The rs1883832 Polymorphism (CD40-1C>T) Affects the Intensity of IgA Responses after BNT162b2 Vaccination

The effectiveness of coronavirus disease 2019 (COVID-19) vaccination strategies is affected by several factors, including the genetic background of the host. In our study, we evaluated the contribution of the functional polymorphism rs1883832 affecting the Kozak sequence of the TNFSF5 gene (c.-1C>T), encoding CD40, to humoral immune responses after vaccination with the spike protein of SARS-CoV-2. The rs1883832 polymorphism was analyzed by PCR-RFLP in 476 individuals (male/female: 216/260, median age: 55.0 years, range: 20−105) of whom 342 received the BNT162b2 mRNA vaccine and 134 received the adenovirus-based vector vaccines (67 on ChAdOx1-nCoV-19 vaccine, 67 on Ad.26.COV2.S vaccine). The IgG and IgA responses were evaluated with chemiluminescent microparticle and ELISA assays on days 21, 42, and 90 after the first dose. The T allele of the rs1883832 polymorphism (allele frequency: 32.8%) was significantly associated with lower IgA levels and represented, as revealed by multivariable analysis, an independent risk factor for reduced anti-spike protein IgA levels on days 42 and 90 following BNT162b2 mRNA vaccination. Similar to serum anti-spike IgA levels, a trend of lower anti-spike IgA concentrations in saliva was found in individuals with the T allele of rs1883832. Finally, the intensity of IgA and IgG responses on day 42 significantly affected the prevalence of COVID-19 after vaccination. The rs1883832 polymorphism may be used as a molecular predictor of the intensity of anti-spike IgA responses after BNT162b2 mRNA vaccination.

Innate Immune Gene Polymorphisms and COVID-19 Prognosis.

COVID-19 is characterized by a heterogeneous clinical presentation and prognosis. Risk factors contributing to the development of severe disease include old age and the presence of comorbidities. However, the genetic background of the host has also been recognized as an important determinant of disease prognosis. Considering the pivotal role of innate immunity in the control of SARS-CoV-2 infection, we analyzed the possible contribution of several innate immune gene polymorphisms (including TLR2-rs5743708, TLR4-rs4986790, TLR4-rs4986791, CD14-rs2569190, CARD8-rs1834481, IL18-rs2043211, and CD40-rs1883832) in disease severity and prognosis. A total of 249 individuals were enrolled and further divided into five (5) groups, according to the clinical progression scale provided by the World Health Organization (WHO) (asymptomatic, mild, moderate, severe, and critical). We identified that elderly patients with obesity and/or diabetes mellitus were more susceptible to developing pneumonia and respiratory distress syndrome after SARS-CoV-2 infection, while the IL18-rs1834481 polymorphism was an independent risk factor for developing pneumonia. Moreover, individuals carrying either the TLR2-rs5743708 or the TLR4-rs4986791 polymorphisms exhibited a 3.6- and 2.5-fold increased probability for developing pneumonia and a more severe disease, respectively. Our data support the notion that the host's genetic background can significantly affect COVID-19 clinical phenotype, also suggesting that the IL18-rs1834481, TLR2-rs5743708, and TLR4-rs4986791 polymorphisms may be used as molecular predictors of COVID-19 clinical phenotype.