Cervical cancer is the third most common cancer in women and the fourth most common cause of death worldwide.1 Infection with certain types of human papillomavirus (HPV) is necessary to develop cervical cancer.2–4 This has led to an increase in effectiveness of screening for cervical cancer using Pap smears and the development of primary prevention through the use of prophylactic vaccines against HPV.5–11

The prophylactic vaccine stimulates the development of the humoral immune response, which occurs after contact with the “virus-like particles” (VLPs), which are non-infectious structures and simulate a natural HPV infection. The two oncogenic types included in both vaccines are HPV 16 and 18, responsible for at least 70% of the cases of cervical cancer worldwide. In the case of the quadrivalent vaccine, it also included two non-oncogenic types of HPV, 6 and 11, responsible for approximately 90% of cases of anogenital condylomata acuminata.12

Safety and tolerability of both vaccines have been evaluated extensively with similar profiles in the vaccinated and control groups, irrespective of age or ethnicity.1 Studies about safety assessment indicated that local and systemic injection-related symptoms were generally mild. Serious adverse effects (AE) that are considered to be vaccine related are rare and similar to other vaccine types.13,14

Studies indicate that the most common AE is injection-related local reaction, such as pain, swelling and erythema with a rate of 95% of light to moderate intensity.15,16 Regarding systemic symptoms, fever, nausea, vomiting, dizziness, myalgia and diarrhea were reported.15,17,18 Severe AE, such as severe headache with hypertension, gastroenteritis and bronchospasm, were described in 0.5%.15 There are more data available of AE associated with the quadrivalent vaccine than the bivalent vaccine; however, the major AE for the latter vaccine is also in the injection-related local pain (78%).15

Both HPV vaccines are classified as Pregnancy Category B by the FDA. Therefore, the vaccine is not recommended for pregnant women, because there are not enough data to ensure safety to the fetus.19,20

Studies have also demonstrated efficacy and safety of the vaccine in heterosexual and homosexual men.21 This is important as HPV also causes disease in men.

The safety profiles of HPV vaccines have been confirmed by their huge use worldwide, and they has been included in immunization schedules of 28 countries. So far, there has not been any absolute contraindication for the use of these vaccines.15 The vaccines are well tolerated and the number of systemic AE, serious AE, and discontinuations due to a serious event are similar between the two vaccines and control groups.19

The purpose of this study was to evaluate safety and AE of HPV vaccines.

This study adhered to PRISMA guidelines.22 As a secondary study, no Institutional Review Board approval was required.

Search and selection of literature

The studies were identified by a wide literature search of databases (PubMed, Embase, Scielo and Cancerlit) following medical subject heading terms and/or text words: (vaccines OR vaccination) AND (randomized controlled trial) OR (controlled clinical trial) OR (randomized controlled trials) OR (random location) OR (double blind method) OR (single blind method) OR (clinical trial) AND (Human papillomavirus) OR (HPV) OR (papilloma virus) OR (papillomavir*). Reference lists of the identified publications for additional pertinent studies were reviewed. No language restrictions were imposed. Three researchers (AGM, HMR and RNC) searched for articles published up to March 2013.

Study identification and selection is illustrated in the flow diagram in Fig. 1. After searching the databases, 2494 potentially relevant papers were identified, of which 2426 were excluded: 2267 after reviewing the title, and 159 after reviewing the abstract. Reviews were done by AGM, HMR, and RNC; disagreements were solved by a fourth reviewer (AKG). Thus, 68 papers met the criteria and were reviewed in full. There were no articles in languages other than English, which, based on the abstract review, met the inclusion criteria. After full review, 46 papers were not considered to have adequate methodological quality according to the Jadad Scale.23 Finally, nine repeated studies were found (they were present in two databases at the same time), and two studies that used the same group, showing the same results (in this case, only the first publication was included). Finally, 12 papers were approved for data extraction (Fig. 1).

Fig. 1.

Inclusion and exclusion of trials in study selection. RCTs, randomized controlled trials.

(0.17MB).

Twelve reports of HPV vaccine safety and AE involving 29,540 subjects were included. The design features of the clinical trials to assess safety of the chosen HPV vaccines are indicated in Table 1. Eight studies17,18,25–30 evaluated HPV 16/18 vaccines, including 23,085 subjects; two studies18,30 approved for systematic review were not included in the meta-analysis as they did not compare data from experimental and control groups. Four studies16,31–33 including 6455 subjects evaluated HPV 6/11/16/18 vaccine (Table 1).

Tables 2 and 3 show a summary of the main AE. The most common AE seen with HPV 16/18 vaccine were, in this sequence: pain, fatigue, redness, swelling, fever, GI symptoms (diarrhea, nausea, vomiting), headache, myalgia and arthralgia. The global Odds Ratios (M-H, Fixed, 95% CI – calculated after meta-analysis) compared to their respective control groups are shown in Table 2. Three studies17,25,27 separated their results as general symptoms and injection-site symptoms; each was analyzed separately. The injection-site events most related to the bivalent vaccine were pain (OR 3.29; 95% CI: 3.00–3.60), swelling (OR 3.14; 95% CI: 2.79–3.53), and redness (OR 2.41; 95% CI: 2.17–2.68). GI symptoms and general symptoms did not appear to be vaccine related (OR 1.13; 95% CI: 1.00–1.28 and OR 1.07; 95% CI: 0.82–1.41 respectively) (Table 2 and Figs. 2 and 3).

Fig. 2.

Meta-analysis of HPV 16/18 vaccines’ side effects (part one).

(0.87MB).

Fig. 3.

Meta-analysis of HPV 16/18 vaccine side effects (part two).

(0.93MB).

With the HPV 6/11/16/18 vaccine, fewer AE were reported because only four papers were ultimately approved. AE were general symptoms, pain, and swelling (Table 2). Again, general symptoms did not appear to be vaccine related. Pain and swelling, however, were vaccine related: OR 2.88; 95% CI: 2.42–3.43 and OR 2.65; 95% CI: 2.0–3.44, respectively (Table 2 and Fig. 4).

Fig. 4.

Meta-analysis of HPV 6/11/16/18 vaccine side effects.

(0.52MB).

It was possible to perform a meta-analysis comparing HPV 6/11/16/18 and HPV 16/18 vaccines. The statistical method was again Odds Ratio (M-H, Fixed, 95% CI) considering HPV 6/11/16/18 vaccine as control group and HPV 16/18 as experimental group. Thus, HPV 6/11/16/18 vaccine appears to be less associated with swelling, fever, and general symptoms than the HPV 16/18 (Table 3). Fever was not associated to any of the vaccines.

Administration of HPV vaccine has been well tolerated in different groups. The proportion of subjects reporting AE or discontinuing due to an AE is low and similar for the two vaccines.

Occurrence of AE was reported in all randomized control trials.16–18,25–33 As anticipated, the most commonly reported AE were injection-site reactions16–18,25–33; most of these AE were mild or moderate in intensity. These AE were more common among those who received HPV vaccines when compared with placebo subjects. Headache and fatigue were the most common vaccine-related systemic AE seen in approximately 50–60% of all participants.25–30 On the other hand, most of these AE were mild or moderate in intensity.16–18,25–33 Similarly to another study,34 serious vaccine related AE were not significantly different, and there were no registered vaccine related deaths in all studies.16–18,25–34

On the other hand, a very recent systematic review also reported barriers to preventive human papillomavirus vaccination among adolescent girls and young women: 21 barriers to vaccination were identified. Cost was the most frequently reported barrier, followed by beliefs that vaccination was unnecessary, and concerns regarding vaccine safety and side effects.35

Recently an interesting cohort study conducted in Denmark and Sweden identified no safety signals with respect to autoimmune, neurological and venous thromboembolic adverse events after immunization of adolescent girls with quadrivalent human papillomavirus vaccine. In this multicenter study, 997,585 girls aged 10–17 were approached from whom 296,826 received a total of 696,420 quadrivalent HPV (qHPV) vaccine doses. In this research, incident hospital diagnosed autoimmune, neurological or venous thromboembolic events (53 different outcomes) up to 180 days after each qHPV vaccine dose was observed. There was no association between exposure to qHPV vaccine and venous thromboembolism (RR 0.86; 95% CI 0.55–1.36). Regarding neurological events, the relative risk for five occurrences were not significantly increased, and there were inverse associations with epilepsy (RR 0.66; 95% CI 0.54–0.80) and paralysis (RR 0.56; 95% CI 0.35–0.90). However, with respect to autoimmune events exposure to qHPV vaccine was significantly associated with Behcet's syndrome (RR 3.37; 95% CI 1.05–10.80), Raynaud's disease (RR 1.67; 95 CI 1.14–2.44), and type 1 diabetes (RR 1.29; 95% CI 1.03–1.62). These findings corroborate those from a cohort study of 189,629 women in two managed care organizations in California, who found no safety signal when investigating the risk of 16 autoimmune events.15 That study did find an inverse association between exposure to qHPV vaccine and type 1 diabetes (RR 0.57; 95% CI 0.47–0.73), lending further support to the conclusion that the initial signal for type 1 diabetes that was seen in our study might be a false positive.36

Nevertheless, our results and the latter findings need to be confirmed in studies with longer follow-up time, validation of results, and data on time of onset of disease. Further monitoring of HPV vaccine safety is warranted in other populations where use and coverage have increased.

Despite these interesting data, there are several limitations to the evidence presented here. The heterogeneity of studies associated with methodological diversity would indicate that the studies suffer from different degrees of bias that prevented the conducting of a meta-analysis. Concerning AE, more studies evaluating both vaccines are still necessary.

Nonetheless, safety is not a major barrier to vaccination. The cost of vaccines is still the main limiting factor for their use in developing countries.

The authors declare no conflicts of interest.