Antibodies fighting original virus may be weaker against omicron

New research may explain why so many vaccinated and boosted individuals experienced breakthrough coronavirus infections caused by the omicron variant. Researchers at Johns Hopkins Medicine and the National Institute of Allergy and Infectious Diseases at the National Institutes of Health have uncovered evidence that while fully vaccinated and boosted people produce a high level of antibodies that work against the original strain of SARS-CoV-2, the same tiny defenders don't do as well in preventing the omicron strain from attacking healthy cells.

The research findings were posted online in the Journal of Clinical Investigation Insight.

"Previous research has shown vaccine-induced antibodies respond to the original strain of SARS-CoV-2 by inhibiting the virus's ability to bind to angiotensin-converting enzyme 2 [commonly known as ACE2], the receptor on a cell's surface through which SARS-CoV-2 gains entry," says study senior author Joel Blankson, professor of medicine at the Johns Hopkins University School of Medicine. "Our study suggests those same antibodies yield less ACE2 inhibition with the omicron strain, opening the door to a breakthrough COVID-19 infection."

To conduct their study, Blankson and his colleagues analyzed two types of immune responses to SARS-CoV-2: the humoral immune response, marked by virus-specific antibodies circulating in the bloodstream and produced by B lymphocytes, or B cells; and the cellular immune response, which is a direct attack on the virus by T lymphocytes, or T cells. Researchers observed these immune responses in 18 healthy and fully vaccinated people, ages 23-62, who experienced breakthrough infections within 14 to 92 days after receiving a booster COVID-19 vaccine. Of the participants, 14 received a booster of the Pfizer-BioNTech mRNA vaccine, one was boosted with the Moderna mRNA vaccine, and the remaining three had an mRNA booster following their initial dose of the Johnson & Johnson viral vector vaccine.

The humoral and cellular immune responses of those participants with breakthrough infections were compared with those from a control group of 31 participants, ages 21-60, who received similar COVID-19 vaccinations and boosters and had no prior infection with SARS-CoV-2.

Although the researchers were not able to document that the breakthrough infections were from the omicron strain, they say it's a strong probability because the omicron variant accounted for more than 90% of the COVID-19 cases treated at the Johns Hopkins Hospital, where the study was conducted, during the time when the study participants became symptomatic.

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"When we tested antibody-mediated inhibition of SARS-CoV-2 spike protein binding to ACE2, we found that serum from study participants with breakthrough COVID-19—most likely the result of omicron infection—had antibodies that strongly stopped binding by the original strain virus as expected but didn't carry out that function as well when responding to the omicron strain," says Blankson.

The specific reduction in ACE2-inhibiting antibodies responding to omicron, Blankson says, differs from what was seen in previously studied breakthrough infections with the alpha variant. In those cases, infected individuals were found to have lower overall antibody levels to the original virus strain. The levels of antibodies that inhibited the spike protein binding to ACE2—high for the original strain of the virus but reduced for omicron—were similar for both the participants with breakthrough infections and those in the control group.

Moreover, the level of cellular immunity—as measured by the amount of responding T cells documented—remained strong in the breakthrough and control groups for both the original and omicron strains. This was shown in a second recent study, also co-authored by Blankson, looking at the blood plasma of 15 mRNA vaccine recipients.

"The comparable strong T cell responses for the original and omicron strains in both studies could explain why people, like our study participants, who have breakthrough COVID-19 cases typically experience only mild symptoms during the course of their illness," he explains.