Experts agree – the pandemic is not over. Infections grow again, fueled by new variants for which our immune system is not prepared.
That’s according to a U of T study that found antibodies generated in people who were vaccinated and/or contracted COVID-19 before 2022 failed to neutralize the variants circulating today.
The study was led by Igor Staglar, professor of biochemistry and molecular genetics, in the Donnelly Center for Cellular and Biomolecular Research, Temerty School of Medicine, and Sean Owen, associate professor of pharmacy and pharmaceutical chemistry, at the University of Utah.
The diary Nature Communications published their findings.
The researchers expect that the antibody test they developed to measure the immunity of study participants will become a valuable tool for deciding who needs a booster and when, helping to save lives and avoid future blockages.
“The truth is, we still don’t know how often our shots need to be to prevent infection,” Staglar said. “To answer these questions, we need rapid, inexpensive, and quantitative tests that specifically measure Sars-CoV-2 neutralizing antibodies that prevent infection.”
Many antibody tests have been developed in the past two years. But only a few authorized ones are designed to monitor neutralizing antibodies that coat the viral spike protein so that it can no longer bind to its receptor and enter cells.
This is an important distinction because only a fraction of all Sars-CoV-2 antibodies generated during infection are neutralizing. And although most vaccines are specifically designed to produce neutralizing antibodies, it’s unclear how well they protect against variants.
“Our method, which we have named Neu-SATiN, is as accurate as, but faster and cheaper than, the gold standard, and can be quickly adapted for new variants as they emerge,” he said.
Neu-SATiN stands for nneutralization Serological Assay based on split TrI-part nanoluciferase and is a newer version of SATiN that monitors the full IgG pool that they developed last year.
The development of Neu-SATiN was led by Zhong Yao, a senior research fellow in Stagljar’s lab, and Sun Jin Kim, a postdoctoral fellow in Owen’s lab, who co-authored the paper.
The prick test is powered by the fluorescent luciferase protein from a deep-sea shrimp. It measures the binding between the viral spike protein and its human ACE2 receptor, each of which is attached to a luciferase fragment. Engagement of the spike protein with ACE2 pulls the fragments together, and this catalyzes the recovery of full-length luciferase, with an accompanying glow of light captured by the luminometer. When the patient’s blood sample is added to the mixture, the neutralizing antibodies bind and wipe out all of the spike protein, while ACE2 remains in an inactive state. As a result, the luciferase remains fragmented and the light signal drops. The researchers say the plug-and-play design of the test means it can be adapted to emerging variants by engineering mutations into the spike protein.
Researchers applied Neu-SATiN to blood samples collected from 63 patients with varying COVID-19 and vaccination histories through November 2021. Patient neutralization capacity was assessed against the original Wuhan strain and variants, Alpha, Beta, Gamma, Delta and Omicron.
“We thought it was important to monitor people who had been vaccinated to see if they still had protection and how long it lasted,” said Owen, who did his postdoctoral training at the Donnelly Center with distinguished bioengineer and university professor Molly Scheuchett. “But we also wanted to see if you’re vaccinated against one variant, does it protect you from another variant?”
Neutralizing antibodies have been found to last for about three to four months, when their levels will drop by about 70 percent, regardless of infection or vaccination status. Hybrid immunity acquired through both infection and vaccination produced higher levels of antibodies at first, but these also declined significantly four months later.
Most worryingly, infection and/or vaccination provided good protection against the previous variants, but not against Omicron or its sub-variants BA.4 and BA.5.
The data match those of a recent study in the UK, which showed that both neutralizing antibodies and cellular immunity, a type of immunity provided by memory T cells, offered no protection against either infection or vaccination or both against Omicron infestation. In a surprising twist, the UK group also found that Omicron infections boosted immunity against earlier strains, but not against Omicron itself, for reasons that remain unclear.
“It is important to emphasize that vaccines still provide significant protection against severe disease and death,” Staglar said. Still, he added that the findings from his team and others call for vigilance in the period ahead, given that the more transmissible BA4 and BA5 subvariants may escape immunity acquired from earlier Omicron infections, as confirmed from increasing re-infections.
“There will certainly be new options in the near future,” Staglar said. “Monitoring and boosting immunity for circulating variants will become increasingly important, and our method can play a key role in this as it is rapid, accurate, quantitative and inexpensive.”
It is already collaborating with Canadian vaccine maker Medicago to help determine the efficacy of their candidates against Omicron and its sub-variants. Meanwhile, U of T is negotiating to license Neu-SATiN to a company that will expand it for real-world uses such as population immunological monitoring and vaccine development.
The research was supported by funding from the Toronto COVID-19 Action Fund, the Office of the Vice-President for Research and the 3i Initiative at the University of Utah.
Reference: Kim SJ, Yao Z, Marsh MC, et al. Homogeneous surrogate virus neutralization assay for rapid assessment of neutralizing activity of anti-SARS-CoV-2 antibodies. Nat Common. 2022; 13 (1): 3716. doi: 10.1038/s41467-022-31300-9
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