In just over a year after its emergence, scientists enabled the defeat of COVID-19 with mRNA vaccines from Pfizer/BioNTech and Moderna. The vaccines worked against the initial strains of COVID-19, and they are still critical in nearly eliminating hospitalizations for any strains of the illness.
But stopping deaths due to COVID-19 was just the first step, albeit an incredibly important one. Still, as evidenced by the various variants of concern, SARS-CoV-2 has not disappeared, nor may it ever.
Now, researchers from the University of Virginia (UVA) have shown that an intranasal vaccine boost can help mRNA vaccines keep people healthy in the face of new variants—something they haven’t quite been able to do.
“The omicron variant almost completely escaped neutralization by mucosal antibodies in individuals who received mRNA vaccines and in previously infected individuals,” said Jie Sun, the professor of medicine at UVA. “Our data showed that mRNA vaccination also did not induce sufficient tissue-residing cellular immunity in the airways, another arm of our immune system to prevent the entry of the virus into our bodies.”
In their study, the researchers analyzed SARS-CoV-2 antibody responses, as well as B and T cell immunity in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19 vaccinated individuals and hospitalized patients. In this cohort, the researchers say their data shows that COVID-19 vaccination did not provoke robust IgA responses in the respiratory tract. Only severe SARS-CoV-2 infection provoked RBD-specific IgA in the respiratory mucosa, as well as elevated IgM responses in the BAL and higher S-specific IgG levels in blood.
Additionally, the convalescent group showed about 3x higher neutralizing antibody activity than the vaccinated group. And, unlike SARS-CoV-2 natural infection, mRNA vaccination did not appear to induce significant B and T cell memory in the respiratory mucosa. Although memory T and B cells do not confer immunity, they are important in limiting viral dissemination and protecting against severe disease once a virus breaches immunity.
Given those results, the research team decided to focus on intranasal immunization as a possible immunity boost. They immunized mice with two doses of mRNA plus an intranasal of adenovirus type 5 encoding S protein (Ad5-S). Compared with mice that received two or three doses of mRNA vaccine, the Ad4-S mice showed:
- greatly increased BAL RBD-specific B cells,
- potent mucosal CD8+ and CD4+ T cell responses,
- significant increases of both S1 and RBD-specific IgA in the BAL,
- the highest RBD-specific IgA in the respiratory mucosa, and
- significantly higher levels of plasma IgA, IgM and BAL IgM than other groups.
According to the study, published in Science Immunology, the elevated immune response of the mRNA vaccine plus intranasal Ad5-S was seen in the ancestral virus, as well as the omicron variant.
Ultimately, the scientists says their study further validates the hypothesis that greater immunity to the coronavirus can be developed starting where the virus first takes root—the mucus membranes of the nose.
“We think the robust antibody responses in the respiratory tract would neutralize the virus immediately upon viral entry when the individual contracts the virus, preventing the establishment of viral infection and subsequent passing of the infection to others,” said Sun.
Labs are working on COVID-19 nasal vaccines but to date, none have been approved for use. McMaster University scientists have an “inhaled aerosol” version that targets the lungs and upper airways that is currently in a Phase I clinical trial. However, adenovirus-based nasal vaccines are different. In fact, none have been approved for use in humans yet, mostly due to concerns about harmful side effects. A previous study linked an influenza nasal vaccine specially formulated to create a stronger immune response with Bell’s palsy, a condition that causes muscle weakness in the face.
“For a nasal vaccine, we do need to be more careful about the safety profiles,” said Sun. “I think we need a step-up trial from a mouse to human study in the United States. A human trial has been performed in China already using nasal adenovirus spray, which suggests it is generally safe and can boost good immune responses, but mucosal immunity was not examined.”