How can vaccines be effective against respiratory viruses when it is the innate immune system that is the primary response to such pathogens?

Question

I don't understand how vaccines can be thought to be effective against respiratory viruses. We have influenza "vaccines" and now the new mRNA vaccine against COVID-19. However, my understanding is that vaccines inform only the adaptive immune system, which acts within the body. In other words, the adaptive immune system only reacts to virions that have penetrated the body's exterior defenses and entered into the body itself. For example, the adaptive immune system primarily uses lymphocytes as its agents. Lymphocytes are not normally used against respiratory viruses.

The virions of respiratory viruses exist primarily in mucus (on the exterior of the body) and infect primarily apical epithelial cells, which are on the outer surface of the body. This means that respiratory viruses never need to enter the body to either infect a mammal or to spread from one mammal to another. Normally, the immune system that defends against this is the innate immune system, a part of the immune system that has nothing to do with vaccines.

Therefore, while I certainly can understand how a vaccine might prevent a respiratory virus from getting into the body and attacking cells in the interior of the body, I don't understand how they could prevent a respiratory virus from either infecting epithelial cells or spreading to other hosts.

Could someone please explain how these vaccines are supposed to work in light of the above?

Answer 1

Summary:

To answer the bounty question

I am looking for a simple and straightforward answer which describes in a few sentences the mechanism by which the adaptive immune system, informed by a vaccine, would prevent infection of the epithelia of the respiratory system by a virus.

a (not the) mechanism by which the adaptive immune system affects respiratory viruses before cell entry is antibodies presence in mucus, which does seem to have a noticeable [counter]effect on viral particle mobility in mucus for the specific viruses against which the host has antibodies. (See last section of this answer for details.)

However, I'll also that (adaptive) humoral immune system response in the mucus is hardly the end of the adaptive immune system relevance to the epithelium, as avoiding cellular infection altogether cannot be guaranteed by mucus (even with antibodies in it). The epithelium is also "guarded" by adaptive cellular mechanisms (e.g. T cells) that preferentially attack [epithelium] cells infected with specific viruses, as "bits" of these viruses are exposed on infected cells' surface via MHC I.

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Basically, the immune system does function in the respiratory epithelium contra to your theory, and the usual cascade of innate mechanisms triggering the adaptive ones also works in the epithelium:

Several immune cell populations are resident in epithelium including CD103+ CD8+ T cells and CD103+ conventional dendritic cell populations which act as sentinel cells. Other immune cell populations including innate lymphoid cells (ILCs), mucosal associated invariant T cell (MAIT), natural killer cells (NKT) and γδ T cells are in close proximity to the epithelium. [...]

The airway epithelium utilizes structural and barrier defence provided by the mucociliary escalator and their incumbent anti-microbial proteins, and intra- or epithelial-associated immune cells like resident dendritic cells, invariant natural killer T (iNKT) cells, γδ T cells and intra-epithelial lymphocytes.

You're correct that respiratory viruses often have the epithelium as their preferred/evolved target, but this is also where they are usually "defeated" (in fact if they're not defeated there, the host is usually in big trouble). Furthermore, experimentally interfering with this signalling cascade results in much worse outcomes--see emphasized part on dendritic cells further below.

Upon binding sialic acid receptors on the epithelial cell surface, IAV are internalised via receptor-mediated endocytosis [...] The host cell begins sensing IAV as soon as it is internalised, utilising pathogen recognition receptors (PRRs), primarily the Toll-like receptors (TLRs) and RNA-sensing RIG-I–like receptors (RLRs), such as retinoic acid–inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA-5) [...]

Those (TLRs, RLRs etc.) are indeed part of the innate immune system, but that's not the end of the story:

Activation of type I interferons is the key consequence of intracellular recognition of IAV infection by TLRs and RLRs. These cytokines bind to the IFN-α/β receptor (IFNAR) on infected as well as neighbouring cells and induces the transcription of a large group of genes (interferon stimulated genes or ISG) whose main task is to limit spread of infection. [...] In epithelial cells, type I IFN has the additional task of acting as an early warning system, communicating viral threat between infected and uninfected cells. [...]

But epithelial cells also signal "the invasion" through a more specific mechanism: type III interferons (IFN-λ). In any case:

Activation of both type I and III IFN results in induction of hundreds of ISGs. ISGs trigger apoptosis, shut down protein synthesis and activate key components of the innate and adaptive immune systems, including antigen presentation and production of cytokines involved in activation of T, B, and natural killer (NK) cells.

So, thanks to interferons the adaptive immune system does get triggered, even in the epithelium. Furthermore

There is substantial cross-talk between epithelial and immune cells sequestered in the epithelium. CD103+cDCs continuously sample the airway via extended dendrites and respond to chemokines and cytokines (including type I and III IFNs) and DAMPs secreted by IAV- infected epithelial cells

Intra-epithelial dendritic cells are essential to generate protective IAV-specific CD8+ T cells; mice lacking this DC subset succumb to severe disease and impaired viral clearance.

Basically, not having the adaptive immune system active/functional in the epithelium is usually fatal for the host, even in relation to "mere" influenza infection. DCs "act as messengers between the innate and the adaptive immune systems."

Also, at least the epithelium of the lungs has additional defenses (iNKT cells). If you look at their Wikipedia page, the NKT cells are somewhat of a hybrid of adaptive (T cells) and innate (NK cells) immune system; they in turn release a plethora of signalling molecules "large quantities of interferon gamma, IL-4, and granulocyte-macrophage colony-stimulating factor, as well as multiple other cytokines and chemokines (such as IL-2, IL-13, IL-17, IL-21, and TNF-alpha)" that activate the adaptive immune system, although I think NKTs mostly respond to bacterial rather than viral infections. (I could be wrong though on this.) But if they do "get triggered", e.g. in a co-infection scenario (not uncommon in pneumonias), NKTs seem to help with the viral [part of the] infection as well (going back to quoting from the review paper [1st link]):

In the mouse, presence, and exogenous activation, of lung iNKT cells by α-GalCer, protects against lethal H1N1 and H3N2 influenza in prophylactic settings.

But to reiterate again the more common mechanisms:

The epithelial cells’ attempt to clear IAV results in inevitable tissue injury, in part because of collateral damage from the accompanying innate immune response and direct induction of apoptosis by IAV, but also because cytotoxic T cells will eventually kill cells with IAV peptides presented on their MHC class I molecules. If epithelial cells are not killed they undergo apoptosis or de-differentiation. If IAV reaches the alveolar epithelium, various injurious events can occur. [...]

Speaking of that last (emphasized) issue, the influenza viruses "try pretty hard" to make themselves invisible to the MHC I pathway.

we showed that infection of several cell types, including epithelial A549 cells, with a panel of IAV and IBV viruses downregulated the surface MHC-I expression on IAV/IBV-infected cells during the late stages of influenza virus infection in vitro. [...] Importantly, the two viruses utilized two distinct mechanisms for MHC-I downregulation.

If MHC I (triggering T cells) wasn't a problem for them, why would they have evolved these camouflage/countermeasures?

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Since you confusion (or argument) seems to be whether Cytotoxic CD8+ T cells are or aren't part of the adaptive immune system (they are), let's side-step such categorization discussion and simply observe that a Covid-19 mRNA vaccine trains them so that significant fraction recognize the virus bits:

Fractions of RBD-specific IFNγ+ CD8+ T cells reached up to several per cent of total peripheral blood CD8+ T cells in immunized individuals

RBD here means the receptor binding domain (protein) of the specific virus (SARS-CoV-2 in this case).

(The same is true for vaccines that target the full spike protein, which are the ones actually approved by regulators, although the corresponding paper(s) still seem to be in the preprint stage. The latter paper speaks of "S-specific CD8+", meaning SARS-CoV-2 spike-specific.)

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Now, if you want to focus/ask only what happens before any cell entry, the humoral immune system is present in mucus. It (also) has innate (e.g. mucins, lactoferrin) and adaptive components; antibodies are present in the mucus.

Antibodies importance (relative to innate mechanism) in mucus has been less studied, but their presence in mucus has surely been (commonly) observed, and some studies comparing viral movement speeds in mucus do suggest that specific antibodies slow down the corresponding viruses in mucus e.g.:

To investigate whether trapping of influenza in airway mucus can be attributed primarily to haemagglutinin binding to mucin-associated sialic acid, we prepared VLPs fluorescently labelled internally using HIV-1 GAG-mCherry capsid proteins in the core, and expressing both neuraminidase and haemagglutinin from H1N1 (influenza A/PR/8/34) (WT-Inf), or the same neuraminidase and haemagglutinin that has the sialic acid-binding domain deleted (ΔSAB-Inf) and hence cannot bind directly to mucins. Interestingly, both WT-Inf and ΔSAB-Inf were trapped in airway mucus to a similar extent as H1N1 and H3N2, with roughly 98% of WT-Inf and 97% of ΔSAB-Inf immobilised in airway mucus and average diffusivities ∼1700- and ∼1100-fold lower than expected speeds in buffer, respectively (figure 1b, online supplementary movies S4 and S5). [...]

Using whole-virus ELISA assays, we detected substantial quantities of endogenous IgG and IgA against influenza in airway mucus (data not shown), as well as against both WT-Inf and ΔSAB-Inf VLPs. [...] This leaves open the possibility that influenza-specific antibodies in airway mucus may immobilise virions by cross-linking the antibody–virus complex to mucus constituents, such as mucins. We sought to measure virus and VLP mobility in airway mucus devoid of antibodies; however, we were not able to adequately remove Ig by dialysis, possibly due to membrane clogging, and mucus secretions isolated from air–liquid interface cultures of bronchial epithelial cells did not produce a sufficiently rigid matrix to immobilise mucoadhesive latex nanoparticles. We also attempted to “saturate” the mucus–antibody barrier by mixing >20-fold more unlabelled than labelled influenza viruses into airway mucus prior to adding labelled viruses, and still observed no discernible difference in the trapping of the labelled influenza viruses. Therefore, we investigated whether the lack of binding antibodies in mucus correlates to greater virus mobility by tracking HIV VLPs that were prepared similarly to the influenza VLP, but expressing HIV YU2 gp160. We found no detectable HIV-binding IgG or IgA in airway mucus (figure 1d, e), and HIV VLPs exhibited markedly greater diffusivity in airway mucus (figure 1b, online supplementary movie S6; p<0.05), with >45% of HIV VLPs classified as mobile and ∼10-fold higher ensemble effective diffusity than WT-Inf and ΔSAB-Inf. HIV VLP mobility was similar to that of PS-PEG in the same airway mucus samples (data not shown).

Together, these results demonstrate that influenza virus can be trapped in human airway mucus without binding to sialic acids on mucins, in good agreement with the evidence that human influenza viruses possess haemagglutinin that preferentially binds α2,6-linked sialic acids on the airway epithelium rather than α2,3-linked sialic acids on mucins. Trapping of influenza in human airway mucus can probably be attributed to the presence of influenza-binding antibodies that can cross-link individual virions to the mucus mesh network. Importantly, adhesive interactions between the array of pathogen-bound antibodies and mucus gel provide a universal strategy that enables the otherwise relatively nonadaptive and nonspecific biochemistry and microstructure of mucus secretions across different mucosal surfaces to be fortified with adaptive antibodies against an ever-changing spectrum of pathogens.

But before you get too excited about this finding, remember that the immune systems is "defense in depth", some virus particles will make it through the mucus, even if you do have specific antibodies against them there; this is when the cellular mechanisms kick in. There's no one mechanism that is going to be 100% foolproof.

Answer 2

Trying to understand your question:

a. Can vaccination, by inducing antibodies, prevent infection, i.e. shield off the virus before it enters any cell, in locations that seem to be inaccessible for antibodies and lymphocytes?

b. If innate immunity successfully hinders infection and renders vaccination superfluous and redundant can the latter be considered effective?

c. Considering vaccination being able to prevent symptomatic or severe illness but not infectivity and epidemic spread what is the role of innate versus adaptive immunity in both, prevention of disease and epidemic spread?

If c. were correct understanding one prospective answer might be: Whereas, indeed, innate immunity prevents the spread of the virus, adaptive immunity prevents symptomatic disease. Another intricacy: In case innate immunity cannot prevent infection and epidemic spread, why doesn't vaccine/adaptive immunity come in stopping the spread - if it successfully prevents symptomatic disease? I see that point to your question and that's why I am out to publish my personal view, see inverted text at the end.

Answering:

According to not very basic textbook knowledge antibodies/immunoglobulins are able to cross the blood tissue barrier. Immunoglobulins' sizes permit the evasion from blood and the invasion of interstitium/tissue/epithelia. IgE is a known example of specialized immunoglobulins that take care of outer epithelia. There do exist local lymphocytes, Langerhans cells, that make it across the vessel wall under regular circumstances, no inflammation or infection needed beforehand; they are in place.

In fact, not IgE, but IgA seems tailored for mucosa.

"IgA is the 2nd most common serum Ig. IgA is the major class of Ig in secretions - tears, saliva, colostrum, mucus. Since it is found in secretions secretory IgA is important in local (mucosal) immunity. Normally IgA does not fix complement, unless aggregated. IgA can bind(...) to some cells - PMN's and some lymphocytes." http://www.microbiologybook.org/mayer/IgStruct2000.htm

While the question whether antibodies not only cross the blood-epithelial barrier but the blood-air-barrier as well is to be answered to the affirmative, there is a debate about the extent to which this holds for the fencing off of respiratory at the blood-air-barrier (not blood-tissue barrier), which makes your question non-trivial:

"...Translocation of large serum proteins (e.g., albumin, IgG) via paracellular routes by restricted passive diffusion does not appear to be the primary route, although under pathological conditions such passive diffusion may become the main route of protein leak." Protein transport across the lung epithelial barrier Kim/Malik, 2003

As the quote above might suggstest the response of the adaptive immune system might seem late or reluctant, in accordance with the intention of your question I assume. Adaptive immunity might set in when infective spread has already happened. Even if antibodies have not waned they do not seem to be very willing to fit in where or when needed, in the mucosa.

On the other hand, imagine just one single epithelial cell the infection of which adaptive immunity could not prevent. If any shedding of virions from that one cell will encounter antibodies, and any lysis of that one cell will immunize local lymphocytes in between infected single cells of the epithelial you may consider vaccination/adaptive immunity effective.

Effectiveness of adaptive immunity may not being perturbed if it allows the transfection of one single cell as this signal of invasion is needed to trigger defence cascade.

Antibodies in between cells of epithelia and local lymphocytes, "Langerhans cells", may not be able to "prevent infection", however in principle, these elements of the adaptive immune response are able to prevent any further spreading.

Regarding the argument that there are no antibodies in the mucus, on the outside to prevent any "one cell" being invaded by virus one must admit that, in principle, this goes for the innate immune system as well as far as it is based on cell signaling, too. In other words: adaptive immunity needs initiating infection to start a signaling cascade and does not prevent such infection; it would logically stop itself from starting. However, same applies to the interferon system of innate immune system that needs infection to start the interferon cascade.

*The following is my personal opinion that tries to answer your question "in deep". "How can vaccines be effective against respiratory viruses when it is the innate immune system that is the primary response to such pathogens?"

Yes, you are right in some way. Indeed, there seem to be many variants or even species of respiratory viruses where vaccines are able to prevent symptomatic disease, however are not able to restrict viruses in replication sufficiently in order to prevent epidemic spread and non-symptomatic infection.

For instance, he Omicron variant of the Corona virus CoV-19, arguably a new serotype, may well illustrate a yet non-accepted principle of mutational viral evolution that pertains to balancing the innate and the adaptive immune system, assuming that the virus renders itself, paradoxically, more vulnerable to the innate system or other factors of the non-adaptive innate immunity, thereby not contacting the adaptive immune system and circumventing it, not even causing "much" immunity. This principle of escape from immunitiy is different from the strategy of hiding away by turning silent, especially by integrating, as retro viridae do, into the genome. My point is that from a single cell, compare the above, there might leak out into the air, lung a very large amount for infectious virus particle, so there is no latency at all. There is only a restriction by the innate immunity, that, in the intention of your question, is "just" not strong enough to stop infectivity and shedding of infectious virus by isolated cells.

Counterintuitively mutations turn out to be successful that render the virus less pathogenic and/or less infectious because the virus refrains from defending itself against the innate response as it is rewarded by non-immunizing and non-coping with existing adaptive immunity. It is the price the adaptive defence pays out to the virus for the virus weakening itself to a point of being beaten in first line by the innate immune system. In that mutational to and fro there are limits: for the virus there is a minimum of infectivity that must be "left over". Otherwise there will be some remake of the weakened.

Thus, vaccines may tend not to prevent the infectious spread. This is no trivial posting: the adaptive immune systeme accepts infectivity that is not pathogenic, not intrusive enough for to be bothered. The being late and the ineffectiveness is the price mutations certain respiratory viruses are being awarded if they let themselves be restricted to no invasiveness of the body, thus, in principle, harmlessness, paired with high incidental rates and epidemic spread. If there is hiding away of retro viruses, there is retreat of certain respiratory viruses.

The principle of evolution I hereby postulate thus pertains to the selective advantage for the virus that lies in not inducing immunity by not encountering antibodies and/or antigen presenting cells. Stated principle is that adaptive immunity, hence vaccination, by evolutionary art, does not fill the gap of infectiousness, epidemic infectivity, that innate immunity may or may not open.

It is the selective advantage viral evolution must have: the spread. Let me explain the spread. To spread is the reward adaptive immunity does not take away. Only then viral mutations find succes in letting the viruses being dampened, at the verge of extinction, by the interferon system of innate immnity. Thus vaccination, by principle, in many cases can only prevent disease, not infection.

Known mechanisms of adaptive immunity seen anew show that adaptive immunity "comes late":

1. Antigen presenting cells take up antigens that are derived from already infected, then succumbed, lysed cells.

2. T-cytotoxic cells await the apoptotic signal of already infected cells - most important, as an argument: specific T-Killer cells are known to become "anergic" when encountering their target, they have to wait until they get primed in lymph nodes, they come very late

3. The only defense of the adaptive system seems to be "neutralizing" antibodies that throw themselve in between the virus and the cell, theoretically. But then: they wane very quickly, and in my opinion, this regular waning fast of antibodies is coherent with the stated principle of reluctancy of the adaptive response.

What regards the viral turning itself either more or less exposed to the innate system of immunity I name two mechanisms, there may be more:

1. Syncytialization

2. Interferon signalling

Respiratory Syncytial Virus by its name exemplifies: like Corona-Viridae this respiratory virus induces syncytialisation, i.e. fusion of one infected cell with others that surround it. While this is considered circumventing the adaptive immune system as far as more and more cells are infected without virus entering the interstitial or humoural space in between cells it is - in terms of my arguing - a mechanism of balancing and modulation: known are viral mutations that change binding of viral factors to syncytialization promoters of the host cell thus changing the degree of pushing back the entry of adaptive immune response.

As far as respiratory virus mentioned in your question use the way of syncytialization of infection one can say vaccines will be dampened. Vaccination sets in only as soon as there is lysis of syncytia (for the APS to uptake antigen, after "persistence ended" and/or MHC-presentation by syncytia with preexisting immunity).

Very intriguing in the context of your question is the barely popular fact of the placenta more or less being a syncytia that prevents the adaptive system of immunity from working, as it is said to block contacting the father's foreign antigens. Viral genes in the humane genome are held responsible. Analogy permitted, the pneumocytes type II, target cells of CoV, are very extended in form and appear as large extended shields. It is rare knowledge that CoV induces their syncytialisation, and if the latter is considered "infection", it is hidden and cannot be coped with by adaptive response nor vaccination. Thus, if induced by viral infection, syncytia of the lung cells can not only be seen as hideaways from the adaptive immune system but also as,in principle, fencing off a separate room - the mucosal room - which antibodies and lymphocytes cannot enter, which refers to your question.

Some references:

[Liangyu Lin et al. 2021],14Syncytia formation during SARS-CoV-2 lung infection: a disastrous unity to eliminate lymphocytes

Cattin-Ortolá et al.https://pubmed.ncbi.nlm.nih.gov/34504087/ Sequences in the cytoplasmic tail of SARS-CoV-2 Spike facilitate expression at the cell surface and syncytia formation*

"Placental transfer - IgG is the only class of Ig that crosses the placenta. Transfer is mediated by a receptor on placental cells for the Fc region of IgG."

The Omikron variant of Cov might be an example of a presumably highly infectious, (in many cases) but non-symptomatic disease that still manages to cause the formation of antibodies. According to my reasoning and in the intention of your question I assume their building up might be weak, which, in result, has already be confirmed by re-infection with Omicron - within same season - being reported in Great Britan. Even if there were adapted vaccination against a respiratory virus variant, according to my reasoning, it should "not work well" against infectivity, non-pathgenicity only following suit the non-contacting of the realms of adaptive immunity, to affirmatively answer your question and putting my reasoning up for test in the near future, hopefully.

I will reference all this by tomorrow if allowed to.