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Intranasal SARS-CoV-2 Vaccines: Indispensable and Inevitable

  • Eli Y. Adashi
    Correspondence
    Address correspondence to: Eli Y. Adashi, MD, MS, Department of Medical Science, The Warren Alpert Medical School, Brown University, 222 Richmond Street, Providence RI 02903.
    Affiliations
    Department of Medical Science, The Warren Alpert Medical School, Brown University, Providence, Rhode Island
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  • Philip A. Gruppuso
    Affiliations
    Department of Pediatrics, The Warren Alpert Medical School, Brown University, Providence, Rhode Island

    Molecular Biology, Cell Biology and Biochemistry, The Warren Alpert Medical School, Brown University, Providence, Rhode Island
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      Their extraordinary efficacy notwithstanding, the parenterally administered mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have proven incapable of preventing breakthrough infections in otherwise fully vaccinated subjects.
      • Hacisuleyman E
      • Hale C
      • Saito Y
      • et al.
      Vaccine breakthrough infections with SARS-CoV-2 variants.
      Interpersonal transmission of SARS-CoV-2 through respiratory droplets and aerosols by fully vaccinated subjects has also proven resistant to vaccine-induced immunity.
      • Hacisuleyman E
      • Hale C
      • Saito Y
      • et al.
      Vaccine breakthrough infections with SARS-CoV-2 variants.
      These relative shortcomings of the parenterally administered mRNA vaccines are hardly unanticipated because upper airway protection against SARS-CoV-2 replication and shedding requires local mucosal rather than systemic humoral immunity.
      • Lavelle EC
      • Ward RW.
      Mucosal vaccines – fortifying the frontiers.
      Mucosal protection would entail a secretory IgA antibody response replete with tissue-resident CD4+ helper T cells and CD8+ cytotoxic T lymphocytes.
      • Lavelle EC
      • Ward RW.
      Mucosal vaccines – fortifying the frontiers.
      Intranasal SARS-CoV-2 vaccines offer the potential to produce such a response, thereby preventing breakthrough infections, diminishing person-to-person transmission, and reducing ongoing viral multiplication and mutation.
      • Lund FE
      • Randall TD.
      Scent of a vaccine.
      • Chavda VP
      • Vora LK
      • Pandya AK
      • Patravale VB.
      Intranasal vaccines for SARS-CoV-2: from challenges to potential in COVID-19 management.
      • Alu A
      • Chen L
      • Lei H
      • Wei Y
      • Tian X
      • Wei X.
      Intranasal COVID-19 vaccines: from bench to bed.
      In this article, the authors review the import of mucosal immunity, explore current intranasal SARS-CoV-2 vaccine candidates, and discuss the significance of added upper airway protection to the moderation of the coronavirus disease 2019 (COVID-19) pandemic.
      The introduction of intramuscular mRNA vaccines against SARS-CoV-2 in record time will go down in the annals of medicine and public health as one of the greatest medical achievements of all time. Although they have been critical in restraining the impact of COVID-19, the mRNA vaccines against SARS-CoV-2 have a number of relative shortcomings. Among their drawbacks is their waning effectiveness, which necessitates booster programs.
      • Hacisuleyman E
      • Hale C
      • Saito Y
      • et al.
      Vaccine breakthrough infections with SARS-CoV-2 variants.
      Other drawbacks include the persistence of breakthrough infections and of ongoing person-to-person transmission through respiratory droplets.
      • Hacisuleyman E
      • Hale C
      • Saito Y
      • et al.
      Vaccine breakthrough infections with SARS-CoV-2 variants.
      These latter observations indicate the absence of adaptive mucosal immunity in the nasopharyngeal region in otherwise fully vaccinated subjects.
      • Lavelle EC
      • Ward RW.
      Mucosal vaccines – fortifying the frontiers.
      Addressing these limitations by the development and deployment of intranasal SARS-CoV-2 vaccine should be viewed as an imperative. Preliminary experimental evidence in support of the feasibility of such an undertaking is in hand.
      • Lund FE
      • Randall TD.
      Scent of a vaccine.
      • Alu A
      • Chen L
      • Lei H
      • Wei Y
      • Tian X
      • Wei X.
      Intranasal COVID-19 vaccines: from bench to bed.
      The mucosal immune system is by some measures the most prominent component of the immune apparatus.
      • Lavelle EC
      • Ward RW.
      Mucosal vaccines – fortifying the frontiers.
      The quantity of secretory IgA antibodies that is produced by the mucosal immune system far exceeds that of all the other immunoglobulin isotypes combined.
      • Lavelle EC
      • Ward RW.
      Mucosal vaccines – fortifying the frontiers.
      The IgA antibody class stands out further by dint of its resistance to proteases, which renders it uniquely suited to function in mucosal secretions.
      • Lavelle EC
      • Ward RW.
      Mucosal vaccines – fortifying the frontiers.
      Although heavily reliant on the tonsils and the adenoids (i.e., Waldeyer's ring), the mucosal immune system of the upper respiratory tract encompasses the entire nasopharynx.
      • Lavelle EC
      • Ward RW.
      Mucosal vaccines – fortifying the frontiers.
      Intranasal vaccination against SARS-CoV-2 could thus add a local mucosal immune dimension to the containment of the virus at its principal site of entry. It is in this site that secretory IgA antibodies along with tissue-resident CD4+ helper T cells and CD8+ cytotoxic T lymphocytes stand to arrest potential incursions of SARS-CoV-2.
      • Lavelle EC
      • Ward RW.
      Mucosal vaccines – fortifying the frontiers.
      ,
      • Lund FE
      • Randall TD.
      Scent of a vaccine.
      At the time of this writing, intranasal vaccines approved for clinical use remain a rarity. A sole, live, attenuated, intranasal influenza vaccine (FluMist Quadrivalent) in the form of a nasal spray is currently available and approved for use in healthy nonpregnant subjects aged ≥50 years. An intranasal SARS-CoV-2 vaccine of Cuban origin was afforded emergency authorization in Cuba, Venezuela, and Vietnam.
      • Lund FE
      • Randall TD.
      Scent of a vaccine.
      In addition, a total of 11 intranasal SARS-CoV-2 vaccine candidates are presently the subject of early clinical trials.

      ClinicalTrials.gov, NIH U.S. National Library of Medicine. https://clinicaltrials.gov/ct2/home. Accessed May 13, 2022.

      Seven of these intranasal vaccine candidates deploy live attenuated influenza virus, parainfluenza virus, respiratory syncytial virus, Newcastle disease virus, or an adenovirus as their lead vector.

      ClinicalTrials.gov, NIH U.S. National Library of Medicine. https://clinicaltrials.gov/ct2/home. Accessed May 13, 2022.

      Two other intranasal vaccine candidates deploy simian adenovirus vectors heretofore unencountered by humans.

      ClinicalTrials.gov, NIH U.S. National Library of Medicine. https://clinicaltrials.gov/ct2/home. Accessed May 13, 2022.

      Yet, another intranasal vaccine candidate is making use of the adenovirus type 5 vector.

      ClinicalTrials.gov, NIH U.S. National Library of Medicine. https://clinicaltrials.gov/ct2/home. Accessed May 13, 2022.

      A candidate vaccine developed at the Gamely Research Institute of the Russian Federation utilizes a combined vector approach. The COVI-VAC vaccine, developed by Codagenix, Inc., is unique in its use of a live, attenuated SARS-CoV-2 virus. The other vaccines utilize either the SARS-CoV-2 spike host receptor protein or its receptor-binding domain.

      ClinicalTrials.gov, NIH U.S. National Library of Medicine. https://clinicaltrials.gov/ct2/home. Accessed May 13, 2022.

      Both antigens have been shown in preclinical studies to generate long-lived virus-neutralizing antibodies in the respiratory tract of nonhuman primates.
      • Hassan AO
      • Feldmann F
      • Zhao H
      • et al.
      A single intranasal dose of chimpanzee adenovirus-vectored vaccine protects against SARS-CoV-2 infection in rhesus macaques.
      Whether or not use will be made of any of the earlier-mentioned intranasal SARS-CoV-2 vaccine candidates on a large population scale remains to be seen. Glaringly absent from the earlier-mentioned listing of intranasal SARS-CoV-2 vaccine candidates are intranasal mRNA vaccines against SARS-CoV-2. Preclinical evidence in support of the feasibility of an intranasal mRNA vaccine (against tuberculosis) was first reported more than a decade ago.
      • Lorenzi JC
      • Trombone AP
      • Rocha CD
      • et al.
      Intranasal vaccination with messenger RNA as a new approach in gene therapy: use against tuberculosis.
      Herd immunity is a state of collective immunity wherein interpersonal infectivity is at a nadir.
      • Aschwanden C.
      Five reasons why COVID herd immunity is probably impossible.
      It is at this point that SARS-CoV-2‒positive subjects infect <1 other susceptible individual.
      • Aschwanden C.
      Five reasons why COVID herd immunity is probably impossible.
      Achieving this desired equilibrium in a large, open, globally connected, yet-to-be fully immunized society is beset by ongoing vaccine hesitancy on the part of SARS-CoV-2 naïve as well as recovered individuals.
      • Aschwanden C.
      Five reasons why COVID herd immunity is probably impossible.
      The exercise of populist expediency by policymakers stands in the way as well.
      • Aschwanden C.
      Five reasons why COVID herd immunity is probably impossible.
      Additional obstacles to the attainment of herd immunity include the long and highly infectious incubation period of SARS-CoV-2, the emergence of novel SARS-CoV-2 variants, and the waning of immunity of SARS-CoV-2 vaccines and natural infection.
      • Aschwanden C.
      Five reasons why COVID herd immunity is probably impossible.
      One area in which a modicum of progress toward herd immunity could be made is in the prevention of breakthrough infections and of interpersonal transmission in otherwise fully vaccinated subjects.
      • Hacisuleyman E
      • Hale C
      • Saito Y
      • et al.
      Vaccine breakthrough infections with SARS-CoV-2 variants.
      It is here that user-friendly (needle-free) intranasal SARS-CoV-2 vaccines could enhance mucosal immunity and thus reduce COVID-19 morbidity and mortality.
      At present, it seems unlikely that SARS-CoV-2 will be eradicated. Instead, breakthrough infections and person-to-person transmission are likely to result in a state of cohabitation with the virus. Although their efficacy is far from certain, intranasal SARS-CoV-2 vaccines offer the potential to markedly ameliorate this state of affairs. Relevant authorities worldwide, led by the WHO, would do well to pool their resources to accelerate the clinical trials of intranasal vaccine candidates. Failure to do so stands to prolong the pandemic and delay its potential transition to an endemic phase. Inaction is not an option.

      ACKNOWLEDGMENTS

      No financial disclosures were reported by the authors of this paper.

      CRediT AUTHOR STATEMENT

      Eli Y. Adashi: Conceptualization, Writing - original draft. Philip A. Gruppuso: Writing - review and editing,

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