Researchers at Karolinska Institutet have shown that nasal drops with IgA antibodies can protect mice from infection with COVID-19. The findings imply a new way to protect high-risk people from different variants of the SARS-CoV-2 virus and possibly other infections.
The results of the study were published in PNAS.
Nasal spray with antibodies: a valid treatment against Covid19?
Different types of antibodies have different functions in the body. IgA antibodies are part of the so-called adaptive immune system and reside naturally in the mucous membranes of the airways. Absence or low levels of mucosal IgA are known to be associated with an increased risk of breakthrough Covid19 infections.
Current vaccines primarily stimulate an IgG antibody response in the body, and previous studies have shown that their ability to protect against infection with new omicron variants of the virus is limited.
To overcome this problem, the team led by Professor Qiang Pan-Hammarström from Karolinska Institutet used genetic engineering to create IgA antibodies that bind to the Covid19 spike protein in a similar way to IgG antibodies.
Mice infected with the omicron variant received IgA antibody treatment via nasal administration. The nasal drops significantly reduced the viral load in the trachea and lungs of infected mice. IgA antibodies were shown to bind stronger to the Covid19 spike protein and were more effective at neutralizing the virus than the original IgG antibodies.
“The results show that these genetically modified antibodies can strengthen protection against new viral variants, but are not intended to replace current vaccines,” says Harold Marcotte, associate professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, and the first author of the article.
“Traditional vaccines elicit an active immune response from the body, whereas this is a passive immunization strategy,” he continues. “An active immunization approach that induces a mucosal immune response would be ideal, but we hope that our approach is suitable to protect more vulnerable individuals, such as the elderly or immunocompromised people.”
There are also hopes that the method could be used to neutralize other current and emerging variants of the virus.
“We believe that this will be a very promising strategy, not only for Covid19 and new variants, but also for other infectious diseases, including influenza and other respiratory infections and gastric mucosal infections such as Helicobacter pylori, for which there is no vaccine. available at the moment,” says Qiang Pan-Hammarström, professor at the same department and last author of the article.
Elevated levels of mucosal antibodies in the airways reduce the risk of contracting omicron infection, but many people do not get detectable antibodies in the airways despite three doses of the Covid19 vaccine. These are the results of a study conducted by researchers from Karolinska Institutet and Danderyd Hospital in Sweden.
The COMMUNITY study enrolled 2,149 healthcare workers in spring 2020 at Danderyd Hospital, Sweden. Since then the study participants and their immune responses against Covid19 have been monitored every four months.
A substudy between January and February 2022 examined 338 triple-vaccinated healthcare workers for Covid19 infection. Antibody levels in the blood and airways were determined at the start of the screening period, and one in six (57 participants) was subsequently infected with omicron during the four-week screening period.
This allowed the research team to study immunity against omicron breakthrough infection as well as immune enhancement following breakthrough infection.
Levels of mucosal IgA (immunoglobulin A) antibodies were measured in the airways because they play an important role in protecting against respiratory infections.
All participants had elevated levels of systemic antibodies (for example, in the blood) after three doses of the vaccine, but only 62% had detectable mucosal airway antibodies (for example, in the nose). Elevated levels of mucosal airway antibodies more than halved the risk of contracting omicron infection.
“It is not surprising that antibodies in the respiratory tract neutralize the virus locally, but these results show, for the first time, that Covid19 mucosal antibodies in the airways actually protect against omicron infection,” says lead author Charlotte Thålin, MD and associate professor at the Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet.
High mucosal antibodies in the airways were also associated with lower viral replication among omicron-infected subjects. After omicron infection, a 40-fold increase in mucosal airway antibodies was found in most participants, even if the infection had been mild.
The researchers also showed that participants with Covid19 infection before vaccination had significantly higher levels of airway mucosal antibodies after vaccination compared to thrice-vaccinated subjects without prior SARS-CoV-2 infection. This could explain why so-called hybrid immunity, the combination of infection and vaccine, provides stronger protection against infection than vaccines alone.
“We now find ourselves in a situation where omicron infects people despite having received several doses of the current intramuscular vaccines,” says Charlotte Thålin. “It is tempting to think that a vaccine administered through the nose or mouth, where Covid19 enters the body, could provoke a local immune response preventing infection at an earlier stage.
Several vaccines in the form of a nasal spray are now available being studied in clinical trials with the hope of being able to reduce the spread of the infection and
therefore reduce the risk of developing new viral variants.”
The COMMUNITY study continues with regular blood and mucous sampling, monitoring immune responses after repeated Covid19 infections and vaccinations.
The study is conducted in close collaboration between Danderyd Hospital, Karolinska Institutet, Uppsala University, the Swedish Public Health Agency, KTH Royal Institute of Technology and SciLifeLab.
As public health experts cautiously anticipate how Covid19 will develop this fall, a University at Buffalo scientist reiterates that substantial immunity against the SARS-CoV-2 virus will only be possible with a vaccine that can be administered through the nose.
“The best protection against initial coronavirus infection, as well as its transmission, compared to the development of the Covid19 disease, will be achieved most effectively by intranasal vaccines,” said Michael Russell, Ph.D., professor emeritus of microbiology and immunology at UB's Jacobs School of Medicine and Biomedical Sciences.
The reason, he explained, is that the strongest immunity against Covid19 occurs following an infection that occurs in the upper respiratory tract and mouth and gives rise to mucosal immunity through the secretion of immunoglobulin A (IgA) . antibodies.
“This type of immunity is not induced to a large extent by existing injectable vaccines,” Russell said. But he said mucosal immunity is exactly the kind of immunity that would protect against initial infection, rather than protecting against severe disease after infection, the goal of current COVID vaccines.
“It all stems from a widespread lack of understanding of how the mucosal immune system works,” Russell said, “despite the fact that this has been known for at least 40 years but is poorly covered in most medical curricula.”
The expert said that evidence is accumulating showing that mucosal IgA antibodies have a significant impact on the acquisition of Covid19, the subsequent course of the disease and further transmission of the virus.
Vaccines administered through the nose would not only induce mucosal immunity and thus prevent individuals from becoming infected, but could also suppress community spread, which results from the circulation of aerosol particles and droplets generated from these respiratory secretions and superior oral.
“Our main point, therefore, is that protection against initial infection (rather than protection against the development of Covid19) and subsequent transmission of the virus will be achieved more effectively by intranasal vaccines,” Russell said. “In other words, the much-discussed and elusive outcome of herd immunity, which is not effectively generated by existing injected vaccines, will be more likely to be achieved with mucosal immunity induced by intranasal vaccines.”
The article also argues that despite the fact that antibody responses to Covid19 have been almost entirely concentrated in serum, it turns out that the level of antibodies circulating in the blood does not reflect the level of antibodies in mucosal secretions.
Meanwhile, mucosal IgA antibodies against SARS-CoV-2 antigens have been detected in saliva, nasal fluids, tears, tracheobronchial secretions, and even breast milk of infected individuals.
The authors admitted that although numerous studies have been initiated in animal models to develop intranasal vaccines against SARS-CoV-2, many have not continued beyond the preclinical phase.
In part, they explained, this may be due to an inadequate understanding of the differences between the human and animal mucosal immune systems. “Mucosal IgA antibodies present in secretions are much more effective at viral neutralization than circulating IgG antibodies, which are found in serum,” Russell said.
The authors noted that the success of flu vaccines administered through the nose indicates that this is a feasible delivery method for a vaccine. A recent article in Nature reports that around 100 intranasal Covid19 vaccines are in development around the world, two of which were approved last week in China and India. However, details of the trials supporting these approvals have not yet been released.
Russell concluded that “if even a fraction of the time, effort and resources that went into developing the first generation of COVID-19 vaccines were applied to intranasal vaccines, the world could benefit from an intranasal COVID-19 vaccine. widely available right now.”
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