
      3. Fries JF,
      4. et al
      . The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7.
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      1. Opalka D,
      2. Lachman CE,
      3. MacMullen SA,
      4. et al
      . Simultaneous quantitation of antibodies to neutralizing epitopes on virus-like particles for human papillomavirus types 6, 11, 16, and 18 by a multiplexed luminex assay. Clin Diagn Lab Immunol 2003;10:108–15.
      OpenUrlCrossRefPubMed
    11. ↵
      1. Buyon JP,
      2. Petri MA,
      3. Kim MY,
      4. et al
      . The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Ann Intern Med 2005;142(12 Pt 1):953–62.
      OpenUrlCrossRefPubMedWeb of Science
    12. ↵
      1. Petri M,
      2. Hellmann D,
      3. Hochberg M
      . Validity and reliability of lupus activity measures in the routine clinic setting. J Rheumatol 1992;19:53–9.
      OpenUrlPubMedWeb of Science
    13. ↵
      1. Walboomers JM,
      2. Jacobs MV,
      3. Manos MM,
      4. et al
      . Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189: 12–19.
      OpenUrlCrossRefPubMedWeb of Science
    14. ↵
      1. Collins S,
      2. Mazloomzadeh S,
      3. Winter H,
      4. et al
      . High incidence of cervical human papillomavirus infection in women during their first sexual relationship. BJOG 2002;109:96–8.
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      1. Paavonen J
      . Human papillomavirus infection and the development of cervical cancer and related genital neoplasias. Int J Infect Dis 2007;11 Suppl 2:S3–9.
      OpenUrlCrossRefPubMed
    16. ↵
      FUTURE I/II Study GroupDillner J, Kjaer SK, et al. Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial. BMJ 2010;341:c3493.
      OpenUrlAbstract/FREE Full Text
    17. ↵
      1. Conti F,
      2. Rezai S,
      3. Valesini G
      . Vaccination and autoimmune rheumatic diseases. Autoimmun Rev 2008;8:124–8.
      OpenUrlCrossRefPubMedWeb of Science
    18. ↵
      1. Abu-Shakra M
      . Safety of vaccination of patients with systemic lupus erythematosus. Lupus 2009;18:1205–8.
      OpenUrlAbstract/FREE Full Text
    19. ↵
      1. Caulfield MJ,
      2. Shi L,
      3. Wang S,
      4. et al
      . Effect of alternative aluminum adjuvants on the absorption and immunogenicity of HPV16 L1 VLPs in mice. Hum Vaccin 2007;3:139–45.
      OpenUrlCrossRefPubMed
    20. ↵
      1. Eisenbarth SC,
      2. Colegio OR,
      3. O'Connor W,
      4. et al
      . Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 2008;453:1122–6.
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      1. Chao C,
      2. Klein NP,
      3. Velicer CM,
      4. et al
      . Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine. J Intern Med 2012;271:193–203.
      OpenUrlCrossRefPubMed
    22. ↵
      Food and Drug Administration. Gardasil (human papillomavirus quadrivalent (types 6, 11, 16, 18) vaccine, recombinant): product information and supporting documents. http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm094042.htm (accessed 27 Dec 2011).
    23. ↵
      1. Slade BA,
      2. Leidel L,
      3. Vellozzi C,
      4. et al
      . Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA 2009;302:750–7.
      OpenUrlCrossRefPubMedWeb of Science

    Footnotes

    • Funding Merck, Sharp & Dohme (MSD) Ltd Asia.

    • Competing interests This investigator-initiated study supported by MSD (Asia) provided the investigators with samples of GARDASIL for the participants and performed assays of the anti-HPV antibodies at the central Merck laboratory in the USA. MSD was not involved in the design and conduct of the study. The principal investigator is independent of the sponsoring drug company in the data analysis. He has full access to all of the data and takes responsibility for the integrity of the data and the accuracy of the data analysis. None of the authors has any financial interests in the sponsoring drug company.

    • Patient consent Obtained.

    • Ethics approval The protocol was approved by the Research and Ethics Committee of Tuen Mun Hospital and registered in the US ClinicalTrials.gov (number NCT00911521).

    • Provenance and peer review Not commissioned; externally peer reviewed.