Currently Approved Prophylactic HPV Vaccines

Diane M Harper

Disclosures

Expert Rev Vaccines. 2009;8(12):1663-1679. 

In This Article

Immunogenicity

The purpose of the prophylactic HPV vaccines is to induce antibodies to the specific vaccine-relevant HPV types that will be sustained for the duration of time the woman is susceptible to HPV infections. Both Cervarix and Gardasil induce antibody titers after three doses that far exceed the titers a natural infection induces in women 16–26 years of age who were seronegative and PCR negative for the vaccine-relevant HPV types at baseline.

The antibody titers, measured in ELISA units/ml, induced by Cervarix remain 13- and 12-fold higher than natural infection titers at 6.4 years for HPV-16 and -18, respectively, with over 98% of the women vaccinated maintaining initial seroconversion through 6.4 years. An increased memory B-cell response has been demonstrated in women 18–30 years of age who were seronegative and PCR negative for HPV-16/18 at the time of vaccination at 1 month after the three doses of Cervarix compared with the HPV-16/18 VLPs adjuvanted with aluminum alone.[13] The pseudovirion-based neutralization assay (PBNA, ED50 unit) titers for HPV-16 and -18 were likewise high and sustained throughout 6.4 years, and correlated well with the ELISA titers. In addition, the PBNA titers correlated tightly with the measured type-specific cervical mucous antibodies transudating across the basement membrane over 24 months. Antibody titers induced by Cervarix measured in women 15–55 years of age were titers still eightfold higher than natural infection titers for even the oldest 46–55-year-old age cohort after 24 months.[46] The strong and sustained immunogenic properties of Cervarix offer the possibility of long-term protection for women of many ages.

The neutralization antibody titers induced by Gardasil have been measured by competitive Luminex immunoassay (cLIA) for each HPV type 6, 11, 16 and 18 in milliMerck units/ml. Over 99% of women seroconverted for each HPV type after three doses of vaccine. For HPV-18, however, 28% of women lost their initial seroconversion at 2 years, increasing to 35% of women losing their seroconversion by 3 years. Of those with remaining HPV-18 titers, the levels continued to drop through the studies' end. After an average of 44 months of follow up, 40% of women lost all measurable antibody titers to HPV-18..[47] In over 14,000 women followed for at least 3 years, there were only 60 cases of HPV-18 infection in the placebo arm for a very low attack rate of less than five infections per 1000 woman-years in an age range of maximal HPV exposure. Such a low attack rate does not allow inferences to be drawn about the duration of the vaccine's efficacy or the immunologic correlate of protection, as there has not been much infectious challenge to the women's waning serostatus. Overall, 10% of women lost their antibody titers to HPV-6 and 5% lost them to HPV-11 within 44 months; of those with remaining seropositivity, the titers dropped to natural infection titers by 24 months, opening the possibility of waning protection. Strong immunogenicity is seen for HPV-16. Over 98% of women maintained seroconversion to HPV-16 and maintained titers tenfold above natural infection titers at 44 months (Figures 2, 3 & 4).

Figure 2.

Induced anti-HPV-16 titers after Cervarix® and after Gardasil® administration in women 15–26 years of age. These graphs show the subsequent titers for HVP-16 after peak (month 7) responses over time. For Cervarix, the peak titer is 124-fold higher than natural infection titers and remains 11-fold higher 6.4 years later.[15] For Gardasil, the peak titer is encircled, and is 104-fold higher than natural infection titers and remains tenfold higher 5 years later.
*Denotes when vaccination occurred.
cLIA: Competitive Luminex immunoassay; GMT: Geometric mean titer; HPV: Human papillloma virus; NIT: Natural infection titer; PBNA: Pseudovirion-based neutralization assay (measured in ED50 units).
Redrawn with permission from [50,75].

Figure 3.

Induced anti-HPV 18 titers after Cervarix® and after Gardasil® administration in women 15–26 years of age. These graphs show the subsequent titers for HVP 18 after peak (month 7) responses over time. For Cervarix, the peak titer is 107-fold higher than natural infection titers and remains fivefold higher 6.4 years later.[15] For Gardasil, the encircled peak titer is 27-fold higher than natural infection titers and returns to natural infection titer levels at 18 months, with 35% of Gardasil-vaccinated women losing their anti-HPV-18 titers by 3 years. Anti-HPV-18 titers for Gardasil become equivalent to natural infection titers at 18 months and remain equivalent to natural infection titers through 5 years.
*Denotes when vaccination occurred.
cLIA: Competitive Luminex immunoassay; GMT: Geometric mean titer; HPV: Human papilloma virus; NIT: Natural infection titer; PBNA: Pseudovirion-based neutralization assay (measured in ED50 units).
Redrawn with permission from [50,75].

Figure 4.

Induced anti-HPV-6 and anti-HPV-11 titers after Gardasil® administration in women 16–26 years of age. These graphs show the subsequent titers for HVP-6 and -11 after peak (month 7) responses over time. The encircled peak titer for HPV-6 is 11-fold higher than natural infection titers. The titers for HPV-6 become statistically indistinguishable from the natural infection titers at 18 months, staying at that level over 5 years. The titers for HPV 11 return to baseline natural infection titers at 18 months, dropping slightly lower than natural infection titers over 5 years. cLIA: Competitive Luminex immunoassay; GMT: Geometric mean titer; HPV: Human papilloma virus; NIT: Natural infection titer; PBNA: Pseudovirion-based neutralization assay (measured in ED50 units).
*Denotes when vaccination occurred.
Redrawn with permission from [50].

The neutralizing antibody titers to HPV-16 and -18 have been measured in the same assay in a head-to-head trial of Cervarix and Gardasil[48] in order to remove the confusion of different proprietary measurement systems. In all circumstances, Cervarix produced significantly higher antibody titers for HPV-16 than did Gardasil (3.7-fold higher) at month 7, the peak titers; and even greater fold higher for HPV-18 (7.3-fold higher). As the duration of vaccine efficacy is the most important public-health parameter of mass vaccination programs, and because antibody titers are the closest surrogate measure to efficacy as evidenced by our use of immunobridging, and despite not having a correlative titer identified, it is likely that Cervarix will have a longer duration of efficacy than will Gardasil. Long-term studies are necessary to prove this (Table 10).

The head-to-head trial also reported cervicovaginal mucous antibody titers present in the vaccinated women. Cervicovaginal secretion mucous antibodies are believed to be central for protection against HPV infection and cervical disease, evidenced by natural history studies in which both IgA and IgG antibodies appear several months after HPV clearance, with the IgG antibody action predominating.[49] A similar proportion of HPV-specific neutralizing antibodies transudates from the serum to the mucous for both vaccines. The ratios of titers in the serum to titers in the mucous were threefold higher for Cervarix than for Gardasil as measured by the PBNA.

Memory B cells induced after Cervarix and Gardasil were equivalent for HPV-16 measured at 1 month after the series of three vaccinations at nearly 90%. For HPV-18, nearly 90% of the women vaccinated with Cervarix responded with memory B cells, but only 66% of the women vaccinated with Gardasil had so responded at the time of maximal potential response. This is another indicator of the potential necessity for a booster for HPV-18 durability by Gardasil.

An anamnestic response was elicited by an intramuscular injection of a single dose of Gardasil at the end of the 5-year Phase II trial.[50] Antibodies to HPV-6 were induced in 75% of women who had lost their HPV-6 seropositivity with only a third of the responders mounting titers that exceeded the initial antibody response. Antibodies to HPV-11 were induced in 86% of women who had lost their HPV-11 seropositivity, with 70% of the responders mounting titers that exceeded the initial antibody response. This is worrisome that the boosted titers were not completely regained after only 5 years between the initial series and the booster injection. Antibodies to HPV-18 were induced in 97% of women who had lost their HPV-18 seropositivity, with 73% of the responders mounting titers that exceeded the initial antibody response. It is reassuring to note that the loss of HPV-18 efficacy may be regained by booster shots, certainly within 5 years. The anamnestic studies were not continued to show the rate of decay in the response over time. It is not known how the anamnestic response will behave if the booster is not given until 10 years after the initial vaccination series.

HPV-16 immunogenicity remains strong for Gardasil with anamnestic challenge. There was only one woman who lost her seropositivity to HPV-16 at 60 months, and she responded to the booster shot with titers above the initial antibody response 1 month after the booster. Since no trials of Gardasil have been extended beyond 44 months for the Phase III trials and 5 years for the Phase II trial, the meaning of the loss of antibody titers is unclear for possible future declines in vaccine efficacy.

Both Cervarix and Gardasil were tested in young adolescents 9/10–15 years of age who were seronegative at study entry for the vaccine-relevant HPV types for safety and antibody responses.[51–54] Both studies showed that young adolescents mounted an antibody response that was significantly higher than the response induced in 16–26-year-old seronegative, PCR-negative women. The concept of immunobridging was invoked to infer a similar efficacy for adolescent females to that seen in the 16–26-year-old female cohort because there was a similar or greater immune response in the young adolescents compared with the 16–26-year-old women.

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