Detailed immune profiling in long-term care populations reveals that SARS-CoV-2 vaccines and infections drive powerful virus-specific responses while leaving lifelong common cold immunity largely unchanged.
Study: Endemic penetrance of SARS-CoV-2 has impacted marginally on immunity to spike protein of human coronaviruses. Image Credit: r.classen / Shutterstock
In a recent study published in the journal Communications Biology, researchers investigated whether immunity to COVID-19 induces cross-reactive immune responses against older, endemic common cold viruses. The study leveraged data from the VIVALDI study (ISRCTN14447421; n = 369 participants) to elucidate antibody and cellular responses in adults across the spectrum of infection and vaccination.
Study findings revealed that while COVID-19 infection and vaccination produce substantial and detectable antibody responses against SARS-CoV-2, these responses are highly specific and offer only marginal cross-reactive immune recognition with seasonal coronaviruses. These findings suggest that SARS-CoV-2 has established its own ecological niche without significantly disrupting established immunity patterns against other coronaviruses.
Seasonal Coronaviruses and Immune Similarities
Before 2019, four seasonal coronaviruses (OC43, HKU1, NL63, and 229E) circulated globally, causing mild respiratory illnesses widely recognized as the common cold. With the emergence of SARS-CoV-2 and the subsequent COVID-19 pandemic, humanity faced a fifth member of this viral family.
A growing body of epidemiological and molecular research has revealed close genetic and structural similarities between SARS-CoV-2 and endemic coronaviruses, particularly within spike proteins responsible for host recognition and virulence. These similarities prompted hypotheses that immunity against one coronavirus could generate immune responses capable of recognizing others.
Spike proteins are composed of two major regions: the S1 domain, which is highly variable and virus-specific, and the S2 domain, which is more conserved across coronaviruses. Determining whether immune responses preferentially target S1 or S2 is critical, as dominant targeting of S2 would suggest broader coronavirus recognition rather than virus-specific immunity.
Study Design and Immune Profiling Approach
The study aimed to inform epidemiological understanding and public health policy by examining antibody and cellular immune responses across all combinations of SARS-CoV-2 infection and vaccination status.
Researchers analyzed data from the VIVALDI study, a prospective cohort of staff and residents in long-term care facilities (LTCFs) in England. This population was particularly informative given the strong association between older age and severe COVID-19 outcomes, as well as the unique exposure and health characteristics of LTCF settings.
Participants were categorized into four groups: uninfected and unvaccinated, infected and unvaccinated, uninfected and vaccinated, and individuals with hybrid immunity (both infected and vaccinated).
Blood samples were analyzed using multiplex antibody assays to measure IgG responses against spike proteins of SARS-CoV-2 and the four endemic coronaviruses, as well as the SARS-CoV-2 nucleocapsid protein. Cellular immunity was assessed using FluoroSpot assays to quantify interferon-gamma and interleukin-2 responses following viral peptide stimulation, alongside cytokine profiling of assay supernatants and plasma samples.
Antibody and T Cell Responses Across Coronavirus Strains
Participants exhibited widespread pre-existing immunity to seasonal coronaviruses, with dominant antibody responses against OC43 and 229E. Exposure to SARS-CoV-2 did not disrupt these baseline immunity patterns.
Natural SARS-CoV-2 infection markedly increased virus-specific antibodies but produced only minimal increases in antibodies against related betacoronaviruses. Vaccination generated a far stronger SARS-CoV-2–specific antibody response, with hybrid immunity producing the highest levels observed. In contrast, antibody responses to endemic coronaviruses increased only modestly following vaccination or hybrid immunity.
Further analyses demonstrated that vaccine-induced antibodies were overwhelmingly directed toward the SARS-CoV-2–specific S1 domain. Removal of S1-binding antibodies eliminated the vast majority of spike-binding IgG, confirming limited overlap with conserved coronavirus regions.
T cell analyses showed that SARS-CoV-2–specific responses targeted both S1 and S2 domains but were substantially stronger than responses to endemic coronaviruses. In contrast, T cell responses to common cold viruses were strongly biased toward the conserved S2 domain. Additional experiments revealed that stimulation with betacoronavirus spike proteins triggered the release of CXCL8, indicating activation of a distinct inflammatory signaling response under experimental conditions.
Implications for Coronavirus Immunity and Vaccination
This study demonstrates that SARS-CoV-2 has integrated into the human viral ecosystem without erasing or substantially reshaping pre-existing immune memory to endemic coronaviruses. While COVID-19 vaccines induce exceptionally strong and specific antibody responses, they do not provide broad or durable immune recognition of other human coronaviruses.
The findings suggest a fundamental difference between vaccine-induced immunity, which is narrowly focused on the variable S1 domain, and natural lifetime-acquired immunity, which tends to broaden toward conserved viral regions such as S2. The modest increases in endemic coronavirus antibodies observed after vaccination or hybrid immunity are unlikely to translate into meaningful or lasting cross-protection.
Overall, the study underscores that current COVID-19 vaccines are highly effective against SARS-CoV-2 itself but should not be interpreted as conferring pan-coronavirus immunity.