A new study analyzing the immune response to COVID-19 in a Catalan cohort of health workers sheds light on an important question: does it matter whether a person was first infected or first vaccinated?
According to the results, the order of the events does alter the outcome, at least when it comes to long-term protection against omicron.
The study, published in Nature Communications, was led by the Barcelona Institute for Global Health (ISGlobal) in collaboration with the Catalan Health Institute (ICS) and the Jordi Gol Institute (IDIAP JG), and with support from the Daniel Bravo Andreu Private Foundation (FPDBA).
Since the start of the pandemic, scientists have studied how the body responds to SARS-CoV-2, focusing on antibodies and on T-cell responses. Today, most people have what is known as hybrid immunity, meaning a combination of vaccination and infection.
“Previous studies have shown that hybrid immunity provides stronger protection than either vaccination or infection alone,” says ISGlobal researcher Carlota Dobaño, “but whether the order of these exposures affected the outcome remained an open question.”
A unique four-year dataset
The study was conducted among health care professionals from ICS Central Catalonia, a group that was particularly exposed to SARS-CoV-2 throughout the different waves of the pandemic.
The team led by Dobaño analyzed blood samples collected repeatedly between 2020 and 2023 from 357 health care professionals in the COVIDCatCentral cohort. Of these, 160 were vaccinated before becoming infected, while 197 were infected first. Among the latter, almost all (98%) were infected with the original Wuhan variant.
“This long-term follow-up has made it possible to build a solid and highly relevant database to analyze the immune response to COVID-19 over time,” says Anna Ruiz-Comellas, a researcher at ICS–IDIAP Jordi Gol who led the fieldwork.
Thanks to regular serological testing, it was possible to detect both symptomatic and asymptomatic infections. The team assessed antibody and T-cell responses to five different viral antigens.
Stronger antibodies to omicron in those vaccinated first
The study found that, compared to those initially infected, people who were first exposed to SARS-CoV-2 through vaccination developed higher levels of IgG and IgA antibodies against six omicron lineages (particularly, to the receptor binding domain of the spike protein). This difference became smaller as individuals accumulated more exposures to the virus.
“In contrast, those infected first mounted a somewhat stronger T-cell response, which may result from being exposed to a wider repertoire of antigens or higher viral loads,” says ISGlobal researcher and senior co-author Gemma Moncunill . However, the authors note that the number of participants evaluated for T-cell immunity was limited, so these results should be interpreted with caution.
Antibody dynamics reflect clinical protection
These antibody differences were reflected in clinical protection over time. People infected first were better protected early in the pandemic, when variants were closer to the original strain. But with the arrival of omicron, the advantage shifted: those vaccinated first were better protected from breakthrough infections.
“Our results provide new evidence that first exposure to SARS-CoV-2 antigens via vaccination strengthens the long-term protective effect of hybrid immunity,” says Otavio Ranzani, first author of the study.
Overall, the study highlights the role of the vaccination campaigns against SARS-CoV-2 by helping shape a strong immune response as new variants emerge.
This study is part of the END-VOC project, which aims to support the response to COVID-19 and other pandemics.
More information
Otavio Ranzani et al, Primary SARS-CoV-2 exposure by vaccination or infection shapes immune responses to omicron variants among a Spanish cohort, Nature Communications (2025). DOI: 10.1038/s41467-025-67577-9
Journal information: Nature Communications
News
Cancer’s Hidden Antioxidant Shield Helps It Escape the Immune System
Blocking an antioxidant protein that tumors use to suppress immune attacks improved cancer immunotherapy responses in mice. Cancer cells can release antioxidants that interfere with the immune cells trying to kill them. Researchers have [...]
Scientists Find a Berry Compound That Helps Muscle Cells Burn Fat
Pterostilbene, a compound found naturally in some foods, affects how skeletal muscles process fats by stabilizing a protein called PPARδ and increasing its signaling activity. Pterostilbene, a natural compound found in blueberries, grapes, and [...]
Two Hidden Forces Help Build the Human Brain Before Birth
Scientists have uncovered two surprising forces that help guide how the human brain forms before birth. Before birth, the human brain is shaped in large part by an unusual class of stem cells known [...]
Researchers Uncover a Hidden Trigger Behind Chronic Inflammation
The findings offer new insights that could help guide the development of future therapies. A protein called human resistin may help flip on one of the immune system’s most powerful inflammatory switches. Researchers at [...]
Scientists Have Uncovered Previously Hidden Microbial Activity on Human Skin
The most abundant microbes on your skin may not be the ones doing most of the work. Human skin supports vast communities of bacteria, fungi, and viruses that can influence its protective barrier, immune [...]
Brazilian Tree Compounds Fight COVID-19 on Multiple Fronts
Scientists found compounds in a Brazilian tree that hit SARS-CoV-2 on multiple fronts, revealing a promising new lead in the search for COVID-19 treatments. Researchers have found that galloylquinic acids extracted from the leaves [...]
Cutting Two Amino Acids Slowed Prostate Cancer in Mice
A newly identified link between amino acid metabolism and cholesterol production may help prostate tumors adapt to hormone therapy. Prostate cancer can find ways around treatments designed to deprive tumors of the hormones they [...]
Largest-Ever Physics Survey Raises New Doubts About Our Model of the Universe
Physicists around the world remain deeply divided on key mysteries of the universe, from dark matter to quantum gravity. The standard cosmological model failed to gain majority support, and no leading theory dominated the [...]
Scientists Just Overturned a 100-Year-Old Belief About Bacteria in the Lungs
New findings raise questions about the role of microbes living in the lungs. More than 35 trillion bacteria live throughout the human body, forming microbiomes in the gut, mouth, lungs, skin, and urogenital tract. [...]
GHCE Concept
From the preface of the book Global Health Care Equivalency in the Age of Nanotechnology, Nanomedicine and Artificial Intelligence, Edited by Frank Boehm: Since the publication of my first book (Nanomedical Device and Systems [...]
Novartis, Ionis drug failure spurs questions
Pelacarsen didn’t protect heart health despite lowering levels of a protein particle, “Lp(a),” in a large clinical trial — a result with important implications for cardiovascular drug research. Dive Brief: An RNA drug from [...]
New injectable treatment helps the brain rebuild after stroke
Biomedical engineers at Duke University have created an injectable biomaterial that may help the brain recover from damage left behind by an ischemic stroke. In experiments with mice, the material transformed the cavity created [...]
Scientists Discover a Hidden “Immune Organ” Inside the Skull
Researchers discovered lymph node-like immune hubs inside skull bone marrow that appear to act as rapid-response centers for the brain. For decades, the brain was thought to operate largely apart from the immune system. [...]
Engineered tRNAs and lipid nanoparticles target nonsense mutation cystic fibrosis
Researchers have developed a potential new approach for treating a form of cystic fibrosis caused by so-called nonsense mutations, combining chemically modified transfer RNAs with lipid nanoparticles designed to deliver the therapy directly to [...]
New pancreatic cancer drug carries a $39,800 monthly list price
A groundbreaking treatment for one of the most common forms of pancreatic cancer has been approved in pill form by the FDA. Revolution Medicines’ oral tablet daraxonrasib, branded as Rasonque, reduced the risk of [...]
Researchers Have Discovered a New Way To Reduce Chronic Nerve Pain
A cancer-linked protein called BRAF may help drive chronic nerve pain, and existing cancer drugs targeting it reduced pain sensitivity in preclinical models. Chronic nerve pain can persist long after an injury and often [...]
