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How Immunity Generated from COVID-19 Vaccines Differs from an Infection

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Orginal viral spike is shown binding to antibody from vaccine and from infection. Variant spikes only bind to antibody from vaccine.

A key issue as we move closer to ending the pandemic is determining more precisely how long people exposed to SARS-CoV-2, the COVID-19 virus, will make neutralizing antibodies against this dangerous coronavirus. Finding the answer is also potentially complicated with new SARS-CoV-2 “variants of concern” appearing around the world that could find ways to evade acquired immunity, increasing the chances of new outbreaks.

Now, a new NIH-supported study shows that the answer to this question will vary based on how an individual’s antibodies against SARS-CoV-2 were generated: over the course of a naturally acquired infection or from a COVID-19 vaccine. The new evidence shows that protective antibodies generated in response to an mRNA vaccine will target a broader range of SARS-CoV-2 variants carrying “single letter” changes in a key portion of their spike protein compared to antibodies acquired from an infection.

These results add to evidence that people with acquired immunity may have differing levels of protection to emerging SARS-CoV-2 variants. More importantly, the data provide further documentation that those who’ve had and recovered from a COVID-19 infection still stand to benefit from getting vaccinated.

These latest findings come from Jesse Bloom, Allison Greaney, and their team at Fred Hutchinson Cancer Research Center, Seattle. In an earlier study, this same team focused on the receptor binding domain (RBD), a key region of the spike protein that studs SARS-CoV-2’s outer surface. This RBD is especially important because the virus uses this part of its spike protein to anchor to another protein called ACE2 on human cells before infecting them. That makes RBD a prime target for both naturally acquired antibodies and those generated by vaccines. Using a method called deep mutational scanning, the Seattle group’s previous study mapped out all possible mutations in the RBD that would change the ability of the virus to bind ACE2 and/or for RBD-directed antibodies to strike their targets.

In their new study, published in the journal Science Translational Medicine, Bloom, Greaney, and colleagues looked again to the thousands of possible RBD variants to understand how antibodies might be expected to hit their targets there [1]. This time, they wanted to explore any differences between RBD-directed antibodies based on how they were acquired.

Again, they turned to deep mutational scanning. First, they created libraries of all 3,800 possible RBD single amino acid mutants and exposed the libraries to samples taken from vaccinated individuals and unvaccinated individuals who’d been previously infected. All vaccinated individuals had received two doses of the Moderna mRNA vaccine. This vaccine works by prompting a person’s cells to produce the spike protein, thereby launching an immune response and the production of antibodies.

By closely examining the results, the researchers uncovered important differences between acquired immunity in people who’d been vaccinated and unvaccinated people who’d been previously infected with SARS-CoV-2. Specifically, antibodies elicited by the mRNA vaccine were more focused to the RBD compared to antibodies elicited by an infection, which more often targeted other portions of the spike protein. Importantly, the vaccine-elicited antibodies targeted a broader range of places on the RBD than those elicited by natural infection.

These findings suggest that natural immunity and vaccine-generated immunity to SARS-CoV-2 will differ in how they recognize new viral variants. What’s more, antibodies acquired with the help of a vaccine may be more likely to target new SARS-CoV-2 variants potently, even when the variants carry new mutations in the RBD.

It’s not entirely clear why these differences in vaccine- and infection-elicited antibody responses exist. In both cases, RBD-directed antibodies are acquired from the immune system’s recognition and response to viral spike proteins. The Seattle team suggests these differences may arise because the vaccine presents the viral protein in slightly different conformations.

Also, it’s possible that mRNA delivery may change the way antigens are presented to the immune system, leading to differences in the antibodies that get produced. A third difference is that natural infection only exposes the body to the virus in the respiratory tract (unless the illness is very severe), while the vaccine is delivered to muscle, where the immune system may have an even better chance of seeing it and responding vigorously.

Whatever the underlying reasons turn out to be, it’s important to consider that humans are routinely infected and re-infected with other common coronaviruses, which are responsible for the common cold. It’s not at all unusual to catch a cold from seasonal coronaviruses year after year. That’s at least in part because those viruses tend to evolve to escape acquired immunity, much as SARS-CoV-2 is now in the process of doing.

The good news so far is that, unlike the situation for the common cold, we have now developed multiple COVID-19 vaccines. The evidence continues to suggest that acquired immunity from vaccines still offers substantial protection against the new variants now circulating around the globe.

The hope is that acquired immunity from the vaccines will indeed produce long-lasting protection against SARS-CoV-2 and bring an end to the pandemic. These new findings point encouragingly in that direction. They also serve as an important reminder to roll up your sleeve for the vaccine if you haven’t already done so, whether or not you’ve had COVID-19. Our best hope of winning this contest with the virus is to get as many people immunized now as possible. That will save lives, and reduce the likelihood of even more variants appearing that might evade protection from the current vaccines.


[1] Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection. Greaney AJ, Loes AN, Gentles LE, Crawford KHD, Starr TN, Malone KD, Chu HY, Bloom JD. Sci Transl Med. 2021 Jun 8.


COVID-19 Research (NIH)

Bloom Lab (Fred Hutchinson Cancer Research Center, Seattle)

NIH Support: National Institute of Allergy and Infectious Diseases


  • Dr. Dan O’Connell says:

    I am fully vaccinated with Pfizer . I believe I have a breakthrough infection with possibly delta variant, but haven’t had a test to verify yet.
    Will the antibodies generated by the breakthrough infection possibly function like a booster Pfizer is contemplating, much like for persons who had Covid 19 and then had full vaccinations later? Doesn’t seem to be much discussion or conjecture about this. I realize this is probably not studied yet, but am curios what you think these breakthrough infections could cause

    • Joanne M Giannini says:

      When I had COVID back in February (not vaccinated as they were not even available then), I used the I-Mask+ protocol and my symptoms were extremely mild (like a cold with a 99 degree temperature). My husband didn’t even have any temp – just felt a bit unwell. No headaches, loss of smell or taste, etc. and no long-term issues at all. Early treatment is important!! Right now the data coming out of Israel indicates a reinfection rate of 0.0086% for previously infected individuals. No one knows how long the immunity will last, but so far it looks to be great protection. I also wish there was more study on this issue as it affects MILLIONS of us! Best wishes to you for a super speedy recovery.

      • Lisa says:

        Joanne I agree with you. Why are other countries studying Natural Immunity and the US is not?

        • Joanne M Giannini says:

          Lisa – I wish the NIH/CDC would realize that THIS issue – that the natural immunity of MILLIONS of Americans is not recognized and people who have previously recovered are being FORCED to accept shots that numerous studies have shown offer no demonstrated benefit or lose their employment, access to education, and/or loss of freedom due to their recommendations – is what is causing so much distrust for the government. There needs to be a risk versus reward analysis done on this issue. Yes, vaccination in the previously infected causes an increase in CERTAIN antibodies, but does this really offer any benefit, especially in light of the increasing amount of Delta variant breakthrough cases? Real-life results seems to indicate it does not. At the same time, “Self-reported real-world safety and reactogenicity of COVID-19 vaccines: An international vaccine-recipient survey” shows an increased incidence of vaccination side effects by 2-3 times. It all just doesn’t make any sense. I am against mandates in general, but Certificates of Recovery could easily be issued to recovered individuals, even if for just a specified period of time until more data comes in. Europe is currently offering these to individuals for a six-month period after recovery (and they state that amount of time may increase as more data becomes available). Additionally, this would free up vaccine doses for other underserved areas of the world. Isn’t it just selfish not to direct the resources towards the most needy?

          • Lisa says:

            I agree 100% with all you’ve stated. I had no idea that Europe was offering the Certificate of Recovery. It would make so much sense to monthly or quarterly test recovered covid patients for antibody levels. I still can not taste and smell 7 months after having covid. The last thing I want to do right now when I feel I am still recovering is to be forced or shamed into taking a vaccine that is made up of a chemical compound that my body reacts to.

          • Sandy says:

            I agree. I came across information about the Certificate of Recovery on the EU Commission site last week. Ireland went so far as to recommend 9 months but I think they are going with the six months like other EU (27 countries) and EEA.

            The Commission also proposed that people who have received a single dose of a two-dose vaccine after having previously been infected with COVID-19 should be considered fully vaccinated for the purpose of travel.

            This is based on multiple studies and at least 640,000 participants. Why is the conversation and the guidance for those who have recovered not given serious time and attention. It’s always, just get the vaccine.

          • JR says:

            ” …….This is based on multiple studies and at least 640,000 participants. Why is the conversation and the guidance for those who have recovered not given serious time and attention. It’s always, just get the vaccine…………” Isn’t that most curious? Somehow the brilliant medical authorities heading our nations health bureaucracies have either not noticed or considered the immunity of the recovered, or maybe more likely, decided to put a lid on that discussion. It is impossible to look at that logically and not suspect something nefarious going on. Exactly what, I do not know. All I know is that they are blatantly ignoring the science by ignoring those of us who have survived the disease and our resulting immunity to COVID-19. It is not right or ethical for them to ignore it, but that is exactly what is happening.

          • Lisa says:

            I concur with you JR. Why are our blood types not being studied as Diana stated and why is our blood not being used to create new safer vaccines with known natural antibodies instead of chemical compounds made to replicate the virus?

          • Ryan Shaffer says:

            Joanne, One additional thing I found interesting from the Israeli study I didn’t seen your comment is that vaccinated people are almost 7 times more likely to become reinfected than those who have natural immunity. Like with most viruses, natural immunity appears to be stronger and longer lasting then the vaccination. I think there must be a political component To why natural immunity is not being recognized like vaccines are.

          • Joanne M Giannini says:

            Ryan – Agreed it must be political as all the recent data coming out supports the notion that natural immunity is AT LEAST as good as vaccination (it actually appears that natural is indeed much better, but I will even accept “as good as” recognition). So many of us put ourselves out there as first responders, kept the country running, got sick and recovered, and now get nothing for our sacrifice. Instead, we get bombarded with mandates which should not apply to us. All the recent data indicates we are much less of a risk to others than the vaccinated. Meanwhile, our doses could be sent to other countries to help with the overall global situation. The whole thing just makes no logical sense!!

        • Greg says:

          Because there is no money to be made or control to be leveraged with such a study.

      • Ryan Shaffer says:

        One other thing I wanted to add is that the 6.72 increased infection rate for vaccinated individuals from the Israeli study is being suppressed by google and you can’t easily find it by doing a google search, yet you can easily find it doing a search on bing. The attempted suppression of this information also bothers me.

        • dk says:

          Ryan, do you have a citation for the “7 times more likely” infection in vaccinated vs natural immunity?

          • Ryan Shaffer says:

            It doesn’t look like this blog lets you post links to websites…but I will give you the relevant part of the study and if you post some of it in bing, you should be able to come up with the citation…again, this really disturbs me that you cannot find this doing a google search…even if it was “fake news” (which it is not), it is complete big tech censorship and very ugly…

            “Health Ministry data on the wave of COVID outbreaks which began this May show that Israelis with immunity from natural infection were far less likely to become infected again in comparison to Israelis who only had immunity via vaccination.”

            “With a total of 835,792 Israelis known to have recovered from the virus, the 72 instances of reinfection amount to 0.0086% of people who were already infected with COVID.

            By contrast, Israelis who were vaccinated were 6.72 times more likely to get infected after the shot than after natural infection, with over 3,000 of the 5,193,499, or 0.0578%, of Israelis who were vaccinated getting infected in the latest wave.”

          • D Hart MD says:

            As for posting links, you are correct that they apparently are not allowed in the comments.

            The workaround is to post the title of the article you would have linked, along with (if possible) the date, the name of the journal (if relevant) or the name of the website, or any other localizing/identifying information that might also help.

          • Markie_marc says:

            Do you need a citation for legitimacy? Sounds like the Israeli study reasoning.

  • DB Cooper says:

    Wow, so we are assigning ALL immunity to COVID to a single binding site on the virus? Not a bad study just a very presumptive title for something we know very little about. Does natural immunity target other parts of the virus that the vaccine does not? Seems to be very little appetite, aka grant funding, to even look into this.

  • DianaDiMaggio says:

    No mention of the study posted on this site as to key study showing blood type may predict outcomes and severity of Covid.

  • Mr D HUDES says:

    Oxford University and the Office of National Statistics have found the opposite.

    Once someone has fully recovered from an infection there is statistically zero chance of being infected with a high viral load again.
    (Low viral loads have been detected, but this is at levels where the subject isn’t I’ll or able to pass it on).

    Whereas, vaccinated people are regularly becoming infected and very ill.

    • D Hart MD says:

      Axios has an article from July 26 (“GOP Rep. Clay Higgins says he has COVID for second time”) showing just the opposite of your claim. According to him, “this episode is far more challenging.”

      • JR says:

        I wouldnt accept an anecdotal claim from him as any reliable evidence of reinfection. Perhaps he didn’t have a verified case of COVID-19 one or both times. The tests have a history of both false negatives and false positives. In addition, does he even say he was tested? We also know that a lot of Flu cases have been misdiagnosed as COVID-19, especially back in 2020. Most likely, the politcian didn’t have COVID-19, but rather, had the Flu or something else on one of, if not on both occasions.

    • Michelle Staley says:

      I am currently recovering from my 3rd bout with Covid 19 AND got my second Pfizer shot in May. My first & worst Covid infection was Jan. 2020. I was contact traced and there was a direct link to China. I was contact traced with the current infection from a salon I went to two weeks ago. My first hair cut in over a year and the stylist ended up in the hospital with Covid, she was not vaccinated. I rarely leave my property and have always worn a mask in public. I am retired medical and know how to wash my hands and do so often. I don’t want there to be another lockdown but am ready for it. I don’t have enough faith that more people will get vaccinated . . .

      • Joanne M Giannini says:

        Have you tested positive for the virus each time? Or just feel like you have it again? It might be that you have a “long haulers” case, which would involve your body experiencing “flare ups” on occasion due to a number of factors. Dr. Mobeen Syed has done some excellent videos on the subject. HIs latest one with Dr. Bruce Patterson is a must see! Dr. Bruce Patterson’s team has discovered that the S1 pieces of the spike proteins persist in the monocytes resulting in immune dysregulation and long-haul syndrome. I hope his research brings you and others in your same situation much needed relief.

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