VSports - Efficacy of the HPV-16/18 Vaccine: Final according to protocol results from the blinded phase of the randomized Costa Rica HPV-16/18 Vaccine Trial

Introduction

Three programs launched in the 2000s evaluated prophylactic virus-like particle (VLP) human papillomavirus (HPV) vaccines [1-3]. Two of these programs were led by manufacturing companies, Merck Pharmaceuticals and GlaxoSmithKline Biologicals, who licensed the HPV-VLP technology and developed vaccines to prevent cervical cancers caused by HPV-16 and HPV-18, two HPV types that account for up to 70% of cervical cancers worldwide V体育2025版. Results from trials by these companies demonstrated that the vaccines have an acceptable safety profile and are highly effective for the prevention of HPV infections and lesions associated with vaccine types, and in some instances to additional, related types. As a result, both vaccines are licensed for use in adolescents and young adults in many countries [4-10].

The third program initiated pre-licensure was a community-based trial in Costa Rica (NCT00128661) sponsored by the US National Cancer Institute (NCI) that utilized the HPV-16/18 AS04-adjuvanted vaccine (Cervarix®, hereafter referred to as the HPV-16/18 vaccine) provided to NCI by GlaxoSmithKline Biologicals [11]. This trial was designed to evaluate the efficacy, safety, impact and immune mechanisms associated with HPV vaccination, and to extend natural history studies to vaccinated groups. To date, results from the Costa Rica HPV-16/18 Vaccine Trial (CVT) have shown that 1) the vaccine is highly effective at preventing new persistent infections with HPV-16/18[12], 2) the vaccine confers partial protection against HPV types phylogenetically related to HPV-16/18 [13], 3) the vaccine does not help treat infections [14], 4) fewer than 3 doses of the vaccine appear to protect as well as the full 3-dose series for at least 4 years against persistent HPV-16/18 infections [15], 5) there are indications that the vaccine protects against HPV infection at the anus and oral cavity [16, 17], 6) the vaccine does not impact overall rates of pregnancies/pregnancy outcomes [18], 7) the impact of vaccination declines with increasing age at vaccination [12], 8) the initial impact of young adult vaccination on colposcopy referral/treatment rates in well-screened populations are modest [19], 9) within the same age group, levels of antibodies achieved long-term following two doses (0 and 6 months) of the vaccine are high and only slightly lower than those observed after three doses and antibodies achieved long-term following one dose of the vaccine are lower than those observed with 3 doses but stable [20], 10) vaccination induces cross-neutralizing potential in sera of vaccinees [21], and that 11) modest antibody levels generated by natural HPV infection provide partial protection against re-infection [22] VSports.

We now extend those findings by presenting results from the blinded analysis conducted at the end of the first four years of follow-up. These results focus on the according to protocol (ATP) efficacy findings submitted to the FDA under BB-IND #7920; separate submissions focus on findings from intent-to-treat and naïve analyses from our trial [12, 23] VSports app下载.

Materials and Methods

"V体育官网" Results

Participants in the HPV and Control arms of the trial and included in the ATP cohort for efficacy were comparable with respect to age, clinic, sexual behavior and HPV-16/18 serology and DNA results at entry (Supplemental Table 1).

Number of CIN2+ events, rates and efficacy are presented in Table 1. Efficacy against incident HPV-16/18 associated CIN2+ was 89.8% (95% CI = 39.5–99.5; Rate Reduction = 3.4/1,000 women) using our a-priori algorithm for HPV type attribution and 88.7% (95% CI = 31.3–99.5; Rate Reduction = 3.0/1,000 women) using the alternative (exploratory) definition that considers viral persistence when making HPV type attribution. A total of 11 HPV-16/18 associated CIN2+ events were observed using our a-priori definition; 10 were CIN2 and one was a CIN3. The single HPV-16/18 CIN2+ event in the HPV arm occurred in a participant who at entry had antibodies against both HPV-16 and HPV-18, and evidence (by DNA test) of infection with a non-oncogenic HPV type (HPV-66), and who was positive (by DNA test) for HPV-16 and -45 11 months after enrollment and diagnosed with CIN3 15 months after enrollment. Efficacy estimates against CIN2+ associated with non-HPV-16/18 oncogenic HPV types were 59.9% (a-priori definition) and 78.7% (exploratory definition). The breakdown of HPV types detected by arm is summarized in Figures 2a (a-priori definition) and 2b (exploratory definition). Efficacy estimates irrespective of HPV type were 61.4% (95% CI = 29.5–79.8; Rate Reduction = 8.4/1,000 women; N = 37 in Control arm and 14 in HPV arm) by our a-priori and 75.3% (95% CI = 48.1–89.3; Rate Reduction = 9.2/1,000 women; N = 33 in Control arm and 8 in HPV arm) by our exploratory definition of incident outcomes. Results for individual oncogenic HPV types are summarized in Supplemental Tables 2a-b.

Efficacy against incident HPV-16/18 infections during the study was 79.5% (95% CI = 74.0–84.0; Rate Reduction = 115/1,000 women) (Table 2). Efficacy in this group of young adults was lowest in the first year of follow-up (57.1%; 95% CI = 33.2–73.0) and higher in subsequent years (82.6% in year 4+; 95% CI = 73.0–89.2).

Safety findings are summarized in Table 3. Rates of solicited local and general AEs were comparable in the two arms in the hour following vaccination. The rate of local solicited AEs within 3-6 days following any vaccination was higher among those in the HPV arm (53.7% for all; 1.8% for grade 3 AEs) compared to the Control arm (19.9% for all; 0.0% for grade 3 AEs). Unsolicited AEs reported in the month following any vaccination were comparable between arms. The proportion of participants with SAEs, SAEs possibly related to vaccination, medically significant conditions, new-onset chronic diseases, autoimmune AEs, neurological AEs, and deaths were comparable between arms. All but 12 SAEs possibly related to vaccination were pregnancy related [18]. For the 12 remaining SAEs possibly related to vaccination, 7 occurred in the HPV arm (1 Crohn's disease, 1 ulcerative colitis, 1 rheumatoid arthritis, 1 haematuria, 1 thyrotoxicosis, 1 excessive and frequent menstruation with irregular cycle, and 1 somatoform autonomic dysfunction) and 5 in the Control arm (2 anaphylactic shock events, 1 generalized skin eruption, 1 acute appendicitis, and 1 unspecified abnormalities of gait/mobility). The 43 autoimmune events were equally distributed across arms (22 in HPV arm; 21 in Control arm) and were due to goitre (8 in HPV arm; 9 in Control arm), rheumatoid arthritis (4 in HPV arm; 6 in Control arm), inflammatory bowel disease (3 in HPV arm including 1 Crohn's disease; 2 in Control arm), systemic lupus erythematosus (2 in HPV arm; 1 in Control arm), insulin-dependent diabetes mellitus (1 in HPV arm; 1 in Control arm) and other conditions (4 in HPV arm; 2 in Control arm). The 15 deaths observed were equally distributed across arms (8 in HPV arm; 7 in Control arm) and were due to suicides (4 in Control arm), automobile accidents (1 in HPV arm; 2 in Control arm), physical assault (2 in HPV arm), cancer (1 in HPV arm; 1 in Control arm), Crohn's disease (1 in HPV arm), systemic lupus erythematosus (1 in HPV arm), HIV-associated conditions (1 in HPV arm), and acute myocardial infarction (1 in HPV arm).

Immunogenicity results are summarized in Figures 3a-d. GMTs peaked at one month following last dose, declined thereafter and remained relatively stable beyond 12-24 months post-vaccination. By ELISA, we observed that 100% of vaccinated participants were seropositive against HPV-16 and HPV-18 after three doses and remained seropositive at the end of the 4-year follow-up period. By EIA, we observed that 100% and 99.5% of vaccinated participants were seropositive against HPV-16(V5) and HPV-18(J4), respectively, after three doses. At the end of the 4-year follow-up period, 92.3% and 45.8% of vaccinated participants remained seropositive against HPV-16(V5) and HPV-18(J4), respectively.

Discussion

This report summarizes results from the final ATP analysis of the NCI-sponsored CVT under GlaxoSmithKline Biologicals' FDA-BB-IND-7920. Our results confirm the high efficacy of VLP-based vaccines against incident CIN2+ associated with HPV-16/18 [4-10]. It is reassuring that high efficacy against infections and lesions associated with the HPV types in the vaccine formulation has now been reported for VLP-based vaccines from multiple trials conducted in different populations, despite differences in study methodology [4-10, 26, 27] (Table 4). Furthermore, our report is consistent with previous results suggesting that vaccination with the HPV-16/18 vaccine might confer partial protection against some oncogenic HPV types not included in the vaccine formulation [28]. We observed 60% efficacy against CIN2+ associated with incident oncogenic HPV infections with types other than HPV-16/18, an effect that increased to near 80% when we considered evidence of HPV persistence preceding referral to colposcopy. Although limited by small numbers, our findings suggest some efficacy (point estimates ranging from 42%-100%) for all HPV types phylogenetically related to HPV-16 (A9 species – including HPV types 31,33,35,52,58). For HPV types phylogenetically related to HPV-18 (A7 species – including HPV types 39,45,59,68), evidence was mixed, with suggestion for efficacy against HPV-68 (which in our testing system was indistinguishable from non-oncogenic HPV-73) but not for other types related to HPV-18. Finally, when CIN2+ cases were examined irrespective of HPV type, we observed over 60% efficacy, an effect that increased to >75% when our exploratory criteria were used to define incident outcomes. It is important to note that such estimates of overall efficacy are likely to be population specific and to vary depending on the proportion of infections in the population attributable to vaccine types, non-vaccine HPV types for which there is cross-protection, and non-vaccine HPV types for which there is no cross-protection. In fact, vaccine efficacy against non-vaccine types or irrespective of HPV type reported from phase III randomized clinical trials to date have varied considerably as summarized in Table 4. It is not fully understood to what extent these observed differences are due to differences in study design and analysis (e.g., differences in colposcopy algorithm, sensitivity/specificity of HPV assays, and analytical cohorts evaluated), chance (95% confidence intervals tend to overlap), population differences (e.g., differences in relative distribution of non-vaccine HPV types in different study populations), or vaccine differences (i.e., real differences in cross protection between the bivalent and quadrivalent vaccines). In a recent evaluation of this issue, we have noted that differences observed in efficacy estimates between FUTURE I/II and PATRICIA are likely explained by a combination of these various factors [23].

We saw no evidence of waning efficacy during the study period. When we evaluated efficacy against HPV-16/18 infection over time, high efficacy (>80%) was observed in years 2-4+ and the lowest efficacy estimate was observed in the first year of follow-up (57%). The high efficacy observed in the out years is consistent with evidence of long-term protection up to 8.4 years (HPV-16/18 vaccine) and 5 years (HPV-6/11/16/18 vaccine) in the pharmaceutical trials [29, 30]. We interpret the somewhat reduced efficacy in year 1 as suggestive that some outcomes might have resulted from undetected infections present before vaccination in our group of largely sexually experienced women [12].

The safety and immunogenicity profile of VLP-based vaccine have been evaluated in large-scale trials and results suggest that that vaccine has an acceptable safety profile, is generally well tolerated, and induces a robust and sustained immune responses [7, 30-35]. Safety results from our trial are consistent with these previous reports. Similarly, consistent with previous reports, we noted robust antibody levels (measured by ELISA) following vaccination that persisted throughout the four years of follow-up – 100% of participants evaluated were seropositive against HPV-16 and HPV-18 at the end of follow-up. This is consistent with the high clinical efficacy observed. By the EIA inhibition assay that targets neutralizing epitopes for HPV-16 and HPV-18, we also observed robust responses following vaccination. These responses were measurable after four years for nearly all participants evaluated for HPV-16 (92.3%) and for roughly half of participants evaluated for HPV-18 (45.8%). Since efficacy remained high throughout the four years of follow-up for both HPV-16/18, the fact that about half of the vaccinees sero-reverted to HPV-18 by the EIA assay suggests that protective levels are lower than the minimum detectable level by the assay or that antibodies against additional epitopes can also be protective.

Limitations of our trial include the modest number of CIN2+ events among women naïve to specific HPV types during the vaccination period, which limited our ability to evaluate efficacy against individual HPV types other than HPV-16/18 and against CIN3+. Our study size also limited the ability to evaluate efficacy against lesions by time.

A distinguishing characteristic of our trial is its community-based design; we enrolled women from a well-defined area based on a census [11]. As a result, our trial represents a unique large-scale community-level trial conducted pre-licensure and affords an opportunity for follow-up studies to address many questions of interest. These include questions regarding long-term safety, immunogenicity and efficacy; natural history of infections in vaccinated women and the impact of vaccination on cervical disease associated with non-vaccine HPV types; the impact of vaccination on screening; and the utility of novel screening tools in vaccinated populations. The results presented herein serve as a benchmark to help interpret results from some of these planned efforts.

Our findings provide additional independent evidence of the efficacy, immunogenicity and safety of the HPV-16/18 vaccine for prevention of HPV infections and cervical cancer precursor lesions in previously unexposed women and further support the establishment of vaccination programs that target individuals prior to exposure.

Supplementary Material