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Short Report

Evaluation of safety and immunogenicity of a quadrivalent human papillomavirus vaccine in healthy females between 9 and 26 years of age in Sub-Saharan Africa

Nelly MugoKenyatta National Hospital; Nairobi, KenyaCorrespondence[email protected]
,
Nana Akosua AnsahNavrongo Health Research Center; Ghana Health Service; Navrongo, Ghana
,
Deborah MarinoMerck & Co. Inc.; Kenilworth, NJ, USA
,
Alfred SaahMerck & Co. Inc.; Kenilworth, NJ, USA
&
Elizabeth IO GarnerMerck & Co. Inc.; Kenilworth, NJ, USA
Pages 1323-1330 | Received 02 Oct 2014, Accepted 12 Dec 2014, Published online: 18 Jun 2015

Abstract

Due to sporadic and not easily accessible cervical cancer screening, human papillomavirus (HPV)-related cervical cancer is a leading cause of cancer death in Sub-Saharan African women. This study was designed to assess the safety and immunogenicity of a quadrivalent human papillomavirus (qHPV) vaccine in sub-Saharan African women. This seven month, double-blind study enrolled 250 healthy, human immunodeficiency virus (HIV)-uninfected females ages 9–26 residing in Ghana, Kenya, and Senegal. Thirty females ages 13–15 and 120 females ages 16–26 received qHPV vaccine. In addition, 100 females ages 9–12 y were randomized in a 4:1 ratio to receive either qHPV vaccine (n = 80) or placebo (n = 20 ). The primary immunogenicity hypothesis was that an acceptable percentage of subjects who received the qHPV vaccine seroconvert to HPV6/11/16/18 at 4 weeks post-dose 3, defined as the lower bound of the corresponding 95% confidence interval (CI) exceeding 90%. The primary safety objective was to demonstrate that qHPV vaccine was generally well tolerated when administered in a 3-dose regimen. The pre-specified statistical criterion for the primary immunogenicity hypothesis was met: the lower bound of the 95% exact binomial CI on the seroconversion rate was at least 98% for each vaccine HPV type and all subjects seroconverted by 4 weeks post-dose 3. Across vaccination groups, the most common adverse events (AE) were at the injection site, including pain, swelling, and erythema. No subject discontinued study medication due to an AE and no serious AEs were reported. There were no deaths. This study demonstrated that qHPV vaccination of sub-Saharan African women was highly immunogenic and generally well tolerated.

Invasive cervical cancer (ICC) is the third most common cancer in women worldwide.Citation1 Of the 530,000 new cases per year diagnosed worldwide, half will die from the disease.Citation1 Eighty percent (80%) of these deaths occur in developing countries.Citation2–5 In many parts of Africa, ICC is a leading cause of cancer death in women.Citation2-7 Though rates of ICC vary considerably in different sub-regions, cervical cancer ranks first or second (after breast cancer) in all individual sub-Saharan African countries.Citation8 In sub-Saharan Africa, over 70,000 new cases occur annually with an age standardized incidence rate of 31.0 per 100,000 women.Citation9 This high burden of disease is largely attributable to the lack of organized national screening programs.Citation8 To put this into context, the overall age-standardized incidence rate in European countries with established screening programs is 11.0 per 100,000 women.Citation9

Human papillomavirus (HPV), the necessary cause of cervical cancer, is endemic in Africa.Citation10 Although there are a few published studies on HPV prevalence in sub-Saharan Africa, a recent review found HPV16 and HPV18 to be the most common HPV types in ICC, as seen in all other world regionsCitation8 but other carcinogenic HPV types such as HPV45 and 35 are relatively more frequent compared to other world regions.Citation8 Data on other HPV-related anogenital cancers such as those of the vulva, vagina, anus, and penis are limited.Citation8 Genital warts are also common in sub-Saharan Africa, and like other world regions, are associated with HPV6 and 11. HPV, more predominantly HPV16 in addition to tobacco and alcohol, is considered a major factor of the etiology of oropharyngeal cancers; in addition, HPV6 and 11 also cause a disease of the respiratory tract - recurrent respiratory papillomatosis.Citation11

A prophylactic quadrivalent human papillomavirus (qHPV) type 6/11/16/18 recombinant vaccine (GARDASIL/SILGARD, Merck & Co, Inc., Kenilworth, NJ), received United States (US) Food and Drug Administration (FDA) approval in June 2006 for use in girls and women aged 9 to 26 y.Citation12-17 Prior to the current study, all studies of the immunogenicity, safety, and efficacy of the qHPV vaccine had been conducted in North America, Latin America, Europe, Asia, and Oceania.Citation12,13,18-24 The efficacy and/or immunogenicity of vaccines and the pathogenicity of the organisms that they target can differ in subpopulations defined by race/ethnicity, behavior, age, and socioeconomic status.Citation24 Data from the qHPV vaccine program to date support no clinically relevant impact of these baseline covariates on responses to the qHPV vaccine in a sub-Saharan African population.Citation24 Although these observations suggest a similar immune response and safety profile in sub-Saharan African women, given the high burden of HPV 6/11/16/18-related disease in Africa, the present study was designed to assess the safety and immunogenicity of the qHPV vaccine in women aged 9 to 26 y in Africa.

Merck Protocol V501–046 (NCT 01245764) was a 7-month, partially double-blind study to observe the safety, tolerability and immunogenicity of a 3-dose regimen of qHPV vaccine in healthy sub-Saharan African females residing in Ghana, Kenya, and Senegal. The study enrolled 250 healthy females between the ages of 9 and 26 y (). Thirty females ages 13–15 and 120 females ages 16–26 received qHPV vaccine. In addition, 100 females between the ages of 9–12 y were randomized in a 4:1 ratio to receive either qHPV vaccine (n = 80) or placebo (n = 20). At the study's conclusion, all subjects who originally received placebo were offered the option to return to the study site and receive a 3-dose regimen of qHPV vaccine. The study was conducted in conformance with applicable country or local requirements regarding ethical committee review, informed consent, and other statutes or regulations regarding the protection of the rights and welfare of human subjects participating in biomedical research.

Table 1. Subject disposition and summary of exclusionsa from the per-protocol immunogenicity populations

For the older population, participants were required to be generally healthy and have an intact uterus, no evidence of gross purulent cervicitis, no history of genital warts, no previous abnormal Papanicolaou (Pap) tests, no history of cervical intraepithelial neoplasia, and a lifetime history of no more than 4 sexual partners. Individuals were excluded from participation if they were pregnant, were allergic to any vaccine component, had received any blood product or component in the previous 6 months, had any known immune or coagulation disorder, or had received any inactivated vaccine product within 14 d before enrollment or any live vaccine product within 21 d before enrollment.

The qHPV vaccine with amorphous aluminum hydroxyphosphate sulfate adjuvant and visually indistinguishable aluminum-containing placebo have been described previously.Citation25 Subjects received qHPV vaccine or placebo at day 1, month 2, and month 6 after having a negative result on a pregnancy test (post-pubertal females only) of the urine.

The primary hypothesis was that the percentage of subjects receiving qHPV vaccine who seroconverted to HPV6, 11, 16, and 18 at 4 weeks post-dose 3 would be acceptable. Seroconversion rates to each of HPV6, 11, 16, and 18 were summarized by exact 95% confidence intervals (CI). Each seroconversion rate was declared acceptable if the lower bound of the corresponding 95% CI exceeded 90%. For geometric mean titers (GMT) to each of HPV6, 11, 16, and 18, 95% CIs were provided with no hypothesis testing. Similar to previous studies, the analyses of immunogenicity was based on the per-protocol population, which consisted of subjects who had received all 3 vaccinations within acceptable day ranges, were free of protocol violations, were negative to the relevant HPV type at enrollment, and had provided a blood sample for month 7 serology testing within an acceptable day range.Citation12-15

The primary safety objective was to demonstrate that qHPV vaccine was generally well tolerated when administered in a 3-dose regimen. Each subject received a Vaccination Report Card (VRC) on which to record oral temperatures approximately 4 hours following each vaccination and daily for the next 4 days; any systemic or injection-site adverse event (AE) that occurred on the day of vaccination or within 14 calendar days following vaccination; and any concomitant medications or concomitant vaccinations received on the day of vaccination or during the 14 calendar days following vaccination. The analysis of safety was carried out according to a tiered approach. VRC-prompted injection-site AEs of pain, swelling and redness, temperature elevations (oral temperature ≥37.8°C [≥100.0°F]) and serious AEs were considered Tier 1 events. In addition, the percentage of patients with any AE, any injection-site AE, any systemic AE, any vaccine-related AE, any serious AE, any serious vaccine-related AE, and who discontinued due to an AE were considered Tier 2 endpoints. p-Values (Tier 1 only) and 95% CIs (Tier 1 and Tier 2) were calculated for between-treatment differences (qHPV vaccine vs placebo) following the methods of Miettinen and Nurminen.Citation26 Since randomization between qHPV vaccine and placebo was confined to the 9 to 12 y age group, all comparisons within the tiered approach were restricted to this age group. Descriptive summaries of AEs among subjects receiving qHPV vaccine were also provided across the entire population age range (9 to 26 years).

For all injection-site AEs, except erythema and swelling, subjects were instructed by the VRC to estimate the severity of the AE as mild (awareness of symptom, but easily tolerated), moderate (discomfort enough to cause interference with usual activities), or severe (incapacitating with inability to work or do usual activity). For erythema and swelling, subjects were instructed by the VRC to measure an injection-site reaction at its greatest width from edge to edge in maximum units ranging from 0 to >7 on the VRC, rounding up to the next unit if in between 2 units (each unit on the VRC measured approximately 1 inch). Intensity of erythema and swelling was categorized as follows: mild (maximum size of approximately 0 to 1 inch), moderate (maximum size of approximately 1 to 2 inches), and severe (maximum size of approximately over 2 inches).

Sexual history was obtained at all study visits in subjects 13 to 26 y of age. In subjects 13 to 26 y of age who were sexually active, labial/vulvar/perineal and perianal and endo/ectocervical swabs were collected at day 1 and month 7. The collection of swabs was voluntary in non-sexually active subjects. Swabs were tested for the 4 vaccine HPV types (6/11/16/18) using a polymerase chain reaction (PCR)-based assay as previously described.Citation25,27,28 Subjects 13 to 26 y of age who were sexually active and fulfilled local screening guidelines had Pap tests performed at day 1. Any subject with an abnormal Pap test was referred for treatment outside the context of the study according to the study site's standards and practices.

Serum samples for anti-HPV testing were obtained at day 1 and month 7 and measured using a competitive Luminex immunoassay (cLIA) as previously described.Citation29,30 A subject was defined to be anti-HPV6, anti-HPV11, anti-HPV16, or anti-HPV18 seropositive if her anti-HPV serum cLIA level was ≥20 , ≥16 , ≥20 , or ≥24 , milli Merck Units/mL (mMU/mL), respectively.

A total of 257 subjects were screened for inclusion in this study and 250 subjects were randomized. Among the 250 randomized subjects, a total of 27 subjects (10.8%) discontinued prior to month 7 (18 discontinued due to a protocol violation; 8 were lost to follow-up; and 1 withdrew consent). A total of 224 subjects (89.6%) completed the 3 dose vaccination regimen (207 subjects who received qHPV vaccine and 17 who received placebo).

At study entry, 29.3% (44/150) of subjects 13 to 26 y of age had experienced sexual debut. The median age at first sexual intercourse was 20 y (range 14 to 26 years) and the median number of lifetime sex partners was 1.5 (range 1 to 3). Overall, 9 subjects (7.5%) in the 16- to 26-year-old age group had a genital tract infection or sexually transmitted disease, the majority (7/9) being vaginal candidiasis. Approximately 6.0% (15/250) of the study subjects reported at least one or more prior pregnancies. Among the 42 total subjects with a satisfactory day 1 Pap test result, 7 (16.7%) had either borderline abnormal or abnormal Pap results, with low-grade squamous intraepithelial lesions (LSIL) being the most common single abnormal Pap result (2 subjects, 4.8%).

Among the subjects randomized to qHPV vaccine and with a valid day 1 serology result, 11.3% (8/71) of the 9- to 12-year-old subjects and 19.2% (5/26) of the 13- to 15-year-old subjects were positive to exactly one vaccine type. For the 16- to 26-year-olds, 20.3% (24/118) were positive to at exactly one vaccine HPV type (6 were positive to >1 type). Eight of the 16- to 26-year-old subjects were positive to exactly one vaccine-HPV type by PCR (6.8%; 8/117). Among the 9- to 12-year-old subjects treated with placebo and with a day 1 serology result, 1 of 17 (5.9%) was positive to exactly one vaccine HPV type (HPV6) and none were positive by PCR.

The most common reasons for exclusion from the per-protocol immunogenicity analysis were: vaccination 2 or 3 outside acceptable day ranges, protocol violations (i.e. the subject was not native to sub-Saharan African [n = 7] or the subject was consented by a legal guardian without legal guardianship documentation [n = 18]), positivity to HPV6, 11, 16, or 18 at day 1, or specimens (e.g., serum, swab) missing or not collected within acceptable day ranges ().

presents a summary of the percentages of subjects who seroconverted for each vaccine HPV type by 4 weeks post-dose 3. Estimated seroconversion rates and associated 95% CIs are shown for each vaccine HPV type. The pre-specified statistical criterion for the primary hypothesis was met: the lower bound of the 95% exact binomial CI on the seroconversion rate exceeded 90% for each vaccine HPV type and all subjects seroconverted by 4 weeks post-dose 3. There was also a robust response to all 4 vaccine HPV types as shown by the observed anti-HPV6, anti-HPV11, anti-HPV16 and anti-HPV18 GMTs measured 4 weeks post-dose 3 in the qHPV vaccine treatment group ().

Table 2. Summary of anti-HPV cLIA seropositivity percentages by vaccination group (per-protocol populationa)

Table 3. Summary of anti-HPV geometric mean titers at 1 month post-dose 3 by vaccination group (per-protocol populationa)

A summary of the number and percentage of subjects who reported clinical AEs days 1 to 15 following any vaccination by age group is shown in . The proportion of subjects reporting at least one AE within 15 d of any vaccination was generally higher among the subjects who received qHPV vaccine in the 3 age groups (81.0% [9–12 years], 79.3% [13–15 years] and 87.4% [16 to 26 years]) compared to those who received placebo (78.9% [9–12 years]). The proportion of subjects who reported at least one injection-site AE within 15 d of any vaccination was higher among subjects who received qHPV vaccine (68.4% [9–12 years], 72.4% [13–15 years], and 73.9% [16–26 years] in the 3 age groups) compared to those who received placebo (47.4% [9–12 years]). Across vaccination groups and age strata, the most common injection site AEs following any vaccination visit were pain, swelling, and erythema. The proportion of subjects who reported at least one systemic AE within 15 d of any vaccination was similar among subjects who received qHPV vaccine (48.1% [9–12 years], 58.6% [13–15 years] and 61.3% [16–26 years]) compared to those who received placebo (57.9% [9–12 years]). The most common vaccine-related systemic AEs of incidence >5% in qHPV vaccine recipients were abdominal pain, pyrexia and headache (). No subject discontinued study medication due to an AE and no serious AEs were reported. There were no deaths.

Table 4. Adverse event summary (days 1 to 15 following any vaccination visit) - all vaccinated subjects by age group

The proportion of subjects aged 9 to 12 y who reported at least one injection-site AE was higher in the qHPV vaccine group (54/79 [68.4%]) compared to the placebo group (9/19 [47.4%]) but the increased incidence of injection site AEs did not reach statistical significance (p = 0.11). Non-statistically significant differences between vaccine and placebo recipients (subjects aged 9 to 12 years) were also observed for injection site pain (p = 0.11), erythema (p = 0.51) and swelling (p = 0.48), though these finding should be interpreted with caution due to the small sample size. In a previous study across 5 phase 3 clinical trials, statistically significant differences were observed for vaccine (n = 6,160) and placebo (n = 3,740) recipients for injection site erythema, pain, and swelling (p <0.05).Citation32 In the present study, for the majority of subjects, injection-site AEs were mild in nature. The majority of subjects who experienced injection-site erythema and/or swelling reported a maximum size of 0 to ≤ 1 inch across both treatment groups.

This study demonstrated that qHPV vaccination of sub-Saharan African women was highly immunogenic and generally well tolerated. The pre-specified statistical criterion for the primary immunogenicity hypothesis was met: the lower bound of the 95% exact binomial CI on the seroconversion rate exceeded 90% for each vaccine HPV type and all subjects seroconverted by 4 weeks post-dose 3. Across vaccination groups, the most common adverse events (AE) were at the injection site, including pain, swelling, and erythema.

This is the first study to evaluate the qHPV vaccine in Africa. Though vaccine efficacy was not an endpoint, in this study a prior sub-analysis of the black women who were enrolled in the large phase 3 efficacy trials of the qHPV vaccine showed vaccine efficacy against disease caused by HPV6, 11, 16, and 18 was 100% for cervical, vulvar, and vaginal intraepithelial neoplasia, and condylomata accuminata, among women who were negative to the vaccine types at study entry.Citation31 When subjects aged 15 to 26 who were enrolled in the clinical trials of the qHPV vaccine were stratified by race/ethnicity (White, Black, Asian, Hispanic, and other), anti-HPV GMTs for HPV6, 11, 16, and 18 ranged from 540–617, 720–890, 2702–3499, and 549–663 mMU/ML, respectively, and for women who self-identified themselves as Black, the corresponding GMTs were 598, 887, 3499, and 637 mMU/mL, respectively. These findings are similar to our study, where the anti-HPV6, 11, 16, and 18 GMTs were 602, 626, 3786, and 811 mMU/mL, respectively.Citation24 Our observed safety findings are also similar to that of other studies, whereby vaccine recipients have higher rates of injection site pain, erythema and swelling, but similar rates of systemic AEs.Citation32 Given the high vaccine efficacy seen in the clinical trials, and the fact that in the 8 y since its original licensure, the qHPV vaccine has been shown to be highly effective at the population level, with marked reductions in the prevalence of HPV vaccine-type related infection and disease in many countries,Citation33-50 our findings suggest the vaccine should be equally effective in sub-Saharan African women.

The qHPV vaccine is currently approved in 27 African countries. Of note, Rwanda, a country where cervical cancer is the most common cancer among women and where neither cervical cancer screening nor HPV vaccination was available in public health facilities before 2011, vaccinated more than 80% of its female teenage population in just one year (2011).Citation51 There are extensive challenges with implementing cytology-based cervical cancer screening programs in areas with limited health care services and personnel,Citation52,53 though a recent study suggests it would cost less than US $10 per woman screened to decrease by 50% the cervical cancer deaths that will occur in sub-Saharan Africa over the next 10 y.Citation54 With the introduction of primary prevention of HPV infection through vaccination, there is a new paradigm for cervical cancer prevention; however, the use of and widespread implementation of the prophylactic vaccines in sub-Saharan Africa has posed several challenges, including affordability, implementation challenges (e.g., cold chain), public acceptability, and prediction and monitoring of the population-level impact of cervical cancer prevention programs, as the time course from infection to disease spans several decades.Citation55 Although HPV vaccination is not a replacement for cervical cancer screening, data from the present clinical trial, along with existing extensive post-licensure data, suggest that high vaccine uptake in African countries would result in similar marked decreases in HPV infection and disease as seen in high income nations.

Disclosure of Potential Conflicts of Interest

Nelly Mugo reports receiving funds from Merck Ltd to conduct the study referenced in current manuscript and being a grantee for a Merck funded study Nana Akosua Ansah reports nothing to disclose Deborah Marino, Alfred Saah, and Elizabeth I.O. Garner are current or former employees of Merck and may hold stock/stock options.

Acknowledgments

The authors thank Heather L Sings and Karyn Davis (Merck) for assistance in the preparation of this manuscript.

Funding

Funding for this study was provided by Merck & Co., Inc., Kenilworth, NJ USA.

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