Tasty research: vaccines under the tongue.

 

CD71 targeting boosts immunogenicity of sublingually delivered influenza haemagglutinin antigen and protects against viral challenge in mice

Vaccines are complicated. The research and development, the pricing, the delivery (getting them to the right people), the acceptance (getting the right people to take them) are all complicated. Vaccines are unlike other forms of medicine because they are universally prescribed as a preventative rather than a cure. When vaccines are successful, they can be self-defeating because they reduce the disease and therefore the fear of the disease, which gets people to use them in the first place.

Vaccine uptake varies for various sensible and less sensible reasons, which you can track live at the vaccine confidence project run by the London school of hygiene and tropical medicine. One reason for poor vaccine uptake is fear of needles and therefore one approach to improve vaccines is to develop vaccines that don’t need needles.

Going needle free

Finding alternatives to needles is more than a ‘first world problem’. There has been, historically, an issue with the re-use of dirty needles and the spread of blood borne diseases. This has been reduced by moving to syringes that can only be used once. Vaccines without needles may also be scientifically better. Delivering vaccine to the site of infection (or mucosal delivery) can improve the response to the vaccine. The mucosa refers to internal body surfaces that face the outside (and have mucus): it includes the nose and lungs, mouth, stomach and guts and genital tract. These tissues are a major route into the body for a wide range of infectious organisms, so require extra vigilant immunity. But, critically, mucosal surfaces are sites of exchange (lungs – oxygen, guts – food, genitals – babies). They therefore need to be porous enough to allow in beneficial material but not so porous that bugs can get in. Balancing these two needs leads to specialised immune responses at mucosal surfaces. In our current study: “CD71 targeting boosts immunogenicity of sublingually delivered influenza haemagglutinin antigen and protects against viral challenge in mice”, we exploited our knowledge of mucosal immunology to develop better vaccines.

On the tip of your tongue

Paul and Jamie (co-authors on the paper) have previously shown that targeting a specific molecule called the transferrin receptor (whose normal purpose is to pump iron into the body, also known as CD71) can improve the quality of vaccine responses. It has been shown that applying vaccines under the tongue (sublingually) can lead to a better response. The current study looked at combining these two approaches – targeting the transferrin receptor on the tongue to deliver vaccines. When used, the immune response to influenza was significantly improved, leading to a more protective vaccine. This approach could be used for a range of diseases, removing needles and improving the response.

Being an academic is great, so start enjoying yourself

Yay! This job is great – just don’t tell anyone.

At the start of the year, I bravely made the statement that we should be happy academics. Well, not so bravely, as I did it anonymously in a Guardian article.

This optimistic message flew in the face of the normal academic narrative: evil reviewers, no money, too much teaching. Hence the anonymity. Some of the instant feedback that others felt brave enough to leave anonymously in return suggested that I was an overly optimistic, delusional, Pollyannaish outlier.

Luckily, this esteemed website that you are currently reading performs a workplace survey each year so I can benchmark my optimism against the sector. Seventy per cent of people answering the survey said that they found working in higher education rewarding and 64 per cent were proud of the institution they work in. So based on the survey’s findings, I am not an outlier (take that, naysayers!).

Three themes emerge from the workplace analysis. University staff are, on the whole, happy with their jobs; struggle with the work-life balance; and have issues with authority. I wanted to share with you why I think these three themes emerged and some suggestions about how to improve the bad bits.

Happier, more productive academics

As I’ve said, there are a number of reasons why I think we should enjoy our jobs. These include: the relative freedom to do what we like, the company of other brilliant minds, working with students and doing something with societal value.

Yes, it isn’t always chocolate boxes and roses, but it can be good – even great – at times. Yes, the sector has changed since the 1960s (for good and bad). And yes, if you met me in person three days out of five, you would get a very different view. But I encourage you to seek out the parts you do enjoy and to fix the parts you don’t.

Balancing work life and academic life

Work often feels like surfing: some of the time you are triumphantly riding the crest, but most of the time getting tumbled in the wave and heading towards some very big rocks (hopefully one of you got the Point Break reference).

For example, this blog was meant to coincide with February's 2016 University Workplace Survey, but in common with more than 50 per cent of academic respondents, I failed to achieve work-life balance, and this article sadly fell by the wayside. I was failing to get the balance right due to a gruelling teaching-grant/thesis-correcting cycle, combined with having to do my share of the childcare (the horror).

During this period, there was much gnashing of teeth and rending of hair about how terrible things were. However, there was also a euphoric sense of relief when the worst of the deadlines passed.

There is no doubt that work, like nature, abhors a vacuum and will seep into any available space. The best thing is to seal off the rest of your life – I spent some of last weekend writing a grant for a scheme that got cancelled, so I would have clearly been better off gardening, taking some exercise or playing FIFA with my son. There are some good tips here for working smarter, not harder, in order to finish on time.

I had a colleague who clocked off every day at 5pm. When asked how they managed to be so efficient, they replied: “I’m not. Each evening I scold myself, saying that I must try harder to get everything done tomorrow and go home with a clear conscience.” Finish at a sensible time, tell yourself to try harder tomorrow, go home and do something else, because the work will still be there tomorrow and the world won’t have come to an end.

Scholars: the spanners in the works?

The largest discrepancy in the survey between professional/support staff and academics was with regard to management.

Academics tend to regard two functions as management: process management and strategic management. Process management makes the university tick and stops academics from doing stupid things in the name of research. It is there to pay our wages, help us recruit better staff and fix the stuff  that we break. But more importantly, it is there to stop us killing ourselves, breaking laws or (worst of all) bankrupting the university.

As academics, especially when we have left deadlines too late, it is very easy to blame a faceless someone from central admin for our own failings. And I am sure that from a compliance, health and safety, accounting, reporting, logistics or purchasing point of view, universities would run a lot more smoothly if it wasn’t for us pesky academics.

The Sword of Damocles

Leadership is the other function of management. This strategic management tends to come in the form of edicts from a central source, structuring and restructuring our departments, setting up virtual centres and matchmaking collaborative partnerships between people who hate each other.

This metric-driven nonsense is caused by the research excellence framework, the teaching excellence framework and university rankings. Sadly, strategic management has both a perceived and a direct impact upon our workplace. The perceived impact is the fear of wholesale job cuts, department closures and performance reviews. The direct impact is when the job cuts, reviews and closures actually happen.

However, the perceived impact – the fear of things to come – is the most toxic, contributing to work-life imbalance and the academic dissatisfaction with management. Worst of all, creative thought is stifled by fear of job loss. Having the Sword of Damocles dangling over our jobs leads us to focus on short-term metrics, particularly the dreaded impact.

But there are solutions. And here they are:

1. Enjoy your work – you can either spend the whole time working hard, being miserable and ultimately losing your job or you can spend the whole time working hard, being happy and lose your job. With the happy option, at least the time spent doesn’t feel wasted.
2. Branch out – make sure that if the axe falls you have a sufficiently good CV to move onwards or even change path.
3. Get some clarity – find out what is expected of you – the KPI (key performance indicators). If you are not costing the university any money, they will probably keep you on.
4. Take over – critically, the senior leadership of universities are academics. If your institution is not being run the way you like, get involved, join the union, go to committees, become part of the management yourself.

This article first appeared on THE on 11th May 2016.

57 Varieties

Global Traveller: Chlamydia infection varies by region

A Multi-Component Prime-Boost Vaccination Regimen with a Consensus MOMP Antigen Enhances Chlamydia trachomatis Clearance.

Vaccines come in various flavours. Some are purified from the toxic by-products of bacteria (tetanus), some are made of sugar (pneumonia), some are made of protein (HepB), some are made of sugar mixed with protein (meningitis), some are live but weakened (BCG) and some are dead (flu). There are various reasons for making them from different things, including cost, formulation and the part of the bug we are trying to target with the vaccine.

Form follows function

The make up of vaccine has a direct effect on the type of immune response it induces. Sometimes, vaccines can induce an immune response, but the immune response they induce is not able to kill the bug. For example there are 2 whooping cough (Bordatella pertussis) vaccines available: whole cell or wP (made up of whole bacteria that have been killed) and acellular aP (made up of 3 or 4 individual proteins from pertussis). Most higher income countries switched to aP about 20 years ago because the vaccine is less reactogenic – wP can lead to a high temperature and a sore arm. However we are seeing a resurgence of whooping cough in the countries that switched vaccines. Dissecting the response to the 2 different vaccines has shown that the wP vaccine leads to a different type of immune response to aP, switching the way the T cells (a white blood cell) react to the bug (from Th1 to Th2 if you need to know). This switch in response, is associated with the reduced effectiveness of the vaccine. NB – aP still works, it is still safe, you should still get it for your children and when pregnant, it just doesn’t work as long as wP.

Number 1 bacteria

Chlamydia trachomatis is the most common STI caused by a bacteria – over 141 million infections occurred in 2013: those of you paying attention will remember this also causes eye disease. It is mostly asymptomatic (you can’t tell if you’ve got it), but in about 5% of cases it can cause a condition called pelvic inflammatory disease, which if not treated can level to infertility. Treating Chlamydia is expensive – over US$3 billion are spent in the US alone each year. Based on the burden of disease and the cost of treatment, there is a strong case to make a vaccine against chlamydia. However, this has proved difficult, this is in part because we don’t know what type of immune response would be best to stop it. We therefore set out to explore this, exploiting the fact that different vaccine types lead to different immune responses. Alex (the lead author) made 4 different vaccines based on the same protein derived from chlamydia (the major outer membrane protein or MOMP). These were a DNA vaccine, an Adenovirus, a Modified vaccinia Ankara and a Protein, conveniently leading to the acronym DAMP.

DAMP-proof course

In our recently published study we investigated the effect of changing the types of vaccine on the immune response. We could make a response that was just antibody (PPP) or just T cells (DDD) or a mix of the two (DAMP.) We then measured whether these different types of response altered the outcome of infection. Only the DAMP (which gave a mixed immune response) regime reduced the number of chlamydia bacteria after infection. This protection disappeared when the T cells were blocked, suggesting they were required. Based on these studies, we believe a Chlamydia vaccine needs to induce a mixed response, with both T cells and antibody. This work has informed a clinical trial in healthy volunteers to test the ideas further. It is yet another example of work funded by the EU, which if we left, would not be possible.

Parental Advisory

IT’S TRICKY

Can you combine being a parent and being a scientist? The answer is yes, it is possible; but it is tricky. If you have children, you know this already and my telling you that it is tricky won’t help. So I have selflessly done some grade A research/ went drinking with some other parents to come up with the following tips.

WHERE’S YOUR NEGATIVE CONTROL?

Essentially, parenthood is a sociology experiment, with no control arm: unless you have identical twins – in which case all kinds of (ethically questionable) studies are open to you. Remember that your children have nothing to compare against: they only have one childhood and have no objective way to assess their situation relative to their peers. This is not a call to be a terrible parent, rather a salve to the conscience. Missing the year 3 show, failing to buy a new costume for world-bloody-book day or sending them in wearing uniform on mufti day isn’t going to cause, too much, long term damage. Being a tiger parent does not make your child a better person, so relax, it’ll be ok.

OUTSOURCE

More broadly, there is a lot of stuff that needs doing, is relentlessly dull and not going to improve you, your science or your children. This includes renewing the car tax, going to the tip, ironing pants, tidying the garden, sorting the recycling and making pack lunches. Many of these functions can be done by someone else – for example thanks to Jamie Oliver (at least according to Jamie Oliver himself) school meals are now delicious, nutritious and don’t have turkey twizzlers, so sign your kids up for school dinners and spare yourself 15 minutes of stress every morning. Where possible, outsource.

GET UP AND LEAVE

There is a clear exception to my laissez faire attitude to child raising - failing to collect kids at the end of the day. The day’s activities need to be juggled to make sure you are in the right place at the right time. Some activities merit re-arranging childcare – vivas, experiments, group networking in the pub. Others do not. If a seminar is over running and the alternative is being late for nursery then you have to get up and leave. Likewise with meetings that drag on after 5pm when you are on pick up, politely apologise, and get up and leave. I know many parents find this difficult and it is: but sometimes you have to get up and leave.

MARTINI MONDAYS

Essentially the major challenge of balancing parenting and science is juggling: working out which parent is doing what and when. Rather than doing this piecemeal make it a social event. Set aside an hour a week to sit down together and sync diaries with a drink. Include the other admin necessary to make the house run.

THE UNCOMFORTABLE TRUTH

The sad fact is that to be a parent and a scientist, there is little space to do anything else. There are only 168 hours in the week. Use them as efficiently as possible, but even with clever outsourcing, smart timetabling and being a martini fuelled admin ninja, there is a limit to resources, mental capacity and time. Career, hobby, children, carer, partner, community service, exercise, charity work, social-life: pick three, do them well, if you try to do more, something will give.

YOU CAN DO ANYTHING YOU LIKE AS LONG AS IT IS SCIENCE AND KIDS

These methods should help you balance work and childcare, but, as I said, they leave little room for anything else. This is problematic because the ‘anything else’ is important for mental wellbeing, improves your science and generally makes life worthwhile. Maybe I should qualify my statement, there is little room to excel at anything else. You have to accept you won’t be winning the Epsom Common Allotment Society marrow growing contest, breaking the 4 minute mile or eating out with friends any time soon. It may mean taking your foot off the gas at work occasionally, but find time to do a little exercise, potter around the garden and snatch the occasional after work pint here and there.

This blog first appeared on the Imperial College London webpage. It was in response to the Royal Society's campaign ‘Parent Carer Scientist’.

Build your academic brand, because being brilliant doesn’t cut it any more

One of the recurring portrayals of academics is unworldliness. There was a mortifying episode of The Apprentice when the token PhD candidate buckled in the boardroom because they failed to meet their sales target. The ability to sell rubber dog turds for an egocentric billionaire may not seem a core skill compared with pipetting, coding or whatever research-specific thing you do; however, salesmanship is central, and increasingly so as you progress away from the bench.
This was re-emphasised when listening to a presentation recently. I knew the work was brilliant, smartly executed and highly impactful, but somehow the presenter lost the audience and failed to convey their brilliance. It wasn’t that the presentation was poorly delivered or ill rehearsed, far from it. The problem was the sales pitch. I have also been to some extremely data-light presentations which have conveyed the story brilliantly. Reluctantly, we need to accept that sales is a major part of the job: demonstrably so when grant writing, but no less in papers, seminars, blogs and even thesis writing.
Be the brand: you are the product
We have two things to sell, our ideas (more of which another time) and ourselves. Of the two, and this may sound a bit “self-help seminar”, the main product we sell is ourselves. This product is defined by our CV: where we have worked, on what and with whom. But these strands need to be pulled together into a single memorable “personal brand” – the lung T cell expert, the insect neurobiologist, the DNA crystallographer. This brand comes into play when meeting potential collaborators, conference organisers and funders. Interactions with other academics tend to have three levels: an entry-level overview of your work to check you are in the same field, followed by a description of a specific piece of work and, if you really click, detailed dissection of experimental design. There is no space for English modesty: don’t say “you know, this and that, some stuff on respiratory infections”. Do define your brand and develop a snappy single-line pitch that summarises what you do, backed up with an exciting case study. You are pitching this brand so that when other academics need someone with a particular skill set they think of you.
Develop the brand: publish or perish
Having crafted your academic brand, you need to generate brand awareness. This can be achieved in a range of ways, but publishing is central. One hurdle is the volume of academic material – 93 per cent of humanities articles, 45 per cent of social sciences and 25 per cent of science articles never get cited. Yes, the ideal is the big “impact” (glossy, single-word title) journals, but don’t get fixated on these to the detriment of getting stuff out there. It can take some time to generate sufficient reputation to overcome the editorial activation energy for the glossies (another example where having a personal brand can open doors). Target the journals that are most widely browsed in your field: high-volume, good (but not superstar) quality output is as good as large gaps between superstar papers and potentially better early in your career. And while traditional publishing has to be the central strand to your brand, don’t neglect blogging, tweeting and public engagement.
Sell the brand: break the bread
The final component is networking, which has to be face to face and not just electronically. Get out there and meet people – you have to be shameless, but not rude. Invite yourself to give talks in your friends’ departments, talk to people in lifts and in the departmental tearoom. Go to conferences, consortia and congresses. I prefer small conferences where you avoid that “total perspective vortex” moment – being exposed to just how big your field is and how insignificant your place in it is. Ask questions at meetings, and use the formula: “Hi, I am Dr X at university Y, in our system we see Z which relates to your findings because…have you seen the same?” Corner the speaker after talks, ask them more questions, sit next to people at meals, go to the drinks. Any (positive) way of getting yourself known is a good thing.
What you waiting for?
I am sure you are all brilliant, you are after all reading this article! But brilliance in a vacuum is not going to get you a permanent position or enable you to secure the funding to test your brilliant theories. You have to sell your brilliance. So this year, get out there, hone your personal brand to Kardashian levels and start selling yourself.

This article first appeared on the Times Higher Education on Feb 24 2016

Shiny, shiny, shiny beads of latex

Part of the reason I got into science blogging, was to drum up more readership for scientific papers. The main reason was to share my comedy genius with the world (193 Twitter followers can’t be wrong: that’s almost as many people as live on Tristan da Cunha!). Oh and the need to feed my ego, obviously a pretty major component.

I’m too sexy for my lab book

Sometimes, however, it is hard to think of a way to sell my research to you, the great unwashed. Some science sells itself by being cutting edge, earth shattering, game changing. This is the stuff all the scientists in the field read, the papers where the authors are known by name. It’s the science  that leads to oversold newspaper headlines promising to “Cure cancer in 3 years” and staged interviews with senior Profs in the lab for the first time in years, normally wearing someone else’s lab coat with assorted minions pipetting colourful liquids in the background.

Journeyman science

There is other work that is less headline-worthy, but equally useful. It could build upon the work of others, applying novel methodology from the big papers to different areas. Alternatively it may reproduce work performed elsewhere, increasing the validity of the original findings. Or it could be small incremental steps that adds to the overall pool of knowledge, laying the foundations for future work. 99% of the scientific literature falls into this bracket.

The premiership of publications

How do we judge the quality of scientific research? Part of the science writing process is to refer to other published studies that support our findings. Sometimes we look for papers that draw completely opposite conclusions so we can make passive aggressive comments about why their study is no good. Each mention of another study in a paper is called a citation. As a rule of thumb, papers that are cited more have made a bigger splash (good or bad). My current record is 279 for my ‘classic’ work on edible vaccines in transgenic plants, a corker if I say it myself. You might imagine that the highest cited papers would be those sexy headline grabbers as these are the ones that get the most attention. Though this is using sexy in a very loose sense, no one ever got tumescence from a western blot (deeply lame, unnecessarily crass science joke number 73).

Transgenic tobacco plants doing blue steel

Method to my madness

However, this is not the case. Of the top 10 cited papers of all time, seven are methods papers. These are very important, but somewhat dry descriptions of how to do science. Believe me, if you weren’t finding the ‘sexy’ papers sexy, methods papers will not be doing it for you. Which finally brings me around to our latest paper: ‘Development of a custom pentaplex sandwich immunoassay using Protein-G coupled beads for the Luminex® xMAP® platform’ in the Journal of Immunological methods. In this page-turner we describe a better way to do Luminex. Now you will either know what Luminex is, in which case read the paper or not, in which case may I recommend something from my back catalogue like a fruit number on early life antibody or a saucy look at mouse genetics. If neither of these whet your whistle, click the advert at the bottom – I get 5p a click, Academics got to live after all!

Are you using protein G to couple your Luminex beads? If not why not

EU Supports science

As a final piece of drum banging. This work was funded by our good friends in the European Union, for which I say Merci Beaucoups. No EU = no papers about niche analytical techniques in immunology and we can all agree that would be a shame. That and the fact that for every pro brexit vote a fairy dies. 

See the world in a grain of sand

Use of the microparticle Nano-SiO2 as an adjuvant to boost vaccine immune responses in neonatal mice against influenza.

There is a paradox at the heart of vaccine development, the people need the vaccines the most are one in whom the vaccines work the least. This is particularly the case for the elderly, the immunocompromised (people whose immune systems are impaired for some reason) and the patient group my research focuses on, the very young.

Baby Steps

In our first 28 days of life (known as the neonatal period) we are particularly susceptible to infection. In part, this is because neonates have not previously been exposed to infections – the womb, for the most part is sterile, and so haven’t built up a protective immune memory. However, this is not the only difference in the neonatal immune system. When the body is first infected, there is an early wave of responses called the innate system. For reasons unknown (though I am applying for funding to solve this of this highly important question – funders take note) this early innate immune system in early life is less responsive than later in life. In particular, babies are not very good at spotting bacterial infections.

This lack of immune response enable infection of babies, bacteria can get a greater toehold prior to be being recognised. But additionally this has an impact on vaccine responses. Vaccines, as you may or may not know, work by tricking the body into thinking it has been infected, leading it you build up a protective memory that prevents subsequent infection with the real bug. This trickery is achieved by either smashing the bugs into little bits or by using weakened (attenuated versions). Those of you paying attention will know how we have been researching methods to weaken viruses and make better vaccines; if not now’s the time to catch up.

Super Sand

However, given babies struggle to detect full fat pathogens they do even worse with the lite, vaccine versions of bacteria. This is where our current research comes in. It is possible to pep up a vaccine by adding substances called adjuvants. Adjuvants are often made of bits of bacteria, which trigger the immune system through a family of receptors called the TLRs (Nobel Prize fans – which year and who won the Nobel for discovering this – bonus point for knowing which animal they were found in). But as you now know, babies don’t recognise bacteria and therefore bacterial and therefore bacterial derived adjuvants are ineffective in early life. We took a different tack. The immune system, doesn’t just recognise infection, it recognises damage to cells. This cellular damage is detected by something called the inflammasome. We therefore tried a number of compounds which have been described as inflammasome activators. We settled on three – NanoSiO2 (which is really, really tiny grains of sand), CPPD (Calcium pyrophosphate dehydrate which causes an arthritis like disease called pseudogout) and the M-Tri-Dap (or N-acetyl-muramyl-L-Ala-γ-D-Glu-meso- diaminopimelic acid, part of the bacterial wall). We combined the compounds with flu vaccines to test whether it would improve the response. Amazingly mixing flu with sand, significantly improved the response. But then again, maybe it wasn’t that surprising as everyone knows, sand gets everywhere, is irritating and leads to a strong reaction ‘No you may not have a sand pit’. You’ll find all the details here.

Science, it's good for EU

This project was funded by the EU, which is something to consider very carefully – if we Brexit no-one would fund us to put sand in vaccines and the world would be a worse place. Britain is a huge net beneficiary of EU science. Not only in monetary value, but also in access to the best minds, facilities and resources.