Efficacy of Single-Dose Human Papillomavirus Vaccination among Young African Women
Abstract
Background
Single-dose human papillomavirus (HPV) vaccination, if efficacious, would be tremendously advantageous, simplifying implementation and decreasing costs.
Methods
We performed a randomized, multicenter, double-blind, controlled trial of single-dose nonavalent (HPV 16/18/31/33/45/52/58/6/11 infection) or bivalent (HPV 16/18 infection) HPV vaccination compared with meningococcal vaccination among Kenyan women 15 to 20 years of age. Enrollment and 6-monthly cervical swabs and a month 3 vaginal swab were tested for HPV deoxyribonucleic acid (DNA). Enrollment sera were tested for HPV antibodies. The modified intent-to-treat (mITT) cohort comprised participants who had an HPV antibody-negative result at enrollment and an HPV DNA-negative result at enrollment and month 3. The primary outcome was incident persistent vaccine-type HPV infection by month 18.
Results
Between December 2018 and June 2021, 2275 women were randomly assigned and followed. A total of 758 participants received the nonavalent HPV vaccine, 760 received the bivalent HPV vaccine, and 757 received the meningococcal vaccine; retention was 98%. Thirty-eight incident persistent infections were detected in the HPV 16/18 mITT cohort: one each among participants assigned to the bivalent and nonavalent groups and 36 among those assigned to the meningococcal group. Nonavalent vaccine efficacy (VE) was 97.5% (95% confidence interval [CI], 81.7 to 99.7%; P≤0.0001), and bivalent VE was 97.5% (95% CI, 81.6 to 99.7%; P≤0.0001). Thirty-three incident persistent infections were detected in the HPV 16/18/31/33/45/52/58 mITT cohort: four in the nonavalent group and 29 in the meningococcal group. Nonavalent VE for HPV 16/18/31/33/45/52/58 was 88.9% (95% CI, 68.5 to 96.1; P<0.0001). The rate of serious adverse events was 4.5% to 5.2% by group.
Conclusions
Over the 18-month timeframe we studied, single-dose bivalent and nonavalent HPV vaccines were each highly effective in preventing incident persistent oncogenic HPV infection, similar to multidose regimens. (Funded by the National Institutes of Health, the Bill and Melinda Gates Foundation, and the University of Washington; ClinicalTrials.gov number, NCT03675256.)
Introduction
Almost 90% of the more than 600,000 new cervical cancer cases and 340,000 cervical cancer deaths in 2020 occurred in low- and middle-income countries (LMICs).1 Vaccination to prevent human papillomavirus (HPV) infection, the primary cause of cervical cancer, is a key intervention in the World Health Organization’s (WHO) Global Cervical Cancer Elimination Strategy, which calls for vaccination of 90% of girls.2,3 HPV vaccines, licensed as two to three intramuscular injections administered over the course of 6 to 12 months, reduce an individual’s risk of acquiring persistent oncogenic HPV infection by more than 90%.4-6 At the population level, increasing vaccine coverage increases effectiveness; vaccination of multiage adolescent cohorts (9 to 14 years) with catch-up vaccination (to 26 years of age) doubles the prevention of HPV-associated precancerous lesions.7 However, HPV vaccine coverage remains low8; in 2019, the global coverage for HPV vaccination was 15% among adolescent girls.9
In LMICs, low vaccine coverage is attributable, in part, to the cost and logistics of reaching girls with the standard multidose vaccine schedule. Single-dose vaccination could halve vaccination costs, potentially increase coverage, and simplify the logistics compared with multidose administration. Currently, four HPV vaccines are licensed, all targeting high-risk (oncogenic) HPV types that cause 70% of cancers (HPV 16/18) and two also targeting low-risk HPV types that cause genital warts (HPV 6/11). The bivalent vaccine (Cervarix [GlaxoSmithKline, London, UK]) and Cecolin [Xiamen Innovax Biotech Co. Ltd. Xiamen, China]) prevents HPV 16/18 infection, the quadrivalent vaccine (Gardasil; Merck Sharp & Dohme, Kenilworth, NJ) prevents HPV 16/18/6/11 infection, and the nonavalent vaccine (Gardasil-9; Merck Sharp & Dohme Corp.) prevents HPV 16/18/31/33/45/52/58/6/11 infection (including five additional high-risk HPV types).10
Observational studies suggest that single-dose HPV vaccine effectiveness is equivalent to a two- or three-dose regimen: however, vaccination guidelines recommend multidose strategies and questions persist regarding single-dose efficacy.11-14 In Kenya, multidose HPV vaccination was planned for 9- to 14-year-old girls through a national immunization program since October 2019. However, because of supply constraints, HPV vaccination has been offered to 10-year-old girls only. To date, an estimated 10% of 10-year-old girls have received their first HPV vaccine dose and 3% have received the second dose.15 Catch-up vaccination for adolescent girls and young women 15 years of age and older is not provided, with cervical cancer screening offered to older women. Testing the efficacy of single-dose HPV vaccination among young women 15 years of age and older, within the context of cytological screening for dysplastic lesions in a clinical trial, was determined to be ethical, as vaccination for this age group in Kenya and many LMICs is not currently supported through national programs or global immunization bodies. Specifically, we evaluated zero versus single-dose HPV vaccination against the backdrop of substantial disparities in cervical cancer incidence.16 Also, a superiority design was chosen, compared with a noninferiority design, as the smaller sample size and shorter timeline would support robust, feasible, and timely evidence. In this study, we report the findings of an efficacy trial of single-dose bivalent and nonavalent HPV vaccination among young women in Kenya.
Methods
Trial Design and Oversight
This randomized, multicenter, double-blind, parallel, three-arm, controlled superiority trial tested the efficacy of single-dose bivalent (HPV 16/18) and single-dose nonavalent (HPV 16/18/31/33/45/52/58/6/11) HPV vaccination, as described in the published protocol.17 Kenya’s HPV National Immunization Program, launched in October 2019, offers two doses of the quadrivalent HPV vaccine to 10-year-old girls and is not provided through the national immunization program for persons 15 years of age and older; meningococcal vaccination is used during outbreaks.18 Meningococcal vaccination was chosen as the comparator because meningococcal antibodies offer potential clinical benefits and do not affect HPV outcomes. Participants were randomly assigned to immediate nonavalent HPV vaccination and delayed (36 months after enrollment) meningococcal vaccination, immediate bivalent HPV vaccination and delayed meningococcal vaccination, or immediate meningococcal vaccination and delayed HPV vaccination. The primary analysis was planned for month 18, with the final analysis at month 36 evaluating durability (not reported herein). At this time, the trial is ongoing. After the 18-month results presented in this article, we are continuing follow-up in a blinded crossover design to evaluate vaccine durability.
The Kenya Medical Research Institute (KEMRI) Scientific and Ethics Review Unit and the University of Washington Institutional Review Board approved this study. The study is registered with ClinicalTrials.gov (NCT03675256).
Participants
Participants were recruited through community outreach. Participants were eligible for randomization if they were able to provide informed consent, were 15 to 20 years of age, were of female sex assigned at birth, were sexually active (reporting one to five lifetime partners), and resided within the study area. Study exclusion criteria were a positive human immunodeficiency virus (HIV) diagnostic test result, history of HPV vaccination, allergies to vaccine components or latex, current pregnancy, hysterectomy, or history of immunosuppressive conditions.
Setting
This study was conducted at three KEMRI clinical sites in Thika, Nairobi, and Kisumu, Kenya. All participants (and their parents/guardians, in the case of minors) provided informed consent, which included counseling about randomization, risks and benefits of participation, study procedures, and their rights as research participants.
Screening and Enrollment
Potential participants completed eligibility screening with a provider, including a detailed medical history, collection of external genital (labial/vulvar/perineal) and cervical swabs for HPV deoxyribonucleic acid (DNA) testing, and serum for HPV antibody testing. Participants received cytological cervical cancer screening at enrollment. Sexual and reproductive health services (contraception, sexually transmitted infection diagnosis and treatment, and HIV preexposure prophylaxis) were offered at enrollment and every visit. All questionnaires were conducted using electronic case report forms (DF/Net Research Inc., Seattle, WA).
Randomization and Vaccination
Randomization was stratified by site, using a fixed block size of 15 and a 1:1:1 allocation. Study staff, participants, investigators, clinic staff, laboratory technicians, and other study team members did not have access to the randomization codes, except for the unblinded statistical analysts and unblinded pharmacists at each site. Blinded study assignment was implemented via Randomize.net (Ottawa, ON, Canada; https://www.randomize.net). An unblinded pharmacist entered the participant identification number on Randomize.net, obtained the next sequential intervention assignment, recorded the participant identification number and randomization identifier on an electronic case report form, drew up the vaccine in a masked syringe, and administered the vaccination.
Study Follow-up Procedures
Participants were seen at months 3 and 6 and then every 6 months for 18 months after enrollment. Providers administered clinical questionnaires and collected a cervical swab at each 6-month visit. Participants self-collected vaginal swabs using validated instructions at month 3; self-collected swabs, which have similar accuracy compared with provider-collected cervical swabs,19 were available at subsequent follow-up visits by participant choice or to comply with Covid-19 research restrictions.
Laboratory Methods
HPV DNA genotyping was conducted using the Anyplex II HPV28 assay (Seegene, Seoul, South Korea), a multiplexed type-specific real-time polymerase chain reaction (PCR)–based assay,20,21 at the University of Washington–University of Nairobi East Africa STI Laboratory in Mombasa, Kenya, with standard proficiency testing.22 For HPV-positive samples, a low (+), intermediate (++), or high (+++) positivity was indicated; samples + or greater were considered positive. All runs included negative and positive controls and the housekeeping human gene, β-globin, as an internal control. Runs were performed with the CFX96 Real-Time PCR System (Bio-Rad, Hercules, CA).
Serum specimens were shipped to the University of Washington in Seattle, and tested at the Galloway Laboratory at Fred Hutchinson Cancer Research Center. HPV immunoglobulin G antibodies were detected using a multiplex Luminex assay.23,24 The preestablished mean fluorescent intensity seropositivity cutoffs for HPV 16/18/31/33/45/52/58 were used (Table S14 in the Supplementary Appendix).
Sexually transmitted infections (Neisseria gonorrhoeae, Chlamydia trachomatis, or Trichomonas vaginalis) were assessed by nucleic acid amplification testing (APTIMA; Hologic/GenProbe, San Diego, CA) at the University of Washington–University of Nairobi East Africa STI Laboratory; herpes simplex virus 2 was evaluated by the Focus enzyme-linked immunosorbent assay (ELISA), and bacterial vaginosis was evaluated using the Nugent score.
Outcomes and Assessment
The primary trial end point was incident persistent cervical HPV infection among participants who had an HPV DNA-negative test result (external genital and cervical swabs) at enrollment and month 3 (self-collected vaginal swab) and an HPV antibody-negative test result at enrollment (the modified intent-to-treat [mITT] cohort). For inclusion in the HPV 16/18 mITT cohort, participants were HPV 16/18 naive. Similarly, for the HPV 16/18/31/33/45/52/58 mITT cohort, participants were HPV 16/18/31/33/45/52/58 naive. Persistent HPV, a surrogate marker for cervical dysplasia/precancer, was defined as high-risk vaccine type–specific HPV (i.e., HPV 16/18 for the bivalent vaccine and HPV 16/18/31/33/45/52/58 for the nonavalent vaccine) detected at two consecutive time points no less than 4 months apart after month 3 and up to and including month 18 (same HPV type at both time points) for the primary analysis.5 Participants without swabs after month 3 did not contribute follow-up time in the primary analysis. Participants in the bivalent vaccine group were not included in the HPV 16/18/31/33/45/52/58 analysis, as the study was not powered to detect cross-protection. Cervical swabs were tested for the primary end point; vaginal swabs were substituted if necessary. Sensitivity analysis was planned for the following subset: participants who had an HPV DNA-negative test result at enrollment, month 3, and month 6 and had an antibody-negative test result at enrollment (extended sensitivity cohort) to match the analysis cohort for HPV vaccine licensure trials. The extended sensitivity cohort analysis used all available data, including visits after the prespecified month 18 data cutoff. Safety was assessed through adverse event reporting following the U.S. National Institute of Allergy and Infectious Diseases guidelines.25
Statistical Analysis
Sample size calculations assumed that 52% of participants would meet requirements for inclusion in the mITT cohort based on the observed prevalence of HPV infection in similar settings.26 The sample size calculations also assumed a combined persistent HPV 16/18/31/33/45/52/58 annual incidence of 5%, single-dose vaccine efficacy (VE) of 75%, and loss-to-follow-up of 10% with a fixed follow-up time of 12 months. Assuming a proportional hazards model (seqDesign in R) with 80% power to detect 75% efficacy, a sample size of 2250 participants was planned.
We used Cox proportional hazards models stratified by site to estimate the hazard ratios of the interventions versus control for the primary and sensitivity analyses. Models for the sensitivity analyses used crude incidence rate ratios instead of Cox proportional hazards models when no events were observed in a group. Follow-up was calculated as days since the month 3 visit for the primary analysis and as days since month 6 for the extended sensitivity analysis. Participants who did not reach the efficacy end points were censored at the time of the last negative test result at or before the month 18 visit. VE was expressed as 1 minus the hazard ratio (or relative risk). The log-rank test stratified by site was used to calculate the P value. Cumulative incidence Kaplan-Meier curves of time to infection were calculated by intervention group. Efficacy analyses were performed on the month 18 mITT cohorts. In post hoc analysis, we evaluated the absolute difference in cumulative incidence of HPV from the Kaplan-Meier curves at month 18. We calculated the cumulative incidence of chlamydia and gonorrhea during follow-up by assigned group.
Safety was assessed among all participants; the three groups were compared using Fisher’s exact test. We performed all analyses using SAS software (version 9.4; SAS Institute, Cary, NC) and double coded in R (version 4.1; R Core Team, Vienna, Austria).
An independent data and safety monitoring board (DSMB) was constituted to review study progress, participant safety, and the primary outcome; the DSMB met annually.
Results
Participants
Between December 20, 2018, and November 15, 2019, 3090 participants were screened for study eligibility and 2275 (74%) were enrolled. Of ineligible individuals, 132 (32%) had a positive pregnancy test, 51 (12%) declined study procedures, 34 (8%) had a positive rapid HIV test, and 202 (48%) met other exclusion criteria. Enrolled participants were randomly assigned (Fig. 1): 758 to the nonavalent HPV vaccine group, 760 to the bivalent HPV vaccine group, and 757 to the meningococcal vaccine group. At enrollment, 1301 participants (57%) were 15 to 17 years of age and 1392 (61%) had one lifetime sexual partner; baseline characteristics were comparable between the groups (Table S1). The group was representative of the population who would be eligible for HPV vaccination in this manner should such a decision be made (Table S22).
Figure 1
Randomized Trial Profile.
Ab denotes antibody, HIV human immunodeficiency virus, HPV human papillomavirus, ITT intention to treat, m month, and mITT modified intention to treat.
* Of the 419 people who were ineligible for randomization, 132 (32%) had a positive pregnancy test, 51 (12%) were not willing to follow study procedures or be randomly assigned, 34 (8%) had a positive rapid HIV diagnostic test, and 202 (48%) met other exclusion criteria.
† Complete baseline data include HPV antibody results at month 0 and HPV DNA results at months 0 and 3.
For the HPV 16/18 analysis, participants who had a positive test result for the HPV 16/18 antibody or HPV 16/18 DNA at enrollment or for HPV DNA at month 3 (n=661), who had missing antibody results (n=1), or who were a missing month 3 swab (n=155) were excluded. Among the 1458 participants who met the criteria for the primary HPV 16/18 mITT analysis, 496 were in the nonavalent group, 489 were in the bivalent group, and 473 were in the meningococcal group. For the HPV 16/18/31/33/45/52/58 analysis, participants who had a positive test result for HPV 16/18/31/33/45/52/58 antibody or HPV 16/18/31/33/45/52/58 DNA at enrollment or HPV DNA at month 3 (n=792), who had missing antibody results (n=1), or who were a missing month 3 swab (n=106) were excluded. Of the 615 participants eligible for the primary HPV 16/18/31/33/45/52/58 analysis, 325 were in the nonavalent vaccine group and 290 were in the meningococcal vaccine group. One participant in the meningococcal vaccine group did not have at least one post–month 3 end-point swab. The median age was 17 years for the HPV 16/18 and HPV 16/18/31/33/45/52/58 mITT cohorts; overall, the baseline characteristics by study groups were comparable (Tables 1 and S27).
Table 1
| Characteristic | HPV 16/18 mITT, n (%) | HPV 16/18/31/33/45/52/58 mITT, n (%) | |||
|---|---|---|---|---|---|
| Nonavalent HPV (n=496) | Bivalent HPV (n=489) | Meningococcal (n=473) | Nonavalent HPV (n=325) | Meningococcal (n=290) | |
| Age group (yr) | |||||
| 15–17 | 299 (60.3) | 278 (56.9) | 278 (58.8) | 197 (60.6) | 168 (57.9) |
| 18–20 | 197 (39.7) | 211 (43.1) | 195 (41.2) | 128 (39.4) | 122 (42.1) |
| Marital status | |||||
| Never married | 478 (96.4) | 462 (94.5) | 446 (94.3) | 315 (96.9) | 269 (92.8) |
| Married | 14 (2.8) | 24 (4.9) | 20 (4.2) | 7 (2.2) | 15 (5.2) |
| Previously married | 3 (0.6) | 3 (0.6) | 7 (1.5) | 2 (0.6) | 6 (2.1) |
| Other | 1 (0.2) | 0 (0.0) | 0 (0.0) | 1 (0.3) | 0 (0.0) |
| Education (highest level) | |||||
| No schooling | 1 (0.2) | 2 (0.4) | 1 (0.2) | 1 (0.3) | 1 (0.3) |
| Primary school, some or complete | 40 (8.1) | 30 (6.1) | 36 (7.6) | 27 (8.3) | 27 (9.3) |
| Secondary school, some or complete | 359 (72.4) | 368 (75.3) | 355 (75.1) | 241 (74.2) | 220 (75.9) |
| Postsecondary school | 96 (19.4) | 89 (18.2) | 81 (17.1) | 56 (17.2) | 42 (14.5) |
| Earns an income of her own | |||||
| No | 437 (88.1) | 417 (85.3) | 417 (88.2) | 284 (87.4) | 248 (85.5) |
| Yes | 59 (11.9) | 72 (14.7) | 56 (11.8) | 41 (12.6) | 42 (14.5) |
| Has a current main or steady sexual partner | |||||
| No | 144 (29.0) | 152 (31.1) | 145 (30.7) | 98 (30.2) | 95 (32.8) |
| Yes | 352 (71.0) | 337 (68.9) | 328 (69.3) | 227 (69.8) | 195 (67.2) |
| Age when first had vaginal intercourse (yr) | |||||
| <15 | 123 (24.8) | 116 (23.7) | 103 (21.8) | 80 (24.6) | 65 (22.4) |
| 15–17 | 265 (53.4) | 274 (56.0) | 282 (59.6) | 185 (56.9) | 173 (59.7) |
| ≥18 | 96 (19.4) | 93 (19.0) | 79 (16.7) | 54 (16.6) | 46 (15.9) |
| Do not remember | 12 (2.4) | 6 (1.2) | 9 (1.9) | 6 (1.8) | 6 (2.1) |
| Lifetime sex partners (n) | |||||
| 1 | 322 (64.9) | 332 (67.9) | 289 (61.1) | 217 (66.8) | 184 (63.4) |
| 2 | 121 (24.4) | 100 (20.4) | 113 (23.9) | 78 (24.0) | 65 (22.4) |
| ≥3 | 53 (10.7) | 57 (11.7) | 71 (15.0) | 30 (9.2) | 41 (14.1) |
| Condom use with last vaginal sex | |||||
| No | 153 (30.8) | 155 (31.7) | 140 (29.6) | 98 (30.2) | 78 (26.9) |
| Yes | 237 (47.8) | 235 (48.1) | 238 (50.3) | 156 (48.0) | 144 (49.7) |
| No sex in past year | 106 (21.4) | 99 (20.2) | 95 (20.1) | 71 (21.8) | 68 (23.4) |
Baseline Characteristics for the mITT Cohort.*
*
The baseline characteristics of the intention-to-treat population are shown in Table S1. HPV denotes human papillomavirus, mITT modified intention to treat.
One hundred percent of participants received their assigned vaccine, without administration error. By the month 18 visit, retention for assessment of the primary end points was 98% for two swabs and 94% for three swabs; 94% of swabs were cervical swabs and 6% of swabs were self-collected vaginal swabs (Tables S5 to S8 and S13). The cumulative incidence of chlamydia, gonorrhea, and persistent nonvaccine HPV types was comparable across the three study groups (Tables S16 and S26).
Primary Outcome
A total of 38 incident persistent infections were detected in the HPV 16/18 mITT cohort: 1 each among participants assigned to the bivalent and nonavalent vaccine groups and 36 among those assigned to the meningococcal vaccine group (Table 2). The incidence of persistent HPV 16/18 was 0.17 per 100 woman-years in the bivalent and nonavalent vaccine groups, compared with 6.83 per 100 woman-years in the meningococcal vaccine control group. Bivalent VE was 97.5% (95% CI, 81.6 to 99.7% and nonavalent VE was 97.5% (95% CI, 81.7 to 99.7%; P<0.0001) (Fig. 2). Thirty-three incident persistent infections were detected in the HPV 16/18/31/33/45/52/58 mITT cohort: 4 in the nonavalent vaccine group and 29 in the meningococcal vaccine group (Table 3). The incidence of persistent HPV 16/18/31/33/45/52/58 was 1.03 per 100 woman-years in the nonavalent vaccine group compared with 9.42 per 100 woman-years in the meningococcal group. Nonavalent VE for HPV 16/18/31/33/45/52/58 was 88.9% (95% CI, 68.5 to 96.1%; P<0.0001) (Fig. 3).
Figure 2
Kaplan-Meier Curves for the Primary Modified Intention-to-Treat Analyses.
HPV 16/18 infection. HPV denotes human papillomavirus.
Figure 3
Kaplan-Meier Curves for the Primary Modified Intention-to-Treat Analyses.
HPV 16/18/31/33/45/52/58 infection. HPV denotes human papillomavirus.
Table 2
| Arm | Enrolled (n) | HPV 16/18 Naive (mITT) (n)* | Incident Persistent HPV 16/18 (n) | Woman-yr of Follow-Up† | Incidence of Persistent HPV 16/18 per 100 Woman-yr | 95% CI‡ | Statistical Comparisons§ | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Lower Bound | Upper Bound | Comparison | VE (%) | 95% CI (%) | P Value (Log-Rank) | ||||||
| Nonavalent HPV | 758 | 496 | 1 | 596.27 | 0.17 | 0.00 | 0.93 | Nonavalent vs. meningococcal | 97.5 | 81.7– 99.7 | <0.0001 |
| Bivalent HPV | 760 | 489 | 1 | 589.38 | 0.17 | 0.00 | 0.95 | Bivalent vs. meningococcal | 97.5 | 81.6–99.7 | <0.0001 |
| Meningococcal | 757 | 473 | 36 | 527.35 | 6.83 | 4.78 | 9.45 | ||||
Incidence of Persistent HPV 16/18 Infection and Vaccine Efficacy by Month 18 (mITT Cohort).
*
Participants who were HPV 16/18 naive had an HPV 16/18 antibody-negative test result at enrollment and an HPV 16/18 DNA-negative test result at enrollment and month 3. CI denotes confidence interval, HPV human papillomavirus, mITT modified intention to treat, and VE vaccine efficacy.
†
Follow-up time begins at 3 months and includes only women who had an HPV 16/18 DNA-negative test result at month 0 and month 3 and an antibody-negative test result at month 0.
‡
Exact 95% CIs for incidence rate were computed using the Poisson distribution.
§
Hazard ratios with 95% CIs were estimated using a single Cox proportional hazards regression model with a three-way class variable for vaccine arm. The model was stratified by site, with the Efron method for handling ties, and vaccine arm was the only covariate. VE and 95% CIs were computed from the hazard ratio as 100 × (1 − hazard ratio). P values (log-rank) were computed for each comparison using the log-rank test.
Table 3
| Arm | Enrolled (n) | HPV 16/18/31/33/45/52/58 Naive (mITT) (n)† | Incident Persistent HPV 16/18/31/33/45/52/58 (n) | Woman-yr of Follow-Up‡ | Incidence of Persistent HPV 16/18/31/33/45/52/58 per 100 Woman-yr | 95% CI§ | Statistical Comparisons¶ | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Lower Bound | Upper Bound | Comparison | VE (%) | 95% CI(%) | P Value (Log-Rank) | ||||||
| Nonavalent HPV | 758 | 325 | 4 | 389.18 | 1.03 | 0.28 | 2.63 | Nonavalent vs. meningococcal | 88.9 | 68.5– 96.1 | <0.0001 |
| Meningococcal | 757 | 290 | 29 | 307.81 | 9.42 | 6.31 | 13.53 | ||||
Incidence of Persistent HPV 16/18/31/33/45/52/58 and VE by Month 18 (mITT Cohort).*
*
CI denotes confidence interval, HPV human papillomavirus, ITT intention to treat, mITT modified intention to treat, and VE vaccine efficacy.
†
Participants who were HPV 16/18/31/33/45/52/58 naive had an HPV 16/18/31/33/45/52/58 antibody-negative test result at enrollment and an HPV 16/18/31/33/45/52/58 DNA-negative test result at enrollment and month 3.
‡
Follow-up time among women with an HPV 16/18/31/33/45/52/58 DNA-negative result at months 0 and 3 and an antibody-negative result at month 0.
§
Exact 95% CIs for incidence rate were computed using the Poisson distribution.
¶
Hazard ratios with 95% CIs were estimated using a single Cox proportional hazards regression model with a three-way class variable for vaccine arm. The model was stratified by site, with the Efron method for handling ties, and vaccine arm was the only covariate. VE and 95% CIs were computed from the hazard ratio as 100 × (1 − hazard ratio). P values (log-rank) were computed for each comparison using the log-rank test.
In the extended sensitivity analysis, there were 16 incident persistent infections in the HPV 16/18 mITT cohort: 0 each among participants assigned to the bivalent and nonavalent vaccine groups and 16 among those assigned to the meningococcal vaccine group (Table S9). HPV 16/18 incidence was 0 per 100 women-years in the nonavalent and bivalent vaccine groups and 3.9 per 100 women-years in the meningococcal control group; nonavalent VE was 100% and bivalent VE was 100% (Table S9). In the extended sensitivity analysis, there were 15 incident persistent infections in the HPV 16/18/31/33/45/52/58 mITT cohort: 1 among participants assigned to the nonavalent group and 14 among those assigned to the meningococcal group; nonavalent VE was 95.0% (95% CI, 62.1 to 99.4%) (Table S10). VE results were similar in the sensitivity analysis, including participants with HPV antibodies at enrollment (Tables S23 and S24).
In post hoc analysis using only provider-collected end-point cervical swabs and excluding self-collected vaginal swabs, the results for the primary analysis were not different: the VE was 97.3% (95% CI, 80.0 to 99.6%) for each of the bivalent and nonavalent vaccines in the HPV 16/18 mITT cohort. Nonavalent VE was 91.4% (95% CI, 71.8 to 97.4%) in the HPV 16/18/31/33/45/52/58 mITT cohort (Tables S11 and S12).
In post hoc analysis, the absolute reduction in the HPV 16/18 mITT cohort for cumulative incident persistent HPV 16/18 infection was −7.7% (95% CI, −10.4 to −5.0%) for both the bivalent and nonavalent vaccines. The absolute incidence was 0.2% (95% CI, 0.0 to 0.6%) in the bivalent and nonavalent vaccine groups compared with 7.9% (95% CI, 5.4 to 10.4%) in the meningococcal group. For the HPV 16/18/31/33/45/52/58 mITT cohort, the absolute reduction in persistent HPV 16/18/31/33/45/52/58 infection was −9.3% (95% CI, −13.6 to −5.1%) for the nonavalent vaccine; there was an absolute incidence of 1.3% (95% CI, 0.0 to 2.5%) in the nonavalent vaccine group compared with 10.6% (95% CI, 6.9 to 14.2%) in the meningococcal group.
Safety
There were 112 participants who experienced serious adverse events (SAEs), which included 57 with pregnancy-related SAEs, 46 with infections or inflammatory conditions (of which 31 were malaria), 7 with injuries, and 5 with mental health illnesses. Overall, the frequency was similar between groups (Table 4). There was one death in the study as a result of a septic abortion and systemic sepsis. Five participants had abnormal cytology at enrollment, which were all followed until the lesions resolved or the participant received treatment. Social harms were reported by two participants (0.09%) and included a lack of social support from friends and family for trial participation.
Table 4
| Serious Adverse Event | Randomized Arm, n (%) | |||
|---|---|---|---|---|
| Nonavalent HPV Vaccine (n=758) | Bivalent HPV Vaccine (n=760) | Meningococcal Vaccine (n=757) | All (n=2275) | |
| Any | 34 (4.5) | 39 (5.1) | 39 (5.2) | 112 (4.9) |
| Any pregnancy related | 24 (3.2) | 19 (2.5) | 14 (1.8) | 57 (2.5) |
| Any infection/inflammation | 9 (1.2) | 16 (2.1) | 21 (2.8) | 46 (2.0) |
| Any injury | 0 (0.0) | 3 (0.4) | 4 (0.5) | 7 (0.3) |
| Any mental health | 2 (0.3) | 1 (0.1) | 2 (0.3) | 5 (0.2) |
Participants Experiencing Adverse Events.*
*
Participants may have more than one event across, but not within, event type categories. HPV denotes human papillomavirus.
Discussion
Over the first 18 months of this ongoing trial, the efficacy of single-dose bivalent or nonavalent HPV vaccine was very high among Kenyan adolescent girls and young women, demonstrating high levels of protection against vaccine-specific oncogenic HPV infection. Protection against HPV 16/18 infection was 97.5% for both vaccines. Together with observed high reductions in the absolute cumulative incidence, this finding suggests, should the protection have a durable effect, the potential for public health impact in the context of disparities in outcomes for cervical cancer cases and deaths (Table S22). Saliently, we were able to exclude single-dose HPV 16/18 VE less than 81%, the lower limit of the CI for both vaccines. Overall, the rate of HPV infection in this population of African adolescent girls and young women was high at 9.42 per 100 woman-years in the control group, approximately a third higher than in previous trials, highlighting the need for effective, scalable vaccine programs that can achieve high coverage and reduce this high incidence of HPV infection and potential cervical cancer.4,27 The high level of efficacy builds on observational data11,12 and provides, should the effect be sustained, evidence for single-dose HPV vaccination to prevent persistent HPV infections, which could increase vaccine access and coverage, offering a cost-effective strategy for cervical cancer prevention.28
Strengths of this study include the randomized, double-blind, controlled design, high retention, measurement of cervical HPV DNA as the outcome, determination of persistent HPV DNA, and the head-to-head comparison of the licensed bivalent and nonavalent HPV vaccines in protection against persistent infection with oncogenic HPV types included in the vaccines. In addition, the trial successfully enrolled persons exposed to HPV infection who were successfully retained in all randomized groups, allowing rapid assessment of single-dose efficacy.
We acknowledge that the study has limitations. First, the duration of follow-up at this report is 18 months, and the durability of single-dose VE remains to be demonstrated. However, observational data for single-dose HPV vaccination support efficacy over a decade.11 Following these results, participants will receive blinded crossover29 vaccination, ensuring that all receive HPV vaccination, with an additional 18 months of follow-up to evaluate single-dose durability, and access to the second dose following guidelines. The blinded crossover design will allow us to calculate the durability of the VE demonstrated to date. Second, the proportion of randomized participants who were naive to HPV 16/18/31/33/45/52/58 was lower than expected (∼40%), potentially decreasing the study power; however, incidence was higher than assumed and the efficacy result is statistically significant. Third, 6% of primary end-point swabs were self-collected, and 94% were provider collected. Ideally, collection would be identical; however, the correlation between self-collected vaginal and provider-collected cervical swabs is high19 and there was no difference in the results when self-collected swabs were excluded. An additional concern is whether antibody levels were declining over the observation period such that the high efficacy observed initially would be sustained. However, in a study conducted in India over a 10-year duration, antibody levels at plateau were such that VE is high (>95%),11 suggesting that even higher antibody levels could only demonstrate a small further increase in VE. In addition, the plateau level for single-dose HPV vaccination is reached by month 12.30 Lastly, while the glutathione S-transferase–ELISA multiplex assay used to exclude participants with HPV antibodies at enrollment demonstrated overall agreement of 89% with the gold-standard secreted alkaline phosphatase pseudovirion-based neutralization assay,31 misclassification of participants as antibody naive would not be different by study group. Furthermore, in sensitivity analysis including participants with HPV antibodies at baseline, overall VE was in keeping with the primary findings (Tables S23 and S24).
Cervical cancer is the fourth most common cancer among women globally, is the second most frequent in sub-Saharan Africa, primarily affects women between 30 and 49 years of age, and is the leading cause of cancer deaths in sub-Saharan Africa.32,33 Cervical cancer is almost entirely preventable through HPV vaccination. If the effects of single-dose HPV vaccination are durable, as we have reason to believe they will be, this approach could serve to close the gap between the WHO’s goal of 90% HPV vaccination coverage by 2030 and the 15% of girls currently vaccinated globally,9,34 alleviate vaccine supply constraints,35 and provide global policy makers with options to allocate existing HPV vaccine supply.
Notes
The KEN SHE Study was funded by the Bill and Melinda Gates Foundation (grant OPP1188693) and by the University of Washington King K. Holmes Endowed Professorship in STD and AIDS (to Dr. Barnabas). Dr. Pinder was supported by a University of Washington T32 Fellowship (5T32CA009515-34). The content is solely the responsibility of the authors and does not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated or the KEN SHE Study funders.
Disclosure forms provided by the authors are available with the full text of this article.
A data sharing statement provided by the authors is available with the full text of this article.
We thank the adolescent girls and young women who participated in this study for their motivation and dedication, and we also thank the parents of minor participants for their support. We are grateful to the members of the trial’s DSMB (Chair Dr. Helen Weiss and Drs. Lynette Denny, Dorothy Mbori-Ngacha, Saidi Kapiga, Fred Were, and Fred Sawe), the community advisory boards at each trial location, and the overseeing ethics review committees for their expertise and guidance. We also thank Dr. Peter Dull and Ms. Carolyn Wendell from the Bill and Melinda Gates Foundation for their attentive oversight. Finally, we are grateful to the KEN SHE Study Team for their dedication and perseverance.
The article is dedicated to Kowselia Ramaswami Ramiah, Sarah Kanyi Mugo, Reginalda Auma Onono, Edwina Muga, Mary Nduta, and all of our mothers.
Supplementary Material
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Published online: April 11, 2022
Published in issue: April 26, 2022
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