Are Common Cold Coronaviruses a Hidden Variable in COVID-19 Vaccine Effectiveness?

A new peer-reviewed study published in npj Vaccines by researchers at Sanofi Vaccines R&D and academic collaborators has provided important clarity on a long-debated immunological concern: whether immunity from past infections with common cold coronaviruses affects the body’s response to SARS-CoV-2 vaccination. The answer, based on a detailed analysis of over 430 healthy adult trial participants, appears to be no.

The study is based on data from the VAT00001 Phase I/II clinical trial, which evaluated stabilized prefusion SARS-CoV-2 spike protein vaccine candidates later licensed as booster shots. It aimed to assess whether pre-existing antibodies to four endemic human coronaviruses (HCoVs)—OC43, 229E, NL63, and HKU1—could interfere with the generation of neutralizing or binding antibodies following SARS-CoV-2 vaccination.

No Interference from Prior Coronavirus Exposure

Researchers found that every participant had detectable antibodies to all four common cold coronaviruses at baseline—an expected finding given their widespread circulation. However, these pre-existing antibodies did not influence the magnitude or quality of the immune response to the SARS-CoV-2 spike protein vaccine. Neither neutralizing antibody titers nor spike-binding antibody levels showed any significant relationship to HCoV antibody levels prior to vaccination.

“We found no meaningful predictive association between pre-existing binding antibody responses to four endemic coronaviruses and either neutralizing or binding responses to SARS-CoV-2,” the authors wrote.

Vaccine Formulation and Dosing—Not HCoV Exposure—Drove Response

Instead of prior viral exposure, the key factors influencing the vaccine-induced immune response were the dose and schedule of vaccine administration. The study reaffirmed that optimized vaccine formulation is the dominant determinant of immune response quality, not host exposure history to other coronaviruses.

Public Health and Biosecurity Implications

This research offers crucial validation for continued confidence in SARS-CoV-2 vaccines—especially important as global vaccine strategies diversify beyond mRNA platforms. Concerns about “immune imprinting,” or original antigenic sin, have loomed large in discussions about vaccine effectiveness and safety. Theoretical risks of vaccine-associated enhanced respiratory disease (VAERD), particularly among individuals with prior exposure to other coronaviruses, were a major hurdle in the early days of COVID-19 vaccine development.

This study directly addresses and dispels one such concern, showing no immunological interference from the body’s memory of endemic coronaviruses. It also aligns with findings from mRNA vaccine studies that reached similar conclusions in different populations.

Why This Matters

The findings are not only relevant to immunologists and vaccine developers—they have direct implications for public health strategy and global health security. Broad immunization coverage remains a cornerstone of pandemic preparedness. Demonstrating that nearly universal prior exposure to common cold coronaviruses does not impair vaccine-induced immunity against SARS-CoV-2 strengthens the case for using protein-based vaccine platforms in diverse populations.

This evidence helps support rapid deployment in future coronavirus outbreaks, without the need to account for individual differences in prior HCoV exposure.

Future Directions

Additional studies could further clarify whether very recent HCoV illnesses might transiently affect immune system behavior. Still, in the context of this well-controlled clinical trial, the lack of any predictive effect across age groups and dosing regimens offers strong evidence that past common cold coronavirus infections are not a barrier to effective SARS-CoV-2 vaccination.


de Bruyn G, Adhikarla H, Brackett CK, et al. Prior human endemic coronavirus exposure does not affect humoral responses to SARS-CoV-2 protein vaccines. npj Vaccines. 13 July 2025.

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