ABSTRACT
The main objective of this post hoc analysis is to compare the magnitude of the immune response to HPV31/33/45/52 and 58 after a dose of 9vHPV vaccine given to naïve (previously unvaccinated) subjects and subjects previously vaccinated with a dose of 2vHPV or 4vHPV vaccine. Results from two clinical trials conducted in the same region, in comparable populations and by the same research team were included in this analysis. In study A, a dose of 9vHPV was administered 6 months after a single dose of 2vHPV as well as to naïve subjects. In study B, a dose of 9vHPV was administered 36–96 months (mean 65 months) after a single dose of 4vHPV. Blood samples were collected just before and one month post-9vHPV vaccine administration. For both studies, antibody responses were measured using the same 9-plex virus-like particle based IgG ELISA (M9ELISA). One month after 9vHPV dose administration, all subjects were seropositive to HPV 31/33/45/52 and 58. Subjects who had previously received 2vHPV or 4vHPV had significantly higher (1.8–8.0-fold) GMTs than naive subjects for HPV31/33/45/52 types but not for HPV58. GMTs to HPV31/33/45/52 and 58 were not significantly different between subjects who received a 2vHPV or 4vHPV dose prior to 9vHPV. The strong anamnestic response to one dose of 9vHPV given as late as 3–8 years after a single dose of 2vHPV or 4vHPV vaccine indicates these vaccines induced priming to types only included in the 9vHPV vaccine.
KEYWORDS: Human papillomavirus, Vaccination, Immunogenicity, Clinical trial
Introduction
The bivalent (2vHPV: contains AS04 adjuvanted HPV 16 and 18 virus like particles (VLPs)) and the quadrivalent (4vHPV: contains AAHS adjuvanted HPV 6, 11, 16, 18 VLPs) HPV vaccines have been successfully used in immunization programs in different jurisdictions for over a decade.1 Both vaccines induce immunity to HPV 16 and 18. These two high risk (carcinogenic) types are responsible for ≥70% of cervical cancers and a great majority (≥85%) of other HPV related cancers. The 4vHPV vaccine also protects against infection with HPV 6 and 11, two low-risk HPV types responsible for ≥85% of anogenital warts.2 More recently, a 9vHPV vaccine including five additional HPV VLPs (31, 33, 45, 52, 58, also AAHS adjuvanted) became available.3 Although the prevalence of these five additional types in HPV related cancers varies by geographical region, they are considered responsible for around 20% of cervical cancers and to a lesser extent for other types of HPV-associated cancers.4 Several clinical trials with two or three doses of 2vHPV and 4vHPV reported the presence of antibodies to several HPV types not included in these vaccines,5 as well as significant cross-protection against infections and lesions related to HPV31/33 and 45.6–14 However, this cross-protection seems to be limited when compared to direct protection induced by the 9vHPV.3
We previously reported that a substantial proportion of subjects vaccinated with a single dose of 2vHPV (50–71%) or 4vHPV (58–87%) were seropositive to the five HPV VLP types included only in the 9vHPV. Although these antibody titers were relatively low, they increased significantly after the administration of a dose of 9vHPV.15,16 It is unclear if this increase in antibody titers was a prime or a booster response given the paucity of data regarding the magnitude of the immune response after a single dose of 9vHPV vaccine.
The objective of this post hoc analysis is to compare the magnitude of the immune response to HPV31, 33, 45, 52 and 58 after a dose of 9vHPV vaccine given to naïve (previously unvaccinated) subjects and subjects previously vaccinated with a dose of 2vHPV or 4vHPV vaccine, as well as to explore the potential impact of different intervals between two vaccine doses on the priming induced by the first dose of vaccine.
Methods
The results from two clinical trials conducted in the same region (Québec City, Canada), by the same research team, in comparable populations, recruited during the same years (2015–2017) were included in this analysis.15,16
In study A (NCT02567955), a dose of 9vHPV was administered 6 months after a single dose of 2vHPV (n = 86) as well as to naïve subjects (n = 88). In this study, 9–10 year-old subjects were recruited by invitation letters sent through schools to parents. Subjects were randomly assigned (1:1) to naïve or 2vHPV group.13 In study B (NCT03431246), a dose of 9vHPV was administered 36–96 months after a single dose of 4vHPV (n = 31). In study B, vaccination registry was used to assess the number of vaccine doses received by potential subjects. Vaccination status of girls who previously received a single dose of 4vHPV and were potentially eligible to participate in the study was validated by using personal vaccination card. Potential subjects were excluded if there was any discrepancy between information contained in the vaccination registry and personal vaccination card or answers to questions regarding the number of doses received. In study A, the first dose of vaccine was administered at the age of 9–10 and in study B at the age of 9–14 years. The 9vHPV dose was administered at the age of 9–11 and 13–18 years in study A and B, respectively. In study A, girls and boys were included and in study B, girls only. As no difference in the magnitude of the immune response was observed between girls and boys,15 the results were pooled. In both studies, 98–100% of subjects were Caucasians living in the same region with comparable socio-demographic characteristics.
In naïve subjects, a blood sample was collected 1 month post-9vHPV vaccine administration and in subjects vaccinated with a dose of 2vHPV or 4vHPV samples were collected just before and 1 month post-9vHPV vaccine administration. Study designs and participant characteristics are presented in Table 1.
Table 1.
Study design and participant characteristics in studies of one dose of 9vHPV with or without preceding HPV vaccination.
| Study | A | B | |
|---|---|---|---|
| Randomized (1:1): naïve subjects and subjects vaccinated with one dose of 2vHPV |
Yes |
No |
|
| Gender |
Girls and Boys |
Girls |
|
| Study groups (number of subjects) | Naive (previously unvaccinated) (n = 88) |
Vaccinated with one dose of 2vHPV (n = 86) | Vaccinated with one dose of 4vHPV (n = 31) |
| Age at first dose administration | 9–11 years (mean 9.7 years) |
9–11 years (mean 9.6 years) |
9–14 years (mean 10.1 years) |
| Interval between the first dose administration and blood collection prior to second dose administration* | Not collected | 6 months (mean 6.0 months) |
36–96 months (mean 65.3 months) |
| Interval between the first and the second dose administration (2vHPV + 9vHPV or 4vHPV + 9vHPV) | 6 months (mean 6.0 months) |
6 months (mean 6.0 months) |
36–96 months (mean 65.3 months) |
| Interval between the 9vHPV administration and blood collection | 1 month (range: 22–40 days) |
1 month (range: 21–41 days) |
1 month (range: 28–35 days) |
* Blood samples were collected only in prior vaccinated subjects; naive subjects were 9–11 years old at the time of 9vHPV administration and at very low or no risk of natural exposure to HPV.
The serological testing for both studies were performed using a 9-plex VLP-based IgG ELISA (M9ELISA) at the Centers for Disease Control and Prevention (CDC, Atlanta, USA).17 The M9ELISA used VLPs for HPV6, 11, 16, 18, 31, 33, 45, 52 and 58 pre-coated on 10-spot standard plates (Meso Scale Discovery, MSD, Gaithesburg, MD). Test sera were 3.16 fold serially-diluted for at least 3 dilutions starting at 1:100 or higher. Dilutions of reference sera were used in each plate to allow titer determination using the parallel line method (PLL). PLL analysis was performed as described in the WHO HPV Labnet Manual, using raw signal for each HPV type. Cutoff values (COV) were determined using serum samples from children (n = 50, Gift from Dr. J Dillner, Lund University). Antibody titers were measured in International Units (IU/ml) for HPV16 and 18. In the absence of international standards for HPV 31, 33, 45, 52 and 58 antibody titers were measured in Arbitrary Units (AU/ml). Test samples were considered positive if they passed PLL conditions as well as were above Median+2 Standard Deviations of the PLL/titer generated from the children sera. The seropositivity cut off values: for HPV 31, 33, 45, 52 and 58 were 0.5 AU/ml, 1.3 AU/ml, 2.5 AU/ml, 0.7 AU/ml and 1.2 AU/ml, respectively. These values were used in both studies. Samples were coded and tested without knowledge of vaccination status.
We compared the proportion of anti-HPV31, 33, 45, 52 and 58 seropositive subjects, geometrical mean titers (GMTs), and antibody titer distributions after a dose of 9vHPV given to naïve subjects and to subjects previously vaccinated with a dose of 2vHPV or 4vHPV.
Fisher’s exact test was used for the comparison of proportions and Wilcoxon test for continuous variables. All statistical tests were 2-tailed. P values of 0.05 or less were considered significant. SAS Institute software version 9.4 (Cary, NC, USA) was used for statistical analysis.
The two clinical trials were approved by Laval University Research Hospital Center Research Ethics Committee and are registered with ClinicalTrials.gov: NCT03431246 and NCT02567955.
Results
One month after 9vHPV dose administration, all subjects in all three groups included in this analysis were seropositive to HPV31, 33, 45, 52 and 58. Subjects who had previously received 2vHPV or 4vHPV had significantly higher (1.8–8.0-fold) GMTs than naïve subjects for HPV31, 33, 45, 52 but not for HPV58 (Figure 1 and Table 2). GMTs to HPV31, 33, 45, 52 and 58 were not significantly different between subjects who previously received a dose of 2vHPV or a dose of 4vHPV (Table 2).
Figure 1.
Antibody titer distributions and 95% confidence intervals one month after 9vHPV vaccine administration to naïve (previously unvaccinated) subjects and to subjects who previously received a dose of 2vHPV or 4vHPV vaccine.
Table 2.
Anti-HPV geometrical mean titers (GMTs) one month after a dose of 9vHPV* given to naïve subjects and to subjects who previously received a dose of 2vHPV or 4vHPV vaccine.
| HPV type | Naïve (previously unvaccinated) (n = 88)¶ |
2vHPV + 9vHPV (6 month interval) ** (n = 86) |
4vHPV + 9vHPV (36–96 month interval)† (n = 31) |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Post–9vHPV |
Pre-9vHPV |
Post-9vHPV |
Pre-9vHPV |
Post-9vHPV |
||||||
| % seropositive (95% CI) | GMTs (AU/ml) (95% CI) |
% seropositive (95% CI) | GMTs (AU/ml) (95%CI) |
% seropositive (95% CI) | GMTs (AU/ml) (95%CI) |
% seropositive (95% CI) | GMTs (AU/ml) (95% CI) |
% seropositive (95% CI) | GMTs (AU/ml) (95% CI) |
|
| HPV31 | 100 (95.9–100) |
23.9 (19.8–29.0) |
70.9 (60.1–80.2) |
1.6 (1.2–2.1) |
100 (95.8–100) |
123.0 (101.0–148.1) |
87.1 (70.2–96.4) |
2.2 (1.4–3.2) |
100 (88.8–100) |
192.0 (121.7–302.8) |
| HPV33 | 100 (95.9–100) |
33.3 (28.0–39.6) |
50.0 (39.0–61.0) |
4.0 (3.0–5.3) |
100 (95.8–100) |
58.4 (47.9–71.2) |
64.5 (45.4–80.8) |
1.6 (1.0–2.3) |
100 (88.8–100) |
107.0 (66.6–172.0) |
| HPV45 | 100 (95.9–100) |
31.9 (25.9–39.3) |
50.0 (39.0–61.0) |
7.9 (6.0–10.4) |
100 (95.8–100) |
167.0 (137.1–203.0) |
58.1 (39.1–75.5) |
2.9 (2.0–4.0) |
100 (88.8–100) |
103.5 (66.7–160.5) |
| HPV52 | 100 (95.9–100) |
21.7 (18.1–26.0) |
54.7 (43.6–65.4) |
3.6 (2.5–5.1) |
100 (95.8–100) |
59.0 (42.7–60.7) |
67.7 (48.6–83.3) |
1.0 (0.7–1.6) | 100 (88.8–100) |
71.1 (50.9–99.2) |
| HPV58 | 100 (95.9–100) |
75.1 (60.8–92.7) |
52.3 (41.3–63.2) |
4.1 (3.1–5.5) |
100 (95.8–100) |
77.8 (65.5–92.3) |
64.5 (45.4–80.8) |
1.8 (1.1–2.8) |
100 (88.8–100) |
118.5 (81.3–172.5) |
¶Not tested pre-9vHPV administration;*9vHPV – nonavalent HPV vaccine; **2vHPV – bivalent HPV vaccine; †4vHPV – quadrivalent vaccine, AU = Arbitrary Units
One month after the 9vHPV dose administration, the distribution of antibody titers for the 5 HPV types were comparable in subjects previously vaccinated with 2vHPV (6 month interval to 9vHPV dose) or 4vHPV (36–96 months interval) (Figure 1).
Discussion
To our knowledge, this is the first analysis to compare magnitude of the immune response to a single dose of 9vHPV vaccine administered to naïve subjects and to subjects previously vaccinated with a dose of 2vHPV or 4vHPV.
The significantly greater antibody response to HPV31, 33, 45 and 52 after a single dose of 9vHPV given to subjects previously vaccinated with one dose of 2vHPV or 4vHPV vaccine compared to unvaccinated subjects indicates cross-reactive priming has occurred. This observation is supported by prior study reports on the presence of detectable antibodies against these HPV types in a large proportion of subjects vaccinated with either 2vHPV or 4vHPV,5,18–21 and by existing robust data regarding partial cross-protection ensured by these vaccines.6–14,22,23 As the time-intervals were different for receipt of 9vHPV in subjects previously vaccinated with 2vHPV (6 months apart) or 4vHPV (36–96 months apart), it was not possible to disentangle the effect of the type of vaccine and that of the interval before the 9vHPV on the persistence of priming. The similar priming activities is rather surprising considering that peak and plateau titers after the standard three doses against HPV16 and 18 are higher for 2vHPV than for 4vHPV,24 and the longer interval between prime and boost for 4vHPV in our study.
Interestingly, a prior publication found that one or three doses of 9vHPV administered to subjects previously vaccinated with three doses of 4vHPV, resulted in a vigorous immune response after the first dose of 9vHPV but no further increase in titer with the subsequent two doses of 9vHPV against the four HPV types common to both vaccines. Antibody titers to HPV31, 33, 45, 52 and 58 increased with subsequent doses of 9vHPV, however, the anti-HPV GMTs to these 5 types were higher in subjects who received 3 doses of 9vHPV alone compared to those who received 3 doses of 9vHPV after 3 doses of 4vHPV.25,26 The above observations might be helpful when deciding about the completion of vaccination in individuals who started the vaccination series with 2vHPV or 4vHPV but due to shortage of a given vaccine or program transition to a different vaccine have to complete the vaccination course with the 9vHPV. Our results support the recommendation that any vaccine formulation can be used to complete a series if the original formulation is unknown or unavailable.27
Our results need to be considered in view of the limitations of this analysis. First, this was not a head-to-head randomized comparison but rather the combination of results from two separate clinical trials including one without randomization. Nevertheless, the similarity of the methods (population, serological assay, age at first dose administration, interval between the 9vHPV administration and blood samples collection) the comparison between these three groups is likely valid. Additionally, given that in both studies subjects received their first dose of vaccine at a mean age of 9.6 and 10.1 years, and in the two study groups (naïve and vaccinated with 2vHPV) the 9vHPV was administrated at the mean age of 10.2 years, the probability of natural priming to 5 HPV types as a result of sexual contact is probably nil. However, we cannot exclude some natural exposure in the group which received 4vHPV and 9vHPV at a mean interval of 65 months. These girls were 13–18 years old (mean 15.5 years) at the time of 9vHPV administration. If an exposure had occurred in this group, it would have happened after the 4vHPV administration.
Second, the number of subjects who received 9vHPV after a dose of 4vHPV was relatively small (n = 31) leading to larger confidence intervals for GMTs than for those previously given 2vHPV. The large confidence intervals and the time difference between two doses administration (6 months vs. 65 months) limits the capacity of drawing strong conclusions regarding differences in priming induced by 2vHPV and 4vHPV. However, the results suggest a comparable priming effect despite longer interval between 4vHPV and 9vHPV. Larger studies with similar time intervals between vaccine doses are warranted to evaluate the potential differences between the priming effects induced by the two vaccines. Another limitation is related to the absence of pre-9vHPV blood testing in naïve (unvaccinated) subjects. However, this is unlikely to bias the results as they were 9–11 years old at the time of 9vHPV administration and so considered sexually naive and not exposed to HPV yet. Furthermore, the clinical importance of different antibody titers remains unknown because no correlates of protection have been established. Given that 100% of naïve subjects included in this analysis were seropositive to all 9 HPV types after a single dose of 9vHPV, it is possible that they are protected despite their relatively low antibody titers compared to the titers observed in subjects vaccinated with a dose of 2vHPV or 4vHPV prior to a dose of 9vHPV.
In summary, a single dose of 2vHPV and 4vHPV seem to induce priming of antibody response to HPV types only included in the 9vHPV as evidenced by the strong anamnestic response to one dose of 9vHPV given as late as 8 years. These results may explain the previously reported cross-protection against HPV types not included in the administered vaccines and may alleviate worries that such priming is short-lived.
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Disclaimer
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, the Quebec Public Health Institute, or The National Cancer Institute.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Citations
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