Project name: COVID-HLA-GENOME

Project leader: Seiamak Bahram

Steering committee: Martin Maiers (NMDP, US), Marco Colonna (Wash. U., US), Luca Vago (EFI, EU), Hidetoshi Inoko (JSHI, Japan) and Eric Spierings (IHIWS, The Netherlands), Robert Zeiser (Freiburg, Germany), Raphael Carapito (Strasbourg, France)

International Scientific Advisory Committee:

  • Erin J. Adams, University of Chicago, IL, USA
  • Pamela J. Bjorkman, Caltech, Pasadena, CA, USA
  • Dominique Charron, Hôpital Saint-Louis, Paris, France
  • James McCluskey, University of Melbourne, Australia
  • Alessandro Sette, La Jolla Institute for Immunology, CA, USA

Detailed project description:

The human Major Histocompatibility Complex (MHC) (also known as HLA Region) class I (HLA-A, -B, and -C) gene products present viral peptide antigens to the T-cell receptor (TCR) of cytotoxic T lymphocytes (CTL). This triggers the initiation of the adaptive immune response leading to the destruction of the infected cell. MHC-I genes are the most polymorphic genes of the human genome with nearly 20000 alleles known to date. It is firmly believed (yet not directly proven), that at a population level, this extraordinary level of diversity allows a collective resistance to a viral infection, epidemics, pandemics. Yet amongst the legion of known HLA-disease associations, the highest degrees of association are not with infectious diseases but rather with autoimmune/inflammatory disorders e.g. Narcolepsy and HLA-DQB1*06:02; Ankylosing Spondylitis and HLA-B27 etc. The association of HLA alleles with infectious diseases, although expertly documented – Malaria, HIV, HBV, etc. – is orders of magnitude lower than those with autoimmune/inflammatory disorders. This is believed to result from successive waves of infection by different viruses that have counterbalanced the HLA alleles selected within the previous infection.

The current COVID-19 pandemic is a unique “opportunity” to catch HLA-disease association “in the act”. This might be also of interest to future vaccine design.

The international project outlined here, under the auspices of IHIWS, aims to answer this important question in an expedited manner, not only through the implication of the entire HLA community but by further including all interested medical/research communities across the world.

Milestones in years:
May 2020: project initiation.
January 2021: end of inclusion period.
May 2021: end of analysis.

Patient/sample description (if applicable, details, inclusion/exclusion criteria):
10000 patients/individuals genomic DNA and a minimal set of clinical information (see below) are needed for this project. This number (10000) is in no terms absolute and can be revised up or down given the advancement of the project and its interim data.

The 10000 is broken into four groups, each of 2500 individuals/patients (see below).

General inclusion/exclusion criteria:
All individuals should be under 50 years of age at the time of diagnosis with no known co-morbidities (e.g. normal BMI, absence of any history of cardiovascular, pulmonary, kidney, etc. disease).

All individuals (with the exception of the first group below) must be/have been SARS-CoV-2 positive thru the detection of the viral genome in respiratory sample(s). For group 1 serology is sufficient and mandatory.

The first two categories below are outpatient individuals/patients; the next two categories, inpatient.

Group 1 are asymptomatic individuals whereas group 2, 3, and 4 are clinically symptomatic individuals.

Group 1 (G1). OUTPATIENT: ASYMPTOMATIC (ASM) INDIVIDUALS: (SARS-CoV-2 virus genome and/or IgG positive). This group is called G1:ASM.

Group 2 (G2). OUTPATIENT: INFLUENZA-LIKE ILLNESS (ILI) including COVID-19-specific symptoms (anosmia, ageusia…). This group is called G2:ILI.

Group 3 (G3). INPATIENT: respiratory dysfunction needing supplemental oxygen therapy without the need for mechanical ventilation in the ICU. This group is called G3:OXYGEN.

Group 4 (G4). INPATIENT: Acute Respiratory Distress Syndrome (ARDS) treated in an intensive care unit (ICU). G4:ICU.

NB. Of course, these are non-communicable groups, i.e. it should be ascertained that a patient definitely belongs to his/her group. For instance, if an individual in G1 has gone ultimately into G2, a patient in G2 has moved up to G3, or a G3 patient has ultimately been transferred to the ICU, he/she will only be assessed as a member of the latter (more severe) group.

Data required (number, type of data, inclusion/exclusion criteria):
Anonymized data will include the following:
Age, sex, SARS-CoV-2 genome and/or IgG data allowing documented and definitive inclusion into one of the four groups above.
Signed informed consent for typing of HLA/MIC/KIR loci. If necessary, we shall provide an umbrella IRB for the whole study (underway).

Samples required (if applicable, number, type of samples, inclusion/exclusion criteria):
5 micrograms of high molecular weight genomic DNA from each individual.

Reagents/additional assays required:
There are two options in order to contribute HLA data to the project:
Option 1: high resolution 2 fields HLA class I typing provided by the participating center.
Option 2: full HLA/MIC/KIR will be performed (free of cost for the participating center) at the project sequencing hubs (US, Europe, Asia).

A unified centralized hub will be designed, under the auspices of IHIWS for secure data exchange.
All costs for HLA typing will be covered within 3 sequencing hubs (US, Europe, Asia).
A minimum of 100 samples per participating center is mandatory in order to participate into the study.
Possibility to discuss the inclusions on a center-by-center basis.
This is a fully academic collaborative project with standard implications in terms of publication etc.