by Lay Leng TAN
ancer accounted for 7.6 million (13%) of all deaths worldwide in 2005. According to World Health Organization (WHO) projections, global deaths from cancer will rise to an estimated 9 million in 2015 and 11.4 million in 2030.
About one-quarter of cancer incidence arises from chronic infection, primarily from hepatitis B viruses (liver), human papilloma viruses (cervix), Helicobacter pylori (stomach), schistosomes (bladder), liver flukes (bile duct), and human immunodeficiency viruses (Kaposi sarcoma and lymphomas). Cervical cancer, the second most common cancer among women worldwide, remains the most common form in developing countries. In 2002, WHO reported cervical cancer -- caused by human papilloma viruses (HPV) -- was responsible for some 12% of all women's cancers, or about 250,000 deaths annually. About 10 varieties of HPV are responsible for the disease, with types 16 and 18 accounting for more than 70% of incidence.
HPV infect up to half of women within the first five years of their commencing sexual activity. Even though most women naturally clear the infection, about 2% of those with the virus will develop cancer. Pap smears effectively detect HPV and prevent progression of the disease; however, many women, especially those in developing countries, have no access to screening or the necessary follow-through.
How then to tackle this problem? Ian Frazer, a researcher at the University of Queensland in Australia, has been studying cervical cancer as a viral infectious disease and using a vaccine to target it. He and his late colleague Jian Zhou made the discovery in 1991 that led to the development of the vaccine 15 years later in conjunction with the Australian biomedical company CSL Ltd and international pharmaceutical company Merck & Co. For this landmark work, Frazer was named Australian of the Year 2006.
Merck markets the vaccine under the brand name Gardasil. GlaxoSmithKline (GSK) has developed its own version, Cervarix, with technology licensed from the University of Rochester in New York State and from CSL Ltd.
Gardasil, a prophylactic HPV vaccine, prevents viral infection. The vaccine protects against HPV types 16 and 18 as well as genital warts. Administered in three shots over a period of six months, it provides life-long immunity. The cost varies from country to country: in Australia, the full course costs A$460, in the US about US$360, and in Singapore about S$600.
In Australia, 20,000 women out of a population of 20 million undergo cervical surgery to forestall getting cervical cancer every year. The high 1-in-1000 incidence has spurred the government to make Gardasil freely available to all girls from 12 to 26 in 2007 and 2008, after which it will scale down the programme to those in the 12ĘC13 age group.
The high price tag arises from the vaccine's complexity: it comprises four vaccines, making it many times more expensive to make than, say, the hepatitis B vaccine. The complicated fermentation technology and process -- making virus-like particles, breaking them up, cleaning them, putting them back again -- pushes up manufacturing costs.
Frazer has worked with the Gates Foundation and the WHO's Expanded Vaccine Initiative to help make the drug available as cheaply as possible in the developing world. His team is researching the optimal age for receiving it and the best delivery system in these countries.
Scientists recommend that vaccinated women continue to undergo regular Pap screening as other types of HPV may still cause cervical cancer. Gardasil does not render any protection to
Can researchers modify the vaccine to treat the infection? Frazer's team is conducting a clinical trial using virus-like particles without adjuvant on a group of infected people, and they expect to have the results in late 2008. The Australian group also collaborates with doctors in Wenzhou and Shinjiang in China, researching a therapeutic vaccine against HPV-caused genital warts and cancers such as recurrent respiratory papillomatosis in children.
HPV shows no evidence of being subject to any selection pressures. If scientists can develop a drug to kill HPV type 16, the most virulent, no other more potent variety will replace it. Studies of sex workers in Scandinavia suggest that each type of HPV infection has no impact on the others.
Frazer, founder and director of the Centre for Immunology and Cancer Research at the Princess Alexandra Hospital in Brisbane, Australia, reveals that his lab is working on a vaccine for hepatitis C virus, which causes liver cancer. The group chose hepatitis C because a proven need exists for the vaccine. Evidence suggests that the particle technology used against HPV might work for hepatitis C as well.
Vaccines prevent infection by producing antibodies against proteins and protective mechanisms on the virus's surface. HPV, a very simple virus with no defences, provides a relatively easy target. The ones difficult to penetrate are such viruses as herpes and HIV bristling with defences against the immune system.
Frazer believes that vaccines against all these viruses will be available in 20 years' time. Although he admits that no perfect vaccine against HIV will exist because of the virus' chameleon-like defences, a vaccine 50% effective is better than none.
A vaccine against hepatitis C has to be almost 100% effective whereas that against Epstein-Barr virus (EBV) must prove fully 100% effective. Most children with this virus do not get sick and usually get rid of it naturally; only 1% of cases will develop into cancer. Delayed infection is generally associated with more severe disease. Thus the vaccine must lick the EBV completely to be useful.
Frazer explores extending to other diseases the recombinant technology by which he makes virus-like particles -- such as arboviruses (arthropod-borne viruses) that cause dengue fever and Japanese encephalitis. The challenge does not lie in the technology but rather on successful vaccine application, he explains. When a person who has earlier contracted dengue has another attack, the symptoms exacerbate. A vaccine may further aggravate the situation if it provides only partial immunity to some viral serotypes -- the patient will worsen or even die when exposed to a new serotype, especially as this re-exposure can lead to dengue haemorrhagic fever. "We really have to make sure the vaccine will prevent the disease it seeks to prevent," he cautions.
According to Frazer, the opportunity for vaccine improvement comes from novel adjuvants that render vaccines more powerful for better immunity. For instance, new adjuvants developed by GSK appear to boost and prolong the immune response to the vaccines such as hepatitis B to which they have been added.
Another technological trend takes the form of recombinant DNA and viruses. The scientist bets on DNA vaccine as the next-generation preventive treatment. Walking the talk, he cofounded Coridon, an Australian start-up company with platform technologies for developing DNA therapies.
Frazer expects that big pharmaceutical companies initially will be reluctant to adopt new DNA immunotherapies, should they prove effective, because of their commitment to their current technology and the desire to avoid competing with their existing products. However, he believes competition and consumer demand will propel these companies into using the most effective technology and processes when the next-generation vaccines come on-line. Such a move will improve global healthcare as vaccination represents the most effective public health measure ever introduced.
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