Intranasal vaccine confers broad mucosal and systemic immunity against SARS-CoV2
nature.com
nature.com
>For proof of principle purposes, 5 co-authors of this report voluntarily took an intranasal spray of Ad5-S-Omicron that was prepared for clinical trial.
They then tested for immune response in "nasal lavage fluids," which apparently is the fluid collected after flushing out a test subject's nose with a saline solution, against the virus' spike and a psuedovirus. I don't know how the results in lavage fluids compares to similar neutralization studies they do for other kinds of vaccines, except that they also use psuedovirus sometimes.
The only saving grace of the existing vaccines is that the T/B-cell response induced is long-lasting and protective. Antibody response is a proxy for what you really care about (survival), and it's a crappy proxy for that, because antibodies rise and fall quickly even if your immune system is well-prepared for future exposures.
The traditional problem with nasal vaccines is that they induce a quick spike in antibodies in the mucosa, which then go away without the corresponding long-term rise in cellular immunity that is seen with injected vaccines.
Are you talking about traditional vaccines or mrna ones for covid? Because aside from mucosa it sounds like you're describing the short term durability of mrna vaccines that need to be perpetually redosed months not years later. If that's the baseline, what is there to lose by adding or replacing them with short term mucosal immunity?
> Because aside from mucosa it sounds like you're describing the short term durability of mrna vaccines that need to be perpetually redosed months not years later.
So...it's worth saying this out loud: we have no absolutely no good evidence that we need to keep re-dosing these vaccines. None. The bi-valent booster was approved based on a trial with a handful of mice. Do these vaccines improve outcomes in young people? We have no idea. People who have had Covid? No idea. Old, sick people with 5+ prior doses? We can maybe guess, but we don't know. There's no data.
I'm not exaggerating. It's an absolute embarrassment that the FDA keeps approving these shots without proper trials. It's all a nasty stew of partisan politics, financial incentives, and "science" so bad that it wouldn't pass muster at a high-school science fair.
Anyway, point is that you can't conclude anything scientific from the mRNA Covid vaccine dosing schedules, since they're fundamentally not scientific. The best science we have suggests that the initial two-dose series provided long-lasting cellular immunity.
Nonsense. We have data that shows vaccine effectiveness wanes with time. We know boosters improve immunity. We've been giving out bivalent booster for over a year and we have data that they're effective.
> I'm not exaggerating. [...] "science" so bad that it wouldn't pass muster at a high-school science fair.
You are exaggerating. You're engaging in hyperbole that's an embarrassment to yourself. Armchair scientists should leave the medical decisions to the professionals.
No, we don't. We have confounded, poorly controlled observational studies, and extrapolation from antibody titres.
> We know boosters improve immunity.
No, we don't. The necessary studies have never been done. Increasing antibodies for a while (in mice) does not equal "improving immunity" in humans.
> We've been giving out bivalent booster for over a year and we have data that they're effective.
Well, if you say so. But actually...no. Or you'd cite it, instead of just asserting things.
> Armchair scientists should leave the medical decisions to the professionals.
Such as Paul Offit, FDA VRBPAC member, co-creator of the Rotavirus vaccine, and director of the vaccine education center at the Children's Hospital of Philadelphia?
https://time.com/6246525/bivalent-booster-not-very-effective...
https://www.nejm.org/doi/full/10.1056/NEJMp2215780
> In his perspective piece, Offit cites data from two leading virologists—Dr. David Ho, director of the Aaron Diamond AIDS Research Center at Columbia University, and Dr. Dan Barouch at Harvard Medical School—who reported that when serum from people boosted with the bivalent Omicron booster was compared to that from people boosted with a dose of the original vaccine, their levels of neutralizing antibodies against BA.4/5 were comparable. Ho’s work also showed that the bivalent booster did not produce appreciably different antibody responses against newer Omicron variants, such as BQ.1, BQ.1.1, XBB, and now XBB.1.5, which together account for 83% of new infections in the U.S. as of the first week of January.
These are for antibodies, mind you...the most reactive short-term signal to a booster vaccination. There's simply no good evidence backing these new vaccines. Anyone who says otherwise doesn't know the data.
But, let's look at your link. First paragraph:
"And the latest data show that the newest booster shot, which targets the Omicron BA.4/5 strain and original virus variants in a bivalent formulation, isn’t that much more effective in generating virus-fighting antibodies than the original vaccine when used as a booster."
So this doesn't even back up your claim. It doesn't say boosters aren't effective, just that the bivalent vaccine isn't "that much more effective" than the original vaccine as a booster.
The "problem" with these kinds of debates is that people who have absolutely no ability to read or evaluate scientific literature confidently assert things that they cannot know, based on what they heard someone else say on social media.
> So this doesn't even back up your claim. It doesn't say boosters aren't effective, just that the bivalent vaccine isn't "that much more effective" than the original vaccine as a booster.
My "claim" was that there's no evidence supporting the dosing schedule for these boosters (this isn't a claim, it's a fact. The booster doses were approved without a single human efficacy trial [1]). Arguing that antibody titers go up after boosting is not a rebuttal...because that's what antibodies do when you inject things into the body. It's the entire topic of the thread. Antibodies go up, then they go back down. It's a poor proxy for immunity.
[1] Here's the announcement from the FDA on the latest dosing recommendations:
https://www.fda.gov/news-events/press-announcements/coronavi...
You'll see fun facts such as:
* the single-dose schedule for Moderna bivalent is based on antibody responses in about 1500 people, only 145 of whom had Covid in the past. This doesn't reflect any aspect of the real world, where most of us have had it at least once.
* they didn't have enough data to justify their decision, so they just grouped together stuff from prior vaccines because "these vaccines are manufactured using the same process."
* for Pfizer, effectiveness of a single dose is supported by OBSERVATIONAL DATA from England on the effectiveness of one dose of monovalent Pfizer-BioNTech COVID-19 Vaccine.
* "Among individuals 12 to 17 years of age who had received only one dose of Pfizer-BioNTech COVID-19 Vaccine, those who had evidence of previous infection with alpha, delta or omicron variants had increased protection against symptomatic omicron infection compared with those with no evidence of previous infection"
That last one is an absolutely mind-blowing bit of doublespeak, by the way. They're literally saying that they're justifying this as a single-dose vaccine because people who were previously infected show more protection after one dose than those who were never infected.
Think about that.
Clearly.
> people who have absolutely no ability to read or evaluate scientific literature assert things that they cannot know.
That's quite an assumption on HN. Half the people on here have a significant scientific background.
I've got a PhD (computational biology), papers published etc. I'm quite happy to read and get the gist of scientific literature in this field.
What I don't have is the specific expertise that comes from being a medical expert, having years of experience in the field, and having the time to look at this in great detail full-time. For that I am happy to defer to the experts here.
Is your claim that all the experts from all of the countries who have approved the booster programmes are all incompetent?
> The booster doses were approved without a single human efficacy trial
I don't think that's true at all. I seem to remember several studies.
How about this CovBoost one? https://www.covboost.org.uk/results
I linked the FDA announcement for the latest dosing changes. You can see how they justify it.
It's funny that you link the CovBoost thing. They're summarizing this paper:
https://www.thelancet.com/journals/lancet/article/PIIS0140-6...
Which is not about the bivalent vaccines (it's from 2021, concerning dose 3, not...6? 7?), and it's by this fellow, who...let's just say that he's not taking your side of the argument:
https://twitter.com/apsmunro/status/1466707690332340227
It's a good paper, it just doesn't support the argument you're making. Overall, it shows that third dose boosting seems to play a minimal role in otherwise healthy people who have had two doses and been infected.
Bar-On YM, Goldberg Y, Mandel M, Bodenheimer O, Amir O, Freedman L et al. Protection by a Fourth Dose of BNT162b2 against Omicron in Israel. New England Journal of Medicine. 2022. doi: 10.1056/NEJMoa2201570.
Magen O, Waxman JG, Makov-Assif M, Vered R, Dicker D, Hernán MA et al. Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting. N Engl J Med. 2022. doi: 10.1056/NEJMoa2201688.
Gazit S, Saciuk Y, Perez G, Peretz A, Pitzer VE, Patalon T. Relative Effectiveness of Four Doses Compared to Three Dose of the BNT162b2 Vaccine in Israel. medRxiv. 2022:2022.03.24.22272835. doi: 10.1101/2022.03.24.22272835.
Arbel R, Sergienko R, Friger M, Peretz A, Beckenstein T, Yaron S et al. Effectiveness of a second BNT162b2 booster vaccine against hospitalization and death from COVID-19 in adults aged over 60 years. Nature Medicine. 2022;28:1486–90. doi: 10.1038/s41591-022-01832-0.
Regev-Yochay G, Gonen T, Gilboa M, Mandelboim M, Indenbaum V, Amit S et al. Efficacy of a Fourth Dose of Covid-19 mRNA Vaccine against Omicron. New England Journal of Medicine. 2022;386:1377-80. doi: 10.1056/NEJMc2202542.
Muhsen K, Maimon N, Mizrahi AY, Boltyansky B, Bodenheimer O, Diamant ZH et al. Association of Receipt of the Fourth BNT162b2 Dose With Omicron Infection and COVID-19 Hospitalizations Among Residents of Long-term Care Facilities. JAMA Internal Medicine. 2022. doi: 10.1001/jamainternmed.2022.2658.
Amir O, Goldberg Y, Mandel M, Bar-On YM, Bodenheimer O, Freedman L et al. Protection against omicron severe disease 0-7 months after BNT162b2 booster. medRxiv. 2022:2022.05.04.22274647. doi: 10.1101/2022.05.04.22274647.
Cohen MJ, Oster Y, Moses AE, Spitzer A, Benenson S, Israeli-Hospitals 4th Vaccine Working G. Association of Receiving a Fourth Dose of the BNT162b Vaccine With SARS-CoV-2 Infection Among Health Care Workers in Israel. JAMA Network Open. 2022;5:e2224657-e. doi: 10.1001/jamanetworkopen.2022.24657.
Grewal R, Kitchen SA, Nguyen L, Buchan SA, Wilson SE, Costa AP et al. Effectiveness of a Fourth Dose of COVID-19 Vaccine among Long-Term Care Residents in Ontario, Canada. medRxiv. 2022:2022.04.15.22273846. doi: 10.1101/2022.04.15.22273846.
That's a pretty conditional statement. We're also not on dose four, we're on dose...seven? And young, healthy people are still being mandated to get these things.
I stand by my comment: the studies you are citing are all low-quality, observational data, in older populations. I'll just start working down the list from the top...
> Bar-On YM, Goldberg Y, Mandel M...
Garbage study.
Observational. Confounded (vaccine-seeking behavior). Old people (>60). No control (the "internal control" was not a control).
> Magen O, Waxman JG, Makov-Assif M...
Obeservational study. Confounded (vaccine-seeking). Effect size was miniscule:
"In days 7 to 30 after a fourth vaccine dose, the difference in the absolute risk (three doses vs. four doses) was 180.1 cases per 100,000 persons (95% CI, 142.8 to 211.9) for Covid-19–related hospitalization and 68.8 cases per 100,000 persons (95% CI, 48.5 to 91.9) for severe Covid-19."
That's a difference of 0.18% for hospitalization, in a population of people over 60.
> Gazit S, Saciuk Y, Perez G
Observational study. Older population (60+). Confounded (vaccine-seeking). Found that effectiveness against infection was short-term, and that the fourth dose had very little impact on severe disease or hospitalization.
"vaccine effectiveness against infection varied over time, peaking during the third week with a VE of 64% (95% CI: 62.0%-65.9%) and declining to 29.2% (95% CI: 17.7%-39.1%) by the end of the 10-week follow-up period. Unlike VE against infection, the relative effectiveness of a fourth dose against severe COVID-19 was maintained at high level (>73%) throughout the 9-week follow-up period. Importantly, severe disease was a relatively rare event, occurring in <1% of both fourth dose and third dose only recipients."
> Arbel R, Sergienko R, Friger M
Observational study. Older population (60+). Confounded (vaccine-seeking). Tiny effect size (hospitalization in 4-shot cohort: %0.08; 3-shot cohort: 0.2%)
"A total of 563,465 participants met the eligibility criteria. Of those, 328,597 (58%) received a second booster dose during the 40 day study period. Hospitalization due to COVID-19 occurred in 270 of the second-booster recipients and in 550 participants who received one booster dose (adjusted hazard ratio, 0.36; 95% confidence interval (CI): 0.31–0.43). Death due to COVID-19 occurred in 92 second-booster recipients and in 232 participants who received one booster dose (adjusted hazard ratio, 0.22; 95% CI: 0.17–0.28)."
> Regev-Yochay G, Gonen T, Gilboa M...
Small sample size (N=1050). Not blinded. Not randomized. Lower PCR testing adherence in control group. Short follow-up period. Overall insignificant clinical effect:
"25.0% of the participants in the control group were infected with the omicron variant, as compared with 18.3% of the participants in the BNT162b2 group and 20.7% of those in the mRNA-1273 group. Vaccine efficacy against any SARS-CoV-2 infection was 30% (95% confidence interval [CI], −9 to 55) for BNT162b2 and 11% (95% CI, −43 to 44) for mRNA-1273"
In other words, the VE confidence interval crossed zero for both vaccines -- it's possible the extra dose made things worse.
I've run out of time and this post is getting long, but the remaining studies are no different. Is it possible that there's some tiny effect size for elderly people? Sure. But this data doesn't support shot 7 (or 6, or 5...), and it definitely doesn't support the boosters in people younger than 60.
This is absolutely incorrect, unless you're using a sleight of hand by using "keep redosing" to refer to a strawman of continuous indefinite dosing (something nobody has proposed).
There is copious evidence that a third dose provides lasting, long-term benefits in humans. There is also evidence that the bivalent booster - which may eventually replace the first dose, as more data comes in - provides significant benefit in adults as well.
Could you link some? From what I recall the effects were either severely limited in duration, or limited to high-risk demographics.
But ANTIBODY LEVELS ARE NOT THE POINT. With intranasal booster to complement intramuscular vacination for respiratory diseases what you're doing is recruiting specialized immune cells to become resident in the upper respiratory mucosa. Both B and T cells. It's harder to test for them then for antibody binding but there are many studies showing such tissue resident virus-specialized immune cells stick around functionally for years.
The point is to get these tissue resident immune cells up there and ready so they can get to work killing off infected cells and pumping out new antibodies immediately after the first few cells are infected. The faster your immune system goes into action the less damage is done. An intranasal booster complements intramuscular vaccination by getting your immune system ready in the immunological compartment infection is most likely to start in. Rolling the dice by actually getting infected to get mucosal+humoral immunity (hybrid immunity) is like crashing your car so you won't crash your car. You'll probably be fine even if it'll hurt a lot. But there's a real risk of worse. It's not a reasonable option if you can avoid it.
I still haven't been infected with sars-cov-2. I'm waiting on an approved intranasal vaccine in the USA before I stop wearing N95s in public and non-home indoor spaces (and limiting my time in them). I really, really wish vaccine development for sars-cov-2 was still a priority.
Let's be clear: that's the goal, not the reality. There is no such intranasal vaccine, and your understanding of IgA/IgG/IgM/etc. is incomplete, because even though these different antibody types are associated with different tissues, it's not a categorical thing. Likewise, it's not like T- and B-cells never make it to the mucosa -- the fundamental issue is that neither form of immunity stays ramped to 11 forever, and cellular immunity takes time to spin up post-infection.
To a first approximation: antibodies ramp up quickly and decline quickly, and cellular responses ramp up more slowly, and last longer. When you get infected with a respiratory pathogen, the IgA levels in your nasal mucosa spike early in part because that's the tissue the virus encounters first. If the virus lives long enough to make it elsewhere in the body, it encounters IgG/IgM and ultimately, T- and B-cells.
Researchers have been chasing this idea that they can cause persistent cellular immune responses in the nasal mucosa for decades, but there's no good reason to believe it will ever happen.
> I'm waiting on an approved intranasal vaccine in the USA before I stop wearing N95s in public and non-home indoor spaces (and limiting my time in them).
This is not going to work. You are going to get it. If you have been vaccinated with two doses of the current vaccines and are not severely immunocompromised (e.g. currently undergoing a bone-marrow transplant), you are as well-protected as you are ever going to be.
> I really, really wish vaccine development for sars-cov-2 was still a priority.
I will emphasize this again: the current vaccines work. You are putting your life on hold while waiting for (effectively) a cure to the common cold. This is not remotely guaranteed to happen in your lifetime.
Get two doses -- or more if you like (though there's no evidence for it) -- and be confident that you've done everything practical you can do to reduce your risk.
Those are what prevent severe disease, but they don't prevent infection.
The protection against severe disease from a 3-shot series of the mRNA vaccine is in all likelihood completely permanent.
For the nasal vaccines to fail to produce that cellular immunity would be a massive failure.
The short term durability of neutralizing antibodies seen with EVERY SARS-COV-2 VACCINE NOT JUST THE MRNA ONES is likely a feature of immunity to respiratory viruses. The "one series of shots to never contract the disease again in your lifetime" style of immunity probably doesn't exist for this virus. Certainly we don't know how to create one right now.
There are at least 44 intra-nasal vaccines in pre-clinical development.[1] Something is probably going to work.
[1] https://medicalxpress.com/news/2023-04-potential-mucosal-cov...
https://impfung.biontech.de/en/impfung/project-lightspeed.ht...
They are fully capable of producing mRNA vaccines just as well as the West. IP rights have never been an issue for China. The claim that it's stubborn pride is also weak because they could simply tweak a few meaningless details and claim it's superior to the West's version.
Why did a huge company like Pfizer team up with a small one like BioNTech?
China does have at least a couple of mRNA vaccines (Walvax COVID-19 vaccine and CanSino Biologics Inc COVID-19 mRNA Vaccine), but it took them until 2021/2022 to get them to trials. They just didn't seem to have the experience in making and testing mRNA vaccines that Western companies did.
You made two mistakes in one sentence.
First of all, Chinese companies have multiple mRNA vaccines in development and at least one of them has been approved. I can get it today in my neighbourhood clinic if I want. See link below.
https://www.bbc.com/news/world-asia-china-65036474
Secondly, when there is something that is not produced or produced in China, it doesn't mean it is useless or fancy. China doesn't make 3nm chips not because it is not cool, it is because the advanced tech is simply not available in China. China does make high end LCD panels which the US doesn't build on its own, it is not because the tech is fancy and the US couldn't do it, it is simply because the industry is not considered economically viable in the US but a good money making business in China.
I count myself fortunate to live in an area where they were administering A-Z.
This is a pretty common story with the mRNA and DNA/AAV vaccines as well. Did any of them wind up in the hospital?
I mean, if they really were completely worthless, I'd have expected China to have been much worse off after their lockdowns ended.
Better vaccines everywhere would be good. mRNA vaccines were laughably crappy - essentially just a temporary prophylactic.
SARS-CoV-2 infection starts in the upper respiratory system, where the nasopharyngeal tract is at the forefront. To prevent viruses from attaching and replicating at the mucosal epithelium, effective mucosal immunity in the airway is critically important.
Although only in mice, it does at least have a solid hypothesis for why they wish to do it this way.
But intranasal is like the pharynx and nasal passages and turbinates stuff, not all the way down in the lungs.
> Comparison of traditional intranasal and aerosol inhalation inoculation of mice with influenza A viruses
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725743/
I suppose an intranasal agent could accidentally get inhaled, but I think it's not meant to, it would probably elicit a choking reaction and not make it very deep into the lungs. Inhaled stuff is like smoke and nebulizer things.
Just like the platypus exists because nature didn't ask humans how we wished to categorize animals before deciding nature was OK with an egg-laying mammal, even though most mammals don't lay eggs.
> Also you don't risk the accidental intravenous delivery which can have terrible outcomes when the syringe isn't first aspirated to sample if you hit some open vasculature along the way.
From what I heard that whole process fell out of favor to optimize for comfort and rapidity over the possible futzing with a syringe still embedded in the body.
It would be far more convincing if the authors explicitly acknowledged that in the abstract, and gave a good reason why they think their approach is more promising.
From the link:
> Some studies on respiratory viruses such as respiratory syncytial virus (RSV) and influenza virus provide substantial evidence that mucosal immunity is key to the effective control of respiratory viruses.
> However, almost all COVID-19 vaccines approved for human usage, including inactivated virus, lipid nanoparticle-encapsulated mRNA, protein subunit of spike or RBD, and adenovirus vectored vaccines, are administered via intramuscular injection. These vaccines can induce a systemic immune response that protects against severe disease and mortality but not a mucosal immune response and are insufficient in preventing upper respiratory infection and transmission, especially with the emergence of highly transmissible Omicron subvariants.
"In mice" should be a prefix, not a suffix, eg. "Don't get your hopes up, but" or DGYHUB in short.