by David Isaacs
CHAPTER 8
Vaccines and cancer
Anti-immunisation groups sometimes assert that vaccines can cause cancer. But researchers have studied links between vaccines and cancers very carefully, and not only is there no suggestion that vaccines cause cancer, there is also the strongest possible evidence that two vaccines prevent cancer and at least one vaccine can cure cancer. The reason we can prevent cancer is that some cancers are caused by chronic virus infections, so preventing these infections can prevent cancer. The reason we can cure cancer is that we need our immune system to get rid of cancer, and some vaccines stimulate our immune system.
A critical question when thinking about cancers is why one person gets cancer and not another. The reasons are complex, but in simple terms they boil down to a combination of genetics, environment and time.
Legendary reggae musician Bob Marley died of malignant melanoma at just 36 years of age. Marley’s father was a 50-year-old white itinerant overseer, Norval Marley, who falsely claimed to have been a captain in the British Caribbean army. He seduced Cedella, a 17-year-old Jamaican. Although he married her when she fell pregnant with Bob, he then ran away to Kingston and hardly ever visited his wife or son. Bob Marley later said bitterly that the only thing his father ever gave him was melanoma. He was correct.
White-skinned people have a rate of melanoma 20 times higher than black-skinned people, because melanin in the skin protects against melanoma: the darker the skin, the more melanin. Your skin colour is inherited from your parents, but the rate of melanoma is twice as high for white-skinned people in Australia as it is for white-skinned people in the United Kingdom, showing that increased exposure to sunlight increases the risk. Thus, your risk of getting melanoma depends on both your genes and your environment.
We know that the major environmental trigger for lung cancer is tobacco smoke. But in 18th century England, there were others. A London apothecary, John Hill, wrote that snuff could cause cancer of the lip, mouth and throat. Ten years later, a surgeon, Sir Percivall Pott, described chimney sweeps with scrotal cancer and made the link between the cancer and chimney soot, which stuck in their groin as they climbed chimneys near-naked. (He later identified Pott’s disease of the spine, caused by tuberculosis, which can cause the hunchback gibbus deformity described in Chapter 5).
Tobacco smoke, snuff and soot are all examples of what we now call carcinogens, chemicals that cause chronic irritation and inflammation, and can change normal cells into abnormal ones. These changes can then progress to cancer.
To prevent cancer we also need a healthy immune system. Cancers are cells that reproduce abnormally and uncontrollably; immune cells can detect them, treat them as foreign and destroy them before they spread. Children born with severe immune deficiency, a genetic disorder, not only suffer from recurrent infections but also have a hugely increased risk of developing cancers. Just as their immune system does not recognise foreign organisms that cause infections, it also does not recognise cancer cells well.
Half the people living in an industrialised country will get cancer at some time in their life. The incidence of cancer has risen and continues to rise. The main reason for this is that we live longer: our immune system gradually deteriorates as we age, and over three-quarters of cancers occur in people over 60. One of the major reasons why we live longer is immunisation. There is an irony here: immunisations prolong our lives long enough for us to get cancer.
The antidote to the irony is that there are two cancers in humans that are potentially vaccine-preventable: liver cancer, which is usually caused by chronic hepatitis B virus infection; and cervical cancer, which is caused by human papillomaviruses. We also have vaccines that can be used to stimulate the immune system to treat cancer, such as BCG vaccine to treat bladder cancer, and there are more cancer-fighting vaccines on the way. This chapter will discuss some of these exciting developments.
Hepatitis B
James Nguyen was 41 years old when he came to the emergency department of the hospital where I was working. He was a charming, well-spoken, hardworking man with a wife and three children. He had been born in Vietnam and had immigrated to Australia with his parents when he was a teenager. Recently he had had some abdominal pain, vomited a few times and lost weight, which he put down to the vomiting and his poor appetite.
When I examined him, I found his liver was enlarged and tender and had a rather knobbly feel to it. Mr Nguyen had liver cancer. The reason he had liver cancer was that he was chronically infected with hepatitis B virus, almost certainly passed on to him at birth from his mother.
I was a 25-year-old doctor, not long qualified. I had to tell Mr Nguyen and his distraught wife and children about his diagnosis, and that it was too advanced for us to be able to operate on him.
Mr Nguyen died four weeks later, in his home, surrounded by his family. I have changed his name, but his story is true, and it still haunts me.
He did not need to die. More than half the cases of liver cancer – hepatocellular carcinoma or hepatoma – in the world are caused by chronic hepatitis B virus infection, and this infection is vaccine-preventable.
What is not generally appreciated is that if a pregnant woman has chronic hepatitis B infection, she can inadvertently pass the virus on to her baby around the time of birth. Babies who catch the infection at birth never get acute hepatitis. They usually remain asymptomatic into adulthood, if not for the whole of their life. But they never produce antibodies to the virus, which will stay in their liver till they die.
The scientific explanation of this is a phenomenon called immunological tolerance. The foetus of an infected pregnant woman is usually exposed to small amounts of hepatitis B in the womb, and the growing baby thinks the virus is part of itself, so becomes tolerant to it. The body should not make antibodies against itself; people who do so develop autoimmune diseases. Immunological tolerance was first described by the British scientists Sir Peter Medawar and Rupert Billingham, based on work by the Australian scientist Sir Macfarlane Burnet, and this discovery, so important for transplant surgery, won the three of them the Nobel Prize in 1960.
Although babies chronically infected with hepatitis B are asymptomatic, the virus lurking in their liver can start to cause chronic inflammation. This can lead to scarring called cirrhosis, which we usually associate with liver damage from chronic alcohol abuse, but which can occur in people with chronic viral infection who drink no alcohol. As Mr Nguyen’s story demonstrates, the virus can also cause cancer of the liver.
Before the availability of vaccines, a quarter to a third of people with chronic hepatitis B infection died young from cirrhosis or liver cancer. In countries like Indonesia, Thailand, Cambodia, South Korea, Macau, Taiwan, China and Vietnam, in the 1970s and 1980s before routine hepatitis B immunisation was introduced, an astonishing one in seven children (15%) were infected at birth. Even today, there are 350 million people in the world with chronic infection, and about 600,000 of them die from hepatitis B complications every year.
Thanks to the vaccine, though, people like Mr Nguyen need never be infected at birth and need never have to suffer the way he did. The virus responsible for hepatitis B was discovered in 1965 – not by the many virologists and cancer specialists trying vainly to find a virus that caused cancer, but by a Philadelphia biochemist called Baruch Blumberg. This discovery would win him the Nobel Prize, although, initially at least, his discovery owed a great deal to serendipity.
Blumberg was interested in how genetic variations might make populations more susceptible to diseases, and this was his excuse to travel the world, from Africa to Asia to Australia, collecting blood samples from remote tribespeople and testing their blood for proteins called antigens. Blumberg found a blood antigen present in some Australian Aborigines that was also found in some people in Africa and Asia, but rarely in people in America or Europe. Blumberg thought this was a genetic factor, and called it ‘Australia antigen’. His studies showed a link with liver cirrhosis, and he thou
ght he had found an inherited protein antigen that predisposed people to chronic liver inflammation. However, one day in 1966, an American patient whom Blumberg had been studying who was known to have no Australia antigen suddenly developed acute hepatitis, and at the same time tested positive for Australia antigen. Clearly, the protein antigen was not inherited but one that the man had just acquired.
Blumberg’s real achievement was to labour diligently to identify this protein. Within a few years, his laboratory had shown that the protein antigen was produced by a virus, which he purified and called the hepatitis B virus. The Australia antigen was renamed hepatitis B surface antigen (HBs), because it sat on the surface of cells. By 1979, Blumberg’s team had developed the first ever hepatitis B vaccine from purified surface antigen.
A critical finding was that patients in Africa and Southeast Asia with liver cancer were far more likely to have chronic hepatitis B virus infection than patients without liver cancer. One possible explanation was that chronic hepatitis B caused chronic scarring (cirrhosis) that could lead to liver cancer. The implication was that a vaccine that prevented hepatitis B infection could prevent many liver cancers.
Today the newborn babies of women who are chronically infected with hepatitis B respond well to the vaccine. The difference between this response and the baby’s response to natural infection is that the vaccine contains aluminium (alum) as an adjuvant to boost the baby’s immune response and thus overcome the tolerance. This illustrates the importance of vaccine adjuvants; people who worry unduly about trace amounts of aluminium in vaccines do not usually understand that the vaccines would not work without them.
In 1984, Taiwan became the first country in the world to introduce routine neonatal (newborn) hepatitis B immunisation. Within 13 years, the incidence of liver cancer in children aged six to nine dropped from 0.52 to 0.13 per 100,000, a fall of 75%. This is strong evidence. Most European countries (47 of 53) and some countries in Southeast Asia have introduced universal hepatitis B vaccines.
The WHO has set a goal for hepatitis B vaccination to become part of universal childhood vaccination programs in all countries. By the end of 2016, 186 countries had introduced nationwide vaccination, and by 2015, the WHO estimated that 84% of the world’s children had been immunised, 114 of the world’s countries had achieved better than 90% coverage, and only six countries were below 50% coverage.
Hepatitis B is a virus that causes misery, cancer and early death, and which we will eventually eliminate from the world by immunisation.
Human papillomaviruses
In 1913, George Papanicolaou arrived in New York by boat, to seek his fortune. He had trained in medicine in Athens and Munich, yet now he was penniless with no job, so he resorted to selling carpets on 33rd Street. Later he applied to Cornell University and was employed in the research laboratory, investigating the menstrual cycle of guinea-pigs. He learned from scratch how to obtain cells from the female guinea-pig’s cervix – an eye-watering process (I shall spare you the details).
Papanicolaou was fascinated by how he could tell the stage of the menstrual cycle from the cells obtained by these cervical smears. He started to experiment on humans. I can’t resist adding that his wife was his first guinea-pig: Maria submitted to daily cervical smears while George perfected his technique. When you talk about long-suffering wives, do bear Maria in mind.
Cervical smears were an invasive way of predicting the menstrual cycle. But Papanicolaou started to examine smears from women with different gynaecological conditions and found that women with cervical cancer shed bizarre cells that he could see when he did a smear.
In 1928 he published a paper named ‘New Cancer Diagnosis’, giving the first description of what we now call the Pap smear. Yet it took over 20 years of research for Papanicolaou to crystallise his thoughts. It was only in 1950, when challenged at a Christmas party as to the use of his smears, that Papanicolaou was able to give voice to his dreams: the real purpose of Pap smears was to detect early pre-malignant changes and intervene before the cells became cancerous.
Two years later, 150,000 women in Shelby County, Tennessee, were given a Pap smear. Of these 555 had cervical cancer, while another 557 had early, precancerous lesions. (These could be removed by a simple surgical procedure called a cone biopsy, because it involved removing a cone-shaped chunk of tissue.) These women were well and symptom-free and were on average 20 years younger than those with cancer. The Pap smear had the potential to detect cervical cancers 20 or more years earlier than previous screening methods.
Regular Pap smears have undoubtedly prevented many thousands of cases of cervical cancer, but they cannot prevent all. On current figures, more than 900 women in Australia will develop cervical cancer in 2018, and 250 women will die from it. In the United States there will be in excess of 13,000 cases and more than 4000 deaths.
Harald zur Hausen is a German virologist who moved to the United States in 1965 to collaborate with Werner and Gertrude Henle in the virus laboratory of the Children’s Hospital of Philadelphia. The Henles were married German Jews who had fled Nazi Germany in 1936. Their field of interest was oncoviruses, viruses that could cause cancer. In 1968 Werner Henle became the first person to show that a virus could change normal cells into cancer cells, by using Epstein-Barr virus to infect normal white blood cells.
In 1976, zur Hausen published a paper hypothesising that human papillomaviruses were an important cause of cervical cancer. Papillomaviruses are wart viruses: some cause skin warts or plantar warts (verrucas); some are sexually transmitted and can cause ano-genital warts; and some can cause mouth papillomas. In 1983 and 1984, zur Hausen and his team identified two human papillomaviruses, HPV-16 and HPV-18, in specimens of cervical cancer. The following year he cloned HPV-16 and HPV-18. Although this did not prove that human papillomaviruses cause cervical cancer, subsequent studies showed that he was right. Harald zur Hausen was awarded a Nobel Prize in 2008.
Harald zur Hausen’s discovery paved the way for the development of vaccines to prevent human papillomavirus infection. The first vaccine against HPV was developed by Ian Frazer and Jian Zhou at the University of Queensland.
Ian Frazer was born in Glasgow, as was my scientist father, Alick. Like my father before him, Frazer travelled to the Walter & Eliza Hall Institute in Melbourne to enhance his training. On sabbatical to Cambridge University in 1989, Frazer met Jian Zhou, a younger virologist who had trained in China. Frazer persuaded Jian to join him in Queensland. They used DNA-recombining techniques to produce virus-like particles that do not contain any viral genetic material, so are non-infectious. Jian died in 1999 before seeing their work come to full fruition. (Sadly, he died from complications of chronic hepatitis B infection, which, as we’ve just heard, can cause cancer and can be prevented by immunisation.)
Two pharmaceutical companies led the way in bringing HPV vaccines to market: Merck in the United States introduced Gardasil, and GlaxoSmithKline (GSK) in the United Kingdom produced Cervarix. Cervarix provided immunisation against two strains of HPV, while Gardasil protected against four strains.
In 2007, Professor Suzanne Garland of the Royal Women’s Hospital in Melbourne published the results of a three-year trial of over 5000 women aged 16 to 24. Half the women had received three doses of Gardasil and half had received three doses of a placebo. Pre-malignant cervical cell changes developed in 65 women who had received the placebo but in none of the women given the vaccine. However, the vaccine did not protect women already infected with HPV. These results, while impressive, clearly show that HPV vaccines should be given before women are infected. Merck has now developed a newer version of Gardasil vaccine that protects against five additional HPV strains.
The evidence strongly suggests that HPV infection is the major cause of cervical cancer, and that HPV vaccine has the potential to prevent a huge proportion of all cervical cancers. Scientists can also detect HPV in anal cancer, penile cancer and oropharyngeal cancer (cancer of the throat), but they are less ce
rtain that HPV actually causes those cancers, and therefore less certain that HPV vaccine can prevent them.
Globally, it is estimated that over 500,000 new cases of cancer a year are caused by chronic HPV infections and can potentially be prevented by vaccines. Eventually we will probably have HPV vaccines that will almost eradicate cervical cancer. How remarkable is that?
Some fascinating ethical issues have arisen with HPV vaccines, however. One issue (which will be dealt with in Chapter 13) is the use of HPV vaccines on boys. Another issue (which we’ll hear about in Chapter 12) surrounds the way the United States company Merck’s vaccine, Gardasil, was marketed in the United States.
A third issue is the question of cost. The initial price of the HPV vaccine was high, around US$450 for a course of three doses. Merck and GSK said they needed to recoup the huge costs of vaccine development. When Gardasil and Cervarix were considered by the Pharmaceutical Benefits Advisory Committee in Australia, it found the high price was justified by the considerable benefits. The price paid in Australia is completely prohibitive for developing countries, but once uptake was guaranteed in some resource-rich countries, both companies supplied their vaccines at a fraction of the price to resource-poor countries.
It seems eminently reasonable that rich countries should pay a high but affordable price that in turn allows the companies to minimise costs in poor countries. Pharmaceutical companies can never be accused of excessive altruism, but this pragmatic equity deserves praise. The lowest current prices are around US$12.80 a dose in Brazil and South Africa. Many countries still cannot afford that price, and Gavi, the Vaccine Alliance – funded by the Bill and Melinda Gates Foundation – subsidises some of the poorest countries.
By 2014, 33.6% of all women aged 20 to 40 in wealthy countries had received a full course of HPV vaccine, compared with only 1 in 40 (2.7%) in low- or middle-income countries. An estimated 47 million people worldwide had been fully vaccinated against HPV by 2015, thus preventing 379,000 cases of cervical cancer and 156,000 deaths. Australia leads the way: it was the first country in the world to introduce a routine school-based program for girls, in 2007, and the first to immunise all boys, beginning in 2013; vaccinations were also offered to some older women. Projections suggest that Australia will be the first country in the world to eliminate cervical cancer, and possibly within your lifetime if not mine. What a thrilling prospect: to prevent thousands of young women dying from cancer through immunisation.