Cross-reactive humoral and CD4+ T cell responses to Mu and Gamma SARS-CoV-2 variants in a Colombian population

The SARS CoV-2 antibody and CD4+ T cell responses induced by natural infection and/or vaccination decline over time and cross-recognize other viral variants at different levels. However, there are few studies evaluating the levels and durability of the SARS CoV-2-specific antibody and CD4+ T cell response against the Mu, Gamma, and Delta variants. Here, we examined, in two ambispective cohorts of naturally-infected and/or vaccinated individuals, the titers of anti-RBD antibodies and the frequency of SARS-CoV-2-specific CD4+ T cells up to 6 months after the last antigen exposure. In naturally-infected individuals, the SARS-CoV-2 antibody response declined 6 months post-symptoms onset. However, the kinetic observed depended on the severity of the disease, since individuals who developed severe COVID-19 maintained the binding antibody titers. Also, there was detectable binding antibody cross-recognition for the Gamma, Mu, and Delta variants, but antibodies poorly neutralized Mu. COVID-19 vaccines induced an increase in antibody titers 15-30 days after receiving the second dose, but these levels decreased at 6 months. However, as expected, a third dose of the vaccine caused a rise in antibody titers. The dynamics of the antibody response upon vaccination depended on the previous SARS-CoV-2 exposure. Lower levels of vaccine-induced antibodies were associated with the development of breakthrough infections. Vaccination resulted in central memory spike-specific CD4+ T cell responses that cross-recognized peptides from the Gamma and Mu variants, and their duration also depended on previous SARS-CoV-2 exposure. In addition, we found cross-reactive CD4+ T cell responses in unexposed and unvaccinated individuals. These results have important implications for vaccine design for new SARS-CoV-2 variants of interest and concern

Cross-reactive humoral and CD4+ T cell responses to Mu and Gamma SARS-CoV-2 variants in a Colombian population

Las respuestas del anticuerpo SARS CoV-2 y de las células T CD4 + inducidas por la infección natural y/o la vacunación disminuyen con el tiempo y reconocen de forma cruzada otras variantes virales en diferentes niveles. Sin embargo, existen pocos estudios que evalúen los niveles y la durabilidad del anticuerpo específico del SARS CoV-2 y la respuesta de las células T CD4 + contra las variantes Mu, Gamma y Delta. Aquí, examinamos, en dos cohortes ambispectivas de individuos infectados naturalmente y/o vacunados, los títulos de anticuerpos anti-RBD y la frecuencia de células T CD4+ específicas del SARS-CoV-2 hasta 6 meses después de la última exposición al antígeno . . En personas infectadas de forma natural, la respuesta de anticuerpos contra el SARS-CoV-2 disminuyó 6 meses después de la aparición de los síntomas. Sin embargo, la cinética observada dependió de la gravedad de la enfermedad, ya que los individuos que desarrollaron COVID-19 grave mantuvieron los títulos de anticuerpos vinculantes. Además, hubo reconocimiento cruzado de anticuerpos de unión detectables para las variantes Gamma, Mu y Delta, pero los anticuerpos neutralizaron mal a Mu. Las vacunas COVID-19 indujeron un aumento en los títulos de anticuerpos entre 15 y 30 días después de recibir la segunda dosis, pero estos niveles disminuyeron a los 6 meses. Sin embargo, como se esperaba, una tercera dosis de la vacuna provocó un aumento en los títulos de anticuerpos. La dinámica de la respuesta de anticuerpos tras la vacunación dependió de la exposición previa al SARS-CoV-2. Los niveles más bajos de anticuerpos inducidos por la vacuna se asociaron con el desarrollo de infecciones irruptivas. La vacunación dio lugar a respuestas de células T CD4 + específicas de picos de memoria central que reconocían de forma cruzada péptidos de las variantes Gamma y Mu, y su duración también dependía de la exposición previa al SARS-CoV-2. Además, encontramos respuestas de células T CD4 + con reactividad cruzada en individuos no expuestos y no vacunados. Estos resultados tienen implicaciones importantes para el diseño de vacunas para las nuevas variantes de interés y preocupación del SARS-CoV-2.Q1Q1The SARS CoV-2 antibody and CD4+ T cell responses induced by natural infection and/or vaccination decline over time and cross-recognize other viral variants at different levels. However, there are few studies evaluating the levels and durability of the SARS CoV-2-specific antibody and CD4+ T cell response against the Mu, Gamma, and Delta variants. Here, we examined, in two ambispective cohorts of naturally-infected and/or vaccinated individuals, the titers of anti-RBD antibodies and the frequency of SARS-CoV-2-specific CD4+ T cells up to 6 months after the last antigen exposure. In naturally-infected individuals, the SARS-CoV-2 antibody response declined 6 months post-symptoms onset. However, the kinetic observed depended on the severity of the disease, since individuals who developed severe COVID-19 maintained the binding antibody titers. Also, there was detectable binding antibody cross-recognition for the Gamma, Mu, and Delta variants, but antibodies poorly neutralized Mu. COVID-19 vaccines induced an increase in antibody titers 15-30 days after receiving the second dose, but these levels decreased at 6 months. However, as expected, a third dose of the vaccine caused a rise in antibody titers. The dynamics of the antibody response upon vaccination depended on the previous SARS-CoV-2 exposure. Lower levels of vaccine-induced antibodies were associated with the development of breakthrough infections. Vaccination resulted in central memory spike-specific CD4+ T cell responses that cross-recognized peptides from the Gamma and Mu variants, and their duration also depended on previous SARS-CoV-2 exposure. In addition, we found cross-reactive CD4+ T cell responses in unexposed and unvaccinated individuals. These results have important implications for vaccine design for new SARS-CoV-2 variants of interest and concern.Revista Internacional - IndexadaS

Antiviral effect of compounds on bunyavirus replication.

Vero cells were infected with either RVFV ZH501 (A) or LACV (B) then treated with decreasing concentrations of antiviral compound. Viral growth was measured by FFA. Data represents three independent experiments completed with biological replicates. Error bars represent standard deviation.</p

Representative structures of RFVF inhibitors.

(A) Inactive and active troponoid natural products, illustrating preference for oxygen triad, along with common nuclease inhibition mode for αHTs. (B) Synthetic αHTs with activity under 10 μM against RVFV, demonstrating broad substitution tolerance. (C) Representative examples of alternative scaffolds with activity against RFVF.</p

EC₅₀ value against RVFV.

(XLSX)</p

Structures of all confirmed hit compounds.

(PDF)</p

Top antiviral hits.

Top antiviral hits.</p

EC₅₀ against RVFV replication.

EC50 against RVFV replication.</p

Development and validation of RVFV antiviral screen.

A. Identification of optimal mAb for the detection of RVFV by mAb staining of a serial dilution of RVFV strain MP-12 in an FFA. B. Impact of cell number on the sensitivity of antiviral compound screen. C. Evaluation of the sensitivity of the antiviral compound screen based upon the evaluation of ribavirin and β-D-N4-Hydroxycytidine N4-Hydroxycytidine (NHC/EIDD-1931), a known antiviral for RVFV. Data is presented as focus forming units. These data are the cumulation of three independent experiments with technical duplicates.</p