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Currently available COVID-19 vaccines are highly effective at reducing symptom severity, but they don’t appear to prevent SARS-CoV-2 from gaining a toehold in the nose. Ensconced there, the virus can stealthily replicate and then, expelled by coughing or sneezing, go on to infect others.
The vaccines, all administered as intramuscular injections, induce circulating antibodies in the blood but not mucosal antibodies in the lining of the nose.
“It’s actually very hard to protect the upper respiratory tract with these [injected] systemic vaccines,” Vincent Munster, PhD, chief of the Virus Ecology Section of the National Institute of Allergy and Infectious Diseases (NIAID) Rocky Mountain Laboratories, said in an interview.
But what if a COVID-19 vaccine could be sprayed or squirted into the nose? Could such a vaccine induce an immune response in the nasal mucosa, thus stopping SARS-CoV-2 from hitching a ride and spreading?
That’s the goal of Munster and other scientists in a handful of countries who’ve been investigating intranasal COVID-19 vaccine candidates. Tests in animal models have looked promising, and phase 1 clinical trials in healthy, COVID-19 vaccine–naive individuals are underway.
“We think intranasal vaccines are important because they have the potential to block transmission,” unlike the available injected vaccines, said Martin Moore, PhD, the CEO and cofounder of Meissa Vaccines in Redwood City, California, which has launched a phase 1 trial of its intranasal vaccine.
Studies suggest that individuals who receive injected COVID-19 vaccines may be protected against serious illness from SARS-CoV-2 but can still become infected and spread the virus.
For example, research by Munster and coauthors found that the intramuscular Oxford/AstraZeneca vaccine, which isn’t authorized in the US, protected rhesus monkeys exposed to SARS-CoV-2 against pneumonia but didn’t reduce viral shedding from their upper respiratory tract. And in the 469 cases identified in this past July’s COVID-19 outbreak in Provincetown, Massachusetts, diagnostic testing found that viral loads were similar in vaccinated and unvaccinated individuals’ noses. That finding helped spur the US Centers for Disease Control and Prevention (CDC) to reverse a May guidance that stated fully vaccinated people could remove their mask in most indoor settings.
Besides blocking transmission, intranasal vaccines’ potential advantages over injected vaccines include ease of administration, perhaps even self-administration.
“There’s a lot of interest in using an intranasal vaccine in an international setting,” Paul Spearman, MD, director of infectious diseases at Cincinnati Children’s Hospital Medical Center, said in an interview. “The administration is incredibly simple. You just have to squirt it in the nose. That doesn’t require years of training.” Plus, noted Spearman, who is principal investigator for a phase 1 trial of such a vaccine, intranasal delivery would likely be a welcome option for people who have needle phobia.
Beyond the Nose
One question about intranasal COVID-19 vaccines has been whether they could induce as strong a systemic immune response as vaccines injected intramuscularly.
Both intranasal mucosal and systemic immunity are important, Munster noted. That’s because aerosol exposure deposits SARS-CoV-2 in both the upper and lower respiratory tract, so infection can originate in the lungs, Munster explained, citing a recent virus transmission study he coauthored.
Another recent study led by Munster suggested that an intranasal vaccine could effectively induce both types of immunity. He and his coauthors compared intranasal with intramuscular delivery of the Oxford/AstraZeneca vaccine. They found that both the intranasal and injected vaccines produced high systemic antibody levels in hamsters, and the nasal spray even elicited higher levels than the injection. The scientists exposed the vaccinated and unvaccinated hamsters to SARS-CoV-2; both routes of administration protected the animals from serious disease compared with no vaccination.
“We were hoping that at least it [intranasal vaccine] would stack up [against the injected vaccine], but it actually looks really good in inducing that strong systemic response,” Munster said.
In addition, the researchers found less infectious virus in nasal swabs obtained from hamsters that had received the intranasal vaccine compared with hamsters that had not.
Munster’s team also gave 2 doses of the intranasal vaccine to 4 rhesus monkeys, eliciting antibody levels similar to those seen in people who’d recovered from COVID-19. After exposure to SARS-CoV-2, the 4 vaccinated monkeys had less virus in their nose and lung tissue than 4 unvaccinated monkeys; none of the vaccinated monkeys developed pneumonia symptoms, while 3 unvaccinated monkeys did.
Too few animals were vaccinated to establish clear correlations, but the findings warrant further investigation of intranasal vaccine delivery, Munster and his coauthors concluded. University of Oxford researchers are now conducting an open-label trial of the Oxford/AstraZeneca intranasal vaccine in healthy human volunteers.
While the Oxford/AstraZeneca COVID-19 vaccine uses a novel chimp adenovirus–based vector, an investigational intranasal vaccine developed by CyanVac LLC, with offices in Athens, Georgia, and Los Gatos, California, uses a parainfluenza virus 5 (PIV5) vector, which is also known as canine parainfluenza virus.
The company’s website notes that PIV5 has been used for more than 40 years as part of a canine distemper, or kennel cough, vaccine. Many veterinarians and dog owners have antibodies against PIV5, according to CyanVac. The humans likely were exposed when dogs sneezed after receiving an intranasal distemper vaccine and continued to shed the virus for a few days.
And yet, PIV5 has never been known to cause disease in people or, for that matter, dogs, said Spearman, a principal investigator for a phase 1 trial of the CyanVac COVID-19 vaccine. “We’re not putting anything in the protocol about staying away from your dog.”
The open-label trial aims to enroll at 3 sites a total of 80 healthy adults who have not yet received a COVID-19 vaccine. One concern with intranasal vaccines is that they could trigger respiratory illnesses, Spearman said, so the trial excludes people with lung disease, asthma, and other respiratory tract conditions.
The study has 4 groups: both high dose and low dose in one group aged 18 to 55 years and in another group aged 56 to 75 years. “We know that it’s not easy now to do a trial in vaccine-naive individuals,” Spearman noted. “We’re still able to enroll those trials with some extra effort.” Some individuals with needle phobia have expressed an interest in participating but changed their mind after learning that trial participants must have blood drawn, he said.
Spearman’s laboratory is also working on a universal coronavirus vaccine based on virus-like particles (VLPs), which bear virus antigens from multiple variants of concern on their surface but contain no infectious material. “It’s not nearly as far along” as the CyanVac vaccine, and it would have to be injected, said Spearman, who is also a member of the US Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee.
In the future, he said, he could see combining the 2 vaccines, using the intranasal vaccine for primary immunization and then following it with a VLP vaccine boost.
Monkeys See (Benefit), Humans, Too?
Meissa’s intranasal COVID-19 vaccine candidate uses live attenuated respiratory syncytial virus (RSV) that has been engineered to express the SARS-CoV-2 spike protein in place of the RSV membrane surface proteins.
The company’s AttenuBlock platform incorporates 10 years of research and development at Emory University by former faculty member Moore and colleagues, according to Meissa. (Meissa is also enrolling children aged 6 months to 24 months in a clinical trial of a candidate RSV vaccine based on the AttenuBlock platform.)
“As a live virus, it should be immunogenic in the nose,” Moore noted. “As an attenuated virus, it should be safe.” (However, the CDC recommends against administering live attenuated virus vaccines to people who are severely immunocompromised or pregnant, the latter because of the theoretical risk to the fetus.)
It’s unlikely that messenger RNA vaccines, such as Pfizer-BioNTech’s and Moderna’s COVID-19 vaccines, could be formulated as effective intranasal vaccines, he said. “You can’t just take any old vaccine and put it in the nose and call it an intranasal vaccine.”
In a recent study Moore coauthored that has not been peer-reviewed, a single dose of Meissa’s candidate intranasal COVID-19 vaccine protected African green monkeys against SARS-CoV-2 challenge, reducing peak viral shedding in their nose by more than 200-fold.
“Historically, live virus vaccines provide better immunogenicity with a single dose because they’re self-replicating,” Moore said.
Oliver Medzihradsky, MD, MPH, senior director of clinical development at Meissa, is directing the open-label intranasal COVID-19 vaccine trial. It’s evaluating 3 different doses in people aged 18 to 55 years and then, after reviewing safety data from the younger cohort, in volunteers aged 56 to 69 years. In an interview, he acknowledged that recruiting vaccine-naive people into COVID-19 vaccine trials is becoming more difficult, but “I’m getting inquiries every week, if not every day or 2, from individuals who are…very keen to receive a nasal-delivered vaccine.” More than 50 of the estimated 130 participants needed were enrolled by early September, Medzihradsky said.
Moore said he foresees primary immunization of children as the first indication for Meissa’s intranasal COVID-19 vaccine candidate “I feel a real sense of urgency to develop this vaccine for kids,” said Moore, the father of a 9-year-old son, noting that schools in his Georgia hometown had reverted to remote learning by early September because of COVID-19 outbreaks.
“That’s not to say that we’re not interested in exploring the properties of the vaccine in other populations,” added Meissa Chief Medical Officer Robert Walker, MD, formerly chief medical officer and director of clinical development at the Biomedical Advanced Research and Development Authority in the US Department of Health and Human Services.
What appears to be promising in animals doesn’t always pan out in humans.
The only known completed phase 1 trial of an intranasal COVID-19 vaccine failed to live up to expectations generated by animal studies, according to Altimmune, its manufacturer. The Gaithersburg, Maryland–based company announced in late June that its AdCOVID vaccine didn’t stimulate an adequate immune response in a trial involving approximately 80 healthy volunteers aged 18 to 55 years.
The vaccine appeared to be well tolerated, with an adverse event profile similar to that of the intranasal saline placebo, but the magnitude of the immune response and the percentage of participants who responded were substantially lower than what has been seen with injected COVID-19 vaccines authorized for emergency use, Altimmune said in its announcement.
The company did not respond to JAMA’s request for an interview, but in the announcement Altimmune President and CEO Vipin Garg, PhD, called the phase 1 clinical data disappointing, “given the encouraging preclinical data,” and said the company has decided to focus on its obesity and liver disease therapeutics. Altimmune Chief Scientific Officer Scot Roberts, PhD, speculated that the company’s intranasal vaccine didn’t meet expectations because trial participants lacked immunity from prior infection or vaccination.
Matthew Memoli, MD, MS, who wasn’t involved with the Altimmune vaccine and had only the press release rather than published findings to go on, questioned Roberts’ explanation. “I don’t think automatically you have to have prior exposure for a mucosal vaccine to work,” Memoli, director of the NIAID Clinical Studies Unit, said in an interview.
Altimmune’s phase 1 results could have appeared to be disappointing because of how the immune response was assessed, he said. “We don’t really know how to do that. I’m afraid that some groups will drop their investigation of [intranasal vaccines] because they’re not seeing the immune response they expect to see.”
Based on circulating antibodies, “intranasal vaccine is always going to look inferior,” Memoli said. However, he pointed out, “high levels of antibodies in the blood don’t always equate to good protection against a disease.”
Because so little is understood about mucosal immunity in the respiratory tract, “we don’t really know how to evaluate [intranasal vaccines], other than do they protect people?” said Memoli, adding that he has been looking for a respiratory immunologist with whom to collaborate on an intranasal COVID-19 vaccine.
A phase 1 trial can’t answer whether an intranasal vaccine adequately protects people, he said. “Somebody’s going to have to take a chance and try this thing at a phase 2 level.”
Conflict of Interest Disclosures: Dr Spearman reports that his division is conducting trials with AstraZeneca, Pfizer, and Moderna COVID-19 vaccines and that it has a contract with CyanVac to conduct the phase 1 trial of its intranasal vaccine. His VLP vaccine research is funded by a local philanthropic source. Drs Moore, Walker, and Medzhiradsky are employees of Meissa Vaccines and own options or stock or both in the company. The work at Meissa has been described in at least 1 provisional pending patent application.
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Rubin R. Trying to Block SARS-CoV-2 Transmission With Intranasal Vaccines. JAMA. 2021;326(17):1661–1663. doi:10.1001/jama.2021.18143
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