An experimental vaccine, designed to enlist the body’s own immune system to target cancer cells, has shown promise for treating and preventing cancer in mice.
The vaccine was created to target a gene called KRAS that is involved in the development of many types of cancer, including lung, bowel and pancreatic cancer.
Researchers from the same team have also found a new way to spot and treat aggressive forms of lung cancers that are able to evade the body’s immune system.
Both studies will be presented on Sunday at the 32nd EORTC-NCI-AACR  Symposium on Molecular Targets and Cancer Therapeutics, which is taking place online.
Scientists have known for decades that the KRAS gene goes wrong – or mutates – in many cancers. However, until now, researchers have struggled to find a way to turn this knowledge into an effective treatment.
The vaccine study  was carried out by Dr Rachel Ambler, a postdoctoral research fellow, and colleagues at The Francis Crick Institute, London, UK. She said: “We know that if KRAS goes wrong, it enables cells in our bodies to start multiplying and turning into cancer cells. Recently, we’ve learned that, with the right help, the body’s immune system might be capable of slowing this growth.
“We wanted to see if we could use this knowledge to create a cancer vaccine that could not only be used to treat cancer, but also give long-lasting protection against cancer, with minimal side-effects.”
Dr Ambler and her colleagues created a set of vaccines that are capable of stimulating an immune response towards the most common KRAS mutations.
The vaccines are made up of two elements joined together. One element is a fragment of the protein produced by cancer cells with a mutated KRAS gene. The other element is an antibody that helps to deliver the vaccine to a cell of the immune system called a dendritic cell. These cells play a key role in helping the immune system spot and destroy cancer cells, an ability that could be boosted by the vaccines.
The team tested the vaccine on mice that already had lung tumours and mice that were induced to grow tumours. Researchers studied the mice for indications that their immune systems were responding to the vaccine and for signs that tumours were shrinking or not even forming in the first place.
In mice with tumours, 65% of those treated with the vaccine were alive after 75 days, compared to 15% of mice that were not given the vaccine.
In mice treated to induce tumours, 40% of vaccinated mice remained tumour-free after 150 days, compared to only 5% of unvaccinated mice (one mouse). By vaccinating the mice, researchers found that the appearance of tumours was delayed by an average of around 40 days.
Dr Ambler said: “When we used the vaccine as a treatment, we found that it slowed the growth of cancers in the mice. And when we used it as a preventative measure, we found that no cancers grew in the mice for quite a long period of time and, in many cases, cancers never developed.
“Previous trials of cancer vaccines have failed because they have not been able to create a strong enough response from the immune system to find and destroy cancer cells. This research still has a long way to go before it could help prevent and treat cancer in people, but our results suggest that the design of this vaccine has created a strong response in mice with very few side-effects.”
Researchers from the same team have also made an important discovery about how lung cancers are able to evade the body’s immune system, making them harder to treat. Their findings will be discussed in two further presentations at the 32th EORTC-NCI-AACR Symposium. [3,4]
Dr Sophie de Carné, a postdoctoral researcher, and Dr Phil East, deputy head of bioinformatics, from The Francis Crick Institute used a collection of hundreds of human tumour samples with information on which genes are mutated and which genes are active inside the tumours. They were also interested in the KRAS gene and its role in the development of hard-to-treat cancers.
Dr de Carné said: “In patients with some of the most aggressive cancers, we discovered that the activity of the KRAS gene results in the build up of a chemical called adenosine. Higher levels of adenosine are known to dampen the body’s immune response, making it harder for immune cells to target and destroy cancer cells.”
The researchers then studied cancers with similar KRAS activity in mice to see whether it was possible to manipulate the levels of adenosine to make it easier to treat the cancer. By giving the mice a drug designed to lower adenosine, oleclumab made by AstraZeneca, alongside existing cancer drugs that help the immune system fight cancer, the researchers found that they could improve survival.
Dr East added: “Together these results suggest it could eventually be possible to identify patients who have this aggressive type of lung cancer and use a combination of drugs to support their immune system and successfully treat their tumours.”
Dr James L. Gulley is co-chair of the 32th EORTC-NCI-AACR Symposium for the NCI and Director of the Medical Oncology Service, Center for Cancer Research, NCI, USA, and was not involved in the research. He said: “These studies focus on types of cancer – such as lung and pancreatic cancer – that are difficult to treat. Survival rates for these cancers remain very poor so we urgently need new treatments for patients.
“Boosting the immune system with drugs to treat cancer or even developing a vaccine to prevent cancer are both exciting possibilities, especially if they can be achieved with minimal side effects. We hope that these promising approaches will one day be reproduced in patients.”
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
Phase I/II data presented at ID Week show that the two FDA fast-tracked candidate vaccines trigger robust immune response and are well-tolerated
There is currently no vaccine for respiratory syncytial virus (RSV), which causes significant morbidity and mortality in infants and older adults
Phase III studies are on track to start in the coming months
LONDON, UK I October 21, 2020 I GSK today announced that its Respiratory Syncytial Virus (RSV) candidate vaccines for maternal immunisation (GSK3888550A) and older adults (GSK3844766A) were well-tolerated and highly immunogenic in Phase I/II clinical studies. The data were presented virtually at the ID Week Congress.
RSV is a leading cause of respiratory infections such as bronchiolitis (inflammation and congestion of the small airways or bronchioles of the lung) and pneumonia (an inflammatory condition of the lung small air sacs or alveoli) in infants and older adults. It is estimated to cause about 3 million hospitalisations of children under 5 year of age globally, and 177,000 hospitalisations of older people in the US alone.
Both candidate vaccines contain a recombinant subunit pre-fusion RSV antigen (RSVPreF3) which is believed to trigger the required immune response. The vaccine for older adults also includes GSK’s proprietary AS01 adjuvant system to boost the immune response as this population tends to show weaker immune response to vaccination than younger adults.
The vaccine candidate for older adults was first tested in 48 healthy adults (18-40 years old) and then in 1,005 healthy older adults (60-80 years old) with different dosages of antigen and adjuvant compared with a placebo. The interim data 1-month post-immunisation show that:
the candidate vaccine elicited a robust humoral and cellular immunity compared with baseline
a close to 10 times increase of protective antibodies (RSVPreF3 IgG and RSV-A neutralising antibodies) was induced in the vaccinated group
importantly, the cellular immunity (RSVPreF3-specific CD4+ T-cells) of the vaccinated older adults was boosted to reach similar range to that observed in the younger adults after vaccination with the non-adjuvanted formulation, despite the initial lower baseline level observed in older adults compared with young adults.
The maternal RSV candidate vaccine was tested with 3 different doses compared with placebo in 502 healthy non-pregnant women over monthly visits (Day 8, Day 31 and Day 91 post immunisation). The data show that, compared with baseline:
the investigational vaccine was able to rapidly boost the pre-existing immunity at all dose levels, leading to high levels of protective neutralising antibodies
at Day 8, a 14-fold increase in RSV-A and RSV-B neutralising antibodies titers was observed.
These two vaccines are part of a tailored, portfolio approach GSK is pursuing with three RSV candidate vaccines – maternal, paediatric and older adults – using different novel technologies aiming to help protect the populations most impacted: infants and older adults. All three candidate vaccines have received FDA fast-track designation.
Emmanuel Hanon, Senior Vice-President and Head of Vaccines R&D, said: “RSV is an infectious disease that can have a very serious impact on families and societies. We are delighted to see these positive results confirming our approach to develop dedicated vaccines building on the strategic use of our platform technologies for the populations most at risk from RSV infections – young infants and older adults. Our portfolio strategy takes into account the unique needs of the immune system of these vulnerable populations and we look forward to progressing these assets to Phase III trials to evaluate their potential efficacy”.
Vaccines for RSV prevention could lead to significant reductions in disease, doctor’s visits, and hospitalisations in infants, toddlers, and older adults, thus having the potential for a significant benefit to individual health in the most vulnerable populations as well as a positive impact on the burden and costs of healthcare systems around the world.
Based on available data and engagement with regulators, Phase III studies for both older adults and maternal RSV candidate vaccines are in preparation and on-track to start in the coming months, while the Phase I/II (in RSV-seronegative infants) and Phase II (in RSV-seropositive infants) studies with the paediatric RSV candidate vaccine are ongoing. Phase I/II safety and immunogenicity data on the paediatric RSV candidate vaccine in RSV-seropositive infants will be presented at European Society for Paediatric Infectious Diseases (ESPID) on 26-29 October 2020.
About GSK’s RSV candidate vaccine for older adults (GSK3844766A)
The Phase I/II study investigates the safety, reactogenicity and immune response of GSK’s RSV candidate vaccine in older adults aged 60 to 80 (NCT03814590). This candidate vaccine contains GSK’s proprietary AS01 adjuvant, which is also used in GSK’s shingles vaccine. The safety, reactogenicity and immune responses (humoral and cellular-mediated) were first assessed in 48 healthy adults aged 18–40 years who were vaccinated with either 30, 60 or 120 μg dose level of RSVPreF3 non-adjuvanted vaccine or placebo. Following favourable safety outcomes, 1005 adults aged 60–80 years were randomised in a 2-step staggered manner to receive 1 of the 9 RSV vaccine formulations containing either 30, 60 or 120 μg dose level of RSVPreF3, non-adjuvanted or adjuvanted with AS01E or AS01B, or placebo.
Interim data presented at ID Week show that within one-month post-immunisation, the adjuvanted candidate vaccine has been well tolerated with no safety concerns identified. The most frequently reported adverse events were pain at injection site, fatigue and headache.
Moreover, data 1-month post-immunisation show that the candidate vaccine elicited a robust humoral and cellular immunity compared with baseline:
High levels of RSVPreF3 IgG antibodies (geometric mean antibody concentrations were 8.4–13.5 for the 18-40 year old vaccinees, and 7.2–12.8 fold-higher in the 60–80-year-old vaccinees) and RSV-A neutralising antibodies (geometric mean antibody titers were 7.5–13.7 in the 18–40 year old vaccinees, and 5.6–9.9 fold-higher in 60–80-year-old vaccinees) were induced in all vaccinated groups.
Before vaccination, deficiency of RSVPreF3-specific T-cells (hypothesised to help promote viral clearance) was observed in older adults compared to younger adults. After vaccination, a robust RSVPreF3 CD4+ T-cells response in older adults had been boosted to reach a similar range than the one observed in younger adults, with significantly higher immune response in the groups who received the adjuvanted formulation.
About GSK’s maternal RSV candidate vaccine (GSK3888550A)
The goal of this candidate vaccine is to prevent RSV-associated lower respiratory tract infections in infants during the first months of life by transfer of maternal antibodies – an approach based on GSK’s strong expertise in maternal immunisation acquired through pertussis and flu vaccine programmes. The polyclonal nature of the humoral response boosted by this vaccine could potentially offer broad protection across a large number of RSV strains and addressing the potential issue of virus escape mutation. Maternal immunisation could help to protect infants too young to be immunised from RSV-associated infections in their first months of life – when they are the most vulnerable – without any medical intervention required thanks to the passive transmission of neutralising antibodies from the vaccinated mother to the unborn child in the last weeks of pregnancy.
In this Phase I/II study (NCT03674177), 502 healthy non-pregnant women received 1 dose of either 30, 60 or 120 μg of recombinant protein-based RSVPreF3 or placebo. The safety, reactogenicity and immunogenicity was monitored for 6 months. The data 1-month post-immunisation show that all vaccine dose levels were well-tolerated, with no safety concerns identified: the most frequently reported solicited adverse events were minor and included pain at injection site and headache.
Moreover, the data show that the candidate vaccine elicited a rapid and persistent immune response in all RSVPreF3 groups. The immune response peaked at Day 8 with a 14-fold increase in neutralising RSV-A and RSV-B titers from baseline. The neutralising titers declined over time but a >6-fold increase was still maintained at Day 91. Anti-RSVPreF3 IgG antibodies were boosted substantially in all groups with geometric mean concentrations of anti-RSVPreF3 IgG antibody (≥ 12-fold at Day 8 and ≥ 6-fold until Day 91 vs baseline). The 60 and 120 μg dose levels of RSVPreF3 were more immunogenic than the 30 μg formulation.
Safety and immunogenicity data from the first time in pregnant women study will be presented in the first half of 2021. The data currently available provide the confidence to advance to late stage clinical work.
About respiratory syncytial virus
Globally, there are an estimated 33 million cases of RSV annually in children less than 5 years of age, with about 3 million hospitalised and approximately 120,000 dying each year from complications associated with the infection. Nearly half of these pediatric hospitalisations and deaths occur in infants less than 6 months of age. According to the Centers for Disease Control and Prevention, virtually all children in the US get an RSV infection by the time they are 2 years old and one to two out of every 100 children younger than 6 months of age with RSV infection may need to be hospitalised.
It also represents a significant health threat for older adults, with an estimated 177,000 hospitalisations and 14,000 deaths associated with RSV infections occurring in the US alone. Without robust surveillance systems in several countries, global data on the burden of RSV in older adults is either lacking or likely to underestimate its significance. As global population ages, morbidity and mortality of respiratory infections including RSV to be steadily increasing.
GSK is a science-led global healthcare company with a special purpose: to help people do more, feel better, live longer. For further information please visit www.gsk.com.
Cold viruses often don’t get much of a look when it comes to R&D; they are annoyances, but ones that usually make us feel miserable for a few days then clear up.
But some cold viruses can hit vulnerable people much harder, leading to pneumonia and hospitalizations. These are colds caused by the respiratory syncytial virus (RSV), which, in the elderly and in children under 5, can cause serious complications and sometimes can prove fatal.
In younger children, it can cause bronchiolitis (inflammation and congestion of the small airways or bronchioles of the lung) and pneumonia in both infants and the elderly, and it’s thought to cause about 3 million hospitalizations of children under 5 globally, with around 177,000 hospitalizations of older people in the U.S.
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There have been a number of Big Pharma attempts at a vaccine, but the road has been fraught with setbacks and flops. There is a monthly preventive shot from Swedish Orphan Biovitrum’s Synagis used against RSV in high-risk infants, but a fully protective vaccine remains elusive.
GlaxoSmithKline took a step closer to finding that vaccination, announcing data from several candidates at IDWeek 2020 from several midstage trials, as it now plots a late-stage make-or-break series of tests.
The RSV candidate vaccines were for two distinct groups: one for maternal immunization (GSK3888550A) and one for older adults (GSK3844766A). Top-line, GSK says both “were well-tolerated and highly immunogenic in phase 1/2 clinical studies.”
The former was tested with three different doses compared with placebo in 502 healthy non-pregnant women over monthly visits and showed the vaccine was able to “rapidly boost the preexisting immunity at all dose levels, leading to high levels of protective neutralising antibodies.”
And, just over a week after the shot, GSK said it saw a 14-fold increase in RSV-A and RSV-B neutralizing antibody titers. The idea is for the vaccine, which uses the Big Pharma’s AS01 adjuvant system, to give pregnant women the ability to confer immunity to their unborn children.
This has not been proven in this latest study, but GSK said it will be presenting data from pregnant women in the first half of next year to see whether its theory is borne out.
The latter candidate, in older adults, was first tested in 48 healthy adults (18-40 years old) and then in 1,005 healthy older adults (60-80 years old) with different dosages of antigen and adjuvant compared with a placebo.
The interim data, out one month after the shot, showed a “robust humoral and cellular immunity compared with baseline” and “a close to 10 times increase of protective antibodies” in the vaccinated group.
A phase 3 program for both patient populations is expected to begin in the “coming months.” Several other early-to-midstage trials are also ongoing in younger children either with exposure to RSV or without, with data for RSV-seropositive infants to be published at the European Society for Paediatric Infectious Diseases next week.
All three candidate vaccines have been given an FDA fast-track label.
“RSV is an infectious disease that can have a very serious impact on families and societies,” saidEmmanuel Hanon, GSK senior vice president and head of vaccines R&D. “We are delighted to see these positive results confirming our approach to develop dedicated vaccines building on the strategic use of our platform technologies for the populations most at risk from RSV infections: young infants and older adults.
“Our portfolio strategy takes into account the unique needs of the immune system of these vulnerable populations and we look forward to progressing these assets to Phase III trials to evaluate their potential efficacy.”
GSK is in a race with Johnson & Johnson and Moderna, which are also hard at work on vaccinations for COVID-19, for an RSV shot.
Vaccines are a pillar of good public health. And as the world continues to fight COVID-19, there’s much anticipation for a safe and effective vaccine that can help get the pandemic under control.
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Vaccines save millions of lives each year from deadly diseases caused by viruses or bacteria. “Diseases such as smallpox and polio that were killers a century or two ago are now barely blips in our conscience,” notes pulmonologist Daniel Culver, DO.
They’re crucial to fighting infectious diseases — yet there’s still a lot of misinformation floating around about vaccines. Here’s what you should know about how they’re developed, how they work and how scientists are making progress on vaccines for COVID-19.
How do vaccines work?
You encounter thousands of germs every day. While your immune system can fight most of them on its own, vaccines help it fight the disease-causing ones (pathogens) it can’t handle.
Vaccines familiarize your immune system — which makes antibodies to defend your body against harmful invaders — with a certain pathogen so that it will know what to do if you become infected with that pathogen in the future.
There are several different ways that vaccines can achieve this triggering of the immune system, Dr. Culver says. They contain either:
A weakened (attenuated) form of a pathogen.
An inactivated form of a pathogen.
Certain parts of the pathogen, such as its proteins.
A weakened toxin made by the pathogen.
Vaccines may also contain other ingredients such as adjuvants, which help boost your body’s immune response to the vaccine, and stabilizers, which keep the active ingredients working after the vaccine is made.
It’s important to note that vaccines don’t make you sick with the pathogen they’re designed to protect you from. Rather, they give your immune system a practice run at taking out a weaker, inactivated or partial version of the pathogen.
Very rarely, vaccines can cause severe physical reactions, but usually they’re mild — like some soreness where the vaccine was injected, a low-grade fever or achiness. “This really means the immune system is sitting up and taking notice of the vaccine,” Dr. Culver says.
In some cases, like with the MMR vaccine, you need more than one dose of a vaccine to build strong immunity. With others, like the tetanus vaccine, your immunity wears off over time and you need occasional “booster” vaccines. In the case of the flu vaccine, the main targets of the immune response shift slightly from year to year, depending on which flu virus strains are circulating most that year, so you need a vaccine every year.
How vaccines protect you (and others)
Most vaccines won’t prevent you from becoming infected with a certain pathogen. Rather, they allow your body to stop the infection before you get sick, or they prevent you from becoming seriously sick when you get infected.
For example, the flu shot reduces your risk of getting the flu by 40% to 60%, according to the CDC. That might not seem like a lot, but studies also estimate that getting the flu vaccine makes you 82% less likely to be admitted to an intensive care unit with flu-related illness than someone who isn’t vaccinated.
This helps you, and it also helps those around you, including people in your community who can’t be vaccinated because of serious allergies or a medical condition that weakens their immune system. Pathogens can spread quickly from person to person. When a large number of people in a community are vaccinated, the pathogen can’t spread as easily.
“If that number gets high enough, we’ll have what’s called herd immunity, where there aren’t enough people in a community who can spread it in a significant way,” Dr. Culver says.
What vaccines do we need?
In the U.S., the Centers for Disease Control and Prevention recommends that children be vaccinated against:
Diphtheria, tetanus and pertussis (whooping cough).
Haemophilus influenza type b.
Measles, mumps and rubella.
There are also some vaccines you should get later in life, including tetanus boosters. The CDC’s recommended immunization schedules for children and adults are available on its website.
How are vaccines developed?
Like medicines, vaccines go through a long process of research, development and approval before they’re made available to the public. “The usual timeline for developing a vaccine is certainly more than 10 years and probably closer to 15 or 20 years,” Dr. Culver says.
Exploratory and pre-clinical research
It starts in a lab, where scientists work to understand a pathogen and figure out how they could trigger the immune system to produce antibodies against it. When they identify a substance they think could work (an antigen), they start by testing it in cell cultures and then animals.
In the U.S., the sponsor of a new vaccine must submit an application to the Food and Drug Administration before they can begin testing it in humans.
Vaccine developers must complete a three-phase clinical trial process to show that their product is safe and effective before it can be approved. This includes:
Phase 1: A small number of people (usually healthy people) receive the vaccine. The purpose of a phase 1 trial is to see whether, or how, the vaccine generates an immune response in humans and if it causes any potentially dangerous side effects.
Phase 2: The vaccine is given to more people (at least several hundred) of various ages and levels of health. Phase 2 studies allow researchers to better evaluate how safe and effective the vaccine is and learn what the ideal dosage is.
Phase 3: Hundreds or thousands of people receive the vaccine, and its safety and effectiveness are monitored for a longer period of time.
In the U.S., the FDA must approve a new vaccine before it can be made available to the public. “Regulators look at all the safety and effectiveness data collected from lab studies and clinical trials and then make a determination on whether or not this will be a product that actually will be helpful for the population,” Dr. Culver explains.
Once it’s approved, the vaccine then must be manufactured and distributed, which is a complex and time-consuming process. But not a lot of vaccines actually make it this far.
“Vaccines are very hard to develop,” Dr. Culver says. “Sometimes they may look very good in early-phase trials but then may not turn out to effective in phase 3 trials.”
If a vaccine is approved, regulators and drug companies continue to monitor its safety and effectiveness as more people take it.
What’s going on with development of a COVID-19 vaccine?
Because of the global crisis at hand, work on a vaccine to protect against COVID-19 is happening at lightning speed. “Biopharmaceutical companies and the academic industry — with a lot of support from organizations and governments around the world — are all working in partnership to try to move this very fast,” Dr. Culver says.
That doesn’t necessarily mean they’re skipping important steps along the way, though. “The process of developing this vaccine is being done very rigorously,” he says. “Many of these steps have been collapsed so that they’re overlapping. For example, manufacturing is already happening so that we can go ahead and start distributing those almost immediately if they are given emergency use authorization by the FDA.”
With nearly 200 vaccines currently in development or testing, there’s a lot of opportunity to find at least one that’s safe and effective. A few vaccines have already progressed to phase 3 clinical trials, and Dr. Culver says data from some of those studies could be available by the end of the year.
Different groups are taking different approaches to triggering an immune response. Some are using an inactivated, weakened or partial version of the coronavirus that causes COVID-19 to trigger an immune response. But Dr. Culver points out that many are using newer, gene-based approaches that deliver genetic code to our cells instructing them to make a specific protein contained in the coronavirus. This, in turn, triggers the immune system to make antibodies against that protein.
There are three main ways vaccine developers are hoping to get that genetic code into our cells:
Viral vector vaccines, which use a common cold-causing virus to deliver the genetic code to our cells.
DNA vaccines, which contain small, circular pieces of DNA called plasmid.
RNA vaccines, which contain RNA carried in fatty molecules that can pass easily into cells.
“We’re going to see which one of these is most effective – and I certainly hope that more than one is effective,” Dr. Culver says.
Will a vaccine end the pandemic?
While an effective vaccine is a key part of the strategy for squashing COVID-19, it’s important to remember that it won’t be an “off” switch for the pandemic.
“I think a vaccine will be part of the solution for getting control over this, but I think it’s highly unlikely that a vaccine will be 100% effective and will be used by enough of the population regularly enough to completely eliminate this virus from our world,” Dr. Culver says.
“I think we’ll need to have a strategy that includes several things, including vaccination, continued social distancing measures, rigorous testing and contact tracing — and if we can combine all of those elements, we can get back to something that’s very close to a normal life.”
In the meantime, the best way to protect yourself and those around you is by doing the things you’re probably tired of hearing about: good social distancing, wearing a mask in the appropriate setting, hand-washing and staying out of crowds.
“It’s important to remember that the extent to which we can open the economy and go back to school and do the sorts of things we all enjoy as part of life really depends on personal responsibility from each of us,” Dr. Culver says.
Unlike fine wine, the human body does not improve with age. Hearing fades, skin sags, joints give out. Even the body’s immune system loses some of its vigour.
This phenomenon, known as immunosenescence, might explain why older age groups are so hard-hit by COVID-19. And there is another troubling implication: vaccines, which incite the immune system to fight off invaders, often perform poorly in older people. The best strategy for quelling the pandemic might fail in exactly the group that needs it most.
Scientists have known for decades that ageing immune systems can leave the body prone to infection and weaken their response to vaccines. In June, the US Food and Drug Administration announced that a COVID-19 vaccine would have to protect at least half the vaccinated individuals to be considered effective, but protection in older adults might not even meet that bar. “No vaccine is going to be as effective in the elderly as it is in young people,” says Matt Kaeberlein, a gerontologist at the University of Washington in Seattle. “That’s an almost certainty.”
The human immune system is mind-bendingly complex, and ageing affects nearly every component. Some types of immune cell become depleted: for example, older adults have fewer naive T cells that respond to new invaders, and fewer B cells, which produce antibodies that latch on to invading pathogens and target them for destruction. Older people also tend to experience chronic, low-grade inflammation, a phenomenon known as inflammageing (see ‘Depleted defences’). Although some inflammation is a key part of a healthy immune response, this constant buzz of internal activation makes the immune system less responsive to external insults. “This overarching, chronic inflammatory state is what’s driving much of the immune dysfunction that we see,” says Kaeberlein. The upshot is a poorer reaction to infections and a dulled response to vaccines, which work by priming the immune system to fight off a pathogen without actually causing disease.
With about 50 COVID-19 vaccine candidates currently being tested in humans, researchers say it’s not yet clear how they will fare in older adults. In its phase I study of 40 people aged 56 and over, Moderna in Cambridge, Massachusetts, reported that its candidate mRNA-1273 elicited similar antibody levels as those elicited in a younger age group1. The Chinese biotech Sinovac in Beijing, which trialled its CoronaVac candidate in a phase I/II study that included 421 adults between 60 and 89 years of age, announced in a press release on 9 September that it seems to work as well in older adults as it does in younger ones. However, a phase I study by international pharma company Pfizer and BioNTech in Mainz, Germany, showed that their vaccine BNT162b2 provokes an immune response that is about half as strong in older adults as it is in younger ones2. The older adults still produced more antibodies in response to the vaccine than people of a similar age who had had COVID-19, but it’s not known how these levels translate into protection from the virus.
Most COVID-19 vaccine trials include at least some older adults. But a recent analysis of 18 such trials found that the risk of exclusion is high3. More than half had age cut-offs and many were at risk of excluding older participants for other reasons, including underlying conditions.
If COVID-19 vaccines perform less well in older adults, researchers might be able to find ways to tweak the shot itself to elicit a stronger response. Some influenza vaccines, for instance, include immune-boosting ingredients or higher doses of the viral antigen. But some scientists say there is a better option. They are developing and testing drugs that could improve how older adults respond to vaccines and might also help them fight viruses more effectively in the first place. Rather than working with the limitations of the ageing immune system, they are planning to rejuvenate it.
Many researchers have grown old trying to pinpoint ways to reverse the ageing process. In the past decade, however, they have made serious progress in identifying particular molecular targets that might help in this quest.
One promising class of anti-ageing drug acts on pathways involved in cell growth. These drugs inhibit a protein known as mTOR. In the laboratory, inhibiting mTOR lengthens lifespan in animals from fruit flies to mice. “mTOR is one of probably multiple biologic mechanisms that contribute to why we age and why our organ systems start to decline,” says Joan Mannick, co-founder and chief medical officer of resTORbio, a biotech company based in Boston, Massachusetts, that aims to develop anti-ageing therapies.
In a study published in 2018 and carried out when Mannick was at the Novartis Research Institutes in Cambridge, Massachusetts, she and her colleagues tried damping down mTOR in elderly adults to see if this could improve immune function and lower infection rates4. The 264 participants received a low-dose mTOR inhibitor or a placebo for six weeks. Those who received the drug had fewer infections in the year after the study and an improved response to the flu vaccine. On the basis of her work on mTOR inhibition, Mannick, by then at resTORbio, launched a phase III trial in 2019 to see if a similar mTOR inhibitor called RTB101 could stave off respiratory illnesses in older adults.
That trial failed to show the desired effect, perhaps because infections were monitored by self-report of symptoms rather than requiring a lab test to confirm infection, as in the earlier trial. That created “a lot more noise”, says Ilaria Bellantuono, co-director of the Healthy Lifespan Institute at the University of Sheffield, UK, who was not involved in the trial. “A much bigger group would have been required to see a difference.”
Still, the data from this and an earlier trial suggested that participants who received the mTOR inhibitor had fewer severe infections from circulating coronaviruses and recovered faster from them than the placebo group. The trials pre-date the emergence of SARS-CoV-2, but they suggest that RTB101 could lessen the severity of infection. resTORbio is now testing that idea in 550 nursing-home residents aged 65 and over.
RTB101 is similar to an already approved mTOR inhibitor, the immune-suppressing drug rapamycin. At least four other groups are testing rapamycin in small numbers of infected individuals as a possible COVID-19 therapy; one group is trialling the drug exclusively in adults aged 60 or older.
The type 2 diabetes drug metformin also dampens down mTOR’s activity, albeit indirectly. Some studies suggest that people who take metformin are less likely to be hospitalized or die if they contract COVID-19. A small retrospective study in China found that the mortality among hospitalized individuals with COVID-19 taking metformin was 2.9% compared with 12.3% in people who didn’t take the drug5. Researchers at the University of Minnesota in Minneapolis analysed data on hospitalized individuals with COVID-19 who had an average age of 75, some of whom were already taking metformin for obesity or diabetes. They found a significant reduction in mortality among women taking metformin, but not among men6.
Carolyn Bramante, an obesity researcher who led the University of Minnesota study, points out that diseases such as diabetes and obesity lead to some of the same immune deficits as occur in older age. She and her colleagues plan to launch a trial of 1,500 people aged 30 and over to determine whether metformin could help stave off SARS-CoV-2 infection or prevent the worst outcomes in people already infected.
Meanwhile, Jenna Bartley, who studies ageing at the University of Connecticut in Storrs, is assessing whether metformin can boost responses to flu vaccine in a small trial of older adults. The idea, based on her work in mice, is that metformin can improve the energy metabolism of the T cells of the immune system, making them better at detecting new threats. Bartley has finished collecting data, but because her lab was shut down owing to COVID-19, she won’t have the results analysed for a few more weeks.
If metformin works against COVID-19, researchers will still have to tease out why. Kaeberlein points out that no one is quite sure how metformin works because it has so many targets. “It’s about the dirtiest of dirty drugs out there,” he says. It was originally used as an anti-influenza drug; Bramante says it helps tamp down inflammation. Aside from the mechanistic unknowns, the advantage is that metformin has been used for decades and is generally safe. Children can take it, as can pregnant women. “Metformin is a medication that you actually could give prophylactically for 12 months without having to do any follow-up,” Bramante says, “and it costs less than US$4 a month.”
mTOR is a classic anti-ageing target, but it’s far from the only one. In fact, many anti-ageing pathways seem to be linked, says James Kirkland, who studies cellular ageing and disease at the Mayo Clinic in Rochester, Minnesota. “That is, if you target one, you tend to affect all the rest,” he says. Many of the immune changes that come with ageing lead to the same result: inflammation. So researchers are looking at drugs that will calm this symptom.
Arne Akbar, an immunologist at University College London, has shown that the anti-inflammatory drug losmapimod, which is being developed as a therapy for muscular dystrophy, might help boost immunity. In a 2018 study, the researchers injected chickenpox virus into the skin of elderly adults7. Although these people had already been exposed to chickenpox, their immune response was lacklustre, hampered by excess inflammation. When the team gave the study participants losmapimod, it ratcheted down inflammation by about 70% and improved their immune responses.
In June, the company currently developing losmapimod — Fulcrum Therapeutics in Cambridge, Massachusetts — launched a 400-person phase III study to investigate whether the drug could prevent death and respiratory failure in older people hospitalized with COVID-19.
Another class of drug, called senolytics, helps to purge the body of cells that have stopped dividing but won’t die. These senescent cells are typically cleared by the immune system, but as the body ages, they begin to accumulate, ramping up inflammation. In August, Kirkland and a team at the Mayo Clinic launched a 70-person trial to test whether a senolytic called fisetin, which is found in strawberries and sold as a health supplement, can curb progression of COVID-19 in adults aged 60 or older. They also plan to test whether fisetin can prevent COVID-19 infection in nursing-home residents.
“Senescence is really a key factor in ageing,” says Eric Verdin, president and chief executive of the Buck Institute for Research on Aging in Novato, California, who is not involved in the fisetin research. No senolytics have currently been approved for clinical treatment, however. “This is one area that has been much less studied,” he says.
Kaeberlein says it’s likely that most companies will pursue anti-ageing drugs as therapies before they test them as prophylactics. “It’s much easier to get a therapy approved in people who are already sick,” he says. He thinks that mTOR inhibitors hold the most promise. “If I had the power to go back to the beginning of this whole COVID pandemic and try one thing, I’d pick mTOR inhibitors — rapamycin specifically,” he says. According to his back-of-the-envelope calculations, if rapamycin works in the same way in people as it does in mice, it could reduce COVID-19 mortality by 90%.
Kirkland says he can envisage giving one of these anti-ageing drugs as a primer before vaccination. “We have to figure out ways to target fundamental ageing mechanisms at around the time that we’re vaccinating people,” he says, “but we have to find ways of doing this that are safe and effective.”
If tweaking the immune system proves too challenging, there might be ways to juice up the vaccine itself. For flu, there are two vaccines aimed specifically at people over 65, which help worn immune systems to stage a response. One, Fluzone High-Dose, contains four times the standard amount of flu virus antigens, and the other, Fluad, relies on an immune-boosting molecule called an adjuvant.
A team led by vaccinologist Ofer Levy at Boston Children’s Hospital in Massachusetts is working on a COVID-19 vaccine specifically for older adults, using an in-vitro screening system to identify the best adjuvants. “Vaccines were typically developed as one-size-fits-all,” he says. But a lot of features — age, sex, and even the season — affect vaccine responses, Levy says. The best combinations of adjuvant and vaccine they find will be tested in mice and then in humans.
But, in general, developing medications to improve immune function seems like a much smarter strategy than creating vaccines specifically for elderly people, says Claire Chougnet, an immunologist at Cincinnati Children’s Hospital Medical Center in Ohio, who is studying inflammation in aged mice. Vaccine development is costly and time-intensive. “In the case of an emerging virus, when you want a quick response, that makes things even more complicated if you have to do two types of vaccine,” she says. Plus, individual vaccines target specific pathogens, but an immune-boosting medication could be used with any vaccine. “That could work for flu, that could work for COVID-19. That would work for COVID-25,” she says. The approach is “extremely versatile”.
Verdin agrees that supporting the older immune system should be a priority. “I think the net result of all this will be renewed interest in understanding the defect in the immune response in the elderly.” That has implications not only for the coronavirus, but also for a host of other diseases, including other viral infections and even cancer. “COVID-19 has brought to the front something that a lot of people have ignored.”
Newswise — Fighting clever parasites requires smart vaccines that can trigger critical immune responses. A University of Chicago-based research team has found a novel way to do that. These experts, specialists in toxoplasmosis and leaders in vaccine design, have focused on one of the most frequent parasitic infections of humans.
The parasite, Toxoplasma gondii, can cause lifelong infection. It lives in the brain (and sometimes the eyes) of about 30 percent of all humans. When someone drinks contaminated water, eats infected undercooked meat or is exposed to these parasites in soil, it can result in lasting damage. Infection from unrecognized exposure to this microscopic parasite can harm the eyes, damage the brain and, in some cases, lead to death. Toxoplasmosis, according to the CDC, is the second most frequent cause of foodborne-associated death in the United States.
These parasites tend to attack unborn babies, newborns, children and adults. While most healthy adults who are exposed to the parasite never experience any serious symptoms, dormant, unrecognized, smoldering infections can emerge years later in immune-compromised patients. There is currently no vaccine to protect people from this infection.
“We urgently need a vaccine, as well as new and better medicines, to prevent and treat this infection,” said the study’s senior author, Rima McLeod, MD, Professor of Ophthalmology and Visual Science and Pediatrics at University of Chicago and a leading authority on toxoplasmosis.
“Millions of people suffer from these infections,” McLeod said. These neglected infections are often detected too late to prevent irreversible damage, and some patients die if the infection is untreated. Until now, no vaccine has been available for humans and no known medicine in clinical use has been able to eliminate the chronic, encysted form of Toxoplasma.
The team used cell-based and murine models. These mouse models have human immune-response genes to mimic how people can fight the infection. The SAPN scaffold serves as a stimulus, boosting the innate immune response and delivering components of the vaccine to relevant target cells.
“Especially important,” McLeod said, “these novel SAPNs have been engineered to have the size, shape and ability to produce immune responses against Toxoplasma gondii. This triggers a protective effect.”
The team’s approach has been quickly adopted by other investigators. There is ongoing work to immunize against herpetic eye disease, SARS-CoV-2 (COVID19), HIV, malaria and influenza viruses.
The researchers found that their SAPN scaffold can fold reliably into a stable shape. As the immune system perceives it as a foreign invader stimulating a protective immune response, the scaffold can incorporate components that stimulate an immune response against the genetic variants of the parasite.
This can be tailored for people of differing genetic backgrounds. The vaccine becomes a multisystem targeting weapon. The researchers named their new weapon “ToxAll.” They describe it as a “multi-epitope, multi-functional, toxoplasmosis nano-vaccine.”
It contains crucial immunity-stimulating components, mixed with an adjuvant, known as GLA-SE, that appears to be powerful and safe in humans. This type of vaccine, with components from plasmodia, has already been tested in primates for malaria, and is moving into the clinic.
Prior infections with T.gondii before pregnancy can protect a pregnant woman from passing the infection to her unborn child. But when a mother first acquires the infection during pregnancy – before her body can mount an immune response – the parasite can cause significant harm to the unborn child.
The investigators first created a live, attenuated vaccine that can protect mice against toxoplasmosis. Prior natural infection of humans can confer protection, and live vaccines could protect mice. These live vaccines, however, can have safety concerns.
ToxAll was created as a synthetic vaccine that could stimulate danger signals, alerting the immune system to focus on foreign invaders. A crucial part of the process is to create a design with the right properties, assembling particles into predictable shapes that resemble viruses, then enabling the fragments of components of the parasite to educate the “adaptive memory” of the immune system. This creates a long-lasting immune response, including antibodies and protective T lymphocytes.
Protection with the full SAPN, at this point, is not yet available, “but is under development with promising results,” McLeod said. The team is working to expand the use of additional fragments of the parasite. They hope to create a next generation vaccine that could provide lasting immunity against toxoplasmosis – one that could offer a novel, safe, synthetic vaccine to prevent this disease.
The next step is to develop vaccines as part of a “toolbox” that also includes new medicines and novel use of older medicines for prevention and treatment of toxoplasmosis. The team has applied their clinical and laboratory experiences to understand the infection and devise ways to prevent it, using immunology, genetics, bioinformatics and systems biology to develop and enhance the vaccine and make certain it can help humans worldwide.
“We now think we are reaching the next stage,” McLeod said. “Our toolbox could be developed to prevent and treat human T. gondii and P. falciparum infections.” This approach for vaccines, she added, “can generate innate immunity, cell-mediated adaptive immunity, and host-neutralizing antibodies that are critical to protect against different pathogens.”
McLeod’s team includes Kamal Bissati and Ying Zhou. Peter Burkhard, the inventor of the SAPN scaffold, led a team in Switzerland. Additional investigators were from the Infectious Diseases Research Institute, Seattle, where they made GLA-SE. Investigators from the La Jolla Institute of Allergy and Immunology, Paxvax, HTD Biosystems and Walter Reed Medical Center also contributed, along with collaborators in Strathclyde, Scotland; the Massachusetts Institute of Technology; and the Hubbell/Swartz Lab at The University of Chicago. The teams worked together to define how the vaccine elicits an immune response to parasites before they can establish an infection in humans. San Diego-area scientists Jeff Alexander, John Sidney and Alessandro Sette also collaborated in this work by creating mouse models with specific human genes critical in the making of a human vaccine.
About the University of Chicago Medicine & Biological Sciences
The University of Chicago Medicine, with a history dating back to 1927, is one of the nation’s leading academic health systems. It unites the missions of the University of Chicago Medical Center, Pritzker School of Medicine and the Biological Sciences Division. Twelve Nobel Prize winners in physiology or medicine have been affiliated with the University of Chicago Medicine. Its main Hyde Park campus is home to the Center for Care and Discovery, Bernard Mitchell Hospital, Comer Children’s Hospital and the Duchossois Center for Advanced Medicine. It also has ambulatory facilities in Orland Park, South Loop and River East as well as affiliations and partnerships that create a regional network of care. UChicago Medicine offers a full range of specialty-care services for adults and children through more than 40 institutes and centers including an NCI-designated Comprehensive Cancer Center. Together with Harvey-based Ingalls Memorial, UChicago Medicine has 1,296 licensed beds, nearly 1,300 attending physicians, over 2,800 nurses and about 970 residents and fellows.
Newswise — While researchers around the world race to develop an effective and safe COVID-19 vaccine, a team from the San Diego Supercomputer Center (SDSC) at UC San Diego contributed to a study led by Vanderbilt Vaccine Center of Vanderbilt University Medical Center (VUMC) on T cell receptors, which play a vital role in alerting the adaptive immune system to mount an attack on invading foreign pathogens including the Coronavirus SARS-CoV-2.
SDSC’s Comet supercomputer was recently used to perform complex calculations on the receptor sequence data from sorted human T cells to allow scientists to better understand the size and diversity receptor repertoire in healthy individuals. The team’s findings were published last month in Cell Reports as a follow-up study to earlier findings about B cells published in the journal Nature last year.
Both B cells and T cells are constituents of the adaptive immune system and form the second line of defense against viruses, bacteria, cancer, and other toxic pathogens that slip past the innate immune response. The adaptive immune system remembers the invading pathogen after first encounter and forms the basis of effective vaccines. To advance our understanding, the researchers sequenced receptors from the transcriptome of billions of cells to assess the somatic recombination of different gene segments that comprise the circulating B and T cell receptors from healthy Caucasian individuals. They found that T cell receptors, like B cell receptors, exhibit significantly higher overlap in different individuals than expected by chance.
In addition, the unprecedented scale of this sequencing project revealed that the size and diversity of immune repertoire are at least an order of magnitude larger than the estimation made from previous studies. This work is part of a broader effort supported by the Human Vaccines Project to decipher the components of the immune system, with the ultimate goal of understanding how to generate life-long protective immunity.
“Our most recent study puts us one step closer to truly understanding the extreme and beneficial diversity in the immune system, and identifying features of immunity that are shared by most people,” said James E. Crowe, Jr., director of the Vanderbilt Vaccine Center of Vanderbilt University Medical Center. “Now we continue to identify T cell receptors and antibodies that can be targets for vaccines and treatments that work more universally across populations.”
A primary aspect of the team’s ongoing research is focused on integrating the findings of these two studies toward the development of an effective vaccine against emerging and evolving threats. Crowe explained, “We are getting closer to being able to use these large databases of human immune molecules to rapidly discover natural molecules that can be used as biological drugs.”
Madhusudan Gujral, a senior bioinformatician at SDSC; Robert Sinkovits, SDSC’s director of scientific computing applications; and Cinque Soto, a Vanderbilt computational biologist and lead author of the study, share Crowe’s enthusiasm over the implications of this research and recognize the importance of access to high-performance computing resources, such as Comet, to make it possible.
This work was supported by a grant from the Human Vaccines Project and institutional funding from Vanderbilt University Medical Center. The authors acknowledge support from TN-CFAR grant (P30 AI110527). This work also used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by NSF grant (ACI-1548562), and Comet supercomputer at SDSC, supported by NSF grant (ACI-1341698).
The San Diego Supercomputer Center (SDSC) is a leader and pioneer in high-performance and data-intensive computing, providing cyberinfrastructure resources, services, and expertise to the national research community, academia, and industry. Located on the UC San Diego campus, SDSC supports hundreds of multidisciplinary programs spanning a wide variety of domains, from astrophysics and earth sciences to disease research and drug discovery. In late 2020 SDSC will launch its newest National Science Foundation-funded supercomputer, Expanse. At over twice the performance of Comet, Expanse supports SDSC’s theme of ‘Computing without Boundaries’ with a data-centric architecture, public cloud integration, and state-of-the art GPUs for incorporating experimental facilities and edge computing.
About Vanderbilt Vaccine Center of Vanderbilt University Medical Center
The Vanderbilt Vaccine Center of Vanderbilt University Medical Center is committed to improving global health through fundamental research that fosters development and testing of new vaccines for infectious diseases. The Center’s international team of scientists and physicians focuses on work with major human pathogens, especially microbial threats that affect the most vulnerable subjects such as infants and the elderly.
With flu season fast approaching and COVID-19 continuing to spread, it’s a good time to review whether you’re up-to-date on vaccinations.
Dr. Shannon Becker, a family practice physician at UCHealth Primary Care in Craig, answers common questions about vaccines for adults below.
What is a vaccination?
A vaccination is a medication that helps train your immune system to fight off a certain disease. By introducing molecules from the disease, the vaccination causes an immune response that prepares your body to identify and fight off the disease in the future.
Vaccinations are usually given as shots, but some may be given through nasal sprays or oral medications.
“Vaccinations can either prevent disease completely, or in other cases, make a disease less severe for a person who has received the vaccination,” Becker said.
Are childhood immunizations enough?
No. Some vaccines, such as the vaccine for tetanus, require periodic updates. Others, such as the vaccine that helps prevent shingles, are only available for adults.
Which vaccines should adults consider getting?
Adults as old as 50 commonly receive the flu shot and the Tdap vaccination, which is for tetanus, diphtheria and pertussis or whooping cough. The HPV vaccine, which prevents against the human papillomavirus that can cause cervical cancer, has been approved for adults as old as 45.
In addition to the flu shot and Tdap, adults ages 50 to 64 may get the vaccination for shingles. And after age 65, a pneumonia vaccine is also typically recommended.
“Certain medical conditions may affect this schedule or qualify you for additional vaccines at a different age, so it is important to contact your physician regarding what is right for you,” Becker said.
For instance, someone who is immunocompromised, pregnant or has increased risk of a disease due to their occupation may qualify for vaccinations earlier. Becker recommends patients with diabetes have a pneumonia vaccine before age 65, and those with asthma are encouraged to have a flu shot instead of the flu nasal spray.
In most cases, flu shots are recommended in the fall. Other vaccines can be taken any time of year, based on age and past vaccinations.
What is a booster shot?
A booster shot is an extra dose of a vaccine given at a specific time after the initial dose. “It is designed to boost the immune system and is given when evidence shows that the effectiveness of a vaccine wanes over time,” Becker said. For example, the tetanus shot is often boosted every 10 years.
What common concerns do you hear about vaccines?
“One common concern is that the flu shot gives the person the flu,” Becker said. “The flu shot is a killed vaccine, so cannot give a person the flu. It can ramp up the immune system as it is supposed to, which can make a person feel a bit under the weather for a few days.”
And some adults worry that if they’re allergic to eggs, they can’t get a flu shot, as some forms of the flu shot contain small amounts of egg protein.
“However, this amount is small enough that it should not cause an allergic reaction, and it is recommended that those with egg allergy still get their flu shot,” Becker said.
“Bottom line, talk to your doctor,” Becker said. “They can help guide you regarding what immunizations are recommended for your age and medical condition risk factors.”
Whether flu or coronavirus, it can take several days for the body to ramp up an effective response to a viral infection. New research appearing in the journal Nature Immunology describes how different cells in the immune system work together, communicate, and – in the case of cells called neutrophils – bring about their own death to help fight off infections. The findings could have important implications for the development of vaccines and anti-viral therapies.
“The immune system consists of several different types of cells, all acting in coordination,” said Minsoo Kim, Ph.D., a professor of Microbiology and Immunology at the University of Rochester Medical Center (URMC) and senior author of the study. “These findings show that cells called neutrophils play an important altruistic role that benefits other immune cells by providing key resources for their survival and, in the process, enhancing the body’s immune response against a virus.”
Neutrophils are a key component of the innate immune system, the part of the body’s defenses that is always switched on and alert for bacterial and viral invaders. The vast majority of white cells circulating in blood are neutrophils and, as a result, these cells are the first on the scene to respond to an infection.
However, neutrophils are not fully equipped to eliminate a viral threat by themselves. Instead, when the respiratory tract is infected with a virus like influenza or COVID-19, a large number of neutrophils rush to the infection site and release chemical signals. This triggers the production of specialized T cells, which are part of the body’s adaptive immune system, which is activated to produce a more direct response to specific infections. Once mobilized in sufficient quantities, a process that typically takes several days, these T cells target and ultimately destroy the infected cells.
The new study, which was conducted in mice infected with the flu virus, shows that in addition to jump-starting the adaptive immune response, neutrophils have one more important mission that requires that they sacrifice themselves. As T cells arrive at the infection site, the neutrophils initiate a process called apoptosis, or controlled death, which releases large quantities of a molecule called epidermal growth factor (EGF). EGF provides T cells with the extra boost in energy necessary to finish the job.
“This study represents an important paradigm shift and shows that the adaptive immune system doesn’t generate a successful response without instruction and help from the innate immune system,” said Kim. “The findings reveal, for the first time, how different immune cells work together, and even sacrifice themselves, to accomplish the same goal of protecting the host from the viral infection.”
Kim and his colleagues point out that this new understanding of how the immune system functions opens the door to potential new methods to intervene and optimize the collaboration between different immune cells during viral infection. These efforts could ultimately lead to more effective vaccines and anti-viral therapies for respiratory infections like the flu and coronavirus.
Additional authors of the study included Kihong Lim, Tae-hyoun Kim, Alissa Trzeciak, Andrea Amitrano, Emma Reilly, Hen Prizant, Deborah Fowell, and David Topham with URMC. The research was funded with support from the National Institute of Allergy and Infectious Diseases.
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
Some vaccines have been developed to effectively prevent the spread of infectious diseases such as polio and measles by training the immune system to fight the pathogens. Other illnesses like influenza (common flu), malaria, and HIV-1 also have working vaccines but are not as effective. Researchers analyzed the effectivity of using injectable hydrogels to sustain the delivery of vaccines into the immune system.
Scientists from Stanford University School of Medicine published their paper in the journal ACS Central Science. Developing injectable hydrogels may be one solution to control the timing of antigen and adjuvant presentation to the immune system.
Adjuvants are added to a vaccine to boost the immune system in producing more antibodies. This results in longer-lasting immunity and requires a smaller dose of antigens.
Antigens are certain molecules from the pathogens of a particular infectious disease. The immune system recognizes the antigen from an intruding virus or bacteria, which triggers a response to produce antibodies so that the body will resist the disease.
Hydrogel Encapsulated Vaccine
When a person becomes exposed to the same infectious disease, later on, the immune system would recognize the pathogen and quickly trigger an immune response. During natural infection, the body contains antigens for about two or three weeks but are only exposed to antigens for one or two days from a vaccine.
To mimic a natural infection, Eric Appel and the team developed an injectable hydrogel that allowed a sustained release of the vaccine into the immune system. They had hoped that a vaccine working longer than two days would also boost the body’s immune response.
Vaccine components were mixed with a polymer-nanoparticle hydrogel, which encapsulated the antigen and adjuvant. When the combined material was injected into mice, it formed a region of inflammation in the lymph nodes that triggered specific immune cells called B cells and T cells, resulting in a slow release of the antigen and adjuvant for several days, unlike traditional vaccines.
Results from mice models showed that the hydrogels increased the vaccine’s quality, potency, and lengthened the immune responses. Their immune response had a 1000-fold increase of antigen-specific antibodies compared to the traditional model of the same vaccine.
The next step would be to test if the injectable hydrogels can enhance existing vaccines of specific diseases. Overall, the study “introduces a simple and effective vaccine delivery platform that increases the potency and durability of subunit vaccines.”
Similarly, another type of injectable hydrogel from an extracellular matrix was developed by Mayo Clinic researchers to enhance vascular healing from injuries in arteries and capillaries. Dr. Rahmi Oklu and the team created an innovative embolic agent that can “adapt to unique clinical scenarios presented by each patient and its ability to deliver effective treatment while minimizing any side effects.” The gel forms a solid cast to avoid recurrent bleeding and the failure of blood flow.