The decision to give systemic COVID vaccines to children aged 5–11 is finely balanced, since very few young children suffer severely with SARS-CoV-2 infection, probably because of their more effective innate immunity (1). In addition recent data suggests that Pfizer vaccine efficacy is low in 5–11 year olds (2). Presumably the need to reduce viral transmission and hence the development of new strains is one consideration. Some 12 months after the first COVID-19 vaccine received WHO Emergency Use Listing (EUL), more than 9 billion COVID-19 vaccine doses have been administered globally. These systemic vaccines have been remarkably successful in reducing morbidity and mortality from SARS-CoV-2 but have only modest effect on viral transmission (3), probably because systemic vaccination does not provide sufficient mucosal protection (4).
If there is a need to vaccinate children worldwide then an alternative mucosal route might be safer, simpler and superior in reducing transmission, as well as more acceptable to children and their carers.
SARS-CoV-2 enters the body mainly via the ciliated cells in the upper airway (5). The nose defends the lower airways and the lungs and provides a route for therapy (6). Part of this defence is innate, involving muco-ciliary clearance, interferon, nitric oxide gas; the adaptive (educable) immune system is also involved. This is the mucosal, not the systemic immune system. The major relevant antibody is not IgG, but IgA. Local generation of secretory IgA (SIgA) which constitutes the body's biggest humoral immune system can exclude pathogens, neutralize viruses inside virus-infected epithelial cells and can redirect antigens in the lamina propria to the lumen (7). Viral upper airway infections such as influenza, rhinovirus and SARS-CoV-2 are associated with an increase of S-IgA in nasal lavage. IgA plays an important role in the protection against influenza in humans (8, 9). Mice lacking S-IgA have increased viral load after intranasal challenges (10) and transfer of nasal IgA from immunized to naïve mice leads to protection (11). Volunteers infected with coronavirus 229E had IgA antibody in nasal fluids associated with reduced periods of viral shedding (12). Elite athletes with increased viral colds show decreased salivary S-IgA (13–15). In COVID infection IgA antibodies against SARS-CoV-2 were elevated in nasal fluids, tears, and saliva (16, 17). Salivary antibodies persisted for at least 3 months (18).
Systemic (intramuscular) immunization does not confer significant mucosal immunity (4). The reverse is not true. The advantages of the intranasal route, in addition to rapidity and needle-free administration, include the generation of both mucosal (SIgA) and circulating (IgG and IgA) antibodies, as well as T cell responses. Intranasal vaccination induces resident memory T cells (TRM) which provide stronger protective immunity than circulating T cells (19) and could be particularly beneficial for rapidly mutating pathogens, such as SARS-CoV-2, where antibody-mediated protection is swiftly evaded (20). Intranasal vaccination might achieve desirable results, such as reduced viral transmission, not obtained with systemic immunization. It is also less likely to result in systemic inflammatory problems such as pericarditis and myocarditis, seen in systemically-immunized adolescents. Adverse events of vaccination such as vaccine-associated enhanced respiratory (VAERD) disease (21), as seen in some newly-infected children who have received systemic inactivated measles or RSV immunization, is less likely with a nasal vaccine which should result in inability of the virus to combine with its receptor and immune exclusion by phagocytosis after combination with divalent IgA, linked by secretory piece (6), thus obviating lower respiratory tract infection. Th2 stimulation, seen with COVID infection and with current systemic COVID vaccines, might be avoided by use of a suitable adjuvant (22).
Intranasal vaccines are already available against influenza, others are under development against COVID 19 (23). Used in UK children live attenuated nasal influenza vaccine shows consistently good effectiveness and indirect protection extending to both older and younger age groups has been demonstrated (24). Another advantage of intranasal influenza vaccine over the injection route is the induction of cross-reactive antibodies which provide variant strain protection (25). This concept may also apply to SARS-CoV-2, though as yet there is no evidence. The nasally applied influenza virus has been temperature-adapted so that it can only replicate in an environment as cold as the nose, not in the warmer lung. The Omicron variant of SARS-CoV-2 also appears to be similarly restricted, causing significantly less lung disease than its predecessors, whilst improving immunity against the more pathogenic delta variant (26). Site—directed mutagenesis might provide a similar asymptomatic or minimally symptomatic variant confined to the nose and appropriate as a vaccine.
In order to evoke a nasal mucosal immune response the SARS-CoV-2 virus would need to evade the normal nasal defence mechanisms such as mucociliary clearance, and achieve absorption through the mucosa in order to reach the local nasal associated lymphoid tissue (NALT). The spike protein should enable viral adhesion via its affinity for ACE 2 and TLR4 receptors which are present on the nasal epithelium (27). Children have lower respiratory ACE 2R expression than adults, topical corticosteroids also reduce ACE 2R expression. If the virus fails to interact with the nasal mucosa it will be moved by muco-ciliary clearance to the throat and swallowed, reaching the gut. Here a mucosal response can also be initiated by the local associated lymphoid tissue (GALT), which as part of the mucosal associated lymphoid tissue (MALT), can protect the respiratory tract (28). In COVID-19 infection (GI) symptoms predict better clinical outcomes with significantly lower death rates (29).
If nasal immunization is insufficient to provide protective immunity, then an alternative strategy would be to initiate a response by systemic vaccination, but to boost this nasally (30).
Animal studies suggest the feasibility of a nasal approach. A Newcastle disease virus (NDV)-based SARS-CoV-2 vaccine encoding a human codon-optimized full-length wild-type spike (S) protein of SARS-CoV-2 (rNDV-S) via a reverse genetic approach (31) and given as two intranasal doses to mice resulted in systemic humoral and cell-mediated immune responses with high levels of SARS-CoV-2 NAbs and anti-SARS-CoV-2 immunoglobulin A (IgA) and IgG2a. Similarly, hamsters, nasally vaccinated then challenged with SARS-CoV-2, were protected against lung infection and inflammation with reduced viral shedding into nasal turbinate and lungs. Intranasal immunization of rNDV-S has the potential to control SARS-CoV-2 infection at the site of inoculation, preventing both disease and transmission (32). A single intranasal spray of a cold-adapted live-attenuated COVID-19 vaccine induced potent humoral, cellular, and mucosal IgA immune responses in human-ACE2 transgenic mice who were completely protected from viral challenge without detectable virus in nasal turbinates and vital organs (33). In rhesus macaques, a single intranasal dose of adenovirus-vectored vaccine protects against upper and lower SARS-CoV-2 respiratory infection (34). A state-of-the-art summary of intranasal COVID-19 vaccines in development is recently available including the few in clinical trials (35). An ex-vivo model of the human nose might facilitate development and assessment of putative vaccines (36). When considering the next generation of COVID and other respiratory vaccines the intranasal route should not be completely ignored, as it is in a recent publication (37).
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The author confirms being the sole contributor of this work and has approved it for publication.
Conflict of interest
GS was the (unpaid) Chair of the Data Monitoring Committee for the SNIFFLE Trials of influenza vaccination in egg allergic children.
References
1.
Yoshida M Worlock KB Huang N Lindeboom RGH Butler CR Kumasaka N et al . Local and systemic responses to SARS-CoV-2 infection in children and adults. Nature. (2022) 602:321–7. 10.1038/s41586-021-04345-x
2.
Dorabawila V Hoefer D Bauer UE Bassett M Lutterloh E Rosenberg E . Effectiveness of the BNT162b2 vaccine among children 5–11 and 12–17 years in New York after the emergence of the Omicron Variant. medRxiv. (2022). 10.1101/2022.02.25.22271454
3.
WHO . WHO SAGE Roadmap for Prioritizing Use of COVID-19 Vaccines. (2022). Available online at: https://www.who.int/publications/i/item/who-sage-roadmap-for-prioritizing-uses-of-covid-19-vaccines (accessed February 15, 2022).
4.
Jeyanathan M Afkhami S Smaill F Miller MS Lichty BD Xing Z . Immunological considerations for COVID-19 vaccine strategies. Nat Rev Immunol. (2020) 20:615–32.
5.
Ahn JH Kim J Hong SP Choi SY Yang MJ Ju YS et al . Nasal ciliated cells are primary targets for SARS-CoV-2 replication in the early stage of COVID-19. J Clin Invest. (2021) 131:e148517. 10.1172/JCI148517
6.
Padayachee Y Flicker S Linton S Cafferkey J Kon OM Johnston SL et al . The nose as a route for therapy. Part 2 immunotherapy. Front Allergy. (2021) 2:2021. 10.3389/falgy.2021.668781
7.
Brandtzaeg P . Induction of secretory immunity and memory at mucosal surfaces. Vaccine. (2007) 25:5467–84. 10.1016/j.vaccine.2006.12.001
8.
Igarashi Y Skoner DP Doyle WJ White MV Fireman P Kaliner MA . Analysis of nasal secretions during experimental rhinovirus upper respiratory infections. J Allergy Clin Immunol. (1993) 92:722–31.
9.
van Riet E Ainai A Suzuki T Hasegawa H . Mucosal IgA responses in influenza virus infections; thoughts for vaccine design. Vaccine. (2012) 30:5893–900. 10.1016/j.vaccine.2012.04.109
10.
Asahi Y Yoshikawa T Watanabe I Iwasaki T Hasegawa H Sato Y et al . Protection against influenza virus infection in polymeric Ig receptor knockout mice immunized intranasally with adjuvant-combined vaccines. J Immunol. (2002) 168:2930–8. 10.4049/jimmunol.168.6.2930
11.
Tamura S Funato H Hirabayashi Y Suzuki Y Nagamine T Aizawa C et al . Cross protection against influenza A virus infection by passively transferred respiratory tract IgA antibodies to different hemagglutinin molecules. Eur J Immunol. (1991) 21:1337–44.
12.
Callow KA . Effect of specific humoral immunity and some non-specific factors on resistance of volunteers to respiratory coronavirus infection. J Hyg. (1985) 95:173–89.
13.
Fahlman MM Engels HJ . Mucosal IgA and URTI in American college football players: a year longitudinal study. Med Sci Sports Exerc. (2005) 37:374–80. 10.1249/01.mss.0000155432.67020.88
14.
Gleeson M Pyne DB . Respiratory inflammation and infections in high-performance athletes. Immunol Cell Biol. (2016) 94:124–31. 10.1038/icb.2015.100
15.
Turner SEG Loosemore M Shah A Kelleher P Hull JH . Salivary IgA as a potential biomarker in the evaluation of respiratory tract infection risk in athletes. J Allergy Clin Immunol Pract. (2021) 9:151–9.
16.
Cervia C Nilsson J Zurbuchen Y Valaperti A Schreiner J Wolfensberger A et al . Systemic and mucosal antibody secretion specific to SARS-CoV-2 during mild versus severe COVID19. bioRxiv. (2020) 2020.05.21.108308. 10.1101/2020.05.21
17.
Sterlin D Mathian A Miyara M Mohr A Anna F Claer L et al . IgA dominates the early neutralizing antibody response to SARS-CoV-2. medRxiv. (2020). 10.1101/2020.06.10.20126532
18.
Isho B Abe KT Zuo M Jamal AJ Rathod B Wang JH et al . Persistence of serum and saliva antibody responses to SARS-CoV-2 spike antigens in COVID-19 patients. Sci Immunol. (2020) 5, eabe5511. 10.1126/sciimmunol.abe5511
19.
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. 10.3389/fimmu.2020.611337
20.
Weisberg SP Ural BB Farber DL . Tissue-specific immunity for a changing world. Cell. (2021) 184:1517–29. 10.1016/j.cell.2021.01.042
21.
Munoz FM Cramer JP Dekker CL Dudley MZ Graham BS Gurwith M et al . Vaccine-associated enhanced disease: case definition and guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. (2021) 39:3053–66. 10.1016/j.vaccine.2021.01.055
22.
Li M Wang Y Sun Y Cui H Zhu SJ Qiu H-J . Mucosal vaccines: strategies and challenges. Immunol Lett. (2020) 217:116–25. 10.1016/j.imlet.2019.10.013
23.
Alu A Chen L Lei H Wei Y Tian X Wei X . Intranasal COVID-19 vaccines: from bench to bed. eBioMedicine. (2022) 76:103841. 10.1016/j.ebiom.2022.10384
24.
Pebody R Green H Andrews N Boddington NL Zhao H Yonova I et al . Uptake and impact of vaccinating school age children against influenza during a season with circulation of drifted influenza A and B strains, England, 2014/15. Eurosurveillance. (2015) 20:pii30029. 10.2807/1560-7917.ES.2015.20.39.30029
25.
Mohn KG Smith I Sjursen H Cox RJ . Immune responses after live attenuated influenza vaccination. Hum Vaccin Immunother. (2018) 14:571–8. 10.1080/21645515.2017.1377376
26.
Choudhury A Mukherjee S . In silico studies on the comparative characterization of the interactions of SARS-CoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs. J Med Virol. (2020) 92:2105–13. 10.1002/jmv.25987
27.
Khan K Karim F Cele S San JE Lustig G Tegally H et al . Omicron infection of vaccinated individuals enhances neutralizing immunity against the Delta variant. medRxiv. (2021). 10.1101/2021.12.27.21268439
28.
Matuchansky C . Mucosal immunity to SARS-CoV-2: a clinically relevant key to deciphering natural and vaccine-induced defences. Clin Microbiol Infect. (2021) 27:1724–6. 10.1016/j.cmi.2021.08.008
29.
Livanos AE Jha D Cossarini F Gonzalez-Reiche AS Tokuyama M Aydillo T et al . Intestinal host response to SARS-CoV-2 infection and COVID-19 outcomes in patients with gastrointestinal symptoms. Gastroenterology. (2021) 160:2435–50. 10.1053/j.gastro.2021.02.056
30.
Lapuente D Fuchs J Willar J Vieira Antão A Eberlein V Uhlig N et al . Protective mucosal immunity against SARS-CoV-2 after heterologous systemic prime-mucosal boost immunization. Nat Commun. (2021) 12:6871. 10.1038/s41467-021-27063-4
31.
Rohaim MA Munir M . A scalable topical vectored vaccine candidate against SARS-CoV-2. Vaccines. (2020) 8:472. 10.3390/vaccines8030472
32.
Park J-G Oladunni FS Rohaim MA Whittingham-Dowd J Tollitt J Matthew DJ Hodges MDJ et al . Immunogenicity and protective efficacy of an intranasal live-attenuated vaccine against SARS-CoV-2. Science. (2021) 24:102941. 10.1016/j.isci.2021.102941
33.
Seo SH Jang Y . Cold-adapted live attenuated SARS-Cov-2 vaccine completely protects human ACE2 transgenic mice from SARS-Cov-2 infection. Vaccines. (2020) 8:584. 10.3390/vaccines8040584
34.
Hassan AO Feldmann F Zhao H Curiel DT Okumura A Tang-Huau T-L et al . A single intranasal dose of chimpanzee adenovirus-vectored vaccine protects against SARS-CoV-2 infection in rhesus macaques. Cell Rep Med. (2021) 2:100230. 10.1016/j.xcrm.2021.100230
35.
Alu A Chen L Tian HLYWX Wei X . Intranasal COVID_19 vaccines: from bench to bed. ebioMedicine. (2022) 76:103841. 10.1016/j.ebiom.2022.103841
36.
Rajan A Weaver AM Aloisio GM Jelinski J Johnson HL Venable SF et al . The human nose organoid respiratory virus model: an ex vivo human challenge model to study respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and evaluate therapeutics. ASM J. (2022) 13:e03511–21. 10.1128/mbio.03511-21
37.
Dong Y Dai T Wang B Zhang L Zeng LH Huang J et al . The way of SARS-CoV-2 vaccine development: success and challenges. Signal Transd. Target. Therapy. (2021) 6:387. 10.1038/s41392-021-00796-w
Summary
Keywords
SARS-CoV-2, COVID-19, systemic vaccines, intranasal vaccine, IgA
Citation
Scadding GK (2022) A New Grand Challenge in Rhinology: An Intranasal COVID Vaccine. Front. Allergy 3:881118. doi: 10.3389/falgy.2022.881118
Received
22 February 2022
Accepted
19 April 2022
Published
20 May 2022
Volume
3 - 2022
Edited by
Pongsakorn Tantilipikorn, Mahidol University, Thailand
Reviewed by
Dichapong Kanjanawasee, Mahidol University, Thailand
Updates
Copyright
© 2022 Scadding.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Glenis Kathleen Scadding g.scadding@ucl.ac.uk
This article was submitted to Rhinology, a section of the journal Frontiers in Allergy
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.