Feature: Peter Doherty and the quest for a flu vaccine

This feature appeared in the September/October 2010 issue of Australian Life Scientist. To subscribe to the magazine, go here.

Professor Peter Doherty has written his last grant application. But the 69-year-old Nobel Laureate hasn’t retired quite yet. In fact, he’s co-authored over 20 published papers in the last three years alone. He’s still very much engaged in his core interest of cell-mediated immunity and continues to lend his wealth of experience and insight towards developing better vaccines for the likes of influenza and HIV.

He spoke at OzBio2010 on the continuing efforts to understand how T cells function and the broader endeavour to develop new vaccination strategies building upon this greater understanding of how our immune system responds to viral threats.

Doherty is best known for receiving a Nobel Prize in Physiology or Medicine in 1996 along with Rolf Zinkernagel for uncovering the mechanism by which the immune system recognises virus-infected cells and subsequently sets a legion of cytotoxic T cells upon them (see Complex immunity).

Their discovery of the role of the major histocompatibility complex in cell-mediated immunity was a revelation, and one that transformed immunology and shed light on many perplexing phenomena, such as the body’s often harsh rejection of transplanted cells or organs.

That discovery was made in the mid-1970s, and Doherty has been hard at work ever since on deepening our understanding of the nuances of cell-mediated immunity. He now splits his time between two labs, one at the University of Melbourne’s Department of Microbiology and Immunology, where he’s involved in three research projects looking at T cells. He also holds the Michael F Tamer Chair of Biomedical Research at St Jude Children’s Research Hospital, in Memphis, Tennessee.

Cell-mediated immunity

These two institutions, with Doherty’s aid, have made great strides in understanding the function of T cells. But, according to Doherty, there are still many questions to which he’d love to know the answer.

One of them is the puzzling phenomenon of immunodominance. This is where T cells will only respond to a tiny proportion – often a fraction of a per cent – of the multitude of possible protein fragments, or epitopes, presented to it by a foreign antigen.

While most of the T cells responding to a viral infection will target these select few dominant fragments, other less populous T cells will respond to others, resulting in a immunodominance hierarchy. But why some epitopes will predictably and reliably trigger a greater response rather than others is a mystery, as is why a majority of the potential epitopes trigger no response at all.

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“We get a number of different responses from T cells in any one individual, and some are more prominent than others,” says Doherty. “We don’t know which are good and which are not so good, and we don’t know what determines those. We don’t really know what an optimal T cell response is. We look at bulk responses, but we don’t really know what’s optimal.”

Most research into T cell response focuses on the dominant T cell populations while ignoring the sub-dominant T cell populations, which might also play a significant role in combating infection.

A better understanding of immunodominance would prove a boon to rational drug design, allowing us to understand what triggers a T cell response, and how to engage an optimal response from dominant and sub-dominant T cells rather than shooting (relatively) wildly and hoping we hit the mark without triggering any unwanted responses.

Doherty and his team at Melbourne University are also investigating immunological memory and looking at whether they can influence it. The ability for the immune system to ‘remember’ prior invaders and mount a concerted response to those antigens should they reappear is well known.

In fact, vaccines rely on this response to prime the immune system should the real thing appear down the track. But the question is whether we can fiddle with that memory in other ways to strengthen the immune system against infection.

“We know we can skew memory in different directions by manipulating cytokines early on… or we think we can,” he says. “But we don’t really know what the basic genetics of that are.”

One of Doherty’s colleagues at the University of Melbourne, Associate Professor Stephen Turner, is particularly focused on this problem and is identifying novel transcriptional and epigenetic pathways that might be responsible for immunological memory.

Ultimately, however, Doherty’s aim is to use our understanding of cell-mediated immunity and T cells to produce a cross-reactive vaccine against the scourge of influenza and other viruses, such as HIV. But, as Doherty stresses, this is no mean feat.

“The questions is whether, as immunologists, we can actually do better than nature and somehow target the immune system to things that are much more cross-reactive in infections like influenza and HIV. We have to be smarter than immunity, and I’m not sure we’re that smart. I’m never sure human beings are that smart.”

Whether we are smarter than the immune system or not, Doherty and his colleagues are certainly planning to give a cross-reactive vaccine a red hot go.

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Priming immunity

The immune system is a remarkably complex yet elegant construct, with multiple layers of protection that prevent a majority of invaders from causing even the slightest interruption to our day.

One of the key elements in the immune system are the cytotoxic T cells that are responsible for hunting down and disposing of cells that have been infected with a virus or have been altered in some way.

Given these cells are already adept at identifying and removing suspicious cells from our system, a deeper understanding of how they work can give us an edge in designing vaccines that will prime this response against viruses that currently slip past our natural defences.

We’ve seen great successes in developing vaccines to some pretty nasty characters, including smallpox, polio and measles. These vaccines have remarkable efficacy and are totally protective, to the point that smallpox is now thought to be eradicated except in the lab. But dealing with the wily influenza or HIV viruses is a different matter altogether.

“With influenza and HIV you’ve got the same problem: you’ve got an RNA virus with a very poor proof reading mechanism, so it’s throwing off mutants all the time,” says Doherty. And all these mutations make it difficult for our immune system to keep up, allowing new strains to slip through.

While we can develop vaccines for each individual strain of influenza, it’s a relatively slow and laborious process with an inevitable lag between the time the virus appears and the time we can roll out a vaccine. If the virus is nasty enough, it has ample opportunity to spread amongst a population and inflict a terrible toll before we can contain it.

While the H1N1 swine flu pandemic proved to be relatively mild in the end, we may not be so lucky next time, says Doherty. “Swine flu wasn’t a terrible epidemic. The virus, on the whole, was relatively mild.”

Overall, it didn’t prove virulent enough to cause the widespread deaths that were first feared when it emerged. We’re lucky, because the first outbreak of swine flu occurred over the space of only a few months in 2009, and it took until the end of the year to develop and mass produce a vaccine. Had swine flu been as virulent as H5N1 bird flu, for example, things could have been dramatically different.

“Bird flu is a really nasty virus,” says Doherty. According to the World Health Organization (WHO), the mortality rate from bird flu is around 60 per cent, which is alarming when you consider that even the 1918 flu pandemic had a mortality rate of only 2.5 per cent. Even if the WHO estimate is inflated due to poor reporting, conservative estimates of the mortality rate of bird flu put it around 14 to 33 per cent.

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That’s serious enough to encourage a pre-emptive response, says Doherty. “If we got something even a tenth as virulent as that, and it went around very quickly, we’d have enormous numbers of deaths. And there’s no guarantee Tamiflu would hold it. A lot of the viruses have mutated away from Tamiflu control. Relenza is better – it’s a tougher drug – but it hasn’t been as popular because you have to give it via a spray.”

Producing a cross-reactive vaccine is the ultimate goal. Cross-reactivity is where an antibody or T cell responds not just to its original antigen, but to related antigens on other viruses. “We know we have those cross-reactive responses,” says Doherty. “It’s whether we can manipulate them in a way that will actually be useful in an infection. But there’s been evidence around for years that this gives you a measure of protection against influenza.”

The goal is to produce a vaccine that works against multiple strains of influenza by employing this cross-reactive response. However, this isn’t without its risks. “Also, we’ve got to be careful because with stimulating T cell responses, you can also create some immunopathology situations. You have to be careful you’re not doing any damage.”

The vaccine also wouldn’t have to be totally protective in order to be valuable. All it would have to do is slow the virus down or minimise the damage it does and give time for a virus-specific vaccine to be produced and rolled out. A first line of defence, if you will.

“That would be a totally new approach for vaccines,” says Doherty. “We’d have to convince the regulatory authorities to actually license such vaccines. But you could make it ahead of time in large amounts and you could stockpile it.”

Understanding the system

Doherty is also still closely involved with the St. Jude Children’s Research Hospital in the United States. The team at St. Jude’s is engaged in a multi-institution NIH-funded project to explore the systems biology of influenza, with them looking specifically at genomics, proteomics and lipidomics.

The objective is to gain a deeper understanding into what’s going on during the early stages of influenza infection, and how the virus’ proteins interact with those of the host’s immune cells.

“We’re specifically looking at early flu virus infection in mice, mouse tracheal epithelial cell cultures and in human bronchial epithelial cell cultures using a virulent and an avirulent virus,” says Doherty.

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“It’s relevance to vaccination would be in how the innate immune system sets up the much more specific adaptive response. The information we get from it may also tell us about possible therapy: what should you emphasise early in a flu infection; can we get something that works non-specifically to knock it back, or will help counteract the effects of what we think happens in some very sever flu, which is cytokine shock.”

A project like this is a big departure from his Nobel Prize-winning research in the 1970s, but it’s all connected through a steady continuum of discoveries about the operation of the immune system, a process that will continue into the foreseeable future until we understand the inner workings of this tremendously complex system.

While Doherty continues to contribute to this huge systems biology project, in recent years he has spent most of his time in Australia at the University of Melbourne. It’s here that he’s planning to spend most of his time until he eventually eases himself out of experimental science.

“The drivers of the science today are the young people and the mid-career people in the labs,” he says. “What I’m doing is acting as a discussant – I go to lab meetings, I talk to people about experiments, I help them write papers, I help them write grants. But in three or four years I’ll be out of it. Old scientists can stay on too long. They can be a real pain, that’s if they don’t go completely mad.”

While the latter is unlikely to occur, particularly while Doherty has so much knowledge, experience and passion to offer in immunology, he does intend to wind down his lab time and continue his other passion of spreading the word of science to the general public.

“I want to make the transition to writing more for a general audience,” he says. He’s already authored two very successful books, A Light History of Hot Air and The Beginners Guide to Winning the Nobel Prize, and he has many ideas for future titles. So while he may have written his last grant, he’s not finished writing, and is a long way from being finished with the science that has driven him his entire life.

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Complex immunity

When Peter Doherty and Rolf Zinkernagel were investigating the way T cells react and respond to viruses in mice at the John Curtin School of Medical Research Canberra in 1973, it was already known that T cells react to specific virus antigens, and it was known that a region of the genome, the major histocompatibility complex (MHC), had something to do with the immune response. But the link between the two was unclear. At least, it was until Doherty and Zinkernagel discovered that MHC molecules also play a crucial role in allowing T cells to identify virus-infected cells.

They found that T cells were not only responding to viral antigens that were present on the surface of virus-infected cells, but they were also responding to MHC molecules that were also present on the cell – and not just any MHC antigens, but those that were expressed by the T cell’s own genome. All of our cells have these MHC molecules on their surface, acting as tags to identify the cell as ‘self’. This prevents the immune system from attacking its own cells in normal circumstances. However, if a cell becomes infected by a virus, with viral antigens bound to the correct MHC molecule on the surface of a cell, the immune system then identifies that cell as ‘altered self’, and T cells descend for the kill.

This finding finally clarified the role of the major histocompatibility complex as a method of regulating its own cells, and explained why occasionally our immune system turns on itself – such as in multiple sclerosis, rheumatoid arthritis or diabetes – when this system breaks down. Doherty and Zinkernagel were awarded the Nobel Prize in Physiology or Medicine in 1996 for their groundbreaking discovery.

This feature appeared in the September/October 2010 issue of Australian Life Scientist. To subscribe to the magazine, go here.