Description of the novel HLA-C allele, HLA-C*12:376, identified in a deceased COVID-19 patient.

The new allele HLA-C*12:376 showed one nonsynonymous nucleotide difference compared with the C*12:03:01:01 allele in codon 30.

HLA variants have different preferences to present proteins with specific molecular functions which are complemented in frequent haplotypes.

Human leukocyte antigen (HLA) genes are the most polymorphic loci in the human genome and code for proteins that play a key role in guiding adaptive immune responses by presenting foreign and self peptides (ligands) to T cells. Each person carries up to 6 HLA class I variants (maternal and paternal copies of HLA-A, HLA-B and HLA-C genes) and also multiple HLA class II variants, which cumulatively define the landscape of peptides presented to T cells. Each HLA variant has its own repertoire of presented peptides with a certain sequence motif which is mainly defined by peptide anchor residues (typically the second and the last positions for HLA class I ligands) forming key interactions with the peptide-binding groove of HLA. In this study, we aimed to characterize HLA binding preferences in terms of molecular functions of presented proteins. To focus on the ligand presentation bias introduced specifically by HLA-peptide interaction we performed large-scale in silico predictions of binding of all peptides from human proteome for a wide range of HLA variants and established which functions are characteristic for proteins that are more or less preferentially presented by different HLA variants using statistical calculations and gene ontology (GO) analysis. We demonstrated marked distinctions between HLA variants in molecular functions of preferentially presented proteins (e.g. some HLA variants preferentially present membrane and receptor proteins, while others - ribosomal and DNA-binding proteins) and reduced presentation of extracellular matrix and collagen proteins by the majority of HLA variants. To explain these observations we demonstrated that HLA preferentially presents proteins enriched in amino acids which are required as anchor residues for the particular HLA variant. Our observations can be extrapolated to explain the protective effect of certain HLA alleles in infectious diseases, and we hypothesize that they can also explain susceptibility to certain autoimmune diseases and cancers. We demonstrate that these differences lead to differential presentation of HIV, influenza virus, SARS-CoV-1 and SARS-CoV-2 proteins by various HLA alleles. Taking into consideration that HLA alleles are inherited in haplotypes, we hypothesized that haplotypes composed of a combination of HLA variants with different presentation preferences should be more advantageous as they allow presenting a larger repertoire of peptides and avoiding holes in immunopeptidome. Indeed, we demonstrated that HLA-A/HLA-B and HLA-A/HLA-C haplotypes which have a high frequency in the human population are comprised of HLA variants that are more distinct in terms of functions of preferentially presented proteins than the control pairs.

HLA-C dysregulation as a possible mechanism of immune evasion in SARS-CoV-2 and other RNA-virus infections.

One of the mechanisms by which viruses can evade the host's immune system is to modify the host's DNA methylation pattern. This work aims to investigate the DNA methylation and gene expression profile of COVID-19 patients, divided into symptomatic and asymptomatic, and healthy controls, focusing on genes involved in the immune response. In this study, changes in the methylome of COVID-19 patients' upper airways cells, the first barrier against respiratory infections and the first cells presenting viral antigens, are shown for the first time. Our results showed alterations in the methylation pattern of genes encoding proteins implicated in the response against pathogens, in particular the HLA-C gene, also important for the T-cell mediated memory response. HLA-C expression significantly decreases in COVID-19 patients, especially in those with a more severe prognosis and without other possibly confounding co-morbidities. Moreover, our bionformatic analysis revealed that the identified methylation alteration overlaps with enhancers regulating HLA-C expression, suggesting an additional mechanism exploited by SARS-CoV-2 to inhibit this fundamental player in the host's immune response. HLA-C could therefore represent both a prognostic marker and an excellent therapeutic target, also suggesting a preventive intervention that conjugate a virus-specific antigenic stimulation with an adjuvant increasing the T-cell mediated memory response.

Deep RNA sequencing of intensive care unit patients with COVID-19.

COVID-19 has impacted millions of patients across the world. Molecular testing occurring now identifies the presence of the virus at the sampling site: nasopharynx, nares, or oral cavity. RNA sequencing has the potential to establish both the presence of the virus and define the host's response in COVID-19. Single center, prospective study of patients with COVID-19 admitted to the intensive care unit where deep RNA sequencing (> 100 million reads) of peripheral blood with computational biology analysis was done. All patients had positive SARS-CoV-2 PCR. Clinical data was prospectively collected. We enrolled fifteen patients at a single hospital. Patients were critically ill with a mortality of 47% and 67% were on a ventilator. All the patients had the SARS-CoV-2 RNA identified in the blood in addition to RNA from other viruses, bacteria, and archaea. The expression of many immune modulating genes, including PD-L1 and PD-L2, were significantly different in patients who died from COVID-19. Some proteins were influenced by alternative transcription and splicing events, as seen in HLA-C, HLA-E, NRP1 and NRP2. Entropy calculated from alternative RNA splicing and transcription start/end predicted mortality in these patients. Current upper respiratory tract testing for COVID-19 only determines if the virus is present. Deep RNA sequencing with appropriate computational biology may provide important prognostic information and point to therapeutic foci to be precisely targeted in future studies.

Association between HLA-C alleles and COVID-19 severity in a pilot study with a Spanish Mediterranean Caucasian cohort.

The clinical presentations of COVID-19 may range from an asymptomatic or mild infection to a critical or fatal disease. Several host factors such as elderly age, male gender, and previous comorbidities seem to be involved in the most severe outcomes, but also an impaired immune response that causes a hyperinflammatory state but is unable to clear the infection. In order to get further understanding about this impaired immune response, we aimed to determine the association of specific HLA alleles with different clinical presentations of COVID-19. Therefore, we analyzed HLA Class I and II, as well as KIR gene sequences, in 72 individuals with Spanish Mediterranean Caucasian ethnicity who presented mild, severe, or critical COVID-19, according to their clinical characteristics and management. This cohort was recruited in Madrid (Spain) during the first and second pandemic waves between April and October 2020. There were no significant differences in HLA-A or HLA-B alleles among groups. However, despite the small sample size, we found that HLA-C alleles from group C1 HLA-C*08:02, -C*12:03, or -C*16:01 were more frequently associated in individuals with mild COVID-19 (43.8%) than in individuals with severe (8.3%; p = 0.0030; pc = 0.033) and critical (16.1%; p = 0.0014; pc = 0.0154) disease. C1 alleles are supposed to be highly efficient to present peptides to T cells, and HLA-C*12:03 may present a high number of verified epitopes from abundant SARS-CoV-2 proteins M, N, and S, thereby being allegedly able to trigger an efficient antiviral response. On the contrary, C2 alleles are usually poorly expressed on the cell surface due to low association with ß2-microglobulin (ß2M) and peptides, which may impede the adequate formation of stable HLA-C/ß2M/peptide heterotrimers. Consequently, this pilot study described significant differences in the presence of specific HLA-C1 alleles in individuals with different clinical presentations of COVID-19, thereby suggesting that HLA haplotyping could be valuable to get further understanding in the underlying mechanisms of the impaired immune response during critical COVID-19.

The KIR2DL2/HLA-C1C1 Gene Pairing Is Associated With an Increased Risk of SARS-CoV-2 Infection.

SARS-CoV-2 is the causative agent for the global COVID-19 pandemic; however, the interaction between virus and host is not well characterized. Natural killer cells play a key role in the early phase of the antiviral response, and their primary functions are dependent on signaling through the killer cell immunoglobulin-like receptor (KIR). This study measured the association between KIR/HLA class I ligand pairings and the occurrence and development of COVID-19. DNA of blood samples from 257 COVID-19 patients were extracted and used to detect KIR and HLA-C gene frequencies using single strain sequence-specific primer (SSP) PCR. The frequency of these genes was compared among 158 individuals with mild COVID-19, 99 with severe disease, and 98 healthy controls. The frequencies of KIR2DL2 (P=0.04, OR=1.707), KIR2DS3 (P=0.047, OR=1.679), HLA-C1C1 (P<0.001, OR=3.074) and the KIR2DL2/HLA-C1C1 pairing (P=0.038, OR=2.126) were significantly higher in the COVID-19 patients than the healthy controls. At the same time, the frequency of KIR2DL3+KIR2DL2-/HLA-C1+Others+ was lower in COVID-19 patients than in healthy individuals (P=0.004, OR=0.477). These results suggest that the protective effect of KIR2DL3 against SARS-CoV-2 infection is related to the absence of the KIR2DL2 gene. This study found no correlation between the frequencies of these genes and COVID-19 pathogenesis. Global statistical analysis revealed that the incidence of COVID-19 infection was higher in geographic regions with a high frequency of KIR2DL2. Together these results suggest that the KIR2DL2/HLA-C1C1 gene pairing may be a risk factor for SARS-CoV-2 infection.

HLA Allele Frequencies and Association with Severity of COVID-19 Infection in Northern Italian Patients.

HLA allelic distribution was analysed in a cohort of 96 Northern Italian subjects (53M/43F) (mean age 59.9 ± 13.3 years) from Lombardy who developed COVID-19 during the first two pandemic waves to investigate possible correlations between HLA molecules and disease severity. An important role of HLA- B and HLA-C loci in modulating the clinical severity of COVID-19 disease was identified. In particular, the HLA-B07 supertype was observed to be associated with a significant risk for severe disease; conversely, the HLA-B27 supertype and C*12:02 allele played a protective role as they were associated with milder disease. These associations were confirmed after applying a multinomial regression analysis to adjust the correlation for age, gender and comorbidities with COVID-19 severity. Though the power of results is limited by the small sample size, data herein contribute to shedding light on the role played by genetic background in COVID-19 infection.

Distribution of HLA-A, -B, -C, -DRB1, -DQB1, -DPB1 allele frequencies in patients with COVID-19 bilateral pneumonia in Russians, living in the Chelyabinsk region (Russia).

In this population-based case-control study conducted in the Chelyabinsk region of Russia, we examined the distribution of HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1, in a group of 100 patients with confirmed COVID-19 bilateral pneumonia. Typing was performed by NGS and statistical calculations were carried out with the Arlequin program. HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 alleles were compared between patients with COVID-19 and 99 healthy controls. We identified that COVID-19 susceptibility is associated with alleles and genotypes rs9277534A (disequilibrium with HLA-DPB1*02:01, -02:02, -04:01, -04:02, -17:01 alleles) with low expression of protein products HLA-DPB1 (pc < 0.028) and homozygosity at HLA-C*04 (p = 0.024, pc = 0.312). Allele HLA-A*01:01 was decreased in a group of patients with severe forms of bilateral pneumonia, and therefore it may be considered as a protective factor for the development of severe symptoms of COVID-19 (p = 0.009, pc = 0.225). Our studies provide further evidence for the functional association between HLA genes and COVID-19.

Association of Human Leukocyte Antigen Genotypes with Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine-Induced Subacute Thyroiditis.

Background: Despite mass vaccination, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced subacute thyroiditis (SAT) is rarely seen as a complication. The reason why some individuals are susceptible to developing vaccine-induced SAT is not known. SAT develops in genetically predisposed individuals who carry specific human leukocyte antigen (HLA) haplotypes. It is unknown whether specific HLA alleles are associated with SARS-CoV-2 vaccine-induced SAT. Objective: This study compared the HLA profiles of patients with SARS-CoV-2 vaccine-induced SAT to controls, to assess whether there is an association between specific HLA genotypes and development of SAT. The relationship between HLA genotypes and the clinical course of SARS-CoV-2 vaccine-induced SAT was also evaluated. Methods: A case-control study was conducted in a Turkish tertiary care center. Fourteen patients with SARS-CoV-2 vaccine-induced SAT and 100 healthy controls were included. HLA-A, HLA-B, HLA-C, HLA-DQB1, and HLA-DRB1 frequencies were analyzed by next-generation sequencing. Results: The frequencies of HLA-B*35 and HLA-C*04 alleles were significantly higher in SARS-CoV-2 vaccine-induced SAT cohort when compared with controls (HLA-B*35: 13 [93%] vs. 40 [40%], p < 0.001; HLA-C*04: 13 [93%] vs. 43 [43%], p < 0.001, respectively). More severe thyrotoxicosis was seen in patients having HLA-B*35 and HLA-C*04 homozygous alleles (free thyroxine: 4.47 ng/dL [3.77-5.18] vs. 1.41 ng/dL [1.22-2.63], p = 0.048). Inflammation tended to be more severe in homozygous patients (C-reactive protein: 28.2 mg/dL [13.6-42.9] vs. 4.8 [1.2-10.5], p = 0.07). Conclusions: The frequencies of HLA-B*35 and HLA-C*04 alleles were higher in SARS-CoV-2 vaccine-induced SAT compared with controls. Homozygosity for HLA-B*35 and HLA-C*04 was associated with thyrotoxicosis and a greater inflammatory reaction. Our findings should be confirmed in studies of other populations.

HLA-C*04:01 Affects HLA Class I Heterozygosity and Predicted Affinity to SARS-CoV-2 Peptides, and in Combination With Age and Sex of Armenian Patients Contributes to COVID-19 Severity.

The novel SARS-CoV-2 coronavirus infection has become a global health concern, causing the COVID-19 pandemic. The disease symptoms and outcomes depend on the host immunity, in which the human leukocyte antigen (HLA) molecules play a distinct role. The HLA alleles have an inter-population variability, and understanding their link to the COVID-19 in an ethnically distinct population may contribute to personalized medicine. The present study aimed at detecting associations between common HLA alleles and COVID-19 susceptibility and severity in Armenians. In 299 COVID-19 patients (75 asymptomatic, 102 mild/moderate, 122 severe), the association between disease severity and classic HLA-I and II loci was examined. We found that the advanced age, male sex of patients, and sex and age interaction significantly contributed to the severity of the disease. We observed that an age-dependent effect of HLA-B*51:01 carriage [odds ratio (OR)=0.48 (0.28-0.80), Pbonf <0.036] is protective against severe COVID-19. Contrary, the HLA-C*04:01 allele, in a dose-dependent manner, was associated with a significant increase in the disease severity [OR (95% CI) =1.73 (1.20-2.49), Pbonf <0.021] and an advancing age (P<0.013). The link between HLA-C*04:01 and age was secondary to a stronger association between HLA-C*04:01 and disease severity. However, HLA-C*04:01 exerted a sex-dependent differential distribution between clinical subgroups [females: P<0.0012; males: P=0.48]. The comparison of HLA-C*04:01 frequency between subgroups and 2,781 Armenian controls revealed a significant incidence of HLA-C*04:01 deficiency in asymptomatic COVID-19. HLA-C*04:01 homozygous genotype in patients blueprinted a decrease in heterozygosity of HLA-B and HLA class-I loci. In HLA-C*04:01 carriers, these changes translated to the SARS-CoV-2 peptide presentation predicted inefficacy by HLA-C and HLA class-I molecules, simultaneously enhancing the appropriate HLA-B potency. In patients with clinical manifestation, due to the high prevalence of HLA-C*04:01, these effects provided a decrease of the HLA class-I heterozygosity and an ability to recognize SARS-CoV-2 peptides. Based on our observations, we developed a prediction model involving demographic variables and HLA-C*04:01 allele for the identification of potential cases with the risk of hospitalization (the area under the curve (AUC) = 86.2%) or severe COVID-19 (AUC =71%).

Natural killer-cell immunoglobulin-like receptors trigger differences in immune response to SARS-CoV-2 infection.

BACKGROUND: The diversity in the clinical course of COVID-19 has been related to differences in innate and adaptative immune response mechanisms. Natural killer (NK) lymphocytes are critical protagonists of human host defense against viral infections. It would seem that reduced circulating levels of these cells have an impact on COVID-19 progression and severity. Their activity is strongly regulated by killer-cell immuno-globulin-like receptors (KIRs) expressed on the NK cell surface. The present study's focus was to investigate the impact of KIRs and their HLA Class I ligands on SARS-CoV-2 infection. METHODS: KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 396 Sardinian patients with SARS-CoV-2 infection. Comparisons were made between 2 groups of patients divided according to disease severity: 240 patients were symptomatic or paucisymptomatic (Group A), 156 hospitalized patients had severe disease (Group S). The immunogenetic characteristics of patients were also compared to a population group of 400 individuals from the same geographical areas. RESULTS: Substantial differences were obtained for KIR genes, KIR haplotypes and KIR-HLA ligand combinations when comparing patients of Group S to those of Group A. Patients in Group S had a statistically significant higher frequency of the KIR A/A haplotype compared to patients in Group A [34.6% vs 23.8%, OR = 1.7 (95% CI 1.1-2.6); P = 0.02, Pc = 0.04]. Moreover, the KIR2DS2/HLA C1 combination was poorly represented in the group of patients with severe symptoms compared to those of the asymptomatic-paucisymptomatic group [33.3% vs 50.0%, OR = 0.5 (95% CI 0.3-0.8), P = 0.001, Pc = 0.002]. Multivariate analysis confirmed that, regardless of the sex and age of the patients, the latter genetic variable correlated with a less severe disease course [ORM = 0.4 (95% CI 0.3-0.7), PM = 0.0005, PMC = 0.005]. CONCLUSIONS: The KIR2DS2/HLA C1 functional unit resulted to have a strong protective effect against the adverse outcomes of COVID-19. Combined to other well known factors such as advanced age, male sex and concomitant autoimmune diseases, this marker could prove to be highly informative of the disease course and thus enable the timely intervention needed to reduce the mortality associated with the severe forms of SARS-CoV-2 infection. However, larger studies in other populations as well as experimental functional studies will be needed to confirm our findings and further pursue the effect of KIR receptors on NK cell immune-mediated response to SARS-Cov-2 infection.

Association between the HLA genotype and the severity of COVID-19 infection among South Asians.

Regional variations are found in the incidence and severity of the COVID-19 infection. Human leukocyte antigen (HLA) polymorphism is one of the genetic factors that might have an impact on the outcome of the disease. This study explored the association between the HLA genotype and the severity of COVID-19 among patients from South Asia. Blood samples from 95 Asians (Bangladeshis, Indians, and Pakistanis) with COVID-19 were collected. The patients were divided according to the severity of their infection: mild (N = 64), severe (N = 31), and fatal (N = 20). DNA was extracted from all samples, and HLA genotyping was performed for both class I (A, B, and C) and class II (DRB1, DQA1, and DQB1) using the PCR-rSSO (polymerase chain reaction-reverse sequence-specific oligonucleotide) molecular method. The frequency of HLA-B*51 was significantly higher among patients in the fatal group than among those in the mild infection group (15% vs. 4.7%, p = 0.027). Additionally, the frequency of HLA-B*35 was significantly higher in the mild infection group than in the fatal group (21.1% vs. 7.5%, p = 0.050 [a borderline p-value]). In terms of HLA class II, DRB1*13 was significantly observed in the fatal group than in the mild infection group (17.5% vs. 11.3%, p = 0.049). However, the p-value for all alleles became insignificant after a statistical correction for the p-values (pc = 0.216, pc = 0.4, and pc = 0.49, respectively). Compared with all published data, this study highlights that the association between the HLA system and the COVID-19 outcome might be ethnic-dependent. Genetic variation between populations must be examined on a wider scale to assess infection prognosis and vaccine effectiveness.

HLA-A*11:01:01:01, HLA-C*12:02:02:01-HLA-B*52:01:02:02, Age and Sex Are Associated With Severity of Japanese COVID-19 With Respiratory Failure.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19) was announced as an outbreak by the World Health Organization (WHO) in January 2020 and as a pandemic in March 2020. The majority of infected individuals have experienced no or only mild symptoms, ranging from fully asymptomatic cases to mild pneumonic disease. However, a minority of infected individuals develop severe respiratory symptoms. The objective of this study was to identify susceptible HLA alleles and clinical markers that can be used in risk prediction model for the early identification of severe COVID-19 among hospitalized COVID-19 patients. A total of 137 patients with mild COVID-19 (mCOVID-19) and 53 patients with severe COVID-19 (sCOVID-19) were recruited from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan for the period of February-August 2020. High-resolution sequencing-based typing for eight HLA genes was performed using next-generation sequencing. In the HLA association studies, HLA-A*11:01:01:01 [Pc = 0.013, OR = 2.26 (1.27-3.91)] and HLA-C*12:02:02:01-HLA-B*52:01:01:02 [Pc = 0.020, OR = 2.25 (1.24-3.92)] were found to be significantly associated with the severity of COVID-19. After multivariate analysis controlling for other confounding factors and comorbidities, HLA-A*11:01:01:01 [P = 3.34E-03, OR = 3.41 (1.50-7.73)], age at diagnosis [P = 1.29E-02, OR = 1.04 (1.01-1.07)] and sex at birth [P = 8.88E-03, OR = 2.92 (1.31-6.54)] remained significant. The area under the curve of the risk prediction model utilizing HLA-A*11:01:01:01, age at diagnosis, and sex at birth was 0.772, with sensitivity of 0.715 and specificity of 0.717. To the best of our knowledge, this is the first article that describes associations of HLA alleles with COVID-19 at the 4-field (highest) resolution level. Early identification of potential sCOVID-19 could help clinicians prioritize medical utility and significantly decrease mortality from COVID-19.

A novel allele, HLA-C*15:227, identified when typing COVID-19 patients.

HLA-C*15:227 differs from HLA-C*15:02:01:01 by a single nonsynonymous change (368A → G Tyrosine 99 to Cysteine).

Population Difference in Allele Frequency of HLA-C*05 and Its Correlation with COVID-19 Mortality.

BACKGROUND: coronavirus disease 2019 (COVID-19) causes severe illness including cytokine storms, but mortality among countries differs largely. In the present study, we investigated the association between human leukocyte antigen (HLA) class I, which plays a major role in susceptibility to viral infections, and the mortality of COVID-19. METHODS: data of allele frequencies of HLA-A, -B and -C and COVID-19 mortality were obtained for 74 countries from the Allele Frequency Net Database and worldometer.info. Association between allele frequency of each HLA and mortality was assessed by linear regression followed by multivariable regression. Subsequently, association of HLA-C*05 to its receptor KIR2DS4fl, expressed on natural killer (NK) cells, and differential mortality to historic pandemics were analyzed. RESULTS: HLA-A*01, -B*07, -B*08, -B*44 and -C*05 were significantly associated with the risk of deaths (adjusted p = 0.040, 0.00081, 0.047, 0.0022, 0.00032, respectively), but only HLA-C*05 remained statistically significant (p = 0.000027) after multivariable regression. A 1% increase in the allele frequency of HLA-C*05 was associated with an increase of 44 deaths/million. Countries with different mortality could be categorized by the distribution of HLA-C*05 and its receptor KIR2DS4fl, which in combination cause NK cell-induced hyperactive immune response. Countries with similar ethnic and/or geographic background responded in a similar pattern to each pandemic. CONCLUSIONS: we demonstrated that allele frequency of HLA-C*05 and the distribution pattern with its receptor KIR2DS4fl strongly correlated with COVID-19 mortality. Host genetic variance of innate immunity may contribute to the difference in mortality among various countries and further investigation using patient samples is warranted.

COVID-19 coronavirus vaccine T cell epitope prediction analysis based on distributions of HLA class I loci (HLA-A, -B, -C) across global populations.

T cell immunity, such as CD4 and/or CD8 T cell responses, plays a vital role in controlling the virus infection and pathological damage. Several studies have reported SARS-CoV-2 proteins could serve as ideal vaccine candidates against SARS-CoV-2 infection by activating the T cell responses. In the current study, based on the SARS-CoV-2 sequence and distribution of host human leukocyte antigen (HLA), we predicted the possible epitopes for the vaccine against SARS-CoV-2 infections. Firstly, the current study retrieved the SARS-CoV-2 S and N protein sequences from the NCBI Database. Then, using the Immune Epitope Database Analysis Resource, we predicted the CTL epitopes of the SARS-CoV-2 S and N proteins according to worldwide frequency distributions of HLA-A, -B, and -C alleles (>1%). Our results predicted 90 and 106 epitopes of N and S proteins, respectively. Epitope cluster analysis showed 16 and 34 respective clusters of SARS-CoV-2 N and S proteins, which covered 95.91% and 96.14% of the global population, respectively. After epitope conservancy analysis, 8 N protein epitopes and 6 S protein epitopes showed conservancy within two SARS-CoV-2 types. Of these 14 epitopes, 13 could cover SARS coronavirus and Bat SARS-like coronavirus. The remaining epitope (KWPWYIWLGF1211-1220) could cover MERS coronavirus. Finally, the 14-epitope combination could vaccinate 89.60% of all individuals worldwide. Our results propose single or combined CTL epitopes predicted in the current study as candidates for vaccines to effectively control SARS-CoV-2 infection and development.

[HLA genetic polymorphisms and prognosis of patients with COVID-19]. / Polimorfismos genéticos de los HLA y pronóstico de pacientes con COVID-19.

OBJECTIVE: Different genetic polymorphisms of human leukocyte antigen (HLA) have been associated with the risk and prognosis of autoimmune and infectious diseases. The objectives of this study were to determine whether there is an association between HLA genetic polymorphisms and the susceptibility to and mortality of coronavirus disease 2019 (COVID-19) patients. DESIGN: Observational and prospective study. SETTING: Eight Intensive Care Units (ICU) from 6 hospitals of Canary Islands (Spain). PATIENTS: COVID-19 patients admitted in ICU and healthy subjects. INTERVENTIONS: Determination of HLA genetic polymorphisms. MAIN VARIABLE OF INTEREST: Mortality at 30 days. RESULTS: A total of 3886 healthy controls and 72 COVID-19 patients (10 non-survivors and 62 survivor patients at 30 days) were included. We found a trend to a higher rate of the alleles HLA-A*32 (p=0.004) in healthy controls than in COVID-19 patients, and of the alleles HLA-B*39 (p=0.02) and HLA-C*16 (p=0.02) in COVID-19 patients than in healthy controls; however, all these p-values were not significant after correction for multiple comparisons. Logistic regression analysis showed that the presence of certain alleles was associated with higher mortality, such as the allele HLA-A*11 after controlling for SOFA (OR=7.693; 95% CI=1.063-55.650; p=0.04) or APACHE-II (OR=11.858; 95% CI=1.524-92.273; p=0.02), the allele HLA-C*01 after controlling for SOFA (OR=11.182; 95% CI=1.053-118.700; p=0.04) or APACHE-II (OR=17.604; 95% CI=1.629-190.211; p=0.02), and the allele HLA-DQB1*04 after controlling for SOFA (OR=9.963; 95% CI=1.235-80.358; p=0.03). CONCLUSIONS: The new finding from our preliminary study of small sample size was that HLA genetic polymorphisms could be associated with COVID-19 mortality; however, studies with a larger sample size before definitive conclusions can be drawn.

Correlation of the two most frequent HLA haplotypes in the Italian population to the differential regional incidence of Covid-19.

BACKGROUND: Understanding how HLA polymorphisms may affect both susceptibility, course and severity of Covid-19 infection could help both at the clinical level to identify individuals at higher risk from the disease and at the epidemiological one to explain the differences in the epidemic trend among countries or even within a specific country. Covid-19 disease in Italy showed a peculiar geographical distribution from the northern most affected regions to the southern ones only slightly touched. METHODS: In this study we analysed the regional frequencies for the most common Italian haplotypes from the Italian Bone Marrow Donor Registry (HLA-A, -B, -C and -DRB1 at four-digit level). Then we performed Pearson correlation analyses among regional haplotypes estimated frequency in the population and Covid-19 incidence and mortality. RESULTS: In this study we found that the two most frequent HLA haplotypes in the Italian population, HLA-A*:01:01g-B*08:01 g-C*07:01g-DRB1*03:01g and HLA-A*02.01g-B*18.01g-C*07.01g-DRB1*11.04g, had a regional distribution overlapping that of Covid-19 and showed respectively a positive (suggestive of susceptibility) and negative (suggestive of protection) significant correlation with both Covid-19 incidence and mortality. CONCLUSIONS: Based on these results, in order to define such HLA haplotypes as a factor effectively associated to the disease susceptibility, the creation of national networks that can collect patients' samples from all regions for HLA typing should be highly encouraged.

HLA-B*44 and C*01 Prevalence Correlates with Covid19 Spreading across Italy.

The spread of COVID-19 is showing huge, unexplained, differences between northern and southern Italy. We hypothesized that the regional prevalence of specific class I human leukocyte antigen (HLA) alleles, which shape the anti-viral immune response, might partly underlie these differences. Through an ecological approach, we analyzed whether a set of HLA alleles (A, B, C), known to be involved in the immune response against infections, correlates with COVID-19 incidence. COVID-19 data were provided by the National Civil Protection Department, whereas HLA allele prevalence was retrieved through the Italian Bone-Marrow Donors Registry. Among all the alleles, HLA-A*25, B*08, B*44, B*15:01, B*51, C*01, and C*03 showed a positive log-linear correlation with COVID-19 incidence rate fixed on 9 April 2020 in proximity of the national outbreak peak (Pearson's coefficients between 0.50 and 0.70, p-value < 0.0001), whereas HLA-B*14, B*18, and B*49 showed an inverse log-linear correlation (Pearson's coefficients between -0.47 and -0.59, p-value < 0.0001). When alleles were examined simultaneously using a multiple regression model to control for confounding factors, HLA-B*44 and C*01 were still positively and independently associated with COVID-19: a growth rate of 16% (95%CI: 0.1-35%) per 1% point increase in B*44 prevalence; and of 19% (95%CI: 1-41%) per 1% point increase in C*01 prevalence. Our epidemiologic analysis, despite the limits of the ecological approach, is strongly suggestive of a permissive role of HLA-C*01 and B*44 towards SARS-CoV-2 infection, which warrants further investigation in case-control studies. This study opens a new potential avenue for the identification of sub-populations at risk, which could provide Health Services with a tool to define more targeted clinical management strategies and priorities in vaccination campaigns.