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Background: Coronavirus pandemic is an ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). WHO declared the outbreak as a Public Health Emergency of International Concern in January 2020 & a pandemic in March 2020. In India Oxford University-Astra Zeneca's Covishield vaccine, manufactured by serum institute of India and Bharath Biotech's Covaxin are being used for vaccination programme. In this study, we assess adverse reactions following Covid-19 vaccination & incidence of COVID-19 disease among vaccinated people across Kerala. Since it was newer vaccine and general population was afraid of side effects. The present study aimed to study the adverse effects of COVID-19 vaccination among general population aged above 18 years in Kerala. Method(s): A descriptive cross sectional study was conducted among COVID-19 vaccinated individuals above 18 yrs of age residing in Kerala from July 2021 to December 2021. Pattern of adverse events following COVID-19 vaccination (AEFI) were assessed using a semi structured questionnaire. An online questionnaire using Kobo Toolbox was developed and shared via online platform to record the self-reported adverse events following vaccination. A respondent driven sampling method was used. The data was downloaded in MS Excel and analysed using Microsoft excel. Result(s): Study was conducted among 526 people across Kerala, among which both males(45.63%) and females (54.18%). Majority of them received COVISHEID (92.97%) and rest of them received COVAXIN (6.24%) and SPUTNIK (0.57%). Out of which 65.97% received 2 doses and 34.03% received only one dose of vaccine. More than half of them (61.5%) faced side effects during post vaccination period. The symptoms were very mild in which fever (65.74%) and tiredness (76.85%) were the commonest symptoms. Conclusion(s): In the present study, majority of the vaccinated people experienced very mild and self limiting adverse effects, those were very mild & self limiting. It is a fact that COVID-19 vaccines doesn't provided 100% efficiency, but our study indicates that it does provides protection against COVID-19 infection to a great extend & breakthrough infections are very less severe and asymptomatic for vaccinated people.Copyright © 2023, Dr. Yashwant Research Labs Pvt. Ltd.. All rights reserved.
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Background: COVID-19 pandemic still pose a substantial threat worldwide despite increasing vaccine availability. Patients with haematological malignancies have been shown to have increased risk of contracting COVID-19 and are more susceptible to develop severe illness from SARS-CoV- 2 infection. The immune response to vaccines is impaired in patients with haematological malignancy due to underlying disease or antineoplastic therapies. The monoclonal-antibody combination, Evusheld is composed of tixagevimab and cilgavimab, two neutralising antibodies against SARS-CoV- 2. It has been shown to be safe and have efficacy for the prevention of COVID-19. Our aim of study is to describe the incidence and outcome of breakthrough COVID-19 infection among patients who received Evusheld in our centre and analyse the factors that possibly increase the risk of breakthrough infection. Material(s) and Method(s): A retrospective review of all adult patients with haematological malignancy who received tixagevimab/ cilgavimab 150/150 mg injection in Hospital Pulau Pinang from 1 July 2022 to 31 August 2022 with a follow-up period to 30 November 2022 was conducted. Demographic data, clinical characteristics and outcome will be retrieved from patient's medical records. Data were analysed using Statistical Package for Social Sciences software (version 21.0). Result(s): A total of 96 patients (50 males and 46 females) received tixagevimab/cilgavimab injection during the study period with a median age of 61 years (range 19-82). Majority of them were diagnosed with multiple myeloma (42.7%), followed by lymphoma (33.3%) and leukaemia (24%). One third of them had history of therapy with monoclonal antibody and 20% had haematopoietic stem cell transplantation. No major adverse effects of tixagevimab/cilgavimab injection were noted among the study population. Of the 12 patients (12.5%) who had COVID-19 infection, all of them had mild infection;three were asymptomatic and six patients received Paxlovid antiviral therapy. The median time from tixagevimab/cilgavimab to the onset of COVID-19 infection was 35 days (range 5-97 days). The mean age of patients with breakthrough COVID-19 infection were older compared to those without breakthrough infection but was not statistically significant. The incidence of breakthrough COVID-19 infection was not affected by type of haematological malignancy, history of monoclonal antibody therapy or COVID-19 vaccination. Discussion and Conclusion(s): Our findings showed that tixagevimab/cilgavimab was safe and effective in preventing COVID-19- related morbidity and mortality among patients with haematological malignancy during the study period. However, the limitation is the lack of access to whole genome sequencing for detection of resistant variants for breakthrough infections.
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BACKGROUND: Given the reduced immune response to vaccines in older populations, this study aimed to evaluate the efficacy of COVID-19 vaccinations and its impact on breakthrough infection, hospital admission, and mortality in the elderly. METHODS: We carried out a systemic review and meta-analysis where MEDLINE, Web of Science, EMBASE, ClinicalTrials.gov, and Cochrane Central Register for Controlled Trials were queried to identify relevant literature. We included randomized controlled trials (RCTs), non-randomized trials, prospective, observational cohort, and case-control studies assessing breakthrough infection, hospital admission, and mortality after coronavirus 2 (SARS-CoV-2) vaccination in the elderly (≥ 60 years old). RESULTS: Overall, 26 studies were included in this meta-analysis. Compared with the unvaccinated group, the vaccinated group showed a decreased risk of SARS-CoV-2 infection after 28-34 (relative risk [RR] = 0.42, 95% confidence interval [CI] 0.37-0.49) and 35-60 days (RR = 0.49, 95% CI 0.37-0.62). There was a step-wise increase in efficacy with additional doses with the two-dose group experiencing decreased risk of breakthrough infection (RR = 0.37, 95% CI 0.32-0.42), hospital admissions (RR = 0.25, 95% CI 0.14-0.45), disease severity (RR = 0.38, 95% CI 0.20-0.70), and mortality (RR = 0.21, 95% CI 0.14-0.32) compared with those receiving one or no doses. Similarly three-dose and four-dose vaccine groups also showed a decreased risk of breakthrough infection (3-dose: RR = 0.14, 95% CI 0.10-0.20; 4-dose RR = 0.46, 95% CI 0.4-0.53), hospital admissions (3-dose: RR = 0.11, 95% CI 0.07-0.17; 4-dose: RR = 0.42, 95% CI 0.32-0.55), and all-cause mortality (3-dose: RR = 0.10, 95% CI 0.02-0.48; 4-dose: RR = 0.48, 95% CI 0.28-0.84) Subgroup analysis found that protection against mortality for vaccinated vs. unvaccinated groups was similar by age (60-79 years: RR = 0.59; 95% CI, 0.47-0.74; ≥ 80 years: RR = 0.76; 95% CI, 0.59-0.98) and gender (female: RR = 0.66; 95% CI, 0.50-0.87, male: (RR = 0.58; 95% CI, 0.44-0.76), and comorbid cardiovascular disease (CVD) (RR = 0.69; 95% CI, 0.52-0.92) or diabetes (DM) (RR = 0.59; 95% CI, 0.39-0.89. CONCLUSIONS: Our pooled results showed that SARS-CoV-2 vaccines administered to the elderly is effective in preventing prevent breakthrough infection, hospitalization, severity, and death. What's more, increasing number of vaccine doses is becoming increasingly effective.
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OBJECTIVES: B cell depleting monoclonal antibodies are associated with increased COVID-19 severity and impaired immune response to vaccination. We aimed to assess the humoral and cell mediated (CMI) immune response after SARS-CoV-2 vaccination in rituximab (RTX)-treated rheumatic patients. METHODS: Serum and whole blood samples were collected from rituximab (RTX)-treated rheumatic patients 3-6 months after last vaccination against SARS-CoV-2. Serum was tested by ELISA for quantitative detection of anti-spike SARS-CoV-2 IgG. Cell-mediated variant-specific SARS-CoV-2 immunity (CMI) was assessed by interferon-γ release assay Covi-FERON FIA. Patients were interviewed for breakthrough COVID-19 infection (BTI) 3 months post sampling. RESULTS: Sixty patients were studied after a median (IQR) of 179 (117-221.5) days from last vaccine to sampling. Forty (66.7%) patients had positive Covi-FERON and 23 (38.3%) had detectable anti-spike IgG. Covi-FERON positive patients had lower median RTX cumulative dose [6 (4-10.75) vs 11 (6.75-14.75) grams, (p= 0.019). Patients with positive anti-spike IgG had received fewer RTX cycles [2 (2-4) vs 6 (4-8), p= 0.002) and cumulative dose [4 (3-7) vs 10 (6.25-13) grams, p= 0.002] and had shorter time from last vaccination to sampling [140 (76-199) vs 192 (128-230) days, p= 0.047). Thirty-seven percent were positive only for Covi-FERON and 7% only for anti-spike IgG. Twenty (33.3%) BTI occurred post sampling, exclusively during Omicron variant predominance. The proportion of patients with CMI response against Delta variant was lower in patients who experienced BTI (25% vs 55%, p= 0.03). CONCLUSIONS: Four out of ten RTX-treated vaccinated patients show lasting cell-mediated immune response despite undetectable anti-spike antibodies. Cumulative RTX dose affects both humoral and cell-mediated responses to SARS-CoV-2 vaccines. Cell-mediated immune responses call for attention as a vaccine efficacy marker against SARS-CoV-2.
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Breakthrough infection (BI) after coronavirus disease 2019 (COVID-19) vaccination has exploded owing to the emergence of various SARS-CoV-2 variants and has become a major problem at present. In this study, we analyzed the epidemiological information and possession status of neutralizing antibodies in patients with BI using SARS-CoV-2 pseudotyped viruses (SARS-CoV-2pv). Analysis of 44 specimens diagnosed with COVID-19 after two or more vaccinations showed high inhibition of infection by 90% or more against the Wuhan strain and the Alpha and Delta variants of pseudotyped viruses in 40 specimens. In contrast, almost no neutralizing activity was observed against the Omicron BA.1 variant. Many cases without neutralizing activity or BI were immunosuppressed individuals. The results of this study show that contact with an infected person can result in BI even when there are sufficient neutralizing antibodies in the blood. Thus, even after vaccination, sufficient precautions must be taken to prevent infection.
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Herein, we report the case of a 67-year-old man with severe coronavirus disease (COVID-19) pneumonia and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine breakthrough infection during immunosuppressive therapy for connective tissue disease-related interstitial lung disease (CTD-ILD). The patient received glucocorticoids combined with tacrolimus (TAC) as maintenance therapy. His serum anti-SARS-CoV-2-IgG antibody levels were extremely low at the onset of COVID-19 pneumonia, even after the second dose of SARS-CoV-2 mRNA vaccine (BNT162b2). After treatment for COVID-19 pneumonia, the levels of anti-SARS-CoV-2-IgG antibodies increased. These results indicated a lack of the ability to produce neutralizing antibodies from immune cells despite the booster vaccination. Therefore, we suggest that advanced age patients with CTD-ILD receiving immunosuppressive therapy with polypharmacy require consistent personal protection, vaccination of close caregivers, increased awareness, and booster vaccination. Moreover, we recommend that TAC should be withdrawn for a while after vaccination under controlled conditions.
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Understanding SARS-CoV-2 breakthrough infections in vaccinated healthcare workers is of key importance in mitigating the effects of the COVID-19 pandemic in healthcare facilities. An observational prospective cohort study was conducted in vaccinated employees with acute SARS-CoV-2 infection between October 2021 and February 2022. Serological and molecular testing was performed to determine SARS-CoV-2 viral load, lineage, antibody levels, and neutralizing antibody titers. A total of 571 (9.7%) employees experienced SARS-CoV-2 breakthrough infections during the enrolment period, of which 81 were included. The majority (n = 79, 97.5%) were symptomatic and most (n = 75, 92.6%) showed Ct values < 30 in RT-PCR assays. Twenty-four (30%) remained PCR-positive for > 15 days. Neutralizing antibody titers were strongest for the wildtype, intermediate for Delta, and lowest for Omicron variants. Omicron infections occurred at higher anti-RBD-IgG serum levels (p = 0.00001) and showed a trend for higher viral loads (p = 0.14, median Ct difference 4.3, 95% CI [-2.5-10.5]). For both variants, viral loads were significantly higher in participants with lower anti-RBD-IgG serum levels (p = 0.02). In conclusion, while the clinical course of infection with both the Omicron and Delta variants was predominantly mild to moderate in our study population, waning immune response over time and prolonged viral shedding were observed.
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(1) Background: The clinical implications of COVID-19 outbreaks following SARS-CoV-2 vaccination in immunocompromised recipients are a worldwide concern. Cancer patients on active treatment remain at an increased risk of developing breakthrough infections because of waning immunity and the emergence of SARS-CoV-2 variants. There is a paucity of data on the effects of COVID-19 outbreaks on long-term survival outcomes in this population. (2) Methods: We enrolled 230 cancer patients who were on active treatment for advanced disease and had received booster dosing of an mRNA-BNT162b2 vaccine as part of the Vax-On-Third trial between September 2021 and October 2021. Four weeks after the third immunization, IgG antibodies against the spike receptor domain of SARS-CoV-2 were tested in all patients. We prospectively evaluated the incidence of breakthrough infections and disease outcomes. The coprimary endpoints were the effects of antibody titers on the development of breakthrough infections and the impact of COVID-19 outbreaks on cancer treatment failure. (3) Results: At a median follow-up of 16.3 months (95% CI 14.5-17.0), 85 (37%) patients developed SARS-CoV-2 infection. Hospitalization was required in 11 patients (12.9%) and only 2 (2.3%) deaths related to COVID-19 outbreaks were observed. Median antibody titers were significantly lower in breakthrough cases than in non-cases (291 BAU/mL (95% CI 210-505) vs. 2798 BAU/mL (95% CI 2323-3613), p < 0.001). A serological titer cut-off below 803 BAU/mL was predictive of breakthrough infection. In multivariate testing, antibody titers and cytotoxic chemotherapy were independently associated with an increased risk of outbreaks. Time-to-treatment failure after booster dosing was significantly shorter in patients who contracted SARS-CoV-2 infection (3.1 months (95% CI 2.3-3.6) vs. 16.2 months (95% CI 14.3-17.0), p < 0.001) and had an antibody level below the cut-off (3.6 months (95% CI 3.0-4.5) vs. 14.6 months (95% CI 11.9-16.3), p < 0.001). A multivariate Cox regression model confirmed that both covariates independently had a worsening effect on time-to-treatment failure. (4) Conclusions: These data support the role of vaccine boosters in preventing the incidence and severity of COVID-19 outbreaks. Enhanced humoral immunity after the third vaccination significantly correlates with protection against breakthrough infections. Strategies aimed at restraining SARS-CoV-2 transmission in advanced cancer patients undergoing active treatment should be prioritized to mitigate the impact on disease outcomes.
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COVID-19 , Neoplasms , Humans , COVID-19 Vaccines/therapeutic use , Antibody Formation , SARS-CoV-2 , BNT162 Vaccine , Breakthrough Infections , Neoplasms/drug therapyABSTRACT
For SARS-CoV-2 mutants, the effectiveness of the COVID-19 vaccines is still controversial. In this study, we aimed to investigate the clinical characteristics of Omicron-infected patients who completed primary immunization and booster immunization, respectively, during the rapid propagation of the Omicron variant in China. A total of 932 patients with confirmed SARS-CoV-2 infection from 18 December 2022 to 1 January 2023 were included in this survey by filling out questionnaires online. The enrolled patients were divided into the primary immunization group and the booster immunization group according to their vaccination status. During the whole course of disease, the most frequent symptoms were fever (90.6%), cough (84.3%), weakness (77.4%), headache and dizziness (76.1%), and myalgia (73.9%). Nearly 90% of the patients had symptoms lasting for less than 10 days, and 39.8% of the patients ended the course of the disease in 4-6 days. A total of 58.8% of these patients had a fever with a maximum body temperature of over 38.5 °C. Moreover, 61.4% of the patients had a fever that lasted less than 2 days. There were no obvious differences in initial symptoms, cardinal symptoms, symptom duration time, maximum body temperature, and fever duration time between the two groups of patients. In addition, no significant difference was found in the positive or negative conversion time of SARS-CoV-2 antigen/nucleic acid between the two groups of patients. For mild patients with Omicron breakthrough infection, enhanced immunization has no significant impact on the clinical performance and duration of viral infection compared with primary immunization. The reasons behind the different clinical manifestations of patients with mild symptoms after the breakthrough infection of the Omicron strain are still worth further research. Heterologous vaccination may be a better strategy for enhanced immunization, which can help improve the immune protection ability of the population. Further research should be carried out on vaccines against mutant strains and spectral anti-COVID-19 vaccines.
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There is limited information on the kinetics of the humoral response elicited by a fourth dose with a heterologous mRNA1273 booster in patients who previously received a third dose with BNT162b2 and two doses of BBIBP-CorV as the primary regimen. We conducted a prospective cohort study to assess the humoral response using Elecsys® anti-SARS-CoV-2 S (anti-S-RBD) of 452 healthcare workers (HCWs) in a private laboratory in Lima, Peru at 21, 120, 210, and 300 days after a third dose with a BNT162b2 heterologous booster in HCW previously immunized with two doses of BBIBP-CorV, depending on whether or not they received a fourth dose with the mRNA1273 heterologous vaccine and on the history of previous SARS infection -CoV-2. Of the 452 HCWs, 204 (45.13%) were previously infected (PI) with SARS-CoV-2, and 215 (47.57%) received a fourth dose with a heterologous mRNA-1273 booster. A total of 100% of HCWs presented positive anti-S-RBD 300 days after the third dose. In HCWs receiving a fourth dose, GMTs 2.3 and 1.6 times higher than controls were observed 30 and 120 days after the fourth dose. No statistically significant differences in anti-S-RBD titers were observed in those HCWs PI and NPI during the follow-up period. We observed that HCWs who received a fourth dose with the mRNA1273 and those previously infected after the third dose with BNT162b2 (during the Omicron wave) presented higher anti-S-RBD titers (5734 and 3428 U/mL, respectively). Further studies are required to determine whether patients infected after the third dose need a fourth dose.
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AIM: To explore the risk of breakthrough infection among patients with type 2 diabetes (T2D) and risk of severe clinical outcomes after SARS-CoV-2 infection according to vaccination status. MATERIALS AND METHODS: We conducted a population-based cohort study using South Korea's linked database of nationwide COVID-19 registry and claims data between 2018 and 2021. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breakthrough infections were measured in 1:1 propensity-score (PS)-matched fully vaccinated patients with versus without T2D (full-vaccination cohort), and HRs for all-cause mortality, intensive care unit (ICU) admission/mechanical ventilation (MV) use, and hospitalizations after SARS-CoV-2 infection were measured in 1:1 PS-matched T2D patients with versus without full-vaccination (T2D cohort). RESULTS: After 1:1 PS matching, 2 109 970 patients with and without T2D were identified (age 63.5 years; 50.9% male). Patients with T2D showed an increased risk of breakthrough infections compared to those without T2D (HR 1.10, 95% CI 1.06-1.14). The increased risk of breakthrough infections was more notable among T2D patients receiving insulin treatment. However, the risk of severe COVID-19 outcomes was lower in fully vaccinated T2D patients compared with unvaccinated T2D patients (all-cause mortality: HR 0.54, 95% CI 0.43-0.67; ICU admission/MV use: HR 0.31, 95% CI 0.23-0.41; hospitalization: HR 0.73, 95% CI 0.68-0.78). CONCLUSIONS: While patients with T2D remain a vulnerable population to SARS-CoV-2 infection even after full-vaccination, full-vaccination was associated with a lower risk of adverse clinical outcomes after SARS-CoV-2 infection. These findings support the guidelines recommending patients with T2D as a priority vaccination group.
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Objective: We aim to identify the clinical characteristics and outcome of vaccine breakthrough infection in critically ill COVID-19 patients and to compare the clinical course of disease between vaccinated and non-vaccinated patients. Methods: A retrospective review of all adult patients aged ≥18 years admitted to the ICU in King Fahd Hospital of the University in Saudi Arabia with positive COVID-19 RT-PCR test between the period of January 1st to August 31st, 2021, were included. The recruited patients were grouped in to "vaccinated and non-vaccinated group" based on their immunization status. The demographic data, co-morbidities, modality of oxygen support, ICU length of stay (ICU LOS) and mortality were collected and analyzed. Results: A total of 167 patients were included. Seventy-two patients (43%) were vaccinated. Cardiovascular diseases were higher among the vaccinated group (33.3% vs 12.6%, p value <0.001). Requirements of Non-invasive ventilation was significantly lower in vaccinated group compared to non-vaccinated group (73.6% vs 91.6%, p value <0.011). The rates of intubation were similar between both groups. The total intubation days was longer in non-vaccinated patients compared to vaccinated patients and the median duration of intubation was 8 days vs 2 days, respectively (p value 0.027). In subgroup analysis, the P/F ratio was significantly higher in patients who received two doses of vaccine compared to single dose (p value <0.002). Conclusion: In critically ill COVID-19 patients, the vaccinated group has significantly less need for Non-invasive ventilation, fewer intubation days and less hypoxia compared to non-vaccinated patients. We recommend more policies and public education nationwide and worldwide to encourage vaccination and raise awareness of the general population.
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Background/Aims Immunocompromised patients have a reduced ability to generate antibodies after COVID-19 vaccination, and are at a high risk of SARSPOSTERS CoV-2 infection, complications and mortality. Tixagevimab/Cilgavimab (Evusheld) is a combination of two monoclonal antibodies which bind to the SARS-CoV-2 spike protein, preventing the virus entering human cells. Tixagevimab/Cilgavimab has been approved as COVID-19 prophylaxis for immunocompromised individuals, and is being used in over 32 different countries. The phase III PROVENT clinical trial found that high-risk participants prophylactically administered Tixagevimab/Cilgavimab had a significantly reduced risk of COVID- 19 infection after three and six months compared to controls. However, the PROVENT trial was conducted prior to the SARS-CoV- 2 Omicron wave, and did not include participants who had been previously vaccinated or infected. This systematic review provides an updated summary of the real-world clinical evidence of the efficacy of Tixagevimab/Cilgavimab for immunocompromised patients. The review reports breakthrough COVID-19 infections as its primary outcome. COVID-19-related hospitalisations, ITU admissions and mortality were included as secondary outcomes. Methods Two independent reviewers conducted electronic searches of PubMed and Medxriv, on 03/08/22 and 01/10/22. Clinical studies which reported the primary outcome of breakthrough COVID-19 infections after Tixagevimab/Cilgavimab administration were included. Clinical effectiveness was determined using the case-control clinical effectiveness methodology. Odds ratios and 95% confidence intervals (CI) between intervention and control groups were also calculated. The GRADE tool was used to assess the level of certainty for the primary outcome. Results 17 clinical studies were included in the review, with a total of 24,773 immunocompromised participants from across the world, of whom 10,775 received Tixagevimab/Cilgavimab. One randomised controlled trial, ten retrospective cohort studies (two of which were preprints) and six prospective cohort studies (one preprint) were included. The majority of studies reported clinical outcomes during the SARS-CoV-2 Omicron wave. Six studies compared a Tixagevimab/Cilgavimab intervention group to a control group. Reasons for participant immunocompromise included rheumatology patients treated with immunosuppressant drugs, transplant recipients and those with malignancies. Overall, the clinical effectiveness of prophylactic Tixagevimab/Cilgavimab against COVID- 19 breakthrough infection was 40.47% (CI 29.82-49.67;p<0.0001), COVID-19 hospitalisation- 69.23% (CI: 50.78-81.64;p<0.00001), ITU admission- 87.89% (CI: 47.12-98.66;p=0.0008), all-cause mortality- 81.29% (66.93-90.28;p<0.0001 and COVID-19-specifc mortality- 86.36% (CI:-6.21-99.70;p=0.0351). Conclusion There is a growing body of real-world evidence validating the original PROVENT phase III study regarding the clinical effectiveness of Tixagevimab/Cilgavimab as prophylaxis for immunocompromised groups, notably demonstrating effectiveness during the Omicron wave. This systematic review demonstrates the significant clinical effectiveness of prophylactic Tixagevimb/Cilgavimab at reducing COVID-19 infection, hospitalisation, ITU admission and mortality for immunosuppressed individuals. It is critically important that largerscale and better-controlled studies are performed to highlight the significant clinical benefit of prophylactic antibody treatment in immunocompromised groups.
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Since early 2022, various Omicron variants have dominated the SARS-CoV-2 pandemic in most countries. All Omicron variants are B-cell immune escape variants, and antibodies induced by first-generation COVID-19 vaccines or by infection with earlier SARS-CoV-2 variants largely fail to protect individuals from Omicron infection. In the present study, we investigated the effect of Omicron infections in triple-vaccinated and in antigen-naive individuals. We show that Omicron breakthrough infections occurring 2-3.5 months after the third vaccination restore B-cell and T-cell immune responses to levels similar to or higher than those measured 14 days after the third vaccination, including the induction of Omicron-neutralizing antibodies. Antibody responses in breakthrough infection derived mostly from cross-reacting B cells, initially induced by vaccination, whereas Omicron infections in antigen-naive individuals primarily generated B cells binding to the Omicron but not the Wuhan spike protein. Although antigen-naive individuals mounted considerable T-cell responses after infection, B-cell responses were low, and neutralizing antibodies were frequently below the limit of detection. In summary, the detection of Omicron-associated B-cell responses in primed and in antigen-naive individuals supports the application of Omicron-adapted COVID-19 vaccines, but calls into question their suitability if they also contain/encode antigens of the original Wuhan virus.
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COVID-19 , Humans , COVID-19 Vaccines , SARS-CoV-2 , Antibodies, Neutralizing , Breakthrough InfectionsABSTRACT
Background: Data on the effectiveness of the bivalent booster vaccine against COVID-19 breakthrough infection and severe outcomes is limited. Method(s): Using patient-level data from 54 sites in the U.S. National COVID Cohort Collaborative (N3C), we estimated bivalent booster effectiveness against breakthrough infection and outcomes between 09/01/2022 (bivalent vaccine approval date) to 12/15/2022 (most recent data release of N3C) among patients completed 2+ doses of mRNA vaccine. Bivalent booster effectiveness was evaluated among all patients and patients with and without immunosuppressed/compromised conditions (ISC;HIV infection, solid organ/ bone marrow transplant, autoimmune diseases, and cancer). We used logistic regression models to compare the odds of breakthrough infection (COVID-19 diagnosis after the last dose of vaccine) and outcomes (hospitalization, ventilation/ECMO use, or death <=28 days after infection) in the bivalent boosted vs. non-bivalent boosted groups. Models controlled for demographics, comorbidities, geographic region, prior SARS-CoV-2 infection, months since the last dose of non-bivalent vaccine, and prior non-bivalent booster. Result(s): By 12/15/2022, 2,414,904 patients had received 2+ doses of mRNA vaccination, 75,873 of them had received a bivalent booster vaccine, and 24,046 of them had a breakthrough infection. At baseline, the median age was 52 (IQR 36-67) years, 40% male, 63% white, 10% Black, 12% Latinx, 3.5% Asian American/Pacific Islander, and 14% were patients with ISC. Patients received a bivalent booster were more likely to be female and had comorbidities. Bivalent booster was significantly associated with reduced odds of breakthrough infection and hospitalization (Figure). The adjusted odds ratios comparing bivalent vs. non-bivalent group were 0.28 (95% CI 0.25, 0.32) for all patients and 0.33 (95% CI: 0.26, 0.41) for patients with ISC. Compared to the nonbivalent group, the bivalent group had a lower incidence of COVID-19-related hospitalization (151 vs. 41 per 100,000 persons), invasive ventilation/ECMO use (7.5 vs. 1.3 per 100,000 persons), or death (11 vs. 1.3 per 100,000 persons) in all patients during the study period;the incidence of severe outcomes after bivalent boosting was similar among patients with and without ISC. Conclusion(s): A bivalent booster vaccine was highly effective against COVID-19 breakthrough infection and severe outcomes among patients received 2+ doses of mRNA vaccine and offered similar protection in patients with and without ISC. (Figure Presented).
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Purpose of Study: Previous Osteopathic manipulative treatment (OMT) research has shown evidence of increased lymphatic movement resulting in increased leukocyte and cytokine flow. One study even showed increased antibody titer response in patients when used in conjunction with the Hepatitis B vaccine. Given previous studies, our group conducted a year-long longitudinal randomized controlled clinical trial to evaluate the ability of OMT to improve the COVID-19 vaccine immune response. Methods Used: Subjects were randomized into either the control arm or OMT intervention arm. OMT consisted of myofascial release of the thoracic inlet, pectoral traction, diaphragm release with MFR, splenic pump, and thoracic pump applied the day of and the day following each vaccination session. All subjects in each group received the Pfizer mRNA COVID-19 vaccine. All subjects had blood drawn on day 0 (1st vaccine), day 7, day 21 (2nd vaccine), days 28, 90, 210, and 365. Anti-spike IgG immunoglobulin titers (AS IgG) were measured at all time points for all subjects. Side effects, adverse events, and medication usage in response to the vaccines or OMT was documented. Breakthrough cases with symptomology and medication usage was documented for both groups. The study was approved by the WesternU IRB committee, protocol #FB21/IRB026. Summary of Results: Data for 91 subjects were analyzed with 41 male (45.1%) and 50 female (54.9%). Age distribution was comparable between the two groups. Side effects and medication usage reported by the subjects was similar between groups (p>0.1). AS IgG measured at baseline distinguished between previously infected individuals and those naive to COVID-19, regardless of OMT treatment. For all time points measured, the average AS IgG in subjects trended higher in OMT group than control group. Two-way ANOVA analysis showed statistical significance at 1 week after 2nd injection (p<0.001) in the COVID-19 naive population. 13 symptomatic breakthrough infections were reported in the control group and 12 in the OMT group. Length of symptoms were reported as 8.36 +/- 4.60 days (control) and 4.62 +/- 2.60 days (OMT) (p<0.05). Length of medication usage was 3.64 +/- 3.58 days (control) and 1.23 +/- 1.24 days (OMT) (p<0.1). Conclusion(s): Both groups had comparable side effects after COVID-19 vaccination with no adverse events linked to OMT, indicating that OMT is a safe adjunct that can be used with COVID-19 vaccination. The data showed an enhanced immune response by OMT, as evidenced by increased levels of AS IgG in previously naive subjects. Although both control and OMT groups had similar rates of symptomatic breakthrough infection, the OMT data shows reduced length of symptoms and medication duration in this population when compared to control breakthrough infections. This study is underpowered for statistical significance at each time point and future vaccination studies should recruit more patients to confirm the trends seen here.
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Background: Long-acting cabotegravir (CAB-LA) is highly effective as HIV PrEP and superior to daily oral F/TDF in sexually active adults. We report a 28-yearold gender diverse patient assigned male at birth who acquired HIV-1 91 days after transitioning from F/TAF to CAB-LA despite on-time dosing. Method(s): Electronic medical records were reviewed to assess patient history and CAB-LA administration details. Plasma 4th generation HIV-1/2 Ag/Ab combination immunoassay and HIV-1 RNA quantitative PCR were performed at each injection visit. Result(s): Patient was on daily F/TAF for ten months prior to CAB-LA with acceptable adherence, missing 1 dose per week. Their medical history included hypothyroidism on levothyroxine and unconfirmed hypogonadism with illicit use of IM testosterone cypionate complicated by significantly elevated total testosterone levels. They were sexually active with cisgender men, endorsing condomless oral and anal sex with one primary partner and 20-30 unique partners per month. In the past 6 months, patient was diagnosed with syphilis and mpox. Patient was given 600mg of CAB-LA into their left gluteal medius on Day 0, 27, and 91. Day 0 and 27, plasma HIV 1/2 Ag/Ab was non-reactive and HIV-1 RNA PCR was not detected. Patient reported flu-like illness on Day 76 with positive SARS-COV-2 PCR;they completed a five-day course of nirmatrelvirritonavir with rapid resolution of symptoms. At the third injection of 600mg CAB-LA on Day 91, their plasma HIV 1/2 Ag/Ab was non-reactive but the HIV-1 RNA PCR test was detected at 1.48log c/mL. On repeat testing on Day 100, plasma HIV 1/2 Ag/Ab was reactive with HIV-1 Ab detected on differentiation assay and HIV-1 RNA PCR was detected at 1.30 log c/mL. Patient's primary partner was living with HIV resistant to NRTIs (65R, 118I) and INSTIs (92G) with undetectable plasma HIV-1 RNA for the past 24 months. Patient's viremia was below the threshold to perform standard HIV-1 sequencing;HIV-1 DNA qualitative PCR and HIV-1 proviral DNA resistance testing are currently pending. Patient ultimately started on F/TAF/DRV/COBI and DTG on Day 112. Conclusion(s): This patient's history suggests HIV-1 infection despite on-time and appropriate CAB-LA injections. To our knowledge, this is the first case of CAB-LA PrEP failure outside the setting of a clinical trial and highlights the diagnostic and management challenges that may arise with such breakthrough infections in the real world.
ABSTRACT
Background: In ongoing SARS CoV-2 pandemic, understanding antibody responses have played a key role in measuring extent of exposure, protection from reinfection, vaccine efficacy and serodiagnosis. Antibody avidity is total binding strength of immunoglobulin G (IgG) toward its target epitope. High antibody avidity has been correlated with effective neutralization of the SARSCoV-2 virus. However, the data on avidity responses against COVID-19 infection and vaccination are limited. Objective(s): To understand the avidity responses among sera of naturally infected, recovered COVID-19 patients;naive Covaxin, Covishield vaccinees and breakthrough infections. Material(s) and Method(s): In this study, we utilized an in-house developed SARS-CoV-2 anti-spike receptor binding domain (SRBD) IgG ELISA to optimize the avidity assay. A panel of anti-SARS-CoV- 2 SRBD IgG positive serum samples were treated with known concentration of a chaotropic agent (urea) for disruption of the noncovalent interactions of the antigen-antibody complex. This disruption causes low avidity antibodies to dissociate which gives the percentage of high avidity antibodies present in a serum sample. Additionally, the optimized assay was used to understand the avidity responses among sera belonging to individuals naturally infected and recovered after COVID-19, naive Covaxin and Covishield vaccinees;followed by breakthrough infections. Result(s) and Conclusion(s): The anti-SRBD avidity progressively elevated over a period of twelve months. Moreover, overall antibody avidity responses were similar in the case of natural infection and naive two doses of Covaxin and Covishield vaccinated individuals. However, avidity responses were high among individuals with a breakthrough infection as compared to naive vaccinees.
ABSTRACT
Background: The US Defense Dept launched its COVID-19 vaccination program in Dec 20. The VIRAMP study was designed to address knowledge gaps in US military personnel including vaccine effectiveness against asymptomatic infection, viral carriage and transmission, and durability of protection. Method(s): Military members who had received >=1 dose of an FDA-authorized COVID-19 vaccine were enrolled at 3 sites in Texas May 21-Mar 22 and followed for up to 24 months after first dose. Study activities comprised of three in-person study visits and remote data collection: weekly and monthly questionnaires, self-collection of blood (monthly) and saliva twice weekly (more frequently if symptomatic). Participants shipped self-collected specimens for Ab analyses and SARS-CoV-2 PCR and sequencing. We report an interim analysis on data collected through May 22. Result(s): Participants included 957 military members (60% male, 40% female), with 69% identifying as White, 15% Black/African American, 23% LatinX. Participants were Officers (38%) and Enlisted (62%);54% were healthcare workers. The majority (92.5%) received the Pfizer/BioNTech monovalent A/ Wuhan COVID-19 vaccine;30% of participants received one booster dose. One or more breakthrough infections (bti), defined as positive saliva SARS-CoV-2 PCR, were detected in 228 (24%) participants (36 Delta, 192 Omicron). No differences were detected in rates of symptomatic vs asymptomatic bti by variant or time since last vaccine. Mean age was greater for participants with bti vs those without (35.4 (+/- 7.7) years vs 32 (+/- 8.2) years;p< 0.0001), but no differences were noted by sex, race, or ethnicity. Symptomatic infections (defined as >=2 symptoms) were detected in 43% of participants, whereas 35% of bti were asymptomatic;there were no hospitalizations or deaths. A trend towards reduced duration of saliva positivity was noted in Omicron infections in the 4 months following booster dose compared to infections in the 4 months following primary series (5.3 days vs 12.4 days;p=0.0645). Conclusion(s): Approximately 1/4 of participants had bti in the first year, spanning the evolving epi and vaccination landscape of the pandemic, with about 1/3 demonstrating asymptomatic infection. A trend towards shorter duration of viral carriage following booster dose was noted in Omicron infections. The VIRAMP study demonstrated that prospective surveillance in a large, diverse cohort of US military members utilizing remote specimen and questionnaire collection is operationally feasible.
ABSTRACT
Background: Sero-studies of SARS-CoV-2 have used antibody (Ab) responses to spike (S) and nucleocapsid (N) antigens to differentiate mRNA vaccinated (S+/N-) from infected (S+/N+) individuals. We performed testing on wellcharacterized subjects to determine how repeated vaccination or infection, and time from those exposures, influence these Ab levels. Method(s): Samples from individuals with known infection status: prepandemic negative controls n=462;first-time infected n=237 (~45 days post);vaccinated after infection n= 34 (~40 days post-vaccination and ~180 days post-infection);fully vaccinated n=158 (~50 days post);boosted n=31 (~30 days post);breakthrough n=18 (~14 days post-infection);reinfected n=10 (varied). Longitudinal samples (n=51) from subjects with evidence of reinfection (symptoms and/or positive rapid antigen test), were tested to determine the impact of the order of infection and/or vaccination on the magnitude of the anti-S and anti-N IgG Ab detected in the blood. Testing was performed with MesoScale Diagnostics (Gaithersburg, MD) assay. Outcomes are presented in WHO International Binding Antibody Units (BAU/mL). The cutoff for a positive result was 18 BAU for S and 12 BAU for N. Result(s): The median amount of Ab (IQR) in BAU for each group (Figure A) was: pre-pandemic negative controls S 0.53(0.27,1.03), N 0.55(0.18,1.67);first-time infected S 114(51,328), N 70(29,229);vaccinated after infection S 4367(2479,4837), N 15(7,35);fully vaccinated S 998(586,1529), N 0.31(0.16,0.68);boosted S 2988(1768,3522), N 0.59(0.32,1.03);breakthrough S 2429(2032,3413), N 2.5(0.93,8.6);reinfected S 1533(486,4643), N 7.8(2.6,62). For the breakthrough and second infections 17% and 40% were seropositive to N, respectively. Longitudinal analysis (Figure B) of those with multiple infections showed that all those with a positive rapid antigen test for their second infection had an increase in N Ab. Conclusion(s): The prevalence of antibodies to nucleocapsid cannot be used to determine the proportion of individuals infected to SARS-CoV-2 in a vaccinated population. Booster, repeated, and breakthrough infections are associated with IgG Ab levels to S >400 BAU/mL. A majority of breakthrough infections did not elicit an Ab response to N. For those with repeated infection, a minority elicited antibody responses to N. This could be related to misdiagnosis or the burden of infection, as only those who were positive by rapid antigen assay (indicative of a high viral load) had an increase in N Ab.