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| Professor Frazers excellent adventure |
16-Nov-2005 |
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An unglamorous quest to discover why HIV-positive men were plagued with anal warts led Professor Ian Frazer to a hugely lauded scientific discovery
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a vaccine against cervical cancer. By Bianca Nogrady.
PROFESSOR Ian Frazer radiates energy, albeit an energy tinged with impatience. He may be enthusiastic and talkative throughout this umpteenth media interview, but you can tell he really just wants to get back to his work.
That’s understandable — after all, not only has he led research that could eliminate the spectre of cervical cancer, but he is now on the verge of another breakthrough that has some touting him as Australia’s next Nobel laureate.
Described as “the common cold of sexual activity”, HPV infects an estimated 630 million women around the world, indirectly claiming the lives of about 288,000 each year.
Professor Frazer has already been instrumental in the development of a prophylactic vaccine against HPV and now he is turning his attention to the hunt for a therapeutic vaccine that could eliminate the virus in women who are already infected, reducing the risk of chronic infection and its potentially carcinogenic consequences.
Not bad for someone who originally trained as a renal physician. But, as Frazer tells it, immunology beckoned him from his student days back in his native Scotland. He finally got his chance to indulge his passion when Professor Ian Mackay, who he met while on a student secondment to Melbourne, offered him a position in his clinical immunology unit at the Walter and Eliza Hall Institute. Professor Mackay, now honorary visiting professor at Monash University’s department of biochemistry and molecular biology, had been impressed by the young researcher’s deep-seated interest in immunology and its impact on human wellbeing.
With HIV just rearing its head in Australia, Frazer became interested in why HIV-positive men were so afflicted by anal and penile warts caused by HPV.
“At that time there was nothing known about it [HPV],” says Frazer, in the broad Scottish accent he has retained throughout his 20 years in Australia. “Much of the immunology had been done on the basis that there was one type of virus.
“Back in 1987, we were already thinking about vaccines, and how we might develop them, but at that time we were mostly thinking therapeutically — to treat infection rather than prevent it.”
After moving to the University of Queensland in 1985, Frazer set about working towards a prophylactic vaccine against HPV. He found a like-minded partner in Chinese immunologist Dr Jian Zhou, who he met while on sabbatical in Cambridge.
It was far from a straightforward process. The conventional approach of growing the virus in a cell culture wasn’t going to work because HPV requires differentiating skin cells to replicate. So Frazer and Dr Zhou decided to try to build from scratch the virus’ harmless outer shell — the viral capsid — using DNA recombinant technology.
“The first few attempts didn’t work,” Frazer says. “In retrospect, it’s easy to work out why they failed.”
The first DNA sequence they used to produce the capsid protein had an undiscovered mutation that prevented the protein from folding correctly. Once they fixed that, the next challenge was to work out which part of the gene to use and where to start reading the DNA.
After a lot of frustrating trial and error, the breakthrough came.
“One day when we tested out this new process for doing things, and when we got the [electron micrographs] back, there they were,” Frazer says. On the images, they could clearly see the round, knobbly, virus-like particles they had been striving for.
“That was a real high point,” Frazer says. “When we saw that, we knew we’d got the vaccine, or we knew that we had something that was very likely to be a vaccine.”
There was little time to celebrate. Keenly aware of other research teams around the world working towards the same end point, the pair wrote up their findings and quickly lodged a provisional patent. The task of developing the actual vaccine was put in the hands of Australia’s CSL and US pharmaceutical giant Merck & Co. Clinical trials involving more than 10,000 women around the world, including in Australia, tested new vaccines against HPV subtypes 16 and 18 — which cause 70% of cervical cancers — and six and 11, which cause 90% of genital warts.
The results were spectacular. The vaccines were 90%-100% protective against persistent HPV infection with the targeted subtypes. What’s more, the most recent phase three trial of the quadrivalent vaccine also showed 100% protection against high-grade abnormalities and cervical adenocarcinoma — findings that astounded even the most experienced immunologists.
“It is virtually unknown to have a vaccine that is 100% effective,” says immunologist Sir Gustav Nossal, emeritus professor at the University of Melbourne. “I consider these phase three trials of Ian Frazer’s HPV vaccine an absolute triumph.”
Dr Germain Fernando, an immunologist who has been working with Frazer since 1990, was also caught by surprise. “As a scientist, we always hoped for the best,” he says. “However, I did not think it [would] be 100% efficacious. I would have been happy if it were even 80% efficacious.”
Sadly, Dr Zhou did not live to see the results of his research, succumbing to a chronic illness in 1999. For Frazer, it was the lowest point of the journey. “We were equal partners in the team and we worked on it with the same degree of enthusiasm,” he says.
Now, after almost 20 years of research, the quadrivalent vaccine (Gardasil) is being groomed for its global launch, and it is going to be quite a debut.
“If we can introduce it not just in this country but in the world, it means we should be able to prevent 70% of cervical cancers,” says gynaecological oncologist Professor Ian Hammond, from Perth’s King Edward Memorial Hospital for Women. In the developing world, where cervical cancer is a leading cause of death in women and screening is non-existent, the vaccine would have the same impact as a comprehensive screening program, he says.
In Australia, screening has already slashed cervical cancer morbidity and mortality, so the greatest benefit will come from a reduction in low- and high-grade cervical abnormalities and therefore in the need for costly interventions such as colposcopy. HPV subtypes six and 11, while causing 90% of genital warts, also cause a large number of low-grade cervical abnormalities, Professor Hammond says.
There is no immediate push to add further subtypes to the vaccine, an expensive option that may turn out not to be necessary, given the possibility of a cross-protective effect between related subtypes. “If it turns out that it is broadly protective against the other types that cause cervical cancer, then you wouldn’t be rushing to add extra types,” Professor Hammond says.
But, unfortunately, the vaccine will not completely do away with the need for screening programs. “Even when we have an effective vaccine, we’re still going to need to have a screening program, but possibly not as rigorous,” he says. Women who miss out on vaccination or who have already been exposed to the virus will still need screening, and it is also possible the distribution of subtypes might shift after the vaccine’s introduction, allowing other oncogenic subtypes to become dominant.
Research on such questions is continuing, but the indefatigable Professor Frazer has already moved on to the tantalising prospect of a therapeutic HPV vaccine that could eliminate persistent infection.
One vaccine is being trialed as a treatment for anal intraepithelial neoplasias in HIV-positive men and the results so far are promising, says CSL’s head of research and development Dr Andrew Cuthbertson. “We’ve found it to be safe and it produced quite profound immune responses in patients with HPV infections,” he says.
The approach is very different to that taken for prophylactic vaccines. “In this case, because infection has occurred and lesions have been established, we need to generate a T-cell immune response that can actually target viral proteins that are inside the cell,” Dr Cuthbertson says. “You’re trying to generate mainly a cellular immune response that will actually kill the cells that are infected.”
Professor Mackay believes if Frazer can succeed with the therapeutic vaccine, he could be a contender for a Nobel prize. “If Ian Frazer works out how to eradicate infection that’s already happened, that would be looked on, I think, as a spectacular achievement.”
The prospect of another Australian Nobel win has whipped the media into a frenzy, but all Frazer has to say about the media storm is, “I wouldn’t have chosen to be there.”
Professor Mackay always knew his protege was destined for great things. “[He was] a person who was moved by what I’d call curiosity-driven rather than mission-driven research,” he says. “He did have a capacity for creative lateral thinking which is not given to many — and he’s got a dogged persistence and he carries it all with a certain Celtic charm.
“My faith in him from the beginning has been very amply vindicated. And it’s nice to feel, if you haven’t done it yourself, that you’ve picked a winner that has.”
VACCINATION IN PRACTICE
GARDASIL is set to roll out in Australia next year, although it is still not clear exactly who it will be given to and at what age.
“The key factor it depends on is the duration of protection,” says Associate Professor Raina MacIntyre, from the National Centre for Immunisation Research and Surveillance. “If it can afford a long duration of protection then I think the younger you give it the better, but if it only has finite duration of protection, we need to find that balance of giving it before people become sexually active.”
So far, the vaccine has only been trialed in women, and while some economic studies have suggested there is not much benefit to vaccinating men, Professor MacIntyre questions this. “I don’t think it is possible to control a disease without targeting all the affected populations.” The high burden of disease from genital warts, which affect both men and women, is also a factor, she says.
As to parental acceptance of vaccinating children against what is essentially a sexually transmitted infection, Professor MacIntyre says a lot will depend on how the vaccine is marketed. “If it’s marketed as a cancer-preventing vaccine, there won’t be as much resistance.”
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