  Citation: Gutiérrez-Bautista, J.F.; Sampedro, A.; Gómez-Vicente, E.; Rodríguez-Granger, J.; Reguera, J.A.; Cobo, F.; Ruiz-Cabello, F.; López-Nevot, M.Á. HLA Class II Polymorphism and Humoral Immunity Induced by the SARS-CoV-2 mRNA-1273 Vaccine. Vaccines 2022, 10, 402. https:// doi.org/10.3390/vaccines10030402 Academic Editor: Nicolaas A. Bos Received: 26 January 2022 Accepted: 4 March 2022 Published: 6 March 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Article HLA Class II Polymorphism and Humoral Immunity Induced by the SARS-CoV-2 mRNA-1273 Vaccine Juan Francisco Gutiérrez-Bautista 1,2, * , Antonio Sampedro 3 , Esther Gómez-Vicente 3 , Javier Rodríguez-Granger 3 , Juan Antonio Reguera 3 , Fernando Cobo 3 , Francisco Ruiz-Cabello 1,4,5 and Miguel Ángel López-Nevot 1,4,5 1 Servicio de Análisis Clínicos e Inmunología, University Hospital Virgen de las Nieves, 18014 Granada, Spain; fruizc@ugr.es (F.R.-C.); manevot@ugr.es (M.Á.L.-N.) 2 Programa de doctorado en Biomedicina, University of Granada, 18016 Granda, Spain 3 Servicio de Microbiología, University Hospital Virgen de las Nieves, 18014 Granada, Spain; antonioj.sampedro.sspa@juntadeandalucia.es (A.S.); esther.gomez.vicente.sspa@juntadeandalucia.es (E.G.-V.); javierm.rodriguez.sspa@juntadeandalucia.es (J.R.-G.); jantonio.reguera.sspa@juntadeandalucia.es (J.A.R.); fernando.cobo.sspa@juntadeandalucia.es (F.C.) 4 Departamento Bioquímica, Biología Molecular e Inmunología III, University of Granada, 18016 Granada, Spain 5 Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain * Correspondence: juanf.gutierrez.bautista.sspa@juntadeandalucia.es; Tel.: +34-629-90-80-60 Abstract: The vaccines designed against the SARS-CoV-2 coronavirus are based on the spike (S) protein. Processing of the S protein by antigen-presenting cells (APC) and its subsequent presentation to T cells is an essential part of the development of a humoral response. HLA-class II alleles are considered immune response genes because their codified molecules, expressed on the surface of APCs (macrophages, dendritic, and B cells) present antigenic peptides to T cell via their T cell receptor (TCR). The HLA-class II genes are highly polymorphic, regulating what specific peptides induce follicular helper T cells (TFH) and promote B lymphocyte differentiation into plasma or memory B cells. This work hypothesizes that the presence of certain HLA-class II alleles could be associated with the intensity of the humoral response (amount, length) to the SARS-CoV2 mRNA 1273 vaccine. We have studied the relationship between the HLA-class II typing of 87 health workers and the level of antibodies produced 30 days after vaccination. We show a possible association between the HLA-DRB1* 07:01 allele and the HLA-DRB1*07:01~DQA1*02:01~DQB1*02:02 haplotype to a higher production of antibodies 30 days after the administration of the second dose of mRNA-1273. Keywords: anti-S antibodies; HLA associations; mRNA-1273 vaccine 1. Introduction Since December 2019, the rapid expansion of the SARS-CoV-2 coronavirus has resulted in a severe pandemic affecting the entire planet [1]. The countermeasures carried out, such as confinement, face masks, use of disinfectant gels, etc. have been of great help to combat the spread of the virus [2]. However, the development of vaccines against the virus is vitally important to avoid serious illness and death [3,4]. The mRNA-1273 vaccine employs messenger RNA (mRNA) technology and encodes a stabilized version of the SARS-CoV-2 full-length spike glycoprotein trimer [3]. The administration guideline requires two doses of 100 μg separated by 28 days [3]. Studies that monitor the cellular and humoral response of vaccinated people show dif- ferent degrees of response depending on the vaccine [5,6]. Regarding antibody production, a good general response is observed at the beginning [7]. Subsequently, a decrease in the circulating level of anti-Spike (anti-S) antibodies is observed [8]. Differences in the antibody levels have been observed between individuals who re- ceived the same SARS-CoV-2 vaccine. Factors such as age, health, and immune system Vaccines 2022, 10, 402. https://doi.org/10.3390/vaccines10030402 https://www.mdpi.com/journal/vaccines