Fourth Dose Research Articles

Effectiveness of heterologous third and fourth dose COVID-19 vaccine schedules for SARS-CoV-2 infection during delta and omicron predominance in Thailand: a test-negative, case-control study

The Coronavirus disease 2019 (COVID-19) pandemic has evolved quickly, with numerous waves of different variants of concern resulting in the need for countries to offer continued protection through booster vaccination. To ensure adequate vaccination coverage, Thailand has proactively adopted heterologous vaccination schedules. While randomised controlled trials have assessed homologous schedules in detail, limited data has been reported for heterologous vaccine effectiveness (VE). Utilising a unique active surveillance network established in Chiang Mai, Northern Thailand, we conducted a test-negative case control study to assess the VE of heterologous third and fourth dose schedules against SARS-CoV-2 infection among suspect-cases during Oct 1-Dec 31, 2021 (delta-predominant) and Feb 1-Apr 10, 2022 (omicron-predominant) periods. After a third dose, effectiveness against delta infection was high (adjusted VE 97%, 95% CI 94-99%) in comparison to moderate protection against omicron (adjusted VE 31%, 95% CI 26-36%). Good protection was observed after a fourth dose (adjusted VE 75%, 95% CI 71-80%). VE was consistent across age groups for both delta and omicron infection. The VE of third or fourth doses against omicron infection were equivalent for the three main vaccines used for boosting in Thailand, suggesting coverage, rather than vaccine type is a much stronger predictor of protection. Appropriately timed booster doses have a high probability of preventing COVID-19 infection with both delta and omicron variants. Our evidence supports the need for ongoing national efforts to increase population coverage of booster doses. This research was supported by the National Research Council of Thailand (NRCT) under The Smart Emergency Care Services Integration (SECSI) project to Faculty of Public Health Chiang Mai University.

Immune Response to Third and Fourth COVID-19 Vaccination in Hemodialysis Patients and Kidney Transplant Recipients.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a serious hazard for hemodialysis (HD) patients and kidney transplant (KTX) recipients as they suffer from an impaired immune response to SARS-CoV-2 vaccination. In addition, a definition of SARS-CoV-2 IgG titer that indicates a sufficient immune response, especially against new omicron variants, is urgently needed. In the present study, the immune response to either a third or a fourth dose of a mRNA vaccine was investigated in 309 dialysis and 36 KTX patients. SARS-CoV-2 IgG titer thresholds indicating neutralizing activity against wild type (WT) and the omicron variant BA.1 were quantified. After four vaccine doses, a high-neutralizing activity against WT was evidenced in HD patients, whereas the neutralizing rate against BA.1 was significant lower. Concerning KTX recipients, humoral and cellular immune responses after a third vaccination were still highly impaired. This calls for modified omicron-targeting vaccines.

Antibody Titer Correlates with Omicron Infection in Vaccinated Healthcare Workers.

The advent of vaccines against SARS-CoV-2 has drastically reduced the level of hospitalization with severe COVID-19 disease in infected individuals. However, the diffusion of variants of concern still challenge the protection conferred by vaccines raised against the wild-type form of the virus. Here, we have characterized the antibody response to the BNT162b2 (Comirnaty) mRNA vaccine in patients infected with the Omicron variant. We analyzed a population of 4354 vaccinated healthcare workers (HCW) from 7 different hospitals in Italy and monitored infection with SARS-CoV-2 Omicron. We correlated infection with the antibody response after vaccination. We found that a lower level of IgG, younger age, and the presence of allergies correlate with increased infection during the Omicron wave, and that infections correlate with wild-type spike protein antibody titers below 350 BAU/mL. These results support the necessity of a fourth booster dose, particularly for individuals with lower levels of antibodies.

Saliva and Plasma Neutralizing Activity Induced by the Administration of a Third bnt162b2 Vaccine Dose.

The BNT162b2 vaccine induces neutralizing activity (NA) in serum, but no data are available on whether a third-dose activates specific-immunity within the oral mucosa, representing the primary route of viral-entry. To carefully address this issue, we investigated if such immunity is boosted by SARS-CoV-2-infection; how long it is maintained over-time; and if it protects against the SARS-CoV-2 lineage B.1 (EU) and the emerging Delta and Omicron variants. NA was measured in plasma and saliva samples from: uninfected SARS-CoV-2-Vaccinated (SV), subjects infected prior to vaccination (SIV), and subjects who were infected after the second (SIV2) or the third (SIV3) vaccine dose. Samples were collected immediately before (T0), 15 days (T1), and 90 days (T2) post third-dose administration (SV and SIV), or 15 days post-infection (SIV2 and SIV3). In all the enrolled groups, NA in plasma and saliva: (i) was higher against EU compared to the other variants at all time-points (SV: T0 and T1, EU vs. both Delta and Omicron p < 0.001; T2 p < 0.01) (SIV: T0, EU vs. Delta p < 0.05; EU vs. Omi p < 0.01; T1 and T2 EU vs. Delta p < 0.01; EU vs. Omi p < 0.001); (ii) was boosted by the administration of the third dose; iii) declined over-time, albeit being detectable in almost all subjects at T2. The monitoring of NA over time will be important in clarifying if different NA levels may influence either acquisition or course of infection to properly plan the timing of a fourth vaccine dose administration.

Seasonal use case for the RTS,S/AS01 malaria vaccine: a mathematical modelling study

A 2021 clinical trial of seasonal RTS,S/AS01E (RTS,S) vaccination showed that vaccination was non-inferior to seasonal malaria chemoprevention (SMC) in preventing clinical malaria. The combination of these two interventions provided significant additional protection against clinical and severe malaria outcomes. Projections of the effect of this novel approach to RTS,S vaccination in seasonal transmission settings for extended timeframes and across a range of epidemiological settings are needed to inform policy recommendations. We used a mathematical, individual-based model of malaria transmission that was fitted to data on the relationship between entomological inoculation rate and parasite prevalence, clinical disease, severe disease, and deaths from multiple sites across Africa. The model was validated with results from a phase 3b trial assessing the effect of SV-RTS,S in Mali and Burkina Faso. We developed three intervention efficacy models with varying degrees and durations of protection for our population-level modelling analysis to assess the potential effect of an RTS,S vaccination schedule based on age (doses were delivered to children aged 6 months, 7·5 months, and 9 months for the first three doses, and at 27 months of age for the fourth dose) or season (children aged 5-17 months at the time of first vaccination received the first three doses in the 3 months preceding the transmission season, with any subsequent doses up to five doses delivered annually) in seasonal transmission settings both in the absence and presence of SMC with sulfadoxine-pyrimethamine plus amodiaquine. This is modelled as a full therapeutic course delivered every month for four or five months of the peak in transmission season. Estimates of cases and deaths averted in a population of 100 000 children aged 0-5 years were calculated over a 15-year time period for a range of levels of malaria transmission intensity (Plasmodium falciparum parasite prevalence in children aged 2-10 years between 10% and 65%) and over two west Africa seasonality archetypes. Seasonally targeting RTS,S resulted in greater absolute reductions in malaria cases and deaths compared with an age-based strategy, averting an additional 14 000-47 000 cases per 100 000 children aged 5 years and younger over 15 years, dependent on seasonality and transmission intensity. We predicted that adding seasonally targeted RTS,S to SMC would reduce clinical incidence by up to an additional 42 000-67 000 cases per 100 000 children aged 5 years and younger over 15 years compared with SMC alone. Transmission season duration was a key determinant of intervention effect, with the advantage of adding RTS,S to SMC predicted to be smaller with shorter transmission seasons. RTS,S vaccination in seasonal settings could be a valuable additional tool to existing interventions, with seasonal delivery maximising the effect relative to an age-based approach. Decisions surrounding deployment strategies of RTS,S in such settings will need to consider the local and regional variations in seasonality, current rates of other interventions, and potential achievable RTS,S coverage. UK Medical Research Council, UK Foreign Commonwealth & Development Office, The Wellcome Trust, and The Royal society.

Differences in Humoral and Cellular Response to COVID-19 Vaccine Against Different Variants over Time in Chronic Lymphocytic Leukemia

Background Patients with chronic lymphocytic leukemia (CLL) are at an increased risk of adverse clinical outcomes following COVID-19 infection, due to impaired humoral and cellular response to infection and vaccination. Most of the data available focus on humoral responses to SARS-CoV-2 vaccination or T cell responses following 2-dose vaccine series. However, the effect of emerging variants of concern (VoC) on T cell recognition in this population has not been previously reported. Aim of the study To evaluate functional humoral response and functional SARS-CoV-2 spike-specific T cell response in CLL patients after the second, the third dose, and 12-months since the first dose. To determine the effect of treatment on immune outcomes. To investigate T cell response to Omicron (BA.2) and ancestral strains, and the impact of Omicron-defining mutations on total spike-specific functional response. Methods CLL patients from Mayo Clinic, Rochester who submitted a blood sample soon after the second and the third dose, and 12-months after the first dose of an mRNA-based vaccination were included. The samples collected following a documented SARS-CoV-2 infection were excluded. Spike-specific T cell responses were quantified using IFN-γ ELISpot assay (R&D Systems). PBMCs were stimulated with a peptide pool spanning the complete sequence of ancestral SARS-CoV-2 spike and two 68-peptide pools: the BA.2 mutation pool selectively covering the mutated spike regions, and reference pool containing the wild-type sequences for the same regions (Peptivator pools, Miltenyi Biotec). The results were considered positive if at least two of the following three were met: average spot count > 5 SFUs/2x10^5; mean spot count >3-fold higher than in negative control; and statistically significant difference (paired t-test<0.5) between Ag-specific and negative control wells.For evaluation of humoral response, we utilized an assay measuring antibody capable of blocking spike receptor binding domain (RBD)-ACE2 (cPASS GenScript). Statistical analysis was performed using t-test and Mann-Whitney test for continuous variables; Chi-square (or Fisher's Exact test) was used for comparing categorical variables. The Mayo Clinic IRB approved the study. Results Thirty patients with CLL were included in the study. Eight patients received a fourth vaccine dose before the 12-months blood draw. The rate of positivity for receptor blocking activity was significantly higher in the untreated group after the 2ndand 3rd dose (0% vs. 75%, 38.5% vs. 93.3%, p>0.05). This difference was not observed for the cellular response to spike-specific ancestral in all the three timepoints. At 12 months 54.16 % of the patients had positive IFN-γ ELISpot response, with no significant difference between treated and untreated (58.3% vs. 50%, p=1.0), and patients with and without a fourth dose (62.5% vs. 50%, p=0.67). Among treated CLL patients, seven (70%) and five (41.6%) patients without neutralizing antibodies had detectable cellular response after the 2nd and 3rd dose, respectively. On average, less than 25% of the total spike-specific T cell reactivity was directed against the epitopes in the regions mutated in BA.2 subvariant. Moreover, we did not detect statistically significant differences in IFN-γspot counts between the mutational and reference 68-peptide pools at any timepoint (median spots T1: 1.62 vs. 2.33, p=0.4; T2: 5 vs. 4.33, p=0.31; T3: 5 vs. 6, p=0.49). Conclusion Treatment status impacts humoral, but no cellular response to SARS-CoV-2 vaccination CLL patients. However, the overall rate of positive cellular response one year after the first dose is low. This, combined with no boosting of cellular response upon the 4th dose, reflects an impaired response even after additional doses. Suboptimal cellular immunity may put CLL patients at higher risk of severe COVID-infection. We did not observe significant difference in the cellular response between ancestral and Omicron BA.2 strains, and only the smaller fraction of T cell response was directed against regions harboring BA.2-specific mutations. These findings confirm the greater observed cross-reactivity to VoC with cellular compared to humoral immune responses. They also suggest significant cellular immunity may remain in the face of Omicron circulation, at least among patients who have response to the vaccine. Given the small sample size, our findings need to be confirmed. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Impact of Sars-Cov-2 Vaccination in COVID-19 Outcomes in Patients Diagnosed with Hematologic Malignancies: Real-World Evidence of Two Years of Pandemic

Background: Real-world data about the effectiveness of SARS-CoV-2 vaccination and implementation of booster campaigns in an immunocompromised population such as patients diagnosed with hematologic malignancies (HM) are scarce. Our aim was to compare morbidity and mortality of COVID-19 according to SARS-CoV-2 vaccination status and immunological response to vaccination in a cohort of patients diagnosed with HM, considering a scenario affected by the succession of diverse virus variants and the advent of COVID-19 specific therapies. Methods: We retrospectively collected clinical data from the patients with a current or prior history of HM at Vall d´Hebron Universitary Hospital who suffered a laboratory-confirmed SARS-CoV-2 infection between March 2020 and May 2022. The main endpoints included severity of COVID-19 (WHO classification), rate of hospitalization, ICU admission, need for supplemental oxygen or COVID-19 specific therapy (steroids, antivirals, IL-6 inhibitors, hydroxychloroquine, anti-SARS-CoV-2 monoclonal antibodies). We also genotyped viral variants and assessed humoral immunogenicity induced by the vaccine (anti-spike[S] IgG >260 BAU/mL measured by LIAISON® Diasorin) or the infection (anti-nucleocapsid[N] IgM/IgG/IgA positivization by Elecsys® Roche). Results: A total of 326 patients developed COVID-19, 182 vaccinated cases between 03/21 and 05/22, and 134 unvaccinated cases between 03/20 and 02/22. Both groups were similar in age (median 68 and 71 years) and gender (51% and 46% women, respectively). In both cohorts the main diagnosis was lymphoma (46% and 43%), the majority of patients were under active treatment (73% and 58%) and the most frequent active therapy was anti-CD20 monoclonal antibodies+/- chemotherapy (35% and 30%) (Table 1). Among the 113 vaccinated sequenced cases, 80% were omicron (predominantly BA.1 [36%] and BA.1.1 [28%]), 19% delta (B.1.617.2 [6%] and AY lineage [15%]) and 1% alfa variant. Genotype analysis of 87 unvaccinated cases showed predominance of B.1 and B.1.177 lineages in 53% and 35% of the cases, respectively. The vaccines most frequently administered were mRNA-1273 (70%) and BNT162b2 (25%). A 5% of patients were partially vaccinated (one dose), 26% fully vaccinated (2 doses), whereas 67% received a third boost dose and 2% a fourth dose prior infection. Considering patients with available basal serology prior infection, only 20% (1/5) of partially vaccinated, 39% (13/33) of fully vaccinated patients, and 47% (42/90) of boosted patients had developed positive anti-S IgG antibodies. In 38% (34/90) of patients with basal negative anti-N antibodies a seroconversion was observed after the infection. In the unvaccinated cohort the most frequent COVID-19 specific therapies administered were hydroxychloroquine (46%), steroids (28%), lopinavir/ritonavir (20%) and tocilizumab (19%); while in the vaccinated cohort were remdesivir (38%), steroids (28%), tocilizumab (14%) and anti-SARS-CoV-2 monoclonal antibodies (7%). In comparison with the unvaccinated cohort of patients, vaccinated patients had less severe (17% vs. 27%; p=0.006) and critical (12% vs 38%; p=<0.001) COVID-19, lower rates of hospitalization (32% vs. 80%; p=<0.001) and fewer patients needed supplemental oxygen (28% vs. 64%; p=<0.001). Admission rates to ICU were similar between both cohorts. Mortality rate was lower in the vaccinated patients in comparison with the unvaccinated cohort (HR: 0.48 (95%CI 0.31-0.74); p=<0.001) (Figure 1). Of note, only 15% (6/39) of patients who suffered a severe/critical infection had developed humoral vaccine immunogenicity. In contrast, 56% (50/89) of mild/moderate cases had created vaccine-induced seroconversion. None of the 17 vaccinated patients who died had developed anti-S antibodies. Finally, in 23% (30/131) of the vaccinated cohort the follow-up RT-PCR remained persistently positive >21 days. Conclusion: In this real-world analysis, and despite the heterogeneity of infection by different viral variants and treatment availability for COVID-19 during the evolution of the pandemic, vaccination has resulted widely effective at reducing need of hospitalization, severity and mortality of the SARS-CoV-2 infection in patients with HM. Patients who develop a suboptimal humoral immunogenicity after vaccination are at higher risk to develop a severe/critical infection and would benefit from an early intervention. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Early Transcriptional Activity of Vtr-297 - Results from an Ongoing Phase I Clinical Trial

VTR-297 (Trichostatin A) is a pan-inhibitor of histone deacetylases types 1, 2, 4, 6, and 10. Histone deacetylase inhibitors (HDACi) are well-known small molecules that increase the acetylation of lysine residues by inhibiting the activity of histone deacetylase enzymes. These anticancer agents affect epigenetic and non-epigenetic transcriptional regulation and are already part of effective clinical practice and hematology regimens. As HDACi are known for their relatively wide transcriptional modulation, we have conducted a high throughput screen to elucidate early transcriptional effects related to exposure to Trichostatin A (TSA) on patient-derived, clinical time-series samples. NCT03838926 is an ongoing, open-label, dose-escalation, phase I clinical trial for subjects with relapsed or refractory hematologic malignancies. Enrolled patients were assigned to receive one currently tested dose (1.25 / 2.50 / 5.00 mg; IV infusion) in 28-day cycles, 3-times a week for three weeks with one week off (IV administration days 1,3,5,8,10,12,15,17 and 19) until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was safety/tolerability and maximum tolerated dose (MTD) of VTR-297 (TSA). Currently, twelve patients enrolled in the study, including Multiple Myeloma (MM, n=5), Non-Hodgkin's Lymphoma (NHL, n=5), and Hodgkin's Lymphoma (HL, n=2) across the first three dose-escalation cohorts that completed (1.25 / 2.50 / 5.00mg). No significant drug-related toxicities were reported, and MTD was not reached (recruitment is currently ongoing in the fourth dose cohort of 10mg). As a part of the exploratory analysis of whole blood (PBMC), patient samples were collected on cycle1 day1 (C1D1; pre-infusion, 15min-post, 30min-post, 1h-post, 2h-post, and 6h-post infusion) to capture any transcriptional changes (RNAseq) related to VTR-297 treatment. In the current analysis, samples were collected and analyzed in respective batches (15min / 30min / 1h / 2h / 6h) and compared with combined baseline samples (pre-infusion). Using Deseq2 to ascertain transcriptionally affected genes (pval<0.05, up/down relative fold-change 1.5x), we detected 136 differentially expressed genes across at least one of the time point analyzed. Among the detected genes, we found novel and previously described genes related to the core pathophysiology of myeloid and lymphoid disease (e.g., iron metabolism, vascular metastasis, and tyrosine kinase activity). In conclusion, these preliminary signatures offer early biomarker information related to a specific transcriptional activity elicited by intravenously delivered VTR-297 in the clinical setting. In an ongoing clinical study, we will further monitor, validate, and expand on these findings. Further observations at higher, safe, and clinically meaningful doses will complement our current, early picture of VTR-297 activity and how it can be used to optimize TSA-based treatments.

Impact of Fourth Methotrexate Dose in ATG-Cyclosporine GvHD Prophylaxis in HLA-Matched Unrelated HSCT: A GITMO Study

Background: Although, post-transplant Cyclophosfamide (PT-Cy) is currently spreading as GvHD prevention, the standard GvHD prophylaxis in unrelated haematopoietic stem cell allogeneic transplant (HSCT) series is still represented by Methotrexate (MTX), a CNI and Anti-thymoglobuline (ATG) combination. The dose of MTX (3 or 4 doses), in association with ATG and CNI remains a matter of debate. Aim: The Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari (GITMO) analyzed 568 patients who received unrelated (UD) 10/10 HLA matched HSCT and GvHD prophylaxis based on a combination of cyclosporin (CSA), ATG and Methotrexate. Methods: Patients were grafted in GITMO centers between 2012 to 2015 and GvHD prophylaxis was the same for all patients (ATG-MTX-CSA). The median dose for ATG Fresenius and Thymoglobulin was respectively 30 mg/kg (range 8-60) and 8 mg/Kg (range 4-18); 216 patients received 3 doses of MTX and 352 4 doses. Patient characteristics based on the two groups (MTX 4 and MTX 3 doses) are detailed in table 1. Main differences between the groups concerned conditioning intensity (myeloablative in 75% and 63% for MTX4 and MTX3 respectively, p 0.002), ATG dose (above the median in 59% of MTX4 and in 71% of MTX3 patients, p 0.005), and diagnosis (acute leukemias in 63% of MTX4 and 46% of MTX3, p<0.0001). Statystical analysis: The probabilities of DFS, OS and GRFS were estimated with the Kaplan-Meier method. Cumulative incidence (CI) was estimated for engraftment, GvHD, TRM and relapse to accommodate competing risks. Relapse or progression was a competing risk for TRM, and death from any cause was a competing risk for engraftment and relapse. Relapse or progression and death from any causes were competing risks for GvHD. Univariate comparisons of survival curves were made using the log-rank test and Gray's test was used for univariate comparisons of CI functions. The type I error rate was fixed at 0.05. Statistical analyses were performed with the SPSS (SPSS 22 Inc. IBM, Armonk, NY, USA) and R (R Development Core Team, Vienna, Austria) software. Results In the setting of 10/10 HLA matched unrelated allogeneic HSCT, whose median follow up was 42.5 months (range 3-75), univariate analysis showed that the administration of 3 versus 4 doses of MTX plays a significant favorable impact on the cumulative incidence of engraftment in terms of PMN (94% vs 90%, p=0.04) and PLTS (90% vs 86%, p= 0.04). Moreover, the 3 MTX doses group achieved significant better results in terms of 3-years CI of TRM (15% vs 23%, p=0.03), OS (66% vs 52%, p=0.001), PFS (54% vs 41%, p= 0.001) and GRFS (44% vs 27%, p=0.00001). We built a multivariate Cox model based on the following covariates: patient age (median value), Donor/host gender, Donor/host CMV status, Disease status, HCT-CI Sorror, Karnofsky PS, Conditioning intensity, Source of stem cells (PB vs BM), ATG dose (median value), MTX dose (4 doses vs 3), Center (≥10 transplants/year vs <10 transplants/year), host/donor Italian origin. Multivariate analysis confirmed the significant protective role of 3 MTX doses on grade 3-4 aGvHD (HR 0.41, p=0.03), TRM (HR 0.59, p=0.02), OS (HR 0.59, p=0.001), PFS (HR 0.6, p<0.0001) and GRFS (HR 0.58, p<0.0001). Interestingly, the relapse risk was significantly inferior in patients who received 3 doses of MTX instead of 4 (HR 0.60, p=0.003). Conclusions: A fourth dose of MTX in patients receiving ATG+ CSA may negatively impact on engraftment, aGvHD, TRM, OS, PFS and GRFS. Our data support the need for a prospective investigation of MTX doses in the context of patients receiving unrelated matched HSCT and ATG+a CNI. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Trial in Progress: AB-101, an Allogeneic, Non-Engineered, Cord Blood-Derived Natural Killer (NK) Cell Therapy, As Monotherapy or in Combination with Rituximab in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma

Background: Natural Killer (NK) cells are known to eliminate tumors directly or via antibody-dependent cellular cytotoxicity (ADCC) which is dependent on the maturation, activation and FcγRIIIA (CD16) phenotype of NK cells. Many cancer patients have low NK cell number and dysfunctional innate immunity, which has been correlated with outcomes to monoclonal antibody (mAb) therapy. AB-101 is an allogeneic, non-genetically modified cord blood-derived NK cell therapy, developed to potentially enhance patients' innate anti-tumor activity in combination with approved oncology products with known ADCC mechanism of action. AB-101 has been optimized for combination with mAbs through the novel AlloNK™ proprietary large scale manufacturing process utilizing donor cord blood units. The cord blood unit is selected for key attributes, including an immunoglobulin-like receptor B (KIR-B) haplotype and the natural high-affinity variant of CD16 (158V/V polymorphism). The AlloNK™ process results in an activated and mature NK cell product with increased cell surface expression of CD16, NKG2D, NKp30/44/46, and DNAM-1, without any requirement for genetic engineering. Additionally, the process generates sufficient NK cells to treat hundreds to thousands of patients from a single cord blood unit and produces a consistently active NK cell product, with little donor-to-donor variability. The combination of AB-101 and rituximab has demonstrated strong cytotoxic activity in preclinical studies; the combination led to improved survival over rituximab or NK cells alone in xenograft mouse models. As a cryopreserved, "off-the-shelf", and infusion-ready product, AB-101 is being evaluated for the treatment of hematologic malignancies in combination with standard of care antibody therapies. Study Design, Treatment and Methods: AB-101-01 is a first in human, Phase 1/2, multi-center, open-label study to evaluate the safety and anti-tumor activity of AB-101 as monotherapy and in combination with rituximab in patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) of B-cell origin or CLL. This study has 3 parts: Phase 1, 1b, and 2. Phase 1 will evaluate 2 dose levels as monotherapy or in combination with rituximab using the 3+3 dose escalation method. Phase 1b will enroll up to 45 patients in combination with rituximab to determine the recommended phase 2 dose (RP2D). Phase 2 will enroll an additional 15 patients at the RP2D. AB-101 will be given at 1 or 4 billion cells per dose. All enrolled patients will receive at least 1 treatment cycle of 4 doses of AB-101, administered once weekly. Prior to receiving the first dose of AB-101, patients will receive 3 consecutive days of lymphodepleting chemotherapy consisting of fludarabine (30 mg/m2/day) and cyclophosphamide (250 or 500 mg/m2/day). After each AB-101 infusion, patients will receive interleukin-2 (IL-2) at 1×106 IU/m2/dose or 6×106 IU/dose to potentiate NK cell activation and persistence. If given, 375 mg/m2 of rituximab is dosed on the second day of lymphodepletion and with the second and fourth dose of AB-101. Patients who have a complete or partial response or maintain stable disease with the first cycle of the combination may receive 3 additional cycles such that cycle 2 is given with lymphodepletion and cycles 3 and 4 do not include lymphodepletion. Eligible patients must have a diagnosis of B-cell NHL or CLL and must have received at least 2 prior lines of therapy, including an anti-CD20 antibody therapy. Treatment with prior CD19 CAR T-cell therapy is permitted. Patients must be at least 18 years of age, have ECOG PS of 0 or 1, and have measurable disease per Lugano 2014 at the time of enrollment. The primary objectives of each phase are as follows: in Phase 1, the evaluation of the safety of 1 and 4 billion cells/dose of AB-101 as monotherapy or in combination with rituximab through the incidence of AEs and DLTs; in Phase 1b, determination of the RP2D based on safety and antitumor response to AB-101 with rituximab; and in Phase 2, further characterization of the efficacy profile. The study is currently enrolling at 10 U.S. centers. (ClinicalTrials.gov Identifier: NCT04673617)

The Four Ws of the Fourth Dose COVID-19 Vaccines: Why, Who, When and What.

With the emergence of SARS-CoV-2 variants, vaccine breakthrough is a major public health concern. With evidence of reduced neutralizing antibody activity against Omicron variants and fading antibody level after the third-dose booster vaccine, there are suggestions of a fourth-dose booster vaccine. In this review, the benefits of a fourth-dose booster is evaluated from four perspectives, including the effectiveness of the booster dose against virus variants (Why), susceptible groups of individuals who may benefit from additional booster dose (Who), selection of vaccine platforms to better enhance immunity (What) and appropriate intervals between the third and fourth booster dose (When). In summary, a fourth dose can temporarily boost the immune response against SARS-CoV-2 variants and can be considered for specific groups of individuals. A heterologous vaccine strategy using mRNA vaccine in individuals primed with inactivated vaccine may boost immunity against variants. The timing of the fourth dose should be individualized but an interval of 4 months after the third-dose booster is appropriate. A universal fourth booster dose is not necessary.

Waning of specific antibodies against Delta and Omicron variants five months after a third dose of BNT162b2 SARS-CoV-2 vaccine in elderly individuals.

The emergence of new SARS-CoV-2 variants, such as the more transmissible Delta and Omicron variants, has raised concerns on efficacy of the COVID-19 vaccines. Here, we examined the waning of antibody responses against different variants following primary and booster vaccination. We found that antibody responses against variants were low following primary vaccination. The antibody response against Omicron was almost non-existent. Efficient boosting of antibody response against all variants, including Omicron, was observed following a third dose. The antibody response against the variants tested was significantly higher at one month following booster vaccination, compared with two months following primary vaccination, for all individuals, including the low antibody responders identified at two months following primary vaccination. The antibody response, for all variants tested, was significantly higher at four months post booster than at five months post primary vaccination, and the proportion of low responders remained low (6-11%). However, there was significant waning of antibody response in more than 95% of individuals at four months, compared to one month following booster. We also observed a robust memory B cell response following booster, which remained higher at four months post booster than prior to booster. However, the memory B cell responses were on the decline for 50% of individuals at four months following booster. Similarly, while the T cell response is sustained, at cohort level, at four months post booster, a substantial proportion of individuals (18.8 - 53.8%) exhibited T cell response at four months post booster that has waned to levels below their corresponding levels before booster. The findings show an efficient induction of immune response against SARS-CoV-2 variants following booster vaccination. However, the induced immunity by the third BNT162b2 vaccine dose was transient. The findings suggest that elderly individuals may require a fourth dose to provide protection against SARS-CoV-2.

Investigating the Return Possibility of Covid-19 Mutated Strains and Role of Vaccination in Present and Future

Covid-19 has killed more than 7 million people in the world so far. With general vaccination in 2021, the severity of deaths decreased significantly, but after 6 months, new types of Covid-19 emerged and deaths incidence increased. Epidemiological studies showed that despite high number of deaths, vaccination has reduced the severity of the disease in population. Many researchers did not suggest injecting third and fourth doses due to antigenic changes of virus, but some countries, such as Iran, have continued vaccination. In America and European countries, it has been suggested that vaccination should continue only for high-risk people. Biological science has not rejected dangerous mutations for this virus and has prepared itself to face mutated species of this virus again. Certainly, vaccination is the most important way to deal with the virus in future; but despite millions of mutations in Covid-19 virus structure, the compatibility of vaccine with new viral antigens is important in order to provide effective vaccines with high efficiency.

Reduction in severity and mortality in COVID-19 patients owing to heterologous third and fourth-dose vaccines during the periods of delta and omicron predominance in Thailand

ObjectivesThe COVID-19 pandemic has evolved quickly, with different variants of concern resulting in the need for countries to offer booster vaccinations. Although studies have assessed homologous schedules in detail, the effectiveness of heterologous booster vaccine schedules against severity and mortality with newer variants remains to be explored fully. MethodsUtilizing a Hospital Information System for COVID-19 established in Chiang Mai, Thailand, we conducted a cohort study by linking patient-level data on laboratory-confirmed COVID-19 cases to the national immunization records, during delta-predominant and omicron-predominant periods. ResultsCompared to omicron, COVID-19 cases during the delta period were 10 times more likely to have severe outcomes and in-hospital deaths. During omicron, a third vaccine dose had an 89% reduced risk of both severe COVID-19 and death. The third dose received 14-90 days before the date of the positive test showed the highest protection (93%). Severe outcomes were not observed with the third dose during delta, and the fourth dose during the omicron period. All the vaccine types used for boosting in Thailand offered similar protection against severe COVID-19. ConclusionBooster doses provided a very high level of protection against severe COVID-19 outcomes and deaths. Booster campaigns should focus on improving coverage by utilizing all available vaccines to ensure optimal protection.

The Association Between Prebooster Vaccination Antibody Levels and the Risk of Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

The correlation between anti-severe acute respiratory syndrome coronavirus 2 antibody levels and infection was reported. Here, we estimated the role of pre-fourth dose levels using data from 1098 healthcare workers. The risk of infection was reduced by 46% (95% confidence interval, 29%-59%) for each 10-fold increase in prebooster levels. Prebooster antibody levels could be used to optimally time boosters.

A fourth dose of the inactivated SARS-CoV-2 vaccine redistributes humoral immunity to the N-terminal domain

The effectiveness of a 3rd dose of SARS-CoV-2 vaccines waned quickly in the Omicron-predominant period. In response to fast-waning immunity and the threat of Omicron variant of concern (VOC) to healthcare workers (HCWs), we conduct a non-randomized trial (ChiCTR2200055564) in which 38 HCWs volunteer to receive a homologous booster of inactivated vaccines (BBIBP-CorV) 6 months after the 3rd dose. The primary and secondary outcomes are neutralizing antibodies (NAbs) and the receptor-binding domain (RBD)-directed antibodies, respectively. The 4th dose recalls waned immunity while having distinct effects on humoral responses to different antigens. The peak antibody response to the RBD induced by the 4th dose is inferior to that after the 3rd dose, whereas responses to the N-terminal domain (NTD) of spike protein are further strengthened significantly. Accordingly, the 4th dose further elevates the peak level of NAbs against ancestral SARS-CoV-2 and Omicron BA.2, but not BA.1 which has more NTD mutations. No severe adverse events related to vaccination are recorded during the trial. Here, we show that redistribution of immune focus after repeated vaccinations may modulate cross-protective immune responses against different VOCs.

Abstract 15766: A Perfect [vt] Storm - How All the Wrong Factors Converged During a Dofetilide Load

Background: Dofetilide is a class III antiarrhythmic often used for the treatment of atrial fibrillation. Given its QTc prolonging properties, it is invariably initiated in an inpatient setting. While admissions for this drug are often unexciting, pharmacologic cardioversion in general and dofetilide in particular carry unique hazards. Objective: To review a case where several risk factors converged during a dofetilide load to produce a life threatening event. Case: A 75 year old male in persistent atrial fibrillation was admitted for dofetilide and started on 500 mcg PO Q12 (based on QTc and GFR). He did not experience any QTc prolongation after his first two doses, and converted to sinus rhythm on his second day of hospitalization. With this, he had an abrupt decrease in heart rate from 110 to 60 bpm. Within minutes, he suddenly developed flash pulmonary edema and required treatment for acute heart failure with IV diuresis. Fortunately, he improved with therapy in time to receive his third dose, after which QTc remained at 450. However, he had non sustained polymorphic ventricular ectopy overnight. His full AM dose was given before the monitor was reviewed (given his normal QTc), and within 2 hrs of this fourth dose, QTc prolonged markedly. He developed ventricular bigeminy with long-coupled PVCs. Subsequently, he developed sustained torsades requiring chest compressions and defibrillation. The patient recovered well, and dofetilide was discontinued. Conclusion: Acute heart failure after restoration of sinus rhythm is an uncommon but known complication of cardioversion, both electrical and pharmacologic. Furthermore, hemodynamic derangement is known to decrease arrhythmia threshold, which, along with his abrupt drop in heart rate and recent diuresis, likely contributed to the development of torsades. Furthermore, while his QTc appeared numerically acceptable before the fourth dose was given, later review revealed an abnormal T wave morphology with prolonged T peak to end time, which might have prompted a dose change if recognized. In short, monitoring dofetilide patients involves more than just GFR and QTc - other observable factors can portend poor outcome.

Effect of Previous COVID-19 Vaccination on Humoral Immunity 3 Months after SARS-CoV-2 Omicron Infection and Booster Effect of a Fourth COVID-19 Vaccination 2 Months after SARS-CoV-2 Omicron Infection.

In this study, we aimed to determine the effect of COVID-19 vaccination on 3-month immune response and durability after natural infection by the Omicron variant and to assess the immune response to a fourth dose of COVID-19 vaccination in patients with prior natural infection with the Omicron variant. Overall, 86 patients aged ≥60 years with different vaccination histories and 39 health care workers (HCWs) vaccinated thrice before Omicron infection were enrolled. The sVNT50 titer was significantly lower in patients with incomplete vaccination before SARS-CoV-2 infection with the S clade (p < 0.001), Delta variant (p < 0.001), or Omicron variant (p = 0.003) than in those vaccinated thrice. The sVNT results against the Omicron variant did not differ significantly in patients aged ≥60 years (p = 0.49) and HCWs (p = 0.17), regardless of the recipient receiving the fourth dose 2 months after COVID-19. Incomplete COVID-19 vaccination before Omicron infection for individuals aged ≥60 years conferred limited protection against homologous and heterologous virus strains, whereas two or three doses of the vaccine provided cross-variant humoral immunity against Omicron infection for at least 3 months. However, a fourth dose 2 months after Omicron infection did not enhance immunity against the homologous strain. A future strategy using the bivalent Omicron-containing booster vaccine with appropriate timing will be crucial.

COVID-19 Vaccines and Solid Organ Transplantation: More Doses, More Protection.

COVID-19 Vaccines and Solid Organ Transplantation: More Doses, More Protection.

Humoral response after athird and fourth dose of mRNA-based SARS-CoV-2 vaccine in previously seronegative kidney transplant recipients.

Growing evidence shows diminished response to mRNA-based SARS-CoV‑2 vaccination in kidney transplant recipients. We aimed to investigate the seroconversion rate after a3rd and 4th dose of mRNA vaccination in kidney transplant recipients without prior antibody response to two or three vaccination doses.This retrospective study included 324 prevalent kidney transplant recipients of asingle tertiary transplantation center of which 157 remained seronegative, defined as anti-spike-RBD-IgG antibody titer < 7.1 BAU/ml, after two doses of mRNA-based SARS-CoV‑2 vaccination. Maintenance immunosuppression was not changed. The median patient age was 60.6 years (IQR 51.4-68.1 years), 66.9% were male. Positivity for anti-spike-RBD-IgG (≥ 7.1 BAU/ml) was measured 4-5weeks after administration of a3rd and 4th vaccine dose.Seroconversion rates were 63.9% after a3rd dose and 29.3% after a4th dose of vaccine. Cumulative prevalence of seropositivity was 51.5% after 2 doses, 80.5% after 3 doses and 84.2% after 4 doses.In conclusion, seroconversion can be achieved in the majority of the kidney transplant recipients by administrating three or four doses of mRNA vaccine without changing maintenance immunosuppression.