A study by researchers at Washington University School of Medicine in St. Louis published on 24 May 2021 in NATURE revealed that people still have immune cells in their body pumping out antibodies against the virus that causes COVID-19, months after recovering from mild cases of COVID-19. The good news is the possibility that such cells could persist for a lifetime, releasing antibodies all the while.

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Findings of the study

The findings suggest that mild cases of COVID-19 leave those infected with lasting antibody protection and that repeated bouts of illness are likely to be uncommon. Senior author Dr. Ali Ellebedy, an associate professor of pathology & immunology, of medicine and of molecular microbiology revealed that last fall, there were reports that antibodies wane quickly after infection with the virus that causes COVID-19, and mainstream media interpreted that to mean, that immunity was not long-lived.

"But that's a misinterpretation of the data. It is normal for antibody levels to go down after acute infection, but they don't go down to zero, they plateau. Here, we found antibody-producing cells in people 11 months after first symptoms. These cells will live and produce antibodies for the rest of these people's lives. That's strong evidence for long-lasting immunity," Dr Ellebedy clarified.

The immune response during infection

A press release from the University explained the possible source of long term immunity:

“During a viral infection, antibody-producing immune cells rapidly multiply and circulate in the blood, driving antibody levels sky-high. Once the infection is resolved, most such cells die off, and blood antibody levels drop. A small population of antibody-producing cells, called long-lived plasma cells, migrate to the bone marrow and settle in, where they continually secrete low levels of antibodies into the bloodstream to help guard against another encounter with the virus."

According to Ellebedy, the key to figuring out whether COVID-19 leads to long-lasting antibody protection lies in the bone marrow. How the research work progressed this far is very interesting. To find out whether those who have recovered from mild cases of COVID-19 harbour long-lived plasma cells that produce antibodies specifically targeted to SARS-CoV-2, the virus that causes COVID-19, Ellebedy teamed up with co-author Iskra Pusic, an associate professor of medicine. At the time, Ellebedy was already working with co-authors Rachel Presti, an associate professor of medicine, and Jane O'Halloran, an assistant professor of medicine, on a project to track antibody levels in blood samples from COVID-19 survivors.

The study

Researchers collected blood samples approximately one month after the onset of symptoms from 77 SARS-CoV-2 convalescent volunteers (49% female, 51% male, median age 49), the majority of whom had experienced mild illness (6 of them were hospitalised). They collected follow-up blood samples thrice at approximately 3-month intervals. Twelve convalescent participants received either the BNT162b2 or the mRNA-1273 SARS-CoV-2 vaccine between the last two time points. These post-vaccination samples were not included in their analyses.

Additionally, the researchers collected bone marrow aspirates from 18 of the participants, 7 to 8 months after infection and from 11 healthy volunteers with no history of SARS-CoV-2 infection or vaccination. The researchers collected follow-up bone marrow aspirates from 5 of the 18 and one additional convalescent donors approximately 11 months after infection.

They first performed a longitudinal analysis of circulating anti-SARS-CoV-2 serum antibodies. While anti-SARS-CoV-2 spike (S) IgG antibodies were undetectable in blood from controls, 74 of 77 convalescent participants had detectable serum titres approximately 1 month after the onset of symptoms. Between 1- and 4-month post symptom onset, overall anti-S IgG titres decreased from a mean of 6.3 to 5.7 (mean difference 0.59±0.06). In contrast to the anti-S antibody titers, IgG titres against 2019/2020 inactivated seasonal influenza virus vaccine was detected in all controls and SARS-CoV-2 convalescent participants and declined much more gradually, if at all over the course of the study, with mean titres decreasing from 8.0 to 7.9 (mean difference 0.16±0.06) and 7.9 to 7.8 (mean difference 0.02±0.08) across the 1 to 4 and 4 to11 month intervals post-symptom onset, respectively.

Induction of S-binding long-lived Bone Marrow Plasma Cells (BMPCs)

The most interesting observation was the relatively rapid early decline in anti-S IgG followed by a slower decay. It is consistent with a transition of serum antibodies from being secreted by short-lived plasmablasts to a smaller but more persistent population of long-lived plasma cells generated later in the immune response. The majority of this latter population resides in the bone marrow. To investigate whether SARS-CoV-2 convalescent patients developed a virus-specific long-lived BMPC compartment, the researchers examined their bone marrow aspirates obtained approximately 7 and 11 months after infection for anti-SARS-CoV-2 S-specific BMPCs.

The researchers magnetically enriched BMPCs from the aspirates and then quantified the frequencies of those secreting IgG and IgA directed against the 2019/2020 influenza virus vaccine, tetanus/diphtheria vaccine, and SARS-CoV-2 S protein by ELISpot. Frequencies of influenza and tetanus/diphtheria vaccine-specific BMPCs were comparable between control and convalescent participants. They detected IgG- and IgA-secreting S-specific BMPCs in 15 and 9 of the 19 convalescent participants, respectively, but not in any of the 11 control participants.

“Importantly, none of the convalescent patients had detectable S-specific antibody-secreting cells in the blood at the time of bone marrow sampling, indicating that the detected BMPCs represent bone marrow-resident cells and not contamination from circulating plasmablasts”, the researchers argued. BMPCs were stable among the 5 participants sampled a second time approximately 4m later, and anti-S IgA BMPC frequencies were stable in 4 of the 5, with one decreasing below the limit of detection.

Consistent with their stable BMPC frequencies, anti-S IgG titers in the five participants remained consistent between 7 and 11 months post symptoms' onset. IgG titers measured against the receptor-binding domain (RBD) of S, a primary target of neutralising antibodies, were detected in four of the five convalescent patients and were also stable between 7 and 11 months post symptom onset frequencies of anti-S IgG BMPCs showed a modest but significant correlation with circulating anti-S IgG titers 7-8 months post symptom onset in convalescent participants, consistent with long-term maintenance of antibody levels by these cells.

"It could go either way”, the first author Jackson Turner, an instructor in pathology and immunology was more realistic."Inflammation plays a major role in severe COVID-19, and too much inflammation can lead to defective immune responses. But on the other hand, the reason why people get really sick is often because they have a lot of virus in their bodies, and having a lot of viruses around can lead to a good immune response. So it's not clear. He felt the need to replicate the study in people with moderate to severe infections to understand. The researchers claimed that as per their knowledge, the current study provides the first direct evidence for induction of antigen specific BMPCs after a viral infection in humans.

Limitations of the study

1. The researchers detected anti-S IgG antibodies in serum at least 7 months after infection in all 19 of the convalescent donors from whom they obtained bone marrow aspirates. However, they failed to detect S-specific BMPCs in four donors. Serum anti-S antibody titres in those 4 donors were low, suggesting that S-specific BMPCs may potentially be present at very low frequencies that are below our limit of detection.
2. Another limitation is that the researchers do not know the fraction of the S-binding BMPCs detected in their study that encodes neutralising antibodies. SARS-CoV-2 S protein is the main target of neutralising antibodies and a correlation between serum anti-S IgG binding and neutralisation titres has been documented. Researchers require further studies to determine the epitopes targeted by BMPCs and MBCs as well as their clonal relatedness.
3. Lastly, while their data documents a robust induction of long-lived BMPCs after SARS-CoV-2 infection, it is critical to note that their convalescent patients mostly experienced mild infections. Their data are consistent with a report showing that individuals who recovered rapidly from symptomatic SARS-CoV-2 infection generated a robust humoral immune response. Therefore, it is possible that more severe SARS-CoV-2 infections could lead to a different outcome with respect to long-lived BMPC frequencies due to dysregulated humoral immune responses. This, however, has not been the case in survivors of the 2014 West African Ebola virus outbreak in whom severe viral infection induced long-lasting antigen-specific serum IgG antibodies.

Presently, Ellebedy and colleagues are studying whether vaccination also induces long-lived antibody-producing cells. The results of this study will be more interesting.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India. 

Dr K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and a former Raja Ramanna Fellow, Department of Atomic Energy. A Ph. D. from the University of Leeds, UK, he is a medical physicist with a specialisation in radiation safety and regulatory matters. He was a Research Associate at the University of Virginia Medical Centre, Charlottesville, USA. He served the International Atomic Energy Agency as an expert and member in its Technical and Advisory Committees.