This is a follow-up on an earlier question regarding mechanistics of vaccines: why current vaccines don't block transmission. In summary, they don't engage mucosal immune cells to produce IgA. Thus, they induce production of IgG by systemic B cells and can lower viral load, but not block viral shedding or uptake through mucous membranes. "Herd immunity" is dependent on halting transmission. So, the AstraZeneca trials were the only ones that assessed sterilizing immunity. Their surrogate for transmission was asymptomatic cases. They found that their LD/SD regimen was about 60% effective in blocking new asymptomatic cases. My first question, then: was this simply due to a reduced viral load (and reduced coughing perhaps) which was expressed as a lower transmission rate? Can this even be equated with measles-type herd immunity? Would this 60% effectiveness at blocking asymptomatics on the basis of reduced viral load be sufficient to achieve herd immunity?
I believe the moderna vaccine did show something similar and that the pfizer group simply did not test for this. basically moderna vaccine reduced positive PCR rates in the non-symptomatic vaccinated cohort and in the few that had positive PCR, then shorter window of PCR positivity compared to the control group. the mrna acts like a replicative virus to some extent, and based on vaccine classes, this should induce IgA responses.
The major objective in vaccination is to prevent disease, not to prevent asymptomatic infection. I would even argue that asymptomatic infection post vaccination might be conducive to longer lived and more comprehensive immunity for re-encounter with antigenic drift variants.
Thanks for your response, Lora. Good news, indeed, if the mRNA vaccines can induce IgA. I'm not totally clear about your rationale, though. I assume you are referring to membrane transport of these mRNAs and their lipid envelopes. With respect to your second point, again not clear on your reasoning. But, it would seem that the problem is not the subject's further immunity to variants, but rather their infectivity to others.
Hi Michael, the mRNA is translated, and in doing so this allows it to induce more aspects of immunity compared to subcomponent or inactivated vaccine. The mRNA is also a very potent stimulator of RNA sensor molecules on and inside the host cells, and can induce an early acute inflammatory response to the vaccine that acts to prime local DCs to become efficient APCs. Better APC, more CMI (T cell-mediated immunity) and humoral immune function (antibody response)
as for the second part of my response: mrna vaccine for spike protein has proven to have an achilles heal of sorts. The region coding for spike is one of the more hypermutable regions in the viral genome. As we have seen with the UK and South African Variants, mutations at positions 411 and 501 appear to confer antigenic drift (immune evasion). So my point is that If you are vaccinated and then some time later, acquire an asymptomatic infection, you will be able to mount an immune response against more genetically stable elements, thus obtaining better immunity to sars-Cov-2.
Hi Lora,
I appreciate your taking the time to answer my queries. Have you considered writing a comment piece on this?
Ok, I can understand why mRNA vaccines may lead to a broader immune response -- for those cells they can access. But, my understanding was that dendritic cells are relatively inaccessible to these vaccines. For one thing, I believe that dc's have to be specifically targeted by vaccines (for cancer therapy, using antigens), provided with maturation factors, etc. Why would this be different for an RNA vaccine? In fact, a search turned up a study in the pipeline (currently recruiting) to develop a specific dendritic cell vaccine for covid: https://clinicaltrials.gov/ct2/show/NCT04685603.
Best,
Mike
Hi Michael, the spike protein that is made in the host cells can be picked up by DC in the site. Remember, the mRNA has first signaled for the establishment of a 'pro-inflammatory milieu" that has recruited immune cells, including DC, to the exact locus. Now in proximity and in states of activation, they take up the spike protein and then locomote to the draining lymph node where they orchestrate the B and T cell responses.
DC vaccines is not ideally suited for mass vaccination.
If you would like to co-author an opinion piece with me on this topic, I am happy to do so.
Hi Lora, I would need to understand this better before I'd dare to put pen to paper (well...).
Hi Michael, if you want to learn more about a topic that interests you, writing a paper about it is a very effective way to understand it better. I recommend you read a little about genomic plasticity in rna viruses, mutation rates in different types of viruses and the concept of antigenic drift/ shift. The paradigm for the later is influenza, but it applies to all viruses.
Hi Michael and Lora.
As a mucosal immunologist I like to add to this interesting discussion. For local IgA production (i.e. IgA produced in the mucosa in the oral cavity) it is generally thought that you need to see the antigen at the mucosa or related lymphoid organs - in this case likely the tonsills - for production of antigen-specific IgA-producing cells to home to the mucosa to become plasma cells. In genel it is not likely that this will happen when people are vaccinated with a novel vaccine systemically. However, mucosal homing may happen if you have had a disease before, and then boost systemically (i.e. the vaccine in people who had the disease). Since some recent papers suggest cross-reactivity of antibodies between SARS-CoV-2 and other coronavirus in the early response, it is possible that we will have cross reactive memory B cells formed at the mucosa that may home to the mucosa after vaccination with the systemic vaccines. Also remember, even if you see IgA in serum, this is likely from IgA producing cells in the bone marrow, and is not the same IgA that is produced at mucosal surfaces.
A different question is whether IgG (or IgA) in serum is sufficient to block infection to give sterile immunity - and also if systemically primed T cells play a role in fighting infections at the mucosa. I am not a virologist, but the general thinking is that IgG and T cells may hinder mucosal infections but not totally block them. There is, for example, often a rather good correlation between IgG levels in serum and protection for many diseases.
Nevertheless, IgG and T cells may still decrease the likelihood for infecting others, as this is dependent both on local viral loads at the mucosa and symptoms (sneezing and coughing spreads virus). Thus, it is likely that the vaccine will diminish infection rates even if there is no local IgA production. Similarly, if the virus mutates, even at the spike, this will likely decrease protection, but not total lack of it due to IgG binding other sites or T cell reacting to T cell epitopes.
Again, please remember that I am not a hard core vaccinologist or infection virologist studying coronviruses as my speciality, but my response would reflect the general thinking among most mucosal immunologist around the subject.
Hi Mats, you bring up excellent points. Also want to point out that IgG and IgM can also be secreted across the mucosal epithelium and that systemic IgA can also find its way to the mucosae as well. I do believe that mucosal vaccination with a live attenuated virus, such as with oral polio or nasal flu is preferable with respect to inducing mucosal immunity.
I wanted to mention the CCR9 allelic variant that has shown increased risk in COVID-19. Perhaps you can explain why this variant specifically influences chemotaxis to the mucosa in response to CCL25 -clearly it plays a key role in COVI-19. I would be interested to know how non-mucosal vaccine administration influences the expression of CCR9 on different leukocyte populations to confer migration of DC, B and T cells from the draining lymph node at vaccination sites to the BALT and GALT. Clearly it happens, as SALK vaccine prevents polio.
Lora
Lora Benoit I may take you up on this as I make my way through the lit. Mats Bemark Thanks for the excellent clarifications. To return to my original question, what are the implications for attaining effective herd immunity from these vaccines?
Michael, Good. I am working on a project ...Let me know if you would like me to share references with you.
To answer your question, theoretically, if ~65% of the US population received vaccination, there would be herd immunity (assuming >20% of the US population has virus exposure). But this is a RNA virus and it is subject to considerable mutation as it passes through the population. So much like needing to get revaccinated each year for flu (also and RNA virus) due to antigenic drift and antigenic shift, we may see a similar issue with Covid -especially with the vaccine as it is based on a highly variable region of the viral genome. So my humble opinion is that the herd immunity will be somewhat imperfect, especially overtime. The million dollar question is how much and how long will the herd immunity last. In this line, as Mats mentioned, there is some degree of protection conferred by related strains. For example: exposure to endemic CoV strains seems to confer some level immunity, most notably in the T cell compartment.
Lora Benoit I think that's too pat, given the mechanistics we've been discussing. Even if 65% were vaccinated, and leaving aside the variants, we would need to quantify effective viral transmission, I would think. So, even (optimistically) AstraZeneca indicates a 40% reduction in asymptomatic transmission.
Hi Micheal, we are on the same page here, you would need to have some measurement of efficacy. I should explain that no vaccine is 100% effective. For example, the chicken pox vaccine is only 82% effective, the MMR vaccine is only 93% effective against measles. There are many reasons for this, in part, the immunogenetics of the host. The result is that there will always be a spectrum of vaccine response in the host. Also, the premise underlying vaccination is not to prevent infection per se, but to prevent disease associated with infection. In line with this, my opinion of sterilizing immunity is that it is essentially asymptotic. Even with the best immunity possible aka "sterilizing" immunity, at some point, you walk into a sneeze and 1000's of virion will be inhaled. Most will be neutralized by IgA/IgG/IgM, but not all because of numbers and chance, some will enter the host cells (infect) and replicate. However, the ability of the progeny to infect new host cells will be stymied by the adaptive immune features. So the window is very short, but there is a window that theoretically you could detect with molecular techniques. The point is, the shorter the window, the less likely you will detect, the less likely you will show symptoms, and the less likely you will transmit.
A colleague posted this paper (of which he is one of the co-authors) to the discussion, which might be useful (I haven't read it yet):
Lora Benoit Mats Bemark One other thing that might be of interest -- received on an apha list i'm on:
"The link below connects to an award ceremony last week at Brandeis (well, online through Brandeis) honoring 2 of the scientists whose work opened the door to vaccines for COVID-19. Interesting discussions!"
https://ensemble.brandeis.edu/Watch/Aj7x3G8L
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