Highlights
- There’s a world of difference between mucosal immunity (from nasal shots) vs systemic immunity (from intramuscular shots).
- Nasal vaccines could deliver a knockout blow against SARS-CoV-2 where it matters the most, in the nasal mucosa.
- Intranasal shots have been found effective against the flu since 2003.
- But costly clinical trials need funding support from governments, philantropists in order to advance trials.
The nose is the door through which COVID-19 infects humans. The nostrils are easy entry points for the coronavirus. Fact: If you got both jabs and didn’t develop mucosal immunity, the virus can still get in. Experts call that a “breakthrough” infection.
A peer-reviewed research published in the journal Cell iScience shows the intranasal vaccine would “close the door” of COVID infection. How come there’s no nasal vaccine against COVID-19 approved or widely distributed till now? There’s no straight answer.
What experts say:
What do nasal vaccines do?
Nasal vaccines are designed to confer mucosal immunity in the nasal compartment. Most experts consider the nasal compartment as first point of entry of SARS-CoV-2 before it clobbers the lungs.
“The idea is to shut the door,” researcher Nathalie Mielcarek working with the Lille Pasteur Institute to develop a nasal spray vaccine against whooping cough told AFP.
It is the innermost layer, and functions in absorption and secretion. It is composed of epithelium cells and a thin connective tissue. The mucosa contains specialised goblet cells that secrete sticky mucus throughout the gastrointestinal tract.
What happens to the nasal compartments and lungs when a nasal vaccine is used?
In animal models, researchers say it induces systemic neutralising antibodies (NAbs), immunoglobulin A (IgA) and T-cell responses in the lung.
Some number good news:
- Single-dose intranasal vaccination elicits systemic and mucosal immunity against SARS-CoV-2
- Using genetic sequencing. it showed evidence of coordinated activation of T/B-cell responses within the nasal-associated lymphoid tissues.
This type of immunity is also seen as more "durable". More importantly, it curbs infection in individuals and prevent disease transmission.
Can intranasal vaccines help stop COVID spread?
The experts say intranasal vaccines would significantly curb the pandemic when used alongside the already-approved intramuscular vaccines.
In March 2021, Daniel Oran and Eric Topol from the Scripps Institute published an opinion piece in Scientific American citing their reasons for pursuing intranasal vaccines, and providing financial incentives.
Their arguments are based on known nasal vaccine benefits:
- Ease of administration.
- Eliminating the issue of "needle phobia."
- Direct mucosal immunity.
- Nasal vaccines against COVID-19 can help reduce viral load and break the train of virus transmission.
It appears the biggest hurdle is money: nasal vaccines need to demonstrate efficacy and safety in Phase 3 clinical trials, which need tens of thousands of volunteers to be enrolled. That needs funding support from investors, philanthropists or the government. Nothing of the sort of development activity that happened with intramuscular vaccines happened with intranasal shots.
The higher the titre, the better the protection. An acceptable threshold antibody level for protection is 1:10 dilution of serum in a 50% plaque reduction neutralisation (PRNT).
How many vaccines are approved?
There are currently 22 intramuscular (IM) COVID-19 vaccines authorised/approved by at least one state regulator. Dozens more are underway.
The end point for IM vaccines is to prevent hospitalisations, critical illnesses and death. Evidence, however, shows fully vaccinated individuals who contract the highly contagious Delta variant are still able to transmit live virus. And COVID-19 continues to mutate.
What’s the role of nasal mucosa in enabling — or breaking — the 'chain of transmission' of COVID?
The nasal cavity is the primary entry point of a COVID-19 infection, which activates nasal IgA. Infection usually starts in the nasopharynx. Nasal vaccine is now seen as a new way to reduce viral load at the primary portal of entry: the nasal mucosa.
Is natural infection more effective than vaccination?
Yes and no. Evidence shows that natural infection — with the whole virus — elicits a broader immune response compared to the mRNA vaccines or other platforms — which present just a fragment of the S spike protein or a killed version of the whole virus.
In pain English, it means natural infection confers better protection than vaccination.
At least one study, however, also shows “hybrid vaccination” — giving a booster shot to a person who had prior natural infection — confers up to a 100-fold protection than natural infection.
Is there an approved nasal vaccine?
Yes. The US FDA approved "FluMist", a nasal spray flu vaccine, in 2003. It’s a culmination of 40 years of research by University of Michigan (UM) Prof. Hunein Maassab.
It uses the “live-attenuated" (virus is still alive, but weakened) trivalent influenza virus vaccine platform. It is the first flu shot delivered as a nasal mist made commercially available in the US. Other vaccine makers soon followed the nasal route. FluMist is approved for people ages 2 to 49, but not advised for individuals with a weakened immune system.A preschooler gets a nasal flu vaccine against the H3N2 virus. Vaccine like FluMist is spritzed up the nose. The "FluMist" vaccine was based on technology developed by Arab-American scientist Hunein Maassab, professor of epidemiology at the University of Michigan (UM) School of Public Health. It is approved for use by healthy people ages 5-49.
Why are nasal vaccines not favoured?
It’s not clear. Most of the $12.4 billion “Warp Speed” research and development funding were for intramuscular vaccines. Given what scientists know now, many say IM “winners” like Pfizer, Moderna, J&J are not enough.
“We've successfully blocked serious and critical infections, but we don't have our lives back together, the economy is faltering, our hospitals are on the verge of burnout and collapse, and people are dying,” said Dr Daniel Teres and Martin A. Strosberg, in an article published on September 5, 2021 argued that the nasal vaccine is a “new approach”. Teres, a critical care physician and clinical instructor in public health and community medicine at Tufts University School of Medicine in Boston.
In an article published on September 5, 2021 he wrote with Martin A. Strosberg, he argued that the nasal vaccine is a “new approach” and urged greater investment by governments, private sector and philanthropies to fund costly clinical trials to develop nasal COVID therapies.
Dr. Navin Varadarajan, M.D. Anderson Professor of Chemical and Biomolecular Engineering at UH, stressed: mucosal immunity doesn’t happen when you get one of the currently-available vaccines. “One of the blind spots for systemic vaccines is the upper areas of the nostrils,” he stresed.
Can nasal vaccines be self-administered?
Yes.
What about storage?
Nasal vaccines are easy to store, only standard household refrigeration.
In March 2021, an article published by Gavi the Vaccine Alliance noted other advantages of nasal vaccines — the fact that the sprays don't need refrigeration and don't need to be administered by health professionals. “They are likely to be more popular for the millions of people who don’t like needles,” the group wrote.
What’s the status of human trials of nasal vaccines?
The WHO vaccine landscape lists several such nasal candidate shots against COVID-19, some of which are listed below:
(1) DelNS1
One of the most advanced in terms of clinical trials is DelNS1-2019-nCoV-RBD-OPT1. This nasal vaccine uses a flu-based receptor binding domain co-developed University of Hong Kong, Xiamen University and Beijing Wantai Biological Pharmacy, currently in Phase 2 trials, according to the WHO.
(2) NONS/Enovid
Israeli-Canadian biotech firm SaNOtize Research and Development, based in Vancouver, Canada, has rolled out its Nitric Oxide Nasal Spray (NONS) earlier this year against the COVID-19 virus. It is manufactured under the brand name Enovid in Israel with SaNOtize's partner Nextar Chempharma Solutions Ltd.
Enovid will go on sale at Israeli pharmacies for NIS 139 ($42). According to Dr. Gilly Regev, the Israeli-Canadian scientist who co-founded SaNotize, the company is also finalising an agreement to sell the product in India in partnership with a local pharmaceutical company.
SaNOtize recently announced results of UK clinical trials showing that NONS was an effective in preventing COVID-19 transmission, shorten its course, and reduce the severity of symptoms and damage in those already infected. In New Zealand, SaNOtize has registered its nasal spray with the New Zealand Medicines and Medical Devices Safety Authority, which permits the company to distribute and sell NONS over the counter immediately.
(3) Bharat Biotech Intl Ltd.
In July, Bharat Biotech sent a proposal to the Drugs Controller General of India (DCGI) for conducting the Phase 1 trials of a nasal vaccine against COVID-19.
(4) Washington University
Its School of Medicine scientists showed their intranasal vaccine, which uses an adenoviral spray, can kick up immune response in the mucosa of chimpanzees in a study published in Cell on August 19, 2020. Using the ChAd-SARS-CoV-2 “vector” (carrier), the shot generated robust mucosal B- and T-cell responses in chimps. It also prevented upper and lower respiratory tract infection.
(5) Finland’s nasal shot
This candidate nasal vaccine uses the viral vector (non-replicating) platform developed University of Helsinki & University of Eastern Finland.
(6) NanoSTING
US Biotech firm AuraVax Thrapeutics is working on manufacturing its own intranasal subunit vaccine against COVID-19, known as NanoSTING. The company will coordinate with the FDA with the goal of starting Phase 1 human trials as soon as May or June 2022.
(7) CanSino
On July 26, 2021, China’s CanSino published results of its early clinical trial (Phase 1) using its aerosol version of its Ad5-nCoV, already approved as an intramuscular injectable vaccine. It’s hoped that that since existing intramuscular vaccine can work as an intranasal spray, authorisation would be much easier to get.
(8) Codagenix’s Covi-Vax
Codagenix, from the lab at Stony Brook University, started a Phase I clinical trial of a single-dose inhaled Covi-Vax, which uses an attenuated live virus. Instead of using a backbone virus to carry an antigen or virus particles, Codagenix uses part of the viral genome with capsid proteins altered by hundreds of nucleotide change, seen as a much safer approach.
Q: What are the countries that approved the sale nasal COVID vaccines?
A number of countries have approved nasal COVID vaccines, including:
- Israel
- New Zealand
- Bahrain
- India
In March 2021, both Israel and New Zealand gave an “interim” approval” for the sale of nasal spray against COVID-19.
In July 2021, SaNOtise also begun selling in Bahrain its product Enovid, the company’s Nitric Oxide Nasal Spray (NONS), according to the company.
“The vaccinated animals... showed low levels of the virus so they are not contagious anymore — that's one of the advantages of the nasal spray,” Philippe Mauguin, CEO of the French institute that hopes to patent the vaccine told AFP.
Isabelle Dimier-Poisson who led the research has high hopes. “It could allow us to get back to life before the pandemic, without social distancing, and without masks,” she said.
