SAFETY AND ADVERSE EVENTS OF PROPHYLACTIC HPV VACCINES AMONG HEALTHY WOMEN: A SYSTEMATIC REVIEW & META ANALYSIS

SAFETY AND ADVERSE EVENTS OF PROPHYLACTIC HPV VACCINES AMONG HEALTHY WOMEN: A SYSTEMATIC REVIEW & META ANALYSIS

1. C. Sangar *¹, B. B. Ghongane ¹, G. Mathur ² and A. S. Chowdhary ³
2. J. Govt. Medical College and Sassoon General Hospital ¹, Pune, Maharashtra, India

MSD Pharmaceuticals Private Limited ², Mumbai, Maharashtra, India

Haffkine Institute for Training ³, Research and Testing, Mumbai, Maharashtra, India

ABSTRACT:  Cervical cancer (CaCx) is the third most common female cancer worldwide with an estimated 5, 27, 624 new cases and 2, 65, 653 deaths in 2014. We conducted a systematic review and meta- analysis to assess safety of prophylactic HPV vaccines compared against placebo. Four unique trials were included out of 607 publications. The total patient data evaluated was 1427(852 in vaccinated arm; 575 in the placebo arm). The pain was the major local side effects with 61% followed by swelling 22% and redness 17% in the vaccinated arm and similarly in the placebo arm pain 72% followed by swelling 18% and redness 10%. Headache was the most frequently experienced systemic side effects 42% in vaccine and placebo group. Unsolicited adverse event in vaccinated and placebo group were 39% and 37% respectively. New onset chronic disease in vaccinated and placebo arm were 3% and 2% respectively. Serious adverse event were 3% in vaccinated and 2% in placebo group. Undesirable pregnancy outcomes were same for both vaccinated and placebo arm 3%. As we had limited studies funnelled through our stringent inclusion exclusion criteria we were not able to separate exclusive adverse event in age group 25-34 and 35-45 years of age. In future, it would be interesting if we have 3 arms for comparison vaccine, Al(OH)3 and saline placebo.

HPV vaccine, HPV2,

HPV4, Safety of HPV vaccine,

Meta-analysis

INTRODUCTION: Cervical cancer (CaCx) is the third most common female cancer worldwide with an estimated 5,27,624 new cases and 2,65,653 deaths in 2014.¹ About 86% of the cases occur in developing countries and may constitute up to 25% of all female cancers.^{2, 3} In India, cervical cancer is reported to be responsible for almost 20% of all female deaths and takes the lives of 8 women every hour.⁴ India recorded 122,844 new cases out of these cases 67,477 cases lost their lives. The age-standardized incidence and mortality rate of cervical cancer in India are 22.0 and 12.4 respectively.⁵

The necessary cause of cervical cancer is the HPV infection.⁶ Worldwide 70% of invasive cervical cancer cases are caused by Human Papillomavirus (HPV) 16 or 18 and 90% of genital warts are caused by HPV 6 and 11.⁷ Cervical cancer and other Human papillomavirus associated malignancies might be prevented by two human papillomavirus vaccines namely, Cervarix™- (HPV2) bivalent and Gardasil^®-(HPV4) quadrivalent.^{8, 9} Both HPV vaccines markedly differ in their composition and their adjuvants. These vaccines were approved by Indian regulatory authority in 2008 for use in females.¹⁰

In 2011, Lu et al., performed systematic review and meta-analysis to assess efficacy and safety of prophylactic HPV vaccines against cervical cancer precursor events in women when compared with placebo and Hepatitis vaccines. According to their results, prophylactic HPV vaccines are safe, well tolerated, and highly efficacious in preventing persistent infections and cervical diseases associated with vaccine-HPV types among young females.¹¹ However, in this study we have performed a systematic review with all unique randomized controlled trials in which HPV vaccines were compared against placebo only regarding local and general injection site symptoms.

 MATERIALS AND METHODS:

Identification of Studies:

A comprehensive search on MEDLINE, Cochrane Library and the Cochrane Central Register of Controlled Trials databases was made from June 1996 to November 2014 to identify reports of RCTs of prophylactic HPV vaccines, using a combination of index terms:” ("safety"[MeSH Terms] OR "safety"[All Fields]) AND ("papillomavirus vaccines"[MeSH Terms] OR ("papillomavirus"[All Fields] AND "vaccines"[All Fields]) OR "papillomavirus vaccines"[All Fields] OR ("human"[All Fields] and "papillomavirus"[All Fields] AND "vaccines"[All Fields]) OR "human papillomavirus vaccines"[All Fields]).

Selection Criteria (Inclusion and Exclusion Criteria):

This review focused on randomized, placebo-controlled, double-blind trials in which the vaccines against HPV were evaluated in healthy women. We chose 2 commercial available HPV vaccines that used L1 virus-like particle (L1- VLP): Human papillomavirus bivalent (Types 16 and 18) vaccine, recombinant, AS04 adjuvanted (Cervarix™/ HPV2, GlaxoSmithKline Biologicals) and Human papillomavirus quadrivalent (Types 6, 11, 16, 18) vaccine, recombinant (Gardasil^®/ HPV4, Merck & Co., Inc.,).

RCTs published in English of L1 VLP-based HPV vaccines were included. Articles reporting review article, male vaccination or therapeutic vaccination and trials including interventional HPV vaccines disease conditions were excluded. Additionally, we excluded ad hoc subgroup analyses of existing RCTs or combined analyses of multiple RCTs and policy, advocacy studies. We even excluded those studies whose follow up is more than 1 months after giving last dose of HPV vaccination, having alternative vaccination schedule and alternate route of vaccine administration.

 Outcome:

The primary objective was to evaluate HPV vaccine safety. The secondary outcome was to evaluate detailed classification of adverse events as local, systemic and severe effects.

 Data Extraction:

Data were extracted by three independent reviewers (VCS, BBG and GM) using a standardized data extraction form. Any discrepancies were resolved by consensus or in consultation with another reviewer. We extracted detailed information on trial design, inclusion/exclusion criteria, participant characteristics, vaccine and placebo administered, trial endpoints, efficacy populations, and methodological quality from all included trials.

 Data Synthesis and Statistical Analysis:

Effect sizes were summarized as Risk Ratios (RRs) and associated 95 percent confidence intervals. Heterogeneity between studies was assessed using the Tau ² statistics. All analyses were performed in Open Meta[analyst] 12/3/2013 statistical software following the PRISMA guidelines.

 RESULTS:

Selection of Studies:

Study identification and selection was demonstrated in the flow diagram in (Figure 1). Of 607 publications identified through an initial search of databases, 597 were excluded for reasons elaborated below. Then from total 10 potential studies only four unique RCTs met the eligibility criteria and were included in the current study.

FIG.1: INCLUSION AND EXCLUSION OF TRIALS IN STUDY SELECTION

Table 1: Characteristics of randomized controlled trials included in the review.

Table 2: Baseline Characteristics of randomized controlled trials participants.

 Characteristics of Included Trials and baseline characteristics of Trial Participants:

Characteristics of RCTs included in the current review are summarized in (Table 1). Unique trials were identified by first authors of associated publications. Three trials were multicentre trials with 1:1 randomization scheme except Kim et al., (2011) Korea trial where they used 2:1 randomization scheme. In all trials, HPV2vaccines

(20µg of HPV16 and 18) and controls (placebo) were administered in a three-dose regimen within a 6-month time frame.

Proprietary adjuvant was used with each type of vaccine to enhance immunogenicity. All trials used placebo (500 µg of aluminium as Al(OH)₃) as the comparator are summarized in (Table 2).

Assessment of Adverse Events: Adverse events (AEs) were monitored by the use of daily vaccination report cards within 15 or 30 days of injection, as well as solicitation throughout the study. Occurrence of AEs was reported in all RCTs. Adverse events were categorized into local side effects, systemic side effects, unsolicited adverse events, new onset of chronic disease, medically significant condition, serious side effect and impact on pregnancy outcome. Patients who had received 1 more dose of vaccines or placebo were included in the assessment of adverse events.

Local side effects:

Local side effects were evaluated were pain, redness and swelling. These effects were monitored for 1 month after each dose of vaccination. According to meta-analysis, major local side effects were measured in HPV vaccinated group were pain 773(85%) followed by swelling 274(30%) and redness 213(23%) while in control group major local side effects were pain 436(71%) followed by swelling 106 (17%) and redness 59(10%). Duration of local side effects were longer in vaccinated group as compared into placebo Fig. 2

Pain:

In vaccinated arm, percentage of people reporting pain was 85%(78-94%) while in control the frequency of pain was 71%(59-84%). Participants from Kim et al. (2011) study, experienced pain as major adverse events in both HPV vaccinated (94%) and placebo group (84%).

Redness:

In vaccinated arm, percentage of people reporting redness was 23%(0-73%) while in control the frequency of redness was 10%(0-46%). For this study parameters also participants from Kim et al. (2011) study, experienced pain as major adverse events in both HPV vaccinated (73%) and placebo group (46%).

Swelling:

In vaccinated arm, percentage of people reporting swelling was 30%(16-60%) while in control the frequency of redness was 17%(12-25%). For swelling study parameters participants from Kim et al. (2011) study, experienced swelling as major adverse events in both HPV vaccinated (60%) and placebo group (25%).

FIG. 2: ASSESSMENT OF LOCAL ADVERSE EVENTS (A) PAIN, (B) REDNESS AND (C) SWELLING.

Systemic side effects:

Systemic side effects evaluated were arthralgia, fatigue, fever, GI, headache, myalgia, rash and urticaria. Two most common adverse events were seen in both groups were headache and fatigue Fig.3

 Arthralgia:

For arthralgia as expected from previous studies, participants from vaccinated group 19%(11-29%) experienced higher adverse events than control group 13(9-19%). For this study parameters participants from Lim et al. (2014) study, experienced arthralgia as major adverse events in both HPV vaccinated (29%) and placebo group (19%).

Fatigue:

For fatigue, participants from vaccinated group 38%(25-69%) experienced higher adverse events than control group 34(19-51%). For this study parameters participants from Kim et al. (2011) study, experienced fatigue as major adverse events in both HPV vaccinated (69%) and placebo group (51%).

Fever:

In HPV vaccinated group 25% (5-33%) fever adverse event slightly higher than control group 22% (3-31%). Sow et al., (2012) study participants experienced higher adverse events in HPV vaccinated group (33%) than placebo group (31%).

 Gastrointestinal (GI) Systems:

In HPV vaccinated group 23% (13-35%) fever adverse event slightly higher than control group 19% (13-25%). For this parameter in Kim et al., (2011) study in HPV vaccinated group adverse event was 35% while for placebo adverse event was 25% in Sow et al., (2012) study participants.

Headache:

In HPV vaccinated and control group headache adverse event was found similar 42%. Kim et al., (2011) study in HPV vaccinated group adverse event was 49% while for placebo adverse event was 48% in Sow et al., (2012) study participants.

FIG.3: ASSESSMENT OF SYSTEMIC SIDE EFFECTS (A) ARTHRALGIA, (B) FATIGUE, (C) FEVER, (D) GI, (E) HEADACHE, (F) MYALGIA, (G) RASH AND (H) URTICARIAMYALGIA

In HPV vaccinated group 27% (6-65%) fever adverse event slightly higher than control group 18% (6-43%). For this parameter Kim et al., (2011) study participants experienced higher adverse events in HPV vaccinated group (65%) than placebo group (43%).

Rash:

In HPV vaccinated group 12% (3-19%) fever adverse event slightly higher than control group 9% (4-13%). For this parameter in Kim et al., (2011) study in HPV vaccinated group adverse event was 19% while for placebo adverse event was 13% in Sow et al., (2012) study participants.

Urticaria:

For urticarial, in HPV vaccinated group 10% (2-15%) fever adverse event slightly higher than control group 6% (1-12%). For this parameter Sow et al., (2012) study participants experienced higher adverse events in HPV vaccinated group (15%) than placebo group (12%).

FIG.4: ASSESSMENT OF UNSOLICITED ADVERSE EVENTS.

Unsolicited adverse events:

Unsolicited adverse event was observed higher in HPV vaccinated group 39% (11-54%) than control group 37% (15-65%). For this parameter Sow et al., (2012) study participants experienced lower adverse events in HPV vaccinated group (54%) than placebo group (65%) Fig.4

New onset of chronic disease:

In new onset of chronic disease parameter, control vaccinated group 3% (0-8%) adverse event slightly higher than vaccinated group 2% (0-3%). Kim et al., (2011) study participants experienced higher adverse events in placebo group (8%) than HPV vaccinated group (3%) Fig.5

FIG.5: ASSESSMENT OF NEW ONSET OF CHRONIC DISEASE.

 Medically significant condition:

Medically significant condition event was observed higher in HPV vaccinated group 38% (7-64%) than control group 33% (8-71%). Sow et al., (2012) study participants experienced higher adverse events in placebo group (71%) than HPV vaccinated group (64%) Fig.6

FIG.6: ASSESSMENT OF MEDICALLY SIGNIFICANT CONDITION.

 Serious adverse events (SAE):

In Serious adverse events (SAE), control vaccinated group 3% (1-4%) adverse event slightly higher than vaccinated group 2% (1-3%). Sow et al., (2012) study participants reported higher adverse events in placebo group (4%) than HPV vaccinated group (3%) Fig.7

FIG.7: ASSESSMENT OF SERIOUS ADVERSE EVENTS.

 Pregnancy outcome:

In HPV vaccinated and control group headache adverse event was found similar 2%. For this parameter Sow et al., (2012) study participants experienced higher adverse events in placebo group (4%) than HPV vaccinated group (3%) Fig.8

FIG.8: ASSESSMENT OF PREGNANCY OUTCOME.

Adverse Event in women up to 25 years vs women upto 35 years:

As we analysed the data it was evident that side effects were more in younger age group as compared to older but with the limited no of side effects in both the age group no statistical significance was achieved.

DISCUSSION: Only 4 studies passed the strict inclusion criteria, all the studies were done using the HPV2 vaccines and the placebo used was Al(SO₄). We did not have any study with HPV4 as most of the studies with HPV4 have males included in the study and we had excluded males from our study. The reason why we intended to have females is that in most of the country’s HPV vaccine is recommended for female population only and hence it would be import to understand the adverse event profile in females. We have 2 studies where patient age was up to 25 and 2 studies in which patient age was up to 35 years. As we had limited studies funnelled through our stringent inclusion exclusion criteria we were not able to separate exclusive adverse event in age group 25-34 and 35-45 years of age. The analysis done on adverse event in group upto 35 was overlapping with the other arm of upto 25 years and hence the analysis has to be rerun among specific age groups i.e. 25-34 and 35-45.

The total patient data evaluated was 1427(852 in vaccinated arm; 575 in the placebo arm). The percentage of patients experiencing serious side effects were small and hence absolute number of severe side evaluated was not large enough and we would have to wait and possible include data from other studies to make it more robust and have good powered analysis. The studies only compared the side-effect profile of vaccine against placebo Al(OH)₃ it would be interesting if we have 3 arms for comparison vaccine, Al(OH)₃ and saline placebo. It would be interesting to analysis regional/ geographical/racial difference in pain perception to both vaccine and placebo. This analysis might bring up different precautions to be followed while vaccinating people of different geographical area.       

 CONCLUSION: In the meta-analysis we could find and conclude that pain was the major local side effects with 61% followed by swelling 22% and redness 17% in the vaccinated arm and similarly in the placebo arm pain 72% followed by swelling 18% and redness 10%. Duration of local side effects was longer in vaccinated group as compared into placebo. Headache was the most frequently experienced systemic side effects 42% in vaccine and placebo group. Unsolicited adverse event in vaccinated and placebo group were 39% and 37% respectively. New onset chronic disease in vaccinated and placebo arm were 3% and 2% respectively. Serious adverse event were 3% in vaccinated and 2% in placebo group. Undesirable pregnancy outcomes were same for both vaccinated and placebo arm 3%. We would say that HPV vaccine do have high rate of local side effects but comparable with placebo. Serious adverse events and adverse pregnancy outcomes rates are low and comparable in both the arms.

CONFLICT OF INTEREST: Gaurav Mathur serves as an employee of MSD Pharmaceuticals Pvt. Ltd, India.

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    How to cite this article:

    Sangar VC, Ghongane BB, Mathur G and Chowdhary AS: Safety and Adverse Events of Prophylactic HPV Vaccines among Healthy Women: A Systematic Review & Meta Analysis. Int J Pharm Sci Res 2015; 6(4): 1779-91.doi: 10.13040/IJPSR.0975-8232.6(4).1779-91.

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