Research Progress in Antibody Responses Against SARS-CoV-2 Variants of Concern / 中国医学科学院学报

So far,the coronavirus disease 2019(COVID-19)has been persisting for nearly three years,infecting about 700 million people and causing more than 6 million deaths,which has seriously affected the human society.According to Global Initiative on Sharing All Influenza Data,there are more than 12 million SARS-CoV-2 variants,of which the five major variants of concern are Alpha,Beta,Gamma,Delta and Omicron.Their infectivity,pathogencity,and neutralization resistance have changed greatly compared with the original strain,which has brought great pressure to the prevention and control of the pandemic.Antibody level testing is critical for confirming infection,epidemiological investigation,vaccine development,and neutralizing drug preparation.Focusing on the humoral immunity against SARS-CoV-2,this paper introduces the mutation sites,neutralization resistance,and vaccination efficacy of the five variants of concern,and briefly summarizes the evolutionary characteristics,future mutation directions,and host immunity.

Preparation and immunogenicity evaluation of mRNA vaccine against porcine epidemic diarrhea / 生物工程学报

Porcine epidemic diarrhea (PED) is a highly contagious disease that causes high mortality in suckling piglets. Although several licensed inactivated and live attenuated vaccines were widely used, the infection rate remains high due to unsatisfactory protective efficacy. In this study, mRNA vaccine candidates against PED were prepared, and their immunogenicity was evaluated in mice and pregnant sows. The mRNA PED vaccine based on heterodimer of viral receptor binding region (RBD) showed good immunogenicity. It elicited robust humoral and cellular immune responses in mice, and the neutralizing antibody titer reached 1:300 after a single vaccination. Furthermore, it induced neutralizing antibody level similar to that of the inactivated vaccine in pregnant sows. This study developed a new design of PED vaccine based on the mRNA-RBD strategy and demonstrated the potential for clinical application.

Neutralizing Antibody Responses against Five SARS-CoV-2 Variants and T Lymphocyte Change after Vaccine Breakthrough Infections from the SARS-CoV-2 Omicron BA.1 Variant in Tianjin, China: A Prospective Study / 生物医学与环境科学（英文）

OBJECTIVE@#To investigate whether Omicron BA.1 breakthrough infection after receiving the SARS-CoV-2 vaccine could create a strong immunity barrier.@*METHODS@#Blood samples were collected at two different time points from 124 Omicron BA.1 breakthrough infected patients and 124 controls matched for age, gender, and vaccination profile. Live virus-neutralizing antibodies against five SARS-CoV-2 variants, including WT, Gamma, Beta, Delta, and Omicron BA.1, and T-lymphocyte lymphocyte counts in both groups were measured and statistically analyzed.@*RESULTS@#The neutralizing antibody titers against five different variants of SARS-CoV-2 were significantly increased in the vaccinated population infected with the Omicron BA.1 variant at 3 months after infection, but mainly increased the antibody level against the WT strain, and the antibody against the Omicron strain was the lowest. The neutralizing antibody level decreased rapidly 6 months after infection. The T-lymphocyte cell counts of patients with mild and moderate disease recovered at 3 months and completely returned to the normal state at 6 months.@*CONCLUSION@#Omicron BA.1 breakthrough infection mainly evoked humoral immune memory in the original strain after vaccination and hardly produced neutralizing antibodies specific to Omicron BA.1. Neutralizing antibodies against the different strains declined rapidly and showed features similar to those of influenza. Thus, T-lymphocytes may play an important role in recovery.

Detection of neutralizing antibodies among health care workers and staff fully-vaccinated against COVID-19 in a Baguio City tertiary hospital: A cross-sectional study

Background@#Coronavirus disease 2019, otherwise known as COVID-19 is caused by the novel coronavirus. The WHO stated that as of April 24, 2020, no study has evaluated if the antibodies against COVID-19 confer immunity. The aim therefore of this research is to determine the presence of neutralizing antibodies among fully vaccinated Health Care workers and staff of Notre Dame de Chartres Hospital.@*Methods@#This study is a single-center, cross-sectional study conducted at Notre Dame de Chartres Hospital in Baguio City. This study was designed to determine the presence of neutralizing antibodies 6 months after the 2nd dose of COVID-19 vaccine, either with Sinovac (CoronaVac®), an inactivated virus, or Oxford AstraZeneca, a non-replicating viral vector. The study was approved by the Ethics Review Board of the Baguio General Hospital Medical Center. A total of 206 participants enrolled voluntarily in the study. Descriptive statistics such as frequency and percentage were used to determine the baseline characteristics of the research participants. The mean amounts of antibodies after vaccination against COVID-19 were determined. Independent-sample t-test was utilized to determine if there was a significant difference in antibody production when comparing the two brands of vaccine, according to sex, employee status, presence of at least one comorbidity, and history of COVID-19 vaccination. One-way analysis of variance (ANOVA) was used for the variable age. All statistical tests were conducted at p<0.05 level of significance. Computations were done using SPSS version 22.0.@*Results@#A total of 236 healthcare workers and staff of Notre Dame de Chartres Hospital were included in the study. Among the study participants given either Sinovac or AstraZeneca, 52.97% belong to the 20-30 years old age group. Most of them were females (69.92%). For employment status, healthcare workers comprised the majority of the study population at 71.61% while the rest (28.36%) were hospital staff. Most did not have any comorbidities, while 26.27% reported having comorbidities, with hypertension and asthma identified as the predominant diseases at 9.75% and 9.32%, respectively; followed by allergic rhinitis (5.32%) and diabetes mellitus (2.97%). Among the participants, 74.6% were never diagnosed with COVID-19, while 25.4% reported to have been infected, with 16.5% having only mild symptoms. Most of the study participants (67.4%) were inoculated with Sinovac® while the rest (32.6%) received AstraZeneca.@*Conclusion@#There was no significant difference in the mean amount of antibodies when grouped according to each of the following variables: age, sex, employee status, and comorbidities. These results apply to both SINOVAC and AstraZeneca groups. There was a significantly higher mean amount of antibodies in those who had previously contracted COVID-19 than in those who never had a previous infection. On the other hand, comparing the mean amount of antibodies between the two brands of vaccines, SinovacTM and AstraZenecaTM, those who were vaccinated with AstraZenecaTM developed higher amounts of antibodies than those who were vaccinated with SinovacTM.

Immunogenicity and reactogenicity of heterologous immunization schedules with COVID-19 vaccines: a systematic review and network meta-analysis / 中华医学杂志(英文版)

BACKGROUND@#Data on the immunogenicity and safety of heterologous immunization schedules are inconsistent. This study aimed to evaluate the immunogenicity and safety of homologous and heterologous immunization schedules.@*METHODS@#Multiple databases with relevant studies were searched with an end date of October 31, 2021, and a website including a series of Coronavirus disease 2019 studies was examined for studies before March 31, 2022. Randomized controlled trials (RCTs) that compared different heterologous and homologous regimens among adults that reported immunogenicity and safety outcomes were reviewed. Primary outcomes included neutralizing antibodies against the original strain and serious adverse events (SAEs). A network meta-analysis (NMA) was conducted using a random-effects model.@*RESULTS@#In all, 11 RCTs were included in the systematic review, and nine were ultimately included in the NMA. Among participants who received two doses of CoronaVac, another dose of mRNA or a non-replicating viral vector vaccine resulted in a significantly higher level of neutralizing antibody than a third CoronaVac 600 sino unit (SU); a dose of BNT162b2 induced the highest geometric mean ratio (GMR) of 15.24, 95% confidence interval [CI]: 9.53-24.39. Following one dose of BNT162b2 vaccination, a dose of mRNA-1273 generated a significantly higher level of neutralizing antibody than BNT162b2 alone (GMR = 1.32; 95% CI: 1.06-1.64), NVX-CoV2373 (GMR = 1.60; 95% CI: 1.16-2.21), or ChAdOx1 (GMR = 1.80; 95% CI: 1.25-2.59). Following one dose of ChAdOx1, a dose of mRNA-1273 was also more effective for improving antibody levels than ChAdOx1 (GMR = 11.09; 95% CI: 8.36-14.71) or NVX-CoV2373 (GMR = 2.87; 95% CI: 1.08-3.91). No significant difference in the risk for SAEs was found in any comparisons.@*CONCLUSIONS@#Relative to vaccination with two doses of CoronaVac, a dose of BNT162b2 as a booster substantially enhances immunogenicity reactions and has a relatively acceptable risk for SAEs relative to other vaccines. For primary vaccination, schedules including mRNA vaccines induce a greater immune response. However, the comparatively higher risk for local and systemic adverse events introduced by mRNA vaccines should be noted.@*REGISTRATION@#PROSPERO; https://www.crd.york.ac.uk/PROSPERO/ ; No. CRD42021278149.

Safety and immunogenicity of freeze-dried rabies vaccine (Vero-cells) for human use in healthy people aged 9-65 years / 中华预防医学杂志

Objective: To assess the safety and immunogenicity of freeze-dried rabies vaccine (Vero-cells) for human use on different immunization procedures in healthy people aged 9-65 years. Methods: A randomized, blind, positive-controlled clinical study was conducted in March 2015. The eligible residents aged 9-65 were recruited in Dengfeng city and Biyang County, Henan Province. A total of 1 956 subjects were enrolled. The subjects were randomly (1∶1∶1) assigned to 5-dose control group, 4-dose trial group and 5-dose trial group, with 652 subjects in each group. The subjects of 5-dose control group were immunized with control vaccine on days 0, 3, 7, 14 and 28. The subjects of 4-dose trial group were immunized with trial vaccine on days 0, 7 and 21 (2-1-1 phases) and the subjects of 5-dose trial group were immunized with trial vaccine on days 0, 3, 7, 14 and 28. A combination of regular follow-up and active reporting was used to observe local and systemic adverse reactions till 30 days after the first and full immunization, and the incidence rate of adverse reactions in three groups was analyzed and compared. The venous blood was collected before the first immunization, 7 days after the first immunization, 14 days after the first immunization and 14 days after the full immunization. The neutralizing antibody of rabies virus was detected by rapid fluorescent focus inhibition test (RFFIT), and the seropositive conversion rate and geometric mean concentration (GMC) of antibody were calculated. Results: The adverse reaction rates in 5-dose control group, 4-dose trial group and 5-dose trial group were 41.87% (273/652), 35.43% (231/652) and 34.97% (228/652), respectively. The adverse reaction rates of 4-dose trial group and 5-dose trial group were lower than those of the 5-dose control group (P<0.05). The local reactions were mainly pain, itching, swelling and redness in injection site, while the systemic reactions were mainly fever, fatigue, headache and muscle pain. The severity of adverse reactions was mainly mild (level 1), accounting for 85.33% (518/607), 89.02% (373/419) and 88.96% (427/480) of the total number of adverse reactions in each group. At 14 days after the first immunization and 14 days after the full immunization, the antibody positive conversion rates of three groups were all 100%. At 7 days, 14 days after the first immunization and 14 days after the full immunization, the GMCs of three groups were 0.60, 0.72, 0.59 IU/ml, 20.42, 23.99, 24.38 IU/ml and 22.95, 23.52, 24.72 IU/ml, respectively, with no significant difference (P>0.05). Conclusion: The freeze-dried rabies vaccine (Vero-cells) for human use has good safety and immunogenicity when inoculated according to 5-dose and 4-dose immunization procedures.

Early assessment of the safety and immunogenicity of a third dose (booster) of COVID-19 immunization in Chinese adults / 医学前沿

Inducing durable and effective immunity against severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) via vaccination is essential to combat the current pandemic of coronavirus disease 2019 (COVID-19). It has been noticed that the strength of anti-COVID-19 vaccination-induced immunity fades over time, which calls for an additional vaccination regime, as known as booster immunization, to restore immunity among previously vaccinated populations. Here we report a pilot open-label trial of a third dose of BBIBP-CorV, an inactivated SARS-CoV-2 vaccine (Vero cell), on 136 participants aged between 18 to 63 years. Safety and immunogenicity in terms of neutralizing antibody titers and cytokine/chemokine responses were analyzed as the main endpoint until day 28. While systemic reactogenicity was either absent or mild, SARS-CoV-2-specific neutralizing antibody titers rapidly arose in all participants within 4 weeks, surpassing the peak antibody titers elicited by the initial two-dose immunization regime. Broad increases of cellular immunity-associated cytokines and chemokines were also detected in the majority of participants after the third vaccination. Furthermore, in an exploratory study, a newly developed recombinant protein vaccine, NVSI-06-08 (CHO Cells), was found to be safe and even more effective than BBIBP-CorV in eliciting humoral immune responses in BBIBP-CorV-primed individuals. Together, these results indicate that a third immunization schedule with either homologous or heterologous vaccine showed favorable safety profiles and restored potent SARS-CoV-2-specific immunity, providing support for further trials of booster vaccination in larger populations.

A broadly neutralizing human monoclonal antibody against the hemagglutinin of avian influenza virus H7N9 / 中华医学杂志(英文版)

BACKGROUND@#The new emerging avian influenza A H7N9 virus, causing severe human infection with a mortality rate of around 41%. This study aims to provide a novel treatment option for the prevention and control of H7N9.@*METHODS@#H7 hemagglutinin (HA)-specific B cells were isolated from peripheral blood plasma cells of the patients previously infected by H7N9 in Jiangsu Province, China. The human monoclonal antibodies (mAbs) were generated by amplification and cloning of these HA-specific B cells. First, all human mAbs were screened for binding activity by enzyme-linked immunosorbent assay. Then, those mAbs, exhibiting potent affinity to recognize H7 HAs were further evaluated by hemagglutination-inhibiting (HAI) and microneutralization in vitro assays. Finally, the lead mAb candidate was selected and tested against the lethal challenge of the H7N9 virus using murine models.@*RESULTS@#The mAb 6-137 was able to recognize a panel of H7 HAs with high affinity but not HA of other subtypes, including H1N1 and H3N2. The mAb 6-137 can efficiently inhibit the HA activity in the inactivated H7N9 virus and neutralize 100 tissue culture infectious dose 50 (TCID50) of H7N9 virus (influenza A/Nanjing/1/2013) in vitro, with neutralizing activity as low as 78 ng/mL. In addition, the mAb 6-137 protected the mice against the lethal challenge of H7N9 prophylactically and therapeutically.@*CONCLUSION@#The mAb 6-137 could be an effective antibody as a prophylactic or therapeutic biological treatment for the H7N9 exposure or infection.

Study of three kinds of primary immunization schedules with poliovirus vaccine / 中华预防医学杂志

Objective: To compare the immunogenicity of three kinds immunization programs with poliovirus vaccine. Methods: Healthy infants aged 2 months or over were selected and divided into three groups by complete randomization method. Basic immunization with Sabin inactivated poliovirus vaccine(sIPV) and bivalent oral poliovirus vaccine(bOPV) were completed. Three kinds of basic immunization procedures were 1sIPV+2bOPV,2sIPV+1bOPV and 3sIPV, respectively.Two qualified serums that before basic immunization and 28-42 days later were collected, and measured the poliovirus neutralizing antibody with microcell neutralization method. To compare the difference by analysis of variance, rank test and χ2 test. Results: After the basic immunization, 205 subjects of the positive conversion rate of poliovirus neutralizing antibodies of types Ⅰ, Ⅱ and Ⅲwere all higher than 97.00%, and the positive rates were all higher than 98.00%, the geometric mean titer (GMT) of neutralizing antibody was significantly higher than that before basic immunization in three groups.There were significant differences in the positive rate and GMT before and after basic immunization of typeⅠ, Ⅱand Ⅲ in the three (P<0.05). The highest GMT in three groups after basic immunization were all typeⅠ, followed by type Ⅲ, and the lowest in type Ⅱ. The GMT of type Ⅱin 2sIPV+1bOPV and 3sIPV groups were both higher than that in sIPV+2bOPV group. Conclution: After three kinds of basic immunization, the poliovirus neutralizing antibodies of serum were all at high levels in three groups, which could form an effective immune barrier against poliovirus. The immunogenicity of three kinds of basic immunization programs were all well, but there were certain differences of neutralizing antibodies among three kinds basic immunization programs. The immunogenicity in 2sIPV+1bOPV and 3sIPV groups against typeⅡpoliovirus were better than that in 1sIPV+2bOPV group.

The affinity maturation, characteristics and application of HIV-1 broadly neutralizing antibodies / 中华预防医学杂志

Hundreds of broadly neutralizing antibodies(bNAbs) were successfully isolated from long-term nonprogression(LTNP) of human immunodeficiency virus type 1(HIV-1) infected individuals. Some bNAbs were illustrated could reduce the viral load and the risk of HIV-1 infection. Today, HIV-1 bNAbs are at the center of vaccine development and passive immunization treatment. Usually, the activity of neutralizing antibodies depends on the epitope. The affinity of neutralizing antibodies also plays a vital role in its inhibitory effect. Multiple affinity maturation in vivo actually provides the broad and potent neutralizing activity of HIV-1 bNAbs. When high affinity HIV-1 bNAbs applied in clinic, it can help immune system to remove virus with lower dosage and fewer side effect. While affinity maturation, HIV-1 bNAbs shows unique characteristics, such as extensive of somatic hypermutation(SHM), in-frame insertion and deletion and long CDR 3 region of heavy chain. The key points in the progress that HIV-1 bNAbs affinity maturation will help us understand the relationship between antibodies neutralizing capability and its characteristics.It also potentially provide a reference to design effective HIV-1 immunogen.

Elevacion de anticuerpos neutralizantes contra sars cov-2 post vacunacion con sinopharm y astrazeneca hasta la tercera dosis, en el personal del banco de sangre materno infantil cns la paz - bolivia / Elevation of neutralizing antibodies against SARS CoV-2 after vaccination with Sinopharm and AstraZeneca up to the third dose, in the staff of the Maternal and Child Blood Bank CNS La Paz - Bolivia

Introducción: Después de la COVID-19, surgieron luego de muchas investigaciones un suministro de vacunas aprobadas a nivel mundial, dichas vacunas deben conferir una protección eficaz por un tiempo prolongado, poseer un buen perfil de seguridad, ser asequible y ser fácilmente accesible para todos, un reto difícil de conseguir por el tiempo y las características del virus. Objetivo: determinar la concentración de anticuerpos neutralizantes (A. N.) post vacunación en una población de trabajadores del Banco de Sangre Material y métodos: Se realizó un estudio prospectivo, descriptivo, transversal, tomando como población de estudio a todo el personal del Banco de Sangre, varones y mujeres con un rango de edad entre 26 y 72 años, se evaluó el aumento de A. N. después de inoculada la segunda dosis de Sinopharm en fecha 19/05/21, luego se midió la cantidad de anticuerpos generados en fecha 20/10/21 previo a la tercera dosis de refuerzo de Astrazeneca, evaluando nuevamente a los 35 días luego de la tercera dosis 02/12/2021 para finalmente evaluar estos niveles en fecha 26/01/2022. La técnica utilizada fue (ELISA) de la marca EUROIMMUN Anti-SARS- CoV-2 S1 del tipo IgG. Resultados y conclusiones: Se puede verificar que la concentración de A. N. producidos por la vacunación desde Sinopharm y el refuerzo con Astrazeneca favoreció a que dichos anticuerpos se mantengan altos en el tiempo (322 días luego de la primera dosis) llegando a un 80% de la concentración máxima en la lectura final. Concluimos que con cada refuerzo de vacuna anti SARS-CoV-2 el título de A.N. sube de manera significativa, motivo por el cual consideramos importante en nuestro pais una cuarta dosis como método preventivo y de inmunidad.

Introduction: After COVID-19, emerged after much research a supply of vaccines approved worldwide, these vaccines must confer effective protection for a prolonged time, possess a good safety profile, be affordable and be easily accessible to all, a challenge difficult to achieve due to the time and characteristics of the virus. Objective: to determine the concentration of neutralizing antibodies post vaccination in a population of Blood Bank workers; Material and methods: A prospective, descriptive, observational, cross-sectional study was carried out, taking as study population all the Blood Bank personnel, among men and women with an age range between 26 and 72 years old. the increase of Neutralizing Antibodies was evaluated after inoculation of the second dose of Sinopharm on 05/19/21, then the amount of antibodies generated was measured on 10/20/21 prior to the third booster dose of Astrazeneca, evaluating again 35 days after the third dose on 12/02/2021 and finally evaluating these levels on 01/26/2022. The technique used was the EUROIMMUN Anti-SARS-CoV-2 S1 ELISA. Results and conclusions: It can be verified that the concentration of N.A. produced by vaccination from Sinopharm and the booster with Astrazeneca favored that these antibodies remained high over time (322 days after the first dose) reaching 80% of the maximum concentration in the final reading. We conclude that with each booster of anti SARS CoV 2 vaccine, the titer of N.A. rises significantly, which is why we consider important in our country a fourth dose as a preventive and immunity method.

Respuesta humoral inducida por la vacuna BBIBP-CorV/Sinopharm COVID-19 en trabajadores de primera línea / BBIBP-CorV/Sinopharm COVID-19 vaccine-induced humoral response in frontline workers

Con la llegada de la vacuna contra el COVID-19 se evidenció la disminución de casos de Infección por SARS-CoV-2. El objetivo del estudio fue cuantificar la producción de anticuerpos neutralizantes (An) e inmunoglobulina G (S-IgG) en trabajadores de primera línea inmunizados con dos dosis de la vacuna BBIBP-CorV/Sinopharma. Se realizó un estudio observacional analítico transversal en personal de salud inmunizado con la vacuna inactivada (BBIBP-CorV). Sus muestras sanguíneas se recogieron tres meses después de la segunda dosis, para medir las respuestas de anticuerpos (An, S-IgG). De un total de 172 personas evaluadas, 110 (64%) personas ya habían tenido COVID-19 antes de ingresar al estudio, los títulos de An fueron superiores a 10 AU/mL en el 60,5% de los vacunados y el 89,3% mostró S-IgG superior a 50 UA/mL. Los trabajadores mayores de 60 años fueron el grupo que no desarrolló suficientes anticuerpos. La correlación de An y S-IgG fue positiva (r=0,84) (p<0,001). La administración de dos dosis de la vacuna inactivada BBIBP-CorV/Sinopharma provocó una notable respuesta An y S-IgG, excepto en mayores de 60 años(AU)

With the arrival of the vaccine against COVID-19, the decrease in cases of SARS-CoV-2 infection was evidenced. The objective of the study was to quantify the production of neutralizing antibodies (An) and immunoglobulin G (S-IgG) in frontline workers immunized with two doses of the BBIBP-CorV/Sinopharma vaccine. A cross-sectional analytical observational study was carried out in health personnel immunized with the inactivated vaccine (BBIBP-CorV). Their blood samples were collected three months after the second dose, to measure antibody responses (An, S-IgG). Of a total of 172 people evaluated, 110 (64%) people already had COVID-19 before entering the study, An titers were greater than 10 AU/mL in 60.5% of those vaccinated and 89, 3% showed S-IgG greater than 50 AU/mL. Workers older than 60 years were the group that did not develop enough antibodies. The correlation of An and S-IgG was positive (r=0.84) (p<0.001). The administration of two doses of the inactivated BBIBP-CorV/Sinopharma vaccine caused a notable An and S-IgG response, except in those over 60 years of age(AU)

Immune characterization of a Colombian family cluster with SARS-CoV-2 infection / Caracterización inmunológica de un grupo familiar colombiano con infección por SARS-CoV-2

Abstract | Introduction: Immunological markers have been described during COVID-19 and persist after recovery. These immune markers are associated with clinical features among SARS- CoV-2 infected individuals. Nevertheless, studies reporting a comprehensive analysis of the immune changes occurring during SARS-CoV-2 infection are still limited. Objective: To evaluate the production of proinflammatory cytokines, the antibody response, and the phenotype and function of NK cells and T cells in a Colombian family cluster with SARS-CoV-2 infection. Materials and methods: Proinflammatory cytokines were evaluated by RT-PCR and ELISA. The frequency, phenotype, and function of NK cells (cocultures with K562 cells) and T-cells (stimulated with spike/RdRp peptides) were assessed by flow cytometry. Anti-SARS-CoV-2 antibodies were determined using indirect immunofluorescence and plaque reduction neutralization assay. Results: During COVID-19, we observed a high proinflammatory-cytokine production and a reduced CD56bright-NK cell and cytotoxic response. Compared with healthy controls, infected individuals had a higher frequency of dysfunctional CD8+ T cells CD38+HLA-DR-. During the acute phase, CD8+ T cells stimulated with viral peptides exhibited a monofunctional response characterized by high IL-10 production. However, during recovery, we observed a bifunctional response characterized by the co-expression of CD107a and granzyme B or perforin. Conclusion: Although the proinflammatory response is a hallmark of SARS-CoV-2 infection, other phenotypic and functional alterations in NK cells and CD8+ T cells could be associated with the outcome of COVID-19. However, additional studies are required to understand these alterations and to guide future immunotherapy strategies.

Resumen | Introducción. Se han descrito diferentes marcadores inmunológicos durante la COVID-19, los cuales persisten incluso después de la convalecencia y se asocian con los estadios clínicos de la infección. Sin embargo, aún son pocos los estudios orientados al análisis exhaustivo de las alteraciones del sistema inmunológico en el curso de la infección. Objetivo. Evaluar la producción de citocinas proinflamatorias, la reacción de anticuerpos, y el fenotipo y la función de las células NK y los linfocitos T en una familia colombiana con infección por SARS-CoV-2. Materiales y métodos. Se evaluaron las citocinas proinflamatorias mediante RT-PCR y ELISA; la frecuencia, el fenotipo y la función de las células NK (en cocultivos con células K562) y linfocitos T CD8+ (estimulados con péptidos spike/RdRp) mediante citometría de flujo, y los anticuerpos anti-SARS-CoV-2, mediante inmunofluorescencia indirecta y prueba de neutralización por reducción de placa. Resultados. Durante la COVID-19 hubo una producción elevada de citocinas proinflamatorias, con disminución de las células NK CD56 bright y reacción citotóxica. Comparados con los controles sanos, los individuos infectados presentaron con gran frecuencia linfocitos T CD8+ disfuncionales CD38+HLA-DR-. Además, en los linfocitos T CD8+ estimulados con péptidos virales, predominó una reacción monofuncional con gran producción de IL-10 durante la fase aguda y una reacción bifuncional caracterizada por la coexpresión de CD107a y granzima B o perforina durante la convalecencia. Conclusión. Aunque la reacción inflamatoria caracteriza la infección por SARS-CoV-2, hay otras alteraciones fenotípicas y funcionales en células NK y linfocitos T CD8+ que podrían asociarse con la progresión de la infección. Se requieren estudios adicionales para entender estas alteraciones y guiar futuras estrategias de inmunoterapia.

COVID-T: una plataforma funcional para monitorear la respuesta de linfocitos t específicos de SARS-COV-2 en individuos vacunados y recuperados de COVID-19 / COVID-T: A functional platform to monitor SARS-CoV-2-specific T cell responses in vaccinated individuals and COVID-19 recovered patients

Resumen La rápida propagación del coronavirus SARS-CoV-2, agente causal de la enfermedad pandémica emergente COVID-19 y sus nuevas variantes, requiere del compromiso de la comunidad inmunológica para comprender la magnitud y naturaleza de la respuesta inmunológica adaptativa desarrollada por pacientes recuperados de COVID-19 e individuos vacunados con diferentes estrategias y protocolos, a los fines de imple mentar nuevas políticas sanitarias. En la actualidad, la determinación de la inmunidad contra SARS-CoV-2 se basa principalmente en la detección de anticuerpos específicos y la determinación de su actividad neutralizante. Sin embargo, a pesar de la alta sensibilidad de estos ensayos, un número considerable de pacientes e indivi duos vacunados carecen de respuesta humoral detectable, o evidencian una disminución rápida de la misma en el tiempo. Con el objetivo de estudiar la respuesta inmune celular desencadenada frente a SARS-CoV-2, en nuestro laboratorio desarrollamos la "Plataforma COVID-T" estrategia integral optimizada dirigida a caracte rizar y monitorear la respuesta de linfocitos T específicos de SARS-CoV-2 a partir de muestras de sangre de individuos vacunados y/o recuperados de COVID-19. Esta plataforma permite evaluar la naturaleza, magnitud y persistencia de la inmunidad celular T generada tanto por la infección con SARS-CoV-2, como por distintos esquemas y protocolos de vacunación en diferentes poblaciones de individuos. Asimismo, permite evaluar la respuesta inmunológica T generada frente a nuevas variantes del virus e identificar individuos sanos resistentes a SARS-CoV-2 con inmunidad pre-existente hacia coronavirus estacionales.

Abstract The rapid spread of the SARS-CoV-2, the caus ative agent of the emergent pandemic disease COVID-19, requires the urgent commitment of the immunology community to understand the adaptive immune response developed by COVID-19 convalescent patients and individuals vaccinated with different strategies and schemes, with the ultimate goal of implementing and optimizing health care and prevention policies. Currently, assessment of SARS-CoV-2-specific immunity is mainly focused on the measurement of the antibody titers and analysis of their neutralizing capacity. However, a considerable proportion of individuals lack humoral responses or show a progressive decline of SARS-CoV-2-specific neutral izing antibodies. In order to study the cellular response of convalescent patients and vaccinated individuals, we have developed the 'COVID-T Platform', an optimized strategy to study SARS-CoV-2-specific T cell responses. This platform allows assessment of the nature, magnitude and persistence of antigen-specific T-cell immunity in COVID-19-convalescent patients and vaccinated individuals. Moreover, it gives the opportunity to study cellular responses against emerging coronavirus variants and to identify individuals with cross-reactive immunity against seasonal coronaviruses.

Inmunoterapia pasiva con anticuerpos policlonales equinos (suero equino hiperinmune) para el tratamiento de pacientes con COVID-19 / Passive immunotherapy with equine polyclonal antibodies (hyperimmune equine serum) for the treatment of patients with COVID-19

INTRODUCIÓN: El presente informe es producto del trabajo colaborativo de la Comisión Nacional de Evaluación de Tecnologías de Salud (CONETEC), dependiente del Ministerio de Salud de la Nación y creada por RM N° 623/2018. La CONETEC realiza evaluaciones y emite recomendaciones a la autoridad sanitaria sobre la incorporación, forma de uso, financiamiento y políticas de cobertura de las tecnologías sanitarias desde una perspectiva global del sistema de salud argentino. En sus evaluaciones y recomendaciones, la CONETEC tiene en cuenta criterios de calidad, seguridad, efectividad, eficiencia y equidad, evaluados bajo dimensiones éticas, médicas, económicas y sociales. Sus resultados son consensuados mediante discusiones públicas y ponderados a través de un marco de valor explícito, con la participación de todos los actores involucrados en el proceso de toma de decisiones en salud. Los informes y recomendaciones de esta comisión surgen de este proceso público, transparente y colaborativo, siendo de libre consulta y acceso para toda la sociedad. El objetivo del presente informe es evaluar parámetros de eficacia, seguridad y conveniencia de anticuerpos policlonales equinos (suero equino hiperinmune) para el tratamiento de pacientes con COVID-19. OBJETIVO El objetivo del presente informe es evaluar parámetros de eficacia, seguridad y conveniencia de anticuerpos policlonales equinos (suero equino hiperinmune) para el tratamiento de pacientes con COVID-19. METODOLOGÍA: Realizamos una evaluación "viva" (con un proceso de actualización continua) de una tecnología sanitaria, basada en evidencia proveniente de revisiones sistemáticas "vivas" de referencia y guías de práctica clínica de alta calidad metodológica para brindar parámetros actualizados y balanceados que sean de utilidad para la toma de decisiones en los diferentes niveles de gestión. RESULTADOS: Se identificó una revisión sistemática que cumple con los criterios de inclusión del presente informe. Adicionalmente se identificaron otras dos revisiones sistemáticas con adecuado proceso de desarrollo pero ninguna contestó la pregunta pertinente al presente informe. La revisión sistemática identificada incluyó un estudio aleatorizado con un total de 243 pacientes aleatorizados a suero equino hiperinmune o placebo. Se realizaron múltiples análisis de subgrupo incluyendo uno que comparó pacientes según su severidad al comienzo del estudio. Ninguno de estos análisis mostró resultados que sugieran un efecto diferencial en los subgrupos comparados. CONCLUSIONES: El cuerpo de evidencia disponible hasta el momento muestra que existe incertidumbre en el efecto de los anticuerpos policlonales equinos (suero equino hiperinmune) sobre la mortalidad y el ingreso en ventilación mecánica. El uso de anticuerpos policlonales equinos (suero equino hiperinmune) podría impactar positivamente en el tiempo de mejoría clínica, pero podría no incrementar la proporción de pacientes que alcanzan la recuperación clínica que lleva al alta hospitalaria. Los anticuerpos policlonales equinos (suero equino hiperinmune) podrían no asociarse a afectos adversos severos. La incertidumbre sobre el efecto de la tecnología evaluada sobre los desenlaces críticos para pacientes hospitalizados con COVI-19 (mortalidad y requerimiento de ventilación invasiva) determina que la certeza en los efectos de suero equino sobre la salud de pacientes con COVID-19 sea muy baja. A pesar que la tecnología se produce en Argentina lo que facilitaría su acceso, encontramos barreras relacionadas con una amplia población objetivo y elevado costo comparativo de esta intervención que podrían acarrear problemas de producción y afectar la distribución equitativa en situaciones de alta demanda. No identificamos recomendaciones con el rigor metodológico apropiado para ser incluidas en el informe.

Development of SARS-CoV-2 vaccines / Desarrollo de vacunas contra el SARS-CoV-2

Abstract Background: The coronavirus disease 2019 (COVID-19) pandemic has posed significant challenges globally. Continuous transmission of the virus is mostly due to insufficient infection control measures and a lack of vaccines. Therefore, this review aimed to identify and describe possible vaccines for the prevention of COVID-19. Methods: A systematic review of the scientific literature was performed through electronic searches of the main databases to identify published reports or studies on vaccines under development against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Websites from international organizations, institutes of health and research, Google, and references from identified studies were also reviewed. Studies examining the mechanisms of infection, immunopathology, and genomics were excluded. Results: A total of 141 vaccines in development against SARS-CoV-2 were identified. The technologies used include weakened and inactive viruses, viral vectors, nucleic acids, and proteins. So far, 13 vaccines (9.2%) are under clinical evaluation; only the AZD1222 vaccine is under clinical evaluation Phase II-III. Ad5-nCoV and mRNA-1273 vaccines showed to produce neutralizing antibodies and also to be safe. Conclusions: Despite efforts invested in developing SARS-CoV-2 vaccines, more research is still required. The vaccine developers, international health organizations, and the decision-makers of health policies must carry out conjunct cooperation to face the different challenges and guarantee the development of an effective vaccine.

Resumen Introducción: La pandemia de COVID-19 ha planteado grandes retos en todo el mundo. La transmisión continua del virus se debe, en gran parte, a las medidas deficientes para el control de infecciones y a la falta de vacunas. El objetivo de esta revisión fue identificar y describir las posibles vacunas para la prevención de la COVID-19. Métodos: Se realizó una revisión sistemática de la literatura científica mediante búsquedas en las principales bases de datos electrónicas, para identificar informes o estudios publicados sobre las vacunas en proceso de desarrollo contra el SARS-CoV-2. También se revisaron páginas web de organismos internacionales, institutos de salud e investigación, Google y las referencias de los estudios identificados. Se excluyeron los estudios que examinaron los mecanismos de infección, inmunopatológicos y de genómica. Resultados: En total se identificaron 141 vacunas en desarrollo contra el SARS-CoV-2. Las tecnologías utilizadas incluyen virus debilitados e inactivos, vectores virales, ácidos nucleicos y proteínas. Hasta el momento solo 13 vacunas (9.2%) se encuentran en proceso de evaluación clínica y solo la vacuna AZD1222 se encuentra en fase II-III. Las vacunas Ad5-nCoV y mRNA-1273 han mostrado producción de anticuerpos neutralizantes, además de ser seguras. Conclusiones: A pesar de los esfuerzos invertidos para el desarrollo de vacunas contra el SARS-CoV-2, aún se requiere más investigación. Es necesario que los desarrolladores de vacunas, los organismos internacionales de salud y los tomadores de decisiones de políticas sanitarias cooperen para afrontar los diferentes desafíos y garantizar el desarrollo de una vacuna eficaz.

Neutralizing monoclonal antibodies present new prospects to treat SARS-CoV-2 infections / 医学前沿

The coronavirus disease 2019 (COVID-19) has caused global public health and economic crises. Thus, new therapeutic strategies and effective vaccines are urgently needed to cope with this severe pandemic. The development of a broadly neutralizing antibody against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the attractive treatment strategies for COVID-19. Currently, the receptor-binding domain (RBD) of the spike (S) protein is the main target of neutralizing antibodies when SARS-CoV-2 enters human cells through an interaction between the S protein and the angiotensin-converting enzyme 2 expressed on various human cells. A single monoclonal antibody (mAb) treatment is prone to selective pressure due to increased possibility of targeted epitope mutation, leading to viral escape. In addition, the antibody-dependent enhancement effect is a potential risk of enhancing the viral infection. These risks can be reduced using multiple mAbs that target nonoverlapping epitopes. Thus, a cocktail therapy combining two or more antibodies that recognize different regions of the viral surface may be the most effective therapeutic strategy.

Host metabolism dysregulation and cell tropism identification in human airway and alveolar organoids upon SARS-CoV-2 infection

The coronavirus disease 2019 (COVID-19) pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is spread primary via respiratory droplets and infects the lungs. Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines (transformed or cancer cells) and species differences between animals and humans. Organoids are stem cell-derived self-organized three-dimensional culture in vitro and model the physiological conditions of natural organs. Here we showed that SARS-CoV-2 infected and extensively replicated in human embryonic stem cells (hESCs)-derived lung organoids, including airway and alveolar organoids which covered the complete infection and spread route for SARS-CoV-2 within lungs. The infected cells were ciliated, club, and alveolar type 2 (AT2) cells, which were sequentially located from the proximal to the distal airway and terminal alveoli, respectively. Additionally, RNA-seq revealed early cell response to virus infection including an unexpected downregulation of the metabolic processes, especially lipid metabolism, in addition to the well-known upregulation of immune response. Further, Remdesivir and a human neutralizing antibody potently inhibited SARS-CoV-2 replication in lung organoids. Therefore, human lung organoids can serve as a pathophysiological model to investigate the underlying mechanism of SARS-CoV-2 infection and to discover and test therapeutic drugs for COVID-19.

Amazonian scorpions and scorpionism: integrating toxinological, clinical, and phylogenetic data to combat a human health crisis in the world's most diverse rainfores

Venom from Amazonian scorpions of the genus Tityus contains components capable of eliciting a distinct clinical, mostly neurological, syndrome. This contrasts with the mainly autonomic manifestations produced after envenomation by congeneric southern and northern South American species. Herein, we summarize Pan-Amazonian scorpionism by synthesizing available toxinological, clinical, and molecular data gathered from all affected areas in Amazonia, including Brazil, Ecuador, Colombia, Peru, Venezuela, and French Guiana. We searched multiple databases, as well as our own records, for reports of scorpion envenomations in Amazonia by confirmed Tityus spp., and compared the clinical manifestations. To help uncover clinical and venom relationships among problematic species, we explored phylogenetic relationships with a rate-calibrated analysis of mitochondrial COI data from available species. The possible existence of diversity gradients for venom toxic and immunogenic components despite the predicted strong phylogenetic association among species is underscored by discussed clinical and toxinological findings. A multicentric effort, involving all nations affected by this neglected disease, is urgently needed to offer alternatives for treating and understanding this pathology, including the preparation of neutralizing antibodies with a broad range of efficacy.(AU)

Distribution and infectious characteristics of re-positive cases infected with SARS-CoV-2 / 中华流行病学杂志

Domestic and foreign literatures related to the persistence of SARS-CoV-2 and the re-positive cases infected with SARS-CoV-2 were reviewed, and the characteristics and infectivity of the re-positive cases were analyzed to provide scientific evidence for the improvement of case management and the development of measures to stop the spread of SARS-CoV-2. Existing studies have shown that re-positive rate of SARS-CoV-2 ranged from 2.4% to 19.8%, the median of interval between re-positive detection and discharge was 4-15 days. Following the second course of the disease, the anti-SARS-CoV-2 IgM, IgG and IgA positive rates of the cases were 11.11%-86.08%, 52.00%-100.00% and 61.54%-100.00% respectively, the total antibody and neutralizing antibody positive rates were 98.72% and 88.46%. The viral load of the re-positive cases was lower than that in the initial infection. At least 3 380 re-positive cases have been reported globally. SARS-CoV-2 strains were isolated from the samples of 3 re-positive cases (1 immunodeficiency case and 2 cases with abnormal pulmonary imaging). There were close contacts that were infected by an asymptomatic case taking immunosuppressive agents. In conclusion, the infectivity of re-positive cases infected with SARS-CoV-2 is generally very low. Rare re-positive cases infected with SARS-CoV-2 might cause further transmission. The management approach for the re-positive cases can be based on the assessment of the individual transmission risk according to the pathogen detection results.