Advisory report on the Human Papillomavirus (HPV) Vaccination Schedule
A lot of new data on the immunogenicity, efficacy and effectiveness of fewer than three doses of HPV vaccine have become available since the publication of the CIQ report on the 2012 knowledge update. The two-dose schedule has become a standard that is widely accepted around the world. Such schedules are currently in use in more than half (48/82) of the countries offering HPV vaccination programs. The same schedule has been approved and recommended by the World Health Organization (W HO) and the Global Alliance for Vaccines and Immunization (GAVI).
A number of clinical and ecological studies have even come up with some interesting and promising results in terms of the immunogenicity and efficacy of single-dose HPV vaccination. Immunogenicity studies have shown that sero-conversion rates after a single dose of vaccine are often in excess of 95%, although with considerably lower geometric mean titers (GMTs) than those observed after two or three doses. However, antibody titers observed after a single dose are higher (≈ 4 to 11 times greater) than titers observed in infected women who have managed to eliminate the virus. Antibody avidity after a single dose of vaccine is similar to that observed after two or three doses, and antibody levels remain stable for at least four years. Clinical efficacy studies seem to indicate that a single dose of vaccine protects against incident infections (70–90%) and persistent infections (85–100%) caused by the types of viruses included in the vaccine. This degree of protection is similar to that provided by two or three doses of vaccine. The results of ecological studies show more variance. However, these studies are subject of major biases that could lead to an underestimate of the efficacy of one or two doses of vaccine.
Worldwide, considerable effort has been put in place to better assess the immunogenicity and efficacy of single-dose vaccine schedule or schedules based on two doses administered several months, or even several years, apart. More reliable results on this topic are expected in coming years.
The safety and immunogenicity of a mixed schedule based on the use of different HPV vaccines given to the same individual have been assessed in at least three clinical studies. The results of these studies show that the safety profile of two- or three-dose mixed schedules is acceptable and quite similar to that using one vaccine schedules.
The results of clinical studies carried out in Quebec indicate that after a single dose of vaccine, 99% to 100% of children 9-10 years old have antibodies to viruses covered by the vaccines. The few children who had no antibodies to certain types of HPV, as determined by ELISA (Enzyme- Linked Immunosorbent Assay) and re-tested by PBNA (Pseudovirion-Based Neutralization Assay) had all neutralizing antibodies.
The use of one dose of Gardasil-9 followed by another of Cervarix resulted in an acceptable safety profile. To note, that his mixed schedule induces antibodies against the nine types of HPV covered by Gardasil-9 in all children tested (100%). The GMTs of HPV 16 and 18 antibodies were higher in the group that received one dose of Gardasil-9 and one dose of Cervarix (or vice versa) than in the group that received two doses of Gardasil-9. On the other hand, the GMTs against the 7 types of HPV covered by Gardasil-9 but not by Cervarix were higher in the groups that received two doses of Gardasil-9. In these two studies conducted in Quebec, a three- to nine-fold increase in GMTs against HPV 31, 33, 45 and 52 was observed after Cervarix was administered to participants having received one dose of Gardasil-9. The anti-HPV 58 GMTs were already relatively high after the single dose of Gardasil-9 and increased 1.5-fold after administration of Cervarix. In the same subjects, after one dose of Cervarix, anti-HPV 6 and 11 GMTs increased by a factor of 1.6 to 1.8. Note that the clinical importance of different antibody titers remains unknown. However, the increase in antibodies to virus types not covered by Cervarix is consistent with the results of studies having shown some cross-efficacy from this vaccine.
Economic analysis shows that in Quebec, the cost of a mixed-schedule program would come in at about $3 million less per vaccinated birth cohort than the current two-dose program with Gardasil-9.
It is also estimated that the feasibility of the mixed schedule should be quite similar to the current vaccination schedule, particularly in the case of school-based vaccination.
The schedule making use of Cervarix vaccine alone was not considered because it offers little or no protection against anogentital warts. The current two-dose schedule of Gardasil-9 provides assurance that the province would not sacrifice any acquired immunization against the HPV burden. However, the CIQ believes that a mixed schedule maximizes the type 16 and 18 HPV immune response while providing good immunity against seven other types of HPV covered by the Gardasil-9 vaccine. In other words, assuming the unit price of Cervarix is lower than that of Gardasil-9, the mixed schedule is the most efficacious option.