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Table 2 Summary of the safety endpoint data of HPV vaccines in low and middle income countries

From: Vaccines against human papillomavirus in low and middle income countries: a review of safety, immunogenicity and efficacy

Study Sample Safety end point assessments Results
Perez et al. (2008) (qHPV) [15] Multicenter cohort vaccine n = 3147, placebo n = 2857 Reported adverse experiences that included injection site pain, swelling and erythema and any other systemic adverse experience as filled out on the adverse event card. There was no significant difference in occurrence of serious adverse events between the two groups. However, more adverse experiences were reported by subjects who received quadrivalent HPV vaccine compared to those subjects who received placebo with occurrence of injection-site adverse experiences responsible for the increase in adverse experiences seen in these participants.
Muñoz et al. (2009) (qHPV) [25] Multi-center cohort vaccine n = 1910, placebo n = 1907 Information about adverse events was gathered from participants by general questioning at study visits and by use of a vaccine report card. The participants received the card at every vaccination visit to record temperatures and local and systemic adverse events. The proportion of participants who reported serious adverse event on day 1–15 after any vaccination was comparable between the two groups. Injection-site adverse events were mainly responsible for the slight increase in adverse events that were recorded in the vaccine group
Medina et al. (2010) (bHPV) [16] Multi center cohort vaccine n = 1035, placebo n = 1032 Solicited local and general symptoms (pain, redness, swelling, fever, headache, fatigue, gastrointestinal symptoms, arthralgia, myalgia, rash, and urticaria) were reported for 7 days while unsolicited symptoms were reported for 30 days. The intensity of solicited and unsolicited symptoms was graded on a scale of 0–3. SAEs, NOCDs, medically significant conditions (MSCs), pregnancies and their outcomes were reported up to month 12. All solicited local AEs were considered related to vaccination. Other AEs (solicited general and unsolicited) were assessed for causality by investigators. The occurrence of SAEs was similar in both groups. Between months 7 and 12, 13 girls (1.3 %) and 10 girls (1.0 %) reported SAEs in the HPV-16/18 vaccine and control groups, respectively. The pattern of symptoms was similar in both groups with respect to incidence, severity and duration. The incidence of local and solicited symptoms did not increase with the second and third vaccine doses.
Bhatla et al. (2010) (bHPV) [19] Multicenter study vaccine n = 176, placebo n = 178 For 7 days after each dose, local symptoms (pain, redness and swelling at the injection site) and general symptoms (fever, headache, fatigue, gastrointestinal symptoms, arthralgia, myalgia, rash and urticaria) were solicited and recorded on diary cards. Each symptom was graded from 1 to 3 based on the extent of discomfort that was reported. Investigators actively solicited for any pregnancy information from the participants and confirmed by urine pregnancy tests prior to each vaccine dose. Unsolicited events were followed for 30 days after each vaccination. Serious adverse events (SAE), any new-onset chronic disorders (NOCD and other medically significant conditions (MSC) were followed up. Solicited local injection site symptoms (pain, redness and swelling) were more frequent in the Vaccine group than the Placebo group. Solicited general symptoms (fatigue, headache and fever) were similar in both groups. There was no difference observed between the two groups for any unsolicited symptoms. Six SAE were reported during the study period, two in the Vaccine group (acute appendicitis and lymph node tuberculosis) and four in the Placebo group(bronchogenic cyst, cataract, a miscarriage and pneumothorax of the left lung) with none considered related to vaccination by the investigators. None of these SAE was fatal.
Neuzil et al. (2011) (qHPV) [27] Longitudinal cohort alternate dose schedules n = 903. Events recorded up to 30 days after last dose Solicited adverse events (local reactions and fever) and unsolicited adverse events were recorded. All serious adverse events occurring up to 30 days following the last dose of vaccine were documented. The vaccine was generally well tolerated in each dosing schedule group. Solicited and unsolicited adverse events following any vaccination were comparable across groups. Pain at the injection site was the most common adverse event in all groups with most episodes classified as mild. No serious adverse events occurred within the 30 days of each vaccination. Throughout the study, there were no deaths, vaccine-related serious adverse events reported.
Salif Sow et al. (2012) (bHPV) [14] Randomised cohort (vaccine n = 450/ 1298 doses, placebo n = 226), 0–12 months period Solicited and unsolicited local symptoms (pain or swelling at injection site) and general symptoms (arthralgia, fatigue, fever, gastrointestinalsymptoms, headache, myalgia, rash, or urticaria). Grade 3 symptoms defined as swelling at the injection site >50 mm in diameter, fever >39 °C (axillary), urticaria distributed on ≥4 body areas, as well as other symptoms that prevented normal daily activity. Serious AEs (SAEs), other medically significant conditions. There were no vaccine related serious adverse events and no participant withdrew due to an adverse event. However, the incidence of any solicited symptom was higher for vaccine recipients than for placebo due to a higher incidence of local symptoms.
Khatun et al. (2012) (bHPV) [18] Randomised cohort vaccine n = 50, placebo n = 17 Local symptoms (pain redness and swelling at the injection site) as well as general symptoms(fever, headache, fatigue, gastrointestinal symptoms that included nausea, vomiting, diarrhea and/or abdominal pain, arthralgia, myalgia, rash and urticaria) were assessed for five consecutive days after each dose. The intensity of each symptom was graded on a non-quantifiable scale from mild, moderate and severe based on the extent of discomfort. Unwanted events were followed for 14 days after each vaccination. The vaccine was well tolerated with no reports of serious vaccine-related adverse experiences between enrollment and Month. Fever and injection site pain were the most frequent though most were mild among the vaccinated group.
Watsone-Jones et al. (2012) (qHPV) [44] Cluster-randomized trial 134 primary schools randomly assigned to class-based (school grade [class] 6) or age-based (girls born in 1998; 67 schools per arm) vaccine delivery n = 5532 Vaccinees requested their parents to call in the event of any suspected adverse event (AE) and to go to the nearest health facility. Adverse events were also recorded at each school visit. SAEs or AEs that indicated potential vaccine reactions were investigated by a senior clinician Vaccine-related adverse events were rare. There were 11 AEs reported with 3 SAEs not thought to be related to the vaccine. The vaccine was generally acceptable and safe [43]
Schwarz et al. (2012) (bHPV) [17] Four year follow up. Total vaccinated cohort (TVC) n = 617 Serious adverse events, new onset chronic diseases (NOCDs), medically significant conditions, and pregnancies were recorded in the follow-up month 48. An event was considered a potential NOCD if there was no record of it in the participant history. Analysis of AEs incidence rate per 100,000 subjects per year was performed. No participants withdrew from the study because of an AE, and there were no fatal events. There were no vaccine related SAEs. There was no apparent difference in terms of incidence rates of AEs between the study groups in the cumulative follow-up time. A total of 32 pregnancies were reported throughout the study period in HPV-16/18 vaccine recipients with 29 participants giving birth to healthy babies.
Skinner et al. (2014) (bHPV) [26] Multicenter cohort vaccine n = 2881, placebo n = 2241. Four year follow-up. Solicited symptoms for 7 days and unsolicited symptoms for 30 days after each vaccination were recorded by participants. Serious adverse events, new-onset chronic diseases, new-onset autoimmune diseases, medically significant conditions, pregnancy, and pregnancy outcomes were recorded throughout the 48-month follow-up. Solicited injection-site symptoms and other general solicited symptoms occurred more in the vaccine group than in the control group. Overall, the incidence of unsolicited symptoms, serious adverse events, medically significant conditions, new-onset chronic disease, and new-onset autoimmune disease was similar in both groups, and pregnancy outcomes did not differ between groups. There were seventeen deaths that occurred, 14 (<1 %) of 2881 women in the vaccine group and three (<1 %) of 2871 in the control group. None of these deaths was believed to be related to vaccination with no cluster of disease type noted.