A hundred years ago, the death of a child from infectious disease was a common occurrence. Louis Pasteur, who took Edward Jenner’s ideas about vaccination and suggested they could be applied to any microbial disease, lost three of his five children to typhoid – an illness that’s now almost entirely preventable thanks to the technology he helped develop. Together with improved sanitation and antibiotics, vaccination has utterly transformed our relationship with pathogens. Smallpox has been eliminated, polio is on its way out, while other historic harbingers of death and debility such as measles and diphtheria are extremely rare. According to the World Health Organization, vaccines prevent around 3 million premature deaths per year.
“Vaccination is one of the most demonstrably effective and cost effective public health interventions that there is,” says Andrew Pollard, Professor of Paediatric Infection and Immunity at the University of Oxford and Director of the Oxford Vaccines Group.
However, despite the many success stories, effective vaccines against some of the world’s biggest killers remain frustratingly elusive. Although the BCG vaccine against tuberculosis has been given to many millions of people, its ability to induce protective immunity varies between 18 and 80 percent depending on where you live. Even then, it only protects against severe childhood forms of tuberculosis; it does little to protect against the deadly and widespread adult lung infections. Similarly, RTS,S/AS01 – the most advanced vaccine being developed for malaria – is only 26 to 50 percent effective in infants and young children, even after four doses. And an effective vaccine against HIV remains a distant dream, despite more than 30 years of research and billions of pounds of investment.
In part, it’s because the agents that cause these diseases are masters of disguise and immune system manipulation. However, a fundamental lack of understanding about how the immune system generates immunity has also hampered our best efforts. The good news is that powerful molecular tools are shedding new light on these processes, and this should ultimately lead to the development of better vaccines against these foes, and others.
History of vaccination
The practice of exposing people to a disease to protect them against future infection, known as variolation, can be traced as far back as 10th century China. Scabs from smallpox victims were either placed under the skin, or powdered and snorted up the nose to reduce an individual’s chances of contracting smallpox. But it was Edward Jenner who drove the widespread use of this practice and in effect established the science of vaccinology as we know it today. He deliberately infected people with a less dangerous relative of smallpox called cowpox, and found that it protected them against future infection with both diseases.
Pasteur took this idea and developed it still further, reporting methods for attenuating the virulence of microbes so that they could be safely injected into the body and manufactured in bulk quantities for use around the world.
A hit and miss approach
The same principle underpins the development of pretty much every childhood vaccination we receive today. “You get a bug, you kill or inactivate it and then you inject the product into people – and if you’re lucky it protects them against infection,” says Peter Openshaw, President of the British Society for Immunology and Professor of Experimental Medicine at Imperial College London.
Incredibly, the transformative effects of vaccines on human and animal health occurred with barely any understanding of the immune events taking place in the body. “It was a hit and miss approach, but because there were so many attempts, it resulted in a large number of the vaccines which were partly responsible for the large decline in mortality from infectious disease during the second half of the twentieth century,” Openshaw adds.
Although the development of most existing vaccines relied on trial and error rather than sophisticated immunology, we now know that the formation of this immunological memory involves distinct subsets of immune cells called B cells and T cells. Upon encountering the vaccine components (antigens), cells such as macrophages which specialise in processing and disposing of pathogens engulf the antigens and present them to B and T lymphocytes. The B cells churn out antibodies that protect against infection, while memory cells are also produced that will initiate a rapid response the next time that pathogen is encountered.
“Nearly every useful vaccine that’s been developed to date acts through the production of antibodies,” says Ronald Germain, Chief of the Lymphocyte Biology Section at the National Institute of Allergy and Infectious Diseases in Bethesda, USA.
The advantages of cellular immunity
However, this approach has taken us about as far as we can go. For one thing, the pathogens that cause diseases like tuberculosis, malaria, HIV, and many parasitic infections have all developed complex strategies to control our immune system, and evade detection – even hiding in our own immune cells in the case of HIV. “They control and work with our immune system, and against us,” says Openshaw.
But antibodies alone don’t seem to be enough. We also need T cell directed ‘cellular immunity’ in which our immune system is able to destroy cells that have already been infected by the pathogen. However current vaccines aren’t very good at generating this type of immunity. “Unfortunately, we have not learned yet how to make vaccines that operate at the cellmediated level in a highly effective manner,” says Germain.
One strategy currently being investigated is DNA vaccines. Here, small pieces of DNA encoding antigens from the virus are inserted into a bacterial plasmid, which is then injected in the hope that some of our cells will take up the DNA and essentially become vaccine-antigen factories themselves – manufacturing and secreting the bit of the pathogen which the immune system can react to.
However, even if we could get our T cells to work better, it’s unclear precisely which T cells we should be targeting and in which locations. A major issue is that no-one really knows what the immune system looks like in people who are protected against diseases such as TB. “If we had a measure or a correlate of protective immunity, we’d be able to go about the development of vaccines in a much more rational way,” says Professor Ajit Lalvani, Chair in Infectious Diseases at Imperial College London.
Getting to know the immune system
So how do we go about getting better acquainted with our immune systems? The classic approach has been to focus on a single cell type, protein or signalling molecule at any given time. But technological advances now make it possible to rapidly combine multiple measurements of cells, tissues and blood, in order to build a fuller picture of how they work together to generate immunity. “By learning about what’s happening in the immune system with these measurements, we can potentially see what we need to fix to make the response to vaccines better,” says Germain. “It’s a more rational approach to designing vaccines.”
Already, it’s paying off in the field of influenza research. Although vaccines against seasonal flu exist, the protection they afford is only short-term because the influenza virus is constantly evolving. In 2014, Germain and his colleagues announced that they’d identified an immunological signature which predicted how well people would respond to the seasonal and H1N1 flu vaccines.1 To do so, they measured and compared the frequencies of different immune cell types, the expression of genes, the levels of flu-specific antibodies, and the activity of antibody-producing B cells in 60 volunteers both before and after they were vaccinated.
“These measurements are not related to influenza-specific immunity; they are broader measures of the immune system and they are reasonably stable in individuals over time,” says Germain. “We can begin to distinguish who will be a high and a low responder, and having done that we can say, ‘what is that telling us about the human immune system and is there something we can do to make the low responders better?’”
Lalvani’s team have also identified a subset of T cells present in the blood of people who were exposed to the H1N1 virus during the 2009 flu pandemic, but didn’t develop symptoms.2 Knowing this, they are now looking at ways of stimulating the body to produce more of these cells.
As well as enabling us to develop more effective vaccines, these kinds of insights might also reduce the amount of time it takes to bring new vaccines to market. At the moment, this typically takes around 12–15 years, a large part of which is taken up with field trials that involve injecting the vaccine into large numbers of people and waiting to see how many of them develop the disease. However, “if you could give the vaccine and two weeks later measure an immune response that told you it was going to work, then something which may currently take many years to develop could instead take just a couple of years,” says Openshaw. “The trouble is that we still don’t really know how vaccines work, or why something that should work doesn’t.”
The point of delivery
Understanding the type of immunity needed to protect people against hard-to-vaccinate diseases is only part of the challenge, however. Immunologists also need to figure out how best to generate that protection. For instance, the BCG vaccine against tuberculosis is usually injected into the arm, but the usual route of infection is inhalation through the lungs. It therefore makes sense to try and target immune cells living in the lining of the lungs, which might mean the creation of new types of vaccines, such as inhalable ones.
Researchers are also working on dissolvable skin patches as an alternative to traditional injected vaccines. Diseases like tuberculosis, malaria and HIV disproportionately affect people living in some of the world’s poorest regions – places with poor transport infrastructure and limited access to electricity, which is needed to keep vaccines refrigerated. To this end, researchers are investigating delivering dried live vaccines through dissolvable polymer skin patches studded with tiny needles, which could be kept at room temperature and even be self-administered. Rather than injecting the vaccine into muscle tissue, the microneedles instead target antigen-presenting cells in the skin, but early results suggest the end result may be similar. For instance, when researchers at King’s College London recently loaded a candidate HIV vaccine into such patches and applied them to the skin of mice, they recorded an immune response equivalent to when a liquid version of the vaccine was injected.3
Whatever the next hundred years holds, it’s clear that twentieth century approach of growing a bug, disabling it and injecting it isn’t going to be enough to rid the world of infectious disease and the misery it causes. Some of the pathogens we’re fighting have been with us for millennia and know our immune systems far more intimately than we do, while others are newly-emerged and bring healthcare challenges all of their own. We’ll have to at least match the knowledge and ingenuity of these pathogens if we’re going to beat them.
This article was written by Linda Geddes as part of the BSI's report '60 years of immunology: past, present and future'. This article is licensed under Creative Commons Attribution-NoDerivative Licence (CC BY-ND 4.0). Additional permissions may need to be sort from image licence owners.
- Tsang et al. 2014 Cell 157 499–513
- Sridhar et al. 2013 Nature Medicine 19 1305–1312
- Bachy et al. 2013 Proceedings of the National Academy of Sciences 110 3041–3046