It starts in the nose

And why the entire vaccine campaign may have been wrong from the start.

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Two recent papers published in Science has led to much-needed discussion around the nature of COVID vaccines. In particular, the two studies highlight a critical factor in vaccination that has been overlooked these past few years. That is, the route of vaccine administration is just as, if not more important, than the type of vaccine platform used.

This idea has been raised several times during the pandemic, but it didn’t appear to gain much traction in either COVID zealot or COVID critic circles. I do recall responding to a comment on one of my posts and suggesting that if a vaccine should mimic an infection, we should consider mimicking the route of infection.

This isn’t some groundbreaking idea I might add. In a general sense this should seem intuitive. You would want to prevent an infection from being able to take hold in the first place rather than boosting the means of fighting of an already well-established infection.

If we were to analogize the body as akin to a castle it wouldn’t make sense to send guards to patrol around the kingdom while leaving the front gates unmanned. If enemies are expected to come from the front gates, then the best course of action would be to guard the front gates.

From an immunological perspective targeting mucosal immunity would confer the best mode of protection by both blocking the entry of pathogens into the body while also prevent transmission of infectious agents to other individuals. Neutralizing antibodies released form one’s mucosa can prevent entryway of pathogens into cells along the respiratory tract, as well as into tissues and cells found in more distal parts of the body. And this blockade also works to prevent entryway into other individuals as well- it stops the pathogen from accessing your body as well as the bodies of those around you.

Again, this is a concept that should seem intuitive for most individuals, and yet the standard route of vaccination is incongruent with this intuition.

This has been highlighted in several papers published during the pandemic, including one from Frontiers published in 2022¹ which states the problem with this incongruency in infection and vaccination:

In the first place, SARS-CoV-2 is an infection of the upper respiratory tract (URT) mucosae, i.e., the nasal passages and oropharynx. Only later, when, or indeed if, the virus reaches the lower respiratory tract (LRT) and lungs does it cause the severe acute respiratory syndrome known as COVID-19. It is an airborne infection mostly acquired by inhalation of virus-containing droplets and aerosols into the nose or mouth, or via the conjunctiva of the eyes and drainage into the nasal passages through the lacrimal duct. Enteric infection can also occur, although the quantitative impact of this in the current pandemic is uncertain (1), and it remains predominantly a respiratory infection (2).

The problem is further compounded by the fact that most neutralizing antibody studies rely on circulating antibodies from the blood, which doesn’t tell us much about what is going on within the mucosa:

These two sets of facts should elicit serious attention to mucosal immunity against SARS-CoV-2 (7), yet immunologists have been focused almost exclusively on the evaluation of circulating antibodies, predominantly of the IgG isotype, on cytotoxic T cells, and to a lesser extent on innate mechanisms of immunity. This has been driven in part by the need to develop, as rapidly as possible, treatments as well as vaccines to forestall serious disease and death. To a large extent, this has now been accomplished by the extraordinarily rapid development of several injectable vaccines, which are having a major effect on the outcomes of the pandemic.

Now, part of this incongruency lies in the fact that mucosal vaccines may have difficulty in eliciting an immune response due to the nature of the mucosal environment- the physical and immunological barriers that prevent pathogens may work against vaccines as well.²

But a more serious issue lies in the fact that there’s a false assumption that intramuscular immunization will eventually result in robust mucosal immunity- the guards randomly patrolling the streets will happen to come across the unattended front gates and decide to help guard that area.

Unfortunately, the latter assumption has been used extensively to argue in favor of intramuscular vaccination, and yet it’s the method of immunization that is most likely to carry greater risk of adverse events as it provides vaccine-related agents direct routes of entry into the body.

And so not only is there a question if mucosal vaccines will provide the best protection against respiratory infections, but this also raises a question if many of the adverse events associated with intramuscular vaccines would be mitigated by just changing the route of immunization. Imagine all the unnecessary harm that could have been avoided if we focused on the nose...

This brings us to the two recent studies, which begs the latter point made above- have the intramuscular SARS-COV2 vaccines provided robust mucosal immunity, or is this an area of fault that has never been properly addressed?

Both studies have garnered attention due to their contradictory findings:

One study comes from Lasrado, et al.³ with the authors’ findings suggesting that those who received the XBB 1.5 mRNA COVID booster vaccine in 2023 did not produce any detectable level of antibodies within the nasal mucosa of participants.

In contrast, a study from Declercq, et al.⁴ argued the opposite, suggesting that those who received a COVID mRNA booster showed evidence of neutralizing antibodies within their mucosal membranes.

First off, when two studies present contradictory findings, it becomes important to examine the differences in methodology. That being said, I highly suggest that readers do not look to news sources for those differences in methodology as you will only get the most general and ambiguous of explanations.

Surprisingly, Science published a focus article⁵ that looked at the differences in methodology. I encourage readers to check out that article, although I will point out several of the main methodological discrepancies here.

The following figure is a helpful summary comparing the findings of both studies for those who may find the following information confusing:

From Tang, J. & Sun, J. Fig 1. A summary of findings between

Heterogeneous study designs

For one, note that the Lasrado, et al. study used an extremely heterogeneous study group. Many of the individuals in the study had multiple COVID vaccines including boosters prior to receiving the XBB 1.5 booster, had heterologous immunizations (i.e. a mix of the Pfizer, Moderna, and the J&J platforms), as well as having evidence of having prior SARS-COV2 infections.

Participants had a median of four COVID-19 vaccines, and ~80% of participants had a history of prior COVID-19 infection, although this might be an underestimate because of the high frequency of asymptomatic or minimally symptomatic infections.

Also, the authors were examining the effects of the XBB 1.5 booster on mucosal immunity, and thus had a later timeline relative to the Declercq, et al. study. Thus, the heterogeneous nature of the study isn’t particular surprising. However, it makes for a messy comparison even among participants of the same study as it introduces several confounders including different variant exposures as well as different timeframes between doses and sample collection. Note that there are no measures of antibody titers prior to receiving any vaccines/infections- the baseline measured in this study is a baseline at the time of the receiving the XBB 1.5 booster.

The Declercq, et al. study doesn’t indicate who among the participants may have had prior COVID infections-this is only inferred through examination for anti-N antibodies of participants- and so prior infections could explain some evidence of mucosal antibodies. Although it included heterologous vaccinees the participants who received boosters received mRNA vaccines encoding the original spike sequence. Researchers also collected samples prior to participants receiving any vaccinations, and thus provides a more accurate baseline representation of the participants barring the issues of identifying participants with prior SARS-COV2 exposure. Note here that the timeline of both serum and nasal sample collection was more detailed:

We obtained sera and nasal secretions from study participants before COVID-19 vaccination, 2 to 4 weeks and 6 months after two vaccine doses, and 2 to 4 weeks and 6 months after booster vaccination. Primary vaccination included either two doses of the Pfizer-BioNTech BNT162b2 mRNA-based vaccine or two doses of the AstraZeneca ChAdOx1 nCov-19 AVV-based vaccine. Booster vaccination was performed with an mRNA-based vaccine [Pfizer-BioNTech BNT162b2 (n = 134) or Moderna mRNA-1273 (n = 8)].

What also stands out is the method of nasal sample collection.

Lasrado, et al. collected samples via nasal swabs:

The specimen biorepository at Beth Israel Deaconess Medical Center (BIDMC) obtained peripheral blood and nasal swabs from the study participants. 

There’s no indication for what standard was used, such as time swabbed, intensity of swabbing, and method of swab storage.

In contrast, Declercq, et al. placed sinus packs into the sinuses of participants for five minutes before resuspension in a saline solution stored in tubes and incubated:

Briefly, sinus packs were placed in the nasal cavity for 5 min and subsequently transferred to a 15-ml tube. Two milliliters of physiologic saline (0.9% NaCl) was added, whereafter the sinus packs were incubated at 4°C for 2 hours. Next, sinus packs were transferred in 5-ml syringes, which were consequently put in a 15-ml tube and centrifuged.

Not sure if 5 minutes counts as “briefly”, but nonetheless it’s clear that nasal sample collection is different between the two studies with Declercq, et al.’s likely being more comprehensive. The lack of detecting neutralizing antibodies in the Lasrado, et al. study could represent a poorer method of sample collection.

Note that there is no standard for nasal sample collection method, which unfortunately means that most studies examining mucosal immunity may find conflicting results due to heterogeneous sampling methodologies. This issue can certainly be seen here in which the use of long-held sinus packs may allow for greater absorbance of mucosal antibodies, and therefore would be more detectable in assays.

This same issue doesn’t occur with blood collection which is far more consistent, and possibly why serum antibody levels have been relied on so heavily as a measure for immunity since it allows for more controlled comparisons across immunization studies.

There are differences among the assays utilized in both studies and so differences in sensitivity and data interpretation could also explain the discrepancies in results. Looking into nuances of the assays used will be far too complex for the intext of this post- just bear in mind that this could be one explanation for the differences findings.

So overall the main issue lies in the heterogeneity of study participants across the two studies which consists of differences in timing of sample collection, type of boosters administered, method of nasal sample collection, etc.

What’s going on in the nose?

Focusing on the results of the nasal antibody portion of both studies Lasrado, et al. noticed no statistically significant differences in nasal neutralizing antibody levels before and 3 weeks after receiving the XBB 1.5 booster.

From Lasrado, et al. Fig. 2E: Neutralizing antibody titers of participants were measured before receiving the XBB 1.5 booster as well as 3 weeks post-booster immunization. Changes in nasal neutralizing antibody titers among vaccinated individuals were compared to those who did not receive the booster. In summary, neutralizing titers did not change post immunization, suggesting that the booster did not help to facilitate a more robust mucosal immune response.

(E) looks specifically at those who received the XBB 1.5 booster and their neutralizing capacity for different variants while (F) looks at those who did not receive the booster, possibly serving as a metric to see if antibody titers decline over time and likely served as a comparator for the Week 3 post-booster measures.

Bear in mind that the study isn’t measuring if there are any neutralizing antibody titers in the nose, but rather if boosting would increase the number of antibodies relative to baseline. Here, the data doesn’t appear to suggest that any significant changes in neutralizing capacity occurred as can be noticed by the “4” above each SARS-COV2 variant graph. In fact, many of the individuals in this study appear to show no evidence of nose-related neutralizing antibodies as can be seen by the red line at the bottom of the graphs which denotes the median neutralizing antibody titers of participants.

Bear in mind that these results are relative to the sample collection and assays used in this study.

What’s interesting here is that a few people showed very high levels of neutralizing antibody titers prior to receiving the booster. Given the limited information provided on the participants it’s possible that these higher titers could be due to prior infections, and in some rare cases could be reflective of mucosal immunity conferred by multiple vaccinations. The problem is that us readers cannot discern for ourselves which interpretation is the correct one given that the authors did not provide clear details on the demographic information for those outlier data points.

Also, bear in mind that since this study is intended to examine the XBB 1.5 booster’s effects on increasing nasal neutralizing antibodies it does not take into account whether the prior vaccines may have resulted in mucosal immunity that only then could not be boosted by further vaccination with vaccine encoding a different version of the spike protein.

This is one of the issues related to many studies examining different boosters where additional boosters encoding different spike sequences may not show more variability in neutralizing capacity for pseudoviruses of said variants. Although people have taken this to be an example of Original Antigenic Sin the more plausible explanation is that prior recall may be sufficient enough to neutralize new variants.

Funnily enough, Lasrado, et al.’s own results did appear to show statistically significantly greater nasal IgG antibody titers for the receptor-binding domain of the XBB 1.5 variant post-booster (boxed in black below) while IgA values appeared not to statistically significantly change (Figure 3C & D).

Fig 3C

Remember that IgG antibodies are the most common subclass of immunoglobulins and is generally the subclass referred to when discussing adaptive immunity. IgA antibodies are also widely prevalent but are generally recognized for their abundance in mucosal linings of the body such as the respiratory, nasal, and gastrointestinal tract. Thus, if we were to consider the idea presented at the start of the article we should infer that IgA antibodies would be the one to most readily target and attempt to elevate in numbers as these antibodies would be more prevalent at the initial sites of infection.

In Declercq, et al.’s findings they noted a high level of neutralizing antibodies within the nose relative to baseline antibody measures. Bear in mind that “baseline” here refers to measures prior to receiving any COVID vaccines and prior to any infection.

From Declercq, et al. Fig 1. Repeat vaccinations and boosters appeared to elicit neutralizing antibodies within the nasal passage of participants. “Prior” refer to participants at baseline before they received any vaccines. Both “Primary” and “Booster” refer to antibody levels 2-4 weeks after receiving the respective immunization. Participants who were presented with increased anti-N antibodies between the Primary/Booster and “6 months” period were excluded from the analysis. That being said, remember that anti-N antibody titers are not a clear indication of no COVID infection.

IgG and IgA antibodies are not made distinct in this graph, and thus the antibody titers likely reflect neutralizing capacity of all of the subclasses together.

When separated out both IgG and IgA subclasses appeared to be elevated after COVID vaccination and booster:

Fig 3A & B: Both IgG and IgA nasal antibody titers against the SARS-COV2 spike protein appear elevated after vaccination and booster, suggesting possible mucosal immunity conferred by intramuscular immunization. However, note that the titers don’t change significantly between the primary and the booster dosing. Also, one confounder could be that several of these individuals had prior COVID exposure which would explain the increased titers.

Granted, many of the IgA values measured fell below the designated cutoff. Also, the increase in both IgA and IgG appeared to be more robust after primary vaccination relative to booster which didn’t appear to show a statistically significant change. Nonetheless, these findings would appear to contradict the findings from Lasrado, et al.

However, bear in mind that this increase in nasal IgG and IgA could be driven by infection. This idea could be argued based on the fact that the researchers noticed that some participants did not appear to produce mucosal anti-S1 IgA antibodies and questioned whether this would only occur through infection:

Given that we did not observe mucosal anti-S1 IgA in all participants, we questioned whether natural virus infection was required to prime vaccine-induced mucosal IgA. Whereas nasal anti-S1 IgG titers were not different between participants with and without evidence of natural infection (defined as seroconversion of anti-N IgG before vaccination), we did observe higher serum titers of anti-S1 IgA in those with prior SARS-CoV-2 infection (Fig. 3, E to H). Nasal anti-S1 IgA was detected upon vaccination in almost all anti-N IgG–positive participants, whereas this was not the case for all anti-N IgG–negative participants (Fig. 3, G to H). Yet, half of the latter group also displayed nasal anti-S1 IgA, suggesting that mRNA vaccination can induce mucosal IgA responses.

In essence, given that some participants with no evidence of anti-N IgG antibodies still showed evidence of anti-spike IgA the authors suggested that the nasal antibodies likely came from vaccination.

And yet, within their Discussion they mention that this may not be the case due to the fact that anti-N antibodies only serve as a proxy for infection. Individuals who become infected with SARS-COV2 may not necessarily seroconvert and produce anti-N antibodies:

We also observed mucosal virus-specific IgA in approximately half of the anti-N IgG–negative study participants. Yet, it cannot be ruled out that some of the anti-N IgG–negative individuals did experience SARS-CoV-2 infection, given that seroconversion to anti-N does not always occur after SARS-CoV-2 infection, especially not in vaccinated individuals (37). Moreover, we cannot exclude the possibility that this observation is due to reactivation of mucosal recall responses primed by infection with other coronaviruses.

Therefore, it cannot be determined that any nasal antibodies may be derived specifically from the vaccines.

Declercq, et al. went on to further conduct an animal study which provides additional insights. The results won’t be examined here, but in short when rodent models were repeatedly vaccinated there were noticeable antibody titers within the lungs as indicated by Bronchoscopy and Bronchoalveolar Lavage (BAL) sample collection. This method involves flushing the lungs with a saline solution and reuptaking the fluid, which would ideally take up any antibodies and immune cells within the lungs.

The general findings here were interesting- they seem to suggest that immune cells of the mucosa were not the source of the IgA and IgG antibodies found in the rodent models, leading to the conclusion that repeat vaccination may just result in circulating antibodies that can eventually make their way to the mucosa of rodents.

Again, this is just a mere summary and I encourage readers to view the study for themselves.

Key Takeaways

In summary, the two studies presented provide a tale of how heterogeneous science can be. Even in this instance where two teams have attempted to answer the same question they have reached different conclusions. In fact, conflicting evidence is how science operates, and it’s why care should be taken in understanding the differences between studies and why results may be unconcordant with one another.

Here, the two studies show clear evidence of different sample population with different vaccination rates, different modes of vaccination, as well as different vaccine histories.

Not only that, but the method of sample collection and the assays used differ, resulting in different quantification of antibodies.

Both studies together don’t appear to suggest that robust mucosal immunity is conferred from repeat intramuscular immunizations. Instead, any finding of nasal antibodies could just be a product of circulating serum antibodies eventually translocating to the nose and the upper airway, or may even be a consequence of SARS-COV2 exposure/infection. Although an animal model, the findings in rodents seems to emphasize that immune cells within the nose are not the source of the antibodies that are found there.

That being said, the general findings here seem to point to something that should be considered alarming.

We need to discuss mucosal immunity

The whole narrative around COVID vaccines, and quite frankly for many of the vaccines we have for respiratory infections is to focus on intramuscular injections- this is what’s been done before and the way that it should always be done.

And yet, the immune system is far more complex than just antibodies=good and more antibodies=more gooder. Various cell types and their immune responses are extremely critical in gauging one’s actual immunity. There’s also the dynamics between innate and adaptive immunity that must be considered.

More importantly- as highlighted by these two studies- there is no “one” immune system of the body. The immune response in the arm or in the blood does not tell us the immune response in the nose, lungs, or other organs.

As suggested by Declercq, et al. in particular any antibodies found within the nasal mucosa may just be a product of circulating antibodies produced by constant vaccination, and consequently doesn’t reflect priming of the nasal immune environment to target SARS-COV2 directly.

By all accounts, this should be considered one of the biggest indictments of the entire vaccine campaign. It tells us that the method of vaccination could have been completely wrong as repeat vaccinations may not provide protection at the most critical entry points into the body, explaining why these vaccines neither prevent infection nor prevent transmission.

It also should raise serious questions regarding the amount of unneeded harms that these vaccines could have caused. Imagine how many serious adverse events may have been avoided if the route of administration was altered.

Tang, J. & Sun, J. summarizes the two studies in their focus article in the following way which raises criticisms regarding the lack of mucosal immunity conferred through vaccination-pay attention to how the paragraph ends (emphasis mine):

Declercq et al. demonstrated that circulating neutralizing antibodies induced by current intramuscular mRNA vaccines can be translocated to the respiratory mucosa. However, the efficacy of this transfer is likely limited and may not be sufficient to prevent reinfection. In particular, both studies demonstrate that there is a lack of mucosal antibodies, particularly IgA, being produced locally after mRNA boosters. In contrast, mucosal vaccine boosters have been shown to directly induce robust local antigen-specific B cell and plasma cell responses, potentially leading to more efficient antibody production locally compared with intramuscular vaccines in animal models (6, 8). In addition, mucosal boosters can elicit strong antigen-specific resident memory T cell responses (6), which are crucial for preventing viral dissemination and the development of severe disease, something that intramuscular vaccines may not achieve as efficiently. The totality of current evidence supports the development of mucosal vaccines, further reinforced by the findings of Lasrado et al. (4) and Declercq et al. (5). Such a mucosal immunization approach could patch the gaps in our current “leaky” vaccines and help achieve the ultimate goal of sterilizing immunity (Fig. 1D).

Why is it that years later, after millions upon millions of vaccines have been administered worldwide, with innumerable vaccine harms and mandate harms, are we now seeing a push for mucosal vaccines?

Why wasn’t this considered far before the vaccines came to market, and what good would these vaccines do at this point after so many people have likely been naturally infected and would already have robust innate immunity?

All of this should have been hammered out years ago. All of this should have been in consideration prior to forcing people to take these vaccines.

To think that the entire approach to the pandemic was wrong from the start, and it’s only now that we are able to freely discuss how wrong so much of it was.

It’s another example of the many failures in public health, and why more free discussion was needed right from the beginning.

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1. Russell, M. W., & Mestecky, J. (2022). Mucosal immunity: The missing link in comprehending SARS-CoV-2 infection and transmission. Frontiers in immunology, 13, 957107. https://doi.org/10.3389/fimmu.2022.957107

2. Baker, J. R., Jr, Farazuddin, M., Wong, P. T., & O'Konek, J. J. (2022). The unfulfilled potential of mucosal immunization. The Journal of allergy and clinical immunology, 150(1), 1–11. https://doi.org/10.1016/j.jaci.2022.05.002

3. Lasrado, N., Rowe, M., McMahan, K., Hachmann, N. P., Miller, J., Jacob-Dolan, C., Liu, J., Verrette, B., Gotthardt, K. A., Ty, D. M., Pereira, J., Mazurek, C. R., Hoyt, A., Collier, A. Y., & Barouch, D. H. (2024). SARS-CoV-2 XBB.1.5 mRNA booster vaccination elicits limited mucosal immunity. Science translational medicine, 16(770), eadp8920. https://doi.org/10.1126/scitranslmed.adp8920

4. Declercq, J., Gerlo, S., Van Nevel, S., De Ruyck, N., Holtappels, G., Delesie, L., Tobback, E., Lammens, I., Gerebtsov, N., Sedeyn, K., Saelens, X., Lambrecht, B. N., Gevaert, P., Vandekerckhove, L., & Vanhee, S. (2024). Repeated COVID-19 mRNA-based vaccination contributes to SARS-CoV-2 neutralizing antibody responses in the mucosa. Science translational medicine, 16(770), eadn2364. https://doi.org/10.1126/scitranslmed.adn2364

5. Jinyi Tang, Jie Sun, From blood to mucosa. Sci. Transl. Med.16,eads6271(2024).DOI:10.1126/scitranslmed.ads6271