Newswise — Five years after the start of the COVID pandemic, researchers are looking back at the data on this previously unknown bug – new to our immune defences – that suddenly emerged and rapidly spread all over the globe, causing the death of million people and an economic breakdown due to the stop of most working activities in virtually any country.
Imagine, however, that the scientific community develops in record time a powerful vaccine against the tiny bug. How would you pick who should be vaccinated first? Who is at high risk to develop the severe form of the deadly disease? Who is to be protected with higher priority?
Well, if you find the story familiar, this is what recently happened with the COVID pandemics due to SARS-CoV-2 infection. The whole world was collapsing dealing with so many deaths that couldn’t even be buried in a decent time and all sorts of political, economic, and psychological challenges.
Following up on their earlier study into severe COVID from 2020, a multidisciplinary group of scientists led by Professor **Antonio Giordano, M.D., Ph.D.,** Director of the Sbarro Institute for Cancer Research and Molecular Medicine, has recently shared new results in the **_Journal of Translational Medicine_** (Springer Nature). Published March 10, 2025, the new study showed that the association of Human Leucocyte Antigen (HLA) genotype HLA-C\*01 and HLA-B\*44 with severe COVID risk varied and was eventually lost after the pandemic’s first waves, as could be expected considering the co-evolution of both the coronavirus and the immune response. On the contrary, the expression of HLA-B\*49 allele emerged as a protective factor and was confirmed by the following case-control study in Campania and Calabria.
[The paper titled, “A rapid ecologic analysis, confirmed by a case–control study, identifies class I HLA alleles correlated to the risk of COVID-19,” is available here](https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06285-w?fbclid=IwZXh0bgNhZW0CMTEAAR0WqbHof3YmxKo-DycdK-IQ7BHmjrE-qW6yfci4yvLwHPeZ3bsOI3F0kJw_aem_MjPJrMbU1xLAT6xvsWIqRQ)
The study authors included epidemiologists, pathologists, immunologists, and oncologists, first teaming up to discuss the situation and hypothesize strategies to counteract the deadly bug in 2020. They started by checking whether the high number of COVID hospitalizations in certain Italian provinces could be associated with specific genetic determinants of the resident population. They performed a so called ‘ecological study,’ led by **Giovanni Baglio** from the AGENAS (Italian National Agency for Regional Healthcare Services) using COVID hospitalization data from the Italian Civil Protection Department and genetic data from the widest local repository available: the Italian Bone Marrow Donor Registry. The donor samples were analyzed to determine their HLA genotype and check possible tissue compatibility. The HLA molecules, also called Major Histocompatibility Complex (MHC), are those that can be recognized as foreign (non-self) by the receiving individual upon organ transplantation and determine organ rejection in the absence of adequate compatibility. Indeed, HLA behavior varies among individuals.
“The reason for this diversity is that HLA/MHC role is to present microbial proteins to our immune system to unleash a powerful specific response against the bug to which these proteins belong. From the evolutionary point of view it means that within the population there will be individuals that can mount an effective immune response, while others will eventually succumb to the disease.” Says **Rita Emilena Saladino** an expert of the Tissue Typing Unit of the Grand Metropolitan Hospital Reggio Calabria.
By analyzing HLA data and COVID incidence in the Italian provinces, **Pierpaolo Correale,** Chief of the Medical Oncology Unit, Grand Metropolitan Hospital ‘Bianchi Melacrino Morelli’ of Reggio Calabria and colleagues, identified HLA class I genes, HLA-C\*01, and HLA-B\*44, that seemed permissive to SARS-CoV-2 infection. The earlier study was published in 2020 in the **_International Journal of Molecular Sciences_** and was the first to show the potential of such an economic and rapid way to identify individuals at risk, despite the limits of the ecological approach ([HLA-B\*44 and C\*01 Prevalence Correlates with Covid19 Spreading across Italy.](https://pubmed.ncbi.nlm.nih.gov/32717807/) Correale P, Mutti L, Pentimalli F, Baglio G, Saladino RE, Sileri P, Giordano A.Int J Mol Sci. 2020 Jul 23;21(15):5205. doi: 10.3390/ijms21155205.PMID: 32717807).
In their updated analysis published this week, using data through 2022, Correale and colleagues further investigated the HLA-COVID incidence association during the subsequent pandemic waves and then performed a ‘case-control’ study analyzing HLA genotypes of patients hospitalized for COVID in two Italian regions, Campania and Calabria respectively. The study was possible thanks to the collaboration with **Roberto Parrella**, Chief of the Respiratory Infectious Diseases Unit, and his team from the “Azienda Ospedaliera Specialistica dei Colli,” Napoli.
The findings illustrate how the mutations in the SARS-CoV-2 virus, along with development of immunity among the population lead to the HLA genotypes associated with an early vulnerability to severe infection instead becoming a later sign of the immune system’s strength in fighting the illness.
“Our studies suggest that the ecologic approach, based on publicly available data, can be used in emergency as a rapid and inexpensive method to determine priorities in patient management and during vaccination campaigns,” states **Francesca Pentimalli**, Professor of Pathology at LUM University, Bari and Adjunct Professor at the Sbarro Institute, Temple University, contributor of the studies.