Nasal vaccine

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A nasal vaccine is a vaccine administered through the nose that stimulates an immune response without an injection. It induces immunity through the inner surface of the nose, a surface that naturally comes in contact with many airborne microbes. [1] Nasal vaccines are emerging as an alternative to injectable vaccines because they do not use needles and can be introduced through the mucosal route. Nasal vaccines can be delivered through nasal sprays to prevent respiratory infections, such as influenza.

Contents

History

Nasal inoculation dates as far back as the 17th century in China during the Kangxi Emperor’s reign. Documentation during this period indicates that the Kangxi Emperor vaccinated his family, army, and others for mild smallpox. Manuals detailing vaccination techniques at the time all focused on sending smallpox up the nose of the individual being vaccinated. Although other vaccination techniques were developed using an infected individual’s scabs, a common method was to place a cotton swab with the fluid from an infected person’s pustule up the nose. [2]

Following smallpox, influenza became a prominent focus for nasal vaccine development. The first live attenuated influenza vaccine (LAIV) in the form of a nasal spray was created in Russia by the Institute of Experimental Medicine in 1987. This nasal vaccine development was based on the Russian backbone of LAIV while nasal vaccines since then have been based on other LAIV backbones. [3] The first nasal influenza vaccine was released in the United States in 2001 but was taken off the market due to toxicity concerns. FluMist, one of the most prominent nasal LAIVs, was released in 2003 as nasal LAIVs continued developing. [4]

Nasal vaccine
GI receives an intranasal mist of the flu vaccine at Guantanamo.jpg
Application of an intranasal mist of the flu vaccine
Specialty Vaccine delivery

Anthrax attacks at the beginning of the 21st century caused a demand for nasal vaccine development. As anthrax is an airborne substance that can be inhaled, a nasal vaccine has the potential to be used to protect individuals from the effects it can have on the respiratory system. [5] Following the September 11, 2001 terrorist attacks in the United States, several individuals at news stations and U.S. senators died after being sent letters with anthrax as an act of bioterrorism. [6] Nasal vaccine research and development against anthrax was encouraged by the U.S. government in an effort to vaccinate troops. [5] [7] BioThrax, the current anthrax vaccine that is licensed and administered in the United States, requires up to five intramuscular injections and annual boosters; research within the past decade has developed an alternative nasal vaccine that follows the path of infection for anthrax and induces both humoral and cellular immune responses. [5]

The global COVID-19 pandemic led to a rise in nasal vaccines against coronavirus. International efforts for vaccine development occurred as countries such as India, Iran, Russia, and China created nasal COVID-19 vaccines.[ citation needed ]

Administration

Nasal vaccines are a subsection of mucosal immunization as they use a mucosal route for vaccine delivery. As many pathogens can enter the body through the nose, nasal vaccines take advantage of this mechanism to deliver the vaccine. The nose has multiple lines of defense to prevent pathogens from entering further into the body. Nasal hairs are the first defense as they are at the entrance of the nose and prevent large particles from entering. The mucus layer in the nasal cavity can trap smaller particles that get past the nose hairs. [8] The nasal cavity has a large vascularization network so particles can go through the epithelial layer and directly enter the bloodstream. [9] Intruding particles will interact with the mucosal immune system if they reach the nasal mucosa. The mucosal immune system is composed of lymphoid tissue, B cells, T cells, and antigen-presenting cells. These different types of cells work together to identify intruding particles and trigger an immune response. [8] Nasal vaccines must overcome these barriers and get clearance to deliver the viral antigen to patients. [4] Nasal vaccines must overcome these barriers and get clearance to deliver the viral antigen to patients. [10]

Nasal vaccines can come in different forms such as solutions (liquids), powders, gels, and solid inserts. The most prevalent type of nasal vaccine in research and clinical application is solutions due to its ease of use. Although solutions are usually pipetted into test subjects’ nostrils when conducting animal trials for nasal vaccines, nasal sprays are considered the most practical approach for mass human vaccination using nasal vaccines. [8] A nasal spray is able to bypass the initial layers of the nasal mucosa and deliver the vaccine particles directly to the mucoadhesive layer. [11] The antigen in the nasal vaccine can then trigger an immune response and prevent infection due to nasal vaccines’ accessibility to the immune system. [12] [13]

Human Nasal Anatomy Nose Anatomy.png
Human Nasal Anatomy

Nasal sprays are commonly used for delivering drugs in addition to vaccines. Decongestant drugs are often directly delivered to the nose through nasal sprays. Cold and allergy medication can be administered using nasal sprays for local delivery by bypassing nasal hairs and being introduced to the nasal cavity. Intranasal administration can have less drug degradation compared to oral administration because of direct particle delivery. Peptide drugs used for hormone treatments can be delivered nasally through nasal sprays instead of orally to retain particle integrity. Nasal sprays can also be used to deliver diabetes treatment, steroids, and intranasal oxytocin to induce labor. Nasal administration is also used to deliver anesthetics and sedatives due to direct access to the mucosal immune system and bloodstream. [14]

The olfactory epithelium makes up approximately 7% of the surface area of the nasal cavity and is connected to the olfactory bulb in the brain. Drugs and vaccines can be delivered to the brain past the blood-brain barrier through olfactory nerve cells. [14]

Compared to injectable vaccines, nasal vaccines can be advantageous because they are safe, painless, and easy to use. Nasal vaccines do not require a needle, which eliminates pain from needlestick injuries and safety concerns due to cross-contamination and needle disposal. Some studies also show that intranasal vaccines can generate cross-reactive antibodies that could lead to cross-protection. [8]

Live attenuated influenza vaccine

The live attenuated influenza vaccine (LAIV) in the form of a nasal spray was one of the first nasal vaccines released on the market. Nasal spray LAIVs have been used since the late 1980s as an alternative to the injectable influenza vaccine. [3] Nasal influenza vaccines have become popular as they reduce the risk of intramuscular injuries from administration and are painless. They can also be given more easily to patients because they do not require a needle.

FluMist Quadrivalent 14234CDC Flumist.tif
FluMist Quadrivalent

The most prominent nasal LAIV is FluMist, which was released in 2003. [4] FluMist, officially known as FluMist Quadrivalent in the United States and Fluenz in Europe, is known to be the only flu vaccine on the market that does not use a needle. [15] All nasal LAIVs for recent flu seasons (2022-2023) are considered quadrivalents because “they are designed to protect against four types of flu viruses: an influenza A(H1N1) virus, an influenza A(H3N2) virus and two influenza B viruses.” [16] Although injectable and nasal LAIVs are presented as options for yearly vaccination against influenza, FluMist was pulled off of the United States market from 2016 to 2018 due to its inefficiency against a common influenza strain in children. Since then, FluMist has been reformulated and has re-entered the market. [17]

Fluenz Tetra Fluenz Tetra for 2020 - 21 season.jpg
Fluenz Tetra

The active ingredients in nasal LAIVs are grown in fertilized chicken eggs. The practice of growing viruses in chicken eggs is common in vaccine production because these viruses need to be grown inside cells. [18] Virus fluid from the incubated chicken eggs is extracted and killed for the viral antigen to be purified for LAIV production. [19] Similar to other vaccines, nasal LAIVs contain ingredients in addition to the viral antigen. Stabilizers such as gelatine, arginine hydrochloride, monosodium glutamate, and sucrose are commonly used in vaccines to assure the vaccines are still effective during and after production, transportation, and storage as well as delivery. [20] [21] Stabilizers are especially important for nasal vaccines as proteases and amino-peptidase in the mucosal membrane can degrade proteins and peptides in vaccines. [4] Research continues to improve nasal LAIVs as influenza affects nearly 9 million people. [22] As influenza changes slightly each year, continuous research on new strains can improve vaccine efficiency. Research on nasal vaccine development for nontypeable Haemophilus influenzae shows that the vaccine binding to surface proteins prevented biofilm formation. As a result, this vaccine can have the potential to treat ear infections caused by biofilm from influenza infection. [23] New components like α-galactosylceramide (α-GalCer) are also being researched to be used as nasal vaccines against influenza. Since α-GalCer induced immune responses when immunized with a replication-deficient live adenovirus, there is evidence that nasal LAIVs can be co-immunized with other treatments against influenza. [24]

Intranasal COVID-19 vaccines

Prior to the 2020 global COVID-19 pandemic, animal studies in 2004 on African green monkeys tested a SARS-associated coronavirus (SARS-CoV) vaccine and showed that these monkeys did not emit the virus from their upper respiratory tract after being infected. [25] Since then, several intranasal COVID-19 vaccines have been developed with the onset of the COVID-19 pandemic. inCOVACC, Razi Cov Pars, Sputnik, and Convidicia are nasal COVID-19 vaccines that were developed throughout the world to improve vaccine availability and reduce the spread of COVID-19. [ citation needed ]

COVID-19 SARS-CoV-2 without background.png
COVID-19

In August 2020, during the COVID-19 pandemic, studies in mice and monkeys demonstrated that protection from the new coronavirus might be obtained through the nasal route. Another study postulated that if a COVID-19 vaccine could be given by a spray in the nose, people might be able to vaccinate themselves. [26] Research about the main characteristics of nasal spray vaccines that can affect the efficiency of vaccine delivery for COVID-19 indicates that the spray cone angle can impact the delivery efficiency; droplet initial velocity and composition did not have as much of an impact on nasal vaccine efficiency as the spray cone angle. [27]

India and China approved inCOVACC and Convidecia, respectively, to be used as boosters for those who have already received at least two COVID-19 vaccine doses. [28] Although nasal COVID-19 vaccine research continues in the United States, lack of government funding could prevent this research from moving on to human trials to get approval for public administration. [29] Privately funded research for nasal COVID-19 vaccines is starting to reach clinical trials; a nasal COVID-19 vaccine by Blue Lake Biotechnology has started its Phase 1 clinical trials as of late February 2023. Scientists speculate that nasal vaccines might have an advantage over other types of vaccines because they provide immune defense at the site of administration. [30]

Applications to veterinary medicine

Species other than humans use nasal vaccines to prevent diseases. Intranasal vaccines are used on dogs for Bordetella bronchiseptica to prevent infectious tracheobronchitis (ITB). ITB, commonly known as kennel cough, typically spreads in highly populated environments such as kennels and dog shelters. Consistent vaccination against ITB using an intranasal vaccine can create an immune response to protect the vaccinated dog. Consistent vaccination against ITB using an intranasal vaccine can create an immune response to protect the vaccinated dog. [31]

Bordetella Bronchiseptica Bordetella bronchiseptica.jpg
Bordetella Bronchiseptica

Cattle receive nasal vaccines against diseases such as bovine herpesvirus 1, parainfluenza type 3, and bovine rhinotracheitis virus. [32] [33] As all three of these viruses are related to respiratory infection, using an intranasal route can bring the vaccine directly to the respiratory system.

Recent discoveries indicate that rainbow trout have a previously unknown lymphoid structure in their nasal cavity. This structure allows them to have fast innate and adaptive responses to nasal vaccines. [34]

Research

Nasal spray Nasal Spray (46057881342).jpg
Nasal spray

Current research is exploring new technologies and developments to improve nasal vaccine delivery methods. Particle size and characteristics have become a focus of research as smaller particles can travel more easily to reach the epithelial layer of the nasal cavity compared to larger particles. Nanoparticles and nanosystems are being researched to optimize nasal delivery. Coated nanoparticles are an area of focus due to their properties to induce immune effects. Glycol chitosan-coated nanoparticles induced more of an immune response compared to the other types of nanoparticles. [35] Nanocarriers designed based on the characteristics of the nasal epithelium can be used to deliver nasal vaccines and can therefore make nasal vaccination more accessible. [36] Polymeric nanosystems are also being developed to deliver vaccines to target sites while preventing them from degrading; current research is focused on understanding the material and physical properties of biodegradable materials to be used in nanosystems to improve vaccine efficacy. [37] Research on the movement of nasal vaccine particles is focused on developing more effective ways for these vaccines to enter the body. An animal study on mice tested how a nasal vaccine can bypass issues with entry into the nasal epithelium by taking advantage of ciliary movement. The results indicated that tubulin tyrosine ligase-like family member 1 (Ttll1) knockout mice had higher levels of the vaccine antigen compared to the hetero mice. [38]

See also

Related Research Articles

<span class="mw-page-title-main">Vaccine</span> Pathogen-derived preparation that provides acquired immunity to an infectious disease

A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and recognize further and destroy any of the microorganisms associated with that agent that it may encounter in the future.

<span class="mw-page-title-main">DNA vaccine</span> Vaccine containing DNA

A DNA vaccine is a type of vaccine that transfects a specific antigen-coding DNA sequence into the cells of an organism as a mechanism to induce an immune response.

Antigenic drift is a kind of genetic variation in viruses, arising from the accumulation of mutations in the virus genes that code for virus-surface proteins that host antibodies recognize. This results in a new strain of virus particles that is not effectively inhibited by the antibodies that prevented infection by previous strains. This makes it easier for the changed virus to spread throughout a partially immune population. Antigenic drift occurs in both influenza A and influenza B viruses.

<span class="mw-page-title-main">Influenza vaccine</span> Vaccine against influenza

Influenza vaccines, colloquially known as flu shots, are vaccines that protect against infection by influenza viruses. New versions of the vaccines are developed twice a year, as the influenza virus rapidly changes. While their effectiveness varies from year to year, most provide modest to high protection against influenza. Vaccination against influenza began in the 1930s, with large-scale availability in the United States beginning in 1945.

<span class="mw-page-title-main">Live attenuated influenza vaccine</span> Nasal influenza vaccine

Live attenuated influenza vaccine (LAIV) is a type of influenza vaccine in the form of a nasal spray that is recommended for the prevention of influenza. It was developed by the Syrian-American epidemiologist Hunein Maassab.

Virus-like particles (VLPs) are molecules that closely resemble viruses, but are non-infectious because they contain no viral genetic material. They can be naturally occurring or synthesized through the individual expression of viral structural proteins, which can then self assemble into the virus-like structure. Combinations of structural capsid proteins from different viruses can be used to create recombinant VLPs. Both in-vivo assembly and in-vitro assembly have been successfully shown to form virus-like particles. VLPs derived from the Hepatitis B virus (HBV) and composed of the small HBV derived surface antigen (HBsAg) were described in 1968 from patient sera. VLPs have been produced from components of a wide variety of virus families including Parvoviridae, Retroviridae, Flaviviridae, Paramyxoviridae and bacteriophages. VLPs can be produced in multiple cell culture systems including bacteria, mammalian cell lines, insect cell lines, yeast and plant cells.

<span class="mw-page-title-main">MedImmune</span> Biopharmaceutical company, acquired by AstraZeneca in 2007

MedImmune, LLC was a wholly owned subsidiary of AstraZeneca before February 14, 2019, when it was announced that the MedImmune name and branding would be discontinued in favor of AstraZeneca.

<i>Influenza B virus</i> Species of virus

Influenza B virus is the only species in the genus Betainfluenzavirus in the virus family Orthomyxoviridae.

An attenuated vaccine is a vaccine created by reducing the virulence of a pathogen, but still keeping it viable. Attenuation takes an infectious agent and alters it so that it becomes harmless or less virulent. These vaccines contrast to those produced by "killing" the pathogen.

<span class="mw-page-title-main">Influenza</span> Infectious disease

Influenza, commonly known as "the flu" or just "flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms begin one to four days after exposure to the virus and last for about two to eight days. Diarrhea and vomiting can occur, particularly in children. Influenza may progress to pneumonia from the virus or a subsequent bacterial infection. Other complications include acute respiratory distress syndrome, meningitis, encephalitis, and worsening of pre-existing health problems such as asthma and cardiovascular disease.

A subunit vaccine is a vaccine that contains purified parts of the pathogen that are antigenic, or necessary to elicit a protective immune response. Subunit vaccine can be made from dissembled viral particles in cell culture or recombinant DNA expression, in which case it is a recombinant subunit vaccine.

<span class="mw-page-title-main">2009 swine flu pandemic vaccine</span> Protection against the H1N1/09 virus

The 2009 swine flu pandemic vaccines were influenza vaccines developed to protect against the pandemic H1N1/09 virus. These vaccines either contained inactivated (killed) influenza virus, or weakened live virus that could not cause influenza. The killed virus was injected, while the live virus was given as a nasal spray. Both these types of vaccine were produced by growing the virus in chicken eggs. Around three billion doses were produced, with delivery in November 2009.

Nasal- or nasopharynx- associated lymphoid tissue (NALT) represents immune system of nasal mucosa and is a part of mucosa-associated lymphoid tissue (MALT) in mammals. It protects body from airborne viruses and other infectious agents. In humans, NALT is considered analogous to Waldeyer's ring.

Vaccine shedding is a form of viral shedding which can occasionally occur following a viral infection caused by an attenuated vaccine. Illness in others resulting from transmission through this type of viral shedding is rare. Most vaccines are not attenuated vaccines, and therefore cannot cause vaccine-induced viral shedding, though the idea of shedding is a popular anti-vaccination myth.

mRNA vaccine Type of vaccine

An mRNAvaccine is a type of vaccine that uses a copy of a molecule called messenger RNA (mRNA) to produce an immune response. The vaccine delivers molecules of antigen-encoding mRNA into immune cells, which use the designed mRNA as a blueprint to build foreign protein that would normally be produced by a pathogen or by a cancer cell. These protein molecules stimulate an adaptive immune response that teaches the body to identify and destroy the corresponding pathogen or cancer cells. The mRNA is delivered by a co-formulation of the RNA encapsulated in lipid nanoparticles that protect the RNA strands and help their absorption into the cells.

<span class="mw-page-title-main">Vaxart</span> American biotechnology company based in San Francisco

Vaxart, Inc. is an American biotechnology company focused on the discovery, development, and commercialization of oral recombinant vaccines administered using temperature-stable tablets that can be stored and shipped without refrigeration, eliminating the need for needle injection. Its development programs for oral vaccine delivery include prophylactic, enteric-coated tablet vaccines for inhibiting norovirus, seasonal influenza, respiratory syncytial virus, and human papillomavirus. It was founded in 2004 by Sean Tucker. Originally incorporated as West Coast Biologicals, Inc. in California in 2004, the company later changed its name to Vaxart, Inc. in July 2007, after reincorporating in Delaware. A significant development in the company's history was the reverse merger with Aviragen Therapeutics, Inc. on February 13, 2018, which led to Vaxart becoming a wholly-owned subsidiary of Aviragen. Post-merger, the company continued as Vaxart, Inc.

<span class="mw-page-title-main">Viral vector vaccine</span> Type of vaccine

A viral vector vaccine is a vaccine that uses a viral vector to deliver genetic material (DNA) that can be transcribed by the recipient's host cells as mRNA coding for a desired protein, or antigen, to elicit an immune response. As of April 2021, six viral vector vaccines, four COVID-19 vaccines and two Ebola vaccines, have been authorized for use in humans.

<span class="mw-page-title-main">DelNS1-2019-nCoV-RBD-OPT</span> Vaccine against COVID-19

DelNS1-2019-nCoV-RBD-OPT is a COVID-19 vaccine developed by Beijing Wantai Biological, Xiamen University and the University of Hong Kong. It is administered as a single dose intranasal spray.

Type A influenza vaccine is for the prevention of infection of influenza A virus and also the influenza-related complications. Different monovalent type A influenza vaccines have been developed for different subtypes of influenza A virus including H1N1 and H5N1. Both intramuscular injection or intranasal spray are available on market. Unlike the seasonal influenza vaccines which are used annually, they are usually used during the outbreak of certain strand of subtypes of influenza A. Common adverse effects includes injection site reaction and local tenderness. Incidences of headache and myalgia were also reported with H1N1 whereas cases of fever has also been demonstrated with H5N1 vaccines. It is stated that immunosuppressant therapies would reduce the therapeutic effects of vaccines and that people with egg allergy should go for the egg-free preparations.

Live recombinant vaccines are biological preparations that stimulate immune responses to a pathogen through the use of genetically modified live bacteria or viruses. These live pathogens are biologically engineered to express exogenous antigens in the cytoplasm of target cells, thereby triggering immune responses. This form of vaccine combines the beneficial features of attenuated and recombinant vaccines, providing the long-lasting immunity of attenuated vaccines’ with recombinant vaccines’ genetically engineered precision and safety.

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  38. ↑ Lan, Huangwenxian; Suzuki, Hidehiko; Nagatake, Takahiro; Hosomi, Koji; Ikegami, Koji; Setou, Mitsutoshi; Kunisawa, Jun (August 2020). "Impaired mucociliary motility enhances antigen-specific nasal IgA immune responses to a cholera toxin-based nasal vaccine". International Immunology. 32 (8): 559–568. doi:10.1093/intimm/dxaa029. PMC   9262165 . PMID   32347929 . Retrieved 2023-04-14.
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