London School of Hygiene & Tropical Medicine

Children in developing countries were affected the most, with severe cases up to 10 times higher in African countries. But the bacteria had, and continues to have, a truly global burden.

The offender’s name: streptococcus pneumoniae.

Infection with this pathogen through its multiple identities can cause conditions as mild as sinusitis (inflamed sinuses) and middle ear infections, but it can also cause significantly more severe diseases, including pneumonia, meningitis and septicaemia.

These all combine to be known collectively as pneumococcal disease, with children under the age of two most at risk.

More than 90 serotypes – distinct versions — exist for this particular bacterium, though only a handful cause disease, leading global health experts to have spent the past few decades mastering the one weapon they hoped could kill them all: a vaccine.

“Vaccines have been one of mankind’s greatest inventions,” said Professor Brendan Wren, Dean of the Faculty of Infectious and Tropical Disease at the London School of Hygiene & Tropical Medicine. “[They] have proven to be very useful against strep pneumonia.”

The first vaccine was licensed for use in 2000, after which a trial was conducted by the School and other partners in The Gambia to test its effectiveness. After promising results published in 2005, its introduction became more widespread globally and infection numbers soon fell dramatically.

By 2015, having gone through various iterations, the pneumococcal vaccine had been introduced in 129 countries, and global coverage was estimated to be 37% among children under the age of two.

The challenge, however, has been creating a vaccine that protects against all the harmful strains of streptococcus pneumoniae, as well as one that is affordable to all countries in need.

The first version protected against seven of the strains, then 10, and now some countries are using a form protective against 13 strains, but more still need to be targeted – as many as 76 remaining serotypes. The effect of vaccination is, of course, positive overall. But the increase in non-vaccine types tempers the overall effect of vaccination.

The current method of production also means each dose can cost as much as $50, making it an expensive vaccine.

“More than a million people worldwide still die from the disease (each year) despite the fact that there’s a vaccine,” said Prof Wren. “There’s a real incentive to produce these at lower cost and to be more efficacious and cover as many strains as possible.”

Prof Wren’s team has developed a game-changing technology using E.coli that they believe could create the types of vaccines used to fight pneumococcal disease.  Known as a glycoconjugate vaccine, it protects against a wider range of serotypes and, perhaps more importantly, costs just US$1 per vaccine.

“Our new vaccine technology can make these in E.coli very cheaply, so you have an inexhaustible and renewable supply of pure material,” said Prof Wren.

This platform also goes beyond pneumococcal disease, and could be used to create vaccines against multiple bacterial diseases.

A (cheaper) glycoconjugate future

Glycoconjugate vaccines are a design of vaccine currently used to fight three types of bacteria: Haemophilus influenza, which causes meningitis, pneumonia and cellulitis to name a few, neisseria meningitidis, and streptococcus pneumoniae.

The vaccines work by combining a polysaccharide, also known as a glycan, from the surface of the bacteria being targeted with a protein that helps stimulate a T-cell immune response in the human body. This elicits an immune reaction against the particular bacteria, ready to attack if it were to ever invade the body.

“Glycoconjugate vaccines have been shown to be very effective, because you get long memory – T-cell dependent and T-cell independent response,” said Prof Wren. “This means that they’re very effective and can be used in children as well.”

Though this new method is currently only used to produce three vaccines, these glycoconjugate vaccines have been proven to be very effective, according to Prof Wren. “More than a billion doses have been used in humans worldwide,” he said.

The current production process, however, — not Prof Wren’s new, pilot, method — involves purifying the outer capsule of a bacterium and then growing the intended glycan, or polysaccharide, in the lab. The protein needed for the mixture is also grown in parallel for both components before it’s chemically synthesized to join them together.

“This is a multi-step procedure and is very expensive commercially to produce,” said Prof Wren.

His new platform uses E.coli to conduct all these steps in one place by inserting both components into the E.coli along with an enzyme that binds them together.

“The enzyme couples the sugar to the protein and we were able to put this in E.coli to produce recombinant glycoproteins in E.coli,” he said. “We can almost now pick any protein and put it with any glycan, meaning we can have multiple combinations of proteins and we can go beyond the current glycoconjugate vaccines that are available.”

This extended range applies to diseases beyond the current three vaccines using this approach. Prof Wren is now using his transformed E.coli to develop vaccine candidates against three lesser known, but fatal, diseases: tularemia, affecting people in the US, Q fever, found worldwide (it has affected troops in Afghanistan), and melioidosis, mostly affecting people in Thailand and Northern Australia.

“There are no effective vaccines against these, so there is a need,” he said, adding, “We still don’t have vaccines against all organisms, particularly against some of the most dangerous pathogens.”

Prof Wren’s platform is a bit too efficient, he admits, as candidates can be developed so quickly that the ability to actually test them can’t keep up. Field trials require time and resources.

But he hopes his methodology will at least soon lead to the fruition of more effective pneumococcal vaccines as while the current vaccine has shown stark reductions in numbers infected – as much as 55% in trials in The Gambia – they remain expensive and less potent than they could be.

“If you look at the pneumococcal conjugate vaccine, where the vaccine has been rolled out there is an absolutely clear reduction of the incidence of pneumonia, hospitalisation of pneumonia and deaths from pneumonia,” said Dr Martin Friede, Coordinator of the Initiative for Vaccine Research at the World Health Organization.

“Along with other studies and public health efforts we did contribute quite a lot to restoring public faith in the vaccine.”

Professor Liam Smeeth, London School of Hygiene & Tropical Medicine

Dr Friede highlighted that although the vaccine targets children, older populations have also benefited from the lack of circulating infection. “For old people, pneumonia can be a very severe fatal infection and so by immunising the children, we are preventing the spread of pneumonia and the infection,” he said.

The war on this disease is far from over, as some strains of the bacteria are now rendered powerless, the remaining ones have stepped up to the plate.

“We continue to do a lot of work on pneumococcal vaccination,” said Professor John Edmunds, Dean of the Faculty of Epidemiology and Public Health at the School. “The vaccine has limited coverage … and by vaccinating against those 13 types do we get an increase in the other types? Yes we do, so what’s the impact of that?”

Because streptococcus pneumoniae has as many as 90 serotypes, protecting people against 13 of them has led to the remaining types flourishing and having more impact on the population.

This is something Prof Edmunds has shown through his mathematical modelling work at the School, using data to predict outcomes of various scenarios, such as the spread, or potential spread, of pneumococcal infection.

“We can use mathematical models to see ‘what if we did this’ or ‘what if we introduced a vaccination programme like this’ and ‘what impact might that have’ and ‘should we have a campaign’ and ‘what age group, how many doses?’” he explained.

As a result, his work is crucial in deciding how, once proven effective, or once licensed, a vaccine should be implemented in the real world – and where it should be introduced, if at all.

“I work closely with decision-making bodies in the UK and internationally to help decide what vaccines we should introduce,” said Prof Edmunds.

Once something is then implemented, further data, and the models resulting from that, can monitor how effective the new program is and what could be changed to improve it. “Is the epidemiology evolving in the way we thought, or do we need to make changes or add another dose, or even reduce doses?,” he asks.

Dr Friede agrees that modelling is a crucial part of the entire vaccine development process. “If we don’t model, it’s chaos,” he said. “If we don’t model we don’t really know how limited resources should best be used … and if we don’t have the models, we are walking blindly – maybe the wrong population, not immunising the right people.”

One prime example is the control of seasonal influenza, where new strains of the virus arrive each year and circulate among populations during the winter months.

Vaccines exist to fight the infection, but are not fully protective and are generally targeted at key groups within the population to more effectively — and cost-effectively — control its spread.

“This is a vaccine where we need to adapt the vaccine every single year to the circulating strain. It is at best moderately efficacious,” said Dr Friede.

In recent years, a new subset of the population came to light and those modelling the disease solved a new mystery.

Learning from the ever-evolving influenza

“We’ve been looking at what’s the best way to control flu,” said Prof Edmunds.

At first, the seasonal flu vaccine was targeted to high-risk groups, such as people with heart disease and asthma, but was soon extended to include people over the age of 65.

“It’s an obvious group to vaccinate,” said Prof Edmunds. “Those are the people who are most likely to suffer severe consequences.”

But his team soon realised that this was not necessarily leading to a reduction in the spread of influenza in the population. Though the elderly were the ones most likely to suffer extensively from an infection, they weren’t the ones spreading it within the community.

These “spreaders” came in a much smaller, younger form: children.

“When we started analysing them, it was pretty clear that children play a really key role in the spread of flu and children have a very high incidence of flu,” said Prof Edmunds.

Through models, his team saw that when looking at the incidence of infections from one year to the next, children were the most likely to be infected and carry quite a high burden.

The years of focusing on the elderly had avoided deaths and severe infections, but not reduced spread by very much. “It became pretty clear that vaccinating the elderly and risk groups is not the best way to control flu, because they’re not the key spreaders,” said Prof Edmunds.

This insight and the evidence, through models, backing up this theory led to Prof Edmunds, using his seat on the influenza subgroup of the Joint Committee on Vaccination and Immunisation in the UK, to make recommendations to extend the seasonal influenza vaccine to young children.

A phased introduction of this began in the UK in 2013, and by the 2016/17 flu season guidance was to provide the vaccine to most child age groups as high as primary school ages.

“If you vaccinate children, then it has a direct benefit for the children, who have a high risk of getting flu, but it also reduces the amount of flu circulating in the community, so it’s good for everybody,” said Prof Edmunds.

His team have modelled an extensive range of vaccines over the years, including ones proven to be effective against Ebola towards the end of the 2014 epidemic in West Africa and the somewhat controversial introduction of a vaccine against Human Papillomavirus (HPV) in girls aged 12-13.

The HPV vaccine is given to prevent later infection with this sexually transmitted virus, which in turn can cause cervical cancer. The sexual nature of the infection led to some push-back by parents.

“It was this idea that you vaccinate your daughters against a virus that’s sexually transmitted in hope she won’t get infected, in hope she won’t be at risk long term of cervical cancer,” said Professor Liam Smeeth, Head of the Non-Communicable Disease Epidemiology Unit at the School.

“It was a chain of confidence needed that perhaps some people didn’t have,” he said.

However, the vaccine has, generally, had good uptake and reception among the population, according to Prof Edmunds.

“[These concerns] don’t seem to have had much impact on HPV vaccine coverage,” he said, adding the benefit that, “if you vaccinate the women, you will also protect the heterosexual men, they can’t get it from anywhere else.”