Two Dose vs. Three Dose HPV Vaccine Schedules
Objective. To investigate the incremental cost effectiveness of two dose human papillomavirus vaccination and of additionally giving a third dose.
Design. Cost effectiveness study based on a transmission dynamic model of human papillomavirus vaccination. Two dose schedules for bivalent or quadrivalent human papillomavirus vaccines were assumed to provide 10, 20, or 30 years' vaccine type protection and cross protection or lifelong vaccine type protection without cross protection. Three dose schedules were assumed to give lifelong vaccine type and cross protection.
Setting. United Kingdom.
Population. Males and females aged 12-74 years.
Interventions. No, two, or three doses of human papillomavirus vaccine given routinely to 12 year old girls, with an initial catch-up campaign to 18 years.
Main Outcome Measure. Costs (from the healthcare provider's perspective), health related utilities, and incremental cost effectiveness ratios.
Results. Giving at least two doses of vaccine seems to be highly cost effective across the entire range of scenarios considered at the quadrivalent vaccine list price of £86.50 (€109.23; $136.00) per dose. If two doses give only 10 years' protection but adding a third dose extends this to lifetime protection, then the third dose also seems to be cost effective at £86.50 per dose (median incremental cost effectiveness ratio £17,000, interquartile range £11,700-£25,800). If two doses protect for more than 20 years, then the third dose will have to be priced substantially lower (median threshold price £31, interquartile range £28-£35) to be cost effective. Results are similar for a bivalent vaccine priced at £80.50 per dose and when the same scenarios are explored by parameterising a Canadian model (HPV-ADVISE) with economic data from the United Kingdom.
Conclusions. Two dose human papillomavirus vaccine schedules are likely to be the most cost effective option provided protection lasts for at least 20 years. As the precise duration of two dose schedules may not be known for decades, cohorts given two doses should be closely monitored.
Persistent infection with a high risk human papillomavirus type is necessary for cervical cancer. Two human papillomavirus vaccines are available—a bivalent vaccine with antigens for human papillomavirus 16 and 18 associated with 70-80% of cervical cancers globally (Cervarix) and a quadrivalent vaccine that additionally contains antigens for human papillomavirus 6 and 11 associated with most cases of anogenital warts (Gardasil). Female participants receiving three doses of either vaccine in trials were protected against persistent infection and pre-cancerous lesions associated with human papillomavirus 16 and 18. Universal human papillomavirus vaccination of girls before their sexual debut has been found to be cost effective in both developed and developing countries. However, the high cost of purchase and delivery of vaccine has been a barrier to more widespread implementation—for example, in developing countries and in demographic groups beyond young adolescent girls. Furthermore, the need to deliver three doses of a vaccine to a non-traditional age group can be challenging.
Recent clinical trial and post-introduction data suggest that two doses of human papillomavirus vaccine may be sufficient protection for girls aged 9-14 years when administered in a prime-boost schedule with at least six months between doses to allow affinity maturation of memory B cells elicited by the first dose. Efficacy against persistent human papillomavirus 16/18 infection in vaccinees who received two bivalent vaccine doses was non-inferior for at least three years after vaccination compared with those who received three doses in a post-hoc non-randomised study in Costa Rica. In addition, immune responses in 9-14 year old girls after two bivalent vaccine doses six months apart were non-inferior for at least four years to responses in 15-25 year old female patients receiving three doses, and similar results were seen for the quadrivalent vaccine. Although the Costa Rican study found no evidence of cross protection, an exploratory analysis of a bivalent vaccine trial suggested that antibody responses for human papillomavirus 31 and 45 in 9-14 year old girls after a two dose schedule were comparable to those for three doses in 15-25 year olds. As three doses have been shown to protect against persistent infection for almost a decade with no evidence of waning, two doses will probably also provide long lasting protection. The European Medicines Agency has granted marketing authorisation for two dose schedules of both vaccines for girls below 15 years on the basis of these data.
Although two doses are likely to protect vaccinees for more than a decade, whether protection (and potential cross protection) will be as long lasting or broad as it is for three doses is uncertain, as immunogenicity is inferior to that for three doses in equivalent aged girls (rather than in 15-25 year olds). Consideration of two dose schedules as an alternative to three dose schedules relies on comparing the potential benefits of the two dose schedule (cost savings, logistical simplicity, and potentially higher uptake) with its risks (potentially lower protection). As the precise duration and extent of two dose protection is not yet known for certain, this requires consideration of the range of possibilities that are consistent with the available data. A cost effectiveness framework allows an assessment of whether the economic benefits of two dose schedules compensate for its associated risks and uncertainties.
Several jurisdictions have recently switched from three dose to two dose vaccination schedules for girls aged 9-14 years on the basis of such risk-benefit considerations, including Switzerland, the Netherlands, Mexico, the United Kingdom, and Quebec. In two jurisdictions (United Kingdom and Quebec), the decision was explicitly made after consideration of cost effectiveness modelling. The World Health Organization's Strategic Advisory Group of Experts on Immunization (SAGE) also recommended a two dose schedule for girls aged 9-14 years after reviewing evidence including cost effectiveness modelling.
Here we present a cost effectiveness analysis of two versus three dose human papillomavirus vaccination; this analysis was used to inform the decisions in the United Kingdom and Quebec, as well as by SAGE to recommend a two dose schedule. The work builds on previous modelling showing that two dose vaccination in England and Canada can provide most of the reduction in cervical cancer associated with three dose vaccination. In this analysis, we extend the previous model to consider the full range of human papillomavirus related diseases, including other sites of cancer, anogenital warts, and recurrent respiratory papillomatosis. This allows us to examine the cost effectiveness of vaccination, particularly when the duration of protection of two dose vaccination is assumed to be only 10 years, and hence the difference in reduction of cervical cancer between the two schedules is greatest (assuming no booster dose is administered at the point of waning).
Abstract and Introduction
Abstract
Objective. To investigate the incremental cost effectiveness of two dose human papillomavirus vaccination and of additionally giving a third dose.
Design. Cost effectiveness study based on a transmission dynamic model of human papillomavirus vaccination. Two dose schedules for bivalent or quadrivalent human papillomavirus vaccines were assumed to provide 10, 20, or 30 years' vaccine type protection and cross protection or lifelong vaccine type protection without cross protection. Three dose schedules were assumed to give lifelong vaccine type and cross protection.
Setting. United Kingdom.
Population. Males and females aged 12-74 years.
Interventions. No, two, or three doses of human papillomavirus vaccine given routinely to 12 year old girls, with an initial catch-up campaign to 18 years.
Main Outcome Measure. Costs (from the healthcare provider's perspective), health related utilities, and incremental cost effectiveness ratios.
Results. Giving at least two doses of vaccine seems to be highly cost effective across the entire range of scenarios considered at the quadrivalent vaccine list price of £86.50 (€109.23; $136.00) per dose. If two doses give only 10 years' protection but adding a third dose extends this to lifetime protection, then the third dose also seems to be cost effective at £86.50 per dose (median incremental cost effectiveness ratio £17,000, interquartile range £11,700-£25,800). If two doses protect for more than 20 years, then the third dose will have to be priced substantially lower (median threshold price £31, interquartile range £28-£35) to be cost effective. Results are similar for a bivalent vaccine priced at £80.50 per dose and when the same scenarios are explored by parameterising a Canadian model (HPV-ADVISE) with economic data from the United Kingdom.
Conclusions. Two dose human papillomavirus vaccine schedules are likely to be the most cost effective option provided protection lasts for at least 20 years. As the precise duration of two dose schedules may not be known for decades, cohorts given two doses should be closely monitored.
Introduction
Persistent infection with a high risk human papillomavirus type is necessary for cervical cancer. Two human papillomavirus vaccines are available—a bivalent vaccine with antigens for human papillomavirus 16 and 18 associated with 70-80% of cervical cancers globally (Cervarix) and a quadrivalent vaccine that additionally contains antigens for human papillomavirus 6 and 11 associated with most cases of anogenital warts (Gardasil). Female participants receiving three doses of either vaccine in trials were protected against persistent infection and pre-cancerous lesions associated with human papillomavirus 16 and 18. Universal human papillomavirus vaccination of girls before their sexual debut has been found to be cost effective in both developed and developing countries. However, the high cost of purchase and delivery of vaccine has been a barrier to more widespread implementation—for example, in developing countries and in demographic groups beyond young adolescent girls. Furthermore, the need to deliver three doses of a vaccine to a non-traditional age group can be challenging.
Recent clinical trial and post-introduction data suggest that two doses of human papillomavirus vaccine may be sufficient protection for girls aged 9-14 years when administered in a prime-boost schedule with at least six months between doses to allow affinity maturation of memory B cells elicited by the first dose. Efficacy against persistent human papillomavirus 16/18 infection in vaccinees who received two bivalent vaccine doses was non-inferior for at least three years after vaccination compared with those who received three doses in a post-hoc non-randomised study in Costa Rica. In addition, immune responses in 9-14 year old girls after two bivalent vaccine doses six months apart were non-inferior for at least four years to responses in 15-25 year old female patients receiving three doses, and similar results were seen for the quadrivalent vaccine. Although the Costa Rican study found no evidence of cross protection, an exploratory analysis of a bivalent vaccine trial suggested that antibody responses for human papillomavirus 31 and 45 in 9-14 year old girls after a two dose schedule were comparable to those for three doses in 15-25 year olds. As three doses have been shown to protect against persistent infection for almost a decade with no evidence of waning, two doses will probably also provide long lasting protection. The European Medicines Agency has granted marketing authorisation for two dose schedules of both vaccines for girls below 15 years on the basis of these data.
Although two doses are likely to protect vaccinees for more than a decade, whether protection (and potential cross protection) will be as long lasting or broad as it is for three doses is uncertain, as immunogenicity is inferior to that for three doses in equivalent aged girls (rather than in 15-25 year olds). Consideration of two dose schedules as an alternative to three dose schedules relies on comparing the potential benefits of the two dose schedule (cost savings, logistical simplicity, and potentially higher uptake) with its risks (potentially lower protection). As the precise duration and extent of two dose protection is not yet known for certain, this requires consideration of the range of possibilities that are consistent with the available data. A cost effectiveness framework allows an assessment of whether the economic benefits of two dose schedules compensate for its associated risks and uncertainties.
Several jurisdictions have recently switched from three dose to two dose vaccination schedules for girls aged 9-14 years on the basis of such risk-benefit considerations, including Switzerland, the Netherlands, Mexico, the United Kingdom, and Quebec. In two jurisdictions (United Kingdom and Quebec), the decision was explicitly made after consideration of cost effectiveness modelling. The World Health Organization's Strategic Advisory Group of Experts on Immunization (SAGE) also recommended a two dose schedule for girls aged 9-14 years after reviewing evidence including cost effectiveness modelling.
Here we present a cost effectiveness analysis of two versus three dose human papillomavirus vaccination; this analysis was used to inform the decisions in the United Kingdom and Quebec, as well as by SAGE to recommend a two dose schedule. The work builds on previous modelling showing that two dose vaccination in England and Canada can provide most of the reduction in cervical cancer associated with three dose vaccination. In this analysis, we extend the previous model to consider the full range of human papillomavirus related diseases, including other sites of cancer, anogenital warts, and recurrent respiratory papillomatosis. This allows us to examine the cost effectiveness of vaccination, particularly when the duration of protection of two dose vaccination is assumed to be only 10 years, and hence the difference in reduction of cervical cancer between the two schedules is greatest (assuming no booster dose is administered at the point of waning).
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