August 30th, 2020

Cases of SARS-CoV-2 Reinfection Highlight the Limitations — and the Mysteries — of Our Immune System

A New World of Creatures, Invisible to the Human Eye. J. J. Grandville, 1842.

In case you didn’t notice, or perhaps were “off the grid” taking some well-earned time away from COVID-19 news, this past week we heard about several cases of SARS-CoV-2 reinfection.

We’ll come back to them in a moment, but first, some questions:

  • Why does one parent never get sick when their kids start coughing and sneezing and dripping with colds, while the other gets a cold every single time?
  • Why do some tourists happily dine on delicious street food in Mexico City, while this same cuisine will put others in their hotel bathrooms for the whole trip?
  • Why are some people repeatedly plagued with strep throat, while others never get it in their lifetimes?
  • Why is infection with Epstein Barr virus (nearly 100% in humans by adulthood) most of the time asymptomatic, while a certain unlucky few will be laid up with severe mononucleosis for weeks?
  • Why did some gay men in U.S. cities contract HIV in the early 1980s after relatively few exposures, while some others with multiple known HIV-positive contacts never did? How did some commercial sex workers in Africa in the early 1980s escape HIV?
  • Or, perhaps most relevant to the COVID-19 re-infection cases, why do some people get the flu twice within the same flu season? Or some (rare) people get chicken pox twice? (The second case is usually quite mild, fortunately.) Or even measles!

I start with these examples (and I could have chosen dozens more) to highlight that there’s a ton we don’t know about infection, immunity, and how they interact to protect us — or not to protect us — from disease.

So after hearing anecdotes about SARS-CoV-2 reinfection for months (many of them false-calls based on persistent low-level PCR positivity, not reinfection), now we have actual cases, and it’s worth considering some of the details.

The first occurred in a 33-year-old man 142 days after his initial symptomatic infection. Authorities picked up the infection on a screening test when he went through the Hong Kong airport, as he had no symptoms. In fact, he remained asymptomatic throughout. A brisk antibody response developed shortly after, a response not detected the first time.

Sequencing the virus from the two infections showed sufficient differences to prove reinfection, rather than relapse.

As noted wisely by immunology professor Dr. Akiko Iwasaki, “This is no cause for alarm – this is a textbook example of how immunity should work.”


News then broke with additional cases in Europe and Ecuador, about which we have limited details.

But this U.S. case in a 25-year-old immunocompetent man from Nevada deserves attention, and likely some worry.

Here are the clinical details of the history, summarized from the available pre-print (it has not yet been peer reviewed):

March 25:  Onset of sore throat, cough, headache, nausea, diarrhea.
April 18:  Tested positive for SARS-CoV-2 by PCR.
April 27:  Symptoms resolved.
May 9 and 26:  Tested negative for virus by two methods.
May 28:  Onset of fevers, headache, dizziness, cough, nausea, and diarrhea. Chest x-ray negative.
June 5:  Symptoms worsened, and now with hypoxia; admitted to the hospital and found to have new infiltrates on chest x-ray. PCR positive for SARS-CoV-2.
June 6:  SARS-CoV-2 IgM and IgG antibody positive.

The authors state that the viruses isolated from the first and the second illness show sufficient genetic differences to support reinfection, rather than relapse. The likely source of the second infection was a parent, suggesting household transmission, though the sequences from the parent are not available.

These important case reports raise many questions, about which today we can only speculate, which is why many of the sentences following have question marks.

  • How often does reinfection happen, and why? It doesn’t appear common, but we must conclude from these cases that it does occur. Perhaps with similar frequency to other coronavirus infections in humans?
  • Will cases be as severe as the first infection? Based solely on the Nevada case’s household contact, it’s possible that severity may be related to intensity of exposure. Maybe he was not taking precautions in the household, believing himself immune? Some believe inoculum is an overlooked aspect of COVID-19 disease severity.
  • When reinfection happens, will these new cases carry the same risk of transmission as the first infection? We will have to assume so, but it is plausible that an immune response will render people less infectious to others.
  • How do these cases factor into policies about screening people who have already recovered from COVID-19? Given the long duration of PCR positivity in some people, some infection control specialists have advocated not retesting people who are admitted with prior disease if they are asymptomatic. Same for preprocedural screening. Seems we may need to put this policy change on hold until we have further data on reinfection, and how often it occurs.
  • What are the implications for vaccine efficacy? Will a vaccine even work? If so, for how long? The cases suggest that a vaccine may need to be repeated periodically, but optimists can point to the HPV vaccine as a model of how vaccine immunity can be stronger than natural immunity, so we’ll see.

So remember, there’s a lot we don’t know about our immune system, and how it works — and this is particularly true for a new infection and disease.

But one thing I do know?

“Immunity Passports” are dead.

23 Responses to “Cases of SARS-CoV-2 Reinfection Highlight the Limitations — and the Mysteries — of Our Immune System”

  1. Josep M Llibre says:

    Outstanding summary, done immediately after the paper, preprint, press and email have been released. Agree with all items. Just to highlight that this happened just 3 months after the first wave, when immunity is theoretically still on top. What will happen when time goes by and immunity wanes?. Probably we will witness a surge of reinfections.

  2. Loretta S says:

    As the story of COVID-19 gets more and more complex, I sometimes wonder if mask-wearing, social distancing, etc. will become a new form of universal precautions. Will future generations gasp when we tell them we shook hands *all the time*, the same way my students are shocked when I tell them nurses used to rarely wear gloves and there was one sharps container on a unit, usually far down the hall in a supply room? Will we just assume everyone is potentially infected with SARS-CoV-2, regardless of their vaccination status or history of infection?

  3. Raidan M Alyazidi says:

    Thank you for this timely article. I just wonder if it’s possible that these genetic changes in the re-isloated (rather sequenced since it was not cultured) results from mutations or changes within the host. I know that already corona viruses has better proof reading abilities than flu ones, but they can be perhaps mix community within the host. Then a further wild idea, is it possible that they’re making Hybrid with the host RNA as in this Cell publication by Ho et al. 2020? Or are these viruses rather similar to a newly circulating virus strain. This begs the question of, are these people after getting infected with the Wuhan strain, are now infected with the North American or Italian Strain? & what’s the Epidemiological dynamics of this? Especially in Nevada…

  4. Sergio Serrano-Villar says:

    Brilliant! Excellent points. By now, with a second wave in many countries and a sustained tsunami in others, we should have already witnessed, although not necessarily documented, thousands of reinfections in healthcare workers. I don’t think that this is the case. So far, reinfection seems more an exceptional event. Hopefully, the sustained high burden of SARS-CoV-2 will result in re-exposures with low inoculum that boost memory T cells, limiting the risk of reinfection.

  5. Hassan El Chebib says:

    Viral infections and our immune system is a never-ending fascinating story. Thanks for the summary.

    One thing that lingers in my mind from a pediatric ID side is the possibility of MIS-C spike months after immunization? Is this possibility?

  6. Mahadevan says:

    the safety and immunogenicity of a vaccine for all possible strains of virus looks very remote, because as you say immunogenicity against the virus does not guarentee a prevention against all possible variants

    • Dr. H G Bramhne says:

      Immune response, better called as foreign body response, is very antigen (FB) specific. Very rarely there will be cross reacting antibodies produced ,but their role will be very doubtful in removal/containment of antigen. CMI can have some role,if developed in removal and definitely containment of infectious disease.
      This fundamental principle applies to all infections VS immunity.. In case of corona
      re -infection within short duration ( antibodies are proteins with a life span). Even in case of presence of one type of (specificity)antibodies the extent and type of mutation will decide if the person will land up with disease or not. Very high dose of infective agent can lead to disease even in previously immunized person..
      After all immunity or disease is outcome of offense Vs defense.

  7. Jeff Dickey says:

    Has the role in HLA-B27 in covid been clarified? My understanding is that some of the hep c clearers and hiv non progressors have been B27+. One of my patients who is B27+ had the worst case of mono I’ve ever seen.

  8. Maria S Salvato says:

    The large differences in susceptibility between couples is most likely a difference in their immune systems. Some people are just less susceptible. In the case of the prostitutes who did not get AIDS, they have excellent Cell-mediated immunity that wanes with age, so some showed signs of AIDS as they got older. In the case of re-infections, speculation that the virus has mutated or recombined with self RNA or other viruses is very unlikely. The coronaviruses have a good error-correction mechanism, so the viruses with distinct sequences are likely NEW viruses from new exposures. There are ~6000 published sequences of newly-isolated viruses, and the mapping puts these sequences into approximately 9 clades. If a person suffered from one clade, gets over it and then gets sick from another clade, then that is clearly a new infection and not a mutation-event. These observations bode ill for herd immunity and vaccine immunity. We must be vaccinated against several different clades to be protected, and those who were infected once are not sure to be protected against infection with another clade. I would have hoped for more clade-to-clade cross-protection, but that does not seem to be the case.

  9. Dr. Khalid ALAWFI Oman says:

    We have to be careful to draw conclusions. RNA viruses are known for their high mutation rate. They can actually mutate within the body. These mutations can be triggered even by the judicious use of antiviral, HQC & other medications that have been in the pipeline. So virtually it’s perhaps a difficult task to ascertain whether these were a transformation to a new viral strain or it’s a re-infection. This will only tell us how complex the interaction between infections & immune response is and that intelligence is all what we need in the coming future to base on it developing an effective & durable immunity against our little enemies.

  10. Agustín Muñoz-Sanz, MD, PhD says:

    Hi, Paul. Your ID Observation is excellent, as usual.
    Regarding SARS-Cov2 re-infection, perhaps the answer is not blowing in the wind. In chapter 157, page 1931 of Mandell (2015 8th Edition), Kenneth McIntosh and Stanley Perlman say about coronaviruses: “Reinfection [by respiratory coronavirus] is common and may be due to the rapid diminution of antibody levels after infection” (The authors cite the reference 58: Callow KA, Parry HF, Sergeant M, et al. The time course of the immune response to experimental coronavirus infection of man. Epidemiol Infect. 1990;105: 435-446.). The times when we were (I was) younger.
    Now, SARS Cov2 seems to have invented (or re-invented) a new immunological paradigm. So, the answer will be in Immunology. A New Era.

  11. Joseph Myers says:

    Paul, Spot-on, as always. Bottom line: RNA viruses are “smarter” than we are or there wouldn’t be any of them around any longer!

  12. Debra Brown says:

    It would have been nice to know what each patient was treated with after the first infection and if they had underlying morbidity.

  13. Michael P Dailey says:

    I believe this issue is complicated by the poor predictive value of many PCR tests. When you cannot be sure of the false positives or false negatives of reported testing, anecdotes are just well “anecdotes”.

  14. Kim ey says:

    Is this typo error?

    Is this ‘RT-PCR’ or just ‘PCR’ in your the clinical details of the history box.

    [April 18: Tested positive for SARS-CoV-2 by PCR]

    Two methods are different, as you know….


  15. CTL should also have role in immunity directed against SARS-CoV-2.

  16. P. Clifford Blais, md says:

    As we have now annual influenza vaccination’s sessions that are using quadrivalent combinations of 4 different types of flu-virus immunogens, derived from of 4 different types of flu-epidemic, meaning carrying imunogens derived from 4 different types of strain of inluenza virus, I would not be surprised that eventually there will be quadrivalent type of annual covid vaccinations given at the same time of the annual influenza vaccination’s session, if it comes medically indicated.

  17. Michael Rothfeld says:

    Several well designed recent studies report that approximately 10% of recovered CV19 patients don’t test positive for antibodies. Could Nevada be one of those? In addition, the Swiss immunologist Stadler suggests that in people with weak antibodies, T cells overcompensate resulting in excess inflammation. Could Nevada’s second infection be indicative?

  18. Andehaimanot Yemane says:

    There are reports about false positive of PCR , meaning that the test can be positive for other viruses, (cross reaction) .And there are cases with antibody reaction where IgM become positive continuously for some people for almost three months without development of IgG, creating confusion whether the positivity is false or is due to mystery of the virus.
    Also, we have seen people with mild symptoms or people after contact with known cases become positive for antibodies but negative for PCR in their 14-20 days exposure.

    So, how confidently we can speak about the reinfection of the mentioned cases? Or, let’s say reinfection has happened. Can we say these individuals are exceptional like those of “highly exposed seronegative individuals” of HIV?

  19. James says:

    What are your thoughts about the other questions? I would be very interested to hear your thoughts especially as regards mononucleosis.

  20. Stephen A Raphael says:

    When teaching the introductory immunology courses to first year medical students I always used to remark about those one-day type illnesses we all seem to get and wether they represent mild viral re-exposures with slightly less efficient clearance in some people whose primary exposure and immune response might have been less than optimal because their immune response genetic profile was just a little different than most. And we all think we’re so smart

  21. Jerry Wesch says:

    Excellent review. Not good news but truth wins out.

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

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