Quincy Hofsink et al
Fourth mRNA COVID-19 vaccination in immunocompromised patients with haematological malignancies (COBRA KAI): a cohort study
The Lancet, June 2023 ; doi.org/10.1016/j.eclinm.2023.102040
Abstract
Patients with haematological malignancies have impaired antibody responses to SARS-CoV-2 vaccination. We aimed to investigate whether a fourth mRNA COVID-19 vaccination improved antibody quantity and quality.
Methods
In this cohort study, conducted at 5 sites in the Netherlands, we compared antibody concentrations 28 days after 4 mRNA vaccinations (3-dose primary series plus 1 booster vaccination) in SARS-CoV-2 naive, immunocompromised patients with haematological malignancies to those obtained by age-matched, healthy individuals who had received the standard primary 2-dose mRNA vaccination schedule followed by a first booster mRNA vaccination. Prior to and 4 weeks after each vaccination, peripheral blood samples and data on demographic parameters and medical history were collected. Concentrations of antibodies that bind spike 1 (S1) and nucleocapsid (N) protein of SARS-CoV-2 were quantified in binding antibody units (BAU) per mL according to the WHO International Standard for COVID-19 serological tests. Seroconversion was defined as an S1 IgG concentration >10 BAU/mL and a previous SARS-CoV-2 infection as N IgG >14.3 BAU/mL. Antibody neutralising activity was tested using lentiviral-based pseudoviruses expressing spike protein of SARS-CoV-2 wild-type (D614G), Omicron BA.1, and Omicron BA.4/5 variants. This study is registered with EudraCT, number 2021-001072-41.
Findings
Between March 24, 2021 and May 4, 2021, 723 patients with haematological diseases were enrolled, of which 414 fulfilled the inclusion criteria for the current analysis. Although S1 IgG concentrations in patients significantly improved after the fourth dose, they remained significantly lower compared to those obtained by 58 age-matched healthy individuals after their first booster (third) vaccination. The rise in neutralising antibody concentration was most prominent in patients with a recovering B cell compartment, although potent responses were also observed in patients with persistent immunodeficiencies. 19% of patients never seroconverted, despite 4 vaccinations. Patients who received their first 2 vaccinations when they were B cell depleted and the third and fourth vaccination during B cell recovery demonstrated similar antibody induction dynamics as patients with normal B cell numbers during the first 2 vaccinations. However, the neutralising capacity of these antibodies was significantly better than that of patients with normal B cell numbers after two vaccinations.
Interpretation
A fourth mRNA COVID-19 vaccination improved S1 IgG concentrations in the majority of patients with a haematological malignancy. Vaccination during B cell depletion may pave the way for better quality of antibody responses after B cell reconstitution.
Markus Hovd et al
Humoral vaccine response and breakthrough infections in kidney transplant recipients during the COVID-19 pandemic: a nationwide cohort study
The Lancet, June 2023 ; doi.org/10.1016/j.eclinm.2023.102035
Abstract
Kidney transplant recipients (KTRs) experienced reduced SARS-CoV-2 vaccine response and were at increased risk of severe COVID-19. It is unknown if level of vaccine induced anti-receptor binding domain IgG (anti-RBD IgG) correlates with protection from and survival following COVID-19. We aimed to evaluate the effect of vaccine response on risk of breakthrough infections (BTI) and COVID-19 death in KTRs.
Methods
We performed a nationwide study, examining the competing risk of SARS-CoV-2 infection, COVID-19 related/unrelated death, and vaccine efficacy as assessed by level of anti-RBD IgG response 4–10 weeks after each vaccination. The study included all KTR in Norway alive and with a functioning graft on February 20th, 2020, and events after November 11th, 2022 were right-censored. A pre-pandemic reference-cohort from January 1st 2019 to January 1st 2020 was included to evaluate excess mortality. The study was conducted at Oslo University Hospital, Rikshospitalet, Norway.
Findings
The study included 3607 KTRs (59 [48–70] years) with a functioning graft at February 20th, 2020, who received (median [IQR]) 4 [3–4] vaccines (range 2–6, 99% mRNA). Anti-RBD IgG was measured in 12 701 serum samples provided by 3213 KTRs. Vaccine response was assessed 41 [31–57] days after vaccination. A total of 1090 KTRs were infected with SARS-CoV-2, 1005 (92%) were BTI, and vaccine response did not protect against BTI. The hazard ratio for COVID-19 related death 40 days post-infection was 1.71 (95% CI: 1.14, 2.56) comparing vaccine response levels (≥5 vs. ≥5000 BAU/mL). No excess non-COVID-19 mortality was registered in KTRs surviving SARS-CoV-2 infection compared to a 2019 pre-pandemic reference.
Interpretation
Our findings suggested that SARS-CoV-2 mRNA vaccine response did not predict protection against infection, but prevention of fatal disease progression in KTRs and greater vaccine response further reduced the risk of COVID-19 death. No excess non-COVID-19 mortality was seen during the pandemic.
Evan M Bloch et al.
Guidance on the Use of Convalescent Plasma to Treat Immunocompromised Patients With Coronavirus Disease 2019
CID, February 2023; doi.org/10.1093/cid/ciad066
Abstract
Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) is a safe and effective treatment for COVID-19 in immunocompromised (IC) patients. IC patients have a higher risk of persistent infection, severe disease, and death from COVID-19. Despite the continued clinical use of CCP to treat IC patients, the optimal dose, frequency/schedule, and duration of CCP treatment has yet to be determined, and related best practices guidelines are lacking. A group of individuals with expertise spanning infectious diseases, virology and transfusion medicine was assembled to render an expert opinion statement pertaining to the use of CCP for IC patients. For optimal effect, CCP should be recently and locally collected to match circulating variant. CCP should be considered for the treatment of IC patients with acute and protracted COVID-19; dosage depends on clinical setting (acute vs protracted COVID-19). CCP containing high-titer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, retains activity against circulating SARS-CoV-2 variants, which have otherwise rendered monoclonal antibodies ineffective.
Juliette Villemonteix et al.
HLA Diversity across the HLA-DP locus is associated with improved response to SARS-CoV-2 vaccine in hematopoietic stem cell transplant recipients
Cell, April 2023; doi.org/10.1016/j.isci.2023.106763
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients show lower humoral vaccine responsiveness than immunocompetent individuals. HLA diversity, measured by the HLA evolutionary divergence (HED) metrics, reflects the diversity of the antigenic repertoire presented to T cells, and has been shown to predict response to cancer immunotherapy. We retrospectively investigated the association of HED with humoral response to SARS-CoV-2 vaccine in allo-HSCT recipients. HED was calculated as pairwise genetic distance between alleles at HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 loci in recipients and their donors. Low anti-spike IgG levels (< 30 BAU/mL) were associated with short time from allo-SCT and low donor DPB1-HED, mostly related to donor DPB1 homozygosity. The diversity of donor HLA-DP molecules, assessed by heterozygosity or sequence divergence, may thus impact the efficacy of donor-derived CD4 T cells to sustain vaccine-mediated antibody response in allo-HSCT recipients.
Thi H O Nguyen et al.
Robust SARS-CoV-2 T cell responses with common TCRαβ motifs towards COVID-19 vaccines in haematological malignancy patients impacting B cell immunity
Cell, March 2023; doi.org/10.1016/j.xcrm.2023.101017
Abstract
Immunocompromised haematology patients are vulnerable to severe COVID-19 and respond poorly to vaccination. Relative deficits in immunity are however unclear, especially after 3 vaccine doses. We evaluated immune responses in haematology patients across three COVID-19 vaccination doses. Seropositivity was low after 1st dose of BNT162b2 and ChAdOx1 (∼26%), increased to 59-75% after 2nd dose, and 85% after 3rd dose. While prototypical antibody-secreting cells (ASCs) and T-follicular helper (Tfh) responses were elicited in healthy participants, haematology patients showed prolonged ASCs and skewed Tfh2/17 responses. Importantly, vaccine-induced expansions of spike-specific and peptide-HLA tetramer-specific CD4+/CD8+ T-cells, together with their TCR repertoires, were robust in heamatology patients, irrespective of B-cell numbers, and comparable to healthy participants. Vaccinated patients with breakthrough infections developed higher antibody responses, while T-cell responses were comparable to healthy groups. COVID-19 vaccination induces robust T-cell immunity in haematology patients of varying diseases and treatments, irrespective of B-cell numbers and antibody response.
Miguel A. Hernánand Julia del Amo
Drug Repurposing and Observational Studies: The Case of Antivirals for the Treatment of COVID-19
https://www.acpjournals.org/doi/10.7326/M22-3582
Abstract
Remdesivir and molnupiravir were the only 2 repurposed antivirals that were approved for emergency use during the COVID-19 pandemic. Both drugs received their emergency use authorization on the basis of a single industry-funded phase 3 trial, which was launched after evidence of in vitro activity against SARS-CoV-2. In contrast, for tenofovirdisoproxil fumarate (TDF), little in vitro evidence was generated, no randomized trials for early treatment were done, and the drug was not considered for authorization. Yet, by the summer of 2020, observational evidence suggested a substantially lower risk for severe COVID-19 in TDF users compared with nonusers. The decision-making process for the launching of randomized trials for these 3 drugs is reviewed. Observational data in favor of TDF was systematically dismissed, even though no viable alternative explanations were proposed for the lower risk for severe COVID-19 among TDF users. Lessons learned from the TDF example during the first 2 years of the COVID-19 pandemic are described, and the use of observational clinical data to guide decisions about the launch of randomized trials during the next public health emergency is proposed. The goal is that gatekeepers of randomized trials make better use of the available observational evidence for the repurposing of drugs without commercial value.
Maria Prendecki, Michelle Willicombe
SARS-CoV-2 vaccine strategies in kidney transplant recipients
The Lancet, October 2022; doi.org/10.1016/S1473-3099(22)00666-1
Abstract
Conventional vaccine strategies against SARS-CoV-2 can be insufficient to generate immunological responses to vaccine or provide protection from COVID-19 in kidney transplant recipients (KTRs). In this group, vulnerability to infection remains high.1 In contrast to the general population, in which there is good evidence for booster doses of mRNA vaccine leading to enhanced immunological responses and protection from infection, a significant proportion of KTRs do not benefit from third or even fourth vaccine doses.2 In KTRs, and other patients who are immunosuppressed, investigation of modified vaccination strategies is needed to potentially enhance protection of this vulnerable group.
In The Lancet Infectious Diseases Marcia M L Kho and colleagues report an open-label randomised study of three alternative approaches to enhance vaccine responses: heterologous vaccine administration, double-dose vaccination, or temporary withdrawal of mycophenolate mofetil.3 There is a good rationale for each of these strategies.
In light of the results from Kho and colleagues, modulation of the immunosuppression regimen remains an unproven strategy. The risk of rejection, even if small, might also be unacceptable to patients; cohort 2 in this study was significantly smaller than prespecified due to difficulties with recruitment, largely due to patient anxiety related to withdrawal of mycophenolatemofetil. Alternative vaccine platforms, in development, such as those inducing mucosal immunity, those which make use of nanoparticle technology to display multiple copies of spike immunogens, or vaccines incorporating conserved epitopes beyond the spike region could be of benefit in the future.10 However, as long as it remains effective against the currently circulating variants,pre-exposure prophylaxis, which uses neutralising monoclonal antibodies, might be the best option in vulnerable KTRs with absent or impaired immune responses.
Filardi BA et al.
Age-dependent impairment in antibody responses elicited by a homologous CoronaVac booster dose
Science, February 2023; doi/10.1126/scitranslmed.ade6023
Abstract
The emergence of the SARS-CoV-2 Omicron sublineages resulted in increased transmission rates and reduced protection from vaccines. To counteract these effects, multiple booster strategies were used in different countries, although data comparing their efficiency in improving protective immunity remain sparse, especially among vulnerable populations, including older adults. The inactivated CoronaVac vaccine was among the most widely distributed vaccine worldwide and was essential in the early control of SARS-CoV-2–related hospitalizations and deaths. However, it is not well understood whether homologous versus heterologous booster doses in those fully vaccinated with CoronaVac induce distinct humoral responses or whether these responses vary across age groups. We analyzed plasma antibody responses from CoronaVac-vaccinated younger or older individuals who received a homologous CoronaVac or heterologous BNT162b2 or ChAdOx1 booster vaccine. All three evaluated boosters resulted in increased virus-specific IgG titers 28 days after the booster dose. However, we found that both IgG titers against SARS-CoV-2 Spike or RBD and neutralization titers against Omicron sublineages were substantially reduced in participants who received homologous CoronaVac compared with the heterologous BNT162b2 or ChAdOx1 booster. This effect was specifically prominent in recipients >50 years of age. In this group, the CoronaVac booster induced low virus-specific IgG titers and failed to elevate neutralization titers against any Omicron sublineage. Our results point to the notable inefficiency of CoronaVac immunization and boosting in mounting protective antiviral humoral immunity, particularly among older adults, during the Omicron wave. These observations also point to benefits of heterologous regimens in high-risk populations fully vaccinated with CoronaVac.
Emily Harris
Updated COVID-19 Guidance for People Who Are Immunocompromised
JAMA, February 2023; doi:10.1001/jama.2023.1176
Abstract
In late January, the US Food and Drug Administration announced that Evusheld (the combined monoclonal antibodies tixagevimab and cilgavimab) is not currently authorized for emergency use because it’s likely ineffective against more than 90% of SARS-CoV-2 variants now circulating in the US. Evusheld had been used as COVID-19 preexposure prophylaxis among certain patients who are immunocompromised.
n light of this change, the Centers for Disease Control and Prevention (CDC) released new recommendations for people who are moderately or severely immunocompromised. Up-to-date vaccination, including with the bivalent booster, remains the best option for preventing infection and serious illness, according to the authors from the CDC COVID-19 Emergency Response Team. The report emphasized the importance of wearing an N95 mask, improving indoor ventilation, having a personal COVID-19 action plan, and other strategies.
“Persons who are immunocompromised should discuss a treatment plan with their doctor and identify which COVID-19 treatment would be best for them,” the authors wrote. “Some persons with COVID-19 who are immunocompromised or receiving immunosuppressive treatment might benefit from a convalescent plasma treatment.”
Gliga S. et al.
Rapid Selection of Sotrovimab Escape Variants in Severe Acute Respiratory Syndrome Coronavirus 2 Omicron-Infected Immunocompromised Patients
CID, October 2022; doi.org/10.1093/cid/ciac802
Abstract
Background
Monoclonal antibodies (mAbs) that target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are predominantly less effective against Omicron variants. Immunocompromised patients often experience prolonged viral shedding, resulting in an increased risk of viral escape.
Methods
In an observational, prospective cohort, 57 patients infected with Omicron variants who received sotrovimab alone or in combination with remdesivir were followed. The study end points were a decrease in SARS-CoV-2 RNA <106 copies/mL in nasopharyngeal swabs at day 21 and the emergence of escape mutations at days 7, 14, and 21 after sotrovimab administration. All SARS-CoV-2 samples were analyzed using whole-genome sequencing. Individual variants within the quasispecies were subsequently quantified and further characterized using a pseudovirus neutralization assay.
Results
The majority of patients (43 of 57, 75.4%) were immunodeficient, predominantly due to immunosuppression after organ transplantation or hematologic malignancies. Infections by Omicron/BA.1 comprised 82.5%, while 17.5% were infected by Omicron/BA.2. Twenty-one days after sotrovimab administration, 12 of 43 (27.9%) immunodeficient patients had prolonged viral shedding compared with 1 of 14 (7.1%) immunocompetent patients (P = .011). Viral spike protein mutations, some specific for Omicron (e.g., P337S and/or E340D/V), emerged in 14 of 43 (32.6%) immunodeficient patients, substantially reducing sensitivity to sotrovimab in a pseudovirus neutralization assay. Combination therapy with remdesivir significantly reduced emergence of escape variants.
Conclusions
Immunocompromised patients face a considerable risk of prolonged viral shedding and emergence of escape mutations after early therapy with sotrovimab. These findings underscore the importance of careful monitoring and the need for dedicated clinical trials in this patient population.
Wong CKH et al.
Viral burden rebound in hospitalised patients with COVID-19 receiving oral antivirals in Hong Kong: a population-wide retrospective cohort study
The Lancet, February 2023; doi.org/10.1016/S1473-3099(22)00873-8
Abstract
Background
Viral rebound after nirmatrelvir–ritonavir treatment has implications for the clinical management and isolation of patients with COVID-19. We evaluated an unselected, population-wide cohort to identify the incidence of viral burden rebound and associated risk factors and clinical outcomes.
Methods
We did a retrospective cohort study of hospitalised patients with a confirmed diagnosis of COVID-19 in Hong Kong, China, for an observation period from Feb 26 to July 3, 2022 (during the omicron BA.2.2 variant wave). Adult patients (age ≥18 years) admitted 3 days before or after a positive COVID-19 test were selected from medical records held by the Hospital Authority of Hong Kong. We included patients with non-oxygen-dependent COVID-19 at baseline receiving either molnupiravir (800 mg twice a day for 5 days), nirmatrelvir–ritonavir (nirmatrelvir 300 mg with ritonavir 100 mg twice a day for 5 days), or no oral antiviral treatment (control group). Viral burden rebound was defined as a reduction in cycle threshold (Ct) value (≥3) on quantitative RT-PCR test between two consecutive measurements, with such decrease sustained in an immediately subsequent Ct measurement (for those patients with ≥3 Ct measurements). Logistic regression models were used to identify prognostic factors for viral burden rebound, and to assess associations between viral burden reboundand a composite clinical outcome of mortality, intensive care unit admission, and invasive mechanical ventilation initiation, stratified by treatment group.
Alexander J.L. et al.
The gut microbiota and metabolome are associated with diminished COVID-19 vaccine-induced antibody responses in immunosuppressed inflammatory bowel disease patients
The Lancet, January 2023; doi.org/10.1016/j.ebiom.2022.104430
Abstract
Patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy exhibit attenuated humoral immune responses to vaccination against SARS-CoV-2. The gut microbiota and its functional metabolic output, which are perturbed in IBD, play an important role in shaping host immune responses. We explored whether the gut microbiota and metabolome could explain variation in anti-SARS-CoV-2 vaccination responses in immunosuppressed IBD patients.
Methods
Faecal and serum samples were prospectively collected from infliximab-treated patients with IBD in the CLARITY-IBD study undergoing vaccination against SARS-CoV-2. Antibody responses were measured following two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccine. Patients were classified as having responses above or below the geometric mean of the wider CLARITY-IBD cohort. 16S rRNA gene amplicon sequencing, nuclear magnetic resonance (NMR) spectroscopy and bile acid profiling with ultra-high-performance liquid chromatography mass spectrometry (UHPLC-MS) were performed on faecal samples. Univariate, multivariable and correlation analyses were performed to determine gut microbial and metabolomic predictors of response to vaccination.
Findings
Forty-three infliximab-treated patients with IBD were recruited (30 Crohn's disease, 12 ulcerative colitis, 1 IBD-unclassified; 26 with concomitant thiopurine therapy). Eight patients had evidence of prior SARS-CoV-2 infection. Seventeen patients (39.5%) had a serological response below the geometric mean. Gut microbiota diversity was lower in below average responders (p = 0.037). Bilophila abundance was associated with better serological response, while Streptococcus was associated with poorer response. The faecal metabolome was distinct between above and below average responders (OPLS-DA R2X 0.25, R2Y 0.26, Q2 0.15; CV-ANOVA p = 0.038). Trimethylamine, isobutyrate and omega-muricholic acid were associated with better response, while succinate, phenylalanine, taurolithocholate and taurodeoxycholate were associated with poorer response.
Interpretation
Our data suggest that there is an association between the gut microbiota and variable serological response to vaccination against SARS-CoV-2 in immunocompromised patients. Microbial metabolites including trimethylamine may be important in mitigating anti-TNF-induced attenuation of the immune response.
Gokhan Tut et al.
Strong peak immunogenicity but rapid antibody waning following third vaccine dose in older residents of care homes
Nature, January 2023; doi.org/10.1038/s43587-022-00328-3
Abstract
Third-dose coronavirus disease 2019 vaccines are being deployed widely but their efficacy has not been assessed adequately in vulnerable older people who exhibit suboptimal responses after primary vaccination series. This observational study, which was carried out by the VIVALDI study based in England, looked at spike-specific immune responses in 341 staff and residents in long-term care facilities who received an mRNA vaccine following dual primary series vaccination with BNT162b2 or ChAdOx1. Third-dose vaccination strongly increased antibody responses with preferential relative enhancement in older people and was required to elicit neutralization of Omicron. Cellular immune responses were also enhanced with strong cross-reactive recognition of Omicron. However, antibody titers fell 21–78% within 100 d after vaccine and 27% of participants developed a breakthrough Omicron infection. These findings reveal strong immunogenicity of a third vaccine in one of the most vulnerable population groups and endorse an approach for widespread delivery across this population. Ongoing assessment will be required to determine the stability of immune protection.
Tartof S.Y et al.
Analysis of mRNA COVID-19 Vaccine Uptake Among Immunocompromised Individuals in a Large US Health System
JAMA, january 2023; doi:10.1001/jamanetworkopen.2022.51833
Abstract
Importance Immunocompromised individuals are at increased risk for severe outcomes due to SARS-CoV-2 infection. Given the varying and complex nature of COVID-19 vaccination recommendations, it is important to understand COVID-19 vaccine uptake in this vulnerable population.
Objective To assess mRNA COVID-19 vaccine uptake and factors associated with uptake among immunocompromised individuals from December 14, 2020, through August 6, 2022.
Design, Setting, and Participants This cohort study was conducted with patients of Kaiser Permanente Southern California (KPSC), an integrated health care system in the US. The study included patients aged 18 years or older who were immunocompromised (individuals with an immunocompromising condition or patients who received immunosuppressive medications in the year prior to December 14, 2020) and still met criteria for being immunocompromised 1 year later.
Exposures Age, sex, self-identified race and ethnicity, prior positive COVID-19 test result, immunocompromising condition, immunomodulating medication, comorbidities, health care utilization, and neighborhood median income.
Main Outcomes and Measures Outcomes were the number of doses of mRNA COVID-19 vaccine received and the factors associated with receipt of at least 4 doses, estimated by hazard ratios (HRs) and 95% Wald CIs via Cox proportional hazards regression. Statistical analyses were conducted between August 9 and 23, 2022.
Conclusions and Relevance These findings suggest that adherence to CDC mRNA monovalent COVID-19 booster dose recommendations among immunocompromised individuals was low. Given the increased risk for severe COVID-19 in this vulnerable population and the well-established additional protection afforded by booster doses, targeted and tailored efforts to ensure that immunocompromised individuals remain up to date with COVID-19 booster dose recommendations are warranted.
Cook L.B et al.
Third primary SARS-CoV-2 mRNA vaccines enhance antibody responses in most patients with haematological malignancies
Nature, Novembre 2022; doi.org/10.1038/s41467-022-34657-z
Abstract
SARS-CoV-2 infection, and resulting disease, COVID-19, has a high mortality amongst patients with haematological malignancies. Global vaccine rollouts have reduced hospitalisations and deaths, but vaccine efficacy in patients with haematological malignancies is known to be reduced. The UKstrategy offered a third, mRNA-based, vaccine as an extension to the primary course in these patients. The MARCH database is a retrospective observational study of serological responses in patients with blood disorders. Here we present data on 381 patients with haematological malignancies. By comparison with healthy controls, we report suboptimal responses following two primary vaccines, with significantly enhanced responses following the third primary dose. These responses however are heterogeneous and determined by haematological malignancy sub-type and therapy. We identify a group of patients with continued suboptimal vaccine responses who may benefit from additional doses, prophylactic extended half-life neutralising monoclonal therapies (nMAB) or prompt nMAB treatment in the event of SARS-CoV-2 infection.
Marcia ML Kho et al.
Alternative strategies to increase the immunogenicity of COVID-19 vaccines in kidney transplant recipients not responding to two or three doses of an mRNA vaccine (RECOVAC): a randomised clinical trial
Lancet Infectious Diseases, October 2022; doi.org/10.1016/S1473-3099(22)00650-8
Abstract
Background
An urgent need exists to improve the suboptimal COVID-19 vaccine response in kidney transplant recipients (KTRs). We aimed to compare three alternative strategies with a control single dose mRNA-1273 vaccination: a double vaccine dose, heterologous vaccination, and temporary discontinuation of mycophenolate mofetil or mycophenolic acid.
Methods
Interpretation
Repeated vaccination increases SARS-CoV-2-specific antibodies in KTRs, without further enhancement by use of a higher dose, a heterologous vaccine, or 2 weeks discontinuation of mycophenolate mofetil or mycophenolic acid. To achieve a stronger response, possibly required to neutralise new virus variants, repeated booster vaccination is needed.
Ainsua-Enrich E et al.
Kinetics of immune responses elicited after three mRNA COVID-19 vaccine doses in predominantly antibody-deficient individuals
iScience, October 2022; doi.org/10.1016/j.isci.2022.105455
Abstract
Mass vaccination campaigns reduced COVID-19 incidence and severity. The authors evaluated the immune responses developed in SARS-CoV-2-uninfected patients with predominantly antibody-deficiencies (PAD) after three mRNA-1273 vaccine doses.
Ronza Najjar-Debbiny et al.
Effectiveness of Evusheld in Immunocompromised Patients: Propensity Score-Matched Analysis
CID, October 2022; doi.org/10.1093/cid/ciac855
Abstract
In this study the authors used population-based real-world data to evaluate the effectiveness of Evusheld in immunocompromised patients.
Marcia M L Kho et al.
Alternative strategies to increase the immunogenicity of COVID-19 vaccines in kidney transplant recipients not responding to two or three doses of an mRNA vaccine (RECOVAC): a randomised clinical trial
Lancet, October 2022; doi.org/10.1016/S1473-3099(22)00650-8
Abstract
The suboptimal COVID-19 vaccine response in kidney transplant recipients (KTRs) is an urgent need. In this trial the authors aimed to compare three alternative strategies with a control single dose mRNA-1273 vaccination: a double vaccine dose, heterologous vaccination, and temporary discontinuation of mycophenolate mofetil or mycophenolic acid.
Skaria T.G. et al.
Withholdingmethotrexate after vaccination with ChAdOx1 nCov19 in patients with rheumatoid or psoriaticarthritis in India (MIVAC I and II): results of two, parallel, assessor-masked, randomisedcontrolled trials
Lancet Rheumatology, September 2022; doi.org/10.1016/S2665-9913(22)00228-4
Abstract
There is a necessity for an optimal COVID-19 vaccination strategy for vulnerable population groups, including people with autoimmune inflammatory arthritis on immunosuppressants such as methotrexate, which inhibit vaccine-induced immunity against SARS-CoV-2. The authors aimed to assess the effects of withholding methotrexate for 2 weeks after each dose of ChAdOx1 nCov-19 (Oxford–AstraZeneca) vaccine (MIVAC I) or only after the second dose of vaccine (MIVAC II) compared with continuation of methotrexate, in terms of postvaccination antibody titres and disease flare rates.
N. Babel et al.
Vaccination in patients with kidney failure: lessons from COVID-19
Nature reviews nephrology, August 2022;
Abstract
Infection is the second leading cause of death in patients with chronic kidney disease (CKD). Adequate humoral (antibody) and cellular (T cell-driven) immunity are required to minimize pathogen entry and promote pathogen clearance to enable infection control. Vaccination can generate cellular and humoral immunity against specific pathogens and is used to prevent many life-threatening infectious diseases. However, vaccination efficacy is diminished in patients with CKD. Premature ageing of the immune system and chronic systemic low-grade inflammation are the main causes of immune alteration in these patients. In the case of SARS-CoV-2 infection, COVID-19 can have considerable detrimental effects in patients with CKD, especially in those with kidney failure. COVID-19 prevention through successful vaccination is therefore paramount in this vulnerable population. Although patients receiving dialysis have seroconversion rates comparable to those of patients with normal kidney function, most kidney transplant recipients could not generate humoral immunity after two doses of the COVID-19 vaccine. Importantly, some patients who were not able to produce antibodies still had a detectable vaccine-specific T cell response, which might be sufficient to prevent severe COVID-19. Correlates of protection against SARS-CoV-2 have not been established for patients with kidney failure, but they are urgently needed to enable personalized vaccination regimens.
Arregocés-Castillo L. et al.
Effectiveness of COVID-19 vaccines in older adults in Colombia: a retrospective, population-based study of the ESPERANZA cohort
The Lancet , https://www.thelancet.com/action/showPdf?pii=S2666-7568%2822%2900035-6
CONTENUTO E COMMENTO : : Studio di coorte retrospettivo, population-based, matchato per valutare l’efficacia dei vaccini nei pazienti over 60 nel prevenire le ospedalizzazioni COVID-relate e morte in Colombia, includendo soggetti con schedula vaccinale completa tra 11 marzo 2021 e 26 ottobre 2021, quando la variante mu era prevalente nel paese. Si e’ dimostrata un’alta efficacia, con un’efficacia totale per tutti i vaccnii del 61,6% nel prevenire l’ospedalizzazione, del 79,8% nel prevenire la morte dopo l’ospedalizzazione e 72,8% nel prevenire la mortalita’ prima dell’ospedalizzazione.
In questo studio, l‘efficacia e’ stata negativamente correlata all’eta’, qualunque il vaccino sia stato impiegato : nelle eta’ avanzate, i vaccini piu’ efficaci sono stati quelli a vettore virale e mRNA rispetto ai vaccini a virus inattivato. Nelle fasce di eta’ piu’ anziane, come quelle dagli 80 anni in su, l’efficacia nel prevenire la mortalita’ post ospedalizzazione si e’ ridotta del 22,6% e 26,4% nella prevenzione della morte prima dell’ospedalizzazione.
LIMITI : sola variante mu circolante nel periodo studiato, vaccino CoronaVac favorito in questa fascia di eta’ per maggiore diffusione e quantita’ sul territorio, possibile autoselezione di gravita’ dei pazienti non vaccinati (bias comportamentali), confondenti non noti, possibili ritardi nel registro vaccinazioni da cui gli studiosi hanno attinto e conseguente rischio di misclassificazione, dati incompleti sulla prima vaccinazione per buona parte del campione , corto periodo di follow-up.
Wieske L. et al.
Humoral responses after second and third SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders on immunosuppressants: a cohort study
The Lancet, https://www.thelancet.com/action/showPdf?pii=S2665-9913%2822%2900034-0
CONTENUTO E COMMENTO : Studio di coorte che investiga l’effetto di una terapia immunosoppressiva (monoterapia o combinata) sulla risposta immunitaria umorale al vaccino per Sars-Cov2, in pazienti con disordine infiammatorio immuno-mediato. Sono stati inclusi nello studio partecipanti di età maggiore di 18 anni, con malattie infiammatorie immuno-mediate (AR, vasculiti, LES, morbo di Crohn, SM, miastenia gravis, dermatite atopica…) vaccinati per Sars-CoV2 e non (controlli, insieme a partecipanti sani). La risposta anticorpale (IgG anti-RBD) è stata misurata dopo due dosi di vaccino, e in un sottogruppo anche dopo tre dosi (febbraio-agosto 2021). Il siero di 2339 partecipanti (1869 senza pregressa infezione e 470 con pregressa infezione) è stato analizzato. Non sono state riscontrate differenze nella risposta umorale tra le varie patologie considerate. Le terapie con anti-CD20, modulatori di S1P e micofenolato mofetile combinati con corticosteroidi sono state associate con un minor rischio relativo di raggiungere la sieroconversione rispetto alla monoterapia immunosoppressiva. La dose booster ha portato ad un incremento della sieroconversione nel gruppo in terapia di combinazione con micofenolato, ma non in maniera significativa negli altri gruppi considerati. Nei soggetti con storia di pregressa infezione da Sars-cov2 invece il vaccino ha funzionato come booster della risposta anticorpale, indipendentemente dalla terapia assunta. In conclusione, lo studio mostra un’utilità della dose booster in pazienti con malattia infiammatoria immuno-mediata in terapia con micofenolato e in ogni caso i dati suggeriscono che nonostante la riduzione del titolo anticorpale nei pazienti in terapia immmunosoppressiva, questo non si traduce nella perdita di protezione nei confronti dell’infezione, almeno non a breve distanza di tempo dalla somministrazione.
Masset, Christophe et al.
A fourth SARS-CoV-2 mRNA vaccine in strictly seronegative kidney transplant recipients
Kidney International, Volume 101, Issue 4, 825 – 826,
https://www.kidney-international.org/article/S0085-2538(22)00093-X/fulltext
CONTENUTO E COMMENTO: lettera all’editore di due centri universitari francesi sull’esperienza sulla quarta dose booster di vaccino a mRNA in pazienti sottoposti a trapianto renali e seronegativi ad un mese dalla terza dose. Di 49 non responder, il 42,8% ha seroconvertito, ma solo 4 di loro hanno ottenuto una risposta considerabile come neutralizzante. Non si sono dimostrate differenze statisticamente significative, ma il gruppo con risposta umorale dopo la quarta dose era caratterizzato da minor uso di steroidi (47% vs 64%), minor linfopenia (63% vs 75%), maggior impiego di BNT162b (86% vs 68%) e un maggior intervallo tra una dose e l’altra (93 vs 82 giorni). Una storia di rigetto acuto provato da biopsia sembra piu’ frequente nel gruppo sieronegativo, la cui significativita’ clinica e’ piuttosto difficile da stimare (episodi che risalgono a piu’ di 5 anni prima).
La risposta si e’ mostrata pertanto globalmente piuttosto debole.
Guimaraes De Sousa L. et al.
Spontaneous tumor regression following COVID-19 vaccination
BMJ, https://jitc.bmj.com/content/jitc/10/3/e004371.full.pdf
CONTENUTO E COMMENTO : Case-report riguardante la riduzione dimensionale di metastasi polmonari di un paziente con carcinoma delle ghiandole salivari, dopo la somministrazione di due dosi di vaccino per Sars-Cov2 mRNA-1273. Come già noto, intense risposte immunitarie dovute ad uno stimolo infiammatorio sono alla base di nuove strategie per il trattamento del cancro, ed è proprio in tale contesto che in seguito alla vaccinazione il paziente ha manifestato uno stato di reattogenicità sistemica. Sono state eseguite biopsie delle metastasi polmonari dopo il ciclo vaccinale, con il riscontro di un massiccio infiltrato infiammatorio (T cell CD4+, CD8+, NK, B cell) e scarso materiale tumorale, in netto contrasto con le biopsie eseguite prima del vaccino. Inoltre è stato eseguito un follow-up mediante imaging (TAC a 3,6,9 mesi) con una riduzione dimensionale persistente delle metastasi (50%, 67% e 73%), suggerendo quindi una stimolazione dell’immunità antitumorale dovuta al vaccino.
Ehmsen S. et al.
Antibody responses following third mRNA COVID-19 vaccination in patients with cancer and potential timing of a fourth vaccination
Cancer Cell, https://ars.els-cdn.com/content/image/1-s2.0-S1535610822000630-mmc3.pdf
CONTENUTO E COMMENTO : Studio di coorte monocentrico, osservazionale analitico, della risposta immunitaria dopo il ciclo vaccinale a mRNA con due/tre dosi per Sars-Cov2 in pazienti oncologici (tumori solidi o ematologici). Un totale di 590 pazienti sono risultati eleggibili nello studio, di questi 539 hanno ricevuto almeno due dosi di vaccino e 536 anche la dose booster. Sono stati analizzati i titoli delle IgG anti-S della popolazione oggetto di studio, con il riscontro di una mancata sieroconversione anche dopo il booster nei pazienti trattati con anti-CD20 nei sei mesi precedenti e più in generale una scarsa sieroconversione nei pazienti ematologici. Maggiore invece è risultato essere il beneficio della terza dose nei pazienti con tumori solidi, ove 1/5 del totale non aveva sviluppato anticorpi dopo le prime due dosi mentre solo un paziente della coorte è risultato negativo a tre mesi dal booster. La sieroconversione tra la seconda e la terza dose è risultata più spiccata in pazienti con neoplasie polmonari e gastrointestinali. Mediante una valutazione della rapidità di decadimento del titolo anticorpale gli autori dello studio hanno stimato che nei pazienti ematologici già a due mesi dalle prime due dosi la maggior parte della popolazione risulta essere sieronegativa, ponendo l’accento su una possibile riduzione del lasso di tempo che intercorre attualmente tra la seconda e la terza dose, soprattutto in pazienti fragili. Mediante gli stessi calcoli sono arrivati a stimare che i pazienti riceventi inibitori di BKT e chemioterapia avrebbero già dovuto ricevere una quarta dose di vaccino, a 3-5 mesi di distanza dal booster, al fine di garantire una adeguata protezione. Viceversa, nei pazienti non in trattamento attivo tale intervallo può estendersi fino ad un anno. La limitazione principale dello studio sicuramente risulta essere legata alla sola valutazione delle IgG anti-S, che spesso, ma non sempre, sono correlate alla neutralizzazione del virus e sono predittive di una protezione immunitaria.
Ward H. et al.
Population antibody responses following COVID-19 vaccination in 212,102 individuals
Nature, https://www.nature.com/articles/s41467-022-28527-x.pdf
CONTENUTO E COMMENTO : Studio di prevalenza condotto nel Regno Unito (gennaio-maggio 2021) con lo scopo di valutare la risposta anticorpale di una popolazione vasta di 212.102 individui, ai quali veniva somministrata almeno una dose di vaccino per Sars-Cov2 (BNT162b2 e ChAdOx1). I dati venivano raccolti nell’ambito del programma REACT-2, che prevedeva l’utilizzo di un lateral flow antibody test autosomministrato, in soggetti vaccinati con almeno una dose dei composti sopracitati. Dei 212.102 vaccinati eleggibili (una dose entro le 12 settimane dall’inizio dello studio o vaccinati con due dosi), 71.923 (33.6%) avevano ricevuto BNT162b2, 139.067 (65.6%) ChAdox1 e lo 0.3% mRNA-1273. I dati ottenuti con i test sierologici hanno mostrato un picco di positività anticorpale a 4-5 settimane dalla prima dose, con un costante decremento nelle settimane successive. Dopo due dosi di BNT162b2 la positività anticorpale risultava superiore al 90%, fatta eccezione per la popolazione over75 (86.5%). Dopo due dosi di ChAdOx1 tale positività risultava essere molto più variabile, dal 90% in una popolazione giovane fino al 72.7% negli over70. Fattori favorenti un più elevato livello di risposta anticorpale: sesso femminile, precedente infezione da Sars-CoV2. Viceversa, una positività anticorpale minore veniva riscontrata nei pazienti trapiantati, nei fumatori, in diabetici, cardiopatici, epatopatici o con patologie neurologiche. Tali dati suggeriscono una riduzione della risposta anticorpale dopo 4-5 settimane dalla prima dose, dato importante se contestualizzato nella prima fase della campagna vaccinale del Regno Unito, ove il lasso di tempo consentito tra due dosi di vaccino raggiungeva le 12 settimane.
Alexander J. L. et al.
COVID-19 vaccine-induced antibody responses in immunosuppressed patients with inflammatory bowel disease (VIP): a multicentre, prospective, case-control study
The Lancet, https://doi.org/10.1016/S2468-1253(22)00005-X
CONTENUTO E COMMENTO : CONTENUTO : studio multicentrico, prospettico, caso controllo che indaga l’immunogenicita’ dei vaccini per SARS-CoV2 nei pazienti con IBD trattati con 6 differenti regimi immunosoppressivi, che abbiano ricevuto due dosi di vaccino (ChAdOx1 nCoV-19, BNT162b2, o mRNA1273 [Moderna]) prima dell’arruolamento comparati con un controllo sano, arruolati tra il 31 maggio e il 24 novembre 2021, studio promosso da Pfizer. Per l’analisi primaria (concentrazioni di anticorpi contro RBD della proteina spike misurati a 53-92 giorni), sono stati inclusi 370 partecipanti senza evidenza di precedente infezione.La media geometrica delle concentrazioni di anticorpi contro la proteina spike erano significativamente piu’ basse nei pazienti trattati con infliximab (156·8 U/mL [geometric SD 5·7]; p<0·0001), tiopurine piu’ infliximab (111·1 U/mL [5·7]; p<0·0001), o tofacitinib (429·5 U/mL [3·1]; p=0·0012) rispetto ai controlli (1578·3 U/mL [3·7]).Non ci sono state differenze significative nelle concentrazioni di anticorpi contro la proteina spike nei pazienti trattati con monoterapia di tiopurine (1019·8 U/mL [4·3]; p=0·74), ustekinumab (582·4 U/mL [4·6]; p=0·11), or vedolizumab (954·0 U/mL [4·1]; p=0·50) e i controlli sani.
Nel modello multivariato in cui si sono inclusi i 370 partecipanti con IBD senza evidenza di infezione previa, concentrazioni piu’ basse di anticorpi contro la proteina spike erano independentemente associate a terapia con infliximab (GMR 0·12 [95% CI 0·08–0·17]) e tofacitinib (GMR 0·43 [0·23–0·81]), ma non con ustekinumab (GMR 0·69 [0·41–1·19]), tiopurine (GMR 0·89 [0·64–1·24]), o vedolizumab (GMR 1·16 [0·74–1·83]), maggiore eta’ per decade (GMR 0·79 [0·72–0·87]) (vs i controlli). I vaccini a mRNA (GMR 3·68 [95% CI 2·80–4·84]; vs i vaccini a vettore adenovirus) erano indipendemente associati a piu’ alte concentrazioni di anticorpi. Di rilievo notare come l’importanza della riduzione della risposta anticorpale nei pazienti trattati con inflixiamb (riduzione di 10 volte rispetto ai controlli). Il 10% e il 13% dei pazienti rispettivamente in terapia con Infliximab e quelli con infliximab+tiopurine non hanno montato risposte anticorpali significative dopo la vaccinazione.Il sottotipo IBD, l’etnia, il tabagismo non erano associati ad impatti sulla concentrazioni degli anticorpi. In analisi post-hoc escludenti i partecipanti in terapia cortisonica al momento della vaccinazione, le associazioni sono rimaste significative, mentre in analisi post-hoc di sensibilita’ includenti l’uso di corticosteroidi, BMI e genere, queste ultime variabili non sono state associate a variazioni delle concentrazioni di anticorpi. I partecipanti con IBD e i controlli sani con evidenza di pregressa infezione hanno avuto una risposta anticorpale maggiore alla vaccinazione, come atteso. In linea con quanto gia’ noto del waning anticorpale in popolazioni sane, desta preoccupazione la durabilita’ della protezione anticorpale nei pazienti trattati con tofacitinib, la cui risposta post vaccinazione era significativamente diminuita rispetto ai controlli sani (concentrazione geometrica media 430 U/mL vs 1578 U/mL).
LIMITAZIONI : misurazione della risposta umorale come singolo timepoint ; non dati disponibili sulla dose booster; numerosi fattori confondenti ; il piccolo numero di pazienti trattati con corticosteroidi non permette conclusioni forti sul sull’effetto dei corticosteroidi sulla vaccinazione; grandezza del sottogruppo trattato con tofacitinib piu’ piccola dei restanti gruppi ; aggiustamento per comparazioni multiple non effettuata nell’analisi primaria ; dati prima dell’emergenza di omicron ; studio senza la potenza necessaria per determinare modeste riduzioni della risposta anticorpale.
Tsonas AM et al
Practice of Tracheostomy in Patients with Acute Respiratory Failure related to COVID–19 – insights from the PRoVENT–COVID study
Pulmonology, https://www.sciencedirect.com/science/article/pii/S2531043721001896
CONTENUTO E COMMENTO : Studio osservazionale multicentrico condotto nei Paesi Bassi su 1023 pazienti trattati in Rianimazione durante la prima « ondata » di COVID-19 (marzo-giugno 2020) : quasi un quinto dei pazienti è stato sottoposto a tracheostomia e il confezionamento precoce della tracheostomia è associato in questa casistica a una minore durata di ventilazione meccanica. Si osserva associazione anche con una maggiore mortalità, dato che gli autori ritengono tuttavia derivante da un bias nell’analisi della sopravvivenza dei pazienti (per approfondimento : Immortal Time Bias https://www.bmj.com/content/340/bmj.b5087 ).
Moll V et al
The Coronavirus Disease 2019 Pandemic Impacts Burnout Syndrome Differently Among Multiprofessional Critical Care Clinicians—A Longitudinal Survey Study
Critical Care Medicine,
https://journals.lww.com/ccmjournal/Abstract/9000/The_Coronavirus_Disease_2019_Pandemic_Impacts.95094.aspx
CONTENUTO E COMMENTO : Studio longitudinale cross-sectional sulla prevalenza del « burn-out » nel personale della Rianimazione (infermieri, medici, fisioterapisti respiratori, farmacisti, assistenti sociali e spirituali) di un ospedale universitario confrontando gli anni 2017 e 2020 : si osserva una elevata prevalenza, in particolare nella categoria degli infermieri e fra le donne, con un aumento nel 2020, durante la pandemia, rispetto alla rilevazione precedente.
