Two facts stand in stark contrast. First, existing COVID-19 vaccines provide robust protection against severe disease and death. Second, they do not completely prevent the spread of SARS-CoV-2. As a result, while these vaccines have saved countless lives, it’s unlikely that they will, on their own, stop viral transmission and prevent the emergence of new viral variants.
Part of the reason for this discrepancy could be the way that current COVID-19 vaccines—like most other vaccines—are delivered. Intramuscular injections generate systemic immunity but little or no immune response in the nose, where respiratory viruses such as SARS-CoV-2 typically enter the body. Yet this so-called mucosal immunity, according to experts who spoke with The Scientist, is one of the best ways to completely inhibit infection and thereby abolish community spread.
“In an ideal situation, you would of course entirely block the transmission of the virus in vaccinated people, and I think the consensus right now is that intramuscular vaccines are going to have a really, really hard time reaching that milestone,” says virologist Neeltje van Doremalen, an associate scientist at the National Institute of Allergy and Infectious Diseases (NIAID) who collaborated on preclinical studies of a nasal version of a vaccine made by AstraZeneca and the University of Oxford that is currently in clinical trials. “And I’m not saying that we think that intranasal vaccines are going to easily do that, but I do think that that is going to be an improvement.”
Intranasal vaccines, which can elicit both mucosal and systemic immune responses, are delivered through the nasal cavity, most commonly by an aerosolized spray, although nasally administered drops, powders, and gels have also been considered. A small handful of intranasal flu vaccines are commercially available, such as FluMist, which came on the US market in 2003. Other flu vaccines and immunizations targeting other viruses have been in development since before the COVID-19 pandemic, but none have moved to late-stage trials. Compared with intramuscular injections, “we don’t actually have that much experience in humans with intranasal vaccines,” says Florian Krammer, a virologist and vaccinologist at Icahn School of Medicine at Mount Sinai who is named as an inventor on patent applications related to a COVID-19 vaccine now being tested with intramuscular and intranasal delivery in the US and in Mexico, and who consults for Pfizer and other pharmaceutical companies.
Nasal vaccines are easier to administer, and so do not require trained personnel, making them more accessible for low- and middle-income countries.
In the face of COVID-19, interest in the approach has soared. More than a dozen nasal sprays or drops are now being tested against COVID-19 in humans, either as primary immunizations or as boosters. (See table below.) “There is definitely an uptick in interest,” says Yale School of Medicine immunologist Akiko Iwasaki, who is developing her own patented intranasal COVID-19 booster and who recently cofounded a company called Xanadu Bio to pursue the approach. “At this point in the pandemic what we need is an infection-blocking vaccine and not vaccines that only protect you against severe disease.”
Being a relatively understudied approach to vaccination, nasal vaccines present practical and financial hurdles. For example, approaches for measuring mucosal immunity lag behind those aimed at systemic immunity, making it more complicated to demonstrate the efficacy of nasal vaccines compared with more traditional injected versions. But the advantages overshadow these drawbacks for many developers. In addition to potentially being better at blocking transmission of respiratory viruses, an idea supported by a growing body of animal studies, nasal vaccines are easier to administer, particularly to children and needle phobic individuals, and so do not require trained personnel, making them more accessible for low- and middle-income countries. “It’s much more complicated than just developing a regular injected vaccine,” says Krammer, who consults for several companies involved in vaccine development. “But the benefits if you get it to work are probably huge.”
The rocky history of nasal vaccines
Nasal vaccination has had a long but mixed history. In Russia, a nasal spray against influenza has been in use since 1987, and in 2009, the World Health Organization (WHO) licensed that technology from the owner company, Australian vaccine developer BioDiem. The vaccine has since been manufactured by companies in India, China, and Thailand. Another early nasal vaccine, approved in Switzerland in 1997, was pulled from the market four years later after data revealed an elevated risk of temporary facial paralysis, or Bell’s palsy, in vaccine recipients compared to controls.
The US got its first nasal vaccine in 2003, when the Food and Drug Administration (FDA) approved FluMist, a live attenuated influenza vaccine developed by Maryland-based MedImmune. (The company has since been acquired by UK-headquartered AstraZeneca, which now markets the vaccine and declined to be interviewed for this story.) But in 2016, the US Centers for Disease Control and Prevention (CDC) recommended against FluMist’s use after studies showed that it was less effective than intramuscular flu vaccines. The CDC again cautioned Americans to go the intramuscular vaccination route for the 2017–18 flu season. A reformulated version of FluMist was endorsed by the CDC in mid-2018 and has been available in the US for the past few years. There are also a small number of other intranasally delivered vaccine candidates in development, not just for flu but also for respiratory syncytial virus (RSV) and pertussis.
At this point in the pandemic what we need is an infection-blocking vaccine and not vaccines that only protect you against severe disease.—Akiko Iwasaki, Yale School of Medicine
While many vaccine developers chose to pursue the more established route of intramuscular injection after COVID-19 surfaced in late 2019, several companies have set their sights on formulating a nasal vaccine against SARS-CoV-2. In some cases, no reformulation was required; the intramuscular vaccine could simply be aerosolized into a spray. This applies to adenovirus-vectored vaccines, which feature replication-deficient cold viruses that naturally infect the nasal passageway, where they can deliver their cargo of SARS-CoV-2 antigens or antigen-encoding sequences.
As with nasal vaccination in general, there have already been some setbacks in the context of COVID-19. In mid-2021, Altimmune abandoned AdCOVID, an adenovirus-vectored intranasal COVID-19 vaccine that was one of the first to enter clinical trials. The Gaithersburg, Maryland, company declined to speak with The Scientist for this story but noted in a press release last year that the vaccine had generated lower than expected antibody responses in the blood and in the nose, according to preliminary Phase 1 results. Still, companies with nasal vaccines in the pipeline are forging ahead with clinical programs.
Some companies in the space already have injectable COVID-19 vaccines, such as India-based Bharat Biotech, which in early 2021 earned regulatory approval in that country and elsewhere for its intramuscular vaccine Covaxin. Bharat announced last September that regulators had greenlighted a Phase 2 trial for a nasal vaccine based on a different platform, and in January, the company announced that its nasal vaccine would be moving into a Phase 3 trial both as a two-dose initial vaccine series and as a booster. Separately, a Phase 2/3 trial will test a mixed regimen of the nasal vaccine with Covaxin.
Another player in the intranasal COVID-19 vaccine space is AstraZeneca, which is continuing its collaboration with researchers at the University of Oxford to test a nasally delivered version of their Vaxzevria vaccine (also known as ChAdOx1-S or Covishield), which has been authorized as an intramuscular injection in several countries. In Russia, a nasal version of the Sputnik V vaccine, which President Vladimir Putin claimed last year to have received as part of a booster dose, was approved by the country’s health ministry in April, according to a tweet highlighted in an email to The Scientist by a spokesperson for the vaccine’s principal funder, the state-owned Russian Direct Investment Fund (RDIF). Meanwhile, several other nasally delivered COVID-19 vaccine candidates follow close behind in early-stage trials.
Facing the COVID-19 challenge, nose-on
One company that immediately looked toward a nasal vaccine as the pandemic swept the globe was New York–based Codagenix. While most COVID-19 vaccines use certain SARS-CoV-2 antigens or the genetic material that codes for them, ferried by a different virus or some other delivery vehicle, Codagenix is working with a live attenuated virus, an approach previously employed in FluMist, which today contains four strains of attenuated influenza viruses. Oral rotavirus and polio vaccines also employ live attenuated viruses to exert their protective effects. A commonly cited advantage of this approach is the potential for broader protection against microbial variants: if the immune system is exposed to a virus’s entire suite of antigens, it’s less likely to be thwarted if one or several of those antigens mutate.
See “How Some Vaccines Protect Against More than Their Targets”
Codagenix uses what’s known as codon deoptimization to deliberately introduce into viral genomes hundreds or even thousands of mutations that were computationally determined to achieve some goal—in this case, to slow viral protein translation. “We can convert the virus from foe . . . into live attenuated vaccine,” Codagenix cofounder and CEO Rob Coleman describes. The approach can be used regardless of vaccine delivery mode, but Codagenix was already in the process of developing nasally delivered vaccines for other respiratory viruses when the pandemic hit, so the firm quickly pivoted to develop CoviLiv, an intranasal vaccine consisting of an attenuated version of SARS-CoV-2. In a Phase 1 trial, that vaccine (then called COVI-VAC) induced systemic and mucosal antibodies and cellular immune responses in previously unvaccinated individuals, while later in vitro assays pointed to likely protection against a range of viral variants including Omicron, which hadn’t yet emerged at the time the initial participants were dosed in 2021. A Phase 1 booster trial is now also underway, and the vaccine will be tested as part of the WHO’s global efficacy trial for COVID-19 vaccines.
More than a dozen nasal sprays or drops are now being tested against COVID-19 in humans, either as a primary immunization or as a booster.
Meissa Vaccines in the San Francisco Bay Area has a similar story. Like Codagenix, the company was already using codon deoptimization to create intranasally delivered live attenuated vaccines, specifically for RSV, and pivoted to COVID-19 at the start of the pandemic. Rather than attenuate SARS-CoV-2, however, Meissa researchers decided to stick with their existing nasally delivered RSV construct but engineer it to display the SARS-CoV-2 spike protein. Interim results announced in October from the company’s Phase 1 trial showed that the vaccines induce nasal antibodies in people with and without prior exposure to the virus or a different vaccine. Meanwhile, researchers at vaccine maker CyanVac put the genetic code for the SARS-CoV-2 spike protein in the genome of the attenuated canine parainfluenza virus it was using as a vector for a nasal RSV vaccine in development, and a year later moved the COVID-19 vaccine into a Phase 1 trial.
All three companies are also continuing or resuming development of nasal vaccines for non-COVID diseases, with those for RSV being the furthest along in each case. In December 2020, Codagenix completed dosing in a Phase 1 trial for its RSV candidate; CyanVac announced in March of this year that it was moving forward with a Phase 1 trial for its RSV vaccine; and with its own RSV candidate having done well in Phase 1 trials with adults and toddlers, Meissa is beginning to dose infants. In addition to communicating their excitement about these programs, researchers at each firm spoke about the promise of their platforms for vaccinating against other respiratory viruses as well.
“We have our eyes on all kinds of viruses now,” says Meissa founder and chief executive officer Marty Moore. “If we can establish immunity in the upper respiratory tract against a wide range of respiratory viruses . . . we could not just get back to where we were health-wise, but we could actually improve human health globally against a wide range of viruses. And that’s really exciting.”
TRIALING COVID-19 NASAL VACCINES
Around the world, more than a dozen intranasally delivered COVID-19 vaccines have entered clinical trials, and they run the gamut from adenovirus-vectored genes for viral antigens to recombinant protein–based formulations to live attenuated SARS-CoV-2. A selection is presented below.
Bharat Biotech: BBV154 (Licensed from and developed in collaboration with Washington University in St. Louis)
Chimpanzee adenovirus encoding the SARS-CoV-2 spike protein
• Planned Phase 2 and Phase 3 trials in India to test BBV154 as a primary vaccination and as a booster
• Planned Phase 2/3 trial in India to test a mixed regimen of the vaccine with Bharat’s intramuscular COVID-19 vaccine, Covaxin
Gamaleya National Center of Epidemiology and Microbiology: Sputnik V
Two human adenoviruses encoding the SARS-CoV-2 spike protein
• Nasal version approved by Russia’s health ministry in April, according to a tweet, following the reported success of small clinical trials
University of Hong Kong, Xiamen University, and Beijing Wantai Biological Pharmacy: DelNS1-2019-nCoV-RBD-OPT1
Attenuated influenza virus encoding the SARS-CoV-2 spike protein
• Phase 3 trials ongoing in Ghana and the Philippines
• Booster trial ongoing in China for individuals who have received Pfizer/BioNTech’s mRNA vaccine
Razi Vaccine and Serum Research Institute: Razi Cov Pars
Recombinant SARS-CoV-2 spike protein
• Phase 3 trial underway in Iran testing two injections
• Planned Phase 1/2 trial in Iran to test the vaccine regimen in adolescents
• Will be tested starting this summer as part of the World Health Organization’s global, placebo-controlled Phase 2/3 trial for COVID-19 vaccines
• Phase 1 booster trial underway in the UK
Center for Genetic Engineering and Biotechnology (CIGB): Mambisa
Recombinant SARS-CoV-2 spike protein, along with a hepatitis B virus protein
• Phase 1/2 trial ongoing in Cuba
Icahn School of Medicine at Mount Sinai: NDV-HXP-S (Developed with Laboratorio Avimex and other, noncommercial partners)
Newcastle disease virus displaying the SARS-CoV-2 spike protein
• Phase 1 trial for intranasal and intramuscular delivery
• Phase 2 trial, also for both delivery methods, underway in Mexico
CanSino Bio and Beijing Institute of Biotechnology: Convidecia
Human adenovirus encoding the SARS-CoV-2 spike protein
AstraZeneca: Vaxzevria (Licensed from and developed in collaboration with University of Oxford)
Chimpanzee adenovirus encoding the SARS-CoV-2 spike protein
• Phase 1 trial ongoing in the UK
Meissa Vaccines: MV-014-212 (Spun off from work at Emory University)
Attenuated RSV displaying SARS-CoV-2 spike protein
• Phase 1 trial ongoing in the US
CyanVac: CVXGA1 (Spun off from work at the University of Georgia and the University of Iowa)
Attenuated canine parainfluenza virus encoding the SARS-CoV-2 spike protein
• Phase 1 trial ongoing in the US
Tetherex Pharmaceuticals: SC-Ad6-1
Human adenovirus encoding the SARS-CoV-2 spike protein
• Phase 1 trial ongoing in Australia for intramuscular
Challenges ahead for the nasal route
While researchers who spoke with The Scientist agree that nasal vaccines are promising, they also emphasized the potential hurdles this as-yet uncommon approach might face. “You have a very different development pathway if you have an intranasal vaccine . . . usually harder,” says Mount Sinai’s Krammer.
A big reason for the relative difficulty of going the intranasal route for vaccine development is the lack of standardized tests for mucosal immunity in that context. Researchers can measure systemic immunity through an established assay that determines antibody levels in the blood. Results of this assay, Krammer explains, can be used to support an application for accelerated approval of a novel vaccine before the maker has shown reduced infection in large, real-world efficacy trials, which are time-consuming and costly. He adds that in some countries, similar standards have been used to authorize the use of new COVID-19 vaccines. But because intranasal vaccines tend to elicit lower antibody levels in the blood than do injected vaccines, Krammer notes, they are less likely to meet this standard. That doesn’t mean that they’re less effective, he notes, as these blood tests say nothing about the mucosal immunity that is generated. “It could be that maybe the titers are lower even though the vaccine would work better.”
Krammer adds that “typically there’s not a lot of funding” for studies that could elucidate how nasal vaccines elicit protection and which immune responses correlate most strongly with reduced disease—information that could help reduce the development cost. The vaccine he helped develop, called NDV-HXP-S, is being developed in partnership with NGOs and the biotech Laboratorio Avimex, he says.
Another challenge—one that applies across the board to COVID-19 vaccines—is recruiting enough participants to fill clinical trials, particularly for testing primary immunizations as opposed to boosters. As such, many of the companies developing nasal vaccines are testing them as both. NIAID virologist Vincent Munster, who with van Doremalen collaborated on preclinical studies of AstraZeneca’s nasal vaccine, says that this approach is well timed, as the past two years have revamped the traditional view that boosters are of the same variety as the primary vaccination. “Now of course the market has changed as well, where you have a lot of plug-and-play booster vaccination regimens. I think people are way more comfortable in going in with Moderna first and then Pfizer . . . and vice versa.” As such, he says, it should be “a little bit easier than with FluMist” to bring a nasal COVID-19 vaccine to market.
As for which nasal vaccine candidates will prevail, it’s anyone’s guess, says Krammer. “There’s a lot of approaches,” he says, each with its own advantages and disadvantages. “It’s important to do clinical trials and look at data once there is data. . . . To predict is really hard right now.”