HPV Vaccine (Human Papillomavirus)

1. Basic Information

Diseases Protected Against

Human Papillomavirus (HPV) is the most common sexually transmitted infection globally. There are more than 200 HPV genotypes, of which approximately 40 infect the anogenital tract. Persistent infection with high-risk (oncogenic) HPV types is a necessary cause of cervical cancer and is associated with a proportion of vulvar, vaginal, penile, anal, and oropharyngeal (throat) cancers. Low-risk HPV types (principally types 6 and 11) cause over 90% of anogenital warts and nearly all cases of recurrent respiratory papillomatosis (RRP).

Source: IARC Monographs; CDC Pink Book (HPV chapter); Saraiya et al. (2015) J Natl Cancer Inst.

CDC Recommended Schedule (United States, 2025)

Source: CDC ACIP, 2025 Child & Adolescent and Adult Immunization Schedules. Note: The U.S. schedule has evolved — universal vaccination was initially recommended for females (2006), extended to males (2011), and the age-9–14 2-dose schedule was adopted in 2016 following evidence of non-inferior immunogenicity.

Licensed Products (U.S.)

• Gardasil^® 9 (Merck & Co.) — Licensed December 2014. The only HPV vaccine currently distributed in the United States. Non-infectious recombinant virus-like particle (VLP) vaccine targeting 9 HPV types: 6, 11, 16, 18, 31, 33, 45, 52, and 58. Produced in Saccharomyces cerevisiae (yeast). Adjuvanted with amorphous aluminum hydroxyphosphate sulfate (AAHS).
• Gardasil^® (Merck & Co., quadrivalent) — Licensed June 2006. Targeted HPV types 6, 11, 16, and 18. Voluntarily withdrawn from the U.S. market in 2016 after Gardasil 9 became the predominant product. Safety data from Gardasil remain relevant given the same manufacturing platform and overlapping antigens.
• Cervarix^® (GlaxoSmithKline, bivalent) — Licensed October 2009. Targeted HPV types 16 and 18. Adjuvanted with AS04 (aluminum hydroxide + monophosphoryl lipid A). Withdrawn from the U.S. market in 2016 due to low demand but remains available in many other countries. Included where safety data are informative.

2. Pre-Licensure Clinical Trial Data

Gardasil^® (Quadrivalent) — Pivotal Trials (Licensed 2006)

Gardasil was evaluated in four placebo-controlled Phase 2 and Phase 3 trials (FUTURE I, FUTURE II, and two immunogenicity bridging studies). The combined safety population included approximately ~21,500 participants who received at least one dose of Gardasil (females aged 9–45; males aged 9–26). ~13,700 received Gardasil in the placebo-controlled efficacy populations. The pivotal trials used an aluminum-adjuvant-containing placebo (AAHS) rather than saline. This was intended to preserve blinding given the vaccine's high reactogenicity, but the FDA noted that this design choice may reduce the ability to detect adjuvant-attributable adverse events.

Gardasil^® 9 (9-valent) — Pivotal Trial for U.S. Licensure (2014)

Gardasil 9 was evaluated in a single pivotal Phase 3 trial (Protocol V503-001) that compared Gardasil 9 to Gardasil quadrivalent. A total of ~14,215 participants received at least one dose of Gardasil 9 (females aged 16–26) and ~7,100 received Gardasil quadrivalent. Additional immunogenicity bridging studies were conducted in males, younger children (ages 9–15), and older women.

• Total Gardasil 9 recipients in safety population: ~15,873 across all clinical trials (including bridging studies); primary efficacy trial: ~14,215 females aged 16–26
• All trials combined (pre-licensure): >31,000 participants received any HPV vaccine across the Gardasil/Gardasil 9 development program
• Safety follow-up: Solicited AEs for 7–15 days; unsolicited AEs for 1 month; SAEs and deaths monitored for the entire study period (~4 years); pregnancy outcomes collected from pregnancies occurring during the trial
• Efficacy for HPV 31/33/45/52/58-related disease: ~96.7% reduction in CIN2/3+, AIS, or cervical cancer compared to Gardasil quadrivalent
• Immunogenicity (9–15-year-olds): Anti-HPV GMTs were non-inferior (and higher) compared to those in the 16–26-year-old efficacy population, supporting immunobridging for the younger age group indication

Most Common Adverse Reactions (Pre-Licensure Trials)

Sources: Gardasil 9 and Gardasil prescribing information; FDA clinical review documents. Note: The high rate of injection site pain (>80%) is characteristic of this vaccine. The placebo used contained the same aluminum adjuvant (AAHS), so the incremental reactogenicity attributable to the VLPs specifically is more modest than the absolute rates. Syncope occurred at similar rates across groups; the association is with the injection procedure (vasovagal response) rather than vaccine content.

Key Limitations of Pre-Licensure Trial Data

• Placebo composition: Pivotal trials used an aluminum-adjuvant-containing placebo rather than saline. The FDA noted that this may reduce the ability to detect adjuvant-attributable safety signals, as both groups received the same adjuvant.
• Age group representation: The large Phase 3 efficacy trial was conducted in females aged 16–26. Safety and immunogenicity in ages 9–15 were established through smaller bridging studies (~2,500 Gardasil 9 recipients) with limited duration of safety follow-up.
• Exclusion criteria: Trials excluded pregnant individuals, immunocompromised persons, and those with significant chronic medical conditions. Pregnancy outcomes data derive from incidental pregnancies during the trial (~1,000–2,000 pregnancies per product).
• Rare adverse events: Despite a large pre-licensure database (>31,000 participants), trials were not powered to detect rare autoimmune or neurological events (<1 per 10,000 doses). These outcomes have been the focus of post-licensure surveillance.
• Male efficacy data: Initial Gardasil 9 licensure in males was based on immunobridging rather than direct efficacy data. Gardasil quadrivalent efficacy data in males (for genital warts and anal intraepithelial neoplasia) combined with Gardasil 9 immunogenicity data supported the male indication.
• Limited long-term safety follow-up: While Nordic extension studies provided up to 14 years of follow-up for Gardasil, the primary safety analyses were based on ~3–4 years. Long-term autoimmune outcomes with longer latency would not be detected in the pre-licensure data.

3. Post-Licensure Safety Data

Vaccine Safety Datalink (VSD)

The VSD has conducted active surveillance on HPV vaccine safety since 2006. The population under surveillance includes approximately 9–10 million people annually (~3% of the U.S. population). VSD uses rapid cycle analyses (near-real-time surveillance) and retrospective cohort and self-controlled case series designs.

• Key VSD findings for HPV vaccine:
  • Syncope (fainting): Consistently identified at an elevated rate in adolescents post-HPV vaccination. This is a vasovagal response to injection (not vaccine-specific). ACIP recommends 15-minute post-vaccination observation. Rates are comparable to other adolescent vaccines (MCV4, Tdap).
  • Anaphylaxis: Estimated at ~1–3 per million doses, consistent with other vaccines.
  • Autoimmune conditions: A comprehensive VSD study by Gee et al. (2023) covering >1.2 million HPV vaccine doses evaluated 16 pre-specified autoimmune outcomes and found no statistically significant increased risk for any of them, including rheumatoid arthritis, SLE, type 1 diabetes, thyroiditis, MS, optic neuritis, ITP, and GBS.
  • Venous Thromboembolism (VTE): An initial VSD signal (Yih et al., 2016) was evaluated in a larger subsequent study (Naleway et al., 2022; >650,000 doses) using both self-controlled risk-interval and historical comparison methods. The larger study found no elevated VTE risk. The initial signal was not confirmed.
  • Primary Ovarian Insufficiency (POI): A VSD study (Naleway et al., 2018; ~200,000 females) found 1 confirmed POI case among 58,781 vaccinated females vs. 3 cases among 140,328 unvaccinated females. No elevated risk (RR 0.8; 95% CI 0.04–7.8). A subsequent CDC-funded study (2021) also found no association.
  • Guillain-Barré Syndrome (GBS): VSD analyses have not identified a statistically significant increased risk.

Sources: Gee et al. (2023); Naleway et al. (2018, 2022); Yih et al. (2016); Klein et al. (VSD annual surveillance).

VAERS (Vaccine Adverse Event Reporting System)

VAERS is a passive (spontaneous) reporting system co-managed by the CDC and FDA. VAERS cannot establish causation. HPV vaccine safety data span nearly 20 years. The HPV vaccine has been the subject of substantial public attention, which can influence VAERS reporting patterns through stimulated/heightened reporting.

Major Independent Post-Licensure Reviews

The Japan HPV Vaccine Suspension (2013–2021)

Japan's experience is a significant case study in vaccine safety signal management. After media reports described girls developing chronic pain, motor impairment, and other symptoms temporally associated with HPV vaccination, Japan's MHLW suspended proactive government recommendation in June 2013. The vaccine remained available and on the national schedule, but without active government endorsement. Key findings from the suspension period:

• Nagoya City study (Suzuki & Hosono, 2018): Survey of N=29,846 girls aged 12–23. Among 24 pre-specified symptoms evaluated (chronic fatigue, headache, joint pain, motor impairment, etc.), no statistically significant difference in prevalence was found between vaccinated and unvaccinated girls.
• MHLW Expert Committee analyses (2015–2021): National health insurance claims data and hospital-based surveys did not identify a consistent or replicated pattern of symptoms attributable to HPV vaccination.
• NIID surveillance: No evidence of an increase in the incidence of the described symptom constellation above expected background rates in adolescent females.

Japan resumed proactive recommendation in November 2021 after an 8.5-year suspension. Modelling studies published in The Lancet Public Health (Simms et al., 2020) estimate that the suspension may result in thousands of preventable cervical cancer cases and deaths in Japan. This episode is noted because it represents the most significant regulatory action related to HPV vaccine safety in a high-income country and remains frequently cited in discussions of HPV vaccine safety.

Confirmed Safety Signals Identified in Post-Licensure Data

• Syncope (vasovagal episodes): Elevated rate in adolescents post-vaccination. Vasovagal response to injection procedure, not vaccine-specific. ACIP recommends 15-minute observation.
• Anaphylaxis: ~1–3 per million doses. Consistent with other vaccines.
• Injection site reactions (higher with Gardasil 9 vs. quadrivalent): Gardasil 9 has a higher antigen and adjuvant load and produces higher rates of local reactions. Clinical trial data consistently show this difference.

Note: Safety "signals" identified through post-licensure surveillance require further analytical epidemiological studies to confirm or refute causality. Signals may later be determined to be coincidental.

4. Documented Adverse Events — Evidence of Association

▶ Adverse Events with Strong Evidence of Causal Association

Criteria: Consistent epidemiological data from multiple independent studies, supported by mechanistic plausibility, and reviewed by IOM / WHO GACVS or equivalent authoritative body.

• Injection site reactions (pain, swelling, erythema): Occurring at high rates (~80–90% for pain, ~30–45% for swelling). Gardasil 9 produces higher rates than Gardasil quadrivalent, attributable to higher antigen/adjuvant load. Generally mild-to-moderate and self-limited (1–5 days). Strong
• Syncope (vasovagal episodes): Occurs in adolescents at ~0.1–0.3 per 1,000 doses. Attributable to injection procedure (not vaccine antigen-specific). Comparable to rates with other adolescent vaccines. Risk mitigated by seated administration and 15-minute observation. Strong
• Anaphylaxis: Estimated at ~1–3 per million doses. Contraindication for individuals with known severe allergic reaction to yeast (S. cerevisiae) or a prior dose. Strong
• Systemic reactions (headache, fatigue, myalgia, fever, nausea, dizziness): Reported at rates slightly above placebo in clinical trials. Generally mild-to-moderate and self-limited (1–3 days). Strong

▶ Adverse Events with Moderate or Preliminary Evidence

Criteria: Some epidemiological evidence consistent with a signal, but data are limited by sample size, inconsistent findings across studies, or insufficient mechanistic evidence.

• Venous Thromboembolism (VTE): Initial VSD signal (Yih et al., 2016) was not confirmed in a larger subsequent analysis (Naleway et al., 2022; >650,000 doses). IOM (2012) favored rejection of causality. Evidence trends against association, but active surveillance continues given the initial signal. Moderate (against association)
• Guillain-Barré Syndrome (GBS): Isolated case reports; VSD rapid cycle analyses have not identified statistically significant increased risk. IOM (2012) deemed evidence inadequate to accept or reject causality. Limited
• Postural Orthostatic Tachycardia Syndrome (POTS): A 2017 Danish study reported a possible association, but methodological critiques (diagnostic verification, confounding) limit interpretation. A larger Danish study (Hviid et al., 2021; >1.3 million females) using validated hospital diagnoses found no association (HR 0.86; 95% CI 0.54–1.36). EMA (2015) and WHO GACVS have not confirmed a causal association. Preliminary (trending against association)
• Complex Regional Pain Syndrome (CRPS): Case reports and advocacy campaigns describe CRPS after HPV vaccination. EMA (2015) found no evidence of a causal relationship. VSD data do not show a signal. Limited

▶ Published Evidence Does Not Support a Causal Association

Criteria: Multiple large, well-controlled epidemiological studies have consistently failed to find an association; IOM / GACVS has rejected a causal relationship; or the preponderance of high-quality evidence is against an association.

• Autoimmune diseases collectively: The comprehensive VSD study by Gee et al. (2023; >1.2 million HPV vaccine doses) evaluated 16 pre-specified autoimmune outcomes (including RA, SLE, ITP, AIHA, type 1 diabetes, thyroiditis, MS, optic neuritis) and found no statistically significant increased risk for any outcome. WHO GACVS has affirmed the absence of an autoimmune safety signal. No Association
• Multiple Sclerosis (MS) and CNS demyelinating disorders: A combined Danish/Swedish registry study (Scheller et al., 2015; N ~ 4 million females) found no increased risk of MS (RR 0.90; 95% CI 0.70–1.15). Multiple other large studies are consistent. No Association
• Primary Ovarian Insufficiency (POI): VSD data (Naleway et al., 2018) and a subsequent CDC-funded study found no association. No Association
• Chronic Fatigue Syndrome / ME: A Norwegian registry study (Feiring et al., 2017; >1.7 million girls) found no increased risk of CFS/ME following HPV vaccination. No Association
• Type 1 Diabetes Mellitus: Multiple large cohort and registry-based studies have not identified an association. No Association
• Pregnancy outcomes (miscarriage, stillbirth, congenital anomalies): Multiple studies, including a large Danish registry study (Scheller et al., 2017; >73,000 pregnancies), have not found increased risk of adverse pregnancy outcomes in women vaccinated prior to or during pregnancy (though HPV vaccine is not recommended during pregnancy). No Association

5. Disease Prevention Benefits

5a. Pre-Vaccine vs. Post-Vaccine Era Data (United States)

Because HPV vaccination was introduced relatively recently (2006), long-term cancer incidence data in vaccinated cohorts are still emerging. However, early indicators of impact are available from multiple countries with established vaccination programs.

Sources: NHANES (CDC); Brotherton et al. (Australia); Lei et al. (2020, N Engl J Med); Falcaro et al. (2021, The Lancet).

5b. Current Disease Burden (United States)

• HPV infections: An estimated 42 million persons in the U.S. are currently infected with HPV, and approximately 13 million persons acquire a new HPV infection annually. Most infections are asymptomatic and cleared spontaneously by the immune system within 1–2 years.
• Cervical cancer: Approximately 13,800 new cases of invasive cervical cancer and ~4,300 deaths annually in the U.S. (2024 estimates). Cervical cancer incidence has declined substantially in the U.S. since the introduction of Pap screening (1950s), but the decline attributable to vaccination specifically is expected to accelerate as vaccinated cohorts age.
• Other HPV-related cancers: HPV causes an estimated 37,000 cancers annually in the U.S. across all anatomic sites, including ~12,000 oropharyngeal cancers (now the leading HPV-related cancer in the U.S., predominantly in men), ~7,000 anal cancers, and smaller numbers of vulvar, vaginal, and penile cancers.
• Genital warts: Incidence has declined substantially in young women and men in countries with established vaccination programs. In the U.S., declines have been observed in private insurance claims data and STI clinic surveillance.
• RRP (Recurrent Respiratory Papillomatosis): Rare condition (~0.5–2 per 100,000 in children; lower in adults). Australian and U.S. data suggest declining incidence in children born to vaccinated mothers (juvenile-onset RRP), consistent with reduced maternal HPV 6/11 prevalence.

5c. Real-World Effectiveness Data

• Scotland (Palmer et al., 2019): Routine vaccination of girls aged 12–13 with the bivalent (Cervarix) vaccine achieved an 89% reduction in CIN3+ at age 20 compared to unvaccinated women (2019, BMJ). This was the first demonstration of a near-complete elimination of cervical pre-cancer in a routinely vaccinated population.
• Denmark (Kjaer et al., 2021): Nationwide cohort study evaluating quadrivalent HPV vaccine effectiveness. Vaccination before age 17 was associated with an 86% reduction in high-grade cervical lesions compared to unvaccinated women.
• Herd protection: Multiple countries (Australia, Denmark, U.S.) have documented substantial declines in genital warts and vaccine-type HPV prevalence in unvaccinated males following female-only vaccination programs, demonstrating herd effects.
• U.S. HPV vaccination coverage (2023): Approximately 76% of adolescents aged 13–17 years have received at least one dose of HPV vaccine, and ~62% are up-to-date with the recommended series. Coverage remains below the Healthy People 2030 goal of 80% series completion.

Sources: Palmer et al. (2019) BMJ; Kjaer et al. (2021); CDC National Immunization Survey — Teen (NIS-Teen, 2023).

6. Evidence Summary — Overall Assessment

Quality and Quantity of Safety Data

The HPV vaccine has been in widespread use for nearly 20 years, with >270 million doses administered globally. The evidence base includes:

• Pre-licensure clinical trials involving >31,000 participants across the Gardasil/Gardasil 9 development programs — among the largest pre-licensure safety databases for any vaccine.
• Active surveillance through VSD spanning ~9–10 million persons annually with >17 years of continuous monitoring, including near-real-time rapid cycle analyses.
• Passive surveillance (VAERS) with ~60,000–70,000 reports over ~19 years.
• Registry-based cohort studies from Denmark, Sweden, Norway, and other Nordic countries with near-complete population coverage and >10 years of follow-up (>10 million person-years of data cumulatively).
• Independent reviews by IOM (2012), Cochrane Collaboration (2018), WHO GACVS (ongoing), and EMA (2015).
• Real-world effectiveness data from national vaccination programs in Australia, Scotland, Denmark, Sweden, England, and the U.S. demonstrating reductions in HPV prevalence, genital warts, cervical pre-cancer, and invasive cervical cancer.

Areas Where Data Are Robust

• Effectiveness against vaccine-type HPV infection and cervical pre-cancer: Large, consistent datasets from clinical trials and multiple national real-world programs demonstrate 85–98% effectiveness in preventing vaccine-type HPV infections, genital warts, and CIN2+ lesions.
• Effectiveness against invasive cervical cancer: Swedish (Lei et al., 2020) and English (Falcaro et al., 2021) registry data now provide direct evidence of ~87–88% reduction in invasive cervical cancer in women vaccinated at ages 12–13.
• Syncope and anaphylaxis: Well-characterized adverse events with established risk estimates and management protocols.
• Absence of autoimmune disease association: Extensively studied in VSD (Gee et al., 2023, 16 outcomes) and multiple Nordic registry studies. The evidence against an autoimmune safety signal is robust and consistent.
• Absence of POI association: Multiple studies have not found an association; the evidence base is consistent and sourced from multiple independent datasets.
• Absence of adverse pregnancy outcomes: Large registry studies (Denmark, >73,000 pregnancies) have not identified increased risk of miscarriage, stillbirth, or congenital anomalies.

Areas Where Data Are Limited or Conflicting

• POTS and autonomic dysfunction: While the preponderance of evidence (EMA 2015 review, Hviid et al. 2021, GACVS) does not support a causal association, the diagnosis of POTS is clinically heterogeneous and challenging to validate in large epidemiological datasets. Case reports and advocacy narratives continue to generate discussion. The evidence base is sufficient to conclude no large or moderate increase in risk, but a very small increase (<1 per 100,000) cannot be ruled out with absolute certainty given the diagnostic and methodological challenges.
• Chronic fatigue and pain syndromes: These outcomes are difficult to study epidemiologically due to diagnostic imprecision, long latency, and lack of validated case definitions in electronic health records. Controlled studies have not identified consistent associations, but the limitations of the available data are acknowledged.
• Long-term (>20 years) safety and efficacy: The first cohorts vaccinated as adolescents (age 12–13) are now in their early 30s. Long-term follow-up beyond 20 years is still accumulating. Duration of protection, need for booster doses, and very-long-term safety data are not yet available.
• Safety in males: Safety databases in males are smaller than in females, as the initial licensure and large Phase 3 efficacy trials were conducted predominantly in females. Male safety data are derived from smaller bridging studies and post-licensure surveillance.
• Adjuvant-specific effects and the AAHS placebo issue: The pivotal trials used an aluminum-adjuvant-containing placebo, which was scientifically rational for blinding but limits the ability to detect adjuvant-attributable adverse events. The FDA acknowledged this limitation during review. Post-licensure data compensate for this to some degree, but the issue is inherent to the pre-licensure evidence base.
• Older age groups (27–45): Safety and efficacy data in women aged 27–45 are more limited than for adolescents. The benefit in this age group is likely lower due to prior HPV exposure.

Overall Summary Table

7. Key References

References are organised by category. Links are provided to the original source where available.

Pre-Licensure Trials / FDA Review Documents

1. Merck & Co., Inc. Gardasil^® 9 (Human Papillomavirus 9-valent Vaccine, Recombinant) — Prescribing Information. merck.com
2. Joura EA, Giuliano AR, Iversen OE, et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015;372(8):711–723. DOI: 10.1056/NEJMoa1405044
3. Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007;356(19):1928–1943. DOI: 10.1056/NEJMoa061760
4. FDA. Clinical Review — Gardasil 9 (BLA 125508), 2014. fda.gov/vaccines-blood-biologics/vaccines/gardasil-9

Systematic Reviews & Meta-Analyses

5. Arbyn M, Xu L, Simoens C, Martin-Hirsch PP. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database Syst Rev. 2018;5(5):CD009069. DOI: 10.1002/14651858.CD009069.pub3
6. Drolet M, Bénard E, Pérez N, et al. Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis. The Lancet. 2019;394(10197):497–509. DOI: 10.1016/S0140-6736(19)30298-3

Institute of Medicine / GACVS Reports

7. Institute of Medicine. Adverse Effects of Vaccines: Evidence and Causality. Washington, DC: The National Academies Press; 2012. nationalacademies.org
8. WHO Global Advisory Committee on Vaccine Safety (GACVS). Safety of HPV vaccines — multiple statements (2013–2023). who.int
9. European Medicines Agency. HPV vaccines: EMA confirms evidence does not support that they cause CRPS or POTS. November 2015. ema.europa.eu

Major Post-Licensure Safety Studies

10. Gee J, Weinbaum C, Sukumaran L, Markowitz LE. Quadrivalent HPV vaccine safety review and safety monitoring for nine-valent HPV vaccine in the United States. Pediatrics. 2023 (comprehensive VSD safety study, >1.2 million doses, 16 autoimmune outcomes).
11. Naleway AL, Mittendorf KF, Irving SA, et al. Primary ovarian insufficiency and adolescent vaccination. Pediatrics. 2018;142(3):e20180943. DOI: 10.1542/peds.2018-0943
12. Scheller NM, Svanström H, Pasternak B, et al. Quadrivalent HPV vaccination and risk of multiple sclerosis and other demyelinating diseases of the central nervous system. JAMA. 2015;313(1):54–61. DOI: 10.1001/jama.2014.16946
13. Hviid A, Thorsen NM, Frisch M, et al. Human papillomavirus vaccination and risk of postural orthostatic tachycardia syndrome. Clin Infect Dis. 2021 (Danish registry, >1.3 million females; HR 0.86 for POTS). DOI: 10.1093/cid/ciab855
14. Feiring B, Laake I, Bakken IJ, et al. HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis. Vaccine. 2017;35(33):4203–4210. DOI: 10.1016/j.vaccine.2017.06.040
15. Scheller NM, Pasternak B, Mølgaard-Nielsen D, et al. Quadrivalent HPV vaccination and the risk of adverse pregnancy outcomes. N Engl J Med. 2017;376(13):1223–1233. DOI: 10.1056/NEJMoa1612296

Real-World Effectiveness & Disease Burden

16. Lei J, Ploner A, Elfström KM, et al. HPV vaccination and the risk of invasive cervical cancer. N Engl J Med. 2020;383(14):1340–1348. DOI: 10.1056/NEJMoa1917338
17. Falcaro M, Castañon A, Ndlela B, et al. The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study. The Lancet. 2021;398(10316):2084–2092. DOI: 10.1016/S0140-6736(21)02178-4
18. Palmer T, Wallace L, Pollock KG, et al. Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12–13 in Scotland. BMJ. 2019;365:l1161. DOI: 10.1136/bmj.l1161
19. Suzuki S, Hosono A. No association between HPV vaccine and reported post-vaccination symptoms in Japanese young women: results of the Nagoya study. Papillomavirus Res. 2018;5:96–103. DOI: 10.1016/j.pvr.2018.02.002
20. Simms KT, Hanley SJB, Smith MA, et al. Impact of HPV vaccine hesitancy on cervical cancer in Japan: a modelling study. Lancet Public Health. 2020;5(4):e223–e234. DOI: 10.1016/S2468-2667(20)30010-4

Official Surveillance and Public Health References

21. CDC. Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book) — HPV chapter. cdc.gov/pinkbook
22. CDC. Vaccine Safety Datalink (VSD). cdc.gov/vaccine-safety/about/vsd.html
23. CDC/FDA. Vaccine Adverse Event Reporting System (VAERS). vaers.hhs.gov
24. CDC. 2025 Child & Adolescent Immunization Schedule. cdc.gov/vaccines/hcp/imz-schedules
25. CDC. HPV vaccination coverage data — National Immunization Survey — Teen (NIS-Teen). cdc.gov