Low Antibody Research Articles

Implementation of Continuous Pegasparaginase Dosing without an Asparaginase-Free Interval Reduces Hypersensitivity in Children with Newly Diagnosed Acute Lymphoblastic Leukemia: Results of the DCOG ALL11 Pegasparaginase Randomization

Background: Asparaginase is key in the treatment of pediatric acute lymphoblastic leukemia (ALL). Hypersensitivity is one of its major side effects and hamper its use. Most hypersensitivity reactions occur after an asparaginase-free interval, as neutralizing anti-drug antibodies increase during these intervals. Thus we hypothesized that a continuous PEGasparaginase dosing schedule (without an asparaginase-free interval) would result in less hypersensitivity to PEGasparaginase compared to the standard non-continuous PEGasparaginase dosing schedule. Methods: Medium risk (MR) patients (aged 1-18 yrs) with ALL enrolled in the DCOG ALL11 protocol, were randomized to receive 14 individualized PEGasparaginase doses after an asparaginase-free interval of 3 months or to continue PEGasparaginase treatment following the first 3 doses in induction (EudraCT:2012-000067-25; Dutch Trial Register NL3227). Hypersensitivity included allergies, allergic-like reactions, and silent inactivations, where inactivating hypersensitivity reactions comprised the sum of allergies and silent inactivations. Secondary endpoints included other asparaginase-related adverse event (AEs) (CTCAE >grade 3), such as febrile neutropenia, infection, a thromboembolic event, pancreatitis, and avascular necrosis, as well as antibody levels and treatment outcome. Cumulative incidence of relapse (CIR), cumulative incidence of death (CID) in CR1 and disease-free survival (DFS) were compared between both treatment arms. Results: 312 MR patients were randomized to receive PEGasparaginase in a continuous (n=155) and non-continuous (n=157) dosing schedule. Hypersensitivity reactions occurred in 4 out of 155 (2.6%) patients in the continuous treatment arm versus 17 out of 157 (10.8%) patients in the non-continuous treatment arm (P<0.01), of which 2 (1.3%) versus 13 (8.3%) were inactivating reactions (Figure 1; P<0.01). Patients in de continuous treatment arm were significantly less likely to get an inactivating hypersensitivity reaction (odds ratio: 0.15 (0.032-0.653), P=0.012). Antibody levels were significantly lower in the continuous arm compared to the non-continuous arm (P<0.01). Without the asparaginase-free interval, the antibody levels slightly increased by 1.1-fold between dose 3 and 4 whereas antibody levels in the non-continuous arm increased by 2.5-fold during the asparaginase-free interval. We did not find any significant differences in the total number of asparaginase-associated AEs between the treatment arms (Figure 1). However, the generalized Poisson model analysis revealed that the occurrence of specific AEs, such as a thromboembolic event and pancreatitis, was influenced by both treatment phase and arm. These correlations can be attributed to the timing of asparaginase administrations, since at start of randomization asparaginase treatment was interrupted in the non-continuous arm but uninterrupted in the continuous arm. Consequently, thromboembolic events and pancreatitis occurred more frequently at the beginning of randomization in the continuous arm compared to the non-continuous arm (Table 1). This pattern reversed when the non-continuous arm resumed asparaginase treatment after the asparaginase-free period, while the continuous arm concluded their treatment. The occurrence of infections was not associated with treatment phase and treatment arm. The median duration of treatment phases was comparable between the two arms, with the exception of a longer duration of protocol M in the continuous versus non-continuous arm (median 10.3 versus 9.4 weeks respectively instead of the planned 9 weeks; P<0.01) Estimated median follow-up time was 57.2 months (95%-CI 51.9-61.3). The 5-yr CIR, CID in CR1 and DFS were 5.6% (SE 2.1%), 1.9% (SE 1.1%) and 91.9% (SE 2.4%) for continuous treatment vs 4.0% (SE 1.8%), 0.6% (SE 0.6%) and 95.3% (SE 1.9%) for non-continuous treatment (P=0.710; P=0.308; P=0.289), respectively. Conclusion: A continuous dosing schedule of PEGasparaginase resulted in a 7 times lower incidence of inactivating hypersensitivity reactions and lower anti-drug antibody levels compared with a non-continuous dosing schedule with an asparaginase-free interval. The continuous schedule of asparaginase treatment did not increase toxicity but changed the timing of toxicities and did not affect the efficacy of the therapy.

Engineering Superaffinity Antibody Dependent Cellular Cytotoxcity Receptors into iPSC-Derived NK Cells As Next-Generation Immunotherapies for Cancer

Engineered immune cells have provided an important new approach to treating cancer. Most of the progress so far has focused on autologous CAR-T cell therapy, although this approach has been met with several limitations including high-cost and complexity of manufacturing, donor-to-donor variability, and severe toxicities in some patients. Allogenic natural killer (NK) cell therapies have also been shown to mount potent responses against hematologic malignancies but are less likely to cause high-grade toxicities and can be mass produced for off-the-shelf usage. We have developed an induced pluripotent stem cell (iPSC) derived NK (iNK) platform amenable to engineering multiple features in immune cells to improve efficacy against both solid and liquid tumors. Our previous studies showed that knocking out the CISH gene, which encodes a key regulator of activation, in iNK cells significantly improves their anti-cancer activity, in vivo persistence, metabolic fitness, polyfunctional cytokine production, and resistance to cell exhaustion. In these CISH Knockout (KO) iNK cells, we have screened a library of CAR constructs containing domains from diverse immune cell signaling receptors including NK cell activating receptors, cytokine receptors, and integrins. Our screen identified SLNK12, a CAR signaling domains that performed better than both T cell CARs and previously reported NK cell CARs in the context of CISH KO iNK cells. In this study, we describe the development of iNK cells with enhanced antibody dependent cellular cytotoxicity (ADCC) activity. NK cells normally bind antibodies via their CD16A receptor, which has medium-to-low affinity for the antibody Fc domain and is also typically expressed at a low level in unmodified iNKs. We have constructed a recombinant Fc-receptor that combines a high-affinity Fc-binding domain (to improve antibody binding) with our NK cell optimized SLNK12 CAR signaling domain to enhance ADCC-mediated killing. When co-cultured with multiple NC cell resistant tumor lines such as BT-474 (breast cancer) or FaDu (squamous cell carcinoma), these SuperAffinity ADCC receptor CISH KO iNK cells possess potent anti-cancer activity in combination with several different therapeutic monoclonal antibodies, including anti-EGFR (Cetuximab) and anti-HER2 (Trastuzumab) amongst others (Figure 1). We have assessed efficacy in a variety of different 2D and 3D spheroid cytotoxicity assays, as well as cytokine release and CAR activation assays. In addition, we demonstrate that our SuperAffinity receptor mediates tumor cell killing at lower antibody concentrations than do CD16A variants. Furthermore, introduction of serum IgG inhibits, but does not stop ADCC killing for both our SuperAffinity ADCC receptor and the CD16A receptor. Taken together, our results show that engineering CISH KO iNK cells with NK-optimized CARs for enhanced ADCC improves anti-tumor activity against a variety of solid tumor target lines. Future work will focus on advancing the new cellular therapies into clinical development.

2344. Clinical Profile and Immunologic Response from COVID-19 Vaccine Among People Living with HIV Enrolled in a Treatment Hub in the Philippines

Abstract Background SARS-CoV-2 has caused more than 1 million deaths worldwide. Several studies showed that People with HIV had higher rates of hospitalization and mortality with COVID-19 compared with people without HIV but data on serologic response to COVID-19 vaccine among People Living with HIV (PLHIV) is still limited. Methods A prospective cohort study on determination of serologic response to COVID-19 vaccine among completely vaccinated PLHIV enrolled in a treatment hub in the Philippines until December 31, 2021 was done. Baseline demographics were collected via chart review. History of COVID-19 infection was also asked during enrollment, on follow-up and at the end of 6 months after the 2nd dose of vaccination. Blood Extraction were done on enrollment and on follow-up visit to the treatment hub. All the specimen were processed using the SARS-CoV2 ( RocheElecsys Anti-SARS-CoV2 spike (S) protein assays. Results A total of 261 PLHIV who received vaccination from February 11, 2021 to December 29, 2021 were enrolled in the study. The participants received any of the following vaccine brands: CoronoVac/Sinovac (41%), Oxford-AstraZeneca (20.7%), Pfizer-BioNTech (21.5%), Moderna (14.2% and Janseen (2.7%). Univariate analysis showed that presence of opportunistic infection, HIV Viral load , Antiretroviral(ARV) Status, COVID-19 Vaccine brand were all significant predictors of antibody response. On multiple regression analysis, only the Vaccine Brand and Viral load remained significant. Sinovac gave a lower median antibody level and seroconversion rate as compared to other vaccine brands. HIV Viral load > 1000 copies/ml was predictive of lower antibody response. Conclusion In this study among PLHIV, the type of vaccine and HIV viral load were significant predictors of antibody response to COVID-19 Vaccine. Specifically, Sinovac COVID-19 Vaccine gave a lower Median SARS-CoV-2 IgG(S) Antibody and Seroconversion rate as compared to other Vaccine brands. HIV Viral load > 1000 copies/ml was predictive of lower antibody response to COVID-19 Vaccine . Overall, the antibody response peaked at 2-4 weeks after vaccination and decreases thereafter. Disclosures All Authors: No reported disclosures

2079. Maternal hybrid immunity to SARS-CoV-2 during pregnancy provides more durable infant antibody responses compared to natural infection alone

Abstract Background Immunity from natural infection and vaccination (hybrid) may provide more durable SARS-CoV-2 antibody responses; whether this increases durability of maternally-derived antibody responses in infants is unknown. Methods Participants with prior SARS-CoV-2 infection in pregnancy (anti-nucleocapsid [anti-N] IgG+ on enrollment or prior RT-PCR+ or antigen+) were enrolled between January 2021-August 2022. Blood samples collected in pregnancy, delivery/birth, 0-< 3 and 3-6 months postpartum were tested for anti-S+ IgG by Abbott Architect (positive: ≥50 AU/mL) and neutralizing antibodies (serum dilution inhibited infection by 50% [ND50 heat] ≥20 and R2 ≥0.9). Results Among 107 participants at enrollment in pregnancy, median age was 32 years (IQR 30-35) and median gestational age was 31 weeks (IQR 19.1–37.9). At delivery (median 19.7 weeks [IQR 14.3-30.0] from SARS CoV-2 diagnosis), unvaccinated participants and their infants were less likely to have anti-S IgG+ (maternal 87%; cord 86%) or neutralizing antibodies (maternal 86%; cord 75%) than vaccinated (≥1 dose) participants and their infants (maternal and cord both 100% anti-S IgG+ and neutralizing antibodies) (all p≤0.01). By 6 months of age, the proportion of infants of mothers who remained unvaccinated at birth with anti-S IgG+ and neutralizing antibody declined to 50% and 14% (anti-S IgG+ and neutralizing antibody, respectively) compared to 100% (anti-S IgG+ and neutralizing antibody) among infants with vaccinated mothers (all p< 0.01). Infants with anti-S IgG+ or neutralizing antibodies born to unvaccinated mothers had lower median antibody levels at birth (anti-S IgG log10 2.95 vs. 4.40 AU/ml; neutralization log10 1:2.37 vs. 1:4.00, all p< 0.01) and through 6 months of age (anti-S IgG log10 1.95 vs. 3.84 AU/ml, p< 0.01; log10 neutralization 1:1.34 vs. 1:3.20, p=0.11) vs. infants with mothers vaccinated prior to delivery. Neutralizing antibody responses among A) pregnant people with prior SARS-CoV-2 infection during pregnancy and B) their infants by maternal vaccination status *† *Among participants and their infants with positive neutralizing antibodies (ND50 heat ≥20 and R2 ≥0.9). †Maternal vaccination status is at time of blood sample collection; for infants refers to maternal vaccination status at time of delivery. Conclusion SARS-CoV-2 infection alone during pregnancy did not provide persistent antibody responses in infants through 6 months of age. Maternal vaccination provided more durable antibody responses in participants with prior SARS-CoV-2, potentially providing protection to vulnerable infants in the months prior to their own COVID-19 vaccine eligibility. Disclosures Sylvia M. LaCourse, MD, MPH, Merck: Grant/Research Support Alex L. Greninger, MD, PhD, MS, MPhil, Abbott Diagnostics: central testing|Cepheid: central testing|Hologic Inc: central testing|Janssen Infectious Disease: central testing|Novavax, Inc.: central testing|Pfizer, Inc.: central testing Alisa B. Kachikis, MD, MSc, Merck: Grant/Research Support|Pfizer: Grant/Research Support Janet A. Englund, MD, Ark Biopharma: Advisor/Consultant|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Meissa Vaccines: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant Alison L. Drake, PhD, MPH, Merck: Grant/Research Support

2373. "Longitudinal Investigation of Avidity Maturation following Multiple Doses of BNT162b2 mRNA Vaccine Including Bivalent Boosters among Nursing Home Residents and Healthcare Workers"

Abstract Background Increased breakthrough infections among nursing home residents (NHR) are clinically consequential despite good vaccine coverage and substantial antibody titers. While vaccination blunted severe outcomes, breakthrough infections may arise from lower vaccine-induced antibody quality. We aimed to assess vaccine-induced antibody quality among NHR and younger healthcare workers (HCW) using antibody avidity. Methods We longitudinally sampled 50 NHR and 30 HCWs, with or without prior history of COVID-19, who received the BNT162b2 mRNA vaccine at 0-14 days before, 2 weeks, and 4-6 months after each vaccine dose up to the bivalent (BV) boosters. Primary outcomes included anti-spike, anti-Receptor Binding Domain (RBD), and avidity levels to the ancestral Wuhan, Delta, and Omicron BA.1 strains determined by bead-multiplex immunoassay and ability to bind after 6M urea vs. saline incubation. Results After the primary series, anti-spike and RBD titers increased significantly to all 3 strains in both NHR and HCW. Avidity levels progressively increased across all time points up to the 3rd dose. Interestingly, this increase continued 6-8 months after vaccination suggesting that affinity maturation continues to occur for many months after the primary vaccination series. NHRs without prior infection have the poorest avidity levels to Delta and Omicron, especially before the 3rd dose. The 3rd dose raised avidity levels substantially in all groups and for all strains. Avidity levels after boosting, across the 3rd and 4th doses, demonstrate evidence of durability. Preliminary findings after BV boost show a continuation of avidity maturation with a larger impact on prior infected individuals. Wuhan Spike Avidity Avidity index of the Wuhan spike antibody across different time points among naive and prior infected individuals. Prevax- before primary series; Postvax- 2 weeks after primary series; M6- 6 months after primary series; Postboost- 2 weeks after 1st monovalent booster; M3M6postboost- 3-6months post booster; Postboost 2- 2 weeks after 2nd monovalent booster. NH- Nursing home; HCW- Healthcare Workers Omicron BA.1 spike Avidity Avidity index of the BA.1 spike antibody across different time points among naive and prior infected individuals. Prevax- before primary series; Postvax- 2 weeks after primary series; M6- 6 months after primary series; Postboost- 2 weeks after 1st monovalent booster; M3M6postboost- 3-6months post booster; Postboost 2- 2 weeks after 2nd monovalent booster. NH- Nursing home; HCW- Healthcare Workers Conclusion This study underscores the importance of booster vaccination among NHR and HCWs. The booster dose increases avidity, adding to vaccine-induced antibody functional ability. Higher avidity antibodies have higher cross-reactivity to other SARS-CoV-2 strains, as Wuhan boosting improves Delta and Omicron avidity, and should improve protection from ever-evolving strains. Higher avidities may help explain how the vaccine’s protective effects persist even while antibody titers fade between vaccine doses. Disclosures Stefan Gravenstein, MD, MPH, CDC: Grant/Research Support|Genentech: Advisor/Consultant|Genentech: Grant/Research Support|GSK: Advisor/Consultant|GSK: Honoraria|Janssen: Advisor/Consultant|Janssen: Honoraria|NIH: Grant/Research Support|Pfizer: Grant/Research Support|Pfizer: Honoraria|Sanofi: Advisor/Consultant|Sanofi: Grant/Research Support|Sanofi: Honoraria|Seqirus: Grant/Research Support|Seqirus: Honoraria David Canaday, MD, Pfizer: Grant/Research Support

Immunogenicity and safety of heterologous booster with protein-based COVID-19 vaccine (NVX-CoV2373) in healthy adults: A comparative analysis with mRNA vaccines

Information on the protein-based severe acute respiratory syndrome (SARS-CoV-2) vaccine-NVX-CoV2373 (Novavax), as a heterologous booster remains limited. We investigated the immunogenicity and adverse events of NVX-CoV2373 as a second booster and compared them with those of mRNA vaccines in healthy adults. Healthcare workers who had received an mRNA vaccine (mRNA-1273 or BNT-162b2) as the first booster (third dose) 12 weeks prior were recruited. Participants voluntarily received either NVX-CoV2373 or an mRNA vaccine as a second booster. Participants with a history of SARS-CoV-2 infection were excluded. The primary outcomes included serum anti-SARS-CoV-2 spike protein (SP) and neutralizing antibody titers against B.1.1.7 (Alpha), B.1.1.529 (Omicron) BA2, and BA5 variants on the 28th day after the boost. Secondary outcomes included new SARS-CoV-2 infections and adverse events reported during the study period. A total of 160 participants were enrolled in this study. Compared with the mRNA vaccination group (n=59), the NVX-CoV2373 vaccination group (n=101) had significantly lower anti-SARS-CoV-2 SP antibody titers and neutralizing antibody titers against all variants tested after the boost. During the study period, higher rates of new SARS-CoV-2 infections and a lower incidence of adverse events were observed in the NVX-CoV2373 vaccination group. No significant differences in cellular immune responses were observed between the two groups. Compared to a homologous mRNA booster vaccination, heterologous boosters with NVX-CoV2373 showed lower antibody responses, a higher incidence of new SARS-CoV-2 infections, and fewer adverse events.

Antibody responses after BNT162b2 vaccination in Japanese geriatric intermediate care facilities

BackgroundTo evaluate antibody responses against the primary series of vaccination of severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2] vaccines in the staff and residents of Japanese geriatric intermediate care facilities. MethodsAll subjects (159 staff and 96 residents) received two doses of the BNT162b2 mRNA vaccine 3 weeks apart. Baseline data of subject were collected using a structured form. Serum samples were collected three times: before vaccination, 3 weeks after the first dose, and 4 weeks after the second dose, and anti-receptor binding domain of the spike protein of SARS-CoV-2 [anti-RBD] IgG was measured using two immunoassays. ResultsAfter the second dose, geometric mean titers [GMT] of anti-RBD with both the Abbott and Roche assay were significantly lower in residents than staff (2282 AU/mL vs. 8505 AU/mL, and 258 U/mL vs. 948 U/mL, respectively). Multivariate analysis of characteristics affecting antibody responses (≥1280 AU/mL for Abbott and > 210 U/mL for Roche) showed lower odds ratios [ORs] for older age (adjusted OR per 10 year increase [aOR] = 0.62, 95 % confidence interval [95 %CI]; 0.38–1.02), steroid usage (aOR = 0.09, 95 %CI; 0.01–0.60) and regular nonsteroidal anti-inflammatory drugs [NSAIDs] usage (aOR = 0.16, 95 %CI; 0.03–0.88). ConclusionsElderly people and steroid and NSAID users had lower antibody responses following the second vaccine dose.

Effects of dietary inclusion of Moringa oleifera methanolic extract on productive performance, humoral immunity and nutrient digestibility in Japanese quails

ABSTRACT A total of 180 unsexed, 1-day-old quail chicks were divided into four treatments (three replicates). The treatment groups were designated as MOLE-0, MOLE-1, MOLE-2 and MOLE-3. In the MOLE-0 group, quails received a basal diet without supplementation. For MOLE-1, quails were provided with 100 mg/L of MOLE in their water, while MOLE-2 received 200 mg/L of water with MOLE supplementation. The fourth treatment, MOLE-3, received a concentration of 300 mg/L of MOLE in their drinking water. The findings revealed that MOLE-3 exhibited significantly higher weight gain and dressing percentage, along with a lower feed conversion ratio (P < 0.05), while the control group (MOLE-0) exhibited the least growth performance. MOLE-3 showed statistically higher antibody titres and immune organ weights, followed by MOLE-2 and MOLE-1. Conversely, the control group (MOLE-0) had a lower antibody titre against ND. Additionally, nutrient digestibility analysis indicated that MOLE-3 had higher digestibility of dry matter and crude protein (P < 0.05), while group MOLE-0 exhibited lower digestibility (P < 0.05). We concluded that supplementing Moringa oleifera leaf extract at a rate of 300 mg/L resulted in improved growth performance, immunity and nutrient digestibility in Japanese quails.

Prospective Assessment of Humoral and Cellular Immune Responses to a Third COVID-19 mRNA Vaccine Dose Among Immunocompromised Individuals.

Improved coronavirus disease 2019 (COVID-19) prevention is needed for immunocompromised individuals. A prospective study was performed of health care workers (HCW) and immunocompromised participants with baseline serology following 2 mRNA vaccine doses and who were retested after dose 3 (D3); multivariable regression was used to identify predictors of serological responses. IFN-γ/TNF-α T-cell responses were assessed in a subset. In total, 536 participants were included: 492 immunocompromised (206 solid organ transplant [SOT], 128 autoimmune, 80 hematologic malignancy [HM], 48 solid tumor, 25 HIV), and 44 HCW. D3 significantly increased spike IgG levels among all, but SOT and HM participants had the lowest median antibody levels post-D3 (increase from 0.09 to 0.83 and 0.27 to 1.92, respectively), versus HCW and persons with HIV, autoimmune conditions, and solid tumors (increases from 4.44 to 19.79, 2.9 to 15.75, 3.82 to 16.32, and 4.1 to 25.54, respectively). Seropositivity post-D3 was lowest for SOT (49.0%) and HM (57.8%), versus others (>90%). Neutralization post-D3 was lowest among SOT and HM. Predictors of lower antibody levels included low baseline levels and shorter intervals between vaccines. T-cell responses against spike increased significantly among HCW and nonsignificantly among immunocompromised individuals. D3 significantly improves serological but not T-cell responses among immunocompromised individuals. SOT and HM patients have suboptimal responses to D3.

A third (booster) dose of the inactivated SARS-CoV-2 vaccine elicits immunogenicity and T follicular helper cell responses in people living with HIV.

This study sought to explore the immunogenicity of a booster dose of an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in people living with human immunodeficiency virus (HIV) and identify the factors affecting the magnitude of anti-SARS-CoV-2 antibody levels. A total of 34 people living with HIV (PLWH) and 34 healthy donors (HD) were administered a booster dose of the same SARS-CoV-2 vaccine. Anti-SARS-CoV-2 antibody and immunoglobulin G (IgG) levels were measured using the SARS-CoV-2 S protein neutralizing antibody Enzyme-Linked Immunosorbent Assay (ELISA) and 2019-nCov IgG Chemiluminescent Immunoassay Microparticles, respectively. Spearman correlation analysis was used to measure the correlation between laboratory markers and neutralizing antibody and IgG levels. Peripheral blood mononuclear cells (PBMCs) were extracted from each subject using density gradient centrifugation and the numbers of memory T and T follicular helper (Tfh) cells were determined using flow cytometry. PLWH had a marked reduction in CD4 and B cell levels that was accompanied by a lower CD4/CD8 T cell ratio. However, those who received a supplementary dose of inactivated SARS-CoV-2 vaccines exhibited antibody positivity rates that were analogous to levels previously observed. The booster vaccine led to a reduction in IgG and neutralizing antibody levels and the amplitude of this decline was substantially higher in the PLWH than HD group. Correlation analyses revealed a strong correlation between neutralizing antibody levels and the count and proportion of CD4 cells. Anti-SARS-CoV-2 IgG antibody levels followed a similar trend. The expression of memory T and Tfh cells was considerably lower in the PLWH than in the HD group. PLWH had an attenuated immune response to a third (booster) administration of an inactivated SARS-CoV-2 vaccine, as shown by lower neutralizing antibody and IgG levels. This could be attributed to the reduced responsiveness of CD4 cells, particularly memory T and cTfh subsets. CD4 and cTfh cells may serve as pivotal markers of enduring and protective antibody levels. Vaccination dose recalibration may be critical for HIV-positive individuals, particularly those with a lower proportion of CD4 and Tfh cells.

Impact of Nutritional Status on Antibody Titer After Booster mRNA COVID-19 Vaccine Among Elderly Adults in Japan.

Published studies on mRNA coronavirus disease 2019 (COVID-19) vaccine effects focus on younger individuals, comprising the majority of the workforce. Studies in elderly adults are sparse. In total, 107 subjects were recruited (median age 78; interquartile range [IQR], 58.5-90.5; range, 35-105 years). Factors associated with antibody titer after the third mRNA COVID-19 vaccination were compared between 49 elderly (age ≥80; median, 94; IQR, 86-97; range, 80-105 years) and 58 younger (age ≤79; median, 61; IQR, 46-71; range, 35-79 years) adults. Among body mass index (BMI) categories, the group of underweight elderly adults had a lower antibody titer compared to those with normal weight (P < .01 after 1, 3, and 5 months). Elderly adults were less likely to maintain effective antibody titer (≥4160 AU/mL) compared to younger adults: 76% versus 98%, P < .001 after 1 month, and 45% versus 78%, P < .001 after 3 months. Elderly adults who maintained effective antibody titer for 5 months had a higher BMI (22.9 kg/m2 vs 20.1 kg/m2, P = .02), and were less likely to have underweight BMI (0% vs 31%, P = .02) compared to the subjects who failed to maintain effective antibody titer. These results highlight the impact of nutritional status and the deleterious effect of underweight BMI on antibody titer and its maintenance among elderly adults following booster mRNA COVID-19 vaccination.

Antibody Responses to Influenza Vaccination are Diminished in Patients With Inflammatory Bowel Disease on Infliximab or Tofacitinib.

We sought to determine whether six commonly used immunosuppressive regimens were associated with lower antibody responses after seasonal influenza vaccination in patients with inflammatory bowel disease [IBD]. We conducted a prospective study including 213 IBD patients and 53 healthy controls: 165 who had received seasonal influenza vaccine and 101 who had not. IBD medications included infliximab, thiopurines, infliximab and thiopurine combination therapy, ustekinumab, vedolizumab, or tofacitinib. The primary outcome was antibody responses against influenza/A H3N2 and A/H1N1, compared to controls, adjusting for age, prior vaccination, and interval between vaccination and sampling. Lower antibody responses against influenza A/H3N2 were observed in patients on infliximab (geometric mean ratio 0.35 [95% confidence interval 0.20-0.60], p = 0.0002), combination of infliximab and thiopurine therapy (0.46 [0.27-0.79], p = 0.0050), and tofacitinib (0.28 [0.14-0.57], p = 0.0005) compared to controls. Lower antibody responses against A/H1N1 were observed in patients on infliximab (0.29 [0.15-0.56], p = 0.0003), combination of infliximab and thiopurine therapy (0.34 [0.17-0.66], p = 0.0016), thiopurine monotherapy (0.46 [0.24-0.87], p = 0.017), and tofacitinib (0.23 [0.10-0.56], p = 0.0013). Ustekinumab and vedolizumab were not associated with reduced antibody responses against A/H3N2 or A/H1N1. Vaccination in the previous year was associated with higher antibody responses to A/H3N2. Vaccine-induced anti-SARS-CoV-2 antibody concentration weakly correlated with antibodies against H3N2 [r = 0.27; p = 0.0004] and H1N1 [r = 0.33; p < 0.0001]. Vaccination in both the 2020-2021 and 2021-2022 seasons was associated with significantly higher antibody responses to influenza/A than no vaccination or vaccination in 2021-2022 alone. Infliximab and tofacitinib are associated with lower binding antibody responses to influenza/A, similar to COVID-19 vaccine-induced antibody responses.

XBB.1.5 spike protein COVID-19 vaccine induces broadly neutralizing and cellular immune responses against EG.5.1 and emerging XBB variants

Monovalent SARS-CoV-2 Prototype (Wuhan-Hu-1) and bivalent (Prototype + BA.4/5) COVID-19 vaccines have demonstrated a waning of vaccine-mediated immunity highlighted by lower neutralizing antibody responses against SARS-CoV-2 Omicron XBB sub-variants. The reduction of humoral immunity due to the rapid evolution of SARS-CoV-2 has signaled the need for an update to vaccine composition. A strain change for all authorized/approved vaccines to a monovalent composition with Omicron subvariant XBB.1.5 has been supported by the WHO, EMA, and FDA. Here, we demonstrate that immunization with a monovalent recombinant spike protein COVID-19 vaccine (Novavax, Inc.) based on the subvariant XBB.1.5 induces neutralizing antibodies against XBB.1.5, XBB.1.16, XBB.2.3, EG.5.1, and XBB.1.16.6 subvariants, promotes higher pseudovirus neutralizing antibody titers than bivalent (Prototype + XBB.1.5) vaccine, induces SARS-CoV-2 spike-specific Th1-biased CD4 + T-cell responses against XBB subvariants, and robustly boosts antibody responses in mice and nonhuman primates primed with a variety of monovalent and bivalent vaccines. Together, these data support updating the Novavax vaccine to a monovalent XBB.1.5 formulation for the 2023–2024 COVID-19 vaccination campaign.

Economic optimization of antibody capture through Protein A affinity nanofiber chromatography

In this study we compare a nanofiber device and a resin column, both with the same Protein A ligand, for the capture of four different monoclonal antibodies and a trivalent crystallizable fragments (Fc) of antibody. We show that the dynamic binding capacity of the nanofiber device varies slightly with residence time, with the transfer kinetics slower for the IgG1, than for the IgG4 antibody. Surface plasmon resonance shows that the trivalent Fc binds to multiple Protein A ligand sites due to its three repeating Fc units, whereas multiple IgG antibodies bind to a single Protein A ligand. The nanofiber device gives comparable eluate purity to the resin column but at lower antibody concentrations due to its larger housing volume and lower binding capacity. It can be used for up to 200 cycles without performance loss and gives consistent eluate quality when scaled from 0.4 mL to 3.75 mL. We show that the use of a single nanofiber device to process one 2000 L clarified harvest through multiple cycles can reduce the Cost of Goods fivefold compared with a resin column. Costs are potentially lower for up to thirteen 2000 L harvests if device reuse can be validated. Nanofiber devices are thus an attractive option for manufacture of pre-clinical or clinical trial material where the number of batches is limited.

An auristatin-based antibody-drug conjugate targeting EphA2 in pancreatic cancer treatment

Pancreatic adenocarcinoma, a highly aggressive form of cancer with a poor prognosis, necessitates the development of innovative treatment strategies. Our prior research showcased the growth-inhibiting effects of the anti-EphA2 antibody drug hSD5 on pancreatic cancer tumors. This antibody targets and induces the degradation of the EphA2 receptor while also prompting the antibody's internalization. A deeper dive into the hSD5 Fab crystallographic structure and docking studies revealed that hSD5's CDRH3 drives the primary interaction between hSD5 and the EphA2 active site. In this study, we developed a novel antibody-drug conjugate (ADC)-the auristatin-based hSD5-vedotin specifically targeting EphA2 in pancreatic cancer cells. This ADC aims at the tumor-specific antigen EphA2, triggering endocytosis and releasing the conjugated payload molecule Monomethyl auristatin E (MMAE), amplifying the tumor-killing effect. Upon cellular entry, hSD5-vedotin demonstrated an impressive tumor-killing response, inhibiting tumor cell growth and promoting apoptosis even at lower antibody concentrations. In a pancreatic cancer xenograft animal model, hSD5-vedotin showcased the potential to suppress tumor growth entirely. Notably, potential immune resistance responses were also observed in recurrent pancreatic cancer tumors. Our empirical results underscore the possibility of developing hSD5-vedotin further, which we anticipate will have a broader and more potent therapeutic impact on pancreatic cancer and other EphA2-related cancers.

Extracellular Vesicles Carry SARS-COV-2 Proteins Associated With Lower Antibody Production, Cardiovascular Complications, and Worse Outcomes in Patients With Severe COVID-19

Extracellular Vesicles Carry SARS-COV-2 Proteins Associated With Lower Antibody Production, Cardiovascular Complications, and Worse Outcomes in Patients With Severe COVID-19

Anti-SARS-CoV-2 antibody levels predict outcome in COVID-19 patients with type 2 diabetes: a prospective cohort study

Patients with type 2 diabetes (T2D) constitute one of the most vulnerable subgroups in COVID-19. Despite high vaccination rates, a correlate of protection to advise vaccination strategies for novel SARS-CoV-2 variants of concern and lower mortality in this high-risk group is still missing. It is further unclear what antibody levels provide protection and whether pre-existing organ damage affects this threshold. To address these gaps, we conducted a prospective multicenter cohort study on 1152 patients with COVID-19 from five hospitals. Patients were classified by diabetes and vaccination status. Anti-SARS-CoV-2-spike-antibodies, creatinine and NTproBNP were measured on hospital admission. Pre-specified endpoints were all-cause in-hospital-mortality, ICU admission, endotracheal intubation, and oxygen administration. Propensity score matching was applied to increase comparability. We observed significantly lower anti-SARS-CoV-2-spike-antibodies in diabetic non-survivors compared to survivors (mean, 95% CI 351BAU/ml, 106–595 vs. 1123, 968–1279, p < 0.001). Mortality risk increased two-fold with each standard deviation-decrease of antibody levels (aHR 1.988, 95% CI 1.229–3.215, p = 0.005). T2D patients requiring oxygen administration, endotracheal intubation and ICU admission had significantly lower antibody levels than those who did not (p < 0.001, p = 0.046, p = 0.011). While T2D patients had significantly worse outcomes than non-diabetic patients, the differences were less pronounced compared to propensity-score-matched non-diabetic patients. Anti-SARS-CoV-2 spike antibodies on hospital admission are inversely associated with oxygen administration, endotracheal intubation, intensive care and in-hospital mortality in diabetic COVID-19 patients. Pre-existing comorbidities may have a greater impact on outcome than diabetes status alone.

Potential determinants of antibody responses after vaccination against SARS-CoV-2 in older persons: the Doetinchem Cohort Study

BackgroundImmune responses to vaccination vary widely between individuals. The aim of this study was to identify health-related variables potentially underlying the antibody responses to SARS-CoV-2 vaccination in older persons. We recruited participants in the long-running Doetinchem Cohort Study (DCS) who underwent vaccination as part of the national COVID-19 program, and measured antibody concentrations to SARS-CoV-2 Spike protein (S1) and Nucleoprotein (N) at baseline (T0), and a month after both the first vaccination (T1), and the second vaccination (T2). Associations between the antibody concentrations and demographic variables, including age, sex, socio-economic status (SES), comorbidities (cardiovascular diseases and immune mediated diseases), various health parameters (cardiometabolic markers, inflammation markers, kidney- and lung function) and a composite measure of frailty (‘frailty index’, ranging from 0 to 1) were tested using multivariate models.ResultsWe included 1457 persons aged 50 to 92 years old. Of these persons 1257 were infection naïve after their primary vaccination series. The majority (N = 954) of these individuals were vaccinated with two doses of BNT162b2 (Pfizer) and their data were used for further analysis. A higher frailty index was associated with lower anti-S1 antibody responses at T1 and T2 for both men (RT1 = -0.095, PT1 = 0.05; RT2 = -0.11, PT2 = 0.02) and women (RT1 = -0.24, PT1 < 0.01; RT2 = -0.15, PT2 < 0.01). After correcting for age and sex the frailty index was also associated with the relative increase in anti-S1 IgG concentrations between the two vaccinations (β = 1.6, P < 0.01). Within the construct of frailty, history of a cardiac catheterization, diabetes, gastrointestinal disease, a cognitive speed in the lowest decile of the population distribution, and impaired lung function were associated with lower antibody responses after both vaccinations.ConclusionsComponents of frailty play a key role in the primary vaccination response to the BNT162b2 vaccine within an ageing population. Older persons with various comorbidities have a lowered immune response after their first vaccination, and while frail and sick older persons see a stronger increase after their second vaccination compared to healthy people, they still have a lower antibody response after their second vaccination.

Predictors of lower response to COVID19 vaccine in people living with HIV. A 6-month follow-up study

Abstract Clinical trials demonstrated efficacy and safety of COVID-19 vaccines, although enrolment of immunocompromised individuals, including people living with HIV (PLWH), has been limited. Although cellular immunity is not negligible, recent evidence suggests a strong correlation between neutralising antibody titre and overall protection against infection. Our study aimed to identify potential predictors of lower response to vaccine in PLWH. We conducted a prospective study at the Padua University Teaching Hospital, Italy. Participants were vaccinated with a BNT162b2 2-dose schedule in early 2021. Non-naïve to SARS-CoV-2 were excluded. Anti-S titres were assessed using AdviseDx SARS-CoV-2 IgG II quantitative CMIA assay at 30, 90 and 180 days after completion of vaccination. Non-response was defined as &amp;lt; 50 AU/mL and lower response as the lowest quartile. Information on age, sex, BMI, comorbidities, CD4 count, CD4/CD8, viral load was collected. The association between predictors and lower response was assessed using logistic and linear regression. We enrolled 180 individuals (15 excluded). Mean age 54.0±11.2 years; 17% females; 23% showed CD4 count &amp;lt;500 (none &amp;lt;200), while 18.2% CD4/CD8 &amp;lt;0.5. All responded to vaccine at any follow-up time. Lower response was associated with dyslipidaemias (AOR 4.75; 95%CI: 1.39-16.20; 30 days) and diabetes (AOR 7.11; 95%CI: 1.10-46.10; 90 days), while 1-unit increase in BMI was associated with reduced risk (AOR 0.78; 95%CI 0.64-0.95; 90 days). No correlation was found between anti-S titre and CD4 count (β -0.057; p 0.52), CD4/CD8 (β 0.050; p 0.57) nor viral load (β -0.001; p 0.99). Response to vaccine is good and sustained in well controlled PLWH. Dyslipidaemias and diabetes are associated with a non-concerning lower response. Increased BMI as protective factor may reflect the effect of good nutritional status. Using CD4 count, CD4/CD8 or viral load does not appear to help predict vaccine response in well controlled HIV. Key messages • Well controlled People Living With HIV (PLWH) respond well to BNT162b2 vaccine, and neutralising antibody titres are maintained for up to 6 months after primary vaccination. • PLWH with dyslipidaemias and diabetes have lower antibody persistence, although always above the threshold. Good nutritional status may contribute to longer antibody persistence.

Immune response to COVID-19 vaccines among people living with human T-cell lymphotropic virus type 1 infection: a retrospective cohort study from Iran.

The effectiveness of COVID-19 vaccination is still unclear in individuals with underlying diseases such as HTLV-1 infection. This retrospective cohort study aimed to evaluate the humoral response of COVID-19 vaccines among people living with HTLV-1 (PLHTLV) in northeastern Iran. From December 2021 to October 2022, eighty-six HTLV-1+ subjects (50 males and 36 females; 47.7 ± 11.2 years) and 90 HTLV-1 seronegative individuals (age- and sex-matched convenient samples) were enrolled. The humoral immune response was evaluated by measuring different COVID-19 Abs in serum samples at least 28 days after receiving 2nd or 3rd doses of COVID-19 vaccines. Throughout all three rounds of immunization, Sinopharm was the most commonly used COVID-19 vaccine across all three immunization rounds. Compared to the HTLV-1- group, a significantly lower frequency of all four Abs activity was observed among PLHTLV:anti-nucleocapsid (66.3% vs 86.7%, p = 0·001), anti-spike (91.9% vs 98.9%, p = 0·027), RBD (90.7% vs 97.8%, p = 0·043), and neutralizing Abs (75.6% vs 95.5%, p < 0·001). Also, the frequency of all Abs in 28 patients with HAM/TSP was higher than that of 58 asymptomatic carriers, although this difference was statistically significant only in the case of anti-spike Abs (p = 0.002). Notably, PLHTLV-vaccinated against COVID-19 demonstrated significantly lower antibody activities, indicating a reduced humoral immune response to COVID-19 vaccines.