by David Isaacs
Helicobacter pylori
Barry Marshall was born in the goldfields town of Kalgoorlie in Western Australia. He trained as a doctor in Perth. In the early 1980s he became interested in gastritis (inflammation of the stomach) and peptic ulcers. At the time, the medical community was convinced that stress and lifestyle factors such as smoking were the cause of stomach ulcers.
Barry’s Perth pathologist colleague Robin Warren observed curved, rod-like bacteria in the stomach lining of patients with gastritis. Barry succeeded in growing them, but was unable to infect laboratory animals with them. Barry and Robin called the bacteria Helicobacter pylori, meaning spiral stomach bacteria, and published their findings in a letter to the prestigious journal The Lancet.
Some letter. Their international colleagues thought the bacteria Barry and Robin were seeing down the microscope were not real, but were artefacts induced when processing the specimens. Even if the organisms were real, most critics doubted they could survive in stomach acid.
Desperate to convince the sceptics, Barry Marshall let someone put a tube down his throat to perform a biopsy on his stomach, which proved he had not previously been infected with Helicobacter pylori, then drank a suspension of the organism. Over the next two weeks he developed abdominal pains, and submitted himself to two more biopsies to prove he had gastritis, and to grow the organism from his stomach. He then took antibiotics, which cleared the infection and his symptoms. The mind boggles at the things some people (but not many) will do for science.
We now know Helicobacter pylori causes over 90% of duodenal ulcers and up to 80% of gastric ulcers, and is also associated with gastric cancer. It can usually be eradicated with antibiotics. In 2005, Barry Marshall and Robin Warren were awarded a Nobel Prize for their discovery, which has revolutionised the management and prevention of stomach and duodenal ulcers.
Despite intense research, no effective vaccine is yet available commercially against Helicobacter pylori. But when one is finally developed it will prevent many thousands of cases of stomach cancer.
Other vaccines that treat cancer
As we’ve learned, BCG vaccine is a live attenuated vaccine developed to prevent tuberculosis and made from the cow TB organism Mycobacterium bovis.
Since the 1970s, the non-specific immune stimulation that BCG vaccine provides has often been used to treat patients with bladder cancer. The initial treatment for adults is usually to use a scope to enter the bladder and burn away the cancer. Bladder cancers can also be resected (cut out). However, the cancer has a strong likelihood of recurring, often repeatedly so, despite multiple attempts to burn or cut it away.
We need a working immune system if we are to recover from cancer, just as we need it to recover from infections. BCG vaccine, instilled directly through a catheter into the bladder, works in a non-specific way (nothing to do with its protection against TB) to stimulate immune cells in the bladder, and the increased immunity allows the cells to eliminate the cancer. BCG vaccine reduces the risk of recurrence of bladder cancer by about 20%. If at first that does not sound all that impressive, for many thousands of sufferers it means the difference between having repeated operations for recurrences of bladder cancer and being cured.
Sipuleucel-T was the first cancer vaccine to be licensed. It was approved by the United States Food and Drug Administration (FDA) in 2010 to treat some men with metastatic prostate cancer (prostate cancer that has already spread). It stimulates the immune response to an antigen (foreign substance) called prostatic acid phosphatase. Men with one type of metastatic prostate cancer given Sipuleucel-T in a clinical trial lived just over four months longer than men not given the drug. Many people see an extra four months as being very worthwhile to get their affairs in order and say their farewells.
On target
We can now prevent children and adults from getting liver cancer using hepatitis B vaccine, and we can prevent women from getting cancer of the cervix using HPV vaccines. We can also reduce recurrence of bladder cancer using BCG vaccine, and extend the lives of men with prostate cancer.
In the future, scientists hope to develop many more cancer vaccines, including vaccines that target cancers caused by virus infections, as well as vaccines that stimulate the immune system to fight off cancer.
CHAPTER 9
Vaccines and pregnancy
Riley was the second child of Catherine and Greg Hughes. Riley was a normal, healthy baby, born in February 2015 in Perth. When he was three weeks old, he developed a runny nose and occasional cough. The family doctor said it was only a virus, but Riley became sleepy and went off his feeds.
His parents took him to hospital, where he was found to have pneumonia due to whooping cough. His breathing deteriorated despite intensive care, and after five days in hospital, Riley Hughes died.
Riley was 32 days old. His parents did not know that a local whooping cough outbreak had just started, nor that immunising pregnant women in the last three months of pregnancy reduces the risk that their newborn babies will catch whooping cough.
Riley’s parents posted a video online that was taken in his last days of life, showing him coughing uncontrollably and going blue in the face. They started a movement, Light for Riley, to inform others about the benefits of immunising pregnant women against whooping cough in the third trimester of pregnancy, to try to prevent anyone else from having to go through the same tragedy as them.
Pregnant women are at increased risk from infections because their immune system does not work as well as normal. This reduced immunity is necessary to prevent the immune system from rejecting the foetus as ‘foreign’, which could lead to miscarriage. Thus, a pregnant woman infected with a virus such as chickenpox or influenza may develop a life-threatening disease.
One reason for immunising a woman before or even during pregnancy is to protect her. A second reason is so that she will produce antibodies that can cross the placenta and protect her infant against congenital infection (being born already infected).
Some infections, such as rubella, can pass through the placenta and infect the foetus during pregnancy, causing severe congenital defects. Congenital rubella can be prevented by pre-pregnancy rubella vaccine. Babies are also at risk of catching potentially severe infections at the time of birth, such as tetanus, or soon after birth, such as whooping cough, as Riley did.
Doctors may be reluctant to recommend pregnancy vaccines for fear that the vaccines will harm the unborn child. This is a perfectly rational fear. We know that things that happen to women during pregnancy can affect their foetus. Almost everyone knows about the malformations of babies’ arms and legs caused when pregnant women took thalidomide to prevent morning sickness during the 1950s. Fortunately, there is good evidence that the vaccines currently recommended during pregnancy are safe as well as effective.
This chapter will discuss maternal immunisation before pregnancy to prevent congenital rubella syndrome and neonatal tetanus, and during pregnancy to protect both the mother and her newborn infant against influenza and whooping cough.
Rubella
Rubella vaccine is a live attenuated viral vaccine. As we have seen, it is given to both girls and boys to prevent rubella circulating and thus stop non-immune pregnant women catching rubella. In this way it prevents congenital rubella syndrome. It is not recommended in pregnancy because of the theoretical risk that it might cause congenital rubella syndrome. However, of the more than 3500 women globally who have been inadvertently given rubella vaccine just before they became pregnant or in early pregnancy and elected to continue with their pregnancy, not a single one has had a baby with congenital rubella syndrome.
The breakthrough in understanding rubella and congenital rubella syndrome came during World War II. Norman McAlister Gregg was an Australian ophthalmologist who played cricket and tennis for New South Wales and was later knighted. He worked at the same hospital as I do, the Children’s Hospital at Westmead, then known as the Royal Alexandra Hospital for Children, in Sydney, making h
im a local hero as well as an international one. Gregg had an inquiring mind and was interested in everything, particularly his patients. He was also a kind man, who kept a tin of biscuits in his office for the children who visited him.
In 1941, Gregg suddenly started seeing a large number of newborn infants with eye defects, particularly cataracts. While pondering the cause, Gregg overheard two mothers in the waiting room saying they had both had German measles early in their pregnancy. There had been a rubella epidemic in Sydney during the spring and summer before the babies were born.
Intrigued, and wondering if the cataracts could be due to maternal rubella, Gregg inquired among other mothers of affected infants in his practice, as well as those of his colleagues. Gregg himself had seen 13 affected babies; his colleagues told him about another 65. The majority of the mothers – 68 of the 78 whose babies were affected – remembered having a rubella-like illness with a rash in early pregnancy.
On 15 October 1941, Gregg delivered a paper called ‘Congenital Cataract Following German Measles in the Mother’ to the Ophthalmological Society of Australia. The paper was later published in the society’s journal. The Sydney press reported Gregg’s findings on the Monday morning after the meeting, and before lunchtime the same day two mothers telephoned Gregg to say they had had rubella in early pregnancy and their children were deaf but were otherwise well.
We now know that if a woman catches rubella early in the first trimester (first three months), her baby may have the full congenital rubella syndrome, whereas if she is infected between 14 and 17 weeks, the infant may be deaf but without other defects. This is because the rubella virus attacks organs at a critical stage of their development in the foetus: the eyes, brain and heart develop early in the first trimester and the ears a bit later.
Gregg’s discoveries were doubted until the same clinical findings were documented in an outbreak in the United States. As the first person to recognise that the organisms infecting a pregnant woman could cross the placenta and harm the foetus, Gregg had achieved something truly remarkable. He is a wonderful example of a physician – an eye surgeon, at that – who listened to mothers, thought about what they said and followed through with intelligent inquiry. Gregg’s observation, the first recognition of congenital rubella syndrome, helped hasten the development of rubella vaccine, which has in turn prevented the deaths of many thousands of infants.
Rubella virus was isolated in the early 1960s, and by the end of that decade vaccines were available. Gregg was honoured in his lifetime, but was always a modest and unassuming man. When he received an invitation from an Italian pathologist, Professor Alfonso Giordano, to be nominated for a Nobel Prize, Sir Norman Gregg replied:
I must confess that it comes as a great surprise and rather a shock that my name should even be considered . . . I feel it only fair to you to inform you that I have really no serious publications except those on rubella as I have found very little time or inclination for writing during a very busy life.
Other doctors soon recognised that congenital rubella syndrome was a devastating condition, and could cause microcephaly (a small head), severe intellectual impairment, blindness, deafness and congenital heart disease. Babies with severe congenital rubella syndrome who cannot see and cannot hear become ‘locked in’; it is almost impossible to communicate with them. These are some of the most heartbreakingly damaged children a paediatrician ever sees.
Before immunisation, rubella epidemics occurred every six to nine years, and major pandemics about every 10 to 30 years. Epidemiologists estimate that 10% of all pregnant women developed rubella infection in the last major world pandemic from 1963 to 1965, and 30% of their infants developed congenital rubella syndrome. In the United States, over 12 million people caught rubella during that pandemic, as a result of which 11,000 pregnant women miscarried, over 2000 babies died soon after birth, and 20,000 infants were born with major congenital defects. In recent years, though, there has been on average fewer than one case each year of congenital rubella syndrome in the whole of the United States.
Congenital rubella syndrome has all but been eliminated from first-world countries thanks to rubella vaccine. National rubella vaccine programs had been established in 147 countries by the end of 2015.
But there is no room for complacency. Less than half the world can afford routine rubella vaccine, global coverage is only around 46%, and the WHO estimates that worldwide 100,000 babies a year are still born with congenital rubella syndrome.
Tetanus
We learned in Chapter 7 how tetanus is passed from the soil, and about its prevalence in newborns in Africa. Newborns can be infected by tetanus at or soon after birth if their umbilicus is not adequately cleaned, and particularly if animal dung or even ghee (clarified butter) is applied to their umbilicus, as is the cultural practice in some countries. The bacterium Clostridium tetani that causes tetanus often lives in the intestines of cattle and horses and is found in their dung.
A newborn baby who develops tetanus is almost certain to die. Yet babies can be almost completely protected if their mothers are fully immunised against tetanus, because the mother makes protective antibodies that cross the placenta and enter the baby’s bloodstream. Maternal immunisation prevents 94% of cases of neonatal tetanus.
For 150 years on the island of St Kilda in Scotland’s Outer Hebrides, more than two-thirds of all babies born died from tetanus within two weeks of birth. After a few days they would stop being able to suck; they were said to have a sardonic smile, which was no smile at all, but spasm of the face muscles. The disease was called ‘the sickness of eight days’. Between 1855 and 1876, 41 of the 56 babies born on St Kilda died. In 1885, a Glasgow Herald journalist, Robert Connell, wrote: ‘A great gun of the Free Church was not ashamed to say that this lock-jaw was a wise device of the Almighty for keeping the population within the resources of the island.’
In 1890, a St Kilda minister, the Reverend Angus Fiddes, discovered that the local midwife, who was called the ‘kneewoman’, used to ‘clean’ each newborn baby’s umbilicus with ruby-red oil obtained from a local seabird, the fulmar. The oil was kept in a gourd made from the dried stomach of a bird known locally as a solan goose, although we would call it a gannet. The gourd was never cleaned.
On learning all this, Fiddes threw the gourd over the cliff and ended the disastrous spectre of neonatal tetanus that had haunted women on the island. He persuaded public health nurses from Glasgow to educate the lay midwife about modern birthing practices. No cases of neonatal tetanus occurred on St Kilda after 1891.
Neonatal tetanus occurs when spores contaminate the cut umbilical stump. On St Kilda, the midwife’s gourd was presumably contaminated with tetanus spores. In some African countries, neonatal tetanus is known as ‘no-suck disease’ and is acquired through a traditional practice of putting mud on the umbilical stump. (As I mentioned in Chapter 7, I have witnessed this myself.) Mud of course contains dung, which harbours lots of spores of Clostridium tetani. In India, it was more common to use ghee (clarified butter), but this too could be contaminated with tetanus spores and cause neonatal tetanus.
The WHO estimates that 787,000 newborns died of neonatal tetanus in 1988. This stimulated a campaign to reduce and eventually eliminate neonatal tetanus, through increased immunisation of girls and pregnant women, and through improved umbilical cord hygiene.
While there were initially some problems in implementing the recommended strategies, the WHO has now made considerable progress. In 2015, the WHO estimates that 34,000 newborns died from neonatal tetanus, a 96% reduction from the late 1980s. By the end of 2016, only 18 countries had not succeeded in eliminating neonatal tetanus.
Influenza
Influenza is a respiratory virus that spreads in the air through coughs and sneezes. Hippocrates described influenza’s hacking cough, runny nose, sore throat, fever, headache, aches and pains about 2500 years ago. The name comes from the Latin influentia, ‘influence’, because medieval physicians thought th
e huge outbreaks that came around without fail year after year were influenced by the movements of the heavenly spheres.
Influenza virus still kills up to half a million humans every year. As we saw in Chapter 1, a worldwide influenza pandemic can wipe out millions of people in a few weeks.
Infection can cause a viral pneumonia, which can sometimes be complicated by bacteria, causing a ‘super-infection’ (one infection on top of the other). Influenza infection also causes the body to release proteins such as interferon, which help fight off the influenza virus but themselves cause high fever, shivers and shakes (rigors), headache and severe muscle aches and pains debilitating enough to render healthy youngsters bed-bound for a week or two.
Pneumonia is the usual cause of death if flu proves fatal, but an influenza infection can also affect the heart. Young adults occasionally die from myocarditis if they exercise when they have influenza. People who have a heart attack (myocardial infarction) are twice as likely to have had a recent influenza-like illness as people who do not suffer a heart attack. Even children are not totally safe from death: a small number of previously normal healthy children around two to four years old die suddenly from influenza each year.
Pregnant women are more than twice as likely to be hospitalised if they catch influenza as non-pregnant women of the same age. The infants of pregnant women who catch influenza are significantly more likely to be born premature or underweight.