As SARS-CoV-2 spreads, it changes. This helped it get past our firewalls, the immunity created by vaccines or left behind after we recover from an infection. This is why, already in the third year of the pandemic, we are in the midst of another wave of Covid-19 caused by the most immunogenic variant yet, BA.5. And more variations are coming. Even as vaccine makers scramble to update first-generation vaccines in hopes of improving our protection for the fall, other scientists are taking a different approach, making vaccines delivered through nasal sprays or tablets that will develop more immune defenders on the front end. body lines: the lining of the mouth, nose and throat.
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A student administers the FluMist vaccine, which stimulates mucosal immunity. Jeff Gritchen/Digital First Media/Orange County Register/Getty Images “The hope is to boost the defenses right there in the nose so that the virus can’t even reproduce in the nose,” said Dr. Ellen Foxman, an immunobiologist at Yale School of Medicine. “And then someone who has a really effective mucosal vaccination can’t even really support the replication of the virus or create viruses that can infect other people. “That would be like the holy grail,” said Foxman, who helped plan the International Congress on Mucosal Immunology this week in Seattle, which is sponsored by pharmaceutical companies Pfizer, Janssen and Merck. If it works, there is hope that mucosal immunity could slow the development of new variants of the coronavirus and eventually bring the Covid-19 pandemic under control.
But there is a long way to go before that happens, and many scientists say the approach needs an injection of funding to accelerate the pace of development, in the same way that the billions of dollars provided by Operation Warp Speed provided the first generation of vaccines. Covid-19 in record time.
An old approach meets new technology
The idea behind mucosal grafting — the lining of the “tube” (as immunologists refer to the mucosa) that runs from our nose and mouth to our lungs and intestines — is not new. There are nine existing vaccines that work this way, including mouth drops that protect against polio, cholera, salmonella and rotavirus, and a nasal spray, FluMist, that immunizes against the flu. Most are based on older types of vaccine technologies, using killed or weakened versions of a virus or bacteria to teach the body how to recognize and fight it when a real infection starts. Because of these real pathogens, some people cannot use these types of vaccines. It is dangerous to expose certain groups — including pregnant women and those with weakened immune systems — to even weakened viruses. None have succeeded in preventing the transmission of an infection, but that may be because they haven’t made the same kind of investment as injectable vaccines, says Ed Lavelle, an immunologist at Trinity College Dublin. “What hasn’t really happened with mucosal vaccines is a huge advance in technology that happened with injectable vaccines, even before Covid,” Lavelle said. However, that may be about to change.
Can nasal spray vaccines put the brakes on new variants?
More than a dozen nasal spray vaccines against Covid-19 are being tested around the world. Many are using new kinds of technologies, such as providing instructions for the production of the coronavirus spike protein through harmless Trojan horse viruses. Others aim to develop the mRNA technology that has been so successful in injectable vaccines in nasal spray form. One company, Vaxart, even made a pill that provides instructions for making parts of the new coronavirus in the gut, which then builds immunity in the “tube.” In animal tests, hamsters vaccinated in the nose or mouth were less likely to transmit a SARS-CoV-2 infection to uninfected animals housed in separate cages but sharing the same air. “What we found is that if you gave an oral vaccine, you blocked the ability of this discovery to infect other animals,” said Sean Tucker, chief scientific officer for Vaxart. The Vaxart tablet, which is about the size and shape of an aspirin, uses an adenovirus — the same delivery system used by the Johnson & Johnson and AstraZeneca Covid vaccines — to carry instructions for making parts of the SARS- CoV-2 protein in gut cells, which stimulates the release of antibodies in the nose and mouth. In an early trial involving 35 participants, 46% had a rise in antibodies in their noses after receiving the tablet vaccine. Those who did appeared to build up a wide range of immunity to different types of coronaviruses and appeared to maintain that protection for about a year. This may be slightly greater than injectable vaccines, although more research is needed to confirm these results. Tucker is presenting these first results Monday at the Seattle conference. He says they will also be published as a preprint study in the coming days. A phase 2 trial of a tablet with a slightly different formulation, involving nearly 900 participants, is also underway, Tucker says. It is scheduled to be completed next summer. Most of the mucosal vaccines in development are designed to be given as a nasal spray or mist, and many are intended to be used as boosters in people who have had a full initial course of Covid-19 vaccines. “I don’t think of them as nasal vaccines. I think of them as nasal boosters,” said Jennifer Gommerman, an immunologist at the University of Toronto who specializes in tissue-specific immunity. That’s important, Gommerman says, because nasal vaccines — like FluMist — haven’t really worked that well. The next generation of vaccines will be something different, he says. They will build up the immunity to the whole body created by the shots. They’ll just reposition it in the nose and throat where it’s needed most, he says.
“But here, we’re actually talking about something else, where we’re talking about building the systemic immunity that was induced by a vaccine to three shots of mRNA and then training that systemic immunity to go to the upper respiratory tract. push through the nose,” says Gommerman. Such an approach was recently tested by Akiko Iwasaki, an immunobiologist at Yale University. According to their study preprint, Iwasaki and her team vaccinated mice with a low dose of Pfizer’s Comirnaty mRNA vaccine and followed up two weeks later with a boost of the mRNA vaccine delivered via nasal spray. The low dose of the injected vaccine was intended to simulate the weakening of immunity. Other groups of mice received only one injection or only one dose of vaccine in the nose. Only the group that got the injection followed by the nasal spray developed strong immunity against the Covid-19 virus. “This approach that we have shown in the mouse model is 100% protective against a lethal dose of SARS-CoV-2 infection and dramatically reduces the viral load in the nose and lungs,” Iwasaki said.
Going for IgA antibodies
Mucosal vaccines also target a slightly different part of the immune system than vaccines. The injections cause the body to produce antibodies against the virus that causes Covid-19. Most of them are Y-shaped proteins called IgG antibodies that are programmed to recognize and block specific parts of the SARS-CoV-2 virus along its spikes, the parts of the virus that stick to and infect our cells. A much smaller portion of these are IgA antibodies, and they look like two Ys that come together at the tail and turn sideways, so it looks more like a dog bone, Gommerman says. Like bounces on a bar, IgA antibodies are the primary immune molecules reserved for the mucosa. These molecules are more potent than IgG antibodies. They have four arms instead of two and are special because they are less selective about what they grab than IgG antibodies. “They can be a little more coy about how they recognize different variants. And that’s obviously a plus,” Gommerman said. The shots raise IgA antibodies in the nose for a short time, but the hope is that mucosal vaccines will…
