The strategy for rolling out a Covid-19 vaccine might be undermined by older people’s immune systems.
In a hypothetical alternative universe where we already have a vaccine against Covid-19, world leaders will have a choice about how to deliver it to the population. The most vulnerable people, along with the nurses, doctors and care workers who look after them, are likely to be protected first.
If only it were that straightforward. The most vulnerable age group, the elderly, are particularly tricky to vaccinate.
“We have very few vaccines designed for older populations,” says Shayan Sharif, a professor of vaccinology at the University of Guelph, Canada. “More often than not in the last century, most vaccines have targeted childhood diseases.”
Shingles is one exception, usually given to patients in their 70s, and there are one or two other vaccines for diseases like meningitis or human papillomavirus developed for young adults. But otherwise immunology is skewed in favour of children.
“We have a tremendous amount of knowledge about childhood diseases,” says Sharif. “When it comes to young adults, middle age and old age, we don’t have a lot of experience.”
To understand why older people are harder to vaccinate, we have to look at the differences in their immune system. Many infectious diseases are more severe in older adults than younger adults. Older people have more risk factors – a lifetime of exposure to carcinogens or other infectious diseases will increase the risk of future disease from new infections. But they also undergo something called immunosenescence – ageing of the immune system.
Just like many other parts of the body, our immune system shows signs of our ageing. Some of the immune cells lose their function. The immune system is a very complex network of cell types that interact with each other. If something, somewhere within the system is not working, it interrupts the delicate balance of the immune response.
How does the aging immune system work?
When you are infected by a pathogen, the first layer of the immune system, the innate immune response, starts attacking the pathogen at the site of infection. For respiratory diseases, that could be the lungs, trachea or nose. White blood cells, or macrophages, attack the pathogen, swallowing it up before destroying it.
As those macrophages break apart the pathogen inside themselves, they present bits and pieces of it to another type of immune cell known as T cells. These serve as the “memory” of the immune system. T cells cannot see the pathogen by themselves and need certain macrophages, called antigen presenting cells, to show them the pathogen. That activates the next layer, the adaptive immune system.
There are several types of T cells. Killer T cells, or cytotoxins, attack our own bodies’ cells in order to eliminate those already infected by the pathogen, reducing its proliferation. Helper T cells provide assistance to B cells, another part of the adaptive immune system.
B cells can see the pathogen on their own but for optimum function they need helper T cells. B cells produce antibodies. But to produce the most effective antibodies, they need this complex interaction with T cells.
The goal of a vaccination is to stimulate our immune systems to produce effective antibodies before we are exposed to the pathogen. Much has been made in the news of antibody tests as a way of proving who has had Covid-19. However, not all antibodies work, not everyone who has been infected with Sars-Cov-2 – the virus that causes Covid-19 – has antibodies and some antibodies have a limited lifespan.
The issue for vaccinologists is that the delicate balance between all of these cells in elderly people becomes disrupted. So, what happens in an older person’s immune system?
“Basically all of those cell types are impaired in their function,” says Birgit Weinberger, from the University of Innsbruck, who studies immunosenescence and vaccinations of the elderly. “They produce a different set of cytokines [proteins that aid communication between immune cells]. I think the important issue one has to keep in mind is that none of those cell types act on their own.”
You have to keep in mind how all those different parts of the immune system come together in concert – Birgit Weinberger
If antigen presentation by the macrophages is impaired in old age this could lead to a decrease in T cell activation, less help for the B cells and a lower antibody response. But it might be because of issues with the very first innate response.
“You have to keep in mind how all those different parts of the immune system come together in concert,” says Weinberger.
We also have a finite number of B cells and T cells in our adaptive immune system, says Sharif, and we lose some of them over time. That can create problems in later life. “When we encounter a new pathogen our ability to respond becomes a lot more limited.”
Immunosenescence does not affect all people equally. As with other body parts, some people age better than others either by looking after themselves or being lucky enough to have the right genetic make-up. But it’s not all bad news. Some parts of our immune system improve with age, too.
“There are some cells in our immune system that become more vigorous as we age,” says Sharif. “If we have been exposed to a wide variety of pathogens, we have an immune memory to them so we don’t need to have an armoury of cells to respond to novel antigens.” But Sars-CoV-2 is one virus we have never been exposed to, so we do not have that memory.
This is the balance struck by our immune system: older people have a better immune memory for things they have already been exposed to, but have a more limited repertoire to respond to novel diseases. Ordinarily, this might be fine. But as humans come into contact with more pathogens that jump species (what’s called zoonotic disease) more frequently, our ability to handle novel disease might be more important.
What does this mean for vaccines?
When vaccines undergo in-human clinical trials, at stage one they are tested for safety (usually on only a few individuals), at stage two they are tested for efficacy (whether they produce the response that you intended) and stage three for effectiveness (if they do produce the right response, do they actually work at protecting against disease).
Vaccines have to compromise. While they might work well on one group of people, they might work less well on others. Currently there are a multitude of clinical trials for Covid-19 vaccines, many of which might make it all the way through development to approval. For Weinberger and Sharif, this is a good thing. Having a suite of vaccines that you can rely on means we can pick and choose the right one for the right scenario. One might work better for old people than others.
While all vaccines approved will need to show t they protect against disease, not all vaccines will prevent transmission.
No vaccine is going to be perfect. “There is not one vaccine that can provide 100% efficacy, not one, nada,” says Sharif.
While all vaccines approved will need to show they protect against disease, not all vaccines will prevent transmission. Most vaccines work by preventing the pathogen from causing disease, but they do not necessarily eliminate it from the body, meaning a vaccinated person might still shed viral particles, and so potentially infect others around them.
This has an important implication for how we choose to vaccinate the population. For those having to decide who gets the vaccines, the emphasis should be on the vulnerable. But if we vaccinate nurses, doctors and care workers without first vaccinating their patients, while those key workers might be protected, they might still pass on the pathogen to other vulnerable people.
“A vaccine could disrupt transmission, but it is unlikely we will find a vaccine that will completely stop transmission of the virus,” says Sharif. “Influenza vaccines are actually a good example: they do not do much to reduce transmission, but they reduce disease.”
Weinberger says that a strategy for vaccination is like a complex puzzle of social, medical, political and economic factors. But what should be clear is that while mortality is so much higher in some groups, they should be prioritised. Others need to get used to living with the virus.
How age affects the spread of the virus is still largely a mystery. Weinberger raises concerns about some of the early research that suggested children were less contagious. Those studies, she says, were not optimal for coming to that conclusion, because they were conducted when children in Europe were off school. Might those children now pick up the virus at school and spread it to grandparents when they come to collect them?
Sometimes we put on our blindfold and we say vaccines are the only saviour but that is not the case – Shayan Sharif
Better understanding the spread of the virus will reveal the best strategies for vaccinating the population. “We are doing a very good job to speed up the process [of developing a vaccine], but for some decisions we need the knowledge first,” says Weinberger.
Since we first started treating people for Covid-19, the medical knowledge about therapy drugs has significantly moved forward even if it has rarely been covered in the news – something Sharif finds puzzling. Fewer people may be aware of the progress with immunotherapeutics could be because they are a bit less glamorous, he says. We can all picture a vaccine, we should all be able to remember having one. But if you were asked to picture an immunotherapy, could you summon an image?
“Sometimes we put on our blindfold and we say vaccines are the only saviour, but that is not the case,” says Sharif. “Vaccines can take 14 to 28 days and require multiple injections and exposures. Immunotherapeutics can work in minutes and hours.”
"The most immediate hope for older people suffering with Covid-19 might be when we find a drug that reduces hospital time from weeks to days, says Sharif, or even one that negates the need for intensive care at all.
Hundreds of drugs are currently being researched as potential treatments for Covid-19. At the moment, one of the most promising drugs is Dexamethasone, a steroid proven to reduce the mortality rate of patients receiving oxygen which has been approved for use in the UK and Japan and was given to President Trump when he was hospitalised with the disease earlier this month.
At the moment, there are five drugs authorised for "emergency use", including Dexamethasone, in the US by the FDA. Of these, none have yet received FDA approval following a clinical trial so are used only in very specific cases. But the benefit of searching for a treatment among known drugs is that they have already received approval, and are proven to be safe in other contexts. Their approval following a successful clinical trial should therefore be relatively speedy – much quicker than the amount of approval a new vaccine requires.
Older people hospitalised with Covid-19 might benefit from this treatment research before seeing a vaccine. So, while vaccines might be a little way off, there are other reasons to be positive."Source:BBC FUTURE