Low Spike Antibody Levels and Impaired BA.4/5 Neutralization in Patients with Multiple Myeloma or Waldenstrom's Macroglobulinemia after BNT162b2 Booster Vaccination.

Patients with symptomatic monoclonal gammopathies have impaired humoral responses to COVID-19 vaccination. Their ability to recognize SARS-CoV-2 Omicron variants is of concern. We compared the response to BNT162b2 mRNA vaccinations of patients with multiple myeloma (MM, n = 60) or Waldenstrom's macroglobulinemia (WM, n = 20) with healthy vaccine recipients (n = 37). Patient cohorts on active therapy affecting B cell development had impaired binding and neutralizing antibody (NAb) response rate and magnitude, including several patients lacking responses, even after a 3rd vaccine dose, whereas non-B cell depleting therapies had a lesser effect. In contrast, MM and WM cohorts off-therapy showed increased NAb with a broad response range. ELISA Spike-Receptor Binding Domain (RBD) Ab titers in healthy vaccine recipients and patient cohorts were good predictors of the ability to neutralize not only the original WA1 but also the most divergent Omicron variants BA.4/5. Compared to WA1, significantly lower NAb responses to BA.4/5 were found in all patient cohorts on-therapy. In contrast, the MM and WM cohorts off-therapy showed a higher probability to neutralize BA.4/5 after the 3rd vaccination. Overall, the boost in NAb after the 3rd dose suggests that repeat vaccination of MM and WM patients is beneficial even under active therapy.

Impact of COVID-19 on Motility Practices: New Onset Gastrointestinal and Autonomic Dysfunction After COVID-19 and the Effects of Vaccination in a Nationwide Cohort Study

Using ICD-10 and CPT codes, patients diagnosed with COVID-19 between Jan 1 to Dec 31, 2020 were propensity score matched for risk factors to negative controls (NC), and patients diagnosed with either Influenza, Lyme’s disease (LD), Infectious Mononucleosis (IM), Herpes Zoster (HZ), Varicella Zoster (VZ) and Cytomegalovirus (CMV). A Kaplan-Meier analysis was used to estimate the hazard ratio (HR) and cumulative incidence of new-onset outcomes within 3 months and 1 year after the diagnosis of the respective health event, including: GI symptoms or diagnoses, symptoms of autonomic (AN) sensory (SN), and motor (MN) neuropathy. Kaplan Meier analysis comparing new-onset outcomes between patients diagnosed with COVID-19 and a matched Influenza and negative control cohort New-onset outcomes COVID-19 vs Negative controls (n=1,889,175) COVID-19 vs Influenza (n=698,253) HR (95% CI) Probability COVID Probability NC P-value HR (95% CI) Probability COVID Probability Influenza P-value Gastrointestinal (GI) symptoms or diagnoses 1.37 (1.35 - 1.39) 11.43% 8.44% < 0.001 1.04 (1.03 - 1.06) 11.41% 10.87% < 0.001  Dysphagia 1.37 (1.33 - 1.41) 1.4% 1.03% < 0.001 1.18 (1.14 - 1.23) 1.23% 1.03% < 0.001  Gastro-esophageal reflux disease 1.30 (1.28 - 1.33) 4.21% 3.23% < 0.001 1.13 (1.11 - 1.16) 3.97% 3.5% < 0.001  Heartburn 1.15 (1.09 - 1.21) 0.42% 0.37% < 0.001 1.20 (1.12 - 1.28) 0.44% 0.36% < 0.001  Nausea 1.54 (1.50 - 1.58) 2.39% 1.56% < 0.001 1.12 (1.09 - 1.15) 2.51% 2.24% < 0.001  Vomiting 1.78 (1.71 - 1.85) 0.87% 0.49% < 0.001 1.04 (0.99 - 1.08) 0.9% 0.87% 0.116  Early satiety 1.31 (1.20 - 1.43) 0.15% 0.12% < 0.001 1.63 (1.44 - 1.85) 0.14% 0.09% < 0.001  Abdominal and pelvic pain 1.38 (1.36 - 1.41) 6.38% 4.63% < 0.001 0.97 (0.96 - 0.99) 6.62% 6.74% 0.01  Bloating 1.28 (1.24 - 1.33) 1.01% 0.78% < 0.001 1.29 (1.24 - 1.35) 0.97% 0.75% < 0.001  Gastroparesis 1.47 (1.35 - 1.60) 0.18% 0.12% < 0.001 1.39 (1.25 - 1.55) 0.17% 0.12% < 0.001  Functional dyspepsia 1.09 (1.02 - 1.17) 0.22% 0.2% 0.016 0.79 (0.73 - 0.86) 0.21% 0.27% < 0.001  Constipation 1.35 (1.32 - 1.38) 2.61% 1.94% < 0.001 1.17 (1.14 - 1.21) 2.4% 2.04% < 0.001  Diarrhea 1.53 (1.49 - 1.57) 2.62% 1.71% < 0.001 1.01 (0.98 - 1.03) 2.63% 2.61% 0.631  Irritable bowel syndrome 1.07 (1.02 - 1.12) 0.5% 0.47% 0.006 1.04 (0.98 - 1.10) 0.52% 0.5% 0.188  Inflammatory bowel disease 1.50 (1.45 - 1.56) 1.06% 0.71% < 0.001 0.75 (0.72 - 0.78) 1.05% 1.4% < 0.001 Autonomic neuropathy 1.32 (1.30 - 1.34) 8.69% 6.64% < 0.001 1.15 (1.13 - 1.17) 8.22% 7.1% < 0.001  Postural symptoms 1.43 (1.41 - 1.46) 5.89% 4.15% < 0.001 1.15 (1.13 - 1.18) 5.64% 4.88% < 0.001  Urinary dysfunction 1.22 (1.19 - 1.25) 2.76% 2.26% < 0.001 1.12 (1.09 - 1.16) 2.53% 2.24% < 0.001  Sexual dysfunction 0.99 (0.95 - 1.03) 0.66% 0.66% 0.751 1.04 (0.98 - 1.10) 0.59% 0.56% 0.168  Exocrine gland dysfunction 1.22 (1.18 - 1.26) 1.24% 1.02% < 0.001 1.26 (1.21 - 1.31) 1.17% 0.93% < 0.001 Sensory neuropathy 1.12 (1.09 - 1.15) 1.71% 1.53% < 0.001 0.89 (0.86 - 0.92) 1.69% 1.89% < 0.001 Motor neuropathy 1.22 (1.19 - 1.25) 1.52% 1.25% < 0.001 0.98 (0.95 - 1.01) 1.47% 1.49% 0.247 Outcomes are presented as a HR, in which the numerator consists of the COVID-19 population.

Reduced Antibodies and Innate Cytokine Changes in SARS-CoV-2 BNT162b2 mRNA Vaccinated Transplant Patients With Hematological Malignancies.

Immunocompromised individuals including patients with hematological malignancies constitute a population at high risk of developing severe disease upon SARS-CoV-2 infection. Protection afforded by vaccination is frequently low and the biology leading to altered vaccine efficacy is not fully understood. A patient cohort who had received bone marrow transplantation or CAR-T cells was studied following a 2-dose BNT162b2 mRNA vaccination and compared to healthy vaccine recipients. Anti-Spike antibody and systemic innate responses were compared in the two vaccine cohorts. The patients had significantly lower SARS-CoV-2 Spike antibodies to the Wuhan strain, with proportional lower cross-recognition of Beta, Delta, and Omicron Spike-RBD proteins. Both cohorts neutralized the wildtype WA1 and Delta but not Omicron. Vaccination elicited an innate cytokine signature featuring IFN-γ, IL-15 and IP-10/CXCL10, but most patients showed a diminished systemic cytokine response. In patients who failed to develop antibodies, the innate systemic response was dominated by IL-8 and MIP-1α with significant attenuation in the IFN-γ, IL-15 and IP-10/CXCL10 signature response. Changes in IFN-γ and IP-10/CXCL10 at priming vaccination and IFN-γ, IL-15, IL-7 and IL-10 upon booster vaccination correlated with the Spike antibody magnitude and were predictive of successful antibody development. Overall, the patients showed heterogeneous adaptive and innate responses with lower humoral and reduced innate cytokine responses to vaccination compared to naïve vaccine recipients. The pattern of responses described offer novel prognostic approaches for potentiating the effectiveness of COVID-19 vaccination in transplant patients with hematological malignancies.

Reduced Antibodies and Innate Cytokine Changes in SARS-CoV-2 BNT162b2 mRNA Vaccinated Transplant Patients With Hematological Malignancies

Immunocompromised individuals including patients with hematological malignancies constitute a population at high risk of developing severe disease upon SARS-CoV-2 infection. Protection afforded by vaccination is frequently low and the biology leading to altered vaccine efficacy is not fully understood. A patient cohort who had received bone marrow transplantation or CAR-T cells was studied following a 2-dose BNT162b2 mRNA vaccination and compared to healthy vaccine recipients. Anti-Spike antibody and systemic innate responses were compared in the two vaccine cohorts. The patients had significantly lower SARS-CoV-2 Spike antibodies to the Wuhan strain, with proportional lower cross-recognition of Beta, Delta, and Omicron Spike-RBD proteins. Both cohorts neutralized the wildtype WA1 and Delta but not Omicron. Vaccination elicited an innate cytokine signature featuring IFN-γ, IL-15 and IP-10/CXCL10, but most patients showed a diminished systemic cytokine response. In patients who failed to develop antibodies, the innate systemic response was dominated by IL-8 and MIP-1α with significant attenuation in the IFN-γ, IL-15 and IP-10/CXCL10 signature response. Changes in IFN-γ and IP-10/CXCL10 at priming vaccination and IFN-γ, IL-15, IL-7 and IL-10 upon booster vaccination correlated with the Spike antibody magnitude and were predictive of successful antibody development. Overall, the patients showed heterogeneous adaptive and innate responses with lower humoral and reduced innate cytokine responses to vaccination compared to naïve vaccine recipients. The pattern of responses described offer novel prognostic approaches for potentiating the effectiveness of COVID-19 vaccination in transplant patients with hematological malignancies.

Control of SARS-CoV-2 infection after Spike DNA or Spike DNA+Protein co-immunization in rhesus macaques.

The speed of development, versatility and efficacy of mRNA-based vaccines have been amply demonstrated in the case of SARS-CoV-2. DNA vaccines represent an important alternative since they induce both humoral and cellular immune responses in animal models and in human trials. We tested the immunogenicity and protective efficacy of DNA-based vaccine regimens expressing different prefusion-stabilized Wuhan-Hu-1 SARS-CoV-2 Spike antigens upon intramuscular injection followed by electroporation in rhesus macaques. Different Spike DNA vaccine regimens induced antibodies that potently neutralized SARS-CoV-2 in vitro and elicited robust T cell responses. The antibodies recognized and potently neutralized a panel of different Spike variants including Alpha, Delta, Epsilon, Eta and A.23.1, but to a lesser extent Beta and Gamma. The DNA-only vaccine regimens were compared to a regimen that included co-immunization of Spike DNA and protein in the same anatomical site, the latter of which showed significant higher antibody responses. All vaccine regimens led to control of SARS-CoV-2 intranasal/intratracheal challenge and absence of virus dissemination to the lower respiratory tract. Vaccine-induced binding and neutralizing antibody titers and antibody-dependent cellular phagocytosis inversely correlated with transient virus levels in the nasal mucosa. Importantly, the Spike DNA+Protein co-immunization regimen induced the highest binding and neutralizing antibodies and showed the strongest control against SARS-CoV-2 challenge in rhesus macaques.

Accelerating the Nature Deficit or Enhancing the Nature-Based Human Health during the Pandemic Era: An International Study in Cambodia, Indonesia, Japan, South Korea, and Myanmar, following the Start of the COVID-19 Pandemic

In modern society, the opportunity to experience nature is separate from everyday life, requiring time and effort. Since the start of the COVID-19 pandemic, restrictions on freedom of activity and communication around the world have become a crisis, causing a nature deficit by accelerating the process of separation from nature. At the same time, the pandemic has increased people’s motivation to return to nature, providing an opportunity to seek experiences and health recovery in nature. The authors conducted an international cross-sectional study in five Asian countries, investigating changes in the perception of recreational activities and health restoration in the natural environment, one of the many effects of the COVID-19 pandemic on human society. An online survey, completed by 524 respondents, has confirmed the efficacy of the SEM model, which includes COVID-19 stress, increased indoor activity, a preference for the natural environment, and the perception of health recovery. Although the five countries had different response values for each theme, the stress caused by restricted activities and communication during the pandemic was linked to a preference for natural experiences and the motivation to visit natural environments in all five countries, ultimately affecting perceptions of health recovery in nature. This study has shown that the COVID-19 pandemic, a disaster afflicting all human civilization, has changed people’s perceptions by enhancing their preference for natural recreational activities and health. It has accelerated people’s return to nature and fostered a positive perception of nature’s ability to promote good health.

Sequential Analysis of Binding and Neutralizing Antibody in COVID-19 Convalescent Patients at 14 Months After SARS-CoV-2 Infection.

Durability of SARS-CoV-2 Spike antibody responses after infection provides information relevant to understanding protection against COVID-19 in humans. We report the results of a sequential evaluation of anti-SARS-CoV-2 antibodies in convalescent patients with a median follow-up of 14 months (range 12.4-15.4) post first symptom onset. We report persistence of antibodies for all four specificities tested [Spike, Spike Receptor Binding Domain (Spike-RBD), Nucleocapsid, Nucleocapsid RNA Binding Domain (N-RBD)]. Anti-Spike antibodies persist better than anti-Nucleocapsid antibodies. The durability analysis supports a bi-phasic antibody decay with longer half-lives of antibodies after 6 months and antibody persistence for up to 14 months. Patients infected with the Wuhan (WA1) strain maintained strong cross-reactive recognition of Alpha and Delta Spike-RBD but significantly reduced binding to Beta and Mu Spike-RBD. Sixty percent of convalescent patients with detectable WA1-specific NAb also showed strong neutralization of the Delta variant, the prevalent strain of the present pandemic. These data show that convalescent patients maintain functional antibody responses for more than one year after infection, suggesting a strong long-lasting response after symptomatic disease that may offer a prolonged protection against re-infection. One patient from this cohort showed strong increase of both Spike and Nucleocapsid antibodies at 14 months post-infection indicating SARS-CoV-2 re-exposure. These antibodies showed stronger cross-reactivity to a panel of Spike-RBD including Beta, Delta and Mu and neutralization of a panel of Spike variants including Beta and Gamma. This patient provides an example of strong anti-Spike recall immunity able to control infection at an asymptomatic level. Together, the antibodies from SARS-CoV-2 convalescent patients persist over 14 months and continue to maintain cross-reactivity to the current variants of concern and show strong functional properties.

Kinetics of Nucleocapsid, Spike and Neutralizing Antibodies, and Viral Load in Patients with Severe COVID-19 Treated with Convalescent Plasma.

COVID-19 is an ongoing pandemic with high morbidity and mortality. Despite meticulous research, only dexamethasone has shown consistent mortality reduction. Convalescent plasma (CP) infusion might also develop into a safe and effective treatment modality on the basis of recent studies and meta-analyses; however, little is known regarding the kinetics of antibodies in CP recipients. To evaluate the kinetics, we followed 31 CP recipients longitudinally enrolled at a median of 3 days post symptom onset for changes in binding and neutralizing antibody titers and viral loads. Antibodies against the complete trimeric Spike protein and the receptor-binding domain (Spike-RBD), as well as against the complete Nucleocapsid protein and the RNA binding domain (N-RBD) were determined at baseline and weekly following CP infusion. Neutralizing antibody (pseudotype NAb) titers were determined at the same time points. Viral loads were determined semi-quantitatively by SARS-CoV-2 PCR. Patients with low humoral responses at entry showed a robust increase of antibodies to all SARS-CoV-2 proteins and Nab, reaching peak levels within 2 weeks. The rapid increase in binding and neutralizing antibodies was paralleled by a concomitant clearance of the virus within the same timeframe. Patients with high humoral responses at entry demonstrated low or no further increases; however, virus clearance followed the same trajectory as in patients with low antibody response at baseline. Together, the sequential immunological and virological analysis of this well-defined cohort of patients early in infection shows the presence of high levels of binding and neutralizing antibodies and potent clearance of the virus.

Pre-test probability for SARS-Cov-2-related infection score: The PARIS score.

INTRODUCTION: In numerous countries, large population testing is impossible due to the limited availability of RT-PCR kits and CT-scans. This study aimed to determine a pre-test probability score for SARS-CoV-2 infection. METHODS: This multicenter retrospective study (4 University Hospitals) included patients with clinical suspicion of SARS-CoV-2 infection. Demographic characteristics, clinical symptoms, and results of blood tests (complete white blood cell count, serum electrolytes and CRP) were collected. A pre-test probability score was derived from univariate analyses of clinical and biological variables between patients and controls, followed by multivariate binary logistic analysis to determine the independent variables associated with SARS-CoV-2 infection. RESULTS: 605 patients were included between March 10th and April 30th, 2020 (200 patients for the training cohort, 405 consecutive patients for the validation cohort). In the multivariate analysis, lymphocyte (<1.3 G/L), eosinophil (<0.06 G/L), basophil (<0.04 G/L) and neutrophil counts (<5 G/L) were associated with high probability of SARS-CoV-2 infection but no clinical variable was statistically significant. The score had a good performance in the validation cohort (AUC = 0.918 (CI: [0.891-0.946]; STD = 0.014) with a Positive Predictive Value of high-probability score of 93% (95%CI: [0.89-0.96]). Furthermore, a low-probability score excluded SARS-CoV-2 infection with a Negative Predictive Value of 98% (95%CI: [0.93-0.99]). The performance of the score was stable even during the last period of the study (15-30th April) with more controls than infected patients. CONCLUSIONS: The PARIS score has a good performance to categorize the pre-test probability of SARS-CoV-2 infection based on complete white blood cell count. It could help clinicians adapt testing and for rapid triage of patients before test results.