|Year : 2022 | Volume
| Issue : 1 | Page : 17-21
Nasal vaccines for COVID-19: Current trends and future perspectives
Simran Spal1, Anshul Mahajan2, A Parvesh3, Vipra Kohli4, L V Simhachalam Kutikuppala5, Tarun Kumar Suvvari6
1 Department of General Medicine, Punjab Institute of Medical Sciences, Jalandhar, Punjab, India
2 Department of General Medicine, Government Medical College, Amritsar, Punjab, India
3 Department of General Medicine, PSG Institute of Medical Sciences and Research, Coimbatore, Tamil Nadu, India
4 Department of General Medicine, M.M. Medical College and Hospital, Solan, Himachal Pradesh, India
5 Department of Surgery, Konaseema Institute of Medical Sciences and Research Foundation, Amalapuram, Andhra Pradesh, India
6 Department of General Medicine, Rangaraya Medical College, Kakinada, Andhra Pradesh, India
|Date of Submission||04-Oct-2021|
|Date of Acceptance||16-Jun-2022|
|Date of Web Publication||14-Oct-2022|
Dr. L V Simhachalam Kutikuppala
Konaseema Institute of Medical Sciences and Research Foundation, Amalapuram - 533 201, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Coronavirus disease (COVID-19), a highly contagious viral respiratory illness, has resulted in widespread human losses, as well as posing more newer difficulties to the global health infrastructure. Vaccination has been a powerful public health tool for preventing deadly diseases, and it is still the most effective weapon when dealing with pandemics. Intranasal vaccines form an important part of the next-generation vaccines being developed to bolster our arsenal against infectious diseases. Nasal delivery of vaccines induces both systemic and local mucosal immune responses to help scale up the war against the inhaled pathogens. Owing to its simplicity, ease, convenience, safety, and higher effectivity, intranasal vaccines are turning out to be a promising alternative to the parenteral and other mucosal routes of administration. Intranasal vaccines are considered more efficacious than conventional parenteral injectable vaccines for influenza virus. The vaccination rate can be increased as the intranasal vaccine is directly delivered into nasal cavity and involves less cumbersome and painless procedure than intravenous administration. Nasal mucosa is an easily accessible organ with rich vascular supply and large surface area available for absorption aiding in quick absorption of vaccine. Furthermore, the intranasal vaccines are more affordable than the conventional vaccines.
Keywords: COVID-19, global health, infectious disease, intranasal vaccine, public health
|How to cite this article:|
Spal S, Mahajan A, Parvesh A, Kohli V, Kutikuppala L V, Suvvari TK. Nasal vaccines for COVID-19: Current trends and future perspectives. Ann Indian Acad Otorhinolaryngol Head Neck Surg 2022;6:17-21
|How to cite this URL:|
Spal S, Mahajan A, Parvesh A, Kohli V, Kutikuppala L V, Suvvari TK. Nasal vaccines for COVID-19: Current trends and future perspectives. Ann Indian Acad Otorhinolaryngol Head Neck Surg [serial online] 2022 [cited 2023 Mar 26];6:17-21. Available from: https://www.aiaohns.in/text.asp?2022/6/1/17/358577
| Introduction|| |
SARS-CoV-2 causes coronavirus disease (COVID-19), a highly contagious viral respiratory illness. COVID-19 pandemic has resulted in widespread human losses, as well as posing new difficulties to global health systems.
Vaccination has been a powerful public health tool for preventing deadly diseases, and it is still the most effective weapon when dealing with pandemics. Vaccines not only provide individual protection; they provide community protection by inducing herd immunity, thereby limiting disease transmission within a population.
Currently, eight vaccination classes are licensed for use [Table 1]. The use of technology has enabled the production of newer vaccines to combat emerging diseases. For COVID-19, six vaccine classes are being evaluated in clinical trials [Table 2]. Intranasal and intramuscular delivery methods of vaccines are favored than the traditional subcutaneous approaches due to their stronger immune response.,
|Table 2: Classes of vaccines undergoing clinical trials for coronavirus disease-19|
Click here to view
| Licensed Intranasal Vaccines|| |
Intranasal vaccines form an important part of the next-generation vaccines being developed to bolster our arsenal against infectious diseases. A few nasal vaccines have already been approved for human use.
FluMist® (MedImmune, LLC) is the first live attenuated influenza virus intranasal vaccine that was successfully approved and commercialized in the US and Europe (as Fluenz®). Nasovac® (Serum Institute of India, Ltd.) is an intranasal flu vaccine approved in India. Intranasal influenza virus-inactivated vaccine, namely Nasalflu® (Berna Biotech AG, Switzerland), was made available for a short time period and then discontinued in the year 2001 due to its potential side effects.
| Mechanism of Action of Intranasal Vaccines|| |
There is extensive literature studying the effects of intranasal administration of vaccines against infectious diseases (e.g., measles, meningitis, tuberculosis, and pneumonia).
Nasal delivery of vaccines induces both systemic and local mucosal immune responses to help scale up the war against the inhaled pathogens.
The local microbial-specific immune responses at the mucosal surface come from a dense network of lymphatic tissues associated with the nasal epithelium known as nasopharynx-associated lymphoid tissue (NALT) which is the primary target site for nasally administered vaccines. It is present in the Waldeyer's ring, which also comprises pharynx and tonsils. NALT is covered by mucosal follicle-associated epithelial layer which contains distinctive cells called M-cells. The antigen from the immunized vaccine is actively transported by these M-cells to reach dendritic cells, macrophages, and B-cells for processing and presentation.
Consequently, activated antigen-specific CD4+ T helper cells (Th cells) interact with B-cells which sequentially differentiate into immunoglobulin A (IgA)-producing plasma in the presence of cytokines such as interleukin-5 and interleukin-6, which are released by the Th2 cells and secrete IgA in the form of dimers. Dimeric IgA then becomes S-IgA by binding to the polymeric Ig receptor, which transports IgA to effector sites. S-IgA is able to bind toxins, bacteria, or viruses and neutralize their activity, thus preventing entry into the body or reaching the internal organs, and forms a first barrier of defense against invading antigens. The high vascularity and rich lymphatics in the nose promote the rapid vaccine uptake, eliciting a robust IgG antibody response which helps in clearance of pathogens from systemic sites as well. Current nasal formulations include solutions (drops or sprays), powders, gels, and aerosols.
Most antigens do not have affinity for the nasal epithelium and tend to be removed quickly by mucociliary clearance. To combat this, adjuvants and mucoadhesives such as polylactide-co-glycolide, chitosan, alginate, and carbopol may be added to vaccines to enhance their absorption and residence time to facilitate interaction with the immune system. Overall, nasal administration of vaccines has been shown to achieve a better bioavailability and protection from gastric enzymes compared to parenteral and oral administration.
| Current Stage of Development of Intranasal COVID Vaccines|| |
Intranasal vaccines make up a minor fraction of the COVID-19 vaccines being produced around the world. Some vaccinations are currently in Phase 1 clinical trials [Table 3], whereas others are in preclinical testing [Table 4].
|Table 4: Intranasal coronavirus disease-19 vaccines undergoing preclinical testing|
Click here to view
Altimmune – AdCOVID
AdCOVID is a single-dose adenoviral-vectored intranasal COVID-19 vaccine being developed by Altimmune. It is currently undergoing Phase 1 trial in 180 healthy volunteers aged 18–55 and has completed animal studies which demonstrated strong activation of the three critical arms of the immune system following a single intranasal dose of AdCOVID - namely serum neutralizing activity with serum neutralization titer of 1:580 by the 28th day, T-cell immunity-potent stimulation of antigen-specific CD8+ killer T-cells in the lungs of mice within 10 days after vaccination, and mucosal immunity with a 29-fold increase in mucosal IgA.
AstraZeneca and University of Oxford – ChAdOx1 nCoV-19
ChAdOx1 nCoV-19 is a double-dose COVID-19 vaccine currently being administered intramuscularly. The University of Oxford is currently conducting Phase 1 trials investigating the delivery of the ChAdOx1 nCoV-19 coronavirus vaccine using an intranasal spray device similar to the over-the-counter hay fever nasal sprays. The Phase I trial consists of 30 healthy volunteers aged 18–40.
Bharat Biotech and Washington University in St. Louis – BBV154
BBV154 is an adenoviral-vectored intranasal COVID vaccine currently undergoing Phase 1 clinical trials. Animal trials have been successfully completed in which mice, hamsters, and macaques immunized with a single dose of ChAd-SARS-CoV-2-S conferred superior protection against SARS-CoV-2 challenge. Postchallenge with SARS-CoV-2, viral clearance was observed in both lower and upper airways in all these animal models. The Phase I's 175 participants are divided into three groups. In Group 1, 70 volunteers will receive the single-dose vaccine on day 0 and a placebo on day 28. Meanwhile, 70 participants in Group 2 will receive two doses of the vaccine with a 28-day gap. Some 35 participants in Group 3 will receive placebo in both doses.
Codagenix and Serum Institute of India – COVI-VAC
COVI-VAC is a single-dose, intranasal, live attenuated vaccine against COVID-19, generated using proprietary deoptimization technology. According to Codagenix, COVI-VAC will produce immunity against all SARS-CoV-2 proteins, not just the spike surface protein, positioning it to protect against a range of SARS-CoV-2 strains. They are currently conducting a Phase 1 clinical study in 48 healthy young subjects (18–30 years of age). The subjects, divided into three groups, will receive either two doses of COVI-VAC, 28 days apart, two doses of placebo (saline) or one dose of COVI-VAC and one dose of placebo.
Meissa Vaccines: MV-014-212
MV-014-212 chimeric live attenuated intranasal single-dose COVID vaccine is currently undergoing Phase 1 clinical trials. According to Meissa team, they employed rational and precise codon deoptimization and other genetic strategies to produce hundreds of targeted mutations into the respiratory syncytial virus (RSV) genome, providing exquisite control over viral protein expression wherein they replaced RSV surface proteins with the SARS-CoV-2 spike protein. They claim that candidates generated by synthetic biology have increased antigen expression (S protein for COVID-19) and decreased or eliminated expression of immune suppressors. They incorporated codon deoptimization to reduce the efficiency of translating viral mRNA into proteins. By selecting and replacing commonly used codons with nonpreferred codons in viral genes that inhibit the immune response, the translation of these viral mRNAs into proteins becomes inefficient resulting in heavy attenuation, optimized immunity, and genetic stability.
Laboratorio Avi-Mex: rNDV Vaccine
rNDV Vaccine is a recombinant NDV-vectored vaccine for SARS-CoV-2. It is currently undergoing a Phase 1, open-label, nonrandomized, dose-escalation study using three doses and two schemes (intramuscular and intranasal) of administration of the recombinant vaccine against SARS-CoV-2 based on a viral vector (Newcastle disease virus) in 90 healthy volunteers.
| Merits of Nasal Vaccine Delivery|| |
Owing to its simplicity, ease, convenience, safety, and higher effectivity, intranasal vaccines are turning out to be a promising alternative to the parenteral and other mucosal routes of administration. It offers the advantage of being stable at room temperature, making them easier to store and transport with no cold chain requirements which can potentially improve access to vaccination in remote and resource-poor settings.
It minimizes the risk of transmitting diseases such as HIV, hepatitis B, and other infections arising due to improper injection practices and improves patient compliance in the overall population. In addition, nasal-inactivated vaccines can be administered to vulnerable populations because they have a higher safety profile. The vaccination rate can be increased as the intranasal vaccine is directly delivered into nasal cavity and involves less cumbersome and painless procedure than intravenous administration. Nasal mucosa is an easily accessible organ with rich vascular supply and large surface area available for absorption aiding in quick absorption of vaccine. Moreover, the intranasal vaccines are more affordable than the conventional vaccines.
| Demerits of Nasal Vaccine Delivery|| |
The performance of the vaccines can be significantly influenced by the physical properties of vaccines. Nasal vaccines must be carefully developed to elicit a strong immune response while avoiding local discomfort and other side effects. Despite its ease of access, the nose's narrow and complicated geometry makes it difficult to administer vaccines and medications to the mucosal surfaces in a reliable and effective manner. Traditional spray pumps deliver the dose predominantly to the anterior section of the nasal canal, which is lined with skin rather than mucosa. Hence, a specialized nasal delivery device is required. Every 3–8 h, the nasal cycle, which is present in 80% of humans, generates reciprocal congestion and decongestion of the two nasal passages. There is a restriction of delivery volume (25–200 μL) in the nasal cavity and high-molecular-weight compounds cannot be delivered through this route (mass cutoff ~1 kD).
Normal defense mechanisms such as mucociliary clearance, ciliary beating, and enzymatic inhibition affect the permeability of the drug. Rapid nasal clearance may not allow sufficient retention for antigen to be taken up by antigen-presenting cells in the NALT. Obstructions and alterations in nasal aerodynamics can be caused by septal abnormalities, nasal polyps, and intranasal diseases. As a result, vaccinating both nasal passageways are considered rational.
| Efficacy of Existing Intranasal Vaccines|| |
Intranasal route of vaccine administration is previously being employed for prevention of pulmonary disease caused by influenza virus. In the absence of mucosal immunity, the nasal cavity may become a reservoir for the coronavirus, putting the patient at risk for reinfection or disease transmission to others.
Intranasal vaccines are considered more efficacious than conventional parenteral injectable vaccines for influenza virus. Intranasal vaccines induce both cross-reactive S-IgA providing mucosal immunity and serum IgG Abs whereas the injectable vaccines induce only serum IgG Abs. Cross-reactive antibodies provide cross-protection. S-IgA is a major immune component in upper respiratory tract mucosa. This property can be employed against COVID-19 which causes mainly upper respiratory tract infection, preventing both infection and transmission. On the contrary, S-IgG produced by injectable vaccines induces an immune response in lower respiratory mucosa which makes them less effective as compared to nasal vaccines. Intranasal vaccination can also result in stimulation of Th17 CD4+ cells, which can aid tissue repair and secretion of antimicrobial peptides, which can exert a protective effect in pulmonary infection.
A study conducted in Switzerland revealed that adjuvant was required with intranasal vaccines to induce a humoral immune response comparable to the response observed after parenteral vaccination. Another study revealed that the efficacy of adjuvant combined nasal-inactivated vaccines was found to be 61% with mild side effect profile. Hence, adjuvants appear to be required for enhancing the immune response of nasal vaccines.
Preclinical and Phase 1 clinical trials show that intranasal vaccines induce mucosal immunity, systemic immunity, T-cell activation, and virus-specific neutralizing antibody responses for several months postvaccination. However, the efficacy of intranasal COVID vaccines is difficult to predict as the delivery of vaccine to the nasal mucosa depends on the delivery device used. A specialized nasal delivery device is required to deliver vaccine directly into the olfactory mucosa rather than anterior part of nasal canal. Mucosal surfaces feature a variety of pathogen-repelling barriers, such as high acidity in the upper gastrointestinal tract and sticky mucous layers in the respiratory system, which may prevent vaccinations from reaching and activating the mucosal immune system.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Dhama K, Khan S, Tiwari R, Sircar S, Bhat S, Malik YS, et al
. Coronavirus disease 2019-COVID-19. Clin Microbiol Rev 2020;33:e00028-20.
Orenstein WA, Ahmed R. Simply put: Vaccination saves lives. Proc Natl Acad Sci US A 2017;114:4031-3.
Iwasaki A, Omer SB. Why and how vaccines work. Cell 2020;183:290-5.
Cook IF. Evidence based route of administration of vaccines. Hum Vaccin 2008;4:67-73.
Birkhoff M, Leitz M, Marx D. Advantages of intranasal vaccination and considerations on device selection. Indian J Pharm Sci 2009;71:729-31. [Full text]
Ramvikas M, Arumugam M, Chakrabarti SR, Jaganathan KS. Nasal vaccine delivery. Micro and Nanotechnology in Vaccine Development 2017:279-301.
Bahamondez-Canas TF, Cui Z. Intranasal immunization with dry powder vaccines. Eur J Pharm Biopharm 2018;122:167-75.
Billich A. Technology evaluation: FluMist, University of Michigan. Curr Opin Mol Ther 2000;2:340-4.
Kulkarni PS, Raut SK, Dhere RM. A post-marketing surveillance study of a human live-virus pandemic influenza a (H1N1) vaccine (Nasovac (®)) in India. Hum Vaccin Immunother 2013;9:122-4.
Mutsch M, Zhou W, Rhodes P, Bopp M, Chen RT, Linder T, et al
. Use of the inactivated intranasal influenza vaccine and the risk of Bell's palsy in Switzerland. N Engl J Med 2004;350:896-903.
Yusuf H, Kett V. Current prospects and future challenges for nasal vaccine delivery. Hum Vaccin Immunother 2017;13:34-45.
van de Pavert SA, Mebius RE. New insights into the development of lymphoid tissues. Nat Rev Immunol 2010;10:664-74.
Wu HY, Nguyen HH, Russell MW. Nasal lymphoid tissue (NALT) as a mucosal immune inductive site. Scand J Immunol 1997;46:506-13.
Ogasawara N, Kojima T, Go M, Takano K, Kamekura R, Ohkuni T, et al
. Epithelial barrier and antigen uptake in lymphoepithelium of human adenoids. Acta Otolaryngol 2011;131:116-23.
Zaman M, Chandrudu S, Toth I. Strategies for intranasal delivery of vaccines. Drug Deliv Transl Res 2013;3:100-9.
Johansen FE, Kaetzel CS. Regulation of the polymeric immunoglobulin receptor and IgA transport: New advances in environmental factors that stimulate pIgR expression and its role in mucosal immunity. Mucosal Immunol 2011;4:598-602.
Almeida AJ, Alpar HO. Nasal delivery of vaccines. J Drug Target 1996;3:455-67.
Garg NK, Mangal S, Khambete H, Tyagi RK. Mucosal delivery of vaccines: Role of mucoadhesive/biodegradable polymers. Recent Pat Drug Deliv Formul 2010;4:114-28.
Rawat K, Kumari P, Saha L. COVID-19 vaccine: A recent update in pipeline vaccines, their design and development strategies. Eur J Pharmacol 2021;892:173751.
jpoly4. AdCOVIDTM – Single-Dose Intranasal COVID-19 Vaccine | Altimmune. Altimmune A Clinical Stage Biopharmaceutical Company; April 02, 2020. Available from: https://altimmune.com/adcovid/
. [Last accessed on 2021 Jun 22].
Tanner AR, Dorey RB, Brendish NJ, Clark TW. Influenza vaccination: Protecting the most vulnerable. Eur Respir Rev 2021;30:200258.
Beule AG. Physiology and pathophysiology of respiratory mucosa of the nose and the paranasal sinuses. GMS Curr Top Otorhinolaryngol Head Neck Surg 2010;9:Doc07.
Tarride JE, Burke N, Von Keyserlingk C, O'Reilly D, Xie F, Goeree R. Cost-effectiveness analysis of intranasal live attenuated vaccine (LAIV) versus injectable inactivated influenza vaccine (TIV) for Canadian children and adolescents. Clinicoecon Outcomes Res 2012;4:287-98.
Ehrick JD, Shah SA, Shaw C, Kulkarni VS, Coowanitwong I, De S, et al
. Considerations for the development of nasal dosage forms. Sterile Prod Dev 2013;6:99-144.
Liang J, Lane AP. Topical drug delivery for chronic rhinosinusitis. Curr Otorhinolaryngol Rep 2013;1:51-60.
Hasegawa M, Kern EB. The human nasal cycle. Mayo Clin Proc 1977;52:28-34.
Singh AK. Nasal cavity: A promising transmucosal platform for drug delivery and research approaches from nasal to brain targeting. J Drug Deliv Ther 2012;2:22-33.
Choudhary R, Goswami L. Nasal route: A novelistic approach for targeted drug delivery to CNS. Int Res J Pharm 2013;4:59-62.
Tamura S, Ainai A, Suzuki T, Kurata T, Hasegawa H. Intranasal inactivated influenza vaccines: A reasonable approach to improve the efficacy of influenza vaccine? Jpn J Infect Dis 2016;69:165-79.
Ainai A, Suzuki T, Tamura SI, Hasegawa H. Intranasal administration of whole inactivated influenza virus vaccine as a promising influenza vaccine candidate. Viral Immunol 2017;30:451-62.
Russell MW, Moldoveanu Z, Ogra PL, Mestecky J. Mucosal immunity in COVID-19: A neglected but critical aspect of SARS-CoV-2 infection. Front Immunol 2020;11:611337.
Glück U, Gebbers JO, Glück R. Phase 1 evaluation of intranasal virosomal influenza vaccine with and without Escherichia coli heat-labile toxin in adult volunteers. J Virol 1999;73:7780-6.
Hashigucci K, Ogawa H, Ishidate T, Yamashita R, Kamiya H, Watanabe K, et al
. Antibody responses in volunteers induced by nasal influenza vaccine combined with Escherichia coli heat-labile enterotoxin B subunit containing a trace amount of the holotoxin. Vaccine 1996;14:113-9.
[Table 1], [Table 2], [Table 3], [Table 4]