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If we are blithely ignorant now of rates of COVID-19 infection, it’s largely thanks to vaccines, which kept most people free from serious illness. But the immune defenses we get from vaccines and from infection wane in time. Disease in circulation means the new variants and subvariants are likely, with no guarantee that they will be weaker or less transmissible than previous iterations.
The question for next winter and beyond is whether and how we’ll keep revaccinating the population. The White House convened scientists, doctors and researchers Tuesday to talk about next-generation vaccines. One option that has many excited are nasal spray vaccines, but there is also reason for caution.
Recent research by scientists at the University of Virginia and published in the journal Science Immunology indicates that people who have been infected with COVID-19 have a better immune response in their airways than those who have received messenger RNA vaccines. Jabs use a molecule synthesized in a lab to mimic an invader in order to help the body prepare its defenses. But the vaccines’ neutralizing antibody response in the nose/respiratory system is too weak. Scientists found that the omicron variant easily bypassed mucosal (nasal) antibodies in all but the unvaccinated patients who got seriously ill with COVID-19.
Serious illness is not how most of us want to get our defenses up. And nasal sprays are a cinch to administer. So what’s the problem? I spoke to Bloomberg Intelligence’s director of research Sam Fazeli on whether nasal sprays can help and where the gaps in our knowledge lie.
Therese Raphael: Existing vaccines are doing a very good job at protecting against serious illness. What can we get from nasal or oral vaccines that we’re not already getting?
Sam Fazeli: When vaccines are delivered intramuscularly, as all our current vaccines against COVID-19 are, they induce what is called a “humoral” response that is, represented by antibody production in the blood, as well as short- and long-lived immune B-cells and T-cells. But a SARS-CoV-2 infection takes hold in your respiratory tract by infecting cells which line your nose and lungs. So it would be better to have what is called “mucosal” immunity, made up of much the same types of responses: antibodies and B and T-cells.
With current vaccines, in the few weeks after a shot, there is so much antibody made in the blood that enough of it gets into the membranes of the nose and lungs so you get protected from infection. But as these levels inevitably fall, we find the risk of an initial infection starts to rise. A vaccine administered to the nose or lungs is expected to stimulate a mucosal immune reaction, with the potential to provide better protection for longer against that initial infection.
TR: How is it then, that those of us who have been infected by COVID-19 keep getting reinfections. If mucosal immunity is so good, surely it would protect us better.
SF: That is a very good question and one that hangs over the theory that intranasal or oral vaccines can provide better protection against a reinfection. However, let’s not forget that the situation is complicated by two issues. First, and most important, is the fact that the virus is changing and new variants escape prior immunity. So it may simply be that there is very good immune response in the mucosal surfaces, but that it’s just not able to prevent an infection by a variant that it does not recognize.
There is also another issue which is highlighted in a 2021 Nature Immunology paper: Fewer than 30% of people with moderate covid had high levels of antibodies in their nasopharynx, even though about 80% of these same people had achieved what we call sero-conversion, or high levels of antibodies in their blood. A similar pattern was seen in patients with severe or critical covid-19. So, based on this study, infection is not a guarantee for immune protection at the surface of the respiratory tracts.
TR: How often would we need those mucosal vaccines to limit “immune escape”? Do we want them in addition to mRNA vaccines or instead of them next winter?
SF: No one knows. It’s possible that a couple of boosters, perhaps containing some of the most troublesome variants, such as BA.4/5, may be enough to broaden the immune response enough so that future variants would have a tough time escaping from them. But, let’s be clear: We have very little data to support the notion that an intranasal vaccine will make a massive difference in terms of reducing transmission or reducing the risks of getting infected. Yes, you can theoretically get a much better immune response in the nose, but how long does this last? And will a vaccine be more effective than an infection, given what we discussed above?
TR: Which nasal spray vaccines are out there and what would convince both investors, and health authorities, that they are worth pursuing?
SF: The problem for investors are the uncertainties I already noted above, plus the fact that the only approved intranasal vaccine, Flumist (which is intended to fight common flu), has very little traction in the market. Some solid data is needed to convince people.
The other issue is that health authorities and governments seem to be on a mission to keep boosting people on a regular basis with a vaccine shot that was not designed for and is incapable of providing long-term protection against infection. This leaves investors wondering how anyone with an intranasal vaccine can get the data they need to prove they are better than the current shots.
TR: And yet new variants have been more highly transmissible and some countries, including the US, are still struggling to get people to get vaccinated and get boosters. That seems to boost the case for nasal vaccines. What kind of clinical trials should we be seeing and how long does that take? Should regulators be looking to accelerate this process?
SF: The biggest issue for developing these mucosal vaccines is this: You can’t use the relatively cheap “immuno-bridging” studies that Moderna and Pfizer-BioNTech are using for their infant shots and new variant-adapted booster shots. Basically, and by definition, the immune response induced by an intranasal or oral vaccine is not comparable to one induced by an intramuscular injection. So the only way to prove an intranasal shot works well is to do a head-to-head trial with a large enough number of people and during a wave of infections. And this is very expensive.
There is little regulators can do to speed up this basic need to prove the vaccines. The other issue is, of course, manufacturing. We have seen how tough this is for smaller companies by just looking at all the manufacturing problems that Novavax has had. Any company that wants to get an intranasal vaccine through to market has to deal with the major hurdle of producing large, consistent quantities of vaccine with a good shelf life.
Therese Raphael is a columnist for Bloomberg Opinion covering health care and British politics. Previously, she was editorial page editor of the Wall Street Journal Europe. This column does not necessarily reflect the opinion of the editorial board or Bloomberg LP and its owners.
Sam Fazeli is senior pharmaceuticals analyst for Bloomberg Intelligence and director of research for EMEA.
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