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Currently approved viral vector-based and mRNA-based vaccine approaches against coronavirus disease 2019 (COVID-19) consider only homologous prime-boost vaccination. After reports of thromboembolic events, several European governments recommended using AstraZeneca’s ChAdOx1-nCov-19 (ChAd) only in individuals older than 60 years, leaving millions of already ChAd-primed individuals with the decision to receive either a second shot of ChAd or a heterologous boost with mRNA-based vaccines. However, such combinations have not been tested so far. We used Hannover Medical School’s COVID-19 Contact Study cohort of healthcare professionals to monitor ChAd-primed immune responses before and 3 weeks after booster with ChAd (n = 32) or BioNTech/Pfizer’s BNT162b2 (n = 55). Although both vaccines boosted prime-induced immunity, BNT162b2 induced significantly higher frequencies of spike-specific CD4+ and CD8+ T cells and, in particular, high titers of neutralizing antibodies against the B.1.1.7, B.1.351 and P.1 variants of concern of severe acute respiratory syndrome coronavirus 2.

Highlights d high SARS-CoV-2 IgG but overall reduced T cell immunity in active COVID-19 patients d PD-1, Tim-3, and active caspases in T cells result in impaired T cell function d stable SARS-CoV-2 T cell repertoire yet declining humoral responses during recovery d potentially protective role of pre-existing anti-huCoV CD4 + and CD8 + T cell immunity

The emergence of SARS-CoV-2 variants threatens efforts to contain the COVID-19 pandemic. The number of COVID-19 cases and deaths in India has risen steeply and a SARS-CoV-2 variant, B.1.617, is believed to be responsible for many of these cases. The spike protein of B.1.617 harbors two mutations in the receptor binding domain, which interacts with the ACE2 receptor and constitutes the main target of neutralizing antibodies. Therefore, we analyze whether B.1.617 is more adept in entering cells and/or evades antibody responses. B.1.617 enters two out of eight cell lines tested with roughly 50% increased efficiency and is equally inhibited by two entry inhibitors. In contrast, B.1.617 is resistant against Bamlanivimab, an antibody used for COVID-19 treatment. B.1.617 evades antibodies induced by infection or vaccination, although less so than the B.1.351 variant. Collectively, our study reveals that antibody evasion of B.1.617 may contribute to the rapid spread of this variant.

Histone deacetylase (HDAC)-inhibitors (HDACis) are well characterized anti-cancer agents with promising results in clinical trials. However, mechanistically little is known regarding their selectivity in killing malignant cells while sparing normal cells. Gene expression-based chemical genomics identified HDACis as being particularly potent against Down syndrome associated myeloid leukemia (DS-AMKL) blasts. Investigating the anti-leukemic function of HDACis revealed their transcriptional and posttranslational regulation of key autophagic proteins, including ATG7. This leads to suppression of autophagy, a lysosomal degradation process that can protect cells against damaged or unnecessary organelles and protein aggregates. DS-AMKL cells exhibit low baseline autophagy due to mTOR activation. Consequently, HDAC inhibition repressed autophagy below a critical threshold, which resulted in accumulation of mitochondria, production of reactive oxygen species, DNA-damage and apoptosis. Those HDACi-mediated effects could be reverted upon autophagy activation or aggravated upon further pharmacological or genetic inhibition. Our findings were further extended to other major acute myeloid leukemia subgroups with low basal level autophagy. The constitutive suppression of autophagy due to mTOR activation represents an inherent difference between cancer and normal cells. Thus, via autophagy suppression, HDACis deprive cells of an essential pro-survival mechanism, which translates into an attractive strategy to specifically target cancer cells.

There have been concerns about high rates of thus far undiagnosed SARS-CoV-2 infections in the health-care system. The COVID-19 Contact (CoCo) Study follows 217 frontline health-care professionals at a university hospital with weekly SARS-CoV-2-specific serology (IgA/IgG). Study participants estimated their personal likelihood of having had a SARS-CoV-2 infection with a mean of 21% [median 15%, interquartile range (IQR) 5-30%]. In contrast, anti-SARS-CoV-2 IgG prevalence was about 1-2% at baseline. Regular anti-SARS-CoV-2 IgG testing of health-care professionals may aid in directing resources for protective measures and care of COVID-19 patients in the long run. Keywords COVID-19 • SARS-CoV-2 • Immunoglobulin • IgG • IgA • Health-care worker • ELISA • Seroprevalence • Diagnostics • Health-care professionals Abbreviations COVID-19 Coronavirus disease 19 ELISA Enzyme-linked immunosorbent assay IgG Immunoglobulin G PCR Real-time polymerase chain reaction SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 Despite growing access of broadly available testing systems, uncertain rates of asymptomatic infections have raised concerns about a potentially high rate of thus far undiagnosed SARS-CoV-2 infections, particularly in frontline medical staff [1]. To prevent the breakdown of health-care systems during the current pandemic, the protection of medical personnel and patients from contracting a SARS-CoV-2 infection is central [2]. Consent finding for case definition, COVID-19 diagnosis in suspected cases, and scaling up of suitable diagnostic systems have been challenging since the start of the pandemic. Real-time polymerase chain reaction (PCR)-based nasopharyngeal (or throat) swab testing was rapidly developed and has helped in ascertainment and tracking of the SARS-CoV-2 outbreak [2]. However, the sensitivity of PCR-based testing, which is thus far only applied routinely for symptomatic patients, crucially depends on the timing and type of respiratory sampling and led to false negative rates of up to 70% during the early phase of the pandemic [3, 4]. Serological testing for SARS-CoV-2-specific immunoglobulins (Ig) is relatively easy, inexpensive, and critical for epidemiological studies. SARS-CoV-2-specific B cell responses appear to correlate to disease severity with rising antibody titers typically between 5 to 10 days and fully positive rates at about 18 days after symptom onset [5]. As such, serological testing can be helpful in suspected cases with negative PCR results and in identification of asymptomatic infections [6]. We initiated the COVID-19 Contact (CoCo) study to weekly monitor SARS-CoV-2-specific serology (IgA/IgG) Christine Happle and Alexandra Jablonka contributed equally to this work.

SUMMARYThe emergence of SARS-CoV-2 variants threatens efforts to contain the COVID-19 pandemic. The number of COVID-19 cases and deaths in India has risen steeply in recent weeks and a novel SARS-CoV-2 variant, B.1.617, is believed to be responsible for many of these cases. The spike protein of B.1.617 harbors two mutations in the receptor binding domain, which interacts with the ACE2 receptor and constitutes the main target of neutralizing antibodies. Therefore, we analyzed whether B.1.617 is more adept in entering cells and/or evades antibody responses. B.1.617 entered two out of eight cell lines tested with slightly increased efficiency and was blocked by entry inhibitors. In contrast, B.1.617 was resistant against Bamlanivimab, an antibody used for COVID-19 treatment. Finally, B.1.617 evaded antibodies induced by infection or vaccination, although with moderate efficiency. Collectively, our study reveals that antibody evasion of B.1.617 may contribute to the rapid spread of this variant.

Objectives People living with HIV (PLWH) with low CD4 T‐cell counts may be at a higher risk for severe coronavirus disease 2019 (COVID‐19) outcomes and in need of efficient vaccination. The World Health Organization (WHO) now recommends prioritizing PLHIV for COVID‐19 vaccination. Data on immune responses after messenger RNA (mRNA) vaccination in PLHIV in relation to CD4 counts are scarce. We aimed at assessing the humoral immune response in PLHIV after mRNA vaccination against COVID‐19. Methods We examined a cohort of PLHIV after prime ( n = 88) and boost ( n = 52) vaccination with BNT162b2. We assessed levels of anti‐severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike (S) protein‐specific immunoglobulin G (IgG)/IgA and circulating neutralizing antibodies in plasma and correlated results to the cellular immune status. BNT162b2‐vaccinated health care workers served as controls. Results All PLWH had a viral load of ≤ 200 HIV‐1 RNA copies/mL and 96.5% had a viral load of < 50 copies/mL. Anti‐S IgG and neutralizing antibody responses after BNT162b2 priming were significantly lower in PLHIV having a CD4:CD8 T‐cell ratio of < 0.5. However, we observed robust humoral immunity in the majority of PLWH receiving antiretroviral therapy (ART) irrespective of CD4 T‐cell nadir, current CD4 count or CD4:CD8 ratio after full BNT162b2 vaccination. Nevertheless, HIV‐negative controls produced significantly higher mean anti‐S IgG concentrations with less variability. Conclusions The majority of PLWH mounted robust responses after complete BNT162b2 vaccination but overall amounts of antibodies directed against the SARS‐CoV‐2 receptor‐binding domain were variable. The impact on clinical efficacy remains unclear.