What are the common and serious side effects of the human papillomavirus (HPV) vaccine?

HPV Vaccine Side Effects

The HPV vaccine has an excellent safety profile with primarily mild, self-limited injection site reactions being the most common side effects, while serious adverse events are rare and no causal associations have been established with autoimmune conditions, neurological disorders, or other serious systemic complications. 1, 2, 3

Common Side Effects

Local Injection Site Reactions

• Pain at injection site is the most frequent side effect, occurring in approximately 81% of vaccine recipients compared to 75% with aluminum-containing placebo 4
• Swelling occurs with increased frequency (OR 3.14 for bivalent vaccine, OR 2.65 for quadrivalent vaccine) 5
• Redness at injection site (OR 2.41 for bivalent vaccine) 5
• The 9-valent vaccine (9vHPV) shows slightly more injection site reactions than the quadrivalent vaccine, but remains within acceptable limits 3

Systemic Side Effects

• Headache is the most common systemic side effect, occurring in up to 50% of recipients, with similar rates in vaccine and placebo groups 6
• Fever occurs at similar rates between vaccine and placebo recipients 4
• Fatigue is commonly reported 5
• Gastrointestinal symptoms occur at baseline rates 5
• Dizziness 2

Syncope (Fainting)

Syncope is a recognized adverse event that requires specific management:

• Occurs most commonly in adolescents and young adults aged 10-18 years 1
• Was the second most common report to VAERS through January 2007 1
• Patients should be observed for 15 minutes after vaccination to prevent fall-related injuries 1
• This is a vasovagal reaction, not a direct vaccine toxicity 1

Serious Adverse Events

Overall Safety Profile

• 97.4% of VAERS reports after 9vHPV were non-serious 2
• Treatment-related serious adverse events occurred in only 0.05% of vaccine recipients versus 0.02% of placebo recipients 4
• Deaths occurred at identical rates (0.1%) in both vaccine and placebo groups, with all deaths considered unrelated to vaccination 4
• Crude reporting rate for serious adverse events: 7 per million doses distributed 2

Specific Conditions Evaluated and Found NOT Associated

Multiple large-scale studies have found NO causal association between HPV vaccination and:

• Autoimmune diseases 7, 3, 8
• Guillain-Barré syndrome 6, 3, 8
• Stroke 6
• Venous thromboembolism 6
• Seizures 6
• Anaphylaxis (minimal risk even in yeast-allergic individuals) 6
• Postural orthostatic tachycardia syndrome (POTS) 8
• Chronic fatigue syndrome/myalgic encephalomyelitis 8
• Complex regional pain syndrome 3, 8
• Premature ovarian failure 8
• Infertility 8
• Paralysis 8

Exploratory Finding Requiring Caution

• One systematic review reported increased serious nervous system disorders (RR 1.49,95% CI 1.02 to 2.16, NNH 1325) 9
• However, this was an exploratory analysis from trials not adequately designed to assess harms, and the finding has not been corroborated by large postlicensure surveillance studies 9, 3

Contraindications and Precautions

Absolute Contraindications

• History of immediate hypersensitivity to yeast (Saccharomyces cerevisiae) 1
• History of immediate hypersensitivity to any vaccine component 1

Pregnancy

• Vaccination should be delayed until after pregnancy completion 1
• If a dose is inadvertently given during pregnancy, no intervention is needed 1
• The vaccine has not been causally associated with adverse pregnancy outcomes 1
• Exposure during pregnancy should be reported to the pregnancy registry (800-986-8999) 1

Acute Illness

• Can be administered with minor acute illnesses (diarrhea, mild upper respiratory infections with or without fever) 1
• Defer vaccination in moderate to severe acute illness until improvement 1

Special Populations

• Immunocompromised individuals can receive the vaccine (it is non-infectious), though immune response may be reduced 1
• Lactating women can receive HPV vaccine 1

Postlicensure Surveillance Data

• Over 25 million doses distributed in the US and 50 million globally as of 2009 4
• VAERS received 14,072 reports for quadrivalent vaccine, with only 7% being serious adverse events—about half the average for licensed vaccines in general 4
• For 9vHPV vaccine, 7,244 reports were received through December 2017, with 97.4% non-serious 2
• The benefits of vaccination to prevent genital tract precancers and cancers far outweigh the risks 4

Key Clinical Pitfalls

• Failure to observe patients for 15 minutes post-vaccination increases risk of syncope-related injuries 1
• Unnecessarily withholding vaccine from immunocompromised patients—the vaccine is non-infectious and can be safely administered 1
• Confusing the need to delay vaccination during pregnancy with a contraindication to continuing the series postpartum 1
• Over-attributing non-specific symptoms to vaccination when population-based studies show no causal association 3, 8