Abstract
OBJECTIVES
A single dose of human papillomavirus (HPV) vaccine would simplify logistics and reduce costs of vaccination programs worldwide. We conducted a phase IIa trial to determine the stability of HPV type-specific antibody responses after a single dose of the nonavalent HPV vaccine, Gardasil9.
METHODS
Two hundred-and-one healthy 9 to 11-year-old girls and boys were enrolled at 2 centers in the United States to receive a prime dose of the nonavalent vaccine at baseline, a delayed dose at month 24, and an optional third dose at month 30. Blood samples were collected to measure HPV type-specific antibodies at baseline and at 6, 12, 18, 24, and 30 months after the prime dose. The primary outcomes were serum HPV16 and HPV18 antibody responses.
RESULTS
In both girls and boys, geometric mean concentrations of HPV16 and HPV18 antibodies increased at 6 months, declined between months 6 to 12, and then remained stable and high (at 20- and 10-times those at baseline for HPV16 and HPV18, respectively) throughout months 12, 18, and 24 (prebooster) visits. Both HPV16 and HPV18 antibody responses demonstrated anamnestic boosting effect at 30-months after the delayed (24-month) booster dose.
CONCLUSIONS
A single dose of the nonavalent HPV vaccine induced persistent and stable HPV16 and HPV18 antibody responses up to 24 months. This study contributes important immunogenicity data to inform feasibility of the single dose HPV vaccination paradigm. Further research is needed to assess the long-term antibody stability and individual clinical and public health benefit of the single dose schedule.
What’s Known on This Subject:
A single dose of human papillomavirus (HPV) vaccine would simplify logistics and reduce costs of HPV vaccination worldwide. Studies have shown that a single dose of HPV vaccine could generate durable antibody response that may be associated with clinical efficacy.
What This Study Adds:
This study showed that a single dose of Gardasil9 induced stable HPV16/18 antibody responses up to 24 months in girls and boys, aged 9 to 11. The study adds important immunogenicity evidence around usage of a single-dose schedule of Gardasil9.
Current human papillomavirus (HPV) vaccine regimens require a 2- or 3-dose vaccine series over 6 to 12 months, depending on the age of the individual. Although vaccine initiation rates in the United States have increased steadily since introduction of HPV vaccines in 2006, barriers such as parental vaccine hesitancy, misinformation, and lack of strong provider recommendations continue to hinder widespread coverage. Although HPV vaccine initiation rates are currently around 77%, the series completion rates are still suboptimal at 62%, underscoring the complexities of achieving high vaccine uptake, even in a high-resource setting like the United States.1 Concerns around series completion because of delivery challenges of multiple-dose schedules are among major constraints (along with high vaccine costs and limited availability) to wider implementation in limited resource settings in developing countries.2
Over the past few years, there has been increasing interest in evaluating the role of single dose schedules of HPV vaccines, particularly to simplify logistics, reduce costs, and improve HPV vaccine coverage. Several observational studies have evaluated immunogenicity and efficacy of a single dose in girls and young women randomized to receive 2 or 3 doses of bivalent or quadrivalent HPV vaccines but did not complete their allocated schedule.3 These nonrandomized, observational studies have reported that a single dose of bivalent or quadrivalent vaccines induces a detectable and durable antibody response to the key oncogenic HPV types 16 and 18 and no inferiority in clinical efficacy against incident or persistent HPV infections.3 Recent trials from Tanzania and Kenya have added evidence about immunogenicity and efficacy from single dose schedules of the nonavalent HPV vaccine in girls and young women.4–6
To expand evidence on the durability of immune response to HPV types 16 and 18 in the nonavalent HPV vaccine, and also cover boys in addition to girls, we report results of a prospective clinical trial investigating a deferred booster dose schedule of the nonavalent HPV vaccine in 2 sites in the United States. With a deferred booster at 24 months, instead of the current standard of care schedule of booster at 6 or 12 months, the study was designed to evaluate 6-monthly antibody kinetics over the 24-month deferred booster window. Our study targeted girls and boys ages 9 to 11, the lowest end of the licensed age-range of the nonavalent vaccine so as to optimize the chances that very few, if any, of these participants would have been exposed to HPV within the 2-year period before their deferred booster dose. In addition, younger age children are likely to mount higher immune responses,7 and prior studies have indicated that the immune responses to a single dose of the HPV vaccines among girls aged 9 to 11 years appeared to be comparable to antibody responses of 3 doses in young women 15 to 25 years old.8
Methods
Trial Design
This is a phase IIa, single-arm, open label, nonrandomized trial of the nonavalent HPV vaccine (Gardasil9) among 9 to 11-year-old girls and boys to determine the stability and kinetics of HPV16 and HPV18 antibody response induced over the 24 months following a single dose, and 6 months following a booster dose given at 24 months. When the trial opened, the standard-of-care Centers for Disease Control and Prevention recommendation was 3 doses, which was changed in 2016 to 2 doses for children under ages 15 years. Because the protocol-specified booster was being deferred outside the recommended window of 6 to 12 months, participants were allowed to opt for a third dose at 30 months, following the final blood draw. Study design, objectives, statistical analysis plan, and study procedures have been previously published.9 The trial was sponsored by the National Cancer Institute and conducted at the University of Arizona and University of California Los Angeles. The study was reviewed and approved by the study sponsor and National Cancer Institute Central Institutional Review Board (protocol #UAZ 2015-05-01). Trial oversight was provided by the study sponsor and the University of Arizona Cancer Center Data and Safety Monitoring Board.
Trial Population
The trial opened to accrual in March 2016, reached its accrual target in July 2017, and was closed to follow-up in February 2020. Study participants included healthy 9 to 11-year-old girls and boys recruited from institutional pediatric clinics and collaborating community pediatric clinics at University of Arizona and University of California Los Angeles. The study initially was designed to only focus on girls; but a smaller cohort of boys was added midway to expand the generalizability of the findings. Key exclusion criteria included previous vaccination against HPV; chronic use of immunosuppressive agents or other immune-modifying drugs or chemotherapeutic agents within 6 months before the first vaccine dose; active treatment of cancer or autoimmune conditions; confirmed or suspected immunosuppressive or immunodeficient conditions; or pregnancy.9
Trial Procedures and Interventions
Detailed trial procedures and interventions have been previously published.9 Briefly, participants underwent a prestudy screening evaluation and a baseline visit (combined when feasible), as well as clinic visits at 6, 12, 18, 24, and 30 months after the baseline visit. Participants received vaccine at baseline, a delayed booster dose at month 24, and an optional third dose at month 30. Blood samples were collected for measurement of HPV type-specific antibodies at baseline (month 0) and at 6, 12, 18, 24, and 30 months after the prime dose.
All blood samples underwent on-site serum separation and serum aliquots were stored at 4°C no longer than 24 hours then at −80°C until analysis. HPV type-specific antibodies were measured by a validated virus-like particle enzyme-linked immunosorbent assay, which measures type-specific neutralizing and nonneutralizing immunoglobulin G antibodies.10–12 The assay cutoff was 1.31 and 1.24 IU/mL for HPV16 and HPV18 antibodies, respectively.
Trial Outcomes
The primary outcome was the antibody kinetics measured as the persistence and stability of serum HPV16 and HPV18 antibodies between the 6- versus (vs) 12-month, 12- vs 18-month, and 18- vs 24-month visits. Antibody response was categorized as stable from the prior visit if the change was within 2-fold and as decreased or increased if the change was more than 2-fold.
Statistical Analysis
For the primary analysis, 1-sided paired t tests were performed to compare the difference in the mean of the log-transformed type-specific antibody levels between the 6- and 12-month visits, the 12- and 18-month visits, and the 18- and 24-month visits, respectively, to evaluate whether the type-specific geometric mean concentration (GMC) at 12, 18, and 24 months, respectively, was noninferior to the GMC at 6, 12, and 18 months. Bonferroni correction was used to account for multiple comparisons (ie, a 1.67% significance level for each test). For the secondary analysis, stability was also evaluated by categorizing the changes in antibody level between visits into decrease, stable, or increase, similar to analysis in prior studies.13 The percentage of participants whose type-specific antibody levels decreased, increased, or remained stable between the 6- and 12-month visits, between the 12- and 18-month visits and between the 18- and 24-month visits was reported along with the associated exact (Clopper-Pearson) 95% confidence interval (CI).
The primary outcomes were assessed independently in girls and boys. With evaluable longitudinal outcomes projected for 100 girls, the study had ≥90% statistical power to detect a noninferiority margin no greater than 0.35 standard deviations14 at a Bonferroni-corrected significance level of 1.67% and an exact 2-sided 95% CI with a width of ≤0.203. With evaluable longitudinal outcomes projected for 40 boys, the study had ≥80% statistical power to detect a noninferiority margin no greater than 0.50 standard deviations at a Bonferroni-corrected significance level of 1.67% and an exact 2-sided 95% CI with a width of ≤0.328. The detailed statistical analysis plan can be found in the published protocol.9 Statistical analyses were performed via SAS 9.4 (SAS Institute. Inc., Cary, NC).
Results
Participants
A total of 204 children were screened and consented, 3 were excluded because of not meeting study eligibility criteria. Two hundred and one eligible participants were accrued to study intervention and follow-up. The study maintained a high retention rate (93%) for the 30-month follow-up. Among the 14 participants who discontinued the study, 2 were lost to follow-up, 10 withdrew consent, and 2 received an HPV vaccine outside of study. Participant flow according to CONSORT guidelines is shown in Fig 1.
FIGURE 1.
Patient flow according to CONSORT guidelines.
Baseline characteristics of the 143 girls and 58 boys who received the study vaccine are summarized in Table 1. Approximately 28% percent of the participants were 9 years old, 35% were 10 years old, and 37% were 11 years old at baseline. The racial and ethnic diversity of the accrued participants was generally reflective of the populations seen in the study clinics, including almost half of Hispanic ethnicity, and a diverse racial background.
TABLE 1.
Participant Characteristics at Baseline
| All | Girls | Boys | |
|---|---|---|---|
| (n = 201) | (n = 143) | (n = 58) | |
| Age, y, mean (SD) | 10 (0.8) | 10 (0.8) | 10 (0.8) |
| Race, n (%) | |||
| American Indian or Alaskan Native | 4 (2.0) | 4 (2.8) | 0 (0) |
| Asian | 23 (11.4) | 15 (10.5) | 8 (13.8) |
| Black or African American | 7 (3.5) | 5 (3.5) | 2 (3.5) |
| Native Hawaiian or other Pacific Islander | 1 (0.5) | 1 (0.7) | 0 (0) |
| Unknown | 8 (4.0) | 7 (4.9) | 1 (1.7) |
| White | 131 (65.2) | 92 (64.3) | 39 (67.2) |
| More than 1 race | 27 (13.4) | 19 (13.3) | 8 (13.8) |
| Ethnicity, n (%) | |||
| Hispanic or Latino | 100 (49.8) | 75 (52.5) | 25 (43.1) |
| Not Hispanic or Latino | 100 (49.8) | 68 (47.6) | 32 (55.2) |
| Unknown | 1 (0.5) | 0 (0) | 1 (1.7) |
| BMI, kg/m2, mean (SD) | 19.7 (4.7) | 19.8 (4.6) | 19.6 (4.8) |
| Menarche, yes, n (%) | NA | 9 (6.3) | NA |
Menarche data were only presented for girls. NA, not applicable.
HPV16 and HPV18 Antibody Levels and Kinetics
All available samples were used for measurement of HPV-type specific antibodies. Serum HPV16 and HPV18 antibody GMCs in all participants, girls and boys, before first dose (baseline), at 6, 12, 18, 24 and 30 months as well as the ratios of HPV16 and HPV18 GMCs between 12- to 6-month, 18- to 12-month, and 24- to 18-month visits are summarized in Table 2. The data included 2 participants (1 girl and 1 boy) who declined the booster at 24 months. HPV16 and HPV18 antibody levels were below the assay cutoff at baseline in 96% and 80% of participants, respectively, and the GMCs of HPV16 and HPV18 antibodies at baseline were 0.73 IU/mL and 0.75 IU/mL, respectively. At 6 months after the prime dose, HPV16 and HPV18 antibody GMCs increased to 25.20 IU/mL and 10.67 IU/mL, respectively, and declined to 14.54 and 7.27 IU/mL, respectively, at 12 months. HPV16 and HPV18 GMCs remained stable between 12- and 24-month timepoints as evidenced by the GMC ratios for the 18- vs 12-month and 24- vs 18-month timepoints being 1.03 and 1.00 for HPV16, and 1.00 and 0.98 for HPV18, respectively (P < .0001 for all comparisons made for all participants). The stable GMCs between months 12, 18, and 24 (prebooster) were almost 20-times and 10-times higher than that of the baseline GMCs for HPV16 and HPV18 respectively. In response to deferred booster dose administration, GMCs for both HPV16 and HPV18 were highly elevated at the 30-month visit.
TABLE 2.
Summary of HPV 16 and 18 Antibody Responses
| HPV16 Antibody | HPV18 Antibody | |
|---|---|---|
| All participants | ||
| Time, GMC (95% CI)a | ||
| Baseline (n = 179 for HPV16, n = 178 for HPV18) | 0.73 (0.69–0.78) | 0.75 (0.70–0.80) |
| 6 mo (n = 179) | 25.20 (22.19–28.61) | 10.67 (9.47–12.02) |
| 12 mo (n = 179) | 14.54 (12.60–16.77) | 7.27 (6.33–8.34) |
| 18 mo (n = 179) | 15.01 (12.73–17.71) | 7.23 (6.19–8.44) |
| 24 mo (n = 180) | 15.05 (12.71–17.81) | 7.11 (6.01–8.41) |
| 30 mo (n = 178) | 427.1 (362.2–502.3) | 134.8 (114.9–158.3) |
| Ratio, GMC ratio (lower bound of 1-sided 95% CI; P)b | ||
| 12/6 mo ratio | 0.58 (0.54; >.9999) | 0.68 (0.64; >.9999) |
| 18/12 mo ratio | 1.03 (0.96; <.0001) | 1.00 (0.99; <.0001) |
| 24/18 mo ratio | 1.00 (0.92; <.0001) | 0.98 (0.91; <.0001) |
| Girls | ||
| Time, GMC (95% CI) | ||
| Baseline (n = 130 for HPV16, n = 129 for HPV18) | 0.72 (0.68–0.77) | 0.77 (0.71–0.84) |
| 6 mo (n = 130) | 25.28 (21.66–29.49) | 10.81 (9.32–12.55) |
| 12 mo (n = 130) | 15.59 (13.25–18.35) | 7.71 (6.53–9.11) |
| 18 mo (n = 130) | 15.91 (13.36–18.95) | 7.51 (6.32–8.92) |
| 24 mo (n = 130) | 15.73 (13.08–18.91) | 7.30 (6.01–8.88) |
| 30 mo (n = 129) | 448.2 (369.4–543.8) | 136.5 (112.8–165.2) |
| Ratio, GMC ratio (lower bound of 1-sided 95% CI; P)b | ||
| 12/6 mo ratio | 0.62 (0.58; >.9999) | 0.71 (0.67; >.9999) |
| 18/12 mo ratio | 1.02 (0.95; <.0001) | 0.97 (0.92; <.001) |
| 24/18 mo ratio | 0.99 (0.91; .0001) | 0.97 (0.90; <.001) |
| Boys | ||
| Time, GMC (95% CI) | ||
| Baseline (n = 49) | 0.75 (0.65–0.87) | 0.70 (0.63–0.77) |
| 6 mo (n = 49) | 24.99 (19.91–31.36) | 10.30 (8.51–12.47) |
| 12 mo (n = 49) | 12.07 (8.96–16.25) | 6.20 (4.81–7.99) |
| 18 mo (n = 49) | 12.88 (8.67–19.13) | 6.53 (4.63–9.22) |
| 24 mo (n = 50) | 13.41 (9.16–19.63) | 6.62 (4.72–9.29) |
| 30 mo (n = 49) | 376.3 (277.6–510.1) | 130.5 (96.00–177.3) |
| Ratio, GMC ratio (lower bound of 1-sided 95% CI; P)c | ||
| 12/6 mo ratio | 0.49 (0.42; >.9999) | 0.60 (0.54; >.9999) |
| 18/12 mo ratio | 1.07 (0.86; .0001) | 1.05 (0.88; .0001) |
| 24/18 mo ratio | 1.02 (0.83; <.001) | 1.01 (0.83; <.001) |
GMC, geometric mean concentration (IU/mL).
Derived from log-normal distribution.
Derived from 1-sided pair t test with a noninferiority margin of −0.35 standard deviations. If the lower bound of the 95% CI is above the exp (−0.35 standard deviations of changes in log-transformed HPV16/18), it will produce a 1-sided P value <.05 and indicates the subsequent time point had an noninferior HPV16/HPV18 to the prior time point. To account for multiple comparisons, each individual P value needs to be multiplied by the number of comparisons for the threshold of statistical significance. Hence, a P value of less than .0167 (.0167 × 3 = .0501) is considered necessary for statistical significance after accounting for 3 simultaneous comparisons (12 vs 6, 18 vs 12, and 24 vs 18).
Derived from 1-sided pair t test with a noninferiority margin of −0.50 standard deviations. If the lower bound of the 95% CI is above the exp (−0.50 standard deviations of changes in log-transformed HPV16/18), it will produce a 1-sided P value <.05 and indicates the subsequent time point had an noninferior HPV16/HPV18 to the prior time point. To account for multiple comparisons, each individual P value needs to be multiplied by the number of comparisons for the threshold of statistical significance. Hence, a P value of less than .0167 (.0167 × 3 = .0501) is considered necessary for statistical significance after accounting for 3 simultaneous comparisons (12 vs 6, 18 vs 12, and 24 vs 18).
HPV16 and HPV18 antibody levels and kinetics were similar between girls and boys, although GMCs were generally lower in boys during the plateau phase between 12 and 24 months. There was 1 girl who did not mount any serologic response to HPV16/HPV18 after the prime dose, although a serological response was observed after the booster dose. In addition, antibody responses below the assay cutoff at 2 or more timepoints between months 12 and 24 were observed in 8 participants (4.5% overall; 3.8% of girls and 6.0% of boys), including in 1 participant for HPV16 only, 5 participants for HPV18 only, and 2 participants for both HPV16 and HPV18.
Figure 2 illustrates the kinetics of HPV16 and HPV18 antibody GMCs at baseline and at 6, 12, 18, 24, and 30 months. Both HPV16 and HPV18 antibody response displayed similar kinetics: a 2 to 3 log sharp increase in the GMCs after first dose of vaccine measured at 6 months followed by an approximate 0.5 log decrease at 12 months, which stabilized until 24 months before a second surge in response to a deferred booster dose of Gardasil9, which resulted in a 5 to 6 log rise from baseline.
FIGURE 2.
Plot of HPV16 and HPV18 antibody GMC levels by study visit for all participants, girls and boys. X-axis: visits; Y-axis: GMC levels in IU/mL (log scale with corresponding 95% CIs).
HPV16 and HPV18 Antibody Response Stability
The frequency of participants with decreased (more than 2-fold decrease), stable (within 2-fold change) and increased (greater than 2-fold increase) antibody levels are summarized in Table 3. The majority of participants showed stable antibody levels between months 18 vs 12 or between months 24 vs 18. Protocol-defined significant decreases in antibody concentrations between months 18 vs 12 for HPV16 and HPV18 were observed in 7 out of 179 (3.9% [95% CI: 1.6% to 7.9%]) and 6 out of 179 (3.4% [95% CI: 1.2% to 7.2%]) participants, respectively, and corresponding decreases in antibody concentrations between months 24 vs 18 were observed for 8 out of 179 (4.5% [95% CI: 2% to 8.6%]) and 6 out of 179 (3.6% [95% CI: 1.2% to 7.2%]) participants, respectively. Taken together, these represented a total of 22 out of 179 participants (12.3%), with 9 participants showing declines in HPV16 alone, 8 participants showing declines in HPV18 alone, and 5 participants showing declines in both HPV16 and HPV18 antibody levels. No participant showed evidence of protocol-defined decrease in antibody levels at both time comparisons (ie, months 18 vs 12 and months 24 vs 18) to either HPV16 or HPV18.
TABLE 3.
Summary of Changes in HPV16 and HPV18 Antibody Concentrations
| HPV16 | HPV18 | |||
|---|---|---|---|---|
| Freq (%) | 95% CI,a % | Freq (%) | 95% CI | |
| All participants | ||||
| 6–0 mo | ||||
| Decrease | 0 | NA | 0 | NA |
| Stable | 2 (1.1) | (0.1–4.0) | 2 (1.1) | (0.1–4.0) |
| Increase | 177 (98.9) | (96.0–99.9) | 176 (98.9) | (96.0–99.9) |
| 12–6 mo | ||||
| Decrease | 69 (38.6) | (31.4–46.1) | 43 (24.0) | (18.0–31.0) |
| Stable | 105 (58.7) | (51.1–66.0) | 134 (74.9) | (67.8–81.0) |
| Increase | 5 (2.8) | (0.9–6.4) | 2 (1.1) | (0.1–4.0) |
| 18–12 mo | ||||
| Decrease | 7 (3.9) | (1.6–7.9) | 6 (3.4) | (1.2–7.2) |
| Stable | 162 (90.5) | (85.2–94.4) | 164 (91.6) | (86.6–95.2) |
| Increase | 10 (5.6) | (2.7–10.0) | 9 (5.0) | (2.3–9.3) |
| 24–18 mo | ||||
| Decrease | 8 (4.5) | (2.0–8.6) | 6 (3.4) | (1.2–7.2) |
| Stable | 164 (91.6) | (86.6–95.2) | 165 (92.2) | (87.2–95.7) |
| Increase | 7 (3.9) | (1.6–7.9) | 8 (4.5) | (2.0–8.6) |
| 30–24 mo | ||||
| Decrease | 1 (0.6) | (0.0–3.1) | 1 (0.6) | (0.0–3.1) |
| Stable | 5 (2.8) | (0.9–6.4) | 7 (3.9) | (1.6–7.9) |
| Increase | 172 (96.6) | (92.8–98.8) | 170 (95.5) | (91.3–98.0) |
| Girls | ||||
| 6–0 mo | ||||
| Decrease | 0 | NA | 0 | NA |
| Stable | 1 (0.8) | (0.0–4.2) | 2 (1.6) | (0.2–5.5) |
| Increase | 129 (99.2) | (95.8–100) | 127 (99.0) | (94.5–99.8) |
| 12–6 mo | ||||
| Decrease | 42 (32.3) | (24.4–41.1) | 26 (20.0) | (13.5–27.9) |
| Stable | 84 (64.6) | (55.8–72.8) | 102 (78.5) | (70.4–85.2) |
| Increase | 4 (3.1) | (0.8–7.7) | 2 (1.5) | (0.2–5.5) |
| 18–12 mo | ||||
| Decrease | 3 (2.3) | (0.5–6.6) | 4 (3.08) | (0.8–7.7) |
| Stable | 122 (93.9) | (88.2–97.3) | 120 (92.3) | (86.3–96.3) |
| Increase | 5 (3.9) | (1.3–8.8) | 6 (4.6) | (1.71–9.78) |
| 24–18 mo | ||||
| Decrease | 4 (3.1) | (0.8–7.7) | 3 (2.3) | (0.5–6.6) |
| Stable | 122 (93.9) | (88.2–97.3) | 123 (94.6) | (89.2–97.8) |
| Increase | 4 (3.1) | (0.8–7.7) | 4 (3.1) | (0.8–7.7) |
| 30–24 mo | ||||
| Decrease | 1 (0.8) | (0.0–4.2) | 1 (0.8) | (0.0–4.2) |
| Stable | 2 (1.6) | (0.2–5.5) | 3 (2.3) | (0.5–6.7) |
| Increase | 126 (97.7) | (93.4–99.5) | 125 (96.9) | (92.3–99.2) |
| Boys | ||||
| 6–0 mo | ||||
| Decrease | 0 | NA | 0 | NA |
| Stable | 1 (2.0) | (0.1–10.9) | 0 | NA |
| Increase | 48 (98.0) | (89.2–100) | 49 (100) | (92.8–100) |
| 12–6 mo | ||||
| Decrease | 27 (55.1) | (40.2–69.3) | 17 (34.7) | (21.7–49.6) |
| Stable | 21 (42.9) | (28.8–57.8) | 32 (65.3) | (50.4–78.3) |
| Increase | 1 (2.0) | (0.1–10.9) | 0 | NA |
| 18–12 mo | ||||
| Decrease | 4 (8.2) | (2.3–19.6) | 2 (4.1) | (0.5–14.0) |
| Stable | 40 (81.6) | (68.0–91.2) | 44 (89.8) | (77.8–96.6) |
| Increase | 5 (10.2) | (3.4–22.2) | 3 (6.1) | (1.3–16.9) |
| 24–18 mo | ||||
| Decrease | 4 (8.2) | (2.3–19.6) | 3 (6.1) | (1.3–16.9) |
| Stable | 42 (85.7) | (72.76–94.06) | 42 (85.7) | (72.8–94.1) |
| Increase | 3 (6.1) | (1.3–16.9) | 4 (8.2) | (2.3–19.6) |
| 30–24 mo | ||||
| Decrease | 0 | NA | 0 | NA |
| Stable | 3 (6.1) | (1.3–16.9) | 4 (8.2) | (2.3–19.6) |
| Increase | 46 (93.9) | (83.1–98.7) | 45 (91.8) | (80.4–97.7) |
Decrease is defined as more than 2 fold decrease; stable is defined as within 2 fold change; increase is defined as more than 2 fold increase. NA, not applicable.
Derived from the exact 95% CI.
Discussion
In this study, a single dose of Gardasil9 vaccine induced persistent and stable HPV16 and HPV18 antibody responses up to 24 months in US girls and boys, 9 to 11 years of age at the time of initiating vaccination. This study contributes evidence from the United States about the durability of titers for the nonavalent HPV vaccine among girls and boys and adds to the ongoing evidence being reviewed by national and international guideline bodies that are considering 1 dose HPV vaccine schedules.
Past studies have compared the immunogenicity and efficacy of a single-dose schedule with multidose schedules in girls and young women who were originally randomized to receive 2 or 3 doses of bivalent or quadrivalent HPV vaccines, but did not complete their allocated schedule during the course of these studies, permitting such post hoc analyses.3 In these studies, including the Costa Rica Vaccine Trial (CVT) in women aged 18 to 25 years, and the IARC/India study in girls aged 10 to 18 years, the frequency of incident and persistent infection with HPV16 or HPV18 was similar in participants receiving a single dose compared with those receiving 2 or 3 doses.3 HPV16 and HPV18 antibody levels remained stable for an extended period in all dose groups, even though GMCs were lower with 1 dose than with 2 or 3 doses.3 The stability of the antibody response after a single dose of the bivalent vaccine15 and quadrivalent vaccine16 has been reported for up to 11 and 10 years in the CVT Trial and IARC/India studies, respectively. However, these studies are limited by the post hoc nature of these analyses, differences in eligibility by dosing groups, and likely differences in ages of sexual debut among the dose groups. A larger trial is now underway to validate these findings with a randomized trial design.17
Our study’s findings are similar to the recently published trial from Tanzania, where girls 9 to 14 years of age were randomized to a single-dose or multidose schedules of either the bivalent or nonavalent vaccine.6 That study demonstrated that a single dose induced stable antibody responses to HPV 16 and HPV18 up to 24 months for both vaccines. Further, a companion immunobridging analysis of their results with the CVT and IARC/India trial showed that 1 dose of HPV vaccine in young girls might provide sufficient protection against persistent HPV infection.4 Together with our data, these results suggest that potent HPV16 and HPV18 antibody levels may persist up to 24 months or longer from a single dose of the nonavalent vaccine.
Both girls and boys showed stable responses to HPV16/18 between 12 and 24 months, although HPV16/18 GMCs were numerically slightly lower in boys than those in girls. This finding is interesting as a prior nonavalent HPV vaccine study in 9 to 15 year-old girls and boys showed that boys demonstrated higher GMCs to all 9 HPV types than girls, albeit this was evaluated after 3 doses of vaccination.18 Whether these differences will persist beyond 2 years of follow-up and whether the slight differences would translate to clinically meaningful effects is unknown.
In our study, GMCs of HPV16 and HPV18 antibodies increased at 6 months, followed by a decline from months 6 to 12, then remained stable from months 12 to 24, with levels 20 and 10 times of baseline levels for HPV16 and HPV18, respectively. The kinetics of the antibody responses after 1 dose of Gardasil9 are largely consistent with the data from the study in Tanzania.6 The plateauing of HPV16 and HPV18 antibody levels between 12 and 24 months after a single dose of Gardasil9 confirmed our study hypothesis (ie, antibody responses at 18-vs 12-months and 24- vs 18-months were noninferior). Yet, the perturbations in antibody titers seen in a minority of participants merits further explorations into the quality of antibody responses and correlation with efficacy (ie, infection or precancer) endpoints.
Limitations of this study include the relatively limited duration of follow-up (24 months) before receipt of the booster, and limited representation of African American participants. Further, although HPV enzyme-linked immunosorbent assays have been widely used and shown to have high concordance with other assays, there are inherent assay-specific differences that do not permit direct cross-study comparisons with other assays. That said, the use of the World Health Organization-supported HPV serology reference standard for HPV16 and HPV18 and the subsequent reporting of the data in international units (IU/mL) may permit careful comparisons with studies also utilizing the same reference standard.19
Conclusions
Our study provides the immunogenicity data showing that a single dose of the nonavalent HPV vaccine, Gardasil9, induces persistent and stable HPV16 and HPV18 antibody responses for up to 24 months in 9 to 11-year-old girls and boys in the United States. This study offers supporting evidence for delayed booster schedules in response to vaccine supply shortages and other contingencies (eg, pandemic-related delays). The study also adds important incremental evidence to the ongoing global efforts investigating the efficacy of single-dose HPV vaccination and raises further scientific questions related to the quality of antibody responses that merits further exploration and underscore the need for efficacy trials. This study is among the initial studies that offer insights into antibody kinetics up to 24 months after a single dose of Gardasil9 and these results may ultimately be able to be “immuno-bridged” to outcomes from ongoing randomized clinical trials evaluating single-dose schedules in preventing persistent HPV infection and precancer outcomes.
Acknowledgments
We thank the study participants and their legal representatives (parents and guardians) for their sustained interest and participation in the study over several years; physicians and clinic staff at the University of Arizona pediatric clinic, UCLA West LA Pediatrics Office, and Tucson Central Pediatrics for their support in participant recruitment and study conduct; the study staff, Angelica Mondragon, Susan Vanzzini, Valerie Butler, Bonita Weible, Laura Duckett, Jose Guillen-Rodriguez, and Jerilyn San Jose for their dedication to study recruitment, participant retention, study conduct, study monitoring and data management, Norma Diaz-Mayoral at the NCI Frederick Biorepository for her dedicated efforts in biospecimen management, and Drs Mark Sherman and Francisco Garcia for their guidance and efforts in the initial conception and design of the study.
Glossary
- GMC
geometric mean concentration
- HPV
human papillomavirus
Footnotes
Drs Zeng, Moscicki, Chow, and Woo contributed to conception and design, study supervision, acquisition, analysis, and interpretation of data; Drs Hsu, Kemp, and Pinto contributed to conception and design, analysis, and interpretation of data; Dr Szabo contributed to conception and design, study supervision, and interpretation of data; Ms Dimond contributed to study supervision and interpretation of data; Dr Bauman contributed to study supervision; Dr Sahasrabuddhe contributed to conception and design, study supervision, and analysis and interpretation of data; and all authors contributed to the writing and review of manuscript and approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
This trial has been registered at ClinicalTrials.gov (identifier: NCT02568566).
Data collected for this study, including individual participant data and a data dictionary defining each field in the data set, will be made available to others. Data sharing will be available through NCI's Cancer Data Access System website at https://cdas.cancer.gov/eppt/. The study protocol, statistical analysis plan, and informed consent form are available via clinicaltrials.gov. Data can be requested by anyone by submitting a proposal through the NCI Cancer Data Access System website at https://cdas.cancer.gov/eppt/. The proposals are reviewed by NCI and a data transfer agreement is necessary before getting access to the requested data.
FUNDING: This work was supported, in whole or in part, with federal funds from the National Cancer Institute, National Institutes of Health (contract number HHSN261201500003I, 75N91019D00024 and grant number P30CA023074).
CONFLICT OF INTEREST DISCLOSURES: Dr Moscicki is on the Global Advisory Board for Merck. The other authors have no conflicts of interest relevant to this article to disclose.
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