In a recent study published in Nature Medicine, a team of researchers from the United Kingdom (UK) used data from clinical trials of the Oxford-AstraZeneca 2019 coronavirus disease (COVID-19) ChAdOx1 nCoV-19 vaccine to understand genetic factors that contribute to individual variations in vaccine antibody responses.
Study: Human leukocyte antigen alleles are associated with COVID-19 vaccine immunogenicity and risk of breakthrough infection. Image credit: Tong_stocker/Shutterstock
background
Accelerated vaccine development has mitigated the severity and transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the UK, Pfizer-BioNTech (BNT162b2) and Oxford-AstraZeneca (ChAdOx1 nCoV-19; AZD1222) were early vaccines that showed significant efficacy against hospitalization due to infections of the earlier variants. However, despite the effectiveness of vaccines in reducing morbidity and mortality from COVID-19, breakthrough infections, especially with new variants of concern, are increasing in frequency.
Increased levels of neutralizing antibodies, primarily immunoglobulin G (IgG), against the SARS-CoV-2 spike protein and receptor binding domain (RBD) have been associated with reduced risk of COVID-19 . Variations in anti-spike IgG levels are associated with age and other health conditions, but the genetic basis for different neutralizing antibody responses is not fully understood.
About the study
In the present study, the team used data from five clinical trials conducted in the United Kingdom. All trial participants were also included in genetic studies. The discovery cohort included two clinical trials for the ChAdOx1 nCoV-19 vaccine, while the replication cohort consisted of two trials with participants aged 50 years and older testing intramuscular doses of the ChAdOx1 nCoV-19 vaccines, BNT162b2 or mRNA-1273, or the NVX-CoV2373 Nanoparticle Vaccine and a ChAdOx1 nCoV-19 vaccine trial in children aged six to 17 years.
Advanced infections in the discovery cohort were defined based on self-reported symptoms and a positive nucleic acid amplification test (NAAT) after a minimum of 22 days since vaccination, while advanced infections in the Replication cohorts were defined using only self-reported symptoms.
Serological tests were performed on blood samples on day 28 from the first vaccination, before the second dose of vaccine, and on days 28, 90 and 182 after the second dose. Humoral immune responses were measured against SARS-CoV-2 spike protein, RBD and nucleocapsid protein. Enzyme-linked immunosorbent assay (ELISA) was also used to measure anti-spike antibodies in samples from the replication cohort.
Deoxyribonucleic acid (DNA) was extracted from the blood samples and genotyped. Multiallelic human leukocyte antigen (HLA) alleles were phased and the ternary structure of the HLA-protein-peptide complex was modeled.
Cryopreserved peripheral blood mononuclear cells were used for proliferation assays such as T-cell activation-induced marker assay. Enzyme-linked immunospot (ELISpot) assay was used to measure IgG responses in antibody-secreting plasma cells differentiated from memory B cells. Several statistical analyzes were used to understand genome-wide and HLA allele associations with humoral immune responses to vaccines.
results
The results identified correlations between major histocompatibility complex (MHC) class II alleles and individual variations in neutralizing antibody responses. HLA-DQB1*06 alleles were associated with higher anti-spike and anti-RBD immune responses after immunization with ChAdOx1 nCoV-19 and BNT162b2 vaccines.
Carriers of HLA-DQB1*06 alleles were also seen to have a lower risk of advanced infection from early SARS-CoV-2 variants, including the Alpha variant, than individuals who did not carry the al ยท the HLA-DQB1 * 06.
In addition, the team identified a different HLA spike peptide, indicating that the HLA-DQB1*06 alleles had specific residues that recognized different sites on the spike protein and subsequently increased receptor recognition of T-cell and memory B-cell responses specific to SARS-CoV. -2 spike proteins.
The authors emphasized the need to explore the association between HLA alleles and variations in vaccine-induced immune responses in different groups based on ethnicities and comorbidities. Further research is needed to understand the functional mechanisms of HLA-spike protein binding and differences based on emerging SARS-CoV-2 variants.
Conclusions
In summary, the study used data from clinical vaccine trials in the UK to examine the genetic basis of different immune responses to vaccines. The researchers found that HLA alleles, specifically the HLA-DQB1*06 alleles, correlated with higher antibody responses to vaccines and lower risks of breakthrough infection.
The study also found that HLA-DQB1*06 alleles bind the spike peptide differently, which could explain the difference in humoral immune responses in HLA-DQB1* allele carriers 06. Further research into the mechanisms of this association is needed to improve vaccine design and implementation strategies against emerging SARS-CoV-2 variants.
Journal reference:
- Mentzer, AJ, O’Connor, D., Bibi, S., Chelysheva, I., Clutterbuck, EA, Demissie, T., Dinesh, T., Edwards, NJ, Felle, S., Feng, S., Flaxman , AL, Karp-Tatham, E., Li, G., Liu, X., Marchevsky, N., Godfrey, L., Makinson, R., Bull, MB, Fowler, J. and Alamad, B. ( 2022 ). Human leukocyte antigen alleles are associated with COVID-19 vaccine immunogenicity and risk of breakthrough infection. Natural Medicine. doi: