Fractional dosing can be a cost-effective vaccination strategy to accelerate individual and herd immunity in a pandemic. We assessed the immunogenicity and safety of primary intradermal (ID) vaccination, with a 1/5th dose compared with the standard intramuscular (IM) dose of mRNA-1273 in SARS-CoV-2 naïve persons. We conducted an open-label, non-inferiority, randomized controlled trial in the Netherlands between June and December 2021. One hundred and fifty healthy and SARS-CoV-2 naïve participants, aged 18–30 years, were randomized (1:1:1) to receive either two doses of 20 µg mRNA-1273 ID with a standard needle (SN) or the Bella-mu® needle (BM), or two doses of 100 µg IM, 28 days apart. The primary outcome was non-inferiority in seroconversion rates at day 43 (D43), defined as a neutralizing antibody concentration threshold of 465 IU/mL, the lowest response in the IM group. The non-inferiority margin was set at −15%. Neutralizing antibody concentrations at D43 were 1789 (95% CI: 1488–2150) in the IM and 1263 (951–1676) and 1295 (1020–1645) in the ID-SN and ID-BM groups, respectively. The absolute difference in seroconversion proportion between fractional and standard-dose groups was −13.95% (−24.31 to −3.60) for the ID-SN and −13.04% (−22.78 to −3.31) for the ID-BM group and exceeded the predefined non-inferiority margin. Although ID vaccination with 1/5th dose of mRNA-1273 did not meet the predefined non-inferior criteria, the neutralizing antibody concentrations in these groups are far above the proposed proxy for protection against severe disease (100 IU/mL), justifying this strategy in times of vaccine scarcity to accelerate mass protection against severe disease.

BK polyomavirus-associated nephropathy (BKPyVAN) is a well-known complication of kidney transplantation (KTx). The mainstay of prevention is the reduction of immunosuppression upon detection of BK polyomavirus (BKPyV) DNAemia, which precedes BKPyVAN. However, this reduction may inadvertently increase the risk of alloimmunity particularly in patients with a high BKPyV DNA load, where significant immunosuppression reduction is often necessary. This single-center, retrospective cohort study assesses the risk of de novo donor-specific antibodies (dnDSA) development and biopsy-proven acute rejection (BPAR) following high and low BKPyV DNAemia. All patients who underwent KTx at Leiden University Medical Center between 2011 and 2020 were included. Patients were grouped according to high (maximum BKPyV DNA load > 4log10 copies/mL), low (maximum serum BKPyV DNA load ≤ 10E4 copies/mL), and absent BKPyV DNAemia, and analyzed for the development of dnDSA and BPAR, using Cox regression. Of 1076 KTx recipients included, 108 (10%) developed a BKPyV DNAemia with a maximum DNA load below 4log10 copies/mL, whereas 121 (11.2%) developed a BKPyV DNAemia exceeding 4log10 copies/mL. The risk of dnDSA development was higher in patients with a high BKPyV DNAemia, compared to patients without DNAemia (adjusted hazard ratio of 1.9 (95% CI 1.1-3.2, p = 0.017). No significant difference in dnDSA risk was observed between patients with low and absent BKPyV DNAemia. Risk of BPAR did not differ between groups. Our study shows that higher BKPyV DNA loads in KTx patients are associated with a higher risk for dnDSA development, highlighting the importance of exploring additional strategies for the prevention and treatment of BKPyV infections in KTx recipients.

Torque Teno Virus (TTV) is a non-pathogenic anellovirus, highly prevalent in healthy populations. Variations in its viral load have been associated with states of diminished immunity, as occurs after organ transplantation. It is hypothesized that TTV-load might be used as a diagnostic tool to guide prescription and dosing of immunosuppressive drugs. Not much is known about the effects of combined immunosuppressive drugs on TTV replication in renal transplantation. Belatacept was introduced to counter side-effects of calcineurin inhibitors (CNI). It was never widely adopted, mainly because its association with increased risk of rejection. To investigate the differential effects of a regimen based on calcineurin inhibitors versus belatacept on TTV-loads, we measured TTV-levels in 105 patients from two randomized controlled trials in kidney transplant recipients (KTRs). We observed that time after transplantation was inversely related to TTV-levels of patients that remained on a CNI-containing regime, whereas this decline over time was diminished after conversion to belatacept. In addition, a correlation with tacrolimus-trough levels and age were found. Our study is the first report on the impact of conversion from CNI to belatacept on TTV-levels in KTR. In conclusion, the time-related decline in TTV-levels is mitigated after conversion from CNI to belatacept.

Objectives: The aim of this study was to assess the safety and immunogenicity of a dose -sparing fractional intradermal (ID) booster strategy with the mRNA-1273 COVID-19 vaccine. Methods: COVID-19 naive adults aged 18-30 years were recruited from a previous study on primary vaccination regimens that compared 20 mu g ID vaccinations with 100 mu g intramuscular (IM) vaccinations with mRNA-1273 as the primary vaccination series. Participants previously immunized with ID regimens were randomly assigned (1:1) to receive a fractional ID booster dose (20 mu g) or the standard-of-care intramuscular (IM) booster dose (50 mu g) of the mRNA-1273 vaccine, 6 months after completing their primary series (ID -ID and ID-IM group, respectively). Participants that had received a full dose IM regimen as the primary series, received the IM standard-of-care booster dose (IM-IM group). In addition, COVID-19 naive individuals aged 18-40 years who had received an IM mRNA vaccine as the primary series were recruited from the general population to receive a fractional ID booster dose (IM-ID group). Immunogenicity was assessed using IgG anti -spike antibody responses and neutralizing capacity against SARS-CoV-2. Cellular immune responses were measured in a sub-group. Safety and tolerability were monitored. Results: In January 2022,129 participants were included in the study. Fractional ID boosting was safe and well tolerated, with fewer systemic adverse events compared with IM boosting. At day 28 post -booster, anti -spike S1 IgG geometric mean concentrations were 9106 (95% CI, 7150-11 597) binding antibody units (BAU)/mL in the IM-IM group and 4357 (3003-6322) BAU/mL; 6629 (4913-8946) BAU/mL; and 5264 (4032-6873) BAU/mL in the ID-IM, ID -ID, and IM-ID groups, respectively. Discussion: Intradermal boosting provides robust immune responses and is a viable dose -sparing strategy for mRNA COVID-19 vaccines. The favourable side-effect pro file supports its potential to reduce vaccine hesitancy. Fractional dosing strategies should be considered early in the clinical development of future mRNA vaccines to enhance vaccine availability and pandemic preparedness. Geert V.T. Roozen, dlin Microbiol Infect 2024;30:930 (c) 2024 The Authors. Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).

Abstract The recommended immunosuppressive treatment after kidney transplantation consists of tacrolimus, mycophenolate mofetil, and low‐dose corticosteroids. Drug concentrations are monitored using therapeutic drug monitoring (TDM), which does not necessarily correlate with pharmacodynamic activity. To find the balance between optimal efficacy and minimal toxicity, it might be more informative to monitor patients' immunological status rather than drug concentrations. We selected a panel of T‐cell‐based immune assays, which were used for immunomonitoring of 14 stable kidney transplantation patients. Whole blood was incubated with a T‐cell stimulus, after which T‐cell proliferation, T‐cell activation marker expression and cytokine production were measured to study residual immune activity in vitro (before drug intake; drug added to the incubation) and ex vivo (after drug intake). T‐cell proliferation was completely suppressed in all patients over the full day, while IL‐2, IFN‐γ, CD71, and CD154 showed fluctuations over the day with a strong inhibition (75%–25%) at 2 h post‐dose. The level of inhibition was variable between patients and could not be related to pharmacokinetic parameters or the presence of regulatory or senescence immune cells. Moreover, the level of inhibition did not correlate with the in vitro tacrolimus drug effect as studied by incubating pre‐dose blood samples with additional tacrolimus. Overall, IL‐2, IFN‐γ, CD71, and CD154 seem to be good markers to monitor residual immune activity of transplantation patients. To evaluate the correlation between these pharmacodynamic biomarkers and clinical outcome, prospective observational studies are needed.

Balancing immunosuppression to prevent rejection in solid organ transplant (SOT) recipients remains challenging. Torque teno virus (TTV), a commensal non‐pathogenic virus, has been proposed as marker of functional immunity: higher loads correspond to over‐immunosuppression, and lower loads to under‐immunosuppression. This review offers an overview of the current evidence of the association between TTV‐load and infection and rejection after SOT. A systematic literature search strategy, deposited in the PROSPERO registry, resulted in 548 records. After screening, 23 original and peer‐reviewed articles were assessed investigating the association between TTV‐load, infection and/or rejection in SOT. The Quality in Prognostic Studies (QUIPS)‐tool was used to assess the risk of bias. Meta‐analysis with random‐effects was performed on results with similar outcomes and exposure measures. Most of the included studies involved retrospective cohorts in which the TTV‐load was measured longitudinally, within the first 2 years post‐transplantation. Infection outcomes differed between studies and included viral, bacterial, parasitic and fungal infections. Rejection was defined by biopsy confirmation or initiation of rejection treatment. Twelve out of 16 studies reported an association between high TTV‐load and infections, whereas 13 out of 15 reported an association between low TTV‐load and rejection. Meta‐analysis showed an increased risk of infection (OR: 1.16, 95% CI: 1.03–1.32; HR: 1.05, 95% CI: 0.97–1.14) and a decreased risk of rejection (OR: 0.90, 95% CI: 0.87–0.94; HR: 0.74, 95% CI: 0.71–0.76) per 1 log TTV‐load increase. The qualitative assessment showed varying risks of bias in the included studies. This systematic review and meta‐analysis indicates that blood TTV‐load measured within the first 2 years after SOT is associated with the risk of infection or allograft rejection, although substantial risk of bias in the studies included warrant cautious interpretation. The results in this review provide a rationale for larger, prospective, studies into TTV as marker of infection and rejection after SOT.

PDF file - 45K, Associations between cumulative HPV load and SCC, stratified by skin type and time since transplantation (for OTR). In each case the reference category is HPV negative combined with the lowest load tertile.

Introduction: Immunocompromised kidney patients are at increased risk of prolonged SARS-CoV-2 infection and related complications. Preclinical evidence demonstrates a more potent inhibitory effect of voclosporin on SARS-CoV-2 replication than tacrolimus in vitro. We investigated the potential antiviral effects of voclosporin on SARS-CoV-2 in immunocompromised patients.Methods: First, we conducted a prospective, randomized, open-label, proof-of-concept study in 20 kidney transplant recipients (KTRs) on tacrolimus-based immunosuppression who contracted mild to moderate SARS-CoV-2 infection. Patients were randomized to continue tacrolimus or switch to voclosporin. Second, we performed a post hoc analysis on SARS-CoV-2 infections in 216 patients with lupus nephritis (LN) on standard immunosuppression who were randomly exposed to voclosporin or placebo as part of a clinical trial that was conducted during the worldwide COVID-19 pandemic. Results: The primary end point was clearance of SARS-CoV-2 viral load and that did not differ between voclosporin-treated KTRs (median 12 days, interquartile range [IQR] 8-28) and tacrolimus-treated KTRs (median 12 days, IQR 4-16) nor was there a difference in clinical recovery. Pharmacokinetic analyses demonstrated that, when voclosporin trough levels were on-target, SARS-CoV-2 viral load dropped significantly more (DCt 7.7 [3.4-10.7]) compared to tacrolimus-treated KTRs (DCt 2.7 [2.0-4.3]; P 1/4 0.035). In voclosporin-exposed patients with LN, SARS-CoV-2 infection was detected in 6% (7/116) compared to 12% (12/100) in placebo-exposed patients (relative risk [RR] 1.4 [0.97-2.06]). Notably, no voclosporin-exposed patients with LN died from severe SARS-CoV-2 infection compared to 3% (3/100) in placebo-exposed patients (RR 2.2 [1.90-2.54]).Conclusion: This proof-of-concept study shows a potential positive risk-benefit profile for voclosporin in immunocompromised patients with SARS-CoV-2 infection. These results warrant further investigations on voclosporin to establish an equipoise between infection and maintenance immunosuppression.

The number of identified human polyomaviruses (HPyVs) has increased steadily over the last decade. Some of the novel HPyVs have been shown to cause disease in immunocompromised individuals. The Lyon-IARC polyomavirus (LIPyV) belonging to species Alphapolyomavirus quardecihominis was identified in 2017 in skin and saliva samples from healthy individuals. Since its initial discovery, LIPyV has rarely been detected in human clinical samples but has been detected in faeces from cats with diarrhoea. Serological studies show low LIPyV seroprevalence in human populations. To investigate the possibility that LIPyV is a feline rather than a human polyomavirus, we compared serum IgG responses against the VP1 major capsid protein of LIPyV and 13 other HPyVs among cats (n = 40), dogs (n = 38) and humans (n = 87) using an in-house immunoassay. Seropositivity among cats was very high (92.5%) compared to dogs (31.6%) and humans (2.3%). Furthermore, the median antibody titres against LIPyV were 100–10,000x higher in cats compared to dogs and humans. In conclusion, the high prevalence and intensity of measured seroresponses suggest LIPyV to be a feline rather than a human polyomavirus. Whether LIPyV infection induces diarrhoea or other symptoms in cats remains to be established.

Supplementary Figure Legend from Persistence of Betapapillomavirus Infections as a Risk Factor for Actinic Keratoses, Precursor to Cutaneous Squamous Cell Carcinoma

Introduction: Rapid antigen detection tests (RDT) are suitable for large-scale testing for SARS-CoV-2 among the population and recent studies have shown that self-testing with RDT in the general population is feasible and yields acceptable sensitivities with high specificity. We aimed to determine the accuracy of two different RDT, with two different sample collection methods for one of the RDT among healthcare workers (HCW). Secondary objectives were to determine the accuracy of RDT using a viral load cut-off as proxy of infectiousness and to identify predictors for a false negative RDT. Methods: Centers that participated were secondary care hospitals, academic teaching hospitals, and long-term care facilities. All HCW that met inclusion criteria were asked to perform a RDT self-test next to a regular SARS-CoV-2 nucleic acid amplification test (NAAT). Three study groups were created. Study group 1; Veritor System, Becton Dickinson, Franklin Lakes, USA (BD-RDT) with combined oropharyngeal - mid-turbinate nasal sampling, group 2; BD-RDT with mid-turbinate nasal sampling only and group 3; SD Biosensor SARS-CoV-2 Rapid Antigen Test, Roche, Basel, Switzerland (Roche-RDT) with combined oropharyngeal - mid-turbinate nasal sampling. RDT accuracy was calculated using NAAT as reference standard. For samples processed in the cobas(R) 6800/8800 platform (Roche Diagnostics, Basel, Switzerland), established cycle threshold values (Ct-values) could be converted into viral loads. A viral load cut-off of [≥]5.2 log10 SARS-CoV-2 E gene copies/ml was used as proxy of infectiousness. Logistic regression analysis was performed to identify predictors for a false negative RDT. Results: In total, 7,196 HCW were included. Calculated sensitivities were 61.5% (95%CI 56.6%-66.3%), 50.3% (95%CI 42.8%-57.7%) and 74.2% (95%CI 66.4%-80.9%) for study groups 1, 2 and 3, respectively. After application of a viral load cut-off as a proxy for infectiousness for samples processed in the cobas(R) 6800/8800 platform sensitivities increased to 82.2% (95%CI 76.6-86.9%), 61.9% (95%CI 48.8%-73.9%) and 90.2% (95%CI 76.9%-97.3%) for group 1, group 2 and group 3, respectively. Multivariable regression analysis showed that use of Roche-RDT (p <0.01), combined oropharyngeal - mid-turbinate nasal sampling (p <0.05) and the presence of COVID-19 like symptoms at the time of testing (p <0.01) significantly reduced the likeliness of a false-negative RDT result. Conclusion: SARS-CoV-2 RDT has proven able to identify infectious individuals, especially when upper respiratory specimen is collected through combined oropharyngeal - mid-turbinate sampling. Reliability of self-testing with RDT among HCW seems to depend on the type of RDT, the sampling method and the presence of COVID-19 like symptoms at the time of testing.

Background: Balancing immunosuppression to prevent rejection and infection in solid organ transplant recipients (SOTx) remains a challenge. Torque teno virus (TTV), a commensal non-pathogenic virus, has been proposed as functional marker of immunity: higher loads reflect over-immunosuppression, while lower loads reflect under-immunosuppression. Here we present a systematic review and meta-analysis of the current literature and provide evidence on the association between TTV load and infection and rejection in SOTx recipients. Methods: A systematic literature search strategy, deposited in PROSPERO, resulted in 548 records. After screening, 23 original and peer-reviewed articles were included in qualitative assessment, investigating the association between TTV load, and either infection or rejection in SOTx. The Quality in Prognosis Studies (QUIPS) tool was used to assess the risk of bias. Meta-analysis was performed on studies with similar outcomes measures and exposure using a joint modelling strategy. Results: 23 studies were included, most involved retrospective cohorts in which the TTV load was measured within 1-2 years post-transplantation, once or longitudinally. Defined outcomes differed between studies, and included viral (CMV, BK, respiratory), bacterial, and fungal infections. Rejection outcomes included rejection treatment, with or without biopsy confirmation. QUIPS assessment showed varying risks of bias between studies. Twelve out of 17 studies reported an association between high TTV loads and infection (71%), and 13 out of 15 an inverse association between low TTV loads and rejection (87%). Meta-analysis showed an increased risk of infection (OR: 1.16, CI 1.04-1.30; HR: 1.05, CI 0.97-1.14) and decreased risk of rejection (OR: 0.90, CI 0.87-0.94, HR: 0.74, CI 0.71-0.76) per 1 log TTV load increase. Conclusions: Systematic review of the current literature shows an association between TTV load and each outcome in most studies, and this association is supported by our meta-analysis. However, concerns on study quality and the risk of publication bias warrants careful interpretation. Externally validated prediction models using TTV load remain to be built, as these will offer individualized diagnostic or prognostic value to predict infection and rejection in SOTx recipients.

Arends, Eline J.; Meziyerh, Soufian; Moes, Dirk jan; Kamerling, Sylvia; Van der kooij, Sandra W.; Ogando, Natacha S.; Snijder, Eric J.; Van Hemert, Martijn J.; Visser, Leo G.; Feltkamp, Mariet; Rabelink, Ton J.; van Kooten, Cees; De Vries, Aiko P.; Teng, Yoe Kie Onno; on behalf of all the VOCOVID investigators Author Information

OBJECTIVE:Immunosuppressive agents are known to interfere with T and/or B lymphocytes, which are required to mount an adequate serologic response. Therefore, we aim to investigate the antibody response to SARS-CoV-2 in liver transplant (LT) recipients after COVID-19. DESIGN:Prospective multicentre case-control study, analysing antibodies against the nucleocapsid protein, spike (S) protein of SARS-CoV-2 and their neutralising activity in LT recipients with confirmed SARS-CoV-2 infection (COVID-19-LT) compared with immunocompetent patients (COVID-19-immunocompetent) and LT recipients without COVID-19 symptoms (non-COVID-19-LT). RESULTS:Overall, 35 LT recipients were included in the COVID-19-LT cohort. 35 and 70 subjects fulfilling the matching criteria were assigned to the COVID-19-immunocompetent and non-COVID-19-LT cohorts, respectively. We showed that LT recipients, despite immunosuppression and less symptoms, mounted a detectable antinucleocapsid antibody titre in 80% of the cases, although significantly lower compared with the COVID-19-immunocompetent cohort (3.73 vs 7.36 index level, p<0.001). When analysing anti-S antibody response, no difference in positivity rate was found between the COVID-19-LT and COVID-19-immunocompetent cohorts (97.1% vs 100%, p=0.314). Functional antibody testing showed neutralising activity in 82.9% of LT recipients (vs 100% in COVID-19-immunocompetent cohort, p=0.024). CONCLUSIONS:Our findings suggest that the humoral response of LT recipients is only slightly lower than expected, compared with COVID-19 immunocompetent controls. Testing for anti-S antibodies alone can lead to an overestimation of the neutralising ability in LT recipients. Altogether, routine antibody testing against separate SARS-CoV-2 antigens and functional testing show that the far majority of LT patients are capable of mounting an adequate antibody response with neutralising ability.

Introduction: There is scant evidence to what extent maintenance immunosuppression is quantitatively associated with BK viremia. We investigated the association between tacrolimus (tac) whole blood exposure and mycophenolic acid (mpa) plasma exposure with consecutive BK viremia within the first year posttransplant. Methods: For this retrospective cohort study, 713 kidney transplant recipients (KTRs) transplanted at our center between 2013-2018 and treated with Tac, mpa and prednisolone, were selected from the local database. Both trough levels (C0) and area-under-the-curve (AUC) measurements of tac and BK viral loads were determined according to local protocol. Exposure measurements were carried backwards to assess exposure on landmarks: month 1.5, 3 and 6. Patients with no measurements of tac or mpa exposure within the first year due to switches were excluded, leaving 508 patients for analysis. Incidence and time to BK viremia (with load > limit of detection (LOD) and load > log 4) in the first year posttransplant were outcomes of interest. Hazard ratios (HR) of exposure to tac and mpa were assessed and adjusted for confounders such as donor and recipient age and gender, number of human leukocyte antigen (HLA) mismatch, days on dialysis, induction therapy, and living or deceased donation. Results: In total, 83 out of 508 (16%) KTRs developed a BK viremia (>LOD) in their first year post-transplant. Tac exposure (both C0 and AUC) on day 45 was significantly associated with subsequent development of BK viremia (load > LOD & load >log 4) with respectively unadjusted and adjusted HRs of 1.08 (95% CI: 1.02-1.14) and 1.08 (95% CI: 1.01-1.15) for 1 μg/L increase in C0 and 20 μg*h/L increase in AUC0-12h. Exposure of tac on day 90 or 120 was not associated with incident BK viremia. No association between exposure to mpa and BK-viremia was identified. Moreover, HR for tac remained unchanged if adjusted for mpa exposure and other transplant characteristics. Conclusion: In our population, tac exposure on month 1.5 seems associated with incident BK viremia in a concentration-dependent manner. This was not found for mpa. The explanation for this finding could be that tacrolimus is a more potent suppressor of Th-lymphocytes which play a vital role in boosting viral immunity and memory. To the best of our knowledge, this is the first time that exposure to immunosuppressive drugs has been quantitatively associated with BK viremia. Future research is warranted to investigate causative and predictive impact of tac exposure on BK-incidence, which may aid physicians balance between toxicity and efficacy within the first year of transplantation.

Background Common and plantar warts are caused by human papillomaviruses (HPV). Mode of transmission of wart HPVs within families is largely unknown. Objective To demonstrate similarity of HPV type(s) among wart cases, family members and household linen. Methods In a cross-sectional study, swabs taken from 123 warts and foreheads of 62 index patients and 157 family members and from 58 kitchen towels and 59 bathroom mats were tested for DNA of 23 cutaneous wart-associated HPV types. Generalized estimating equations (GEE) were used to estimate the chance of detecting the same HPV type as was found in the index patients on the family contacts and on the kitchen towels and bathroom mats. Results HPV1, HPV2, HPV27 and HPV57 were the most prevalent types in the warts of the index patients. Altogether, 60 (42.3%) of the 142 family members without warts had HPV DNA on their foreheads. When HPV1 and HPV2 were found in the warts, these types were also frequently (>50%) found on the foreheads of index patients and their family members, as well as on the kitchen towels and the bathroom mats. HPV27 and HPV57 were less frequently found (<25%) on foreheads and linen. No associations were found for age, sex and site of HPV DNA presence. Conclusion Dissemination of skin wart-causing HPV types, from wart cases to household contacts and linen, such as kitchen towels and bathroom mats, is more likely for HPV1 and HPV2 than for HPV27 and HPV57. The role of towels and bathroom mats in HPV transmission deserves further investigation.

Trichodysplasia spinulosa (TS) is a rare hair follicle disorder that develops in immunosuppressed patients and is associated with productive infection by the TSPyV polyomavirus. Affected follicles contain an attenuated hair matrix, expanded compartment of aberrantly proliferating inner root sheath (IRS)-like cells containing viral particles, and a disorganized mass of hair shaft-like cells. The expression of viral early region (ER) genes encoding T antigens (TAgs) that drive cellular proliferation and viral genome replication is tightly restricted to hair follicle matrix cells and IRS-like cells. To probe the potential impact of TAg expression on other aspects of epithelial biology, we generated bitransgenic iK5;TSER mice harboring Cre-inducible TSPyV ER genes that could be activated in K5-expressing cells and their progeny using tamoxifen. As we previously described, expression of TSPyV TAgs in skin of adult mice led to development of numerous dysmorphic hair follicles. Additionally, interfollicular tail epidermis was hyperplastic and contained small collections of TAg+ cells, some of which were multinucleated, with a clear cytoplasm. Many of these cells were proliferating (Ki67+) and strikingly deficient in epidermal keratins (K5, K14, K1, K10). Remarkably, a subset of these aberrant interfollicular cells ectopically expressed the IRS marker trichohyalin and hair-specific keratin. Our findings suggest that in addition to the primary function of ER genes in driving cell cycle progression needed for viral genome replication, TAgs may also contribute to human pathology by modulating the differentiation status of target cells.

Virus-specific cellular and humoral responses are major determinants for protection from critical illness after SARS-CoV-2 infection. However, the magnitude of the contribution of each of the components to viral clearance remains unclear. Here, we studied the timing of viral clearance in relation to 122 immune parameters in 102 hospitalised patients with moderate and severe COVID-19 in a longitudinal design. Delayed viral clearance was associated with more severe disease and was associated with higher levels of SARS-CoV-2-specific (neutralising) antibodies over time, increased numbers of neutrophils, monocytes, basophils, and a range of pro-inflammatory cyto-/chemokines illustrating ongoing, partially Th2 dominating, immune activation. In contrast, early viral clearance and less critical illness correlated with the peak of neutralising antibodies, higher levels of CD4 T cells, and in particular naïve CD4+ T cells, suggesting their role in early control of SARS-CoV-2 possibly by proving appropriate B cell help. Higher counts of naïve CD4+ T cells also correlated with lower levels of MIF, IL-9, and TNF-beta, suggesting an indirect role in averting prolonged virus-induced tissue damage. Collectively, our data show that naïve CD4+ T cell play a critical role in rapid viral T cell control, obviating aberrant antibody and cytokine profiles and disease deterioration. These data may help in guiding risk stratification for severe COVID-19.