How Intranasal COVID Vaccines Could Be 'Holy Grail' of Vaccination

Damian McNamara

July 23, 2021

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

Beyond the obvious advantage for the needle-phobic, the seven intranasal COVID-19 vaccines in development could offer two additional layers of protection against SARS-CoV-2 infection, experts say.

First, intranasal vaccines could produce antibodies and attract other components of the immune system to the nose and upper respiratory tract, forming a first line of defense against infection. Second, if infection does occur, a local response in the nose can be faster than a systemic one, giving SARS-CoV-2 less of a chance to replicate, shed, and be transmitted to others.

At least that's the idea.

Dr Troy Randall

"We'll see how they fare in clinical trials, but research suggests that these types of vaccines should trigger a specialized immune response in the nasal passages that can help stop SARS-CoV-2 at the site of infection and reduce transmission," Troy D. Randall, PhD, told Medscape Medical News.

Randall and co-author Frances Lund, PhD, analyzed the promise of intranasal COVID-19 vaccines in a perspective article published online July 22 in Science.

Applying the vaccine directly to the inside or mucosa of the nose could be an advantage, agreed Deborah H. Fuller, PhD. "Mucosal immunity, especially for respiratory diseases, is a relatively untapped gold mine for vaccines," she told Medscape Medical News when asked to comment.

Recent research from Fuller and colleagues, as well as others, suggests that immune responses on the mucosa can limit viral replication better than immune responses localized in the blood.

"And this makes sense. If you have immune cells localized at the initial site where the virus infects, it could shut down the virus before it gets a chance to replicate," added Fuller, professor of microbiology at the University of Washington School of Medicine and chief of the Division of Infectious Diseases and Translational Medicine at the Washington National Primate Research Center, Seattle, Washington.

Best of Both Worlds?

If one or more of the intranasal formulations of COVID-19 gain US Food and Drug Adminstration emergency use authorization or approval, the ideal strategy might be to combine intramuscular vaccination with an intranasal booster dose, the authors note.

This one-two vaccine punch could increase protection by targeting two immunoglobulin (Ig) immune responses.

"Intramuscular vaccination should elicit systemic or central immunity, which supplies a robust circulating antibody – IgG – response in the blood. Intranasal vaccination should elicit mucosal immunity in the nasal passages and will preferentially trigger an IgA antibody response, mostly in the nasal passages," said Randall, a professor in the Division of Clinical Immunology and Rheumatology in the Department of Medicine at the University of Alabama, in Birmingham, Alabama.

"Having both provides more coverage," he added.

A Potential Breakthrough on Breakthrough Infections?

Intranasal vaccines also could be advantageous in reducing breakthrough infections, Fuller said. "Lately, we're hearing about breakthrough SARS-CoV-2 infections in vaccinated individuals. This is expected, since the current vaccines are designed to protect from disease primarily."

There is a question as to whether people with breakthrough infections, even those without symptoms, could still transmit SARS-CoV-2 to unvaccinated people. "We don't know yet," Fuller said. "With mucosal immunization, the expectation is that the virus won't get a chance to get started."

Time could tell. Six of the intranasal formulations are in phase 1 trials. These vaccines are being developed by the University of Oxford, Altimmune, Bharat Biotech, the University of Hong Kong, Meissa Vaccines, and Codagenix. A seventh product, from the Center for Genetic Engineering and Biotechnology, in Havana, Cuba, is being evaluated in a phase 1/2 trial.

These formulations hold a lot of promise, Fuller said. "Mucosal immunity offers the best hope to achieve the holy grail of vaccination ― sterilizing immunity, or complete protection from infection."

A Team of "First Responders"

Antibodies get a lot of attention, but other components of the immune system play important roles in response to viral infections such as those caused by SARS-CoV-2. Also, long after antibody levels start to wane, "memory cells," such as those from CD8+ T cells, remain in circulation or on mucosal surfaces, where they can recognize pathogens and become reactivated to fight future infections.

Memory B and T cells in the lung and nasal passages also act as nonredundant first responders to challenge infection. They are essential for rapid virus clearance, the authors note.

For these memory cells to lie in wait in the respiratory tract requires direct interaction with a viral antigen. This means that "vaccines designed to recruit resident memory cells to the respiratory tract should be administered intranasally," the authors note.

Live Attenuated Virus Vaccines

Six of the intranasal vaccines in development are live attenuated virus or virus-vectored vaccines; the seventh is a protein subunit vaccine. Live attenuated virus vaccines offer advantages but, historically at least, are of major concern.

The authors explain that, unlike a vectored vaccine that targets a single component of a SARS-CoV-2 virus, such as the spike protein, "live attenuated SARS-CoV-2 has the advantage of expressing (and potentially eliciting immune responses against) all viral proteins, thereby conferring broad-spectrum immunity that should cross-react with and provide some level of immunity against variant strains of SARS-CoV-2."

In the term "live attenuated," the word "attenuated" means that scientists have altered the live virus so that it is unlikely to cause illness but will still trigger a robust immune response. The risk is that a live attenuated virus will develop a mutation that overcomes this safety feature. This process is known as "reversion."

"Although modern molecular techniques minimize the risk of reversion, live attenuated viruses retain replicative capacity and are contraindicated for infants less than 2 years, people aged more than 49 years or immune-compromised persons," the authors note.

When asked to quantify the risk, Randall said, "In my opinion, the risk is minimal for people in that age range with a normal immune system.

"However," he added, "people with immunodeficiency because of genetics or immune suppressive drugs to treat other diseases probably should not get live attenuated vaccines for SARS-CoV-2 or anything else."

"Caution will always be important with regard to the safety of live attenuated viruses," Fuller agreed.

These virus vaccines "are not plug-and-play technologies like the mRNA vaccines where you use the same backbone and simply swap out the sequence for the next variant or virus," she said.

Rather, development of each live attenuated virus is individualized and includes rigorous safety testing to ensure that it cannot revert to wild-type virus, Fuller said. This is one reason live attenuated virus vaccines take longer to develop than mRNA vaccines, she added.

An Important Caveat

Another potential catch with live attenuated virus vaccines ― neutralizing antibodies that can reduce vaccine effectiveness ― raises an important distinction between previous infection and previous immunization.

"People who may have prior exposure to SARS-CoV-2 infection will almost certainly have IgA antibodies in the nose that can neutralize a live attenuated SARS-CoV-2 vaccine. These antibodies may wane after a year or so," Randall said.

In contrast, people who have been exposed to SARS-CoV-2 vaccine through a shot in the arm will primarily have circulating IgG antibodies, he added.

Modest levels of circulating IgG will not show up in the nose and will not neutralize a subsequent vaccination with live attenuated SARS-CoV-2. However, high levels of circulating IgG will allow a little bit of IgG to get to the nose and may reduce the effectiveness of a live attenuated vaccine.

This concern is not unique to SARS-CoV-2 ― it also arises with regard to live attenuated vaccines for influenza, severe acute respiratory syndrome, respiratory syncytial virus infection, and diseases caused by other viruses. Developing an intranasal vaccine that cannot be neutralized by preexisting antibodies would be ideal, Randall added.

Future Promise

Fuller applauded the authors for appropriately outlining the potential hurdles for mucosal vaccines. For example, Randall and Lund address how the intranasal vaccines are designed to target the nose without going deep into the lungs.

"Given that vaccine delivery to the lower respiratory tract may directly cause inflammation or may exacerbate conditions such as asthma or chronic obstructive pulmonary disease (COPD), intranasal vaccines are typically administered to humans in a way that prevents antigen delivery to lungs," they write.

Fuller said that even with some limitations, "Ultimately, mucosal vaccines may offer the best strategy for combating future pandemics." An ideal pandemic vaccine is safe, is stable at room temperatures, can be self-administered, and works well in all demographics, she added.

"Mucosal vaccines offer the potential to meet most, if not all, of these features."

Randall and Lund are consultants and receive research funding from Atimmune Inc. Fuller has disclsoed no relevant financial relationships.

Science. Published online July 22, 2021. Full text

Damian McNamara is a staff journalist based in Miami. He covers a wide range of medical specialties, including infectious diseases, gastroenterology and neurology. Follow Damian on Twitter: @MedReporter.

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