Kinetics of humoral immune response over 17 months of COVID-19 pandemic in a large cohort of healthcare workers in Spain: the ProHEpiC-19 study
Authors: Violán Concepción , Torán-Monserrat Pere , Quirant Bibiana , Lamonja-Vicente Noemi , Carrasco-Ribelles Lucía A. , Chacón Carla , Manresa-Dominguez Josep Maria , Ramos-Roure Francesc , Dacosta-Aguayo Rosalia , Palacios-Fernández Cristina , Roso-Llorach Albert , Pujol Aleix , Ouchi Dan , Monteagudo Mónica , Montero-Alia Pilar , Garcia-Sierra Rosa , Arméstar Fernando , Doladé Maria , Prat Nuria , Bonet Josep Maria , Clotet Bonaventura , Blanco Ignacio , Boigues-Pons Marc , Moreno-Millán Nemesio , Prado Julia G. , Cáceres Eva María Martínez ,   for the ProHEpiC-19 study, Garcia Marta Soldevilla , Roldan Ester Moral , Costa Magda Alemany , Ortega Eva Olivares , Camacho Alba Pachón , Devesa Marta Bujalance , Espinoza Mariella Soto , Palma Antonio Negrete , de San José Mariana Martinez , Varas Ester Lucas , Perich Ester Badia , Rodriguez Mónica Piña , Graells Elena Domenech , Gabriel Eduard Moreno , Cintas Victòria Sabaté , González Mª Jose Argerich , Duran Asumció Vazquez , Roca Alex Ortega , Pradells Anna Devesa , Kielpilanen Athina , Lombarte Oscar Blanch , Lopez Miguel Angel Marin , Carabelli Julieta , Poderós Ruth Peña , Moyano Esther Jimenez , Segura Eulalia Grau , Rosa Laia Bernard , Caballero Raul Pérez , Lozano Felipe Rodriguez , Rivas Gema Fernández , Abos Sonia Molinos , de Osaba Jaume Barallat Martinez , Trigo Lorena Tello , Cano Cristina Perez , Aguilar Juan Matllo , Martínez Anabel López , Iglesias Inmaculada Agüera 
Published: September 2022

Abstract
Background
Understanding the immune response to the SARS-CoV-2 virus is critical for efficient monitoring and control strategies. The ProHEpic-19 cohort provides a fine-grained description of the kinetics of antibodies after SARS-CoV-2 infection with an exceptional resolution over 17 months.

Methods
We established a cohort of 769 healthcare workers including healthy and infected with SARS-CoV-2 in northern Barcelona to determine the kinetics of the IgM against the nucleocapsid (N) and the IgG against the N and spike (S) of SARS-CoV-2 in infected healthcare workers. The study period was from 5 May 2020 to 11 November 2021.We used non-linear mixed models to investigate the kinetics of IgG and IgM measured at nine time points over 17 months from the date of diagnosis. The model included factors of time, gender, and disease severity (asymptomatic, mild-moderate, severe-critical) to assess their effects and their interactions.

Findings
474 of the 769 participants (61.6%) became infected with SARS-CoV-2. Significant effects of gender and disease severity were found for the levels of all three antibodies. Median IgM(N) levels were already below the positivity threshold in patients with asymptomatic and mild-moderate disease at day 270 after the diagnosis, while IgG(N and S) levels remained positive at least until days 450 and 270, respectively. Kinetic modelling showed a general rise in both IgM(N) and IgG(N) levels up to day 30, followed by a decay with a rate depending on disease severity. IgG(S) levels remained relatively constant from day 15 over time.

Interpretation
IgM(N) and IgG(N, S) SARS-CoV-2 antibodies showed a heterogeneous kinetics over the 17 months. Only the IgG(S) showed a stable increase, and the levels and the kinetics of antibodies varied according to disease severity. The kinetics of IgM and IgG observed over a year also varied by clinical spectrum can be very useful for public health policies around vaccination criteria in adult population.

Funding
Regional Ministry of Health of the Generalitat de Catalunya (Call COVID19-PoC SLT16_04; NCT04885478).