Progressive and Parallel Decline of Humoral and T-Cell Immunity in Convalescent Healthcare Workers with Asymptomatic or Mild-to-Moderate Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

We investigated the duration of humoral and T-cell immune response in paired samples among 22 convalescent healthcare workers (HCWs). A median of 1.8 months after diagnosis, T-cell response was significantly lower in HCWs with early loss of antibodies (6 cases [27%]). After 5.1 months, antibody decline was observed in 77% of cases (41% seroreverted; P < .01), and 36% had lost T-cell response (75% lost response to spike protein). Persistence of immune response was observed in those who developed a greater adaptive immune response. Our data point to the initial immune response as the relevant player in coronavirus disease 2019 duration of protection.

Discordant Humoral and T-Cell Response to mRNA SARS-CoV-2 Vaccine and the Risk of Breakthrough Infections in Women with Breast Cancer, Receiving Cyclin-Dependent Kinase 4 and 6 Inhibitors.

Few data are available about the immune response to mRNA SARS-CoV-2 vaccines in patients with breast cancer receiving cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). We conducted a prospective, single-center study of patients with breast cancer treated with CDK4/6i who received mRNA-1273 vaccination, as well as a comparative group of healthcare workers. The primary endpoint was to compare the rate and magnitude of humoral and T-cell response after full vaccination. A better neutralizing antibody and anti-S IgG level was observed after vaccination in the subgroup of women receiving CDK4/6i, but a trend toward a reduced CD4 and CD8 T-cell response in the CDK4/6i group was not statistically significant. There were no differences in the rate of COVID-19 after vaccination (19% vs. 12%), but breakthrough infections were observed in those with lower levels of anti-S IgG and neutralizing antibodies after the first dose. A lower rate of CD4 T-cell response was also found in those individuals with breakthrough infections, although a non-significant and similar level of CD8 T-cell response was also observed, regardless of breakthrough infections. The rate of adverse events was higher in patients treated with CDK4/6i, without serious adverse events. In conclusion, there was a robust humoral response, but a blunted T-cell response to mRNA vaccine in women receiving CDK4/6i, suggesting a reduced trend of the adaptative immune response.

Impact of SARS-CoV-2-specific memory B cells on the immune response after mRNA-based Comirnaty vaccine in seronegative health care workers.

Purpose: To analyze the impact of SARS-COV-2-specific memory B cells (MBC) on the immune response after two doses of mRNA-based Comirnaty COVID-19 vaccine in seronegative health care workers. This study is seeking a rationale for boosting vaccines. Methods: Longitudinal study including 31 seronegative health care workers with undetectable specific MBCs (IgG-MBC- group), 24 seronegative with detectable specific MBCs (IgG-MBC+ group), and 24 seropositive with detectable specific MBCs (IgG+MBC+ group). The level of antibodies that inhibit ACE2-RBD interaction, and anti-Spike IgG, IgA, and IgM antibodies was quantified by ELISA. In addition, specific memory B and T cells were quantified by flow cytometry. Results: The level of specific MBCs, and isotypes, in the IgG-MBC- group was lower compared to that found in IgG-MBC+ (p = 0.0001) and IgG+MBC+ (p < 0.0001) groups, respectively. ACE2-RBD neutralizing antibodies and anti-S IgG antibodies were at lower levels in the IgG-MBC-group after the vaccine. Specific MBCs directly correlated with specific CD4+ T cells (although not significant, p = 0.065), while no correlation was found with specific CD8+ T cells (p = 0.156) after the vaccine. In parallel, ACE2-RBD neutralizing antibodies only positively correlated with specific CD4+ T cells (p = 0.034). Conclusion: IgG-MBC- individuals showed the worst humoral and cellular responses, both in frequency and magnitude, after vaccination. Individuals whose antibodies wane and become undetectable after a given period of time post vaccination and show no specific MBCs are less protected and hence are good candidates for boosting vaccine. On the other hand, seronegative individuals with specific MBC showed faster and higher responses compared to the IgG-MBC- group.

Pre-existing T cell immunity determines the frequency and magnitude of cellular immune response to two doses of mRNA vaccine against SARS-CoV-2.

Little is known about the factors associated with lack of T-cell response to mRNA vaccines against SARS-CoV-2. In a prospective cohort of 61 health care workers (HCWs), 21% and 16% after the first dose of mRNA BNT162b vaccine, and 12% and 7% after the second dose, showed lack of CD4+ and CD8+ T-cell response, respectively. Pre-existing T-cell immunity, due to past infection (46%) or cross-reactive cellular response (26%), was significantly associated with T-cell response in frequency (CD4+ T-cell, 100% vs 82% after two doses; p = 0.049) and in the magnitude of T-cell response during follow up. Furthermore, baseline CD4+ T-cell correlated positively with the titer of specific IgG-antibodies after first and second vaccine dose. Our data demonstrate that cross-reactive T-cells correlate with a better cellular response as well as an enhanced humoral response, and we confirm the close correlation of humoral and cellular response after mRNA vaccination.

Limited T cell response to SARS-CoV-2 mRNA vaccine among patients with cancer receiving different cancer treatments.

INTRODUCTION: Patients with cancer (PC) are at high risk of acquiring COVID-19 and can develop more serious complications. Deeper understanding of vaccines immunogenicity in this population is crucial for adequately planning vaccines programs. The ONCOVac study aimed to comprehensively assess the immunogenicity of mRNA-1273 vaccine in terms of humoral and cellular response. METHODS: We conducted a prospective, single-center study including patients with solid tumours treated with cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i), immunotherapy (IT) or chemotherapy (CT). Patients were enrolled previously to vaccination with mRNA-1273. We also involved health care workers (HCW) to serve as a control group. We took blood samples before first dose administration (BL), after first dose (1D), and after second dose (2D). The primary objective was to compare the rate and magnitude of T cell response after second dose whereas safety and humoral response were defined as secondary objectives. We also collected patient reported outcomes after both the first and second vaccine dose and a six-month follow-up period to diagnose incident COVID-19 cases was planned. RESULTS: The rate of specific anti-S serologic positivity (anti-S IgG cut-off point at 7,14 BAU/mL) was significantly higher in HCW compared to PC after 1D (100% versus 83.8%; p = 0.04), but similar after 2D (100% versus 95.8%; p = 0.5). This difference after 1D was driven by PC treated with CT (100% versus 64.5%; p = 0.001). Cellular response after 2D was significantly lower in PC than in HCW for both CD4+ (91.7% versus 59.7%; p = 0.001) and CD8+ (94.4% versus 55.6%; p < 0.001) T cells. We found a difference on pre-existing CD4+ T cell response in HCW comparing to PC (36% and 17%, p = 0.03); without difference in pre-existing CD8+ T cell response (31% and 23%, p = 0.5). After excluding patients with pre-existing T cell response, PC achieved even lower CD4+ (50.9% versus 95.5%, p < 0.001) and CD8+ (45.5% versus 95.5%, p < 0.001) T cell response compared with HCW. Regarding safety, PC reported notably more adverse events than HCW (96.6% versus 69.2%, p < 0.001). CONCLUSION: We demonstrated that PC showed a similar humoral response but a lower T cell response following two doses of mRNA-1273 vaccination. Further studies are needed to complement our results and determine the implication of low T cell response on clinical protection of PC against COVID-19.

BNT162b2 mRNA COVID-19 vaccine Reactogenicity: The key role of immunity.

We examined the impact of pre-existing SARS-CoV-2-specific cellular immunity on BNT162b2 mRNA COVID-19 vaccine reactogenicity. Of 96 healthcare workers (HCWs), 76% reported any vaccine reaction (first dose: 70%, second dose: 67%), none of which was severe. Following first dose, systemic reactions were significantly more frequent among HCWs with past infection than in infection-naïve individuals, and among HCWs with pre-existing cellular immunity than in those without it. The rate of systemic reactions after second dose was 1.7 and 2.0-times higher than after first dose among infection-naïve HCWs and those without pre-existing cellular immunity, respectively. Levels of SARS-CoV-2-specific T-cells before vaccination were higher in HCWs with systemic reactions after the first dose than in those without them. BNT162b2 vaccine reactogenicity after first dose is attributable to pre-existing cellular immunity elicited by prior COVID-19 or cross-reactivity. Reactogenicity following second dose suggests an immunity-boosting effect. Overall, these data may reduce negative attitudes towards COVID-19 vaccines. Study Registration. The study was registered on clinicaltrials.gov, NCT04402827.

Expansion of CD56dimCD16neg NK Cell Subset and Increased Inhibitory KIRs in Hospitalized COVID-19 Patients.

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) infection induces elevated levels of inflammatory cytokines, which are mainly produced by the innate response to the virus. The role of NK cells, which are potent producers of IFN-γ and cytotoxicity, has not been sufficiently studied in the setting of SARS-CoV-2 infection. We confirmed a different distribution of NK cell subsets in hospitalized COVID-19 patients despite their NK cell deficiency. The impairment of this innate defense is mainly focused on the cytotoxic capacity of the CD56dim NK cells. On the one hand, we found an expansion of the CD56dimCD16neg NK subset, lower cytotoxic capacities, and high frequencies of inhibitory 2DL1 and 2DL1/S1 KIR receptors in COVID-19 patients. On the other hand, the depletion of CD56dimCD16dim/bright NK cell subsets, high cytotoxic capacities, and high frequencies of inhibitory 2DL1 KIR receptors were found in COVID-19 patients. In contrast, no differences in the distribution of CD56bright NK cell subsets were found in this study. These alterations in the distribution and phenotype of NK cells might enhance the impairment of this crucial innate line of defense during COVID-19 infection.

Cellular Responses to Membrane and Nucleocapsid Viral Proteins Are Also Boosted After SARS-CoV-2 Spike mRNA Vaccination in Individuals With Either Past Infection or Cross-Reactivity.

SARS-CoV-2 spike mRNA vaccines have shown remarkable clinical efficacy in the general population, although the nature of T-cell priming is not fully understood. We performed longitudinal spike-, membrane-, and nucleocapsid-specific T-cell analysis in individuals with past infection and infection-naïve individuals with cross-reactivity. We found an additional enhancement of T-cell response to the structural membrane (M) and nucleocapsid (N) SARS-CoV-2 proteins after mRNA vaccine in these individuals. Thus, despite the spike-specific response, we found that the first dose of the vaccine boosted a significant CD8 cell response to M and N proteins, whereas no cellular response to those proteins was found in infection-naïve individuals without pre-existing cross-reactivity who were tested for eventual asymptomatic infection. These findings highlight the additional benefit of mRNA vaccines as broad boosters of cellular responses to different viral epitopes in these individuals and suggest extended protection to other viral variants.

SARS CoV-2 infections in healthcare workers with a pre-existing T-cell response: a prospective cohort study.

OBJECTIVE: T-cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are observed in unexposed individuals. We evaluated the impact of this pre-existing cellular response on incident SARS-CoV-2 infections. METHODS: This was a follow-up study of 38 seronegative healthcare workers (HCWs) with previous evaluation of CD8+ and CD4+ T-cell responses after stimulation with SARS-CoV-2 structural proteins. Infection was considered in the presence of a positive RT-PCR test and/or confirmed seroconversion. RESULTS: Twenty of the 38 HCWs included (53%) had a previous specific CD8+ T-cell response to peptides encompassing the spike protein (S) in 13 (34%), the membrane (M) in 17 (45%), or/and the nucleocapsid (N) in three (8%). During a follow-up of 189 days (interquartile range (IQR) 172-195), 11 HCWs (29%) had an RT-PCR-positive test (n = 9) or seroconverted (n = 2). Median duration of symptoms was 2 days (IQR 0-7), and time to negative RT-PCR was 9 days (IQR 4-10). Notably, six incident infections (55%) occurred in HCWs with a pre-existing T-cell response (30% of those with a cellular response), who showed a significantly lower duration of symptoms (three were asymptomatic). Three of the six HCWs having a previous T-cell response continued to test seronegative. All the infected patients developed a robust T-cell response to different structural SARS-CoV-2 proteins, especially to protein S (91%). CONCLUSION: A pre-existing T-cell response does not seem to reduce incident SARS-CoV-2 infections, but it may contribute to asymptomatic or mild disease, rapid viral clearance and differences in seroconversion.

T-cell response after first dose of BNT162b2 SARS-CoV-2 vaccine among healthcare workers with previous infection or cross-reactive immunity.

OBJECTIVES: Antibody response to the first dose of BNT162b2 SARS-CoV-2 is greater in COVID-19-convalescent than in infection-naïve individuals. However, there are no data about T-cell response in individuals with pre-existing cellular immunity. METHODS: We evaluated T-cell responses in parallel with SARS-CoV-2 antibody level after first dose of BNT162b2 vaccine in 23 infection-naïve and 27 convalescent healthcare workers (HCWs) previously included in a study about humoral and T-cell immunity. RESULTS: Overall, the antibody response was lower in the infection-naïve group than in convalescent individuals (18 895 vs 662.7 AU mL-1, P < 0.001), and intermediate but significantly lower in convalescent HCWs with previous negative serology (25 174 vs 1793 AU mL-1; P = 0.015). Indeed, anti-spike IgG titres after the first dose correlated with baseline anti-nucleocapsid IgG titres (rho = 0.689; P < 0.001). Pre-existing T-cell immunity was observed in 78% of convalescent and 65% of the infection-naïve HCWs. T-cell response after the first dose of the vaccine was observed in nearly all the cases with pre-existing T-cell immunity, reaching 94% in convalescent HCWs and 93% in those with cross-reactive T cells. It was lower in the infection-naïve group (50%; P = 0.087) and in convalescent HCWs with negative serology (56%; P = 0.085). Notably, systemic reactogenicity after vaccination was mainly observed in those with pre-existing T-cell immunity (P = 0.051). CONCLUSION: Here, we report that the first dose of BTN162b2 elicits a similar S-specific T-cell response in cases of either past infection or cross-reactive T cells, but lower in the rest of infection-naïve individuals and in convalescent HCWs who have lost detectable specific antibodies during follow-up.

Papel protector de la bilirrubina en el ser humano / The protective role of bilirrubin in human begins

La bilirrubina no es simplemente el producto final del metabolismo del hem. En la actualidad, se considera que es una sustancia fundamental como antioxidante y antiinflamatoria del suero. Por su capacidad de neutralizar radicales libres evita la peroxidación de los lípidos y hay evidencia de que posee efectos protectores cardiovasculares, neuronales, hepatobiliares, pulmonares e inmunológicos. Recientemente se ha considerado que la utilización de agentes farmacológicos que aumenten la expresión de la hem oxidasa 1 (HO-1) y por ende de sus metabolitos como el monóxido de carbono (CO), la biliverdina (BV) y de la bilirrubina (BR) puede ser una estrategia terapéutica para diferentes enfermedades inflamatorias.

Bilirubin is more than just the final product of heme catabolism. Today it is considered to be a fundamental substance which acts as an antioxidant and anti-inflammatory agent in the serum. It can neutralize free radicals and prevent peroxidation of lipids. In addition there is evidence that it protects the cardiovascular system, neuronal systems, the hepatobiliary system, the pulmonary system and the immune system. Recently the use of pharmacological agents which augment expression of Heme oxygenase 1 (HO-1) has been considered. Consequently its metabolites such as carbon monoxide (CO), biliverdin (BV) and Bilirubin (BR) could become parts of a therapeutic strategy for treatment of various inflammatory illnesses.