Waning COVID-19 Antibodies Expected, No Cause for Alarm

Data Show Robust T-Cell Response

Ricki Lewis, PhD

November 04, 2020

UPDATE // November 5, 2020 The original text has been changed to clarify that Adaptive Technologies is based in Seattle, Washington.

Ominous headlines have been common in recent months declaring that antibodies against COVID-19 decline quickly. But the reports simply describe an expected phenomenon and are not evidence of waning immunity, experts say. And recent data show strong T-cell response in people who had mild or asymptomatic infections.

"A large number of investigators are reporting the antibody response in humans infected with COVID who recover tends to drop relatively quickly. To some people that's an alarm bell. Following recovery from an acute infection, a decline in antibodies is normal B-cell biology and is exactly what we predict," said Dan Barouch, MD, PhD, professor of medicine at Harvard Medical School in Boston, Massachusetts.

"Do titers stabilize? Do antibodies last a long time or not? It's an unknown area, but there are no alarm bells yet," Barouch told Medscape Medical News.

Researchers and clinicians use antibodies as a surrogate for an evolving adaptive immune response because they're far easier to assay than the T cells that drive the response and stimulate B cells to produce the antibodies.

In tracking the ups and downs of antibodies and T cells, researchers seek "correlates of protection." These are measurable signs that an individual is immune to a specific infection. For example, an antibody against the viral spike protein is a correlate of protection because it predicts neutralization of SARS-CoV-2.

The Immune Response to SARS-CoV-2

Both arms of adaptive immunity respond quickly to a viral infection. CD4 ("helper") T cells are activated by day 2 of infection and they stimulate B cells to make antibodies against the infective agent.

Over time, these acute immune responses shift, such that the number of memory T cells peaks during the second week and wanes by 100 days.

In SARS-CoV-2 infections, activated B cells are slightly behind the T cells, secreting IgA and IgM antibodies 5 to 7 days after infection and IgG antibodies 7 to 10 days after symptom onset. IgA and IgM titers decrease by day 28, IgG by 49 days.

Meanwhile, the number of memory B cells crests between weeks 2 and 3. Some become short-lived plasmablasts and differentiate into plasma cells, which secrete low levels of antibody until a subsequent viral encounter. Upon re-infection or exposure, they release even more antibodies, up to 10,000 per second.

Dr Dawn Jelley-Gibbs

Dawn Jelley-Gibbs, PhD, an immunologist who worked on influenza at the Trudeau Institute and is now with Taconic Biosciences in Germantown, New York, describes the connection between T and B cells. "We have millions of T cells, but only a few are COVID-specific, like needles in a haystack. B cells responding to COVID pop antibodies out like little factories, and once they are going, T cells go back to dormancy," which prevents a proinflammatory response that could detonate into a cytokine storm. 

Until clinical T cell tests become widely available and can detect lasting protection, researchers are interested to know how long antibodies persist and the degree of immunity they provide across the gamut of COVID-19 presentations. Population-based investigations provide clues.

Mt. Sinai Data Show Months-Long Antibody Persistence

In March, researchers at the Icahn School of Medicine at Mount Sinai in New York City began screening for antibodies among individuals who had recovered from COVID-19 and were potential convalescent plasma donors. By October 6, 30,082 of 72,401 individuals had tested positive for anti-SARS-CoV-2 antibodies, 90% with neutralizing anti-spike IgGs. About 95% of the individuals had had mild to moderate illness; the other 5% had had more severe disease.

To evaluate longevity of the response, the investigators recalled 121 plasma donors for two more tests, finding antibody titers stable for up to 5 months. The finding counters an earlier study that reported antibody declines at 8 weeks; that study, however, only looked for antibodies directed against a small part of the spike protein and the nucleocapsid protein, thus reflecting just part of the natural polyclonal immune response, researchers explain.

A subsequent cross-sectional analysis reported in Nature from Mt. Sinai captured the pattern of seroconversion as the early epidemic peaked in New York City. Beginning in mid-February, the researchers compared weekly antibody titers among 1067 patients presenting at urgent care facilities enriched with COVID cases to titers among 733 patients visiting doctors or clinics for non-COVID reasons, more closely mirroring the general population. By the end of May, although the rates of antibody ascension differed between the groups, both reached a seroprevalence of about 20%, which persisted through July.

Age-Related Antibody Declines

The Real Time Assessment of Community Transmission (REACT) study, out of the Imperial College London in the UK, analyzed results of fingerprick blood tests from more than 365,000 randomly selected adult volunteers, taken at home three times between June 20 and September 28. The kits detect antibodies above a selected concentration.

Of 17,576 positive results, 30% were from asymptomatic individuals. Antibody prevalence dropped from 6% to 4.8% to 4.4% over the 3 months. Although all ages showed the decline, the smallest was among 18-to-24-year-olds  (7.9% to 6.7%; 14.9% change) and largest among those 75 and older (3.3% to 2%; 39% change). Decline was greatest, 64%, in asymptomatic people.

REACT director Paul Elliott, MD, cautioned that testing positive for antibodies doesn't indicate immunity, advising that it isn't a reason to halt public health measures.

Turning to T Cells

Evidence from SARS and MERS points to "a relatively ephemeral antibody response and more enduring T cell immunity" against SARS-CoV-2, write Daniel Altmann and Rosemary Boyton, of Imperial College London, in Science Immunology.

"SARS and MERS both abruptly ended, so we never had a sense of re-infection. But we found markers of humoral and cellular immunity that lasted 2 to 3 years," said Gregory Poland, MD, director of the Vaccine Research Group at the Mayo Clinic.

Dr Gregory Poland

Insufficient time has passed to thoroughly evaluate the T-cell response to SARS-CoV-2, but a preprint from the UK Coronavirus Immunology Consortium, Public Health England, and Manchester University NHS Foundation Trust reports robust T-cell responses to viral peptides at 6 months among 100 individuals with asymptomatic or mild/moderate COVID-19.

Tracking T cells to complement antibody testing isn't easy. In vitro assays can detect antibodies, but T cells must be collected, kept alive, and separated. In addition, the cells are exquisitely sensitive to factors like the brand of detergent used to clean glassware, or whether a technician shakes a 96-well plate or uses a vibrating platform in protocols, Poland explained. And reproducibility is critical.

Distinguishing T cells is complex because their surfaces bear diverse arrays of receptors keyed to bits of viral topography. Flow cytometry or DNA or RNA sequencing can detect the patterns. A shortcut could be correlating T-cell surface features to viral peptide antigens represented as specific combinations of human leukocyte antigen (HLA) variants. This would make a simple blood test feasible, significantly lowering the cost compared to a test reliant on flow cytometry.

The few existing T-cell tests to detect SARS-CoV-2 are for research, but clinical tests are coming, said Beth Keshishian, director of corporate communications for Adaptive Biotechnologies, headquartered in Seattle, Washington. The company has developed a diagnostic test based on T-cell signatures cataloged from a "real-world" study that tracked 100 patients from active infection through convalescence. The test will serve markets similar to the serology market, including consumers, employer testing, and surveillance programs. "T cells are a more informative signal" of immunity than antibodies, she said. 

The pandemic is still unfolding as surges undulate around the globe. Until we know more, clinicians can perhaps reassure patients by explaining the expected steps of the immune response, Taconic Biosciences' Jelley-Gibbs suggests. "Once pathogens are cleared the immune response goes back to sleep, but upon a re-encounter responds faster and longer. Low levels of resting memory B cells, antibodies, and T cells can reactivate on a second exposure and protect faster than the first time."

Poland consults for several COVID-19 vaccine companies. Keshishian is an employee of Adaptive Biotechnologies. Jelley-Gibbs is an employee of Taconic Biosciences. The other commentators have disclosed no relevant financial relationships.

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