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BackgroundThe durability and cross-neutralizability of protective antibodies against evolving SARS-CoV-2 variants are primary concerns in mitigating (re-)exposures. The role of antibody maturation, the process whereby selection of higher avidity antibodies augments host immunity, to determine SARS-CoV-2 neutralizability was investigated. MethodsSera collected from SARS-CoV-2 convalescent individuals at 2- or 10-months after recovery, and BNT162b2 vaccine recipients at 3 or 25 weeks post-vaccination, were analyzed. Anti-spike IgG avidity was measured on a urea-treated ELISA platform. Neutralizing ability of antibodies was assessed by surrogate virus neutralization. Fold change between variant and wild-type antigen neutralizability was calculated to infer breadth of neutralizability. ResultsCompared with early-convalescence, the avidity index of late-convalescent sera was significantly higher (median 37.7 (interquartile range 28.4-45.1) vs. 64.9 (57.5-71.5), p < 0.0001), indicative of progressive antibody maturation extending months beyond acute-phase illness. The urea-resistant, high-avidity fraction of IgG was best predictive of neutralizability (Spearmans r = 0.49 vs. 0.67 for wild-type; 0.18-0.52 vs. 0.48-0.83 for variants). Higher-avidity convalescent sera showed greater cross-neutralizability against SARS-CoV-2 variants (p < 0.001 for Alpha; p < 0.01 for Delta and Omicron). Vaccinees experienced delayed maturation kinetics, translating to limited breadth of neutralizability at week-25 post-vaccination which was only comparable to that of early-convalescence. ConclusionsAvidity maturation grants broader neutralizability that is resilient against emerging SARS-CoV-2 variants. With immunopotentiation through repeat vaccinations becoming a pivotal strategy to accomplish herd immunity, understanding the variable longitudinal evolutions of the two building blocks of hybrid immunity is crucial.
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BackgroundMore people with a history of prior infection are receiving SARS-CoV-2 vaccines. Understanding the magnitude of protectivity granted by hybrid immunity, the combined response of infection- and vaccine-induced immunity, may impact vaccination strategies. MethodsA total of 36 synchronously infected ( prior infection) and, 33 SARS-CoV-2 naive ( naive) individuals participated. Participants provided sera six months after completing a round of BNT162b2 vaccination, to be processed for anti-spike antibody measurements and neutralization assays. The relationships between antibody titer, groups and age were explored. ResultsAnti-spike antibody titers at 6 months post-vaccination were significantly higher, reaching 13- to 17-fold, in the prior infection group. Linear regression models showed that the enhancement in antibody titer attributable to positive infection history increased from 8.9- to 9.4- fold at age 30 to 19- to 32-fold at age 60. Sera from the prior infection group showed higher neutralizing capacity against all six analyzed strains, including the Omicron variant. ConclusionsPrior COVID-19 led to establishing enhanced humoral immunity at 6 months after vaccination. Antibody fold-difference attributed to positive COVID-19 history increased with age, possibly because older individuals are prone to symptomatic infection accompanied by potentiated immune responses. Durable protection of hybrid immunity deserves reflection in vaccination campaigns.
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IntroductionThis study assessed the immunogenicity and safety of BNT162b2 mRNA vaccine in lung cancer patients receiving anticancer treatment using two immunoassays. Methods: We enrolled lung cancer patients receiving anticancer treatment and non-cancer patients with chronic diseases; all participants were fully vaccinated with the BNT162b2 vaccine. Blood samples were collected before the first and second vaccinations and 4 {+/-} 1 weeks after the second vaccination. Anti-acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein S1 subunit receptor-binding domain antibody titers were measured using the Architect SARS-CoV-2 IgG II Quant (Abbott Laboratory) and Elecsys Anti-SARS-CoV-2 S (Roche Diagnostics). ResultsFifty-five lung cancer patients and 38 non-cancer patients were included in the immunogenicity analysis. Lung cancer patients showed significant increase in the geometric mean antibody titer, which was significantly lower than that in the non-cancer patients after the first (30 vs. 121 AU/mL, p<0.001 on Architect; 4.0 vs 1.2 U/mL, p<0.001, on Elecsys) and second vaccinations (1632 vs. 3472 AU/mL, p=0.005, on Architect; 213 vs 573 A/mL, p=0.002, on Elecsys). The adjusted odds ratio (OR) for seroprotection was significantly lower in the lung cancer patients. Analysis of the anticancer treatment types showed that the adjusted OR for seroprotection was significantly lower in lung cancer patients receiving cytotoxic agents. Lung cancer patients showed no increase in the number of adverse reactions. ConclusionsBNT162b2 vaccination in lung cancer patients undergoing anticancer treatment significantly increased antibody titers and showed acceptable safety. However, the immunogenicity in these patients could be inadequate compared with that in non-cancer patients.
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BackgroundIn vitro drug-screening studies have indicated that camostat mesilate (FOY-305) may prevent SARS-CoV-2 infection into human airway epithelial cells. This study was conducted to investigate whether camostat mesilate is an effective treatment for SARS-CoV-2 infection (COVID-19). MethodsThis was a phase 3, multicentre, double-blind, randomised, parallel-group, placebo-controlled study. Patients were enrolled if they were admitted to a hospital within 5 days of onset of COVID-19 symptoms or within 5 days of a positive test for asymptomatic patients. Severe cases (e.g., those requiring oxygenation/ventilation) were excluded. Patients were administered camostat mesilate (600 mg qid; four to eight times higher than the clinical doses in Japan) or placebo for up to 14 days. The primary efficacy endpoint was the time to the first two consecutive negative tests for SARS-CoV-2. FindingsOne-hundred and fifty-five patients were randomised to receive camostat mesilate (n=78) or placebo (n=77). The median time to the first test was 11 days in both groups, and conversion to negative status was observed in 60{middle dot}8% and 63{middle dot}5% of patients in the camostat mesilate and placebo groups, respectively. The primary (Bayesian) and secondary (frequentist) analyses found no significant differences in the primary endpoint between the two groups. No additional safety concerns beyond those already known for camostat mesilate were identified. InterpretationCamostat mesilate is no more effective, based on upper airway viral clearance, than placebo for treating patients with mild to moderate SARS-CoV-2 infection with or without symptoms. FundingOno Pharmaceutical Co., Ltd. RESEARCH IN CONTEXT PANELO_ST_ABSEvidence before this studyC_ST_ABSSARS-CoV-2 infection (COVID-19), as a significant global health threat, is characterised by broad symptoms and varying disease severity. At the time of planning this study, there were no specific treatments for COVID-19 beyond the use of antiviral drugs, steroids and, in severe cases, ventilation with oxygen. Pre-clinical screening studies revealed the spike (S) protein of SARS-CoV-2 bind to angiotensin converting enzyme II (ACE2) on the host cell membrane. The S protein is then cleaved by a type II transmembrane serine protease (TMPRSS2) as an essential enzyme for the viral entry into host cells. In vitro drug-screening studies have shown that drugs that block binding of the S protein to ACE2 can prevent viral entry into a cell line derived from human airway epithelium. The studies identified 4-(4-guanidinobenzoyloxy)phenylacetic acid, the active metabolite of a serine protease inhibitor (camostat mesilate, FOY-305), as a candidate inhibitor of SARS-CoV-2 entry into humans. A retrospective study of critically ill COVID-19 patients with organ failure revealed a decline in disease activity within 8 days of admission among patients treated with camostat mesilate. In consideration of the preclinical and early clinical evidence, it was hypothesised that camostat mesilate is an effective treatment for patients with COVID-19. Therefore, we planned and executed a phase 3, randomised, double-blind, placebo-controlled study to investigate the efficacy and safety of camostat mesilate for the treatment of patients with mild to moderate COVID-19 infection with or without symptoms. The primary endpoint was the time to the first two consecutive negative tests for SARS-CoV-2. No controlled clinical studies of camostat mesilate had been conducted at the time of planning this study. Added value of this studyThe results of this randomised controlled trial revealed that camostat mesilate, administered at a dose of 600 mg qid for up to 14 days, was no more effective than placebo, based on upper airway viral clearance in patients with mild to moderate SARS-CoV-2 infection with or without symptoms. Furthermore, there were no differences between the study groups in terms of other efficacy endpoints. This study used a dose that was four to eight times higher than the clinical doses of camostat mesilate used in Japan for the acute symptoms of chronic pancreatitis and postoperative reflux oesophagitis. The study identified no additional safety concerns beyond those already known for camostat mesilate. Implications of all available evidenceAfter starting this study, another randomised, placebo-controlled study reported the efficacy and safety of camostat mesilate for the treatment of patients with COVID-19, albeit at a lower dose of 200 mg three times daily. That study also found no difference between camostat mesilate and placebo for the primary endpoint (the time to discharge or a clinical improvement in clinical severity of at least two points on a seven-point ordinal scale). Along with this evidence, our study did not support the use of camostat mesilate as a treatment option for COVID-19. However, since the administration of camostat mesilate was started after the onset of symptoms and presumably the peak viral load, we cannot exclude the possibility that camostat mesilate may be effective if administration is started earlier in the course of infection, or perhaps as prophylactic use in close contacts.
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BackgroundThe impact of novel coronavirus disease 2019 (COVID-19) on healthcare workers (HCWs) has been under-evaluated in Central America. We performed a seroepidemiological survey at a tertiary healthcare facility in El Salvador, where a large number of confirmed and far more suspected cases of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infected HCWs had been documented during the first wave of the pandemic. MethodsDuring January-February 2021, a total 973 HCWs were tested for SARS-CoV-2 antibodies. Participants completed a questionnaire asking of their demographic data. Occupational risk was assessed by statistically comparing the seropositivity rates among different occupational categories. ResultsOverall seroprevalence in HCWs reached 52.6% (512 of 973). Of the seropositive individuals, 61.7% (316 of 512) had experienced a documented COVID-19 diagnosis, while the remaining 38.3% (196 of 512) were unrecognized seroconversions. Differences in seropositivity rates existed between occupational categories; nurses demonstrated the highest at 63.8% (222 of 348, risk ratio 1.44, p < 0.0001), followed by auxiliary HCWs assigned to patient-related work (55.9%, 52 of 93), and medical doctors (46.7%, 50 of 107). Several non-patient-related professions showed above-average seroprevalence, suggesting substantial SARS-CoV-2 contacts outside the workplace: 60.0% (6 of 10) and 68.0% (17 of 25) for nutritionists and pharmacists, respectively. ConclusionsSARS-CoV-2 seroprevalence exceeded 50% among HCWs in El Salvador, with disparity among occupational categories with different workplace exposure risks. Importance of not only nosocomial infection prevention but also screening for transmissions having occurred outside the workplace were highlighted to efficiently control nosocomial spreads during a pandemic wave. Key pointsHealthcare workers in El Salvador were tested for SARS-CoV-2 antibodies. Seroprevalence reached 52.6%, with disparity among occupation; nurses ranked highest at 63.8% seropositivity. Alongside nosocomial transmissions, high seroprevalence associated with non-patient-related work suggested substantial SARS-CoV-2 contacts outside the workplace.
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BackgroundThe symptoms of severe COVID-19 are complex and wide-ranging even in intensive care unit (ICU) patients, who may successfully discontinue respiratory support in a short period or conversely require prolonged respiratory support. Damage in the lungs of COVID-19 patients is characterized pathologically as diffuse alveolar damage, the degree of which correlates with the severity of the disease. We hypothesized that the ventilatory ratio (VR), a surrogate parameter for the dead space fraction, might stratify the severity of COVID-19 and predict the successful discontinuation of respiratory support. MethodsForty COVID-19 patients in our ICU were enrolled in this study. Respiratory variables were collected from 2 hours (day 0) after the initiation of respiratory support. We monitored the longitudinal values of VR and other respiratory parameters for 28 days. Patients successfully discontinued from respiratory support by day 28 of ICU stay were defined as the successfully discontinued group, while those who died or failed to discontinue were defined as the failed to discontinue group. VR and other respiratory parameters were compared between these groups. ResultsExcept for advanced age, prolonged ventilation period, and higher mortality in the failed to discontinue group, there were no significant differences between the groups in terms of any other background or respiratory parameter at 2 hours (day 0) after initiation of respiratory support. Longitudinal VR monitoring revealed significantly higher VR values in the failed to discontinue group than the successfully discontinued group on day 4 of respiratory support. Upon predicting the failure to discontinue respiratory support, the area under the receiver operating characteristic curve of VR values on day 4 of respiratory support was 0.748. A threshold of 1.56 achieved the highest predictive performance with a sensitivity of 0.667 and a specificity of 0.762. This threshold enabled the prediction of the successfully discontinued outcome at 0.810 of the negative predictive value. ConclusionsElevated VR values on day 4 of respiratory support were predictive of successful discontinuation of respiratory support in patients with severe COVID-19. Longitudinal VR values after initiation of respiratory support can be used as a practical index to stratify severe COVID-19.
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We describe the results of testing healthcare workers from a tertiary care hospital in Japan, which had experienced a COVID-19 outbreak during the first peak of the pandemic, for SARS-CoV-2 specific antibody seroconversion. Using two chemiluminescent immunoassays and a confirmatory surrogate virus neutralization test, serological testing unveiled that a surprising 42.2% (27/64) of overlooked COVID-19 diagnoses had occurred when case detection had relied solely on SARS-CoV-2 nucleic acid amplification testing. This undetected portion of the COVID-19 iceberg beneath the surface may potentially have led to silent transmissions and triggered the spread. A questionnaire-based risk assessment was further indicative of exposures to specific aerosol-generating procedures, i.e. non-invasive ventilation, having had conveyed the highest transmission risks and served as the origin of outbreak. Our observations are supportive of a multi-tiered testing approach, including the use of serological diagnostics, in order to accomplish exhaustive case detection along the whole COVID-19 spectrum.
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The prompt rollout of the coronavirus disease (COVID-19) messenger RNA (mRNA) vaccine is facilitating population immunity, which shall become more dominant than natural infection-induced immunity. At the beginning of the vaccine era, understanding the epitope profiles of vaccine-elicited antibodies will be the first step in assessing functionality of vaccine-induced immunity. In this study, the high-resolution linear epitope profiles of Pfizer-BioNTech COVID-19 mRNA vaccine recipients and COVID-19 patients were delineated by using microarrays mapped with overlapping peptides of the receptor binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. The vaccine-induced antibodies targeting RBD had broader distribution across the RBD than that induced by the natural infection. Thus, relatively lower neutralizability was observed when a half-maximal neutralization titer measured in vitro by live virus neutralization assays was normalized to a total anti-RBD IgG titer. However, mutation panel assays targeting the SARS-CoV-2 variants of concern have shown that the vaccine-induced epitope variety, rich in breadth, may grant resistance against future viral evolutionary escapes, serving as an advantage of vaccine-induced immunity. ImportanceEstablishing vaccine-based population immunity has been the key factor in attaining herd protection. Thanks to expedited worldwide research efforts, the potency of messenger RNA vaccines against the coronavirus disease 2019 (COVID-19) is now incontestable. The next debate is regarding the coverage of SARS-CoV-2 variants. At the beginning of this vaccine era, it is of importance to describe the similarities and differences between the immune responses of COVID-19 vaccine recipients and naturally infected individuals. In this study, we demonstrated that the antibody profiles of vaccine recipients are richer in variety, targeting a key protein of the invading virus, than those of naturally infected individuals. Yet vaccine-elicited antibodies included more non-neutralizing antibodies than infection-elicited, their breadth in antibody variations suggested possible resilience against future SARS-CoV-2 variants. The antibody profile achieved by vaccinations in naive individuals pose important insight into the first step towards vaccine-based population immunity.
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BackgroundHealthcare workers (HCWs) who care for patients with the novel coronavirus infectious disease (COVID-19) are at an increased risk and fear contracting the infection themselves. HCWs are chronically exposed to very intense stress, both and physically and mentally. Hospitals must reduce both the physical and mental burden of HCWs on the front lines and ensure their safety. No prospective study has focused on the physical health complaints among HCWs engaged in the care of critically ill COVID-19 patients. This study aimed to investigate the occupational risk among HCWs of experiencing physical symptoms during the current COVID-19 pandemic. MethodsA twice-weekly questionnaire targeting HCWs who care for COVID-19 patients was performed at Osaka City University Hospital from April 30 to May 31, 2020 using a shareable Research Electronic Data Capture tool. The demographic characteristics of the participants, frequency of exposure to at-risk care, and physical complaints were evaluated. ResultsA total of 35 doctors, 88 nurses, and 35 technicians were engaged in the care of these critically ill COVID-19 patients. 76 HCWs participated in this study, of whom 24 (31.6%) were doctors, 43 (56.6%) were nurses, and 9 (11.8%) were technicians. The frequency of experiencing any physical symptom was 25.0% among HCWs. Exposure to at-risk care was significantly higher among nurses than among doctors (p < 0.001); likewise, the frequency of experiencing physical symptoms was higher among nurses than among doctors (p < 0.01). The multivariate analysis revealed that nurses (odds ratio 8.29; p = 0.01) might be independently at risk of experiencing physical symptoms. ConclusionsOur results indicate that occupational health care at hospitals must be allocated to HCWs who are highly exposed to at-risk care, particularly nurses engaged in the care of COVID-19 patients.
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Wild isolates of malaria parasites were preserved in wet ice for 2–12 days and cultivated by a candle jar method. In four isolates of <i>Plasmodium falciparum</i> collected from Myanmar and preserved for 12 days, all failed to grow. In 31 isolates preserved for 5–10 days, nine were transformed to young gametocytes, but 22 isolates grew well. From Ranong, Thailand, nine isolates preserved for 7 days were examined, and six grew well. On the other hand, all of the 59 isolates collected from eastern Indonesian islands failed to establish as culture-adapted isolates, even most of them were preserved only for 2–3 days: 10 isolates stopped to grow, and 49 isolates were transformed to sexual stages by Day 10. These results indicated that a great difference in adaptation to in vitro culture may exist between wild isolates distributed in continental Southeast Asia and in eastern Indonesia and that gametocytogenesis might be easily switched on in Indonesian isolates. In wild isolates of <i>P. vivax</i>, <i>P. malariae</i> and <i>P. ovale</i> preserved for 2–9 days, ring forms or young trophozoites survived, but adaptation to in vitro culture failed. These results indicate that wild isolates can be preserved in wet ice for 9–10 days.
