Vaccines: Life savers against infectious diseases

Vaccines save between 2 to 3 million lives every year. Diseases that used to kill children, such as measles, diphtheria, tetanus and polio, have been almost eradicated from many areas of the world due to vaccination.

However, some diseases are proving extremely difficult to conquer, and have no effective vaccines yet. For example, researchers are still striving to find good vaccine targets to prevent malaria, Strep A and traveller’s diarrhoea. Can genomics help? Scientists at the Wellcome Sanger Institute and elsewhere are using genomic surveillance - sequencing the DNA of disease-causing parasites, bacteria and viruses from around the world - to help speed up the search for new vaccines, and save millions more lives.

Vaccine uptake around the world

Worries about the safety of vaccines threaten to reverse some of the progress made by vaccination programmes. A recent Wellcome survey of people in more than 140 countries revealed that only eight out of ten people worldwide agree that vaccines are safe, with people in richer countries, especially Europe, having lower confidence. This has contributed to outbreaks of measles in places as far apart as France, the Ukraine and New York, with children dying from this preventable disease.

This year the World Health Organisation (WHO) listed vaccine hesitancy – the reluctance to vaccinate despite the availability of vaccines – as one of the top ten threats to global health. As one of the most successful medical interventions ever created, vaccines have been extensively tested for safety and effectiveness and public confidence and acceptance are essential to sustain their global health value.

Prof Heidi Larson is the Director of the Vaccine Confidence Project at the London School of Hygiene & Tropical Medicine. “The good news about the Wellcome report is that the vast majority of people worldwide think that vaccines are both safe and effective,” she said. “The 20 per cent of people who are worried about them are often the loudest though, and this can influence others.”

The Wellcome survey showed that confidence in vaccines was highest in people in developing countries, such as Bangladesh and Rwanda, who are often willing to travel for hours to get their children vaccinated. This could be because they regularly see the effects of diseases such as measles, and are therefore generally more motivated to prevent their child catching it, although episodes of vaccine concerns and refusals also occur in even the poorest countries and also need confidence-building.

Lower visibility of these disabling diseases as a result of vaccination is among the reasons why some parents in more developed nations are less inclined to vaccinate. “People don’t often see polio now, due to the success of the polio vaccine, so don’t always understand why they should vaccinate against it. We’ve also forgotten how dangerous diseases like measles are, so parents can find it difficult to compare risk and benefit,” said Heidi. “It’s important to remember that everyone wants the best for their child, and for doctors and nurses to make time to answer parents’ questions to help them understand the truth about vaccines.”

For more from Heidi Larson and others on global attitudes towards vaccines, listen to https://www.bbc.co.uk/programmes/w3csz4lf

Why is vaccination important?

From stamping out smallpox to reducing rotavirus, vaccines now save millions of lives around the world. Effective vaccines are available for more than 20 diseases including measles, tetanus, flu, tuberculosis, cholera, and typhoid.

Vaccines protect children and the elderly, who are most at risk of dangerous diseases. If enough of the population is vaccinated – creating herd immunity – vaccination also protects vulnerable people who either don’t respond to vaccines, or who have health issues that mean they can’t be vaccinated. This means that by vaccinating their children, parents are also protecting their children’s friends at school and the local community.

Vaccination also helps protect against epidemics and reduces the need for any treatments, lowering the chance of drug resistance developing.

This year the World Health Organisation (WHO) listed vaccine hesitancy – the reluctance to vaccinate despite the availability of vaccines – as one of the top ten threats to global health. As one of the most successful medical interventions ever created, vaccines have been extensively tested for safety and effectiveness and public confidence and acceptance are essential to sustain their global health value.

Prof Heidi Larson is the Director of the Vaccine Confidence Project at the London School of Hygiene & Tropical Medicine. “The good news about the Wellcome report is that the vast majority of people worldwide think that vaccines are both safe and effective,” she said. “The 20 per cent of people who are worried about them are often the loudest though, and this can influence others.”

The Wellcome survey showed that confidence in vaccines was highest in people in developing countries, such as Bangladesh and Rwanda, who are often willing to travel for hours to get their children vaccinated. This could be because they regularly see the effects of diseases such as measles, and are therefore generally more motivated to prevent their child catching it, although episodes of vaccine concerns and refusals also occur in even the poorest countries and also need confidence-building.

Lower visibility of these disabling diseases as a result of vaccination is among the reasons why some parents in more developed nations are less inclined to vaccinate. “People don’t often see polio now, due to the success of the polio vaccine, so don’t always understand why they should vaccinate against it. We’ve also forgotten how dangerous diseases like measles are, so parents can find it difficult to compare risk and benefit,” said Heidi. “It’s important to remember that everyone wants the best for their child, and for doctors and nurses to make time to answer parents’ questions to help them understand the truth about vaccines.”

For more from Heidi Larson and others on global attitudes towards vaccines, listen to https://www.bbc.co.uk/programmes/w3csz4lf

Animation: How vaccinating the whole community helps everyone avoid infection. Image credit: NIAID

Vaccine success stories

The first recorded vaccinations were against the deadly disease smallpox. The disease used to kill about a third of the people who caught it, but rarely affected milkmaids who had caught cowpox from sores on the udders of the cows they were milking. In 1796, Edward Jenner created a vaccine from cowpox, testing it on a young boy who he then injected with the deadly smallpox. Luckily the boy survived and Jenner became known as the founder of immunology. This disease has now been completely eradicated since 1979 due to a worldwide vaccination programme by the WHO. The last known natural case of smallpox was in Somalia in 1977.

Gloucester smallpox epidemic, 1896

Last man on earth to catch and survive smallpox. Image credit: CDC/ Courtesy of J. Wickett and The World Health Organization

Having eradicated smallpox, the WHO turned to other vaccine eradication programmes for diseases such as polio, measles, mumps and rubella. Polio used to paralyse more than 350,000 people a year, but by vaccinating 3 billion children worldwide over the last 20 years, the Global Polio Eradication initiative has reduced polio cases by 99 per cent. Polio is still endemic in Afghanistan, Nigeria and Pakistan, however, and could spread to other countries if left unchecked, so continued monitoring and vaccination is still needed.

Two children with polio learning to use leg braces

Polio patient in an 'iron lung' respirator

Measles is a highly infectious viral disease, which can sometimes lead to serious complications. Since a measles vaccine was introduced in the UK in 1968, Public Health England estimates that 20 million measles cases and 4,500 deaths have been prevented in the UK alone. As measles is so contagious, 95 per cent of the population needs to be vaccinated to achieve herd-immunity. However, currently the UK measles vaccination rate is only at about 92 per cent which means that measles cases are making a comeback.

Vaccination is also helping in the battle against cervical cancer. A vaccine against Human Papilloma Virus (HPV), which causes cervical cancer and anogenital warts, was introduced 10 years ago. Young women in the UK have now received more than 10 million doses of HPV vaccine, reducing HPV infections of women aged 16-21 by 86 per cent and providing herd-immunity protection to older women and men who were not vaccinated. Due to this success, the vaccine will now also be offered to boys aged 12 in the UK. This offers the chance to wipe out cervical cancer in vaccinated areas within decades.

Measles – more vaccination needed to halt the comeback

Measles is a highly infectious viral disease, which can lead to serious complications. An effective measles vaccine was introduced in the UK in 1968 and, according to Public Health England estimates, this prevented 20 million measles cases and 4,500 deaths in the UK alone. In 2017, as a result of sufficiently high vaccination coverage which lead to herd immunity, measles had been completely eliminated from the UK . Because measles is so contagious, maintaining herd-immunity requires 95 per cent of the population to be vaccinated. However, currently the UK measles vaccination rate is only at about 92 per cent and measles cases are making a comeback.

As a result, in August 2019, the UK lost its World Health Organisation (WHO) measles elimination status, along with Albania, the Czech Republic and Greece.

According to a new study by Dr Velislava Petrova from the Wellcome Sanger Institute and her collaborators in the Netherlands and Germany, these measles outbreaks have serious implications for public health. Their research showed that measles virus infection not only causes measles disease, but can also delete part of the immune system’s memory, wiping out previous immunity to other infectious diseases. In addition, measles resets the human immune system back to an immature, baby-like state with only a limited ability to respond to new infections.

Velislava said: “Our study is a direct demonstration in humans of ‘immunological amnesia’, where the immune system forgets how to respond to infections encountered before. This shows the risk that measles could reverse the effects of vaccination against other infectious diseases.

She added, “This shows how vital it is that everyone possible is vaccinated against measles, not only to control measles, but also maintain herd immunity to other infectious diseases within communities.”

Vaccines needed

Many tropical diseases still do not have effective vaccines – malaria is one of these. Malaria is caused by Plasmodium parasites which are spread by infected mosquitos. More than 200 million people a year are infected with malaria and nearly half a million people worldwide, mostly children under five, die from it each year. While one approved malaria vaccine exists, it has low efficacy and an effective vaccine would vastly improve the lives of millions of people.

The challenges of finding a malaria vaccine

The Plasmodium parasites that cause malaria are complex organisms with multiple life stages and are masters at avoiding our immune systems. They are extremely good at changing the shape of most of the proteins they produce, so our antibodies don’t recognise them. They also hide their essential survival proteins, so our immune system can’t reach them. This means that finding a vaccine that targets malaria parasites is especially difficult.

In 2011, Gavin Wright and Julian Rayner at the Sanger Institute were trying to understand how the tricky Plasmodium parasite invades our red blood cells. They discovered a receptor protein on the outside of the red blood cell – basigin – that the malaria parasite uses to invade the red blood cell. From this, they were able to find which parasite protein bound to this blood cell receptor.

Gavin Wright explains, “It was a really exciting time in the lab when we identified the interaction between the red cell receptor basigin and the parasite protein RH5. Showing that this interaction was essential and universally required by all strains of parasite that cause severe malaria changed the way we thought about the invasion process in molecular terms. Importantly, it also immediately suggested that RH5 could be a good vaccine target.”

“We now know that RH5 does not act alone, but works in concert with other parasite proteins so combining these other factors in a multi-component vaccine may increase its potency. There are currently a number of malaria vaccine trials underway that combine the RH5 protein with these other factors and only time will tell if these targets are successful.”

The teams at the Sanger institute are also working backwards from the malaria parasite’s genome to find other potential vaccine targets, using a process termed “reverse vaccinology”. This method was pioneered for the vaccine against type B meningococcal bacteria, a major cause of meningitis and blood poisoning, and has identified five more potential Plasmodium vaccine targets which, if combined, could show promise for further development into new malaria vaccines.

The dangers of diarrhoea

While diarrhorea isn’t pleasant, it can also be fatal for young children. There are vaccines for some major causes of diarrhoea such as rotavirus and cholera, but there is no vaccine available for the Enterotoxigenic Escherichia coli (ETEC). This bacteria causes 400,000 deaths and 400 million cases of diarrhoea each year in low- and middle-income countries.

Computer visualisation of E. coli bacteria. Image credit: CDC/ James Archer

The Sanger Institute’s Astrid von Mentzer is studying ETEC in the search for the best targets for a vaccine. “ETEC is hugely diverse meaning that multiple targets are needed in a vaccine, but finding the targets that provide protection against most strains is difficult,” she said.

During Astrid’s PhD at the University of Gothenburg in Sweden with Prof Ann-Mari Svennerholm, the group developed a potential vaccine based on several ETEC surface proteins and a toxin protein and set up a vaccine trial around the world. Astrid’s role was to use genomic surveillance to find out which strains contained these targets. She studied samples of ETEC collected from adults and children around the world over a 30-year time period, using whole genome sequencing, and compared all the strains to see which had common features. She found the vaccine was likely to be effective for many strains.

“The surveillance data showed that the strategy for the vaccine was a good one,” said Astrid. “We showed that most of the major strains of ETEC around the world contained these vaccine targets, and that they are stable in the ETEC population. This proves that they are good vaccine candidates.”

Now back at the Sanger Institute, Astrid is taking the ETEC surveillance further. By studying ETEC in pigs and cows she is hoping to understand if the same ETEC can infect multiple hosts, and is looking into the possibility of finding vaccine targets that would work not just in people, but also in some farm animals.

Streptococcus A – the search for a global vaccine

Group A Streptococcus bacteria, commonly known as Strep A, is one of the top 10 causes of death from infectious diseases worldwide, especially in low-income nations. It causes many different diseases ranging from severe sore throat and the skin infection impetigo, through to scarlet fever, sepsis, rheumatic fever and the flesh-eating disease necrotizing fasciitis. An effective vaccine for Strep A would prevent millions of infections each year. However, this vaccine search is hampered by the variety of Strep A strains.

Group A Streptococcus bacteria

Dr Mark Davies from the Sanger Institute and Doherty Institute in Australia is one of the researchers carrying out global surveillance of Strep A, including samples from Africa and Australian Aboriginal communities. “By sequencing the DNA of more than 2,000 Group A Streptococcus samples from around the world, we narrowed down common genes in almost all strains of Strep A globally,” he said.

By finding which genes are present in the different strains, Mark and his colleagues are helping to find vaccine targets that could combat Strep A around the world. “There is no effective vaccine against Strep A yet, and this is a tremendous step forward in identifying what may work as a global vaccine candidate,” Mark added.

Improving the Pneumonia vaccine

Over the last ten years, many countries have introduced the pneumococcal conjugate vaccine (PCV). This vaccine targets Streptococcus pneumoniae, the most common cause of bacterial pneumonia globally and has greatly reduced the number of childhood infections. A major problem however is that the vaccine targets the coat covering the bacteria, of which there are over a hundred different types. This means that despite the vaccine, pneumococcal pneumonia rates remain very high, and the bacteria are continuing to evolve to evade the vaccine.

Scanning electron micrograph of colonies of Streptococcus pneumoniae

Prof Stephen Bentley, from the Sanger Institute is one of the leaders of the Global Pneumococcus Survey. “Pneumonia is a huge threat to health worldwide, responsible for the deaths of hundreds of thousands of people a year, with children under five years old being most affected,” he said. The global team, funded by the Bill & Melinda Gates Foundation, launched a worldwide genomic survey of Streptococcus pneumoniae, and discovered 621 different strains across more than 50 countries.

Stephen explains why this is so important, “This work will help predict which strains will be important for new pneumococcal vaccines, and shows the evolutionary changes that lead to vaccine evasion. Now we have an unprecedented view of the global population of S. pneumoniae bacteria.”

“This global view will give crucial information for future vaccine strategy worldwide, and help save lives,” he added.

Are we winning the vaccine fight?

Ongoing research is vital. Genomics is helping researchers speed up the search for new vaccine targets for diseases, to ultimately save the lives of millions more people. Ongoing genomic surveillance is also helping teams understand which disease targets will work best for global prevention, and how wily parasites, bacteria and viruses are changing in response to vaccine use. The perennial fight between humans and disease is continuing, but vaccines are our best chance to win.