Our quest for an “ideal” COVID vaccine heads to the nose.
Right from the outset of the pandemic, Associate Professor Ashley St John from Duke-NUS’ Emerging Infectious Diseases Programme set her focus on finding ways to make vaccines better, a need she knew from previous pandemic experiences that would continue to challenge scientists.
Today, she and her team, together with collaborators from both of Duke-NUS’ parent universities, published the results of a head-to-head comparison of a novel COVID-19 vaccine that is either injected into the arm or sprayed into the nose in eBioMedicine.
Mucosal marvels
Unlike the injections many of us have accepted into our arms, St John’s vaccine candidate can also be given as a spray to target the mucosal tissues lining our nasal passages.
An intranasal vaccine holds exciting implications for “greater cross-protective function” and an immune response that is “more long-lived and retains a longer memory”, remarks St John.
“The idea is that when we’re challenged with a pathogen or a vaccine, our immune system tries to not only record what kind of pathogen it is, and how that pathogen looks, it also tries to record where it sensed it.
“You don’t expect SARS-CoV-2 to be injected in your skin by a mosquito. So, we need a different type of immune response that comes through our nasal passages.”
Switching tacks for changing needs
Working with collaborators from Duke University and the National University of Singapore among others, St John’s team were able to scrutinise the difference in immune reaction between the two administration routes of their vaccine candidate. They also tested the candidate with and without the use of adjuvants—substances added to vaccines to enhance the body’s immune response.
As expected, they found that only giving the vaccine through the nose activated the immune system in the mucosal lining. This protection is defined by a type of antibody called Immunoglobulin A, or IgA. Compared with the common Immunoglobulin G, or IgG, which circulate in the blood and are quick to be activated and deactivated, IgA are abundant in mucosal membranes like those in the nose and throat, and wane more slowly. And being present at the site of entry for the virus means a much faster call to action.
The merits of preserving memory
But it was not just the front-line antibody response that proved to provide stronger protection. The team also observed that T cells seemed to be ‘imprinted’ by the environment where they encountered the virus first. When the vaccine was given through the nose, this triggered the generation of T cells with a systemic response to threats, that were perhaps better suited for identifying pathogens at multiple sites in the body. Given the length of the airways and the diversity of tissue type along the way, these T cells were programmed to not merely protect where they were originally located, but to move out, travel along the bloodstream, and disperse information to diverse tissues along the way.
The main function of these cells, the scientists observed, was not to directly fight the virus but to remember the virus and release daughter cells that could stay behind and fight when the same virus infiltrated the body again.
To top it off, these long-lived memory T cells were produced in far greater numbers when the vaccine was administered through the nose.
St John explains: “It’s almost as if by giving a mucosal challenge, it’s giving this instruction that the nasal passages and lungs are going to need surveillance.” This long-lasting vigilance, built on the memory of the pathogen, is crucial to keeping the body protected beyond the initial challenge.
Skewing away from specialisation: the case for cross-protection
There are also other advantages in using a mucosal challenge.
“The other thing we observed was this neutralising antibody response, which was more cross-protective, and that, I think, is also a very important point. It’s not just that we’re getting better IgA, we’re also getting better IgG,” she notes.
Usually, if the immune system encounters a specific challenge repeatedly, it learns to be very efficient and fast acting in responding to that particular target. However, the broad antibody response elicited by St John’s mucosal vaccine candidate didn’t just effectively neutralise the form of the virus administered, it was also able to take out viruses that looked similar.
“If you keep some antibodies that are not quite as good at neutralising the original virus, you might have the ability to neutralise more viruses,” she says. “And we were able to preserve many of the antibodies that are outcompeted in lymph nodes [when the vaccine is given by injection] by targeting the mucosal tissue.”
The exciting implication, of course, is that a broader cross-protective response potentially protects against a wider spectrum of SARS-CoV-2 variants—variants such as JN.1, which continue to infect millions of people worldwide. In addition, as the memory of the mucosal challenge fades more slowly, fewer booster vaccinations may potentially be required for the same levels of protection.
At this point, we may have moved away from the acute phase of the pandemic, but continually emerging new variants and changing needs, such as a demand for fewer boosters, longer-lived protection or simply a needle-free vaccine alternative, present a need for improving currently available COVID-19 vaccines—and promising developments in vaccine candidates, such as this one, can only chart the way forward.