There are two humoral immune systems that mediate antibody immunity. The systemic, from the bone marrow, that is largely concerned with producing IgG antibodies and the gastrointestinal/mucosal system that largely produces secretory IgA antibodies. The nasal passages contain glandular mucosal tissue that produce mainly IgA and underlying stromal tissue that produce IgG.

The problem seems to be that when a systemic immune response is induced, it is not necessarily communicated to the mucosal IgA system. When a respiratory virus enters the nasal passages, such as with natural infection, mucosal immune responses are expected to be induced in the nasopharynx, both across the nasal epithelium and via the tonsils and adenoids, which are collective called the nasopharynx-associated lymphoid tissue (1). It is likely that with natural infection both humeral immune systems are elicited. But, with vaccination in the arm (blood stream) a systemic response with IgG is produced but not necessarily nasal mucosal immunity.

Clearly, in completely vaccinated persons with intact immunity, infection by SARS-CoV-2 is neutralized in the blood stream and tissue fluids and does not cause lung infection. But in many vaccinated people, it appears that the virus can still induce nasal cold like symptoms, with headache. fatigue and even low-grade fever – sometimes severe. The Oxford University study showed that SARS-CoV-2 viral RNA was detected in nose swabs from all rhesus macaques whether or not vaccinated, and no difference was found on any day between vaccinated and control (unvaccinated) animals although the vaccinated animals showed no pneumonia in the lower respiratory tract while the control animals exhibited pneumonia (2). This information suggests that vaccinated persons who are exposed may carry the live virus for several days but not have systemic disease. This may help explain many breakthrough infections. Moreover, whether or not nasal colonization is necessarily infectious to others is unclear. But such colonization is likely to cause positive PCR results that may even be considered false positives in terms of contagion (3).

Large clinical studies would be needed to confirm whether or not many vaccinated persons remain immuno-sensitive to colonization and to what degree cold-like symptoms may occur. Nevertheless, in this commentary, a simpler way to obtain preliminary information supporting this concept is discussed: such information could be obtained by measuring SARS-CoV-2 specific IgA and IgG antibodies in the nasal passages of a limited number of fully vaccinated persons, those with boosters, naturally infected persons without vaccination and, if possible, persons without infection that have not been vaccinated.

Methods for such a study are relatively simple. Samples of nasal drainage can be obtained using minimally invasive sampling procedures with synthetic absorptive matrix (SAM) (4). Absorption for 60 seconds has been shown to be sufficient for collecting IgA and IgG antibodies using a SAM strip (5). Measurement of IgG and IgA antibodies against nucleocapsid and receptor-binding domain (RBD) of spike protein can be accomplished by standard ELISA methods such as using a second biotin conjugated antibody against IgG-Fc and IgA-Fc in conjunction with avidin label. It would be necessary to measure the antibodies in serum as well to insure appropriate infection status.

Results should be readily interpretable. Previously infected persons should have evidence of a prior positive SARS-CoV-2 PCR. One would expect low IgG antibody titers in the blood of uninfected and unvaccinated persons. These can be used as controls (unexposed). Blood samples obtained prior to the pandemic can also be used. These samples can be used to derive a cutoff above which bloods are positive for infection. As well as a prior positive PCR, infected persons should show elevation above the cutoff for nucleocapsid protein, while vaccinated persons without infection should be positive for spike protein but not nucleocapsid.

The Table below defines nasal antibody expected results:

Natural Infection


Not infected


(2 doses RNA vaccine)

Vaccinated boosted

Vaccinated and infected













*The sign to the left indicates more likely scenario.

This proposal is designed to secure preliminary information as to whether or not breakthrough infection is largely due to immune failure in the nasal mucosa and whether additional boosters may enhance nasal protection. The relative levels of IgA antibodies will be of interest as well. For example, if boosted persons show a statistically significant (p<0.05) increase over vaccinated but not boosted, it would suggest additional boosters may provide appropriate nasal protection. Similarly, the levels of nasal IgG would be of interest.  

Although IgA has little value in interpreting SARS-CoV-2 serologies (6), anti-SARS-CoV-2 nasal antibodies, and particularly, anti-RBD IgA correlated with the resolution of systemic disease symptoms, and viral load was negatively correlated with anti-S and RBD mucosal antibodies (1). Also, a report found (7) that after the appearance of the more infectious viral strains, the rate of infection (reinfection) was between 19.8 and 32.5-fold lower in people with natural infection than was the infection rate in people that were previously not infected and not vaccinated, while in people that were only vaccinated but never infected, the infection rate was 4.5 to 6.2-fold lower than unvaccinated people with no previous infection. Besides, there was little difference in reinfection among people previously infected and vaccinated and people previously infected without vaccination. Thus, natural infection through the nasal system seems to provide better protection than systemic vaccination alone, even though two doses of RNA vaccines have been shown to produce systemic IgG levels as high as convalescent serum (8,9). One explanation is that prior nasal infection initiated the IgA mucosal system that inhibited virus from entry.

Polio is another virus that infects mucosal tissue. Although intravenous systemic vaccination (IPV) is recommended for polio in the United States, and it induces immunity in the mucosal system, IPV induces less mucosal immunity than the oral polio vaccine that directly interacts with mucosal tissue (10). For this reason, four vaccinations are recommended and polio is nonexistent in the United States. It may be expected that this epidemic, with very infectious subtypes, that are more readily spread, will subside as natural infection and vaccination approaches 100%. But it may take several boosters to substantially curtail breakthrough infections. It may ultimately be necessary to develop a nasal vaccine to completely eradicate this virus. This commentary suggests a way to obtain preliminary information that will support the idea that immunity in the mucosal immune system is not sufficiently stimulated by two doses of systemic vaccination to prevent many breakthrough infections.


  1. Russell, M. W., Moldoveanu, Z., Ogra, P. L., and Mestecky, J. (2020) Mucosal Immunity in COVID-19: A Neglected but Critical Aspect of SARS-CoV-2 Infection. Front Immunol 11, 611337
  2. van Doremalen, N., Lambe, T., Spencer, A., Belij-Rammerstorfer, S., Purushotham, J. N., Port, J. R., Avanzato, V. A., Bushmaker, T., Flaxman, A., Ulaszewska, M., Feldmann, F., Allen, E. R., Sharpe, H., Schulz, J., Holbrook, M., Okumura, A., Meade-White, K., Perez-Perez, L., Edwards, N. J., Wright, D., Bissett, C., Gilbride, C., Williamson, B. N., Rosenke, R., Long, D., Ishwarbhai, A., Kailath, R., Rose, L., Morris, S., Powers, C., Lovaglio, J., Hanley, P. W., Scott, D., Saturday, G., de Wit, E., Gilbert, S. C., and Munster, V. J. (2020) ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature 586, 578-582
  3. Levinson, S. S. (2022) False Positive results in Real-time reverse transcription-polymerase chain reaction (rRT-PCR) for SARS-CoV-2?, Revision Ed., AACC, // Science & Research // Scientific Shorts
  4. Thwaites, R. S., Ito, K., Chingono, J. M. S., Coates, M., Jarvis, H. C., Tunstall, T., Anderson-Dring, L., Cass, L., Rapeport, G., Openshaw, P. J., Nadel, S., and Hansel, T. T. (2017) Nasosorption as a Minimally Invasive Sampling Procedure: Mucosal Viral Load and Inflammation in Primary RSV Bronchiolitis. J Infect Dis 215, 1240-1244
  5. Froberg, J., Gillard, J., Philipsen, R., Lanke, K., Rust, J., van Tuijl, D., Teelen, K., Bousema, T., Simonetti, E., van der Gaast-de Jongh, C. E., Bos, M., van Kuppeveld, F. J., Bosch, B. J., Nabuurs-Franssen, M., van der Geest-Blankert, N., van Daal, C., Huynen, M. A., de Jonge, M. I., and Diavatopoulos, D. A. (2021) SARS-CoV-2 mucosal antibody development and persistence and their relation to viral load and COVID-19 symptoms. Nat Commun 12, 5621
  6. Levinson, S. S. (2020) SARS-CoV-2 Serology-Need for Quantitative Testing and Interpretive Reporting. J Appl Lab Med 5, 1420-1422
  7. Leon, T. M., Dorabawila, V., Nelson, L., Lutterloh, E., Bauer, U. E., Backenson, B., Bassett, M. T., Henry, H., Bregman, B., Midgley, C. M., Myers, J. F., Plumb, I. D., Reese, H. E., Zhao, R., Briggs-Hagen, M., Hoefer, D., Watt, J. P., Silk, B. J., Jain, S., and Rosenberg, E. S. (2022) COVID-19 Cases and Hospitalizations by COVID-19 Vaccination Status and Previous COVID-19 Diagnosis - California and New York, May-November 2021. MMWR Morb Mortal Wkly Rep 71, 125-131
  8. Jackson, L. A., Anderson, E. J., Rouphael, N. G., Roberts, P. C., Makhene, M., Coler, R. N., McCullough, M. P., Chappell, J. D., Denison, M. R., Stevens, L. J., Pruijssers, A. J., McDermott, A., Flach, B., Doria-Rose, N. A., Corbett, K. S., Morabito, K. M., O'Dell, S., Schmidt, S. D., Swanson, P. A., 2nd, Padilla, M., Mascola, J. R., Neuzil, K. M., Bennett, H., Sun, W., Peters, E., Makowski, M., Albert, J., Cross, K., Buchanan, W., Pikaart-Tautges, R., Ledgerwood, J. E., Graham, B. S., Beigel, J. H., and m, R. N. A. S. G. (2020) An mRNA Vaccine against SARS-CoV-2 - Preliminary Report. N Engl J Med 383, 1920-1931
  9. Walsh, E. E., Frenck, R. W., Jr., Falsey, A. R., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., Neuzil, K., Mulligan, M. J., Bailey, R., Swanson, K. A., Li, P., Koury, K., Kalina, W., Cooper, D., Fontes-Garfias, C., Shi, P. Y., Tureci, O., Tompkins, K. R., Lyke, K. E., Raabe, V., Dormitzer, P. R., Jansen, K. U., Sahin, U., and Gruber, W. C. (2020) Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. N Engl J Med 383, 2439-2450
  10. Practices, A. C. o. I. (1997) Poliomyelitis prevention in the United States: introduction of a sequential vaccination schedule of inactivated poliovirus vaccine followed by oral poliovirus vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 46, 1-25