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Breakthrough Infections Occur in Those with Lower Antibody Levels, Israeli Study Shows

Posted on by Dr. Francis Collins

A wall of bricks with antibody symbols on them. Where one brick is missing, viruses flood through.

To see how COVID-19 vaccines are working in the real world, Israel has provided particularly compelling data. The fact that Israel is relatively small, keeps comprehensive medical records, and has a high vaccination rate with a single vaccine (Pfizer) has contributed to its robust data collection. Now, a new Israeli study offers some insight into those relatively uncommon breakthrough infections. It confirms that breakthrough cases, as might be expected, arise most often in individuals with lower levels of neutralizing antibodies.

The findings reported in The New England Journal of Medicine focused on nearly 1,500 of about 11,500 fully vaccinated health care workers at Sheba Medical Center, Ramat Gan, Israel [1]. All had received two doses of the Pfizer mRNA vaccine. But, from December 19, 2020 to April 28, 2021, they were tested for a breakthrough infection due to a known exposure to someone with COVID-19 or possible symptoms of the disease.

Just 39 confirmed breakthrough cases were found, indicating a breakthrough infection rate of just 0.4 percent. That’s consistent with rates reported in previous studies. Most in the Israeli study who tested positive for COVID-19 had mild or no symptoms and none required hospitalization.

In the new study, researchers led by Gili Regev-Yochay at Sheba Medical Center’s Infection Control and Prevention Unit, characterized as many breakthrough infections as possible among the health care workers. Almost half of the infections involved members of the hospital nursing staff. But breakthrough cases also were found in hospital administration, maintenance workers, doctors, and other health professionals.

The average age of someone with a breakthrough infection was 42, and it’s notable that only one person was known to have a weakened immune system. The most common symptoms were respiratory congestion, muscle aches (myalgia), and loss of smell or taste. Most didn’t develop a fever. At six weeks after diagnosis, 19 percent reported having symptoms of Long COVID syndrome, including prolonged loss of smell, persistent cough, weakness, and fatigue. About a quarter stayed home from work for longer than the required 10 days, and one had yet to return to work at six weeks.

For 22 of the 39 people with a breakthrough infection, the researchers had results of neutralizing antibody tests from the week leading up to their positive COVID-19 test result. To look for patterns in the antibody data, they matched those individuals to 104 uninfected people for whom they also had antibody test results. These data showed that those with a breakthrough infection had consistently lower levels of neutralizing antibodies circulating in their bloodstream to SARS-CoV-2, the coronavirus that causes COVID-19. In general, higher levels of neutralizing antibodies are associated with greater protection and lower infectivity—though other aspects of the immune system (memory B cells and cell-mediated immunity) also contribute.

Importantly, in all cases for which there were relevant data, the source of the breakthrough infection was thought to be an unvaccinated person. In fact, more than half of those who developed a breakthrough infection appeared to have become infected from an unvaccinated member of their own household.

Other cases were suspected to arise from exposure to an unvaccinated coworker or patient. Contact tracing found no evidence that any of the 39 health care workers with a breakthrough infection passed it on to anyone else.

The findings add to evidence that full vaccination and associated immunity offer good protection against SARS-CoV-2 infection and severe illness. Understanding how SARS-CoV-2 immunity changes over time is key for charting the course of this pandemic and making important decisions about COVID-19 vaccine boosters.

Many questions remain. For instance, it’s not clear from the study whether lower neutralizing antibodies in those with breakthrough cases reflect waning immunity or, for reasons we don’t yet understand, those individuals may have had a more limited immune response to the vaccine. Also, this study was conducted before the Delta variant became dominant in Israel (and now in the whole world).

Overall, these findings provide more reassurance that these vaccines are extremely effective. Breakthrough infections, while they can and do occur, are a relatively uncommon event. Here in the U.S., the Centers for Disease Control and Prevention (CDC) has recently estimated that infection is six times less likely for vaccinated than unvaccinated persons [2]. That those with immunity tend to have mild or no symptoms if they do develop a breakthrough case, however, is a reminder that these cases could easily be missed, and they could put vulnerable populations at greater risk. It’s yet another reason for all those who can to get themselves vaccinated as soon as possible or consider a booster shot when they become eligible.


[1] Covid-19 breakthrough infections in vaccinated health care workers. Bergwerk M, Gonen T, Lustig Y, Amit S, Lipsitch M, Cohen C, Mandelboim M, Levin EG, Rubin C, Indenbaum V, Tal I, Zavitan M, Zuckerman N, Bar-Chaim A, Kreiss Y, Regev-Yochay G. N Engl J Med. 2021 Oct 14;385(16):1474-1484.

[2] Rates of COVID-19 cases and deaths by vaccination status, COVID Data Tracker, Centers for Disease and Prevention. Accessed October 25, 2021.


COVID-19 Research (NIH)

Sheba Medical Center (Ramat Gan, Israel)


  • Lisa says:

    What about testing for Unvaccinated previously infected individuals? This study just shows the vaccine’s protections wain. What about natural immunity? Large, widespread research needs to be done on those of us who have already been infected. Millions worldwide. This can save vaccines for those at more risk or countries with more need. I had it, still suffer loss of T&S and am also vaccinated. I still had antibodies 8 months after contracting. These studies need to done.

    • Peter Jackson says:

      Nature, Oct 21, 2021 issue, Vol 598, pp 393-4, has a report by Ewan Callaway on the greatly enhanced immunity of vaccinated people who had pre-vaccine infections. Immune system components responsible are discussed but it looks like vaccines alone do not stimulate all areas of the immune response as well as natural infections. This is an active area of research. Also Dr. Francis Collins’ NIH Directors Blog reports on Israeli data that breakthrough infections are associated with low antibody levels ( several possible causes exist for lower vaccine responses). So boosters can definitely be of value to maintain/stimulate protection. Next generation vaccines will benefit from such research work.

      • Steve White says:

        I believe people who are at extremely low risk may be better off not getting vaccinated until after they are infected for this reason. The push to vaccinate children may be misplaced for this reason. We have to consider if, long term, the people who get natural immunity are likely to have better resistance to variants the vaccines were not designed to protect against.

        • Steve Bate says:

          “Importantly, in all cases for which there were relevant data, the source of the breakthrough infection was thought to be an unvaccinated person. In fact, more than half of those who developed a breakthrough infection appeared to have become infected from an unvaccinated member of their own household.”
          This quotes “Importantly”…like you can’t decide for yourself…then “relevant data”…with no reference(s)…then “thought to be” and finally “appeared to have become infected” all in just 48 words! It’s like saying you may lose 35 lbs in the first week of this amazing diet (amputation of a limb may be required). Where are the facts to support this? “Thought to be”, “appeared to be”? These are only opinions at best…give us (me) the raw data and let me (us) draw our own conclusions…no more coercion please!!

    • Elisabeth S. says:

      Lisa, i am in the same position as you. Had it in November 2020, lost sense of taste and smell, has not returned yet fully. I got vaccinated (Moderna) in March and April 2021. Would love to be,part,of a study that determines how long antibodies (i seem to have 11,900 BAU) last, be they from infection, vaccination, or a combination.

  • Patsy W. says:

    I have had 3 doses of the Moderna vaccine and was tested for antibodies. I have not one antibody to covid 19. I am 80 years old, with asthma, one kidney and over weight. My doctor warns me that I will not survive Covid.

  • Marianne says:

    How did the .4% breakthrough rate get calculated. If there were 39 cases in 1500 – that’s 2.6%……..

    • Moderator says:

      Thanks for your comment. In total, there were 11,453 fully vaccinated health care workers. 1,497 had a reason to get tested and 39 were positive. So 2.6%. The 0.4% is based on the fact that it’s 39 of almost 11,500 workers. 39/11453= .0034. So actually the number has been rounded up. But it’s about 0.4%.

      • D Hart MD says:

        I’m not sure why you rounded up, rather than rounding down. Typically, if the number at the decimal place that you’ll be discarding is 5 or more, you round up. If the number at the decimal place that you’ll be discarding is 4 or less, you round down. So in this case, the 0.0034 should have been 0.003 (though 0.0034 would have been perfectly fine as well).

      • M.B. says:

        A reason to get tested? Does this mean that they are more likely a lot more breakthrough infections that went unreported?

      • Denise says:

        Your math is not correct. The sample size was not 11,500. The sample size is 1500. Only 1500 were tested. You cannot base the math on the total number of people immunized unless all 11,500 were being tested for a breakthrough virus.

  • Steve White says:

    The basic conclusion of the study, a surfeit of antibodies puts you at higher risk of infection, may hold true for every variant, and any length of time after vaccination, but with Delta variant replacing the type the vaccines were designed to prevent, it is not clear more of the same vaccines, ie boosters, will stop Delta as effectively. I can not suss out what is going on with the FDA and CDC re boosters – Israel went for everyone over 60 getting one – we have gone with a more conservative approach – and even that was criticized as too broad – ????? – we have a big push to vaccinate children, but we do not vaccinate children for influenza, and yet, for the first types at least, influenza is reported to be more dangerous to children than SARS2.
    It would be great if NIH, FDA, CDC would get on TV, and instead of reactively answering obvious unhelpful questions from reporters (“Will more people sick if they use less precautions?”) lay out the odds by writing down the numbers on a board and explaining why some particular policy makes sense.
    And if the numbers do NOT make sense on the board, maybe rethink the policy?

    • D Hart MD says:

      “The basic conclusion of the study, a surfeit of antibodies puts you at higher risk of infection,…”
      Surfeit means an excessive amount of something. I think perhaps you meant “paucity” (or some other synonym for an insufficient amount).

      “…but we do not vaccinate children for influenza,…” Yes, yes we DO vaccinate children for influenza, starting at 6 months of age.

  • Andrew Goldstein says:

    Thank you for this detailed article about the Israeli study. The data are limited but still, the most important study outcome for me was, “…in all cases for which there were relevant data, the source of the breakthrough infection was thought to be an unvaccinated person.” This observation suggests that infections are more likely to be transmitted by unvaccinated individuals, making them more responsible for prolonging this pandemic.

  • Krista A. says:

    My daughter had a breakthrough case, got it from her boyfriend who also had a breakthrough case. They are healthy, cautious, late 30’s early 40’s and most importantly vaccinated. These cases don’t get reported as there is no way to report this! Neither was terribly sick just bad cold like symptoms and loss of taste and smell for her but both tested positive. Studies are one thing but my own feeling from hearing case after case of breakthroughs among friends or friends of friends is that this is much much more common than is being reported.

    • Lisa says:

      Agree. I know of way too many people that have had a “breakthrough case” for it to only be 0.4%. I think the key words here are, “the study was done before the Delta variant”. We didn’t see too many “breakthrough cases” before the Delta arrived. I think if they did the same study now, the outcome would be different, especially with the Pfizer vaccine.

  • David H. Goldsmith says:

    I appreciate your research. But you failed to indicate the infection % for the second study. Thank you.

    • Moderator says:

      Hi David, if you go to the references section and click on the hyperlinked reference 2, you’ll find more information on the CDC site. Thanks.

  • Alan L. Coykendall says:

    I, too, noticed that the rate of cases was 2.6%, as did Marianne. Where did the 0.4% come from?

  • T Kwan says:

    There needs to be better quantitative antibody testing of vaccine generated neutralizing antibodies. Without it we have little information about seroconversion of each dose including booster and the waning rate of effectiveness of vaccines. In L.A. County, the rate of breakthrough cases is bit over 1% of all vaccinated persons and about 12% of daily new cases. Of course, there is no way to determine the time between vaccination and infection without more data. Even with low antibody levels, the cell mediated and innate immune system still may provide protection.

  • clauvel says:

    when patients have a high level of antismoke antibodies, do they have a high timer of neutralising antibodies?thanks

  • Mary says:

    Not all antibodies are the same and diagnostic tests are only as good as what they are designed to detect and the availability of proper reagents. 100 years of technological advancement. 50M died in the 1918 pandemic where the global spread was facilitated through ships and their various routes as a result of WWI; 100 years later, although official numbers are around 4-5M globally, epidemiological studies would suggest the the toll of covid-19 is closer to 15-18M; and a vast majority of the globe has yet to be vaccinated.
    Toto, we are not in Kansas anymore.

  • JR says:

    I know a fully vaccinated man who got a break through infection and had breathing difficulties, fever, and was coughing blood. He also infected his fully vaccinated wife who also suffered more than mild symptoms, along with infecting his 2 unvaccinated very young daughters. His family was infected by a fully vaccinated man, not an unvaccinated person.

    • D Hart MD says:

      Thank you for your anecdotal recounting of the single family.

      For a more comprehensive view of how well vaccinations work against disease, hospitalizations and deaths, look at the “CDC COVID Data Tracker” at the CDC website.

  • Bruce says:

    Did anyone read the second part of the study? Also, is there a reason it was not highlighted in this article when findings are more relevant to the current situation regarding variants/ vaccine?

  • Robin King says:

    I’m personally seeing a lot more break through with the Delta. 50% of our cases were breakthrough. I have not seen anyone with natural immunity test positive again

  • Fahmida P. says:

    Natural immunity is good, but vaccination is a must. But exceptions occur sometimes.

  • Elizabeth says:

    I have been researching the covid and also the vaccines. So many people seem to think that unvaccinated alone are spreading covid. This is totally conflicting to what we are repeatedly seeing in our community. Where even our Health department worker. ( who mainly answered phones and set up appointments in her office) recently died from a breakthrough case. Breakthrough cases exposed others unknowingly because they weren’t very sick and didn’t think they, being vaccinated, had covid.We’ve had many breakthrough cases. In one state it was reported that over 70 percent of the cases were breakthrough cases. My sister in law also had both the shots, (getting very sick from the second for about 4 days) then 2 months later, got a breakthrough case and was sick for 2 weeks and in hospital for 3 days. Then 2 months later given the booster which caused a large very painful knot to form under her breast for about a week, making her sick all over again. How much misery to suffer in the name of a vaccine that doesn’t even work? I had covid about 16 months ago. I’ve cared for 2 with covid at their home and never gotten sick from them. My antibodies are far stronger , for far longer than these shots.

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