Titers of IgG and IgA against SARS-CoV-2 proteins and ...

This study examined antibody titers in Hospital Workers (HWs) with mild COVID-19. IgM&#;+&#;samples had higher titers of IgA and IgG antibodies against specific antigens. Significant differences were found based on time since infection, sex, age, and symptoms. Antibody levels decreased over time but some samples showed increased values. Overall, the study provides insights into antibody dynamics in relation to COVID-19.

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During the acute phase of COVID-19 infection, IgM antibodies are produced rapidly and they serve as the first line of defense against the virus. Typically, these antibodies can be detected within a week or two after the onset of symptoms. As patients transition into the convalescent phase, IgG antibodies are generated, offering more sustained protection against reinfection. IgG antibodies usually become detectable shortly after IgM antibodies, indicating a progression towards longer-term immunity. Since theoretically longer infection time implies IgM negativization, we categorized our samples based on the presence or absence of IgM in HWs&#; blood samples. We unexpectedly found a significant proportion of HWs who remained IgM postive even beyond 40 days after reported infection suggesting considerable variability in the time it takes for IgM antibodies to clear from the system among individuals. Moreover, our analysis revealed notable serological disparities between IgM&#;+&#;and IgM&#;&#;&#;samples. IgM&#;+&#;samples had higher titers of IgG against N and IgA against S1 and S2 antigens than IgM&#;&#;&#;samples. On the other hand, IgM&#;+&#;samples collected&#;<&#;21d had the lowest titers of IgG against N antigen but higher IgA against N titers, possibly indicating recent infection where IgG levels had not yet peaked. Our results are in concordance with previous reports of COVID-19 in which IgM levels were shown to appear first, followed by IgA and IgG, while Ab levels were detectable at approximately two weeks after onset of symptoms. It has been also shown that seroconversion for all Ig isotypes requires at least 6&#;10 days after onset of symptoms15,18,19. In others reports, there was a first IgA seroconversion at two&#;days after onset of the initial symptoms and then IgM and IgG seroconversion at five days, with a median conversion time for IgA, IgM and IgG of 13 and 14 days, respectively20,21,22. Differences in COVID-19 severity and the demographic characteristics of cohorts could explain the complex kinetics of Abs found in different studies. Unlike many studies where serological analysis of IgG and IgM is conducted simultaneously, the focus on IgM positivity allowed us to discern unique patterns in antibody kinetics. All these findings suggest that in addition to the infection time, the exact timing of seroconversion can vary among individuals, influenced by factors such as disease severity and individual immune responses.

To our knowledge, there are few data that analyze correlations between SARS-CoV-2 Ab titers. Only one recent report has found significant correlations among Ab titers against S, N, M (membrane) antigens. Stronger correlations have previously been reported in severe forms23. Here, we found few significant correlations. Although mild COVID-19 patients produced lower titer of Abs, we found significant correlations, the most relevant of which were between titers of Abs against S1 and S2 in mild COVID-19. Our findings suggest that the production of certain Abs is more closely associated than others.

All our findings are consistent with previous studies on seroprevalence, in which there was high variability of Abs based on age, sex, type of institution, participant specific tasks and the incidence in the general population of each geographical area24. We found higher titers among male IgM&#;&#;&#;HWs of IgA against N and IgA anti S2. We also detected a tendency towards increasing Ab titers with age, especially IgA among IgM&#;+&#;HWs. In line with this, a lower seroprevalence has been reported in females with lower IgA responses against N and S2 antigens in a small cohort of patients25,26. Other reports showed lower Abs titers in young people than in older donors, and higher IgA levels against N total antigens in a cohort of patients older than 60 years25,27,28. It is possible that men and older people had prior contact with other coronaviruses and therefore developed faster, stronger or even cross-reacting immunity, reflected as higher Abs titers. However, many other factors could explain sex and age differences, such as hormone influence, immunity status and the presence of soluble blood proteins, as reported previously29,30. In this particular cohort, we were unable to identify differences in titers related to either antecedents or habits such as smoking among HWs. However, a systematic review of some studies has reported that smokers have a weakened immune response to SARS-CoV-2, including reduced levels of Abs31. The low frequency of smokers in our cohort of HWs may explain the different findings.

In agreement with our findings, some authors have suggested that the serological status of SARS-CoV-2 infection depends on vaccination against seasonal influenza because of vaccine-associated virus interferences. However, we found lower titers of IgG against S2 in HWs who had been previously vaccinated against influenza, and Stefanizzi P et al. showed that the titers of IgG anti-SARS-CoV-2 in HWs were more reduced in those receiving influenza&#;+&#;COVID-19 vaccines than in those receiving only COVID-19 vaccine32. Differences in methods, cohorts and antigens could explain the conflicting results.

In our cohort, HWs reported a miscellaneous spectrum of unspecific symptoms. The most frequent were myalgia and fever, followed by cough, anosmia and cephalea. All these symptoms were reported in outpatients as a general febrile syndrome and, according to the Cochrane COVID&#;19 Diagnostic Test Accuracy Group33, any symptom can be considered pathognomonic as COVID-19 disease. Some of these symptoms were related to titers of immunoglobulins. Thus, high levels of IgG and IgA against SARS-CoV-2 N antigen were observed among IgM&#;+&#;HWs who had fever and cough, while anosmia and dyspnea were associated predominantly with lower titers of IgG and IgA anti-N and also IgA anti-S2. In a systematic review, the early testing for SARS-CoV-2 infection was usually carried out when anosmia, ageusia, fever or cough were reported34. However, most of these previous data correspond to severe hospitalized patients35,36. Our observations suggest that mild symptoms are related to responses with stronger and earlier Abs. Fever and levels of IgG antibodies in a virus infection can be attributed to factors such as the activation of the immune response and the release of pro-inflammatory molecules. On the other hand, the correlation between lower levels of antibodies and dyspnea in a virus infection can be attributed to factors such as the severity of the infection, impaired lung function, an exaggerated immune response, inflammation in the lungs, and the interplay of various immune factors. Previous reports have consistently shown that asymptomatic people were more likely to have greater IgA than IgG responses compared to those experiencing severe disease. Therefore, it seems probable that severe complications are related to lower serological Ab titers37,38,39. Lower antibody levels may indicate a weaker immune response, which can potentially lead to more severe respiratory symptoms and dyspnea. However, some authors have described that a robust IgA response may play a pathological role in SARS-CoV-2 infection and IgA at low levels may be able to control the infection. Based on all these findings, we can speculate that IgA contributes to early virus neutralization, leading to non-severe infection, while IgG contributes to longer term protection against more severe forms of disease. It is interesting to note that other studies have found that IgA and IgG are produced relatively late in the course of infection in severe disease36,40,41,42. The correlation between antibodies against a virus and symptoms during infection can be due to factors such as the immune response mounted against the virus, the level of viral replication and disease severity, individual variations in immune responses and host factors, the pathogenesis of the virus, and the formation of immune complexes. One aspect that we were unable to explore in our study was the relationship between the antibodies against SARS-CoV-2 and the duration of symptoms. Although we included a question about the duration of symptoms in the questionnaire, we found that the responses provided by participants were highly subjective and not consistently reliable. As a result, we were unable to incorporate this information into our analysis.

In our cohort of HWs, Ab levels declined over time and the dynamics of Ab titers were similar between IgM&#;+&#;and IgM&#;&#;&#;HWs. When the infection was recent (<&#;21d), there was a tendency to higher IgA and IgG titers. Reports consistent with our results showed that anti-SARS-CoV-2 Abs tended to decrease over the 6&#;13 months after infection. However, in some patients, titers were detectable beyond one year7,43,44,45. It is possible that the duration and intensity of the natural Ab response to SARS-CoV-2 varies according to disease severity and results in mild and severe patients are not comparable. Our results did not show different changes in Ab titers associated with HW antecedents or habits. On the other hand, patients with cough and anosmia had decreasing anti-N IgG and IgA levels. It is interesting to note that there was a proportion of patients with increasing titers at T2, especially when they reported dyspnea. The increasing titers in HWs with dyspnea may be a potential sign of worsening, as suggested by previous reports39,45. It would have been interesting to follow up the patients who went on to report dyspnea in order to observe their long-term outcomes.

Despite the detailed characterization of Ab titers and their short kinetics in mild COVID-19 patients, our study has several limitations. Participants were not randomly selected as a representation of diverse demographic characteristics, since they were all healthcare workers in a particular location. This fact may have introduced a bias in the study. We collected samples from positive HWs at only two post-infection time points, analyzing mildly symptomatic HW donors. Another drawback is that we did not analyze whether the new variants of the virus, with mostly asymptomatic patients and with a similar behavior or mild symptoms, demonstrate vaccine effectiveness46,47.

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Antibodies are developed by the body in response to an infection or after vaccination. SARS-CoV-2 is the virus that causes COVID-19. SARS-CoV-2 antibody tests detect antibodies to the SARS-CoV-2 virus. SARS-CoV-2 antibody tests can help identify people who may have been infected with the SARS-CoV-2 virus or have recovered from COVID-19. Antibody tests should not be used to tell you if you have an active COVID-19 infection.

Scientists continue to learn more about COVID-19 and COVID-19 immunity. At this time, SARS-CoV-2 antibody tests do not tell you if:

• You currently have COVID-19, the disease caused by the SARS-CoV-2 virus,
• You have immunity that will prevent COVID-19,
• You need a COVID-19 vaccine, or
• Your COVID-19 vaccine worked.

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Antibodies and Antibody Tests: The Basics

Q: What are antibodies?

A: Antibodies are proteins made by your body's immune system to help fight off infections, including those caused by viruses. Some antibodies in your body may protect you from getting those infections. Your immune system can also safely learn to make antibodies through vaccination. If antibodies give you this protection and how long this protection lasts can be different for each disease and each person. Antibodies are just one part of your immune response.

Q: Are antibody tests used to diagnose COVID-19?

A: No. An antibody test cannot be used to diagnose current COVID-19 because an antibody test does not detect SARS-CoV-2. Only COVID-19 diagnostic tests can be used to diagnose current COVID-19. A positive antibody test result can be used to help identify people who may have had a prior SARS-CoV-2 infection or prior COVID-19. An antibody test does not show if you have a current SARS-CoV-2 infection or COVID-19 because the antibodies are part of the body's immune response to infection, and antibody tests do not test for the virus itself. It also can take days to weeks after the infection for your body to make detectable antibodies.

Antibody Tests: Not for Use to Check Immunity

Q: Will a positive result on a SARS-CoV-2 antibody test mean I have immunity and I will not get COVID-19?

A: No. At this time, SARS-CoV-2 antibody tests do not tell you if you have immunity that will prevent you from getting COVID-19. A positive SARS-CoV-2 antibody test does not necessarily mean you are immune or have immunity that will prevent COVID-19. More research is needed to understand what SARS-CoV-2 antibody test results can tell us. And, SARS-CoV-2 antibodies detected in your blood reflect only one part of your immune system, which also includes T-cells and other components that are part of your body's immune response.

Q: Should I get a SARS-CoV-2 antibody test to decide if I need a COVID-19 vaccine or after I am vaccinated to see if my vaccine worked?

A: No. At this time, antibody test results should not be used to decide if you need a COVID-19 vaccine or a vaccine booster, or to determine whether your vaccine worked. There is not a clear connection between SARS-CoV-2 antibody test results, the need for a COVID-19 vaccine or booster, or whether a vaccine worked in a person. Also, some SARS-CoV-2 antibody tests may not detect the kind of antibodies created following vaccination. SARS-CoV-2 antibodies detected in your blood reflect only one part of your immune system, which also includes T-cells and other components that are part of your body's immune response.

More research is needed to understand the role of SARS-CoV-2 antibody testing in evaluating a person's immunity or protection against COVID-19 and understanding if antibody tests will be helpful for deciding if a person should receive a COVID-19 vaccine. If you have questions about whether a SARS-CoV-2 antibody test is right for you, talk with your health care provider or your state or local health department.

Want more information on How Accurate is Sars-cov-2 Antibody Igg? Feel free to contact us.

Q. Can a SARS-CoV-2 antibody test tell me if I could infect other people?

A: No. Antibody tests do not tell you whether or not you can infect other people with SARS-CoV-2. Current information indicates people infected with SARS-CoV-2 can still transmit the SARS-CoV-2 virus and infect other people, even if they are COVID-19 vaccinated or have detectable SARS-CoV-2 antibodies from a previous infection.

Antibody Tests: Results and Terms

Q: What does a positive SARS-CoV-2 antibody test result mean?

A: A positive antibody test result could mean you previously had a SARS-CoV-2 infection or COVID-19. A positive antibody test could also mean the test is detecting antibodies in your blood in response to your COVID-19 vaccine. Not all SARS-CoV-2 antibody tests will detect antibodies in response to a COVID-19 vaccine.

Q: What does a negative SARS-CoV-2 antibody test result mean?

A: A negative result on a SARS-CoV-2 antibody test means antibodies to the virus were not detected in your blood.

It is unknown if all people who have a SARS-CoV-2 infection will develop antibodies in their bodies in an amount that can be detected by a SARS-CoV-2 antibody test. Also, even if people do develop antibodies, the antibody levels may decrease over time to levels that can't be detected by a SARS-CoV-2 antibody test. It is also important to note that different antibody tests may detect different antibodies and different levels of antibodies.

A negative result could mean:

• You have not been infected with SARS-CoV-2 previously.
• You had a previous SARS-CoV-2 infection but:
  • Your body did not make antibodies to the infection yet. It can take days to weeks after an infection for your body to make antibodies.
  • Your body made SARS-CoV-2 antibodies but the level of antibodies in your sample is too low to be measured by the test that was used.
• You were vaccinated with a COVID-19 vaccine, but the antibody test does not detect the same kind of antibodies your body produced in response to your COVID-19 vaccine.
• The test result may be wrong, known as a "false negative." This occurs when the test does not detect antibodies even though you may have antibodies for SARS-CoV-2.

Q: What if I get different results on two SARS-CoV-2 antibody tests and they don't agree? Which one is right?

A: Results may be different for several reasons, including:

• The design of the tests - different antibody tests may detect different antibodies and different levels of antibodies.
• The performance of the tests, including the sensitivity and specificity of each test (see What do sensitivity and specificity mean in SARS-CoV-2 antibody testing below).
• The timing of when you took the tests, how long it may take for your body to develop antibodies after a potential SARS-CoV-2 infection, and whether antibody levels may decrease over time.

For this and other reasons, you should always review your test results with your health care provider.

Q: What is the difference between qualitative, quantitative, and semi-quantitative SARS-CoV-2 antibody tests? What do the reported numbers mean?

A: Qualitative, semi-quantitative, and quantitative tests all tell you if SARS-CoV-2 antibodies were detected in your blood sample with the specific test used. These tests report whether SARS-CoV-2 antibodies were detected or not detected over a certain threshold, and this threshold may vary between different SARS-CoV-2 antibody tests. Different antibody tests may also be designed to detect different SARS-CoV-2 antibodies in addition to the different levels of antibodies. This means that different tests may provide different results for the same blood sample.

• Qualitative SARS-CoV-2 antibody tests only report whether SARS-CoV-2 antibodies were detected or not detected and do not provide any indication of the amount of antibodies detected, other than whether it was above or below the detection threshold for that test.
• Semi-quantitative SARS-CoV-2 antibody tests also report the relative concentration of antibodies in a person's blood sample at the time of testing, meaning the level of antibody in your blood sample is assigned a number on a scale that applies only to that specific authorized test. The scale for each test is determined and validated by the test developer but is not comparable to results from any other SARS-CoV-2 antibody test, whether semi-quantitative or otherwise.
• Quantitative SARS-CoV-2 antibody tests produce results that are standardized because quantitative antibody tests are traceable to a certified reference material. This means that numeric results can be compared between different quantitative tests that are traceable to the same certified reference material. However, at this time, there is not enough scientific information to understand what the numerical results mean about an individual's protection from infection.

Q: What do sensitivity and specificity mean in SARS-CoV-2 antibody testing?

A: Sensitivity is the ability of the test to identify people with antibodies to SARS-CoV-2. A highly sensitive test will identify most people who truly have antibodies, and a small number of people with antibodies may be missed by the test (false negatives).

Specificity is the ability of the test to correctly identify people without antibodies to SARS-CoV-2. A highly specific test will identify most people who truly do not have antibodies, and a small number of people without antibodies may be identified as having antibodies by the test (false positives).

The FDA included information about test performance expectations for SARS-CoV-2 serology tests in the Emergency Use Authorization (EUA) serology templates. For information on authorized serology test performance, see EUA Authorized Serology Test Performance.

Q: What does predictive value mean in SARS-CoV-2 antibody testing?

A: Predictive values are probabilities calculated using a test's sensitivity and specificity, and an assumption about the percentage of individuals in the population who have antibodies at a given time (which is called "prevalence" in these calculations).

Positive predictive value is the probability that a person who has a positive test result truly has antibodies. Positive predictive values for SARS-CoV-2 antibody tests are impacted by how common SARS-CoV-2 antibodies are in the population being tested at a certain time.

The lower the prevalence, the lower the positive predictive value. This means that SARS-CoV-2 antibody tests used in areas with low prevalence (small number of people that have SARS-CoV-2 antibodies) will have a positive predictive value lower than in an area with higher prevalence.

Low positive predictive value may lead to more individuals with a false positive result. This could mean that individuals may not have developed antibodies to the virus even though the test indicated that they had. If a high positive predictive value cannot be achieved with a single test result, two tests may be used together to help identify individuals who may truly be SARS-CoV-2 antibody positive.

Negative predictive value is the probability that a person who has a negative test result truly does not have antibodies. Negative predictive values for SARS-CoV-2 antibody tests are also impacted by how common SARS-CoV-2 antibodies are in the population being tested at a certain time. Negative predictive value is higher in areas with low prevalence and lower in areas with high prevalence. This means that in areas where a lot of people have SARS-CoV-2 antibodies, a negative result is more likely to be a false negative result compared to the likelihood of a false negative result in areas where few people have SARS-CoV-2 antibodies. This could mean that individuals may have developed antibodies to the virus even though the test indicated that they had not.

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