CME INDIA Presentation by Dr. S. K. Gupta, MD (Med), FICP, CFM (France) Clinical Asst. Professor GS Medical College, CCSU, Uttar Pradesh, India. Visiting Consultant, Max Super Specialty Hospital, New Delhi.

Currently licensed COVID-19 vaccines are being administered by intramuscular (IM) immunization. Recent trends have shown clearly that vaccination failed to prevent the virus infection through the upper respiratory tract. Pandemic continues despite widespread vaccination. Individuals who receive injectable COVID-19 vaccines may be protected against serious illness but can still become infected by a different version of a higher variant with immune escape capability. It gives an insight that absence of mucosal immunity activation matters. Now next generation of COVID-19 vaccine is in demand. Intranasal (IN) vaccination method has been demonstrated to be potent in inducing both mucosal and systemic immune responses.

Nasal Vaccines-Last Weapon in Our Armoury To End Pandemic!
Courtsey: Reference-2: 1. Mucosal immune responses induced by IN vaccination.

Will nasal vaccine be able to serve as final tool in our fight against deadly contagion?

Do nasal vaccines induce induce a strong a systemic immune response comparable to intramuscular vaccines?

  • Nasal vaccines may be the best way to prevent infections and further transmission in long term, because they provide protection exactly where it is needed to fend off the virus: the mucosal linings of the airways, where the coronavirus first lands.
  • Apparent doubts and fears are many because nasal vaccines are a new tool. But animal studies have so far indicated that intranasal vaccines are actually good in inducing strong systemic response at least in initial trials.
  • In addition, the researchers have found that after intranasal vaccination, the virus isolated from nose was less infectious than in subjects who had not been given nasal spray of vaccine.

Why do we need Nasal Vaccines?

  • Currently available vaccines produce powerful, long-lasting immunity against severe illness, as several studies have recently shown. But their protection against infection from the coronavirus is transient, and can falter as new variants of the virus emerge — a failing that has prompted talk of regular booster shots.

Can we live forever sheltering vulnerable population boosting them again and again?

  • The current Covid vaccines are injected into muscle, and excel at training immune cells to tackle the virus after it has entered the body. They produce antibodies called IgG that circulate in the blood and can be marshalled when needed. But few of these antibody’s travel to the nose and throat, and even those that do wane quickly.
  • So-called mucosal vaccines ideally would coat the mucosal surfaces of the nose, mouth and throat with long-lasting antibodies, and would be much better at preventing infection and spread of the virus. Nasal oral vaccines are being developed and vaccination even by nebulization coating the entire nose throat and lung airways can be tried.
  • With so much population already vaccinated by injectable vaccines world over, will nasal vaccination boost already existing immunity?
  • Nasal vaccine can be used as a primary vaccine as well as a booster, to boost the existing immunity that’s already created.
  • Nasal vaccines have been shown to protect mice, ferrets, hamsters and monkeys against the coronavirus. A recent study offered powerful evidence in support of nasal vaccine use as a booster.

Did scientist falter develop Injectable Vaccines?

  • No. Injected vaccines are the right approach at the beginning of the pandemic. They satisfy the urgent need of generating the systemic immunity needed to prevent death and disease, the urgent goal
  • That was a good first step, but to end pandemic we need to have intranasal vaccines ready for boosting the local and systemic immunity.
  • Immunizing entire populations with a nasal or oral vaccine would be faster in the middle of a surge than injections, which require skill and time to administer. A nasal vaccine is likely to be more palatable to many (including children) than painful shots, and would circumvent shortages of needles, syringes and other materials.

Why are we slow in developing Nasal Vaccine?

  • Injectable vaccines just can’t be used as nasal vaccines. We need more stable and immunogenic vaccines.
  • Existing immunity to the previously exposed virus in NALT (nasopharynx associated lymphoid tissue) may render the vaccine ineffective. So, developing nasal vaccines is complicated.
  • Measuring mucosal IgA antibodies is much more difficult than quantifying antibodies in the blood. The amounts are often low and can fluctuate wildly. For example, the aroma of a delicious meal may flood the mouth with saliva, diluting mucosal antibody levels.
  • Trying to enhance the vaccine with an extra ingredient, called an adjuvant, actually inflamed the nasal mucosa and lead to Bell’s palsy in some cases.

Is Nasal Vaccine a new Concept?

  • No history of nasal vaccination dates back to 18th Century when dried scab from small pox pustules was crushed and powder blown into the nose using a long pipe. See video

Are there any Existing Nasal vaccines?

  • The only nasal vaccine approved (in the United States for respiratory diseases) is FluMist, and even that has been riddled with problems. FluMist relies on a weakened flu virus, so it works well in children who have never been exposed. But in many adults, existing immunity to flu killed the weakened virus and left the vaccine ineffective.
  • Canine distemper is good example of successful nasal vaccine used in puppies.

Which companies are at the forefront of developing Nasal vaccine against Covid?

  • Bharat Biotech is the world’s leading manufacturer. However, there are at least a dozen other nasal vaccines in development worldwide, some of them now in Phase 3 trials. But Bharat Biotech’s vaccine may be the first to become available. In January, the company won approval to begin a Phase 3 trial of the nasal spray in India as a booster for people who have already received two shots of a Covid vaccine.

Nasal vaccines on the Horizon

Since most clinical trial data are yet to be released, preclinical studies are essential for us to explore the immunogenicity and safety of IN COVID-19 vaccines.


  • BBV154 is an intranasal replication-deficient chimpanzee adenovirus SARS-CoV-2 vectored vaccine, in-licensed from the Washington University in St Louis, USA. In Vaccine Chimpanzee adenovirus has been engineered to carry the spike protein gene of SARS CoV-2. Unlike injectable Covaxin, which is difficult to make, manufacturing of nasal vaccine BBV154 can be scaled up fast and easily.
  • The Vaccine has shown to produce high levels of coronavirus antibodies in mice with just a single dose in preclinical trials. Bharat Biotech was licenced in February 2021 to launch a Phase 1 trial of a vaccine. After successful completion of same the company started a Phase 2 trial in September 2021. On Jan. 28, 2022, Drugs Controller General granted approval to company to conduct Phase 3 trial. In the new study, Bharat Biotech is testing BBV154 as a two-dose vaccine for people who have not been vaccinated before, and also as a booster.
  • BBV154 Nasal vaccine being a Chimp adenovirus Vector based vaccine seems like   AstraZeneca Vaccine (Covishield) being used intramuscularly as well as intranasally. What makes them different?
  • AstraZeneca ChAdOx1 nCoV-19, is a chimpanzee Ad-23-based SARS-CoV-2 vaccine that is currently used in humans as intramuscular injections.  ChAd-SARS-CoV-2-S or BBV154 is derived from a different ChAd serotype, simian Ad-36. It has further deletions in the backbone to enhance production, and introduces proline mutations to stabilize the S protein into a pre-fusion form. The technology employs protein engineering to stabilize S in its prefusion conformation, preventing structural rearrangement, and exposing antigenically preferable surfaces. Stabilized S proteins have been shown to elicit superior neutralizing antibody responses
  • Key Attributes:
An intranasal vaccine stimulates a broad immune response – neutralizing IgG, mucosal IgA, and T cell responses.
The nasal route has excellent potential for vaccination due to the organized immune systems of the nasal mucosa
Immunization with ChAd-SARS-CoV-2-S resulted in the development of anti-S, anti-RBD, and neutralizing antibodies as well as T cell responses that prevented or limited infection in nasal swabs, bronchoalveolar lavage fluid, and lung tissues after SARS-CoV-2 challenge. Thus, the administration of a single dose of ChAd-SARS-CoV-2-S vaccine through a non-injection route has the potential to protect at the portal of entry and in distant tissues, which could limit both virus-induced disease and transmission.


  • DelNs1 (DelNS1-2019-nCoV-RBD-OPT1) DNA plasmid based Live attenuated Vaccine (LAIV)
  • In 2019, researchers at the University of Hong Kong and Xiamen University created a nasal-spray vaccine for the flu based on a genetically weakened (live attenuated) form of the influenza virus (H1N1), (H3N2). In early 2020, they engineered the vaccine to produce part of the coronavirus spike protein as well. On Sept. 9, they received approval to start clinical trials in partnership with Beijing Wantai Biological Pharmacy. They registered a Phase 1 trial on March 22, 2021. June 11, it completed Phase 2 trials. And on Sept. 22, the researchers registered a Phase 3 trial. In January 2022, the University of Hong Kong, registered a new trial to test the vaccine as a booster. The researchers are receiving $5.4 million in support from CEPI, the Coalition for Epidemic Preparedness Innovations. PD1-RBD-DNA/LAIV-HK68-RBD regimen prevents SARS-CoV-2 nasal infection by inducing sufficient and long-lasting mucosal NAbs and CD8 T cells.  Further Vaccine may prime strong mucosal CD8 T cells responses in addition to inducing potent NAbs.


  • Gene One Life Science, a South Korean biotech company, developed a DNA-based vaccine that encodes two proteins from the coronavirus. In December 2020, they launched a Phase 1/2 trial with 345 participants. After receiving positive interim results from the trial, GeneOne announced on July 8, 2021 that it would begin Phase 2.
  • GeneOne is also experimenting with different vaccine delivery techniques. On Oct. 20, the company registered a Phase 1 trial to gauge how well their candidate works when injected into a patient’s arm and delivered as a nasal spray. In the study, the researchers will also see if a skin suction device will improve outcomes. In January 2022, GeneOne registered a new trial to test their vaccine as a booster. (Updated Jan. 12)


  • Codagenix: New York-based Codagenix develops vaccines based on live attenuated viruses, but with a twist: they create the viruses from scratch. In the process, the Codagenix researchers rewrite the genomes of the viruses, introducing hundreds of extra mutations. Then they manufacture RNA molecules encoding the rewritten genes. In special host cells, the molecules can give rise to full-blown viruses. But thanks to their numerous mutations, they are too weak to cause Covid-19 when they’re delivered in a nasal-spray vaccine.
  • After successful experiments in animals, a Phase 1 trial was launched in the United Kingdom in January 2021. Codagenix announced on Sept. 22 that they got promising results from the trial and were moving towards a Phase 2/3 trial.


  • AstraZeneca and Oxford are working on a new version of the vaccine tailored to the Beta variant and are testing a version that can be delivered as a nasal spray. On June 28, participants received doses of the Beta variant vaccine, called AZD2816, in a new Phase 2/3 trial.  The University of Oxford is conducting a single dose Phase I study of AstraZeneca’s ChAdOx1 nCOV-19 (Covishield in India and manufactured by the Serum Institute) to be administered intranasal among 54 volunteers in three groups. According to the trial design, the study started in April is estimated to complete the first phase only by February 2022.  


  • Avi-Mex in Mexico also licensed NDV-HXP-S under the name Patria. Their version of the vaccine is delivered as a nasal spray, which they are testing in a Phase 2 trial.


  • CynaVac Scientists at the University of Georgia and the University of Iowa have developed a vaccine based on canine parainfluenza virus, which has never been found to cause disease in humans. They engineered it to carry proteins from the coronavirus. The vaccine, called CVXGA1, is administered as a nasal spray. In July 2021, the researchers published a study showing that a single dose of the vaccine could protect mice and ferrets against Covid-19. A spin-off company called CyanVac took the intranasal vaccine, called CVXGA1, to Phase 1 trials the same month, and enrolled the first participant in late September.


  • Efficacy: Unknown
  • Dose: 1 dose
  • Type: Nasal spray
  • Storage: Refrigerated
  • Maryland-based Altimmune is a biopharmaceutical company that focuses on developing vaccines delivered by nasal spray. They developed a nasal spray vaccine for Covid-19, delivering the Ad5 adenovirus to the airway. Studies on the immune system suggests that a nasal spray could be more effective for blocking the transmission of the virus than vaccines given by injection. In a study on mice, Altimmune researchers found that a single dose of the vaccine gave complete protection from a lethal infection of coronaviruses. On Dec. 22, 2020, the company registered a Phase 1 clinical trial of a single dose of the vaccine.
  • But on June 29, 2021, Altimmune announced they were abandoning their Covid-19 vaccine. In their Phase 1 trial, they gave the spray to 80 volunteers and found that they produced substantially lower levels of antibodies than produced by Covid-19 vaccines that have already been authorized.


  • Cov-Pars Razi on Feb. 7, 2021, Iran announced that it was launching a clinical trial of a second vaccine, known as Cov-Pars Razi and developed by the Razi Vaccine and Serum Research Institute. The vaccine contains fragments of coronavirus spike proteins and is delivered in three doses: two injections and one nasal spray. The researchers began dosing participants for their Phase 2 trial on May 28. In July Razi officials promised that they would be able to produce at least one million doses of the vaccine every month. At the end of August, Iran rolled out a Phase 3 trial.
  • The Tehran Times reported on Oct. 12 that a nasal dose of the vaccine reduces the transmission of the virus by as much as 90 percent. And on Nov. 14, scientists reported that the vaccine stimulates immunity for up to one year. Iranian health officials granted emergency use authorization for the vaccine on Nov. 1. Tasmin News Agency, an Iranian media outlet, reported on Nov. 30 that the researchers have begun a booster trial comparing the vaccine against the Sinopharm shot.


  • Mambisa: Cuban government’s Center for Genetic Engineering and Biotechnology, which developed Latin America’s first COVID-19 vaccine Abdala, is undertaking a Phase I/II study of an intra-nasal three dose protein subunit vaccine candidate Mambisa (CIGB-669). According to the research agency, Mambisa is based on the formulation of the RBD (Receptor Binding Domain) protein and an immune enhancer, Hepatitis B nucleocapsid antigen.   
  • In addition to their Abdala vaccine, the Center for Genetic Engineering and Biotechnology of Cuba announced on Nov. 26, 2020 that it was beginning a Phase 1 trial of a second vaccine, this one delivered as a nasal spray. Known as Mambisa, the vaccine contains a piece of the coronavirus spike protein called the receptor-binding domain, along with a protein from the hepatitis B virus that stimulates the immune system. The name refers to women who fought in Cuba’s nineteenth-century wars of independence. Mambisa is one of two Cuban vaccines tested in a Phase 1/2 clinical trial to assess their ability to increase immunity in those who have already had Covid-19. That trial moved to Phase 2 in November. After releasing promising results from the trial, the researchers announced in January 2022 that they would continue evaluating the vaccine in human trials. Cuban health authorities approved a trial for Mambisa as a booster dose on Nov. 20.
  • Emergency use in: Iran

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Nasal Vaccines-Last Weapon in Our Armoury To End Pandemic!
Courtesy: Reference-2



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