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1.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-334715

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant quickly rose to dominance in mid-2021, displacing other variants, including Alpha. Studies using data from the United Kingdom and India estimated that Delta was 40-80% more transmissible than Alpha, allowing Delta to become the globally dominant variant. However, it was unclear if the ostensible difference in relative transmissibility was due mostly to innate properties of Delta's infectiousness or differences in the study populations. To investigate, we formed a partnership with SARS-CoV-2 genomic surveillance programs from all six New England US states. By comparing logistic growth rates, we found that Delta emerged 37-163% faster than Alpha in early 2021 (37% Massachusetts, 75% New Hampshire, 95% Maine, 98% Rhode Island, 151% Connecticut, and 163% Vermont). We next computed variant-specific effective reproductive numbers and estimated that Delta was 58-120% more transmissible than Alpha across New England (58% New Hampshire, 68% Massachusetts, 76% Connecticut, 85% Rhode Island, 98% Maine, and 120% Vermont). Finally, using RT-PCR data, we estimated that Delta infections generate on average ~6 times more viral RNA copies per mL than Alpha infections. Overall, our evidence indicates that Delta's enhanced transmissibility could be attributed to its innate ability to increase infectiousness, but its epidemiological dynamics may vary depending on the underlying immunity and behavior of distinct populations.

2.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816919

ABSTRACT

Cancer patients display immunomodulation related to malignancy and anti-cancer therapies, but how these factors impact COVID-19 remains unknown. To investigate immune responses in cancer patients with COVID-19, we undertook a prospective case-control study, enrolling hospitalized solid tumor patients with acute COVID-19, as well as age-, gender-, and comorbidity-matched COVID-19 patients without cancer as controls. Using biospecimens collected during hospitalization, we performed virologic measurements as well as in-depth immunophenotyping of cellular, antibody and cytokine responses. We enrolled 17 cancer patients (cases) admitted to Yale-New Haven Hospital between March 15 and June 30, 2020 with COVID-19, as well as 17 matched non-cancer patients (controls) admitted with COVID-19. No significant differences were observed between cases and controls based on patient characteristics (age, gender, race, co-morbidities, smoking history, days from symptom onset to COVID-19 diagnosis) or outcomes (COVID-19 severity, length of hospital stay, rate of intubation or mortality). The most common primary tumor sites were lung (4/17) and gastrointestinal (4/17);all cases had received cancer-directed therapy within 6 months of COVID-19 diagnosis, with 13/17 receiving treatment less than 1 month prior to hospitalization. Three of 17 cases had received immune checkpoint inhibitor therapies. Despite having similar SARS-CoV-2 viral RNA loads at the time of COVID-19 diagnosis when compared with controls, cancer cases had increased viral RNA abundance during hospitalization, suggesting slower clearance. Antibody responses against SARS-CoV-2 were preserved in cancer cases, with cases displaying similar levels of IgM and IgG antibodies directed against SARS-CoV-2 epitopes compared to controls. Cytokine profiling revealed higher plasma levels of CCL3, IL1A and CXCL12 in cancer cases compared to controls. Using flow cytometric immunophenotyping, we found that innate immune and non-T cell adaptive immune parameters were similar between cases and controls hospitalized with COVID-19. However, among cancer cases on conventional therapies, T cell lymphopenia was more profound, and these cases demonstrated higher levels of CD8+ exhausted (CD8+CD45RA-PD1+TIM3+ ), CD8+GranzymeB+ and CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ activated T cells when compared with controls;interestingly, these differences were not observed in patients who had received immune checkpoint inhibition. Thus, we found reduced viral RNA clearance and specific alterations in T cell and cytokine responses in cancer patients hospitalized with COVID-19 compared with matched controls with COVID-19. This dysregulated T cell response in cancer patients, which may reflect immune modulation due to chronic antigen stimulation as well as cancer therapies, may lead to altered virologic and clinical outcomes in this population.

3.
PubMed; 2020.
Preprint in English | PubMed | ID: ppcovidwho-334270

ABSTRACT

BACKGROUND: COVID-19 is caused by the severe acute respiratory syndrome virus SARS-CoV-2. It is widely recognized as a respiratory pathogen, but neurologic complications can be the presenting manifestation in a subset of infected patients. CASE PRESENTATION: We describe a 78-year old immunocompromised woman who presented with altered mental status after witnessed seizure-like activity at home. She was found to have SARS-CoV-2 infection and associated neuroinflammation. In this case, we undertake the first detailed analysis of cerebrospinal fluid (CSF) cytokines during COVID-19 infection and find a unique pattern of inflammation in CSF, but no evidence of viral neuroinvasion. CONCLUSION: Our findings suggest that neurologic symptoms such as encephalopathy and seizures may be the initial presentation of COVID-19. Central nervous system inflammation may associate with neurologic manifestations of disease.

4.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-333683

ABSTRACT

Pregnant women appear to be at increased risk for severe outcomes associated with COVID-19, but the pathophysiology underlying this increased morbidity and its potential impact on the developing fetus is not well understood. In this study of pregnant women with and without COVID-19, we assessed viral and immune dynamics at the placenta during maternal SARS-CoV-2 infection. Amongst uninfected women, ACE2 was detected by immunohistochemistry in syncytiotrophoblast cells of the normal placenta during early pregnancy but was rarely seen in healthy placentas at full term. Term placentas from women infected with SARS-CoV-2, however, displayed a significant increase in ACE2 levels. Using immortalized cell lines and primary isolated placental cells, we determined the vulnerability of various placental cell types to direct infection by SARS-CoV-2 in vitro . Yet, despite the susceptibility of placental cells to SARS-CoV-2 infection, viral RNA was detected in the placentas of only a subset (~13%) of women in this cohort. Through single cell transcriptomic analyses, we found that the maternal-fetal interface of SARS-CoV-2-infected women exhibited markers associated with pregnancy complications, such as preeclampsia, and robust immune responses, including increased activation of placental NK and T cells and increased expression of interferon-related genes. Overall, this study suggests that SARS-CoV-2 is associated with immune activation at the maternal-fetal interface even in the absence of detectable local viral invasion. While this likely represents a protective mechanism shielding the placenta from infection, inflammatory changes in the placenta may also contribute to poor pregnancy outcomes and thus warrant further investigation.

5.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-330706

ABSTRACT

With the emergence of SARS-CoV-2 variants that may increase transmissibility and/or cause escape from immune responses 1-3 , there is an urgent need for the targeted surveillance of circulating lineages. It was found that the B.1.1.7 (also 501Y.V1) variant first detected in the UK 4,5 could be serendipitously detected by the ThermoFisher TaqPath COVID-19 PCR assay because a key deletion in these viruses, spike DELTA69-70, would cause a "spike gene target failure" (SGTF) result. However, a SGTF result is not definitive for B.1.1.7, and this assay cannot detect other variants of concern that lack spike DELTA69-70, such as B.1.351 (also 501Y.V2) detected in South Africa 6 and P.1 (also 501Y.V3) recently detected in Brazil 7 . We identified a deletion in the ORF1a gene (ORF1a DELTA3675-3677) in all three variants, which has not yet been widely detected in other SARS-CoV-2 lineages. Using ORF1a DELTA3675-3677 as the primary target and spike DELTA69-70 to differentiate, we designed and validated an open source PCR assay to detect SARS-CoV-2 variants of concern 8 . Our assay can be rapidly deployed in laboratories around the world to enhance surveillance for the local emergence spread of B.1.1.7, B.1.351, and P.1.

6.
Open Forum Infectious Diseases ; 8(SUPPL 1):S257, 2021.
Article in English | EMBASE | ID: covidwho-1746692

ABSTRACT

Background. Streptococcus pneumoniae (pneumococcus) is a common colonizer of the upper respiratory tract and can progress to cause invasive and mucosal disease. Additionally, infection with pneumococcus can complicate respiratory viral infections (influenza, respiratory syncytial virus, etc.) by exacerbating the initial disease. Limited data exist describing the potential relationship of SARS-CoV-2 infection with pneumococcus and the role of co-infection in influencing COVID-19 severity. Methods. Inpatients and healthcare workers testing positive for SARS-CoV-2 during March-August 2020 were tested for pneumococcus through culture-enrichment of saliva followed by RT-qPCR (to identify carriage) and for inpatients only, serotype-specific urine antigen detection (UAD) assays (to identify pneumococcal pneumonia). A multinomial multivariate regression model was used to examine the relationship between pneumococcal detection and COVID-19 severity. Results. Among the 126 subjects who tested positive for SARS-CoV-2, the median age was 62 years;54.9% of subjects were male;88.89% were inpatients;23.5% had an ICU stay;and 13.5% died. Pneumococcus was detected in 17 subjects (13.5%) by any method, including 5 subjects (4.0%) by RT-qPCR and 12 subjects (13.6%) by UAD. Little to no bacterial growth was observed on 21/235 culture plates. Detection by UAD was associated with both moderate and severe COVID-19 disease while RT-qPCR detection in saliva was not associated with severity. None of the 12 individuals who were UAD-positive died. Conclusion. Pneumococcal pneumonia (as determined by UAD) continues to occur during the ongoing pandemic and may be associated with more serious COVID-19 outcomes. Detection of pneumococcal carriage may be masked by high levels of antibiotic use. Future studies should better characterize the relationship between pneumococcus and SARS-CoV-2 across all disease severity levels.

7.
Open Forum Infectious Diseases ; 8(SUPPL 1):S284, 2021.
Article in English | EMBASE | ID: covidwho-1746632

ABSTRACT

Background. Quickly detecting and isolating individuals positive for SARSCoV-2 is essential for limiting virus spread. Policy makers rely on the number of active cases to make decisions, and individuals use this information to evaluate risk should they return to public spaces. Robust testing strategies have been plagued with limited authorized diagnostic assays and high test prices, with large-scale implementation hampered by worldwide supply chain issues. Methods. Having identified its potential early in the pandemic, we simplified saliva-based COVID-19 diagnostic testing by (1) not requiring collection tubes with preservatives, (2) replacing nucleic acid extraction with a simple enzymatic and heating step, and (3) testing specimens for SARS-CoV-2 in dualplex RT-qPCR. Moreover, we validated this approach ("SalivaDirect") with reagents and instruments from multiple vendors to circumvent supply chain disruptions. Results. SalivaDirect's simplified protocol does not compromise on sensitivity. In our hospital cohort, we found a high positive agreement (94%) between saliva tested with SalivaDirect and nasopharyngeal swabs tested with a commercial RT-qPCR kit. With the National Basketball Association we tested 3,779 saliva specimens from healthy individuals and detected low rates of invalid (0.3%) and false-positive (< 0.05%) results. Using comparative assays and sample types, we also demonstrated SalivaDirect to efficiently detect SARS-CoV-2 in asymptomatic individuals. SalivaDirect is a simplified method for SARS-CoV-2 detection (A) Schematic overview of SalivaDirect workflow depicting the main steps of mixing saliva with proteinase K, heat inactivation, and dualplex qRT-PCR testing. Figure created with Biorender.com. (B) SARS-CoV-2 is stable in saliva for at least 7 days at 4C, room temperature (RT;19C), and 30C without addition of stabilizing buffers. Spiked-in saliva samples of low virus concentrations (12, 25, and 50 SARSCoV-2 copies/mL) were kept at the indicated temperature for 7 days and then tested with SalivaDirect. N1 cycle threshold (Ct) values were lower when kept for 7 days at 30C as compared to fresh specimens (Kruskal-Wallis;p = 0.03). Horizontal bars indicate the median. (C) Comparing Ct values for saliva treated with proteinase K and heat as compared to nucleic extraction yields higher N1 Ct values without extraction (Wilcoxon;p < 0.01). (D) Testing extracted nucleic acid from saliva with the N1 primer-probe set (singleplex) as compared to a multiplex assay showed stronger N1 detection in multiplex (Wilcoxon;p < 0.01). The dotted line in (B)-(D) indicates the limit of detection. Conclusion. Saliva is a valid alternative to swabs for SARS-CoV-2 screening. Importantly, SalivaDirect enables labs to utilize existing infrastructure, improving test implementation time and requiring limited investment to scale-up to meet mass testing needs. With the safe and reliable self-collection of saliva, our vision is to help provide accessible and equitable testing solutions, especially in low-resource and remote settings.

8.
PubMed; 2022.
Preprint in English | PubMed | ID: ppcovidwho-329416

ABSTRACT

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has high transmissibility and recently swept the globe. Due to the extensive number of mutations, this variant has high level of immune evasion, which drastically reduced the efficacy of existing antibodies and vaccines. Thus, it is important to test an Omicron-specific vaccine, evaluate its immune response against Omicron and other variants, and compare its immunogenicity as boosters with existing vaccine designed against the reference wildtype virus (WT). Here, we generated an Omicron-specific lipid nanoparticle (LNP) mRNA vaccine candidate, and tested its activity in animals, both alone and as a heterologous booster to existing WT mRNA vaccine. Our Omicron-specific LNP-mRNA vaccine elicited strong and specific antibody response in vaccination-naive mice. Mice that received two-dose WT LNP-mRNA, the one mimicking the commonly used Pfizer/Moderna mRNA vaccine, showed a >40-fold reduction in neutralization potency against Omicron variant than that against WT two weeks post second dose, which further reduced to background level >3 months post second dose. As a booster shot for two-dose WT mRNA vaccinated mice, a single dose of either a homologous booster with WT LNP-mRNA or a heterologous booster with Omicron LNP-mRNA restored the waning antibody response against Omicron, with over 40-fold increase at two weeks post injection as compared to right before booster. Interestingly, the heterologous Omicron LNP-mRNA booster elicited neutralizing titers 10-20 fold higher than the homologous WT booster against the Omicron variant, with comparable titers against the Delta variant. All three types of vaccination, including Omicron mRNA alone, WT mRNA homologous booster, and Omicron heterologous booster, elicited broad binding antibody responses against SARS-CoV-2 WA-1, Beta, and Delta variants, as well as other Betacoronavirus species such as SARS-CoV, but not Middle East respiratory syndrome coronavirus (MERS-CoV). These data provided direct proof-of-concept assessments of an Omicron-specific mRNA vaccination in vivo, both alone and as a heterologous booster to the existing widely-used WT mRNA vaccine form.

9.
Embase;
Preprint in English | EMBASE | ID: ppcovidwho-327021

ABSTRACT

The recent emergence of the SARS-CoV-2 Omicron variant is raising concerns because of its increased transmissibility and by its numerous spike mutations with potential to evade neutralizing antibodies elicited by COVID-19 vaccines. The Dominican Republic was among the first countries in recommending the administration of a third dose COVID-19 vaccine to address potential waning immunity and reduced effectiveness against variants. Here, we evaluated the effects of a heterologous BNT162b2 mRNA vaccine booster on the humoral immunity of participants that had received a two-dose regimen of CoronaVac, an inactivated vaccine used globally. We found that heterologous CoronaVac prime followed by BNT162b2 booster regimen induces elevated virus-specific antibody levels and potent neutralization activity against the ancestral virus and Delta variant, resembling the titers obtained after two doses of mRNA vaccines. While neutralization of Omicron was undetectable in participants that had received a two-dose regimen of CoronaVac vaccine, BNT162b2 booster resulted in a 1.4-fold increase in neutralization activity against Omicron, compared to two-dose mRNA vaccine. Despite this increase, neutralizing antibody titers were reduced by 6.3-fold and 2.7-fold for Omicron compared to ancestral and Delta variant, respectively. Surprisingly, previous SARS-CoV-2 infection did not affect the neutralizing titers for Omicron in participants that received the heterologous regimen. Our findings have immediate implications for multiples countries that previously used a two-dose regimen of CoronaVac and reinforce the notion that the Omicron variant is associated with immune escape from vaccines or infection-induced immunity, highlighting the global need for vaccine boosters to combat the impact of emerging variants.

10.
MEDLINE;
Preprint in English | MEDLINE | ID: ppcovidwho-326635

ABSTRACT

Prior to the emergence of antigenically distinct SARS-CoV-2 variants, reinfections were reported infrequently - presumably due to the generation of durable and protective immune responses. However, case reports also suggested that rare, repeated infections may occur as soon as 48 days following initial disease onset. The underlying immunologic deficiencies enabling SARS-CoV-2 reinfections are currently unknown. Here we describe a renal transplant recipient who developed recurrent, symptomatic SARS-CoV-2 infection - confirmed by whole virus genome sequencing - 7 months after primary infection. To elucidate the immunological mechanisms responsible for SARS-CoV-2 reinfection, we performed longitudinal profiling of cellular and humoral responses during both primary and recurrent SARS-CoV-2 infection. We found that the patient responded to the primary infection with transient, poor-quality adaptive immune responses. The patient's immune system was further compromised by intervening treatment for acute rejection of the renal allograft prior to reinfection. Importantly, we also identified the development of neutralizing antibodies and the formation of humoral memory responses prior to SARS-CoV-2 reinfection. However, these neutralizing antibodies failed to confer protection against reinfection, suggesting that additional factors are required for efficient prevention of SARS-CoV-2 reinfection. Further, we found no evidence supporting viral evasion of primary adaptive immune responses, suggesting that susceptibility to reinfection may be determined by host factors rather than pathogen adaptation in this patient. In summary, our study suggests that a low neutralizing antibody presence alone is not sufficient to confer resistance against reinfection. Thus, patients with solid organ transplantation, or patients who are otherwise immunosuppressed, who recover from infection with SARS-CoV-2 may not develop sufficient protective immunity and are at risk of reinfection.

11.
MEDLINE;
Preprint in English | MEDLINE | ID: ppcovidwho-326567

ABSTRACT

Since its emergence and detection in Wuhan, China in late 2019, the novel coronavirus SARS-CoV-2 has spread to nearly every country around the world, resulting in hundreds of thousands of infections to date. The virus was first detected in the Pacific Northwest region of the United States in January, 2020, with subsequent COVID-19 outbreaks detected in all 50 states by early March. To uncover the sources of SARS-CoV-2 introductions and patterns of spread within the U.S., we sequenced nine viral genomes from early reported COVID-19 patients in Connecticut. Our phylogenetic analysis places the majority of these genomes with viruses sequenced from Washington state. By coupling our genomic data with domestic and international travel patterns, we show that early SARS-CoV-2 transmission in Connecticut was likely driven by domestic introductions. Moreover, the risk of domestic importation to Connecticut exceeded that of international importation by mid-March regardless of our estimated impacts of federal travel restrictions. This study provides evidence for widespread, sustained transmission of SARS-CoV-2 within the U.S. and highlights the critical need for local surveillance.

12.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-296567

ABSTRACT

The COVID-19 pandemic has revealed the importance of virus genome sequencing to guide public health interventions to control virus transmission and understand SARS-CoV-2 evolution. As of July 20th, 2021, >2 million SARS-CoV-2 genomes have been submitted to GISAID, 94% from high income and 6% from low and middle income countries. Here, we analyse the spatial and temporal heterogeneity in SARS-CoV-2 global genomic surveillance efforts. We report a comprehensive analysis of virus lineage diversity and genomic surveillance strategies adopted globally, and investigate their impact on the detection of known SARS-CoV-2 virus lineages and variants of concern. Our study provides a perspective on the global disparities surrounding SARS-CoV-2 genomic surveillance, their causes and consequences, and possible solutions to maximize the impact of pathogen genome sequencing for efforts on public health.

14.
PUBMED; 2021.
Preprint in English | PUBMED | ID: ppcovidwho-293027

ABSTRACT

As SARS-CoV-2 continues to cause morbidity and mortality around the world, there is an urgent need for the development of effective medical countermeasures. Here, we assessed the antiviral capacity of a minimal RIG-I agonist, stem-loop RNA 14 (SLR14), in viral control, disease prevention, post-infection therapy, and cross-variant protection in mouse models of SARS-CoV-2 infection. A single dose of SLR14 prevented viral replication in the lower respiratory tract and development of severe disease in a type I interferon (IFN-I) dependent manner. SLR14 demonstrated remarkable protective capacity against lethal SARS-CoV-2 infection when used prophylactically and retained considerable efficacy as a therapeutic agent. In immunodeficient mice carrying chronic SARS-CoV-2 infection, SLR14 elicited near-sterilizing innate immunity by inducing IFN-I responses in the absence of the adaptive immune system. In the context of infection with variants of concern (VOC), SLR14 conferred broad protection and uncovered an IFN-I resistance gradient across emerging VOC. These findings demonstrate the therapeutic potential of SLR14 as a host-directed, broad-spectrum antiviral for early post-exposure treatment and for treatment of chronically infected immunosuppressed patients.

15.
MEDLINE; 2020.
Preprint in English | MEDLINE | ID: ppcovidwho-290693

ABSTRACT

Background: COVID-19 is caused by the severe acute respiratory syndrome virus SARS-CoV-2. It is widely recognized as a respiratory pathogen, but neurologic complications can be the presenting manifestation in a subset of infected patients. Case presentation: We describe a 78-year old immunocompromised woman who presented with altered mental status after witnessed seizure-like activity at home. She was found to have SARS-CoV-2 infection and associated neuroinflammation. In this case, we undertake the first detailed analysis of cerebrospinal fluid (CSF) cytokines during COVID-19 infection and find a unique pattern of inflammation in CSF, but no evidence of viral neuroinvasion. Conclusion: Our findings suggest that neurologic symptoms such as encephalopathy and seizures may be the initial presentation of COVID-19. Central nervous system inflammation may associate with neurologic manifestations of disease.

16.
Open Forum Infectious Diseases ; 7(SUPPL 1):S295-S296, 2020.
Article in English | EMBASE | ID: covidwho-1185818

ABSTRACT

Background: Smell loss has been recognized as an important, and potentially early, sign of COVID-19. However, to date smell loss has only been assessed in retrospective, COVID+ cohorts, and largely through self-report. The objective of this study was to implement a daily standardized behavioral test of smell sensitivity in healthcare workers (HCW) to capture changes in smell sensitivity over time and to assess whether these changes occur prior to positive COVID test. Methods: The study enrolled 500 high-risk COVID-negative HCW during the COVID-19 epidemic in Connecticut, beginning March 28, 2020 (80% F, mean age 38, 58% nurses). Initially, HCW received a daily symptom questionnaire with parosmia screening questions. On April 23 we introduced the “Jiffy”, a daily at-home psychophysical test of smell sensitivity, where olfactory stimuli are sampled and rated for perceived intensity. SARS-CoV-2 infection was tested every three days by PCR of nasopharyngeal swabs or saliva Results: Of the first 500 enrolled HCW, 376 HCW (75%) completed the Jiffy 4528 times (mean 12 times/HCW). 17/500 HCW (3.4%) had a COVID+ test, of which 9/17 (53%) reported smell loss through the Jiffy or the daily symptom survey. 6/9 (67%) reported smell loss that preceded or was concurrent with a COVID+ test. 8/17 COVID+ HCW completed the Jiffy, with 5/8 (63%) reporting reductions in smell versus 42/368 (11%) COVID- HCW (OR=13, 95% CI: 2.4-85, p=.001). COVID+ HCW rated their greatest reduction in smell sensitivity as slight (40%) and severe (60%), versus slight (88%) and moderate (12%) in COVID- HCW. 16/17 COVID+ HCW completed a daily symptom survey (mean 14 times/HCW), with 8/16 (50%) ever reporting parosmia versus 90/466 (19%) of COVID- HCW (OR=4.2, 95% CI: 1.3-13, p=.007). Overall, parosmia was the first reported symptom in 3/13 (23%) COVID+ HCW who reported symptoms. Conclusion: We conducted a prospective study of smell testing in a population at high risk for COVID-19 using two parallel approaches. Our results demonstrate the feasibility of at-home smell testing for assessing parosmia during COVID-19, in some cases even prior to a positive PCR result. Given the urgent need for widespread, lowcost, non-invasive testing for COVID-19, we are now developing an easy-to-use app to distribute this survey more widely to high-risk populations. (Table Presented).

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