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COVID-19: Beyond Tomorrow
May 11, 2020

COVID-19 and Postinfection Immunity: Limited Evidence, Many Remaining Questions

Author Affiliations
  • 1US Centers for Disease Control and Prevention, Atlanta, Georgia
JAMA. 2020;323(22):2245-2246. doi:10.1001/jama.2020.7869

In the absence of effective treatment or biomedical prevention, efforts to control the coronavirus disease 2019 (COVID-19) pandemic have relied on nonpharmaceutical interventions such as personal preventive actions (eg, handwashing, face covers), environmental cleaning, physical distancing, stay-at-home orders, school and venue closures, and workplace restrictions adopted at the national, state, and local levels. In addition to these public health interventions, development of herd immunity could also provide a defense against COVID-19. However, whether immunity occurs among individuals after they have recovered from COVID-19 is uncertain. Many human infections with other viral pathogens, such as influenza virus, do not produce a durable immune response.

Understanding whether and how recovery from COVID-19 confers immunity to, or decreased severity of, reinfection is needed to inform current efforts to safely scale back population-based interventions, such as physical distancing. Understanding potential postinfection immunity also has important implications for epidemiologic assessments (eg, population susceptibility, transmission modeling), serologic therapies (eg, convalescent plasma), and vaccines. In this Viewpoint, we describe what is currently known about the immune response to COVID-19, highlight key gaps in knowledge, and identify opportunities for future research.

COVID-19 is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Following infection, detectable IgM and IgG antibodies develop within days to weeks of symptom onset in most infected individuals.1-3 Why some patients seem not to develop a humoral immune response, as reflected by detectable antibodies, is uncertain. Adding to this uncertainty is the unclear relationship between antibody response and clinical improvement. The findings from a small study of 9 patients with COVID-19 found that greater clinical severity produced higher antibody titers.1 However, antibody detection and higher titers have not always been found to correlate with clinical improvement in COVID-19.2,3 Moreover, mild COVID-19 symptoms can resolve prior to seroconversion (as reflected by detectable IgM and IgG), although detectable IgM and IgG antibodies have preceded declines in SARS-CoV-2 viral loads.2,3

What appears more certain is that viral burden typically peaks early in illness, and then declines as antibodies develop and antibody titers rise over the subsequent 2 to 3 weeks.2,3 Success in culturing virus from nasopharyngeal specimens declines quickly during the first week of mild illness, but the absolute duration that a patient might shed infectious virus is unknown.2 Persistent detection of viral RNA many days to weeks after recovery from COVID-19 at concentrations near the detection limit of available assays likely does not represent a meaningful clinical or public health risk, especially in the absence of symptoms2; however, definitive evidence does not yet exist.

The durability of neutralizing antibodies (NAbs, primarily IgG) against SARS-CoV-2 has yet to be defined; persistence up to 40 days from symptom onset has been described.1 Duration of antibody responses against other human coronaviruses may be relevant in this context. For example, following infection with SARS-CoV-1 (the virus that caused SARS), concentrations of IgG remained high for approximately 4 to 5 months before subsequently declining slowly during the next 2 to 3 years.4 Similarly, NAbs following infection with MERS-CoV (the virus that caused Middle East respiratory syndrome) have persisted up to 34 months in recovered patients.5

Detection of IgG and NAbs is not synonymous with durable immunity. With regard to COVID-19, a small, nonpeer-reviewed, preprint report provides the only data thus far on possible postinfection immunity in primates.6 In this study, 4 rhesus macaques were infected with SARS-CoV-2, and following recovery did not become reinfected when rechallenged with the same virus 28 days after the first inoculation.6 Whether persons can be reinfected with SARS-CoV-1 and MERS-CoV is unknown; SARS has not reemerged since 2004 and MERS cases remain sporadic. Reinfections can occur with at least 3 of the other 4 common human coronaviruses—specifically, 229E, NL63, and OC43—all of which generally cause milder respiratory illnesses.7 The reasons for this reinfection are not fully known, but evidence suggests that possibilities include both short-lived protective immunity and reexposure to genetically distinct forms of the same viral strain.

To date, no human reinfections with SARS-CoV-2 have been confirmed. Evidence of reinfection typically requires culture-based documentation of a new infection following clearance of the preceding infection or evidence of reinfection with a molecularly distinct form of the same virus. In one report, among 2 otherwise healthy individuals who had recovered from COVID-19 and had 2 or more sequentially polymerase chain reaction (PCR)–negative upper respiratory specimens at least 24 hours apart, SARS-CoV-2 RNA was detected again in throat swabs sporadically for up to 10 days.8 SARS-CoV-2 RNA has also been detected in throat or nasopharyngeal swabs more than 20 days after negative test results.9 In another report among 18 patients, viral burdens (as determined by PCR cycle threshold) were generally lower than, and had declined substantially from, values during peak of illness.10 At the time of postrecovery positive test results, the patients described in these reports had few, if any, symptoms, and when radiographically examined, they demonstrated stable or improving pneumonia.8,10 There is also no evidence at present that such persons transmitted SARS-CoV-2 to others after they had clinically recovered. However, this possibility of transmission cannot be ruled out, especially for persons who may be predisposed to prolonged shedding of other pathogens, such as due to immunocompromised states.

It is also possible these cases represent persistent or recrudescent COVID-19 illness or even true reinfection. On the other hand, these cases may also represent prolonged sporadic viral RNA shedding at or near the limit of assay detection or variation in collection technique, specimen handling, or storage conditions affecting test performance. Data to effectively differentiate these possibilities are lacking, highlighting an area of substantial uncertainty. Routine collection of such data, specifically viral burden (as measured by PCR assay cycle threshold) and viral culture, and from a larger sample of patients under standard protocols, is needed.

Serological assays to detect SARS-CoV-2 antibodies are rapidly becoming available and will be critical to estimate the prevalence of infections, including those that are asymptomatic. However, it is presently premature to use such assays to determine whether individuals are immune to reinfection. Performance standards, including sensitivity and specificity, for the burgeoning number of serologic assays and the potential for cross-reactivity with other coronaviruses (yielding false-positives) have yet to be determined. Widespread testing of persons who have not had COVID-19, a population with low SARS-CoV-2 prevalence, can generate more false-positives than true-positives. This phenomenon may complicate clinical and epidemiologic interpretation of results, especially if the serologic tests do not have high specificity or some form of confirmatory testing is not used. More fundamentally, it remains to be determined whether a robust IgG response corresponds with immunity. Well-designed longitudinal cohort studies of persons who recovered from COVID-19 are needed to monitor for signs and symptoms of recurrent illness. Such longitudinal studies could also document possible reexposure events, all linked with clinical and laboratory investigations of other alternate etiologies, serologic testing, attempts to isolate virus by culture, and viral genomic comparisons of isolated viral specimens. However, in the short-term, possible recurrences of infection can be identified by monitoring surveillance data and by requesting clinicians and public health authorities to report and investigate cases of possible recurrence to determine whether recurrence can be confirmed.

In summary, existing limited data on antibody responses to SARS-CoV-2 and related coronaviruses, as well as one small animal model study, suggest that recovery from COVID-19 might confer immunity against reinfection, at least temporarily. However, the immune response to COVID-19 is not yet fully understood and definitive data on postinfection immunity are lacking. Amidst the uncertainty of this public health crisis, thoughtful and rigorous science will be essential to inform public health policy, planning, and practice.

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Article Information

Corresponding Author: Robert D. Kirkcaldy, MD, MPH, US Centers for Disease Control and Prevention, 1600 Clifton Rd, US12-2, Atlanta, GA 30329 (rkirkcaldy@cdc.gov).

Published Online: May 11, 2020. doi:10.1001/jama.2020.7869

Conflict of Interest Disclosures: None reported.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention (CDC).

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7 Comments for this article
Michael Young, MD | Retired
I quote your article “More fundamentally, it remains to be determined whether a robust IgG response corresponds with immunity.”

Great thinking. Please get this word out to the policy makers
Further Unanswered Questions About COVID-19 on Transmission and Immunity
Michael McAleer, PhD (Econometrics), Queen's | Asia University, Taiwan
The thoughtful and invaluable contribution by experts at the US Centers for Disease Control and Prevention should be required reading for everyone, whether medical specialists or not, who are concerned about the impact of COVID-19 on their lives.

In Comment 7 on Wu and McCoogan (2020) on February 29, 2020, the following question was asked:

(2) Is there any possibility of reinfection after purported recovery and, if so, how soon can this occur?

In Comment 4 on del Rio and Malani (2020) on March 5, 2020, several "Known Unknowns" (aka "Unanswered Questions") included the following:

(5) Mode and ease of
transmission to and from animals;

(8) Frequency of reinfection after discharge;  

Some of these queries are tackled rigorously in the present Viewpoint.

The issue of postinfection immunity goes to the heart of the problem of whether any patient ever recovers fully from COVID-19.

Further unanswered questions regarding COVID-19 transmission and immunity include:

(1) What are the likely long-term effects of COVID-19 on the heart, liver, lungs, and other internal organs?

(2) Is there any test of permanent recovery from COVID-19?

(3) How quickly can reinfection occur, if at all?

(4) Does a purported reinfection represent a false negative diagnosis?

(5) As transmission of the virus is possible from mammals to mammals and humans, and from humans to humans, is transmission from humans to mammals also possible?

(6) Are domesticated animals, such as cats and dogs, tested for COVID-19?

(7) If COVID-19 is present in domesticated animals, can it ever be controlled or eradicated?

(8) How many mutations of COVID-19 are possible?

(9) How quickly can the SARS-CoV-2 virus mutate, and how quickly can the mutations be detected?

(10) Are the mutations of the virus likely to be deleterious, neutral, or favourable?

(11) If a vaccine is discovered for the SARS-CoV-2 virus, will it also be effective for some or all of the mutations?

(12) Is the virus increasingly likely to remain in the population forever, much like the seasonal flu, but without any seasonal warnings?
The Right Moment for the Right Comments
Giorgio Mustacchi, Emeritus Professor in Medicine | University of Trieste, Itraly
After translation for the lay public this should be the kind of appropriate information given by the media. Unfortunately it is not.
Why Aren't Epidemiological Tools and Models Being Taken into Account When Assessing Reinfectivity?
Brandon Brown, MD/PhD | Community Clinic
The question is not "is there any immunity" but rather how much and for how long. I do not have the latest infection modeling software or algorithms being studied, but I know that these would project drastically different infection trajectories from reality if there were millions vs zero reinfections.

Additionally, given the high rate of infectivity of SARS-CoV-2, we almost certainly would see cases of reinfection after documented resolution at this level of global spread and caseload, while we currently have none documented (obviously I am not suggesting that reinfection is not possible, for it is
most certainly possible, because some unlucky folks who might be able to fight off the acute virus lack fully function immune systems).

In my opinion, the search for the golden specific immunoglobulin and titer that denotes immunity is not as important as simply defining how robust post-resolution immunity is. The initial assumption could be that it is absolute, like measles, with a gradient of possibilities between that and traditional transient/nonexistent immunity to 229E, NL63, and OC43.

We should build models for how infection would spread with these various levels of reinfection, then continually run and reiterate the model based on the enormous case-load building (thanks to now millions of infections, even within the US). Then it can be dialed in how long/robust immunity is, without needing to specifically identify the antibody and necessary titers that will likely be determined over the next couple of years of research.

I think our researchers are losing the forest for the trees on this, focusing on the fundamental, academic immunity, instead of looking at this fire burning throughout the human population and using contact tracing and predictive data analytics to adjust our knowledge based on these conclusions. This type of thinking will be necessary to allow for some return to a new form of normalcy (including little things that keep us going like socialization and procreation).

It is also worth noting that all of the above data, whether the specific immunity-indicating antibody or the general reinfection rate, are based on the current proteomic structure of the outside of the virus, which is obviously subject to change. The rate of change and probability of change even themselves are subject to change, and increasing as the total infected pool of humans increases. Long story short, we are defining an evolving entity, and our tools to define it must evolve similarly.

My $0.02, as a physician scientist and community family physician.
Implications for vaccine.
Steven Reid, M.D., F.A.A.N.S. | Doctor Lifeline
Are there examples of other coronavirus infections in which a vaccine produces longer lasting or more effective immunity than that achieved after recovery from an infection with the wild virus? If we know so little about the natural course of immunity following infection from SARS-CoV-2, what is the basis for the optimism regarding the efficacy of an as yet non-existent vaccine? Is it reasonable to maintain a lockdown scenario until such time as this hoped-for vaccine becomes available? I ask these questions non-rhetorically out of genuine ignorance, concern, and curiosity.
Excessive Caution Hinders CDC's Ability to Act
Mark White, MD, ACP, ID, FACPM | Retired CDC Epidemiologist
WHO reports ten million cases of covid-19 in the world since the beginning of the pandemic. The authors note "to date, no human reinfections with SARS-CoV-2" and conclude that it may be possible that antibodies protect against reinfection "at least temporarily." The conclusion requires more research.

A more balanced treatment would acknowledge that antibodies protect humans against the vast majority of viral diseases and the lack of observed covid-19 recurrences suggests that antibodies are likely to explain this—as is cell-mediated immunity.

Of course, more research is needed.

By emphasizing our lack of knowledge and not acknowledging evidence
that antibodies are usually protective, the authors do a disservice. This is the kind of excessive caution that cost CDC its reputation at the beginning of the pandemic.
CONFLICT OF INTEREST: I own stock in Moderna, which is developing a vaccine against SARS-CoV-2
COVID-19: Understanding theScience of Antibody Testing and lessons from the HIV epidemic
Stanley Weiss, MD, FACP, FACE, FRCP Edin | Rutgers New Jersey Medical School
An article I co-authored, written in April 2020, remains highly relevant to these issues and is available still for free from Elsevier online:

Weiss SH, Wormser, GP. COVID-19: Understanding the science of antibody testing and lessons from the HIV epidemic. Diagnostic Microbiology & Infectious Disease (2020), 98: 115078