COVID-19: four months after infection around 90 percent of individuals have antibodies that block the virus

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New research involving scientists from Queen Mary University of London has found evidence of protective immunity in people up to four months after mild or asymptomatic COVID-19.

The study, published today in Science Immunology, analyzed antibody and T cell responses in 136 London healthcare workers who had mild or asymptomatic COVID-19 infection dating back to March 2020.

The team, including researchers from Queen Mary, Imperial College London and University College London, found that 89 percent of healthcare workers analyzed carried neutralizing antibodies 16-18 weeks after infection.

The researchers found most also had T cells capable of recognizing multiple different parts of the virus, however the two responses did not always persist in harmony, with some individuals showing T cell immunity but no evidence of antibodies, and vice versa.

Mr Joseph Gibbons, a Postdoctoral Research Assistant at Queen Mary, said: “Our study of SARS-CoV-2 infection in healthcare workers from London hospitals reveals that four months after infection, around 90 percent of individuals have antibodies that block the virus.

Even more encouragingly, in 66 percent of healthcare workers we see levels of these protective antibodies are high and that this robust antibody response is complemented by T cells which we see reacting to various parts of the virus.”

“This is good news. It means that if you have been infected there is a good chance that you will have developed antibodies and T cells that may provide some protection if you encounter the virus again.”

Mismatched immune responses

From the outset of the pandemic, scientists across the globe have been working to understand how our immune system protects us against SARS-CoV-2, and how long this protection lasts.

Much of this debate around protective immunity has focussed on the different roles of B cells, which make antibodies, and T cells, white blood cells which work in several different ways to help protect from viruses, including direct killing.

In this study, the researchers show that whilst protective antibody responses were usually complemented by a T cell response, over half of the healthcare workers had mismatched antibody and T cell responses, and did not produce a T cell response specific to proteins found on the outer layer of the SARS-CoV-2 virus.

They also found that T cell responses tended to be higher in those with the classic, defining symptoms of COVID-19, while asymptomatic infection resulted in a weaker T cell immunity than symptomatic infection, but equivalent neutralizing antibody responses.

Reassuring evidence

Understanding how this careful choreography of immune responses works in people with mild or asymptomatic infection is particularly important as they represent the largest infected group.

The new study also provides reassurance for vaccination efforts, suggesting that even following mild infection, individuals carry antibody and T cell immunity to many parts of the virus, known as epitopes. Whilst new variants are appearing, the changes to the virus don’t necessarily occur within these epitopes so it is hoped the vast majority of immune recognition can likely continue unperturbed.

Dr. Corinna Pade, a Postdoctoral Research Scientist at Queen Mary, said: “Our study in asymptomatic and mild cases gives a positive insight into the durability of immunity to SARS-CoV-2 after four months of infection. A remarkable number of around 90 percent of individuals have a joint force of strong antibodies that prevent the virus from entering, coupled with T cell responses to various parts of the virus to interfere with its survival.

This is an important find as mild or even no symptoms of COVID-19 are very common and representative of most infections in the community. Such abundant immune responses also give hope for the long-lasting efficacy of vaccines.”

Áine McKnight, Professor of Viral Pathology at the Blizard Institute at Queen Mary, added: “Finally, here is the evidence of lasting antibody and T-cell immunity to SARS-CoV-2 that many had been waiting for. Queen Mary played a unique role in enabling this study at a time when many laboratories were shutting down at the outset of the pandemic.

Our lab remained active and made fundamental scientific observations that contributed to this paper. We continue to support the scientific effort against COVID-19 working with other London universities, NHS Health Trusts and Public Health England to help control the pandemic.”


Most persons infected with SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), develop virus-specific antibodies within several weeks, but antibody titers might decline over time. Understanding the timeline of antibody decline is important for interpreting SARS-CoV-2 serology results. Serum specimens were collected from a convenience sample of frontline health care personnel at 13 hospitals and tested for antibodies to SARS-CoV-2 during April 3–June 19, 2020, and again approximately 60 days later to assess this timeline.

The percentage of participants who experienced seroreversion, defined as an antibody signal-to-threshold ratio >1.0 at baseline and <1.0 at the follow-up visit, was assessed. Overall, 194 (6.0%) of 3,248 participants had detectable antibodies to SARS-CoV-2 at baseline (1).

Upon repeat testing approximately 60 days later (range = 50–91 days), 146 (93.6%) of 156 participants experienced a decline in antibody response indicated by a lower signal-to-threshold ratio at the follow-up visit, compared with the baseline visit, and 44 (28.2%) experienced seroreversion.

Participants with higher initial antibody responses were more likely to have antibodies detected at the follow-up test than were those who had a lower initial antibody response. Whether decay in these antibodies increases risk for reinfection and disease remains unanswered. However, these results suggest that serology testing at a single time point is likely to underestimate the number of persons with previous SARS-CoV-2 infection, and a negative serologic test result might not reliably exclude prior infection.

Once infected with SARS-CoV-2, most persons develop virus-specific antibodies within 2–3 weeks (2,3). Serology tests are now being used widely in seroprevalence studies to understand patterns of viral spread, cumulative incidence of SARS-CoV-2 infection, and pandemic trajectory (4–6).

Further, serologic testing has been proposed as a way to identify persons who might have developed immunity through a previous infection. Understanding how rapidly SARS-CoV-2 antibody levels decline after seroconversion is critical for interpreting serology results. A limited number of studies have found declines in SARS-CoV-2 antibody levels over time (7–9), but the frequency and timing of seroreversion (the decline in antibody levels below the positivity threshold after initial seroconversion) remains largely unknown.

The Influenza Vaccine Effectiveness in the Critically Ill (IVY) Network, a collaboration of academic medical centers in the United States that studies influenza and COVID-19 (1), enrolled a convenience sample of frontline health care personnel at 13 centers in 12 states,† with a target of 250 participants per center. Health care personnel were eligible if they reported regular direct contact with COVID-19 patients and worked in the emergency department, intensive care unit, or other hospital-based unit that cared for patients with COVID-19.

Participants underwent two study visits: a baseline visit (conducted April 3–June 19, 2020) and a follow-up visit approximately 60 days after the baseline visit. At both visits, blood was collected for SARS-CoV-2 antibody testing, and participants were questioned about demographic characteristics, underlying medical conditions, signs or symptoms of an acute viral infection from February 1, 2020, until the visit date,§ and any previous SARS-CoV-2 testing (e.g., reverse transcription–polymerase chain reaction [RT-PCR]) for acute infection. Blood specimens collected at the baseline and follow-up visits were tested for SARS-CoV-2 antibodies at CDC using an enzyme-linked immunosorbent assay (ELISA) against the extracellular domain of the SARS-CoV-2 spike protein (4).

The assay detects all SARS-CoV-2 immunoglobulin (Ig) types (IgA, IgM, or IgG). Specimens were considered reactive with a signal-to-threshold ratio >1.0 at a background corrected serum dilution of 1:100, with higher ratios indicating higher antibody titers. The assay has a sensitivity estimated at 96% and specificity at 99% (4).

The change in signal-to-threshold ratio between the baseline visit and follow-up visit was quantified, and the percentage of participants who experienced seroreversion was reported. Logistic regression was used to evaluate the association between baseline signal-to-threshold value and seroreversion, adjusting for age, sex, race/ethnicity, number of days between the baseline and follow-up visit, and presence of one or more chronic medical condition. Analyses were conducted using Stata (version 16; StataCorp). The project was determined to be nonresearch public health surveillance by participating institutions and CDC and was conducted consistent with applicable federal law and CDC policy.

Among 3,248 health care personnel, 194 (6.0%) had antibodies to SARS-CoV-2 at the baseline visit (1). Among these, 156 (80.4%) returned for the follow-up visit around 60 days later (range = 50–91 days). Among these 156 participants with a positive baseline serology and follow-up antibody testing performed, median age was 38 years (interquartile range [IQR] = 30–48 years), 94 (60.3%) were female, and 108 (69.2%) reported one or more symptoms of an acute infection consistent with COVID-19 between February 1, 2020 and the baseline visit.

Among the 108 participants who reported symptoms, the median interval between symptom onset and baseline serology testing was 30 days (IQR = 19–40 days). Participants who reported symptoms of an acute viral illness since February had higher baseline signal-to-threshold ratios (median = 3.6; IQR = 3.1–3.9) than did those who did not report symptoms (median = 2.5; IQR = 1.5 to 3.6) (p<0.001). Among these 156 participants, 72 (46.2%) reported past RT-PCR testing for SARS-CoV-2, 46 (63.9%) of whom had positive test results; no hospitalizations were reported.

Among the 156 participants who returned for follow-up, the signal-to-threshold value for 146 (93.6%) had declined since the baseline visit, including 44 (28.2%) participants who experienced seroreversion (Table 1) (Supplementary Figure, https://stacks.cdc.gov/view/cdc/97358), with antibody levels falling below the threshold for positivity.

Among 108 participants who reported previous COVID-19–compatible signs or symptoms, 21 (19.4%) seroreverted, compared with 23 (47.9%) of 48 of participants who did not report symptoms (p<0.001). Among 72 participants with previous RT-PCR testing, one (2.2%) of 46 with a positive test result versus seven (26.9%) of 26 with a negative test result seroreverted. Seroreversion occurred in 64.9% (37 of 57) of participants with a low antibody response (baseline signal-to-threshold value = 1.0–2.9) and 7.1% (seven of 99) of participants with a high antibody response (baseline signal-to-threshold value ≥3.0) (p<0.001) (Figure).

A higher baseline signal-to-threshold ratio was associated with lower odds of seroreversion at the follow-up visit (adjusted odds ratio [aOR] for a 1-unit increase in signal-to-threshold ratio = 0.29; 95% CI = 0.18–0.46) (Table 2). In this model, a 10-year increase in participant age was associated with higher odds of seroreversion (aOR = 1.74; 95% CI = 1.06–2.85). Compared with non-Hispanic White participants, odds of seroreversion were lower among non-Hispanic Black participants (aOR = 0.11; 95% CI = 0.15–0.76) and Hispanic participants (aOR = 0.10; 95% CI = 0.01–0.88).

References

  1. Self WH, Tenforde MW, Stubblefield WB, et al. ; CDC COVID-19 Response Team; IVY Network. Seroprevalence of SARS-CoV-2 among frontline health care personnel in a multistate hospital network—13 academic medical centers, April–June 2020. MMWR Morb Mortal Wkly Rep 2020;69:1221–6. CrossRefexternal icon PubMedexternal icon
  2. Zhao J, Yuan Q, Wang H, et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin Infect Dis 2020;ciaa344. CrossRefexternal icon PubMedexternal icon
  3. Long QX, Liu BZ, Deng HJ, et al. Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat Med 2020;26:845–8. CrossRefexternal icon PubMedexternal icon
  4. Havers FP, Reed C, Lim T, et al. Seroprevalence of antibodies to SARS-CoV-2 in 10 sites in the United States, March 23–May 12, 2020. JAMA Intern Med 2020. Epub July 21, 2020. CrossRefexternal icon
  5. Stringhini S, Wisniak A, Piumatti G, et al. Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SEROCoV-POP): a population-based study. Lancet 2020;396:313–9. CrossRefexternal icon PubMedexternal icon
  6. Anand S, Montez-Rath M, Han J, et al. Prevalence of SARS-CoV-2 antibodies in a large nationwide sample of patients on dialysis in the USA: a cross-sectional study. Lancet 2020;396:1335–44. CrossRefexternal icon PubMedexternal icon
  7. Crawford KHD, Dingens AS, Eguia R, et al. Dynamics of neutralizing antibody titers in the months after SARS-CoV-2 infection. J Infect Dis 2020;jiaa618. CrossRefexternal icon PubMedexternal icon
  8. Patel MM, Thornburg NJ, Stubblefield WB, et al. Change in antibodies to SARS-CoV-2 over 60 days among health care personnel in Nashville, Tennessee. JAMA 2020;324:1781–2. CrossRefexternal icon PubMedexternal icon
  9. Ibarrondo FJ, Fulcher JA, Goodman-Meza D, et al. Rapid decay of anti-SARS-CoV-2 antibodies in persons with mild Covid-19. N Engl J Med 2020;383:1085–7. CrossRefexternal icon PubMedexternal icon
  10. Food and Drug Administration. Emergency use authorization declaration. Washington, DC: US Department of Health and Human Services, Food and Drug Administration; 2020. https://www.fda.gov/media/141477/downloadexternal icon

More information: Discordant neutralizing antibody and T cell responses in asymptomatic and mild SARS-CoV-2 infection. Science Immunology  23 Dec 2020. DOI: 10.1126/sciimmunol.abf3698

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