Post-first Dose Research Articles

Safety and immunogenicity of freeze-dried human rabies vaccines: A phase 3 clinical trial of Zagreb and Essen regimes

ABSTRACT Recently optimized freeze-dried rabies vaccines (Vero cell) are promising for rabies prevention; however, comparisons of Essen 5-dose and Zagreb 4-dose regimens are needed for clinical applications. This phase III clinical trial aimed to assess the safety and immunogenicity of candidate freeze-dried rabies vaccines developed for human use by Shandong Yeedo Biotechnology (Registration No.: CTR20182016, http://www.chinadrugtrials.org.cn/index.html). In total, 40 participants in stage I and 1797 subjects in stage II with an age range of 10–60 years were recruited. Both 4-dose and 5-dose experimental vaccines were well-tolerated in stage 1, with similar overall adverse event (AE) rates. In stage 2, systemic fever (35.39%) and local pain (48.91%) were common, and the rate of Grade 3 AEs was approximately 2.5%. Rates of local reactions and unsolicited AEs differed among groups (p = .045 and 0.011). Immunogenicity analyses showed higher antibody levels, seroconversion rates, and pre-immune seroconversion rates in the 4-dose experimental group versus the 5-dose group (p < .001) on day 7 post-first dose, with similar GMCs (geometric mean concentrations) by day 14. Pre-immune negative subjects had comparable antibody levels in the 4-dose and 5-dose experimental groups, outperforming the 5-dose control group (p = .039). The rate difference (95% CI) for first-dose seroconversion at 14 days post-vaccination among pre-immune antibody-negative subjects indicated non-inferiority between the 5-dose experimental and control groups. Overall, the Shandong Yeedo rabies vaccine demonstrated satisfactory safety and efficacy, offering a new option for rabies prevention.

Myopericarditis following COVID-19 vaccination in children: a systematic review and meta-analysis.

Myopericarditis is a rare but serious coronavirus disease 2019 (COVID-19) vaccine-related adverse event primarily affecting adolescents. Given recent approvals for childhood vaccination, we performed a meta-analysis investigating myopericarditis following messenger ribonucleic acid COVID-19 vaccination in children aged <19 years, focusing on its overall risk and high-risk subgroups. We searched MEDLINE via PubMed, Embase and Scopus from inception to 1 August 2022 for observational studies reporting myopericarditis in temporal relation to paediatric COVID-19 vaccination. We conducted random-effects meta-analyses (DerSimonian and Laird) on myopericarditis (primary outcome), myocarditis and pericarditis (secondary outcomes). Of 2115 studies, 12 (59,229,160 doses) studies were included in our analysis. There were 19.8 (95% confidence interval [CI]: 10.4-37.6) myopericarditis cases reported per million doses in children, compared to 23.7 (95% CI: 12.2-46.1) cases in adults (eight studies, 376,899,888 doses; P = 0.70). Compared to the second dose (34.4, 95% CI: 15.2-77.8), the number of cases post-first dose was significantly lower (9.1, 95% CI: 4.4-18.8; P = 0.017), while the number of cases post-third dose was not higher than that of post-second dose (28.4, 95% CI: 10.4-61.8; P = 0.57, global P = 0.031). Males were at higher risk of myopericarditis (67.4, 95% CI: 36.5-124.5) than females (6.9, 95% CI: 3.1-15.3; P < 0.0001). Finally, the number of cases was higher (overall P < 0.0001) among children aged ≥12 years (39.9, 95% CI: 24.1-66.0) than among children aged <12 years (3.0, 95% CI: 2.3-3.9). Our meta-analysis showed 19.8 cases of myopericarditis per million doses among children, not significantly different from that of adults. Higher risk subgroups included adolescents, males, and those receiving their second dose of vaccination.

Abstract PO-003: Peripheral blood and tumor tissue biomarkers associated with epcoritamab response in patients with relapsed or refractory diffuse large B-cell lymphoma: Data from the dose-expansion cohort of the phase 1/2 EPCORE NHL-1 trial (NCT03625037)

Abstract Introduction: Epcoritamab, a CD3xCD20 bispecific antibody, demonstrated deep and durable clinical responses in patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We evaluated the correlation of peripheral blood (PB) and tumor tissue biomarkers with clinical response to epcoritamab. Methods: Pts received priming (0.16 mg), intermediate (0.8 mg) and full epcoritamab doses (48 mg). Absolute lymphocyte count (ALC) was analyzed locally. Blood immunophenotyping was assessed by flow cytometry, plasma cytokines by MSD assay, and %CD20+ in tumors by immunohistochemistry (n=117). Gene expression in baseline tumor biopsies was evaluated using HTG EdgeSeq (n=70). Microenvironment scores were estimated from gene expression as a sum of immune (B/T, NK, dendritic, and myeloid cells) and stromal scores (adipocytes, fibroblasts, and endothelial cells). Best overall response as of April 21, 2023 was assessed by independent review committee using Lugano criteria. P values were based on Wilcoxon rank-sum test. Results: In PB at baseline, significantly higher ALC (P=0.031), CD4+ (P=0.0038), and CD8+ (P=0.043) T-cell levels were observed in responders (R) vs nonresponders (NR). Similarly, CD4+ (P=0.02) and CD8+ (P=0.03) signatures and immune and microenvironment scores were higher in baseline tumor tissue in R vs NR. In PB CD8+ T cells, NR showed higher %PD1+ (P=0.016), %TIM3+ (P=0.048), and %TIM3+TIGIT+ (P=0.045). High tumor %CD20+ (≥90%) was observed in most pts (n=97/117); lower %CD20+ (&amp;lt;50%) was observed only in 6 NRs and 1 R. Epcoritamab treatment caused a rapid decline in circulating B cells irrespective of clinical response. Transient reductions in PB CD4+ and CD8+ T cells (ie, margination) were observed within 24 hours (H) after each dose during cycle (C) 1 and were more pronounced in R vs NR. Magnitude of margination for CD8+ T cells after the priming and intermediate doses was significantly lower in NR (reduced by median 22 &amp; 41%) vs R (57 &amp; 70%), while the difference in CD4+ T cells was not as pronounced in NR vs R, resulting in a substantially lower CD4+/CD8+ ratio in NR vs R. In C1, epcoritamab led to an increase of PB CD4+ and CD8+ T cells expressing activation/proliferation markers, with significantly higher fold change from baseline in R vs NR, especially within 24H post-priming dose. Early cytokine peaks of IFNy and IL-10 were more pronounced 6–24H post-priming dose and 6–14H post-first full dose in complete R vs pts with progressive disease. Epcoritamab also appeared to modulate NK cell numbers (under further investigation). Conclusions: In pts with R/R DLBCL, T-cell abundance and increased margination, activation, proliferation, and modulation of cytokines differed in R vs NR. These findings are consistent with epcoritamab’s mechanism of action and demonstrate the dependency on proper T-cell engagement for clinical benefit. Our findings also revealed differences in the dynamics of CD4+ and CD8+ T-cell margination in R vs NR, warranting further investigation. Previously submitted in part to EHA 2024. Citation Format: Monica Wielgos-Bonvallet, Jimin Zhang, Han Si, Kubra Karagoz, Melih Acar, Yasmin Karimi, Herve Ghesquieres, Michael Roost Clausen, Iş?l Alt?ntaş, Binhuan Wang, Wissam Assaily, Matthew Loya, Gregg Masters, Anantharaman Muthuswamy, Brandon Higgs, Mariana Sacchi, Tahi Ahmadi, Mark Fereshteh, Edith Szafer-Glusman, David Soong, Maria Jure-Kunkel, Andrew J Steele. Peripheral blood and tumor tissue biomarkers associated with epcoritamab response in patients with relapsed or refractory diffuse large B-cell lymphoma: Data from the dose-expansion cohort of the phase 1/2 EPCORE NHL-1 trial (NCT03625037) [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-003.

Comprehensive insights into COVID-19 vaccine-associated multiple evanescent white dot syndrome (MEWDS): A systematic analysis of reported cases

ABSTRACT Considering the widespread use of COVID-19 vaccines as a preventive measure against the spread of the virus, it’s necessary to direct attention to the adverse effects associated with vaccines in a limited group of populations. Multiple evanescent white dot syndrome (MEWDS) following COVID-19 vaccination is a rare adverse reaction associated with COVID-19 vaccines. In this systematic review, we collected 19 articles with 27 patients up to November 1, 2023, summarizing the basic information, clinical manifestations, examinations, treatments, and recoveries of the 27 patients. The 27 enrolled patients (6 males, 21 females) had a median age of 34.1 years (15–71 years old) and were mainly from 5 regions: Asia (8), the Mediterranean region (8), North America (7), Oceania (3) and Brazil (1). Symptoms occurred post-first dose in 9 patients, post-second dose in 14 (1 with symptoms after both), post-third dose in 1, and both post-second and booster doses in 1, while details on 2 cases were not disclosed. Treatments included tapered oral steroids (6), topical steroids (3), tapered prednisone with antiviral drugs and vitamins (1), and valacyclovir and acetazolamide (1), while 16 received no treatment. All patients experienced symptom improvement, and nearly all patients ultimately recovered. Moreover, we summarized possible hypotheses concerning the mechanism of COVID-19 vaccine-associated MEWDS. The findings provide insights into the clinical aspects of COVID-19 vaccine-associated MEWDS. More attention should be given to patients with vaccine-associated MEWDS, and necessary treatment should be provided to patients experiencing a substantial decline in visual acuity to improve their quality of life.

Association between Gut Microbiota Composition and Long-Term Vaccine Immunogenicity following Three Doses of CoronaVac.

Neutralizing antibody level wanes with time after COVID-19 vaccination. We aimed to study the relationship between baseline gut microbiota and immunogenicity after three doses of CoronaVac. This was a prospective cohort study recruiting three-dose CoronaVac recipients from two centers in Hong Kong. Blood samples were collected at baseline and one year post-first dose for virus microneutralization (vMN) assays to determine neutralization titers. The primary outcome was high immune response (defined as with vMN titer ≥ 40). Shotgun DNA metagenomic sequencing of baseline fecal samples identified potential bacterial species and metabolic pathways using Linear Discriminant Analysis Effect Size (LEfSe) analysis. Univariate and multivariable logistic regression models were used to identify high response predictors. In total, 36 subjects were recruited (median age: 52.7 years [IQR: 47.9-56.4]; male: 14 [38.9%]), and 18 had low immune response at one year post-first dose vaccination. Eubacterium rectale (log10LDA score = 4.15, p = 0.001; relative abundance of 1.4% vs. 0, p = 0.002), Collinsella aerofaciens (log10LDA score = 3.31, p = 0.037; 0.39% vs. 0.18%, p = 0.038), and Streptococcus salivarius (log10LDA score = 2.79, p = 0.021; 0.05% vs. 0.02%, p = 0.022) were enriched in low responders. The aOR of high immune response with E. rectale, C. aerofaciens, and S. salivarius was 0.03 (95% CI: 9.56 × 10-4-0.32), 0.03 (95% CI: 4.47 × 10-4-0.59), and 10.19 (95% CI: 0.81-323.88), respectively. S. salivarius had a positive correlation with pathways enriched in high responders like incomplete reductive TCA cycle (log10LDA score = 2.23). C. aerofaciens similarly correlated with amino acid biosynthesis-related pathways. These pathways all showed anti-inflammation functions. E. rectale,C. aerofaciens, and S. salivarius correlated with poorer long-term immunogenicity following three doses of CoronaVac.

Humoral and cellular immunity to SARS-CoV-2 following vaccination with non-mRNA vaccines in adolescent/young adults with cancer: A prospective cohort study

BackgroundData on SARS-CoV-2 vaccine responsiveness in adolescent/young adult (AYA) cancer patients are sparse. The present study assessed humoral and cellular immune responses post-vaccination in this population. MethodsIn this prospective study, patients aged 12–30 years undergoing cancer therapy (“on therapy”) and survivors (“off therapy”) were recruited. Anti-receptor binding domain (RBD) protein IgG levels were measured at baseline, four weeks post-first vaccine dose (T1), and six weeks post-second dose (T2). Cellular immunity was assessed using activation-induced markers and intracellular cytokine staining in a patient subset. The primary outcome was to quantify humoral responses in both cohorts at T2 compared to baseline. Clinical predictors of log antibody titres at T2 were identified. ResultsBetween April-December 2022, 118 patients were recruited of median age 15.4 years. Among them, 77 (65.2 %) were in the “on therapy” group, and 77 (65.2 %) had received the BBV152 vaccine. At baseline, 108 (91.5 %) patients were seropositive for anti-RBD antibody. The log anti-RBD titre rose from baseline to T2 (p-value = 0.001) in the whole cohort; this rise was significant from baseline-T1 (p-value < 0.001), but not from T1 to T2 (p-value = 0.842). A similar pattern was seen in the “on therapy” cohort. BECOV-2 vaccine was independently associated with higher log anti-RBD titres than BBV152 (regression coefficient: 0.41; 95 % CI: 0.10–0.73; p = 0.011). Cellular immune responses were similar in the “on-” and “off therapy” groups at the three time points. ConclusionAmong AYA cancer patients, a single non-mRNA vaccine dose confers robust hybrid humoral immunity with limited benefit from a second dose.

Safety of an inactivated COVID-19 vaccine (CoronaVac) in children aged 7-14 years in Taizhou, China

Our study aimed to evaluate the safety of CoronaVac, an inactivated vaccine made by Sinovac, in children aged 7–14. We conducted a parent-administered online survey to monitor adverse reactions after vaccinating children in Taizhou, China, from February 15, 2021, to January 19, 2022. 767 parents completed the survey after receiving a questionnaire via WeChat. Overall, 15.3 % (117/767) of children experienced adverse effects after the first dose, and 12.2 % (88/724) after the second. Muscle pain was the most common adverse reaction post-first dose (10.0 %), while localized pain or itching at the injection site was most common after the second dose (7.6 %). In conclusion, the vaccine has a low incidence of side effects. The mild to moderate, transient, and common nature of these effects further boosts parents' confidence in vaccinating their children.

Could Less Be More? Accounting for Fractional-Dose Regimens and Different Number of Vaccine Doses When Measuring the Impact of the RTS,S/AS01E Malaria Vaccine.

The RTS,S/AS01E (RTS,S) malaria vaccine is recommended for children in malaria endemic areas. This phase 2b trial evaluates RTS,S fractional- and full-dose regimens in Ghana and Kenya. In total, 1500 children aged 5-17 months were randomized (1:1:1:1:1) to receive RTS,S or rabies control vaccine. RTS,S groups received 2 full RTS,S doses at months 0 and 1 and either full (groups R012-20, R012-14-26) or fractional doses (one-fifth; groups Fx012-14-26, Fx017-20-32). At month 32 post-dose 1, vaccine efficacy against clinical malaria (all episodes) ranged from 38% (R012-20; 95% confidence interval [CI]: 24%-49%) to 53% (R012-14-26; 95% CI: 42%-62%). Vaccine impact (cumulative number of cases averted/1000 children vaccinated) was 1344 (R012-20), 2450 (R012-14-26), 2273 (Fx012-14-26), and 2112 (Fx017-20-32). To account for differences in vaccine volume (fractional vs full dose; post hoc analysis), we estimated cases averted/1000 RTS,S full-dose equivalents: 336 (R012-20), 490 (R012-14-26), 874 (Fx012-14-26), and 880 (Fx017-20-32). Vaccine efficacy was similar across RTS,S groups. Vaccine impact accounting for full-dose equivalence suggests that using fractional-dose regimens could be a viable dose-sparing strategy. If maintained through trial end, these observations underscore the means to reduce cost per regimen thus maximizing impact and optimizing supply. NCT03276962 (ClinicalTrials.gov).

Effects of COVID-19 mRNA vaccination on HIV viremia and reservoir size.

The immunogenic nature of coronavirus disease 2019 (COVID-19) mRNA vaccines led to some initial concern that these could stimulate the HIV reservoir. We analyzed changes in plasma HIV loads (pVL) and reservoir size following COVID-19 mRNA vaccination in 62 people with HIV (PWH) receiving antiretroviral therapy (ART), and analyzed province-wide trends in pVL before and after the mass vaccination campaign. Longitudinal observational cohort and province-wide analysis. Sixty-two participants were sampled prevaccination, and one month after their first and second COVID-19 immunizations. Vaccine-induced anti-SARS-CoV-2-Spike antibodies in serum were measured using the Roche Elecsys Anti-S assay. HIV reservoirs were quantified using the intact proviral DNA assay; pVL were measured using the cobas 6800 (lower limit of quantification: 20 copies/ml). The province-wide analysis included all 290 401 pVL performed in British Columbia, Canada between 2012 and 2022. Prevaccination, the median intact reservoir size was 77 [interquartile range (IQR): 20-204] HIV copies/million CD4 + T-cells, compared to 74 (IQR: 27-212) and 65 (IQR: 22-174) postfirst and -second dose, respectively (all comparisons P > 0.07). Prevaccination, 82% of participants had pVL <20 copies/ml (max: 110 copies/ml), compared to 79% postfirst dose (max: 183 copies/ml) and 85% postsecond dose (max: 79 copies/ml) ( P > 0.4). There was no evidence that the magnitude of the vaccine-elicited anti-SARS-CoV-2-Spike immune response influenced pVL nor changes in reservoir size ( P > 0.6). We found no evidence linking the COVID-19 mass vaccination campaign to population-level increases in detectable pVL frequency among all PWH in the province, nor among those who maintained pVL suppression on ART. We found no evidence that COVID-19 mRNA vaccines induced changes in HIV reservoir size nor plasma viremia.

Autoantibodies against angiotensin-converting enzyme 2 (ACE2) after COVID-19 infection or vaccination.

Autoantibodies against angiotensin-converting enzyme 2 (ACE2) are frequently reported in patients during coronavirus disease 2019 (COVID-19) with evidence for a pathogenic role in severe infection. However, little is known of the prevalence or clinical significance of ACE2 autoantibodies in late convalescence or following COVID-19 vaccination. In this study, we measured ACE2 autoantibodies in a cohort of 182 COVID-19 convalescent patients, 186 COVID-19 vaccine recipients, and 43 adolescents with post-mRNA vaccine myopericarditis using two ACE2 enzymatic immunoassays (EIAs). ACE2 IgM autoantibody EIA median optical densities (ODs) were lower in convalescent patients than pre-COVID-19 control samples with only 2/182 (1.1%) convalescents testing positive. Similarly, only 3/182 (1.6%) convalescent patients tested positive for ACE2 IgG, but patients with history of moderate-severe COVID-19 tended to have significantly higher median ODs than controls and mild COVID-19 patients. In contrast, ACE2 IgG antibodies were detected in 10/186 (5.4%) COVID-19 vaccine recipients after two doses of vaccination. Median ACE2 IgG EIA ODs of vaccine recipients were higher than controls irrespective of the vaccine platform used (inactivated or mRNA). ACE2 IgG ODs were not correlated with surrogate neutralizing antibody levels in vaccine recipients. ACE2 IgG levels peaked at day 56 post-first dose and declined within 12 months to baseline levels in vaccine recipients. Presence of ACE2 antibodies was not associated with adverse events following immunization including myopericarditis. One convalescent patient with ACE2 IgG developed Guillain-Barre syndrome, but causality was not established. ACE2 autoantibodies are observed in COVID-19 vaccine recipients and convalescent patients, but are likely innocuous.

Management of Immune Thrombotic Thrombocytopenic Purpura without Therapeutic Plasma Exchange: Analysis of Efficacy and Safety Data

Background: Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening autoimmune disorder caused by ADAMTS13 deficiency. Caplacizumab, an anti-VWF nanobody, is approved for iTTP treatment, reducing the need for therapeutic plasma exchange (TPE) and improving platelet recovery and survival. Methods: We conducted a retrospective study on 42 acute iTTP cases in Austria and Germany, treated with a modified regimen aimed at avoiding TPE if platelet count increased post-first caplacizumab dose. An extensive efficacy and safety analysis of this approach was performed, in comparison with a control group of 59 patients with iTTP, receiving frontline caplacizumab treatment with TPE and immunosuppression (standard of care, SOC). The main outcome was time to platelet count normalization. Secondary outcomes included clinical response, exacerbation, refractory iTTP, and iTTP-related deaths. Retrospective safety assessments with evaluation of treatment emergent adverse events (TEAE) were performed in both cohorts. Results: The median time to platelet count normalization was similar between the two cohorts (3 and 4 days; P = 0.31, see Figure 1). There were no significant differences in clinical response, exacerbations, refractoriness, or iTTP-related deaths (see Table 1). Four patients did not respond to the first dose of caplacizumab, and TPE was initiated. Cytomegalovirus infection, HIV/hepatitis B co-infection, and ovarian teratoma may have hindered immediate treatment response. Platelet count doubling and median platelet count change after first caplacizumab dose were unaffected by TPE. The median time to LDH normalization was 11 days in the TPE-free cohort. During overall follow-up at least one adverse event (TEAE) was observed in 11 patients (26.2%) in the TPE-free group and 15 patients (25.4%) in the SOC group (excluding adverse events of iTTP that were evaluated as outcome parameters) (see Table 1). There was one TTP-related death reported in the SOC group (1.7%). The cause of death in this patient was cerebral ischemia due to multiple strokes. Serious adverse events associated with therapeutic plasma exchange were observed in 3 patients (5.1%) exclusively in the SOC cohort. These included (1) in-hospital cardiac arrest (IHCA), (2) generalized seizure and supraventricular tachycardia and (3) a transfusion reaction with hypotension, rigors, pruritus and exanthema. Bleeding complications were reported without a significant difference and mainly comprised gingival bleeding and epistaxis. Two patients in the TPE-free cohort (4.8%) experienced major bleeding events, namely subdural hematoma requiring surgical intervention and gastrointestinal bleeding with mass transfusion. Spontaneous subdural hematoma occurred in one patient after 20 days of caplacizumab treatment. Gastrointestinal bleeding from a colon diverticulum occurred in another patient after a clinical response and resulted in a significant drop in hemoglobin and thrombocytes. Gastrointestinal bleeding worsened with concomitant factor XIII deficiency, which was reconstituted intravenously in addition to mass transfusion. Conclusion: Caplacizumab and immunosuppression, without TPE, rapidly controlled microvascular thrombosis and achieved a sustained clinical response in iTTP. The efficacy was similar to the control group, which received SOC. Standard iTTP treatment with TPE may lead to a prolonged hospital stay, including admission to the ICU, multiple sessions of daily TPE with associated risks, and the associated costs of plasma, equipment, nursing care, and medical supervision. The number of patients experiencing critical adverse events was comparable between groups. Bearing all restrictions of a retrospective cohort in mind, we did not identify a critical safety signal for TPE-free iTTP-treatment. However, TPE itself resulted in three life-threatening adverse events in the SOC cohort, including an in-hospital cardiac arrest. In conclusion, omitting TPE appears to be a viable choice for acute iTTP management that may reduce treatment burden without compromising patient outcomes or safety.

COVID-19 mRNA vaccine-mediated antibodies in human breast milk and their association with breast milk microbiota composition

Newborns can acquire immunological protection to SARS-CoV-2 through vaccine-conferred antibodies in human breast milk. However, there are some concerns around lactating mothers with regards to potential short- and long-term adverse events and vaccine-induced changes to their breast milk microbiome composition, which helps shape the early-life microbiome. Thus, we sought to explore if SARS-CoV-2 mRNA vaccine could change breast milk microbiota and how the changes impact the levels of antibodies in breast milk. We recruited 49 lactating mothers from Hong Kong who received two doses of BNT162b2 vaccine between June 2021 and August 2021. Breast milk samples were self-collected by participants pre-vaccination, one week post-first dose, one week post-second dose, and one month post-second dose. The levels of SARS-CoV-2 spike-specific IgA and IgG in breast milk peaked at one week post-second dose. Subsequently, the levels of both antibodies rapidly waned in breast milk, with IgA levels returning to baseline levels one month post-second dose. The richness and composition of human breast milk microbiota changed dynamically throughout the vaccination regimen, but the abundances of beneficial microbes such as Bifidobacterium species did not significantly change after vaccination. Additionally, we found that baseline breast milk bacterial composition can predict spike-specific IgA levels at one week post-second dose (Area Under Curve: 0.72, 95% confidence interval: 0.58–0.85). Taken together, our results identified specific breast milk microbiota markers associated with high levels of IgA in the breast milk following BNT162b2 vaccine. Furthermore, in lactating mothers, BNT162b2 vaccines did not significantly reduce probiotic species in breast milk.

Kinetics of the Antibody Response to Symptomatic SARS-CoV-2 Infection in Vaccinated and Unvaccinated Individuals in the Blinded Phase of the mRNA-1273 COVID-19 Vaccine Efficacy Trial.

Hybrid immunity is associated with more durable protection against coronavirus disease 2019 (COVID-19). We describe the antibody responses following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vaccinated and unvaccinated individuals. The 55 vaccine arm COVID-19 cases diagnosed during the blinded phase of the Coronavirus Efficacy trial were matched with 55 placebo arm COVID-19 cases. Pseudovirus neutralizing antibody (nAb) activity to the ancestral strain and binding antibody (bAb) responses to nucleocapsid and spike antigens (ancestral and variants of concern [VOCs]) were assessed on disease day 1 (DD1) and 28 days later (DD29). The primary analysis set was 46 vaccine cases and 49 placebo cases with COVID-19 at least 57 days post-first dose. For vaccine group cases, there was a 1.88-fold rise in ancestral antispike bAbs 1 month post-disease onset, although 47% had no increase. The vaccine-to-placebo geometric mean ratios for DD29 antispike and antinucleocapsid bAbs were 6.9 and 0.04, respectively. DD29 mean bAb levels were higher for vaccine vs placebo cases for all VOCs. DD1 nasal viral load positively correlated with bAb levels in the vaccine group. Following COVID-19, vaccinated participants had higher levels and greater breadth of antispike bAbs and higher nAb titers than unvaccinated participants. These were largely attributable to the primary immunization series.

Early humoral response to COVID-19 vaccination in patients living with obesity and diabetes in France. The COVPOP OBEDIAB study with results from the ANRS0001S COV-POPART cohort

BackgroundPatients with diabetes and obesity are populations at high-risk for severe COVID-19 outcomes and have shown blunted immune responses when administered different vaccines. Here we used the ‘ANRS0001S COV-POPART’ French nationwide multicenter prospective cohort to investigate early humoral response to COVID-19 vaccination in the sub-cohort (‘COVPOP OBEDIAB’) of patients with obesity and diabetes. MethodsPatients with diabetes (n = 390, type 1 or 2) or obesity (n = 357) who had received two vaccine doses and had no history of previous COVID-19 infection and negative anti-nucleocapsid (NCP) antibodies were included and compared against healthy subjects (n = 573). Humoral response was assessed at baseline, at one month post-first dose (M0) and one-month post-second dose (M1), through percentage of responders (positive anti-spike SARS-CoV-2 IgG antibodies (Sabs), geometric means of Sabs; BAU/mL), proportion of individuals with anti-RBD antibodies, and proportion of individuals with anti-SARS-CoV-2-specific neutralizing antibodies (Nabs). Potential clinical and biological factors associated with weak response (defined as Sabs < 264 BAU/mL) and presence of non-reactive anti-RBD antibodies at M1 were evaluated. Univariate and multivariate regressions were performed to estimate crude and adjusted coefficients with 95 % confidence intervals. Poor glycemic control was defined as HbA1c ≥ 7.5 % at inclusion. ResultsPatients with diabetes, particularly type 2 diabetes, and patients with obesity were less likely to have positive Sabs and anti-RBD antibodies after the first and second dose compared to controls (p < 0.001). At M1, we found Sabs seroconversion in 94.1 % of patients with diabetes versus 99.7 % in controls, anti-RBD seroconversion in 93.8 % of patients with diabetes versus 99.1 % in controls, and Nabs seroconversion in 95.7 % of patients with diabetes versus 99.6 % in controls (all p < 0.0001). Sabs and anti-RBD seroconversion at M0 and M1 were also significantly lower in obese patients than controls, at respectively 82.1 % versus 89.9 % (p = 0.001; M0 Sabs), 94.4 % versus 99.7 % (p 0.001; M1 Sabs), 79.0 % vs 86.2 % (p = 0.004 M0 anti-RBD), and 96.99 % vs 99.1 % (p = 0.012 M1 anti-RBD). The factors associated with low vaccine response (BAU < 264/mL) in patients with diabetes were chronic kidney disease (adjusted OR = 6.88 [1.77;26.77], p = 0.005) and poor glycemic control (adjusted OR = 3.92 [1.26;12.14], p = 0.018). In addition, BMI ≥ 40 kg/m2 was found to be associated with a higher vaccine response (adjusted OR = 0.10 [0.01;0.91], p = 0.040) than patients with BMI < 40 kg/m2. ConclusionCOVID-19 vaccine humoral response was lower in patients with obesity and diabetes one month after second dose compared to controls, especially in diabetic patients with CKD or inadequate glycemic control. These findings point to the need for post-vaccination serological checks in these high-risk populations.

2142. Safety and immunogenicity of COVID Influenza Combination Vaccine

Abstract Background We developed a COVID-Influenza Combination (CIC) vaccine, comprising recombinant SARS-CoV-2 Spike (rS) and quadrivalent influenza hemagglutinin (HA) protein nanoparticles (qNIV), and Matrix-MTM adjuvant. rS/Matrix-M previously demonstrated efficacy against COVID-19 in Phase 3 trials, while qNIV/Matrix-M previously demonstrated induction of broadly cross-reactive antibodies. Here we report preliminary safety and immunogenicity results of a first-ever Phase 1/2 CIC dose-finding trial. Methods Seropositive (COVID-19 vaccinated ≥ 8 weeks prior) participants (N=642) aged 50-70 years were randomized equally, to receive two intramuscular doses, 56 days apart, to 1 of 14 different dose/formulations of CIC using a design of experiments approach (dose range: rS 2.5-22.5ug, HA 5-60ug; and 50ug Matrix-M), or to 1 of 2 reference formulations of either standalone rS with Matrix-M [2 doses] or qNIV with Matrix-M [1 dose only]. Pre- and post-vaccination (Days 0, 28, 56, 70, 84, 182) immunogenicity assessments including SARS-CoV-2 anti-S IgG and influenza HAI antibodies to vaccine-homologous strains. Reactogenicity was assessed 7 days following each dose, and safety outcomes assessed through Day 70. Multiple regression was used to create predictive models to assess antibody response surfaces and for dose optimization. Results All CIC formulations were well tolerated, with a reactogenicity and safety profile generally comparable to standalone rS or qNIV. Regression modelling of post-first dose responses revealed that both rS and HA antigens in a CIC formulation modestly interfered with each other, however, interference was overcome with dose adjustment across a range of rS/HA doses. Specifically, higher rS dose ( &amp;gt;20ug), in a dose dependent fashion, overcame HA interference, closely matching standalone rS IgG reference responses (GMEU 16,818), whereas lower, intermediate HA dose overcame rS interference, closely matching standalone HA reference HAI responses for H3N2 (GMT 145), H1N1 (GMT 134), and B-Victoria (GMT 66); while modestly (at least 34%) lower than the reference B-Yamagata response (GMT 101). Conclusion CIC formulations were well tolerated and immunogenic, with various dose combinations achieving response comparable to standalone vaccines. Disclosures Vivek Shinde, MD, MPH, Novavax Inc.: Stocks/Bonds Wayne Woo, MS, Novavax Inc.: Stocks/Bonds Sharon Liu, n/a, Novavax Inc.: Stocks/Bonds Sara Cook, n/a, Novavax Inc.: Stocks/Bonds Zenaida Santiago, n/a, Novavax Inc.: Stocks/Bonds Susan Neal, n/a, Novavax Inc.: Stocks/Bonds Joyce S. Plested, n/a, Novavax Inc.: Stocks/Bonds Tim Vincent, n/a, Novavax Inc.: Stocks/Bonds Mingzhu Zhu, n/a, Novavax Inc.: Stocks/Bonds Shane Cloney-Clark, n/a, Novavax Inc.: Stocks/Bonds Iksung Cho, MS, Novavax Inc.: Stocks/Bonds Lou Fries, n/a, Novavax Inc.: Stocks/Bonds Greg Glenn, n/a, Novavax Inc.: Stocks/Bonds.

The effect of immunomodulators on seroconversion after BNT162b2 and AZD1222 vaccines in patients with immune-mediated inflammatory diseases: a prospective cohort study.

Biologic and nonbiologic immunomodulators, used to treat immune-mediated inflammatory diseases (IMIDs), could impair the immune response to COVID-19 vaccines and thus vaccine effectiveness. Our objective was to investigate the association between biologic and nonbiologic immunomodulators and seroconversion following the first and second dose of COVID-19 vaccines in patients with IMIDs. Serum samples were collected following the first or second dose of the BNT162b2 or AZD1222 vaccines from patients receiving biologic and/or nonbiologic immunomodulators for one or more of psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease or systemic lupus erythematosus. Seroconversion was defined as a positive Roche Elecsys® Anti-SARS-CoV-2 S (spike protein subunit S1/receptor binding domain) immunoassay (≥ 0.8 U mL-1). Association between immunomodulator exposure and seroconversion was assessed using logistic regression, adjusting for age and sex. After excluding those with prior COVID-19, post-first vaccine dose samples from 193 participants and post-second dose samples from 312 participants were included in the analysis. Following the first vaccine dose, 17.6% (n = 34) of participants did not seroconvert. Seroconversion was reduced for those on nonbiologic [adjusted odds ratio (OR) 0.29, 95% confidence interval (CI) 0.12-0.69] or combined nonbiologic and biologic treatment (adjusted OR 0.14, 95% CI 0.045-0.45) compared with those on biologic monotherapy. Subgroup analysis demonstrated reduced odds of seroconversion in those on methotrexate (adjusted OR 0.097, 95% CI 0.19-0.49) or prednisolone treatment (adjusted OR 0.044, 95% CI 0.002-1.00) relative to tumour necrosis factor-α inhibitor monotherapy. No participants receiving rituximab (n < 5) seroconverted after the first vaccine dose. Following the second vaccine dose, 1.6% of all participants did not seroconvert. Non-seroconversion was associated with receiving rituximab (n = 3 of 4) compared with those receiving other therapies (n = 2 of 308, P < 0.001). Post hoc analyses demonstrated that non-seroconversion was associated with age [adjusted OR 0.18, 95% CI 0.037-0.93 for those aged 60 years and over (reference category age 18-39 years)], but not sex, ethnicity or vaccine type. Treatment with nonbiologics, particularly methotrexate, is associated with impaired seroconversion following two BNT162b2 or AZD1222 vaccine doses, in patients with IMIDs. These findings are consistent with those of other published studies. While this could indicate reduced protection against COVID-19, the immunological parameters that correlate most closely with vaccine effectiveness need to be defined to reach this conclusion.

High-temporal resolution profiling reveals distinct immune trajectories following the first and second doses of COVID-19 mRNA vaccines.

Knowledge of the mechanisms underpinning the development of protective immunity conferred by mRNA vaccines is fragmentary. Here, we investigated responses to coronavirus disease 2019 (COVID-19) mRNA vaccination via high-temporal resolution blood transcriptome profiling. The first vaccine dose elicited modest interferon and adaptive immune responses, which peaked on days 2 and 5, respectively. The second vaccine dose, in contrast, elicited sharp day 1 interferon, inflammation, and erythroid cell responses, followed by a day 5 plasmablast response. Both post-first and post-second dose interferon signatures were associated with the subsequent development of antibody responses. Yet, we observed distinct interferon response patterns after each of the doses that may reflect quantitative or qualitative differences in interferon induction. Distinct interferon response phenotypes were also observed in patients with COVID-19 and were associated with severity and differences in duration of intensive care. Together, this study also highlights the benefits of adopting high-frequency sampling protocols in profiling vaccine-elicited immune responses.

Evaluation of serum soluble HLA-G levels post-recovery from COVID-19 and post-vaccination (Sinopharm and Pfizer-BioNTech)

Serum soluble HLA-G (sHLA-G) levels have been shown to be upregulated in COVID-19 patients. In this study, sHLA-G levels were examined in COVID-19 patients 14–21 days post-recovery (100 patients) and 80 uninfected controls. In addition, individuals vaccinated with Sinopharm or Pfizer-BioNTech (50 individuals each) were followed 21 days post-first dose and 21 days post-second dose. Serum sHLA-G levels were significantly higher in recovered patients than in controls. The first and second doses of Sinopharm and Pfizer-BioNTech were associated with significantly elevated levels of sHLA-G compared to controls or recovered patients, except for the first dose of Pfizer-BioNTech where sHLA-G levels did not show significant differences compared to recovered patients. In conclusion, recovery from COVID-19, as well as vaccination with two doses of Sinopharm or Pfizer-BioNTech, were associated with up-regulated levels of sHLA-G molecules, but the first dose of Sinopharm had the greatest effect in raising sHLA-G levels.

Longitudinal serologic and viral testing post-SARS-CoV-2 infection and post-receipt of mRNA COVID-19 vaccine in a nursing home cohort-Georgia, October 2020‒April 2021.

There are limited data describing SARS-CoV-2–specific immune responses and their durability following infection and vaccination in nursing home residents. We conducted a prospective longitudinal evaluation of 11 consenting SARS-CoV-2–positive nursing home residents to evaluate the quantitative titers and durability of binding antibodies detected after SARS-CoV-2 infection and subsequent COVID-19 vaccination. The evaluation included nine visits over 150 days from October 25, 2020, through April 1, 2021. Visits included questionnaire administration, blood collection for serology, and paired anterior nasal specimen collection for testing by BinaxNOW™ COVID-19 Ag Card (BinaxNOW), reverse transcription polymerase chain reaction (RT-PCR), and viral culture. We evaluated quantitative titers of binding SARS-CoV-2 antibodies post-infection and post-vaccination (beginning after the first dose of the primary series). The median age among participants was 74 years; one participant was immunocompromised. Of 10 participants with post-infection serology results, 9 (90%) had detectable Pan-Ig, IgG, and IgA antibodies, and 8 (80%) had detectable IgM antibodies. At first antibody detection post-infection, two-thirds (6/9, 67%) of participants were RT-PCR–positive, but none were culture- positive. Ten participants received vaccination; all had detectable Pan-Ig, IgG, and IgA antibodies through their final observation ≤90 days post-first dose. Post-vaccination geometric means of IgG titers were 10–200-fold higher than post-infection. Nursing home residents in this cohort mounted robust immune responses to SARS-CoV-2 post-infection and post-vaccination. The augmented antibody responses post-vaccination are potential indicators of enhanced protection that vaccination may confer on previously infected nursing home residents.

Commentary on Cochrane review: "Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder".

Cochrane recently published a review of esketamine and other glutamate receptor modulators in depression. To address the limitations of the review, analyses of esketamine data were conducted to provide additional perspective to the reviewers' interpretation of their findings. Response rate, remission rate, and change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score were determined using data from all esketamine phase 2/3 registration studies of treatment-resistant depression (TRD) and, separately, all esketamine phase 2/3 registration studies of major depressive disorder (MDD) and active suicidal ideation with intent. Outcomes were assessed at all timepoints (i.e., 24 h, 72 h (MDD with active suicidal intent only), and 1, 2, and 4 weeks). Enrollment criteria of the TRD studies were different than those of the studies of MDD and active suicidal ideation with intent, resulting in differences in patients' clinical characteristics and depression severity between the cohorts. Thus, we did not compare results between these cohorts (as was done in the Cochrane review). In the combined TRD studies, a statistically significant between-group difference favored esketamine plus antidepressant over antidepressant plus placebo at 24 h (based on response, remission, and change in MADRS score), 1 week (change in MADRS score), 2 weeks (response and change in MADRS score), and 4 weeks (response, remission, and change in MADRS score). In the combined studies of MDD and active suicidal ideation with intent, the between-group difference was statistically different, favoring esketamine plus standard-of-care over placebo plus standard-of-care, at 24 h (response, remission, and change in MADRS score), 72 h and 1 week (change in MADRS score), 2 weeks (response), and 4 weeks (response, remission, and change in MADRS score). For both study types, the between-group difference in outcomes was not statistically significant at the other timepoints. Esketamine improves response, remission, and depressive symptoms as early as 24 h post-first dose among patients with TRD and among patients with MDD and active suicidal ideation with intent.