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Ever since the world’s first vaccine – against smallpox – was produced by Edward Jenner in the 1790s, the fight against infection has involved prompting the body to produce antibodies to destroy the invader. It has proven a hugely successful approach, with the measles vaccine alone saving 17 million lives since 2000.
However, research at Trinity College, Dublin, led by Professor of Comparative Immunology Prof Cliona O’Farrelly suggests that the innate immune system in some individuals is capable of clearing out dangerous viruses before the adaptive immune system even gets a chance to respond. This potentially opens the door to a whole new class of anti-infection drugs that are not antibiotics, but ‘immune boosters’.
In Ireland, hundreds of rhesus negative women were infected with hepatitis C from contaminated anti-D blood products they received after they gave birth between 1977 and 1979.
Some readers will recall that 12 years passed before any of the women knew that the anti-D they had received was contaminated, when a major ‘look back’ exercise was initiated. This investigation found that over 600 women had evidence of having been infected; with half having antibodies and the hepatitis C virus (HCV) in their systems and half having antibodies against HCV but no virus. In the latter case, this indicated that the women’s adaptive immune systems had helped resolve their infection. However, some other women that received anti-D showed no sign of having been infected and scientists wondered why.
When scientists at Trinity, led by Prof O’Farrelly, investigated this group of people more closely, they found that many of the women had received anti-D from batches that had very low viral loads – too low to cause infection. The Trinity researchers also estimated that almost 400 women received anti-D that was contaminated with a significant viral load, but were not infected and there was no sign of a strong response by the adaptive immune system.
Prof O’Farrelly started asking questions about why some women had no virus and no antibodies
The lack of signs of infection in hundreds of women exposed to significant concentrations of HCV initially baffled the scientists at the Trinity Biomedical Sciences Institute. Then they began to consider the possibility that these women had a very special innate immune system that was able to dispatch HCV before it could start an infection and before an adaptive antibody-mediated immune response was required.
The preliminary studies that have been done by Prof O’Farrelly’s team suggest that this group of women have more powerful natural killer (NK) cells than ‘normal’ women of the same age. NK cells are those that are spurred into action when an infection enters the body and move quickly to kill off the virus.
The body’s innate immune system has many mechanisms for detecting and responding to viruses, said Prof O’Farrelly. She said this is not surprising given that organisms have been detecting and responding to viruses in the environment for hundreds of millions of years. Squids, slugs and cockroaches have been around for longer than mankind and they all have innate immune systems, according to Prof O’Farrelly. These creatures are also susceptible to viral infections and therefore have evolved diverse antiviral mechanisms, many of which are also present in humans.
The question of why some people get sick and others do not has long interested immunologists. Prof O’Farrelly said our immune system is hugely influenced by our genes, therefore it is clear that response to infection differs from person to person. Over the last 20 years, there has been an explosion in our knowledge of the genes that code for the molecules that regulate and mediate the immune system, she said.
There are environmental and lifestyle influences on the immune system, said Prof O’Farrelly. Factors such as how much people eat or drink as well as their stress levels, will have an impact. Genetics, however, plays a big role. For example, work by Prof O’Farrelly’s colleague, Prof Luke O’Neill, found that a genetic mutation in a gene, if present in an individual, means that that person has greater susceptibility to more severe malaria.
It is easy to understand how genetic variations could have been selected for in the human population over millions of years of evolution, in response to the presence of infection, outlined Prof O’Farrelly. Some people survived, some died. The infections kept changing and the human response had to keep changing too. This is the reason why humans have developed an adaptive immune system, which can be adapted to deal with and respond to new infections.
Scientists have known for centuries that some people were resistant to the smallpox virus, for example. More recently, people resistant to Ebola and Zika viruses have been identified. In the past, people were in fear of those that could survive while many others died, and these individuals arise in various stories and novels, noted Prof O’Farrelly. One story concerned gravediggers who were constantly exposed to illness. Many died but some didn’t and were able to keep working. What did these individuals have that made them resistant?
This was a difficult question for scientists to answer. For ethical reasons, it was not possible to introduce a virus into humans and study the ramifications. It had to be done another way. Prof O’Farrelly was wondering how this could be done for almost 10 years, until she had the idea of studying the women that had received contaminated anti-D in the late 1970s.
She had noticed, when working as a scientist at St Vincent’s University Hospital, Dublin, that some of the women infected had antibodies but no virus, while others had antibodies and the virus and therefore had chronic infection. Others had no antibodies and no virus. Prof O’Farrelly started asking questions about why some women had no virus and no antibodies.
Initially, as Prof O’Farrelly recalls, her questions were met with ridicule. However, she kept pursuing the matter and got a Principal Investigator award from Science Foundation Ireland. The grant, which began in 2013, was to specifically investigate her hypothesis that the women who had no virus or antibodies had a very special innate immune system that protected them.
The Irish Blood Transfusion Service (IBTS) rejected a request to send a letter to women who received contaminated anti-D. This was because bioethicists said that, despite the potential for public good associated with the research project, it was unethical to put them under stress. Prof O’Farrelly put this refusal into her grant proposal and proposed to instead gather a volunteer cohort of women based on a public recruitment campaign.
“It was hugely problematic because there are a whole load of women who got anti-D during those years, but when you find out what batch they got, it turns out it was a batch with very low infectivity,” said Prof O’Farrelly. “The number of women that we are actually looking for is only 350… These are women who all got heavily contaminated anti-D,” she said.
“We launched this campaign about six months ago and we got a lot of public exposure and we were very specific in the call, as to what women we wanted to get in contact,” said Prof O’Farrelly.
Seven hundred women got in contact and have given the researchers permission to further investigate. “From verbal questioning, about 350 of those fitted the criteria of having got anti-D and not being antibody positive.”
Researchers approached the IBTS to precisely identify what batch these women were contaminated from. It appears from the information gained so far that about 20 per cent of this group received a highly infectious viral dose. Further, the team identified five particular genes of the innate immune system that were important in the system’s response to hepatitis C and they searched for variations in these genes.
The researchers then took blood samples from the women that gave their permission so that they could make stem cells, and from this, the plan is to make liver cells. The scientists know that the innate immune system response to hepatitis C is particularly powerful in the liver. They need to test the response of the women’s liver cells in a situation where a biopsy is not ethically possible because these are healthy women, explained Prof O’Farrelly.
The big question is whether these women have a particular innate immune system that is highly effective against hepatitis C but also powerful against other potentially deadly viruses, said Prof O’Farrelly. If this is found to be the case – and the signs are promising – then it could lead to much better vaccine design in the future.
This research is stretching out science’s understanding of the innate immune system, said Prof O’Farrelly. It would show that some people are clearing viruses out of their system without ever using their adaptive immune system, she said. This makes sense because creatures, such as octopuses and lobsters, do not have an adaptive immune system at all and survive viral infections, Prof O’Farrelly explained.
“Clearly adaptive immune systems work really well in many species,” said Prof O’Farrelly. However, since the discovery of vaccination, science and medicine have focussed almost exclusively on boosting the adaptive immune system response as a way to counteract viral infection. There has been little attempt to develop drugs or therapies that combat viruses by boosting the innate system, she said.
Nevertheless, Prof O’Farrelly said the attempt to stimulate the innate response should not downplay the importance of the adaptive response, which is “magical”. This is simply another approach to tackling infection, which hasn’t been tried before and appears to have great potential, she concluded.