People infected with the original COVID-19 strain infection produce antibodies that do not bind to new variants


People infected with the original strain of the virus that causes COVID-19 early in the pandemic produced a consistent antibody response, making two main groups of antibodies to bind to the spike protein on the virus’s outer surface.

However, those antibodies don’t bind well to newer variants, a new study from the University of Illinois Urbana-Champaign found.

Characterizing what kinds of antibodies the body is most likely to make to fight a natural infection is an important roadmap for vaccine design, says study leader Nicholas Wu, an Illinois professor of biochemistry. His research team published its findings in the journal Nature Communications.

“Antibody response is quite relevant to everything from understanding natural infection and how we recover from infection to vaccine design. The body has the capability to produce diverse antibody responses – it’s estimated we could make a trillion different antibodies.

So when you see people are making quite similar antibodies to a particular virus, we call it convergent antibody response,” Wu said.

“That means we can design vaccines trying to elicit this kind of antibody response, and that is probably going to improve the responsiveness of more individuals to the vaccine.”

The researchers mined published papers about COVID-19 patients for data about the sequence of the antibodies they produced. They focused on antibodies against the spike protein, the part of the virus that binds to receptors on human cells to infect them. The spike protein is the target of most vaccines.

They found that many antibody sequences converged into two main groups, indicating a consistent human immune response to the virus, said graduate student Timothy Tan, the first author of the study.

“We really focused on characterizing the antibodies created in those infected with the original strain of the virus,” Tan said. “Before we started the study, variants weren’t much of a problem. As they emerged, we wanted to see whether the common antibodies we identified were able to bind to newer variants.”

The researchers studied the convergent antibodies’ ability to bind to several variants and found that they no longer bound to some. The finding has implications for the ability of new variants to reinfect people who contracted earlier versions of the virus, as well as for the continuing efficacy of vaccines and the design of possible vaccine boosters, Wu said.

“Even though this antibody response is very common with the original strain, it doesn’t really interact with variants,” Wu said.

“That, of course, raises the concern of the virus evolving to escape the body’s main antibody response. Some antibodies should still be effective – the body makes antibodies to many parts of the virus, not only the spike protein – but the particular groups of antibodies that we saw in this study will not be as effective.”

The researchers said they would like to conduct similar studies characterizing antibody responses to delta and other variants, to see whether they also produce a convergent response and how it differs from the original strain.

“We want to design vaccines and boosters, if needed, that can protect a majority of the population,” Tan said. “We expect that the antibody response to those variants would be quite different. When we have more data about the antibodies of patients who have been infected with variants, understanding the difference in the immune response is one of the directions that we would like to pursue.”

Image, graphical abstract

The duration and effectiveness of adaptive immunity directed against SARS-CoV-2 after primary infection are key questions in understanding the COVID-19 pandemic. The present study, involving a large cohort of HCW followed prospectively over one year, provides crucial information on the persistence of circulating SARS-CoV-2 antibodies after mild COVID-19.

Serological monitoring of convalescent COVID-19 individuals up to 422 DSO shows that anti-SARS-CoV-2 antibodies directed against the S protein are well maintained over time up to more than one year, consistently with other recent studies [[23], [24], [25], [26]–27].

These antibody titers follow a tri-phasic decay, potentially reflective of B cell turnover after infection [2]. From M7, anti-RBD antibodies stabilize at a level that neutralizes infectious variants D614G and B.1.1.7, but less B.1.351, suggesting that most COVID-19 positive patients may be protected from reinfection by the former variants. Our hospital faced three waves of COVID-19, from March to June 2020, September 2020 – January 2021 and from March 2021 to present, with the current wave due to the B1.1.7 variant.

During the period April 2020 – April 2021, 69 new infections were reported in COVID-19 negative participants, while only one case of reinfection, which was asymptomatic, was reported in the COVID-19 positive participants. Although antibodies represent only a part of the immune response, this strongly suggests that COVID-19 positive patients develop a robust humoral immune response that reduces the risk of SARS-CoV-2 reinfection within at least one year.

Interestingly, anti-RBD levels increase as early as 6 days after vaccination. This suggests that a robust memory B cell response is established in COVID-19 convalescents, including those with low antibody titers. This is in line with the study of Dan et al. who performed an extensive characterization of memory B cells, revealing that the slight antibody decline occurring in convalescent individuals does not reflect a real waning of humoral immunity, but rather a contraction of the immune response, whilst antibody affinity maturation occurs, and anti-S memory B cells persist [8].

Recently, Wang et al. reported that memory B cell clones expressing broad and potent anti-S antibodies are selectively retained in the repertoire at least one year after infection, and expand after vaccination [28]. These observations are very hopeful for the durability of humoral responses developed after COVID-19, and suggest that protection against SARS-CoV-2 infection may last for years [28,29].

Unlike anti-RBD antibody titers that stabilize over time, we observed a steep decay of anti-N IgG titers after seven to nine months post-infection, with only 20% of COVID-19 positive HCW remaining seropositive after one year. These differences could be explained by an increased avidity or affinity that compensates antibody loss, or by changes in recognized epitopes over time [30].

We evaluated several host factors as potential predictors of antibody titers and of their kinetics up to 7–9 months after primary infection. While no differences in SARS-CoV-2 IgG titers were observed, their kinetics were influenced by sex and rhesus factor. Sex differences in the SARS-CoV-2 immune response were previously described early after infection.

Takahashi and colleagues reported that female patients had more robust T cell activation than male patients in the early phase of SARS-CoV-2 infection [31]. The sex differences in immune responses may be multifactorial, notably based on sex steroid concentrations, on transcriptional factors, and on incomplete inactivation of immunoregulatory genes on the second X chromosome in females [32,33].

Our study presents some limitations. Neutralization experiments were performed on a small subset of the cohort due to insufficient volume of remaining sera. However, the strong correlation between CMIA IgG levels and neutralizing titers observed in this study, which is also reported by the manufacturer as well as by other studies [4,17,21], allows an extrapolation of the results to the entire cohort.

Assessment of reinfection was based on participant reports during visits, as no RT-PCR surveillance was planned in the study. Therefore, it cannot be excluded that the COVID-19 positive participants had unnoticed asymptomatic reinfection during follow-up. However, no COVID-19 positive HCW, except the case of reinfection, had an increase of both anti-RBD and anti-N levels during follow-up.

Another limitation is the unbalanced sex distribution, with a female predominance, which reflects the sex distribution of the healthcare workers in our hospital. Nevertheless, the sex difference in immune response was observed by using univariable and multivariable analysis.

Furthermore, we were not able to investigate the kinetics of memory B cells because of the lack of peripheral blood mononuclear cells. Finally, our results were obtained in participants with a median age of 39 years (IQR 30–51), hence we cannot exclude that older individuals may experience a different evolution of humoral response over time.

However, taken together our data demonstrate a long-term persistence of anti-RBD IgG titers that may reduce risk of reinfection in convalescent COVID-19 patients by variants D614G and B.1.1.7. By increasing the levels of cross-neutralizing antibodies, SARS-CoV-2 vaccination may strengthen protection, especially against variants harboring antibody escape mutations like B1.351. Future work will help to determine whether vaccine-induced antibodies evolve in the same manner, and whether their kinetics differ between the sexes.

reference link :

More information: Timothy J. C. Tan et al, Sequence signatures of two public antibody clonotypes that bind SARS-CoV-2 receptor binding domain, Nature Communications (2021). DOI: 10.1038/s41467-021-24123-7


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