The Original COVID-19 Vaccine Helped Combat Subsequent Variants

Prior COVID-19 vaccination did not stop the immune system from mounting a protective response to the Delta and Omicron strains, though new mutation-specific antibody production dipped slightly, according to a study led by researchers at the University of Arizona Health Sciences and published in Nature Immunology.

The paper, “Intrinsic immunogenicity is a major determinant of type-specific responses in post-vaccination SARS-CoV-2 infections,” could inform future vaccine development efforts and help set vaccination and booster strategies.

“What we really wanted to address is this fundamental question of how the immune system adapts when you’re exposed to a virus and then the virus changes – are you able to generate new responses against those new mutations?” said Deepta Bhattacharya, PhD, inaugural executive director of the U of A Health Sciences Center for Advanced Molecular and Immunological Therapies and professor of immunobiology at the U of A College of Medicine – Tucson. “We found that even though new responses to the mutated parts of the virus are down a bit in vaccinated people who get infected, the overall protective response is much, much higher than in those who were unvaccinated when infected.”

The research team examined antibody responses to Delta and Omicron infections in people who were either unvaccinated or vaccinated against the original SARS-CoV-2 virus.

They found that overall antibody production for the Delta and Omicron variants was greater in people who received the original COVID-19 vaccine than in those who were unvaccinated.

The production of Delta-specific antibodies, though, was partially suppressed in people who were previously vaccinated compared with those who were unvaccinated.

“If you got vaccinated against the original virus strain, and then you got a Delta virus infection, you made a ton of protective antibody responses overall, but slightly fewer against the parts of the virus that had mutated compared with people who hadn’t had that vaccine,” Bhattacharya said, noting that in each variant there are pieces of the virus that did not change. The antibodies aimed at those parts, he said, are extremely protective.

The findings indicate that immune changes due to antigenic imprinting – the suppression of the original immune response when faced with a slightly different version of the virus – may be too small to be of functional consequence for SARS-CoV-2.

“What was really interesting is that even people whose very first exposure was to Delta or to Omicron, so there’s no prior immunity at all, were making very poor responses against the mutant parts of the virus.”

Bhattacharya, who is also a member of the university’s BIO5 Institute, said one of the key takeaways from the study is the potential to develop vaccines in different ways to elicit strong immune responses.

If researchers can determine which parts of the virus are causing evasion from the immune system, they could engineer vaccines to make sure that the immune system is effectively seeing the entire virus. That, he says, is an important part of broadening the immune response to include inevitable viral mutations.

Moving forward, Bhattacharya would like to take a closer look at what is causing the suppression of new antibody responses by prior immunity. That information, he says, could be used to develop logical frameworks for when vaccinations and boosters should be administered.

Reference: Quirk GE, Schoenle MV, Peyton KL, et al. Intrinsic immunogenicity is a major determinant of type-specific responses in SARS-CoV-2 infections. Nat Immunol. 2025. doi: 10.1038/s41590-025-02162-2

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