In a hypothetical alternative universe where we already have a vaccine against covid-19, world leaders will have options on how to distribute it to the population.
The most vulnerable people, along with nurses, doctors and other health professionals who care for them, are likely to be protected first.
It would be nice if it were that simple. The most vulnerable age group, the elderly, is particularly difficult to vaccinate.
“We have very few vaccines designed for older populations,” says Shayan Sharif, professor of vaccinology at the University of Guelph, Canada. “More than ever, in the past century, most vaccines targeted childhood illnesses.”
Herpes zoster is an exception, with a vaccine usually administered 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 other than that, immunology is aimed at children.
“We have a great deal of knowledge about childhood illnesses,” says Sharif. “When it comes to young, middle-aged and elderly adults, we don’t have much experience.”
To understand why the elderly are more difficult to vaccinate, we have to examine the differences in their immune system. Many infectious diseases are more serious in older adults than in younger adults.
Older people have more risk factors – a lifetime of exposure to carcinogens or other infectious diseases will increase the risk of future illness from new infections. But they also experience something called immunosenescence – the aging of the immune system.
Like many other parts of the body, our immune system shows signs of aging. 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 in the system, is not working, it disrupts the delicate balance of the immune response.
How does aging the immune system work?
When you are infected with a pathogen, the first layer of the immune system, the innate immune response, begins to attack the pathogen at the site of the infection. For respiratory diseases, it can be the lungs, the trachea or the nose. White blood cells, or macrophages, attack the pathogen, swallowing it before destroying it.
As these macrophages separate the pathogen within themselves, they present bits and pieces of it to another type of immune cell known as T cells.
They serve as the “memory” of the immune system. T cells cannot see the pathogen on their own and need certain macrophages, called antigen-presenting cells, to show the pathogen. This activates the next layer, the adaptive immune system.
There are several types of T cells. Killer T cells, or cytotoxins, attack cells in our own bodies to eliminate those already infected by the pathogen, reducing their proliferation. Helper T cells provide assistance to B cells, another part of the adaptive immune system.
B cells can identify the pathogen on their own, but for optimal functioning, they need auxiliary T cells. B cells produce antibodies. But to produce the most effective antibodies, they need this complex interaction with T cells.
The purpose of vaccination is to stimulate our immune system to produce effective antibodies before we are exposed to the pathogen. Much has been said in the news about antibody testing as a way to prove 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 life span.
The problem for vaccinologists is that the delicate balance between all these cells in the elderly is disrupted. So, what happens in an elderly person’s immune system?
“Basically, all of these cell types have impaired function,” says Birgit Weinberger, of the University of Innsbruck, who studies immunosenescence and vaccination in the elderly. “They produce a different set of cytokines (proteins that help communication between immune cells). I think the important thing to keep in mind is that none of these cell types act on their own.”
If the presentation of the antigen by macrophages is impaired in old age, this can lead to a decrease in T cell activation, less help for B cells and a lower antibody response. But it may be because of problems with the first innate response.
“You have to keep in mind how all these different parts of the immune system come together,” says Weinberger.
We also have a finite number of B cells and T cells in our adaptive immune system, says Sharif, and we have lost some of them over time. This can create problems when we are older. “When we find a new pathogen, our ability to respond becomes much more limited.”
Immunosensence does not affect everyone equally. As with other parts of the body, some people age better than others taking care of themselves or being lucky enough to have the right genetic makeup.
But it’s not all bad news. Some parts of our immune system also improve with age.
“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 for them, so we don’t need an arsenal of cells to respond to new antigens.”
But Sars-CoV-2 is a virus that we’ve never been exposed to, so we don’t have that memory.
This is the balance achieved by our immune system: older people have a better immune memory for the things they have already been exposed to, but they have a more limited repertoire to respond to new diseases.
This can usually be good. But as humans come into contact with more pathogens that skip species (what’s called a zoonotic disease) more often, our ability to deal with new diseases may be more important.
What does this mean for vaccines?
When vaccines are subjected to clinical trials in humans, in stage one they are tested for safety (usually in just a few individuals), in stage two they are tested for effectiveness (if they produce the response you intended) and in stage three for effectiveness (if they produce the right answer, if they really work to protect against disease).
Vaccines have variations. While they may work well for one group of people, they may work less well for others. Currently, there are a plethora of clinical trials for covid-19 vaccines, many of which can range from development to approval.
For Weinberger and Sharif, this is a good thing. Having a vaccine package you can trust means that we can choose the most suitable one for the right scenario. One may work better for the elderly than others.
No vaccine will be perfect. “There is no vaccine that can provide 100% effectiveness,” says Sharif.
While all approved vaccines need to show that 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, which means that a vaccinated person can still release viral particles and thus potentially infect others around them.
This has an important implication on how we choose to vaccinate the population. For those who have to decide who gets the vaccines, the emphasis should be on the vulnerable.
But if we vaccinate nurses, doctors and healthcare professionals without first vaccinating their patients, although these key professionals can be protected, they can still transmit the pathogen to other vulnerable people.
“A vaccine can slow transmission, but we are unlikely to find a vaccine that will completely stop transmission of the virus,” says Sharif. “Flu vaccines are, in fact, a good example: they don’t do much to reduce transmission, but they alleviate the disease.”
Weinberger says that a vaccination strategy is like a complex puzzle of social, medical, political and economic factors. But what should be made clear is that, although mortality is much higher in some groups, they must be prioritized. Others need to get used to living with the virus.
How age affects the spread of the virus is still a big mystery. Weinberger raises concerns about some of the early research that suggested that children were less contagious.
These studies, she says, were not ideal for reaching that conclusion, because they were carried out when children in Europe were out of school. Can these children catch the virus at school and pass it on to their grandparents when they come to pick them up?
A better understanding of the spread of the virus will reveal the best vaccination strategies for the population. “We are doing a very good job of accelerating the process (of developing a vaccine), but to make some decisions we need knowledge first,” says Weinberger.
Since we started treating people with covid-19, medical knowledge about therapeutic drugs has advanced significantly, even though it has rarely been covered in the news – something Sharif finds intriguing.
Few people can be aware of progress with immunotherapeutics because they are a little less glamorous, he says. We can all imagine a vaccine, we should all be able to remember when we got one. But if asked to imagine immunotherapy, could you invoke an image?
“Sometimes we put on a sale and say that vaccines are the only salvation, but that is not the case,” says Sharif. “Vaccines can take 14 to 28 days and require multiple injections and exposures. Immunotherapy can work in minutes and hours.”
“The most immediate hope for the elderly who suffer from covid-19 may be when we find a drug that reduces hospital stay from weeks to days,” says Sharif. Or even one that does away with the need for intensive treatment.
Hundreds of drugs are being researched as potential treatments for covid-19. At the moment, one of the most promising drugs is dexamethasone, a steroid capable of reducing the death rate of patients receiving oxygen that has been approved for use in the UK and Japan and was given to U.S. President Donald Trump when he was hospitalized with the disease.
There are currently five drugs authorized for “emergency use”, including dexamethasone, in the USA by the FDA, the American equivalent of Anvisa.
Of these, none have yet received FDA approval after a clinical trial, so they are used only in very specific cases.
But the benefit of seeking treatment among known drugs is that they have already received approval and are proven to be safe in other contexts. Its approval after a successful clinical trial must therefore be relatively quick – much faster than the amount of approval that a new vaccine requires.
Seniors hospitalized with covid-19 can benefit from this treatment research before seeing a vaccine. So, although vaccines may be a bit far, there are other reasons to be optimistic.
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