by David Isaacs
Actually, Jackie should have been looking for a vaccine to prevent all known diseases, not a cure. Preventing a disease is much more powerful than trying to cure an ill patient.
We may contemplate the future of immunisation with excitement or apprehension or perhaps a bit of both. Excitement, because there are debilitating conditions, infectious and non-infectious, that can blight our lives and those of our loved ones, for which safe and effective vaccines would undoubtedly benefit us. Apprehension, because increasing technology scares many of us in a Brave New World sort of way.
The past and present of immunisation have been and are fascinating. Like all human activities, there have been bad aspects as well as good, but the overwhelming conclusion is that immunisations have been incredibly important in saving lives, preventing crippling and ruinous illnesses and improving people’s quality of life. We have every reason to believe that immunisation will continue in the future to be overwhelmingly beneficial to humans.
The state of the world’s health
The top 10 causes of death in the world in 2015 according to the WHO were coronary artery disease, stroke, lower respiratory tract infections, chronic obstructive pulmonary disease, lung cancer, diabetes mellitus, dementias including Alzheimer’s disease, diarrhoeal diseases, tuberculosis and road traffic accidents.
Sir Macfarlane Burnet might have been more than a trifle premature in announcing ‘the virtual elimination of the infectious disease’ in 1962, but 100 years ago the top 10 would have included seven infectious diseases, not three – tuberculosis, malaria, influenza, pneumonia, gastroenteritis, diphtheria and smallpox – and infections would have caused well over half of all deaths.
Immunisation has made a huge difference. Nevertheless, we could still save many more lives simply through better use of existing vaccines. Increased access to existing pneumococcus and influenza vaccines would reduce by about half the 3.2 million deaths caused each year by lower respiratory tract infections (pneumonia), and improved access to rotavirus vaccines would prevent about 200,000 of the 1.4 million deaths annually due to diarrhoeal diseases (gastroenteritis).
These goals could be achieved by improving delivery of vaccines to the world’s poorest people. As we heard in the last chapter, this would require better funding through increased philanthropy, more foreign aid and greater investment in health by poor countries.
At present both rich and poor countries spend huge amounts on weapons and armies that could, if governments only agreed on how to do so, be diverted to health and education. Surely it is not being too naïve to suggest that we should all strive to convince governments worldwide that increased spending on health and education would be money well invested, and that a strategy that promotes health at the cost of arms would also help reduce the need for those very weapons.
Vaccine wish list
Vaccine experts sometimes dream of all the diseases they could prevent through immunisation if they could just make the right vaccines, or even a single one that would prevent many diseases.
1. Malaria and HIV
These two very different diseases have dominated the vaccine wish list for the last 30 years. The organisms that cause them share the characteristic of flying beneath the radar to evade the human immune system.
Malaria is caused by a parasite transmitted by mosquitoes; HIV/AIDS is caused by a virus. They both cause chronic infection in people who often remain relatively healthy, yet can transmit the infection to others. Malaria is transmitted by the bite of an infected mosquito – but the mosquito has to bite an infected human to become infected. HIV infection can be transmitted sexually, of course, but also from an infected mother to her infant at birth or through breastfeeding. HIV is carried in the bloodstream and is also transmissible through infected blood products, such as donated blood or the blood-clotting protein Factor VIII, which infected many haemophiliacs before HIV was recognised.
Both these diseases evade our immune system in different ways, but both do so using stealth.
The malaria parasite causes disease by parasitising human red blood cells. The nastiest of the different malaria parasites, Plasmodium falciparum, avoids detection by switching a critical protein on and off, a bit like turning traffic lights on and off. The dangerous time for the parasite is when it is moving in the bloodstream between red blood cells, when it can be susceptible to the human immune system. By switching off the protein, the parasite becomes invisible. Once inside a red cell, it switches the protein on again, beds down and replicates. It’s not exactly reds under the bed – more like an invisibility cloak.
The human immunodeficiency virus, which causes HIV infection, replicates at an enormous rate, and produces mutations that alter the way the host immune system views virus-infected cells. One mechanism is to cover HIV-infected cells with human proteins. This too has been described as using the proteins like an invisibility cloak.
Scientists have tried for many years – with really very limited success – to develop vaccines against malaria. Some vaccines have been able to prevent a proportion of cases, but no specific malaria vaccine has yet been marketed.
Fortunately, the WHO and others have had success in using medicines and innovative measures like insecticide-impregnated bed nets to reduce the global burden of malaria. The number of cases of severe malaria worldwide fell by 29% between 2010 and 2015, and although malaria still killed an estimated 429,000 people in 2015, it used to kill over a million each year.
While Plasmodium falciparum has had millennia to evolve mechanisms to evade the human immune system, HIV has developed the same ability despite having only recently emerged.
It is likely that HIV has only been infecting humans for 100 years at most. AIDS, the most severe illness caused by HIV, was first recognised in 1981, and HIV was identified as the source in 1983.
Scientists assured the public they would be able to develop an effective HIV vaccine rapidly. But their optimism was unfounded. Live attenuated HIV vaccines have been pretty much ruled out by the possibility that they will accidentally cause HIV infection.
Tantalus is a mythological Greek character who stole ambrosia and nectar from the gods. He was condemned to stand forever in a pool of water beneath a fruit tree with low-hanging branches. Every time he tried to grab the fruit, it eluded his grasp. When he went to drink the water in the pool, it always receded. Tantalus was tantalised to punish him for his hubris.
In medicine we talk of low-hanging fruit as something that feels as if it is almost within our grasp. Renowned immunologist Gordon Ada gave many talks on progress towards an HIV vaccine. He told me that in every talk he gave over many years, he found himself saying that the discovery was 10 years away. Maybe we are being punished by the gods for our hubris in thinking we would find an HIV vaccine so easily.
Fortunately, as with malaria, we have made huge strides in controlling HIV without vaccines, mainly through developing highly effective medicines. When they are used optimally, a person with HIV has a life expectancy no different from that of an uninfected person.
There are problems in getting the drugs to people in poor countries, however. In 2015, HIV still killed 1.1 million people. The good news is that this is half as many as in 2005, and that HIV has now dropped out of the top 10 causes of death in the world. The bad news is that three-quarters of the deaths in 2015 were in Africa, where HIV is still the leading cause of death.
At present we are certainly making some progress towards controlling malaria and HIV, but vaccines would have the potential to save many more lives.
2. Dementia vaccines
As the population ages, the two big concerns for the elderly are their bodies and their brains. We have surgical operations, such as hip replacements, to postpone some of the ravages of skeletal deterioration. What we dream of is something that would prevent dementia. What we dread is that our nearest and dearest will suffer from the condition, or that we ourselves will.
Dementias are diseases that cause impaired memory and thi
nking. Alzheimer’s disease is perhaps the best known, but there are several others. British writer Terry Pratchett made light of his own dementia when he wrote: ‘It is possible to live well with dementia and write best sellers like wot I do.’ But he also railed over being an author who lost his facility with words, and he died at just 66.
In 2015, over 1.5 million people in the world died from a form of dementia. In 2015, dementias featured for the first time among the WHO’s top 10 causes of death, coming in at number seven.
Clearly, the rise of dementia is partly because we are living longer. However, we do not know the cause and have no effective treatment. There is some evidence that ‘clean living’ – avoiding drugs, excessive alcohol and tobacco, and using your brain a lot – are preventative to a certain extent. There is also evidence that dementia can run in families.
Scientists have actually made dementia vaccines, but they are being tested on people who already have dementia, whereas the ideal approach would be to vaccinate to prevent the disease.
There is a good reason why these vaccines are only being given to dementia sufferers. The brains of people suffering from Alzheimer’s disease have two characteristics: the accumulation of a protein called amyloid-beta (also written as amyloid-β or Aβ), and an excess of neurofibrillary tangles. ‘Neurofibrillary tangles’ seems like a poignant description of the state of the brains in which they are found. They are actually accumulations of tau protein (named after the Greek letter τ).
Both amyloid and tau proteins occur naturally, but accumulate to excess in Alzheimer’s patients. And there’s the rub. If the proteins occur naturally, would a vaccine against the proteins cause harm if given to someone who is at risk of dementia but is currently normal?
Scientists have developed vaccines against both amyloid-β and tau proteins and have studied them in animals and in humans with Alzheimer’s disease. The vaccines did not cause demonstrable harm, but neither did the subjects show any improvement in cognitive function.
It would be naïvely optimistic to think that a therapeutic vaccine could reverse brain damage in people with dementia, although the idea is not impossible. Perhaps in future we will be able to identify – for example, through genetic testing – people at high risk who might be candidates for a preventative vaccine.
New modes of delivery
Some of people’s resistance to immunisation is based on the invasive nature of injecting foreign substances. Less invasive routes have the potential to deliver vaccines much more cheaply, easily and painlessly.
1. Oral vaccines
We already use oral vaccines containing attenuated strains against polio and rotavirus. Both of these are gut viruses that enter the body through the intestine. Oral vaccines cannot be used for respiratory viruses, because they are destroyed by the acid in our stomachs. Other potential oral vaccines have remained just out of the reach of some of our most innovative and inventive scientists.
In Chapter 8, on vaccines and cancer, we learned about two West Australian scientists, Barry Marshall and Robin Warren, and their discovery of the bacterium Helicobacter pylori. Although there is no vaccine against Helicobacter pylori on the market, in 2005 a Chinese group published a study showing that an oral artificial (not live) vaccine protected 72% of children against Helicobacter pylori infection. An effective oral vaccine would have the potential to prevent cancer of the stomach and save thousands of people from a painful, miserable death.
Edible vaccines are vaccines produced in genetically modified plants that can be eaten. The name was coined by American molecular biologist Charles Arntzen in 1990. An edible vaccine is developed by finding a way of inserting a gene coding into a plant.
Our current hepatitis B vaccines use the protein on the outside of the virus called the surface antigen, which has the genetic code HBsAg. Arntzen and other researchers showed in 1992 that they could grow tobacco plants that incorporated the HBsAg gene. The plants were not edible, but it was proof of the concept of plant-derived vaccines.
Arntzen and others have gone on to develop edible hepatitis B vaccines by inserting the HBsAg gene into tomatoes, bananas, rice and algae. (An edible vaccine is not necessarily palatable, although obviously it will be better tolerated if it tastes good.) Other plants used to make edible vaccines are alfalfa, apples, carrots, lettuce, maize, papaya, potatoes, quinoa and soy beans. The hope was that they would be cheap to produce – at least after the initial cost of developing the vaccine – as well as cheap to deliver and easy to administer. I know a vaccine scientist who dropped everything in the early 1990s and devoted the rest of his career to trying to grow hepatitis B vaccine in potatoes.
Sadly, initial excitement at the prospect of edible vaccines has been tempered by practical issues. The public has often expressed concern about genetically modified crops with regard to human safety, environmental conservation and the risks of ‘tampering with nature’; genetically modified edible vaccines raise similar biosafety issues. There are concerns about traces of pesticides. Allergy to plants is another possible problem. Ensuring the correct dose can be difficult. The cost of preserving and delivering edible vaccines makes them more expensive than hoped. Vaccines grown in plants that are unpalatable when raw, such as potatoes, need to remain active after cooking.
Despite the initial excitement, there are no edible vaccines currently licensed for use in humans. A United States vaccine grown in tobacco cells is available to protect against Newcastle disease, which can decimate poultry. Researchers have made some headway towards developing an edible vaccine against Ebola virus, and the ideal would be to develop an edible Ebola vaccine that not only protected against Ebola but also had nutritional value.
The potential for edible vaccines is huge, but the difficulties remain considerable. Nevertheless, it is possible that safe, effective edible vaccines will be available in the foreseeable future.
2. Nasal vaccines
A family is a unit composed not only of children but of men, women, an occasional animal and the common cold.
Ogden Nash, poet (1902–1971)
Nasal vaccines target cells in the lining of the nose (nasal mucosa), so they have the advantage of stimulating nasal immunity as well as being generally better tolerated than injected vaccines. Researchers have tried for decades to develop nasal vaccines against the respiratory viruses that cause colds and more severe diseases.
The most obvious candidate is influenza. A live attenuated nasal influenza vaccine called FluMist was developed by United States researchers as a nasal spray in the 1990s. It has been used as an alternative to injected influenza vaccine in the United States since 2003, although it has not yet been marketed in Australia.
Respiratory syncytial virus (RSV) is a virus found in almost every country in the world. (We looked at it in the section on pneumonia back in Chapter 7.) It is most virulent when it infects infants, in whom it can cause a life-threatening respiratory infection called bronchiolitis. No one has succeeded in developing a safe, injectable RSV vaccine. Attempts to develop a nasal live attenuated RSV vaccine for infants have been hampered by the tension between causing a low-grade infection that does not stimulate enough immunity, and causing a high-grade infection that results in worrying nasal congestion. The same problem has hampered the development of an effective nasal vaccine against parainfluenza viruses, which can cause croup. Nevertheless, researchers are still hopeful of developing safe, effective nasal vaccines against RSV and parainfluenza viruses that will be easy to deliver and will make a huge difference to children’s health.
3. Skin vaccines
The skin should be an ideal site for vaccine delivery because it contains branching cells called dendritic cells that are involved in the immune response.
Jet injectors can deliver vaccines into the skin under pressure, without the need for a needle. They have been used to give inactivated polio vaccine to young children in Cuba and BCG vaccine to adults and newborns in South Africa. The only study that has compared pain from jet
injectors with pain from conventional immunisation found, however, that the jet injectors were more painful than intramuscular injections in adults. Given that one reason for using needle-free vaccine delivery is to reduce pain, this is an obvious drawback.
One advantage of jet injectors is that they can be used for multiple vaccinations, which saves time and money. However, strict infection control precautions must be observed to prevent transmission of organisms from person to person. An outbreak of hepatitis B infection occurred between 1984 and 1985 in a weight-reduction clinic that gave hormones using jet injectors. The pressing need (no pun intended) to avoid such outbreaks is a major consideration in deciding whether to use jet injectors in immunisation programs.
Professor Mark Kendall is a bioengineer from the University of Queensland who has devoted his career to developing a technology called the nanopatch. Similar to a Band-Aid (sticking plaster), the nanopatch is covered with thousands of minuscule needles coated with vaccine. When you apply the nanopatch it immunises you painlessly through your skin.
This may sound easy, but the technology required to deliver the right amount of vaccine is highly complex. Mark Kendall’s team has published the results of successful experiments in mice, and is now carrying out early human studies. However, teams in other countries, including the United States, are competing to produce the best system of microneedles, and have developed techniques known colourfully as ‘poke and flow’, ‘poke and patch’, ‘poke and release’ and ‘coat and poke’.
In 2017, a research team from Emory University, Alabama, beat Mark Kendall in publishing the first human study. They used sticking-plaster-sized patches containing only 100 needles, not the thousands in Kendall’s nanopatch, and compared the use of a single microneedle patch with the usual intramuscular injection in delivering influenza vaccine to 100 adults, with 50 using a patch and 50 receiving an intramuscular injection.