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.

Executive summary of the consensus document on post-exposure prophylaxis against HIV, HBV and HCV in adults and children.

Post-exposure prophylaxis (PEP) can be a secondary measure to prevent infection by human immunodeficiency virus (HIV) when primary prevention has failed. PEP is advised for people with sporadic and exceptional risk exposure to HIV. This consensus document about occupational and non-occupational PEP recommendations aims to be a technical document for healthcare professionals. Its main objective is to facilitate the appropriate use of PEP. To this end, some recommendations have been established to assess the risk of transmission in different types of exposure, situations where PEP should be recommended, special circumstances to take into account, antiretroviral (ARV) guidelines including start and end of the treatment, early monitoring of tolerance and adherence to the treatment, subsequent monitoring of people exposed, independently of having received PEP or not, and need of psychological support. This document is intended for all professionals who work in clinical practice in the field of HIV infection.

Impact of Previous Common Human Coronavirus Exposure on SARS-CoV-2-Specific T-Cell and Memory B-Cell Response after mRNA-Based Vaccination.

OBJECTIVE: T-cell responses against SARS-CoV-2 are observed in unexposed individuals, attributed to previous common human coronavirus (HCoV) infections. We evaluated the evolution of this T-cell cross-reactive response and the specific memory B-cells (MBCs) after the SARS-CoV-2 mRNA-based vaccination and its impact on incident SARS-CoV-2 infections. METHODS: This was a longitudinal study of 149 healthcare workers (HCWs) that included 85 unexposed individuals that were subdivided according to previous T-cell cross-reactivity, who were compared to 64 convalescent HCWs. Changes in specific T-cell response and memory B-cell (MBC) levels were compared at baseline and after two doses of the SARS-CoV-2 mRNA-based vaccine. RESULTS: A cross-reactive T-cell response was found in 59% of unexposed individuals before vaccination. Antibodies against HKU1 positively correlated with OC43 and 229E antibodies. Spike-specific MBCs was scarce in unexposed HCWs regardless of the presence of baseline T-cell cross-reactivity. After vaccination, 92% and 96% of unexposed HCWs with cross-reactive T-cells had CD4+ and CD8+ T-cell responses to the spike protein, respectively. Similar results to that were found in convalescents (83% and 92%, respectively). Contrarily, higher than that which was observed in unexposed individuals without T-cell cross-reactivity showed lower CD4+ and CD8+ T-cell responses (73% in both cases, p = 0.03). Nevertheless, previous cross-reactive T-cell response was not associated with higher levels of MBCs after vaccination in unexposed HCWs. During a follow-up of 434 days (IQR, 339-495) after vaccination, 49 HCWs (33%) became infected, with a significant positive correlation between spike-specific MBC levels and isotypes IgG+ and IgA+ after vaccination and a longer time to get infected. Interestingly, T-cell cross-reactivity did not reduce the time to vaccine breakthrough infections. CONCLUSION: While pre-existing T-cell cross-reactivity enhances the T-cell response after vaccination, it does not increase SARS-CoV-2-specific MBC levels in the absence of previous infection. Overall, the level of specific MBCs determines the time to breakthrough infections, regardless of the presence of T-cell cross-reactivity.

mRNA-based SARS-CoV-2 Comirnaty vaccine elicits weak and short specific memory B cell response in individuals with no previous infection.

Objectives: The dynamics of the memory B cell (MBC) repertoire after SARS-CoV-2 vaccination is crucial for assessing long-term immunity. We compare spike-specific MBC responses between SARS-CoV-2 unexposed and recovered individuals, and their impact on breakthrough infections during follow-up. Methods: Spike-specific MBC and T cells were quantified at inclusion and after two doses of mRNA vaccine in a longitudinal cohort of 85 naïve and 64 recovered participants (47 with positive serology and 17 with negative serology after infection). Results: At inclusion, there was minimal spike-specific MBC in naïve SARS-CoV-2 individuals. After the second vaccine dose, MBCs were significantly boosted in naïve individuals, but reached a significantly lower level than that observed even in unvaccinated SARS-CoV-2 convalescents (p<0.001). Furthermore, while the secondary memory B cell (MBC) population consisted of 100%, 33%, and 76% IgG+, IgM+, and IgA+ expressing cells, respectively, in the unexposed group, the MBC response showed a significant decrease across all isotypes. Similarly, although secondary specific IgG+, IgM+, and IgA+-MBC isotypes were found in 100%, 39%, and 76% of the unexposed participants, respectively, the magnitude of the MBC levels was significantly lower for all the isotypes compared to convalescents. Interestingly, convalescents without an initial serological response had a lower MBC response, like what found in unexposed subjects. There was an inverse correlation between specific MBCs (r=-0.307; p=0.027), especially for isotype IgA+ (r=-0.279, p=0.045), and the time since the second vaccination dose. Furthermore, during a median follow-up of 434 days (IQR, 339-495), 49 out of 149 individuals (33%) became infected, 29 in naïve and 20 in convalescent individuals, showing a significant correlation between spike-specific MBC magnitude after vaccination and the time for SARS-CoV-2 infection, especially for IgA+/IgG+ MBC isotypes. Conclusions: MBCs were primed by mRNA-based vaccination in most cases, but SARS-CoV-2 naïve individuals had a blunted specific MBC response, and this was associated with a shorter time to breakthrough SARS-CoV-2 infection.

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.

Risk of SARS-CoV-2 Reinfections in a Prospective Inception Cohort Study: Impact of COVID-19 Vaccination.

The risk of reinfection could be related to the initial SARS-CoV-2 clinical presentation, but there are no data about the risk change after SARS-CoV-2 vaccination. We evaluated the rate of reinfection in an inception cohort study of 4943 health care workers (HCWs) according to symptoms and serologic results during March−May 2020. Incidence rates (IR) and IR ratios (IRR) before and after SARS-CoV-2 vaccination were determined by adjusting Poisson models. Overall, 1005 HCWs (20.3%) referred COVID-19 suggestive symptoms during the first surge of disease, and 33.5% and 55% presented a positive PCR or serology result, respectively. Meanwhile, 13% of asymptomatic HCWs had specific antibodies. During a follow up of 3422.2 person-years before vaccination, the rate of reinfection among seropositive individuals was 81% lower for those who were symptomatic compared with those who were asymptomatic (IRR of 0.19; 95% CI, 0.05−0.67; p = 0.003). During the 3100 person-years period after vaccination, an overall 74% decrease in the rate of infection was observed (IRR of 0.26; 95% CI, 0.21−0.32; p < 0.001), with a significant 83% and 70% decrease in seropositive and seronegative HCWs, respectively. In conclusion, the risk of SARS-CoV-2 reinfections is closely related to the clinical and serological presentation of COVID-19. COVID-19 vaccination further decreases the risk of reinfection more markedly among seropositive.

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.

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.

Vaccination adjuvated against hepatitis B in Spanish National Healthcare System (SNS) workers typed as non-responders to conventional vaccines.

TRIAL DESIGN: An interventional, phase 4, single group assignment, without masking (open label), preventive clinical trial was carried out in health workers with biological risk in their tasks, who have been filed as non-responders to conventional vaccination against Hepatitis B. METHODS: 67 health workers with biological risk in their tasks, who have been filed as non-responders to conventional vaccination against Hepatitis B, were enrolled in the Clinical Trial. All participants were from 18 years up to 64 years old. INCLUSION CRITERIA: NHS workers -including university students doing their internships in health centres dependent on the National Health System (inclusion of students is regulated and limited by specific instructions on labour prevention in each autonomous community)- classified as non-responders. The criteria defining them as non-responders to the conventional hepatitis B vaccine is anti HBsAb titers < 10 mUI/ml following the application of six doses of conventional vaccine at 20 µg doses (two complete guidelines). The objective of this study was to provide Health workers-staff with an additional protection tool against hepatitis B infection, and to evaluate the efficacy of the adjuvanted vaccine in healthy non-responders to conventional hepatitis B vaccine. The primary outcome was the measurement of antibody antiHBs before the first Fendrix® dose and a month after the administration of each dose. Other outcome was collection of adverse effects during administration and all those that could be related to the vaccine and that occur within 30 days after each dose. In this study, only one group was assigned. There was no randomization or masking. RESULTS: The participants were recruited between April 13, 2018 and October 31, 2019. 67 participants were enrolled in the Clinical Trial and included the analyses. The primary immunisation consists of 4 separate 0.5 ml doses of Fendrix®, administered at the following schedule: 1 month, 2 months and 6 months from the date of the first dose. Once the positivity was reached in any of the doses, the participant finished the study and was not given the following doses. 68.66% (46 out 67) had a positive response to first dose of Fendrix®. 57.14% (12 out 21) had a positive response to second dose of Fendrix®. 22.22% (2 out 9) had a positive response to third dose of Fendrix and 42.96% (3 out 7) had a positive response to last dose of Fendrix®. Overall, 94.02% (64 out 67) of participants had a positive response to Fendrix®. No serious adverse event occurred. CONCLUSIONS: The use of Fendrix®, is a viable vaccine alternative for NHS workers classified as "non-responders". Revaccination of healthy non-responders with Fendrix®, resulted in very high proportions of responders without adverse events. TRIAL REGISTRATION: The trial was registered in the Spanish National Trial Register (REEC), ClinicalTrials.gov and inclusion has been stopped (identifier NCT03410953; EudraCT-number 2016-004991-23). FUNDING: GRS 1360/A/16: Call for aid for the financing of research projects in biomedicine, health management and socio-health care to be developed in the centres of the Regional Health Management of Autonomous Community of Castile-Leon. In addition, this work has been supported by the Spanish Platform for Clinical Research and Clinical Trials, SCReN (Spanish Clinical Research Network), funded by the Subdirectorate General for Research Evaluation and Promotion of the Carlos III Health Institute (ISCIII), through the project PT13/0002/0039 and project PT17/0017/0023 integrated in the State Plan for R&D&I 2013-2016 and co-financed by and the European Regional Development Fund (ERDF).

Laboratory parameters provided by Advia 2120 analyser identify structural haemoglobinopathy carriers and discriminate between Hb S trait and Hb C trait.

BACKGROUND: Haemoglobinopathies have spread owing to human migration, and the number of people needing diagnosis and management of these conditions is increasing. Clinicians need to accurately identify carriers and provide adequate genetic counselling in order to prevent the occurrence of homozygous or compound heterozygous offspring. OBJECTIVES: To identify red blood cell (RBC) laboratory parameters that discriminate between structural haemoglobinopathy carriers and healthy subjects, and to compare RBC laboratory indices between HbAS and HbAC individuals. METHODS: Samples of 500 variant Hb carriers (355 HbAS, 104 HbAC, 19 HbAD, 7 HbAE, 7 HbAO-Arab, 4 α-chain variants and 4 Hb Lepore) and 251 normal controls were run on an Advia 2120 analyser (Siemens). Classic haematological parameters and RBC populations were assessed in all subjects. A multivariable binary logistic regression model was created to predict the probability of a subject carrying any structural haemoglobinopathy. HbAS (n=355, 71%) and HbAC (n=104, 20.8%) subjects were compared. RESULTS: A clinical prediction rule was developed by assigning one point to each of the most efficient variables: mean corpuscular volume (MCV) <88.4 fL, RBC distribution width >13.4%, percentage of microcytic RBCs (%MICRO) >0.7% and the ratio of microcytic RBCs to hypochromic RBCs >0.8. A score of 0, 1, 2, 3 or 4, resulted in a probability of 9.6%, 36.3%, 66.7%, 85.2% or 98.3%, respectively. Among the most frequent variant Hb, HbAC subjects had lower values of parameters related to cell size (MCV, %MICRO) and higher values of parameters related to haemoglobin concentration (MCHC, %HYPER) than HbAS subjects. Coexistence of α-thalassaemia in both HbAS and HbAC individuals resulted in decreased Hb, MCV, MCH and MCHC. CONCLUSIONS: Structural haemoglobinopathy should be investigated in subjects belonging to ethnic groups with high prevalence of variant Hb and with a score of 3 or 4. Erythrocytes of HbAC subjects are smaller and denser than those of HbAS subjects.