Tampere, Stockholm, Oxford, Heidelberg, Philadelphia and Seattle comprise some of the hubs of the human papilloma virus (HPV) research network.
Research Director Matti Lehtinen, who is also a visiting professor at Karolinska Institutet, Sweden, has studied HPV viruses for twenty-five years. During that time, the role of these viruses in the development of cancer was identified, a vaccine was developed, tested and introduced in the National Immunization Programme in Finland, and the most efficient vaccination strategies were tested. International cooperation has played a major role in these developments.
A doctor of medicine and a virologist, Lehtinen completed his doctoral thesis on herpesviruses in 1985, but soon afterwards became interested in papillomaviruses, which are involved in the development of cervical cancer, as was shown by the German Harald zur Hausen who was the Nobel Laureate in Medicine in 2008.
Some years later in Sweden, Lehtinen became acquainted with Joakim Dillner, who had developed methods for measuring papillomavirus antibodies.
“That encounter marked the start of the active cooperation with Karolinska Institutet,” Lehtinen says.
The University of Tampere had been conducting epidemiological research on cancer since the early 1980s. The research made use of data from the Finnish Cancer Registry and the serum bank collected by the Mobile Clinic Unit of the Social Insurance Institution.
The research was based on the study design of Richard Doll and Richard Peto, who worked at the University of Oxford; they argued that the causes of cancer should be investigated in a longitudinal setting using prediagnostic samples from cancer cases and controls for evidence of exposure to factors that might cause cancer.
“This kind of study setting enables the estimation of whether, and to a certain extent also how, exposure to environmental risk factors, such as the acquisition of infections, causes cancer in later life,” Lehtinen explains.
With the longitudinal study setting and the new methods for determining HPV antibodies, Lehtinen was the first to show that an HPV type 16 infection increases the risk of cervical cancer twelvefold. The research article, published in the British Medical Journal in 1996, is still cited today.
As the research continued, Lehtinen soon became familiar with the virological laboratories at the German Cancer Research Center in Heidelberg and Karolinska Institutet in Stockholm. Their methodologies were faster and more efficient and accurate in measuring serum and biological samples. They were therefore able to find more viruses than the Finnish laboratories and reveal the nature of humoral immune responses to HPV, most importantly the entire spectrum of HPV viruses and neutralising HPV antibodies.
However, Finland’s strength lay in the unique Finnish Maternity Cohort (FMC) serum bank established in the early 1980s by Pentti Koskela in Oulu. The bank contains approximately two million serum samples taken from virtually all (a million) expectant Finnish mothers in early pregnancy.
Among other things, these samples enabled researchers to investigate how the order of different HPV infections in infected individuals affects the risk of cancer.
“It wasn’t until recently that we were able to prove conclusively that if a woman first acquires an infection with a non-oncogenic HPV type, she is not at risk of developing cancer after a subsequent infection with an oncogenic HPV type,” Lehtinen says.
“However, if the woman catches the oncogenic infection first, that infection causes cancer in up to ten per cent of cases.”
Lehtinen went to the University of Oxford to introduce the results of the FMC serum bank and the Finnish Cancer Registry linkages. This started a long-term research cooperation with the British university. Due to the cooperation, the researchers were able to estimate the independent role of various carcinogenic factors (smoking, chlamydia) in the development of cervical cancer. At the same time, the Nordic Cancer Union started to fund the Nordic cooperation of serum banks and cancer registries, which Lehtinen had founded and was coordinating.
“Between 1997 and 2001, we were able to establish how past HPV16/18 infections caused not just cervical cancer but also highly increased the risk of developing other ano-genital cancers and oro-pharyngeal cancer.”
The Nordic cooperation of serum banks lasted for fifteen years and extended elsewhere in Europe after it received funding from the EU’s framework programmes.
In 1995, Lehtinen and Joakim Dillner first approached the vaccine manufacturer Merck Sharp & Dohme (MSD) in Philadelphia and presented the opportunities the Nordic research data offered for testing an HPV vaccine. Finland participated in the first clinical phase II trial four years later.
Other studies required for the licensing of the vaccine followed. They were conducted with a vaccine manufactured by MSD in the five Finnish cities with medical schools – Helsinki, Tampere, Turku, Oulu and Kuopio – plus Espoo and Vantaa. In another trial, a vaccine manufactured by GlaxoSmithKline was tested in twelve provincial capitals in Finland in addition to the cities with medical schools.
Those trials began in 2002 and 2004. The Population Registration Centre assisted by inviting all 16–17-year-old residents of the study site communities to participate in the trial. Half of them received the HPV vaccine and the other half received a placebo or a control vaccine. In addition, an unvaccinated control group, which did not receive any form of intervention, was included in the study in 2003 and 2005 when Lehtinen and Professor of Epidemiology Eero Pukkala sent a survey to the young women who were too old to be included in the tested cohorts. Ninety per cent of the 16,000 respondents said that they would have liked to have participated in the clinical trial.
The Finnish Cancer Registry follow-up is now being conducted for the three different groups, those who were vaccinated, those who received a placebo, and the control group.
“Those who have been vaccinated against HPV have not got cervical cancer. The figures for the group who received the placebo and the control group of girls who were not vaccinated correspond with each other and with the figures for the general population,” Lehtinen says.
“We have now been continuing the population-based follow-up for twelve years. Similar research has not been conducted anywhere else in the world.”
In 2013, the HPV vaccination was included in the National Immunization Programme in Finland.
When clinical trials of the HPV vaccine started in 2000, the researchers organised the first HPV vaccination symposium in Helsinki. The keynote speakers were the renowned vaccine developer Maurice Hilleman from Merck Research Laboratories, Philadelphia, infection epidemiologist King Holmes from University of Washington, Seattle and Harald zur Hausen.
“Holmes spoke about how the research paradigm in epidemiology was changing from nested case-control studies to intervention research with community randomisation,” Lehtinen recalls.
At the University of Oxford, Lehtinen had been introduced to Geoff Garnett, a mathematical biologist who was conducting pioneering research on mathematical models of the HIV epidemic. He had developed models on the effectiveness of low efficacy HIV vaccines assuming different immunisation coverages and vaccination strategies.
The idea was that the low efficacy of HIV vaccines could be compensated by vaccinating a large enough proportion of the population so that a reasonable herd effect would be achieved even if the vaccine itself did not turn out to be that efficacious.
“We wanted to modify this approach in a randomised trial because the HPV vaccine seemed to be highly effective, but its future coverage looked to be quite low.”
“We started to develop the community-randomised trial. With Geoff Garnett and Eero Pukkala, I came up with the idea that reducing the heterogeneity of the communities by stratification would increase the statistical power of the intervention so that the number of plausible study site communities in Finland would be enough.”
The trial to identify the most effective new immunisation strategy was launched in 2007–2009 by giving the HPV vaccine to girls born in 1992–95 in eleven communities and to both girls and boys in eleven other communities. In yet other eleven communities, all boys and girls in early adolescence received a vaccine against the hepatitis B virus. About 20,000, half of the girls invited, and about 20–30 per cent of the boys invited from the entire birth cohorts came forward for vaccination.
Follow-up visits have been conducted since 2009. Those born in 1992 had their first samples taken in 2010, the same year they turned eighteen.
“We are investigating whether there are fewer HPV infections in those communities where both girls and boys were vaccinated in comparison with those where only the girls were given the vaccine.”
It will now be possible to see whether vaccinating both girls and boys will result in sufficient herd effect.
“We have agreed with the National Institute for Health and Welfare and the WHO that when we will get these results next autumn, they will reconsider the question of whether boys should also be vaccinated against HPV,” Lehtinen says.
“This is research information from the top of the hierarchy of evidence. The community-randomised research setting yields information not on the efficacy of the vaccine but on the effectiveness of the different immunisation strategies.”
The HPV vaccine is administered to the young.
• The HPV vaccine is especially protective against cervical cancer and its early stages. The vaccination prevents cancer by stopping the spread of HPV infections.
• The vaccine works best if it is administered before people begin their sex lives.
• The vaccination is included in the National Immunization Programme in Finland and is given free of charge to all girls in the sixth grade. During the first two years of the immunisation programme, it was also given to girls in the seventh to ninth grades.
Source: Finnish National Institute for Health and Welfare
Text: Pirjo Achté
Photograph: Jonne Renvall