LTFU: Long-term follow up of subjects participating in the clinical trials of the HPV-vaccine

LTFU evaluates the long-term effectiveness, immunogenocity and safety of the HPV-vaccines Gardasil and Gardasil-9.
Last updated: 3/14/2022

 

 

Long Term Follow UP (LTFU) is a long-term follow-up of the women who participated in the studies with a vaccine against cervical cancer.

We conduct two LTFU studies at the Cancer Registry of Norway. The studies have several similarities in both research questions and methods, but we follow different participants who have respectively participated in studies with clinical trials of the HPV vaccines Gardasil and Gardasil-9.

HPV vaccine: Gardasil

In 2002, approximately 5500 young women in the Nordic countries participated in the clinical study "FUTURE II", the trial study of the HPV vaccine Gardasil.

In Norway, 1698 women participated. About half of the women received the vaccine, while the other half were given placebo, a delusional vaccine without active ingredients. The women who received placebo were offered an ordinary HPV vaccine after completing their studies.

The women have been followed up via national health registries until 2018. The purpose of the study is to map the duration of the HPV vaccine Gardasil's protective effect and safety.

In use in over 100 countries

Based on very positive results from the FUTURE II study, the US Food and Drug Administration (FDA) has approved the vaccine and it has been used in over 100 countries around the world. In the autumn of 2009, the vaccine was included in the childhood vaccination program in Norway.

Results from the study show that the vaccine has full effect for at least 12 years.

Collaboration and implementation

The Nordic countries have excellent health registries and are therefore well suited to conduct this type of study.

LTFU V501 is carried out by the Cancer Registry of Norway (Norway), Karolinska Institutet (Sweden), the Danish Cancer Society (Denmark) and the Krabbameinsfélgið (the Icelandic Cancer Registry). The Cancer Registry of Norway is the Nordic Coordination Unit (NCC) for the study.

The Food and Drug Administration (FDA) identified the Nordic countries as the most suitable place to conduct this type of study, and instructed the vaccine manufacturer MSD to carry out the study in the Nordic countries.

Status

Data collection and analyses have been completed, the results have been published and the study has been completed.

We are planning an extension of the study with follow-up for another eight years. Participants will be contacted in advance of any expansion.

Publications

Kjaer SK, Nygård M, Sundström K, Dillner J, Tryggvadottir L, Munk C, Berger S, Enerly E, Hortlund M, Ágústsson ÁI, Bjelkenkrantz K, Fridrich K, Guðmundsdóttir I, Sørbye SW, Bautista O, Group T, Luxembourg A, Marshall JB, Radley D, Yang YS, Badshah C, Saah A.
Final analysis of a 14-year long-term follow-up study of the effectiveness and immunogenicity of the quadrivalent human papillomavirus vaccine in women from four nordic countries. EClinicalMedicine. 2020 Jun 20;23:100401.
DOI: 10.1016/j.eclinm.2020.100401, PubMed: 32637895

Kjaer SK, Nygård M, Sundström K, Munk C, Berger S, Dzabic M, Fridrich KE, Waldstrøm M, Sørbye SW, Bautista O, Group T, Luxembourg A (2020)
Long-term effectiveness of the nine-valent human papillomavirus vaccine in Scandinavian women: interim analysis after 8 years of follow-up
Hum Vaccin Immunother, 1-7
DOI 10.1080/21645515.2020.1839292, PubMed 33326342

Enerly E, Berger S, Kjær SK, Sundström K, Campbell S, Tryggvadóttir L, Munk C, Hortlund M, Thomas Group, Joshi A, Saah AJ, Nygård M (2020)
Use of real-world data for HPV vaccine trial follow-up in the Nordic region
Contemp Clin Trials, 92, 105996
DOI 10.1016/j.cct.2020.105996, PubMed 32247041

Kjaer SK, Nygård M, Dillner J, Brooke Marshall J, Radley D, Li M, Munk C, Hansen BT, Sigurdardottir LG, Hortlund M, Tryggvadottir L, Joshi A, Das R, Saah AJ (2018)
A 12-Year Follow-up on the Long-Term Effectiveness of the Quadrivalent Human Papillomavirus Vaccine in 4 Nordic Countries
Clin Infect Dis, 66 (3), 339-345
DOI 10.1093/cid/cix797, PubMed 29029053

Nygard M, Saah A, Munk C, Tryggvadottir L, Enerly E, Hortlund M, Sigurdardottir LG, Vuocolo S, Kjaer SK, Dillner J.
Evaluation of the long-term anti HPV 6, 11, 16 and 18 immune responses generated by Gardasil.
Clin Vaccine Immunol. 2015. Epub. Jun 17.
DOI

 

The Norwegian Institute of Public Health administer the HPV-vaccine. 

HPV vaccine: Gardasil-9

In 2007-2013, more than 4,500 women in Sweden, Denmark and Norway participated in the clinical 9-valent vaccine study against cervical cancer.

About half of the women received the 9-valent vaccine (Gardasil-9), while the other half were given the 4-valent vaccine (Gardasil).

In this follow-up study - LTFU V503 - the Cancer Registry of Norway will follow these women until 2025 to map the duration, safety and protective effect of Gardasil-9.

First in the world

The women who received Gardasil-9 in the clinical vaccine study are among the first in the world to receive this vaccine.

In LTFU V503, these women are followed up via central health registries regarding development of pre-stages of cervical cancer, advanced cervical cancer and other relevant cancers. This is a passive follow-up study that does not involve any additional sampling or examinations of the women.

Effective and safe vaccine

Approximately 90% of cases of cervical cancer are caused by HPV types 16, 18, 31, 33, 45, 52 and 58.

Gardasil protects against types 16 and 18, while Gardasil-9 protects against all seven high risk types of HPV. In addition, both vaccines protect against HPV types 6 and 11, which cause about 90% of genital warts.

Gardasil-9 has been shown to be both safe and effective. A study published in February 2015 showed that the vaccine provided 97% protection against pre-stages of cancer caused by HPV types 31, 33, 45, 52 and 58.

The protection against cervical cancer caused by HPV types 16 and 18 was as good as for the 4-valent vaccine Gardasil.

Collaboration and implementation

The Nordic countries have excellent health registers, and are therefore well suited to conduct such a long-term follow-up study.

The study is carried out by the Cancer Registry of Norway, Karolinska Institutet (Sweden) and the Danish Cancer Society (Denmark). The Cancer Registry of Norway is the Nordic Coordination Unit for the study.

Status

Every other year, we collect archived tissue samples from the study participants who have taken a histological sample in the last two years, as well as register data from the Cancer Registry, the Norwegian Patient Registry and the Norwegian Cause of Death Registry. The collection is part of the project's passive follow-up of the participants, and the purpose is to investigate the effect of the HPV vaccine. In each round, we conduct a meeting with our Nordic Pathology Panel, which consists of 4 expert pathologists who examine the tissue samples collected. The tissue samples are also tested for HPV. Data collection is planned for the years 2017, 2019, 2021, 2023 and 2025.

Recently, an analysis was made of the results that have been collected so far which showed that the protection against severe pre-stages of cervical cancer caused by the HPV types that the 9-valent vaccine should protect against goods for at least six years.

Publications

Kjaer SK, Nygård M, Sundström K, Munk C, Berger S, Dzabic M, Fridrich KE, Waldstrøm M, Sørbye SW, Bautista O, Group T, Luxembourg A (2020)
Long-term effectiveness of the nine-valent human papillomavirus vaccine in Scandinavian women: interim analysis after 8 years of follow-up
Hum Vaccin Immunother, 1-7
DOI 10.1080/21645515.2020.1839292, PubMed 33326342