Flu Vaccines from Tobacco?

Charlotte - Well we've been looking at Influenza virus and heart attacks. We're interested in looking at whether flu can actually trigger heart attacks in some vulnerable people because some of the people who have heart attacks don't have any risk factors and it's not clear why they have their heart attack.

Chris - You mean, people who have a heart attack usually have some kind of antecedent problem like high blood pressure or high cholesterol and you're seeing people who have heart attacks have none of those risk factors but they do have flu potentially.

Charlotte - Well possibly. It's still a grey area. We're really not sure whether there's a strong link or not, which is why we've been doing this research.

Chris - So how did you do it, what did you do?

Charlotte - We used the big general practice research database that contains records of over 5 million patients in the UK. These are all anonymised records but we could see when people went to the GP with a flu-like illness and we used linked data from a heart attack registry database also in the UK, and that gave us detailed information on people who had heart attacks. And so, by linking these two datasets together, we pulled out a group of people who had both the heart attack and had been to the GP with a flu-like illness. And then we began our analysis, and our analysis was looking at something called the self-control case series. So what that means is you take people who have had heart attacks and you look at whether they were more likely to have their heart attack in the time period just after visiting the GP with a flu-like illness compared to other times in their lives.

Chris - That's neat. So in other words, each person is their own control, aren't they because if they're not having a heart attack when they haven't had a flu-like illness, then they're controlling from the time when they have had a flu-like illness.

夏洛特——是的,这是正确的,它使这个泰pe of method quite efficient because you don't need to find control patients to compare them to because when you look at different cases and controls, sometimes there can be other differences as well so you can introduce bias that way. But here, as you say, everyone was acting as their own control.

Chris - And - the million dollar question, what did you find?

Charlotte - Well, what we found was that in the first few days after having a flu-like illness or a respiratory infection, people were nearly four times more likely to have their MI (myocardial infarction - heart attack) than in other time periods. We wanted to look really though whether this was a specific effect of the flu virus or whether it was more of a general effect of any old respiratory infection.

Chris - Did you know they actually were flu cases though?

Charlotte - Well, no. This is one of the problems with using this type of data. It's GP data and you rarely have - these people have rarely been tested for flu, so we had to use various proxy measures for what we thought might be flu such as the codes that GPs use to classify the illnesses or looking at the amount of flu that was actually circulating in the community. When we use those different proxy measures, we actually got very similar results when you compared those illnesses more likely to be due to flu compared to other respiratory illnesses. So to summarize, this didn't seem to be a specific effect of flu. It seems that any sort of respiratory infection that we found inour study could actually have this triggering effect in vulnerable groups and it seem to be the elderly that this was happening in, mostly people over 80.

Chris - How big is the effect?

Charlotte - It's basically a four-fold increase that we saw in the first few days immediately following a respiratory infection and the effect gradually tapered off over time, so about a month after your infection, there was really no increased risk at all. But having said that obviously, most heart attacks are not going to be triggered by respiratory infection and most respiratory infections are not going to trigger a heart attack. So this really was just a very small proportion of people, but quite a significant effect in those particularly vulnerable groups.

Chris - How do you think that having an upper respiratory infection might cause someone to then go on and have a heart attack in that risk window?

Charlotte - I think it's a bit unclear at the moment. Flu is an acute inflammatory event - and when your body is subjected to acute inflammation, particularly something like flu that can affect all parts of your body it's not just the lung, it can cause muscle aches and fever. So it can cause symptoms affecting the whole body and it's suggested that it can cause a systemic inflammatory response, so an inflammation all around the body that might then also include the coronary arteries and might in that way, trigger a heart attack. But I think it's still unclear and there's quite a lot of research going on about potential biological mechanisms at the moment.

Chris - Given you found this then what should we do about maybe raising awareness of the link or is there anything we should do? Is the effect so trivial that it's not actually worth worrying about?

Charlotte - No, I think it is important particularly because we have a good flu vaccine to help prevent flu and this vaccine is quite underutilised particularly in people with some chronic conditions, and the recommendation is that people with chronic diseases such as chronic heart disease should have the flu vaccine every year, so I think it's important to raise awareness in those groups, and amongst their GPs as well so that they do encourage people to come forward for the flu vaccination each year.

Chris - What about also telling GPs, "Look, there is this association that I've found between respiratory infection and then heart attack afterwards. So if you see someone with symptoms that might be an evolving heart attack, maybe have slightly higher index of suspicion, maybe do something about it more than just writing it off as indigestion"?

Charlotte - Yes, I think that definitely true. We wouldn't just take this one study in isolation as evidence. We need to gather evidence from a number of sources. But absolutely, I hope that this study will contribute to the evidence available for GPs and other practitioners.

Chris - Is that what you're going to do? You're now going to say, "Let's go and look at some of the individual viruses and see if there are any particular viruses that are more of a risk than the others"?

Charlotte - Well that would be nice to do. I think it's important though to make sure that this does have some practical applications and I think flu is really one of the respiratory viruses for which there is an effective prevention, so that's why we focused on flu at the moment. But yes, potentially in the future, we could look at other viruses as well.

Brian - So my name is Brian Ward. I'm a Professor at McGill University in infectious diseases and I'm serving as the Medical Officer for Medicago. The platform that's used is a transient transfection in a tobacco plant. What that means is that pretty much all of the cells of the leaves of young tobacco plant are infected transiently by a bacterium that's carrying a little bit of DNA that we instruct the bacterium to deliver to the plant cells. As a non-plant biologist, one of the coolest things about this entire process to me was the fact that you get the bacteria into all of the plant cells by literally turning these young tobacco plants upside down in water and then sucking the air out of the plant with a vacuum. It's called "Vacuum Agroinfiltration" but it's fantastic because what happens is when you suck hard enough on the root of a plant, the leaves collapse like sponges. You submerge them in a bath of these bacterium and then when you release the vacuum, every cell in every leaf of the plant sucks the liquid in containing the bacteria and every plant cell is infected simultaneously.

Chris - So you get little seedlings of tobacco plants which are making proteins from the genes that you've added with this bacterium.

Brian - The bacterium contains the genetic information in a plasmid and that plasmid directs the production of the viral protein within the cytoplasm of the plant cell. So that single viral protein then migrates to the surface of the plant cell and it auto assembles into these small virus-like particles that look from the outside like a virus, but have nothing on the inside. They're empty. They don't contain virus genetic material.

Chris - But critically, they can behave as a virus in terms of their immunogenicity. You can put them in, the body thinks they look like a virus so it makes an immune response against them.

Brian - Yes, these virus-like particles essentially trick the body into believing that there's a viral infection and so, the body makes a response that it would typically make to a virus that's infecting them. But in this case, it's just a response to the surface haemoglutanin protein, and so, you get the benefit without much of the risk.

Chris - How do you get the virus-like particles out and not end up with the whole other plant glup going with it?

Brian - So that's another really interesting thing that the company has done. Initially, they did grind up the plant cells. As it turns out, these virus-like particles collect between the cell wall that surrounds each plant cell and the outside membrane of the plant cell. In these pockets essentially that contain large numbers of virus-like particles. The cell wall can be digested with enzymes that are directed against plant wall but not plant membrane. As a result, you can put the plant mass, just slightly ground up plant material, into a vat with enzymes and the cell walls are digested away because the virus-like particles are between the cell wall and the outside membrane of the plant cell, they are simply released into the liquid in which you're doing the digestion, making the purification very easy.

Chris - Now when we make flu vaccines in egg, you get roughly three doses per egg. So how many doses do you get per tobacco plant?

Brian - It's highly variable. The production facility in North Carolina works with batches of about 15,000 plants. 15 000 plants translate into about 30 kg of plant material - so it looks green - and then that green material can yield about 5 million doses of vaccine.

Chris - So quite a bit and presumably very fast to make.

Brian - That's one of the huge advantages of this platform is that the tobacco plants are young, healthy, growing, they're transfected. When they're harvested between 5 and 8 days later depending on how much sun there is, they look perfectly healthy, and so, you harvest and then process so that the cycle of production is actually very, very fast.

Chris - No risk of people getting hooked on flu vaccines?

Brian - I don't think so. No risk of people getting hooked on flu vaccines.

Chris - But being more serious, when you put the vaccine material into a clinical setting, what have you done with this so far? Has this just gone through animals? Have you just done this in terms of demonstration? Where are you in the sort of approval process?

Brian - So far, the company has done the standard work pre-clinical which means animal studies and toxicity studies, and in fact, two of the products have gone into human trials. One of the products, the H5 monovalent vaccine has gone forward into a phase II study.

Chris - It's against bird flu - H5 N1.

Brian - This is against the bird flu. So that's the product that's furthest advanced. The total number of people involved in those studies is about 300 so far - phase I and phase II, and the seasonal H1 vaccine which is again a monovalent vaccine that targets the circulating H1 virus now, that's gone into 100 people to date.

Chris - Have you actually got to the stage where those people have been challenged with flu so you know that they're making a protective response?

Brian - So, one of the options for testing a flu vaccine is to do a human challenge study, but we haven't done that yet. Right now in phase I and phase II trials, what you're looking for is safety, how well the vaccines are tolerated, and what kind of immune response they make. And so far, these vaccines are very well tolerated, very similar to the kinds of responses that you get from a standard trivalent vaccine. But they also elicit really quite strong immune responses. The H1 vaccine certainly meets all of the criteria for licensure for the trivalent vaccines. So clearly, that's the next step for the company, to actually move from the monovalent H1 vaccine, to incorporate an H3 containing vaccine, and a B type virus to make a trivalent virus-like particle vaccine made in plants.

Chris - And the timeline for that?

Brian - Can I say soon and get away with it? I think that there's a hope that by the end of 2011, that there will be a candidate trivalent vaccine that can be tested at least pre-clinically.

Chris - What about costs?

Brian - That's one of the huge advantages of this platform. Using plants as the bioreactors instead of stainless steel vats in a high production facility allows the cost of goods to be considerably lower. And so, these vaccines can be produced for less than the standard vaccines that are produced in eggs. Furthermore, the facility itself, because it's not based on incubation of eggs and supply chain of high quality eggs, and so on, is also considerably less expensive than the investment in an egg based facility.

Researchers have found that the strain of Human Immunodeficiency Virus most abundantly present in the genital tract is not necessarily the strain that infects a sexual partner.

Unprotected heterosexual sex is the most common way that the HIV is transmitted, particularly in developed countries and Debra Boeras from Emory University in Atlanta and her colleagues studied heterosexual couples in Rwanda and Zambia who were 'sero-discordant' - i.e. one was HIV positive, and the other was only just diagnosed as HIV positive.

An HIV positive person can carry many strains of the virus present in their genital tract, as it mutates so rapidly (which is one of the reasons we're having a hard time trying to figure out a vaccine). But previous studies have shown that a single strain of HIV establishes infection in the new host, known as the 'transmission bottleneck', and through studying vaginal swabs, and semen and blood samples from 8 heterosexual couples the team confirmed that this was the case. If the infection was random, you'd expect that the strain of the virus that was most common in the genital tract would be more likely to cause infection in the sexual partner.

But when the researchers compared the gene sequences for proteins on the outside of the virus that vary between strains, they found that the strain in the blood of the newly infected partner wasnotthe same as the most common strain in the genital tract of the chronically infected partner.

研究小组认为这是由于selection of the viral strain best suited for successful transmission rather than just the most abundant strain. So, many virus particles may be transmitted to the uninfected sexual partner, but most of them will not be able to infect the person. It is only the strain with the right attributes, such as more efficient binding to receptor proteins on host cells, that are able to infect a new host.

This finding is important, because we know that transmission of the virus is via the genital tract, but if the strain that actually manages to infect the other partner is not the commonest one in the genital tract, then there must be a mechanism at work that could affect our strategies to treat the virus and reduce onward infection rate.

New Malaria Vaccine Target

A protein interaction on red blood cells could be a prime target for aneffective Malaria vaccine.

Symptoms of Malaria only begin when the plasmodium parasite causing the disease infects red blood cells to replicate.

Publishing in Nature this week, Julian Rayners team at the Sanger Institute have identified a crucial interaction needed by all strains of the parasite to get into the red blood cells, which if blocked could stop the parasite in its tracks and preventing the onset of disease.

Julian - So the interaction is between a parasite protein called RH5 and protein that's present on the surface of the red blood cell called basigin That if we block that interaction, we can completely prevent invasion down to undetectable levels, so it seems to be an essential interaction, the parasite needs it in order to get inside their blood cells.

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Looking but not Seeing

Looking at an object and paying attention to it involve separate regions of the brains visual system.

Working with human volunteers, Masataka Watanabe's team from the University of Tokyo monitored brain activity in the primary part of the visual cortex, where information is first processed. By changing the visibility of images seen by the volunteers the team saw no different in activity when the images were visible or invisible, meaning their awareness and perception of the images must happen elsewhere in the brain.

Masataka - Even if the visual input is actually there into your brain, when you don't see it there's no modulation in the primary visual cortex. So we need like extra experiments to look where exactly awareness modulates your neural activity.

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A Molecular 'four-wheel drive'

The world's smallest four-wheel electric car has been created by scientistsat the University of Groningen.

Ben Feringa's team have developed a molecular motor using a single molecule, which can move in a chosen direction after the injection of electrons, by using four attached rotary units, The units change shape in response to the incoming electrons propelling the molecule forward along a copper surface.

Paul Weiss, Director of the California Nanosystems Institute comments on the discovery.

Paul - We're really just getting the first glimpses in this field. Single molecule motion is something we can now do, With this beautiful work by Feringa, the excitement there is this four motors and different parts of one molecule around working together in concert to move a structure forward. If we can understand motion at these scales where we know everything about the system, we hope to bring that to bigger systems. So for instance the motors that we have running our automobiles now don't work very efficiently. We may be able to make motors that are more efficient.

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The Rolls-Royce Science Prize

And finally, The Rolls Royce science prize was awarded this week to Staunton-on-Wye Endowed Primary School in Hereford and Mulberry School for Girls in London.

Beating over 2000 schools across the UK who had all developed science teaching projects that helped meet particular needs in their school, the two winning schools were awarded for their excellence in science teaching. Staunton-on-Wye winner and teacher Karen Williams on their winning project.

Karen - The children built quite a large playhouse in our school grounds and they had to reach a joint decision about what materials they were going to use to build the walls in the rough of the huts. During the project, they were very engaged so we had 5-year-olds talking about the pros and cons of different types of roofs and 10-year-olds grilling the architects about the merits of different types of vinyl and rubber as a building material. So it was combining practical science with a commitment to look at how we can make good decisions about what we're using.

Joint winners Mulberry School had developed a hydroponic greenhouse powered by renewable energy. More information on this years entries and runners up can be found online at science.rolls-royce.com.

伊恩-最重要的进步在过去的几个years has been the international health regulations to which all of the major countries that have represented the UN have signed up to. The International Health Regulations' mandate is not only their requirement for improving health surveillance in your own country, but also supporting the improvements in the developing world as well. So, this means that assuming that we follow this through to it's logical conclusion, we will have high quality surveillance all over the world and that people will report in a timely fashion. There are a number of assumptions there of course and one is that there are resources are available to enable this and that's not clear right now and it's become obviously more difficult with the global economic crisis. But nonetheless, there is a firm commitment on the part of the major industrialised nations to make certain that this does come into place.

Sarah - I suppose it'll be a combination of observing at internal, nation wide,levels, but also working between countries at an international level to keep an eye on things and track the movement of such a pandemic.

Ian - That's correct and of course, one of the things that we would like to do would be to prevent or interdict the pandemic by recognising the potential before something moves from animals into the human population. Fully three quarters of emerging infectious diseases originate in wildlife and then either move through domestic animals into people or move into people directly, and there are many examples of these - HIV, SARS, influenza virus, West Nile virus. So one of the things we're trying to do is to extend surveillance from the human community and to the animal community. So there are a number of efforts that have been allowed in the UK, and probably the most support has been found from the Wellcome Trust. In the United States, it's USAID and all these groups are collaborating and trying to support one another in these efforts to identify potential pathogens of humans and animals. Sometimes we focus on gorillas and chimpanzees because we're thinking about the HIV, and so on but over the past four or five years, people are focused on bats. Bats appear to be tolerant to infection with many of these exotic and highly virulent viruses. So examples rabies, and SARS, and Ebola, and Marburg. And the bats don't seem themselves to be affected by most of these pathogens. They seem to be able to coexist with them quite happily until somebody eats some of these bats or there is some sort of transfer of infectious material from a bat to a human.

Sarah - And so, once we know more about the potential for animals like bats and other vectors to carry these infections and pass them on, what can we do with that information?

Ian - There are several things. First of course, you can monitor wildlife for the presence of these infectious agents. They're not all infected and they're not always infected. And by tracking the movement of these infectious agents in wildlife, you can understand the risk that might be associated with humans. In addition, you can develop specific measures to address these, so people are trying to develop vaccines against many of these agents. There can be drugs which can be developed and once you know that a particular agent has a potential to move into humans, it becomes a much larger risk and you're able to focus investment of resources. I'm trying to address those risks. One of the things that we've been trying to do as a field in public health is to try to find ways in which we can streamline the process for creating vaccines for new infectious disease threats. When the pandemic H1N1 influenza virus surfaced in the Americas a couple of years ago, it took us fully 6 months to develop a vaccine, to validate it, to be sure that it was safe and efficacious, and then to begin to distribute it. And using modern molecular techniques, we have the capacity to make many vaccines more rapidly from that and we're trying to find ways in which the regulatory science can be brought up to speed. By regulatory science, I mean the ways in which it will ensure that a vaccine or a drug, or an antibody, or any of the sort of biological intervention is safe and effective. We need to find ways which we can streamline that process and also of course, make it less expensive.

Sarah - So it seems like there's an awful lot of sides to addressing obviously something that is extremely problematic. There's modelling, looking at potential vectors, there's the sequencing of new viruses that come up. When you were approached to do the film, were you really keen to make sure that it addressed the different sides of a potential pandemic?

Ian - Well to be honest, the most important thing was to figure out whether or not these guys were sincere about making a great film. The screenwriter approached me initially, Scott Z. Burns was a very serious guy and he said, "Look, I want to make something that's real. I want to make something that's important. Obviously, we need to fill theatres, but when we're done with this, we want to feel as though we've made a contribution." So we ran through a series of different scenarios - which viruses were of interest, where might a virus originate, how would it spread, and you know - I got sucked in quite frankly because it was a lot of fun thinking about the ways in which we might be able to convey this message.

我认为他们做了很好的工作。我的意思是,基于“增大化现实”技术e a couple of points where I think things might have been done a little bit differently, but by and large, the film is accurate and it's timely, and it has had an impact. Not least in its drawn attention to the people who do this kind of work day in and day out. Many who don't receive much in a way of accolades for the work that they do. Some of them die in the course of doing this work, but we try to emphasize the fact that everyone is at risk. You can't hide from infectious diseases and it's important that everyone be protected. I'm very proud of the film and it was a great deal of fun to make, I have to say. I didn't anticipate it was going to be as much fun as it was.

John - Yeah, that's an interesting one. So probably about a third of people who get infected with flu don't display any obvious symptoms. They may display something very mild that they might not even notice it themselves. And they have the potential at least to spread the infection although to be honest, we really don't know whether they genuinely do or not and I'd love John in Peterborough to log on to the flu survey and tell us more about his illness and the spread because he just seems like a fascinating person.

John - Well obviously, when we set up the flu survey, that was the first thing that we wanted to look at and what we found is, in fact, it doesn't seem to be the case. If anything, women seem to report slightly more flu than men probably because they have more contact with children. Maybe we men like to moan about it a bit more.

Chris - Who knows? I certainly think it's true. I think men probably - if they're not in contact with children as much probably don't get as infected as often. It's certainly true for things like Noro virus isn't it and that kind of sort of gut rot type bug. You often get far more female cases of that just because of contact with the kids.

John - Exactly, kids are a big reservoir for many of these source of infections. Not just the flu but many of them.