Publications by authors named "Edward T Ryan"

258 Publications

Travel associated extensively drug resistant typhoid fever: a case series to inform management in non-endemic regions.

J Travel Med 2022 Jul 29. Epub 2022 Jul 29.

Division of Infectious Diseases, Hospital for Sick Children, Toronto, Ontario.

Background: Extensively drug resistant (XDR) typhoid fever is a threat to travelers to Pakistan. We describe a multicontinental case series of travel-acquired XDR typhoid fever to demonstrate the global spread of the problem, and encourage preventive interventions as well as appropriate empiric antimicrobial use.

Methods: Cases were extracted from the GeoSentinel database, microbiologic laboratory records of 2 large hospitals in Toronto, Canada, and by invitation to TropNet sites. All isolates were confirmed XDR Salmonella enterica serovar Typhi (Salmonella Typhi), with resistance to ampicillin, ceftriaxone, ciprofloxacin, and trimethoprim-sulfamethoxazole.

Results: Seventeen cases were identified in Canada (10), USA (2), Spain (2), Italy (1), Australia (1), and Norway (1). Patients under 18 years represented 71% (12/17) of cases, and all patients travelled to Pakistan to visit friends or relatives. Only 1 patient is known to have been vaccinated. Predominant symptoms were fever, abdominal pain, vomiting and diarrhea. Antimicrobial therapy was started on day 1 of presentation in 75% (12/16) of patients, and transition to a carbapenem or azithromycin occurred a median of 2 days after blood culture was drawn. Antimicrobial susceptibilities were consistent with the XDR Salmonella Typhi phenotype, and whole genome sequencing on 3 isolates confirmed their belonging to the XDR variant of the H58 clade.

Conclusions: XDR typhoid fever is a particular risk for travelers to Pakistan, and empiric use of a carbapenem or azithromycin should be considered. Pre-travel typhoid vaccination and counseling are necessary and urgent interventions, especially for VFR travelers. Ongoing sentinel surveillance of XDR typhoid fever is needed to understand changing epidemiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jtm/taac086DOI Listing
July 2022

Proteomic analysis of cardiometabolic biomarkers and predictive modeling of severe outcomes in patients hospitalized with COVID-19.

Cardiovasc Diabetol 2022 Jul 21;21(1):136. Epub 2022 Jul 21.

Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Background: The high heterogeneity in the symptoms and severity of COVID-19 makes it challenging to identify high-risk patients early in the disease. Cardiometabolic comorbidities have shown strong associations with COVID-19 severity in epidemiologic studies. Cardiometabolic protein biomarkers, therefore, may provide predictive insight regarding which patients are most susceptible to severe illness from COVID-19.

Methods: In plasma samples collected from 343 patients hospitalized with COVID-19 during the first wave of the pandemic, we measured 92 circulating protein biomarkers previously implicated in cardiometabolic disease. We performed proteomic analysis and developed predictive models for severe outcomes. We then used these models to predict the outcomes of out-of-sample patients hospitalized with COVID-19 later in the surge (N = 194).

Results: We identified a set of seven protein biomarkers predictive of admission to the intensive care unit and/or death (ICU/death) within 28 days of presentation to care. Two of the biomarkers, ADAMTS13 and VEGFD, were associated with a lower risk of ICU/death. The remaining biomarkers, ACE2, IL-1RA, IL6, KIM1, and CTSL1, were associated with higher risk. When used to predict the outcomes of the future, out-of-sample patients, the predictive models built with these protein biomarkers outperformed all models built from standard clinical data, including known COVID-19 risk factors.

Conclusions: These findings suggest that proteomic profiling can inform the early clinical impression of a patient's likelihood of developing severe COVID-19 outcomes and, ultimately, accelerate the recognition and treatment of high-risk patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12933-022-01569-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9301894PMC
July 2022

Estimating typhoid incidence from community-based serosurveys: a multicohort study.

Lancet Microbe 2022 Aug 21;3(8):e578-e587. Epub 2022 Jun 21.

Center for Celiac Research and Treatment, MassGeneral Hospital for Children, Boston, MA, USA; Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Boston, MA, USA; Harvard Medical School, Harvard University, Boston, MA, USA.

Background: The incidence of enteric fever, an invasive bacterial infection caused by typhoidal Salmonellae (Salmonella enterica serovars Typhi and Paratyphi), is largely unknown in regions without blood culture surveillance. The aim of this study was to evaluate whether new diagnostic serological markers for typhoidal Salmonella can reliably estimate population-level incidence.

Methods: We collected longitudinal blood samples from patients with blood culture-confirmed enteric fever enrolled from surveillance studies in Bangladesh, Nepal, Pakistan, and Ghana between 2016 and 2021 and conducted cross-sectional serosurveys in the catchment areas of each surveillance site. We used ELISAs to measure quantitative IgA and IgG antibody responses to hemolysin E and S Typhi lipopolysaccharide. We used Bayesian hierarchical models to fit two-phase power-function decay models to the longitudinal antibody responses among enteric fever cases and used the joint distributions of the peak antibody titres and decay rate to estimate population-level incidence rates from cross-sectional serosurveys.

Findings: The longitudinal antibody kinetics for all antigen-isotypes were similar across countries and did not vary by clinical severity. The seroincidence of typhoidal Salmonella infection among children younger than 5 years ranged between 58·5 per 100 person-years (95% CI 42·1-81·4) in Dhaka, Bangladesh, to 6·6 per 100 person-years (4·3-9·9) in Kavrepalanchok, Nepal, and followed the same rank order as clinical incidence estimates.

Interpretation: The approach described here has the potential to expand the geographical scope of typhoidal Salmonella surveillance and generate incidence estimates that are comparable across geographical regions and time.

Funding: Bill & Melinda Gates Foundation.

Translations: For the Nepali, Bengali and Urdu translations of the abstract see Supplementary Materials section.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2666-5247(22)00114-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329131PMC
August 2022

Seroprevalence of SARS-CoV-2 antibodies in Bangladesh related to novel coronavirus infection.

IJID Reg 2022 Mar 2;2:198-203. Epub 2022 Feb 2.

International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh.

Design: A cross-sectional study was conducted amongst household members in 32 districts of Bangladesh to build knowledge about disease epidemiology and seroepidemiology of coronavirus disease 2019 (COVID-19).

Objective: Antibody responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were assessed in people between April and October 2020.

Results: The national seroprevalence rates of immunoglobulin G (IgG) and IgM were estimated to be 30.4% and 39.7%, respectively. In Dhaka, the seroprevalence of IgG was 35.4% in non-slum areas and 63.5% in slum areas. In areas outside of Dhaka, the seroprevalence of IgG was 37.5% in urban areas and 28.7% in rural areas. Between April and October 2020, the highest seroprevalence rate (57% for IgG and 64% for IgM) was observed in August. IgM antibody was more prevalent in younger participants, while older participants had more frequent IgG seropositivity. Follow-up specimens from patients with COVID-19 and their household members suggested that both IgG and IgM seropositivity increased significantly at day 14 and day 28 compared with day 1 after enrolment. : SARS-CoV-2 had spread extensively in Bangladesh by October 2020. This highlights the importance of monitoring seroprevalence data, particularly with the emergence of new SARS-CoV-2 variants over time.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijregi.2022.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8809641PMC
March 2022

Repertoires of SARS-CoV-2 epitopes targeted by antibodies vary according to severity of COVID-19.

Virulence 2022 12;13(1):890-902

Vaccine and Immunotherapy Center, Massachusetts General Hospital, Boston, MA, USA.

Antibodies to SARS-CoV-2 are central to recovery and immunity from COVID-19. However, the relationship between disease severity and the repertoire of antibodies against specific SARS-CoV-2 epitopes an individual develops following exposure remains incompletely understood. Here, we studied seroprevalence of antibodies to specific SARS-CoV-2 and other betacoronavirus antigens in a well-annotated, community sample of convalescent and never-infected individuals obtained in August 2020. One hundred and twenty-four participants were classified into five groups: previously exposed but without evidence of infection, having no known exposure or evidence of infection, seroconverted without symptoms, previously diagnosed with symptomatic COVID-19, and recovered after hospitalization with COVID-19. Prevalence of IgGs specific to the following antigens was compared between the five groups: recombinant SARS-CoV-2 and betacoronavirus spike and nucleocapsid protein domains, peptides from a tiled array of 22-mers corresponding to the entire spike and nucleocapsid proteins, and peptides corresponding to predicted immunogenic regions from other proteins of SARS-CoV-2. Antibody abundance generally correlated positively with severity of prior illness. A number of specific immunogenic peptides and some that may be associated with milder illness or protection from symptomatic infection were identified. No convincing association was observed between antibodies to Receptor Binding Domain(s) (RBDs) of less pathogenic betacoronaviruses HKU1 or OC43 and COVID-19 severity. However, apparent cross-reaction with SARS-CoV RBD was evident and some predominantly asymptomatic individuals had antibodies to both MERS-CoV and SARS-CoV RBDs. Findings from this pilot study may inform development of diagnostics, vaccines, and therapeutic antibodies, and provide insight into viral pathogenic mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21505594.2022.2073025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122311PMC
December 2022

Mucosal-Associated Invariant T (MAIT) cells are highly activated in duodenal tissue of humans with Vibrio cholerae O1 infection: A preliminary report.

PLoS Negl Trop Dis 2022 05 12;16(5):e0010411. Epub 2022 May 12.

Division of Infectious Diseases, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.

Mucosal-associated invariant T (MAIT) cells are unconventional T lymphocytes with a semi-conserved TCRα, activated by the presentation of vitamin B metabolites by the MHC-I related protein, MR1, and with diverse innate and adaptive effector functions. The role of MAIT cells in acute intestinal infections, especially at the mucosal level, is not well known. Here, we analyzed the presence and phenotype of MAIT cells in duodenal biopsies and paired peripheral blood samples, in patients during and after culture-confirmed Vibrio cholerae O1 infection. Immunohistochemical staining of duodenal biopsies from cholera patients (n = 5, median age 32 years, range 26-44, 1 female) identified MAIT cells in the lamina propria of the crypts, but not the villi. By flow cytometry (n = 10, median age 31 years, range 23-36, 1 female), we showed that duodenal MAIT cells are more activated than peripheral MAIT cells (p < 0.01 across time points), although there were no significant differences between duodenal MAIT cells at day 2 and day 30. We found fecal markers of intestinal permeability and inflammation to be correlated with the loss of duodenal (but not peripheral) MAIT cells, and single-cell sequencing revealed differing T cell receptor usage between the duodenal and peripheral blood MAIT cells. In this preliminary report limited by a small sample size, we show that MAIT cells are present in the lamina propria of the duodenum during V. cholerae infection, and more activated than those in the blood. Future work into the trafficking and tissue-resident function of MAIT cells is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pntd.0010411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9129025PMC
May 2022

The Clinical and Economic Impact of Measles-Mumps-Rubella Vaccinations to Prevent Measles Importations From US Pediatric Travelers Returning From Abroad.

J Pediatric Infect Dis Soc 2022 Jun;11(6):257-266

Medical Practice Evaluation Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

Background: Pediatric international travelers account for nearly half of measles importations in the United States. Over one third of pediatric international travelers depart the United States without the recommended measles-mumps-rubella (MMR) vaccinations: 2 doses for travelers ≥12 months and 1 dose for travelers 6 to <12 months.

Methods: We developed a model to compare 2 strategies among a simulated cohort of international travelers (6 months to <6 years): (1) No pretravel health encounter (PHE): travelers depart with baseline MMR vaccination status; (2) PHE: MMR-eligible travelers are offered vaccination. All pediatric travelers experience a destination-specific risk of measles exposure (mean, 30 exposures/million travelers). If exposed to measles, travelers' age and MMR vaccination status determine the risk of infection (range, 3%-90%). We included costs of medical care, contact tracing, and lost wages from the societal perspective. We varied inputs in sensitivity analyses. Model outcomes included projected measles cases, costs, and incremental cost-effectiveness ratios ($/quality-adjusted life year [QALY], cost-effectiveness threshold ≤$100 000/QALY).

Results: Compared with no PHE, PHE would avert 57 measles cases at $9.2 million/QALY among infant travelers and 7 measles cases at $15.0 million/QALY among preschool-aged travelers. Clinical benefits of PHE would be greatest for infants but cost-effective only for travelers to destinations with higher risk for measles exposure (ie, ≥160 exposures/million travelers) or if more US-acquired cases resulted from an infected traveler, such as in communities with limited MMR coverage.

Conclusions: Pretravel MMR vaccination provides the greatest clinical benefit for infant travelers and can be cost-effective before travel to destinations with high risk for measles exposure or from communities with low MMR vaccination coverage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jpids/piac011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9214784PMC
June 2022

The Effect of Vaccine Type and SARS-CoV-2 Lineage on Commercial SARS-CoV-2 Serologic and Pseudotype Neutralization Assays in mRNA Vaccine Recipients.

Microbiol Spectr 2022 04 21;10(2):e0021122. Epub 2022 Mar 21.

Department of Pathology, Massachusetts General Hospitalgrid.32224.35, Boston, Massachusetts, USA.

The use of anti-spike (S) serologic assays as surrogate measurements of SARS-CoV-2 vaccine induced immunity will be an important clinical and epidemiological tool. The characteristics of a commercially available anti-S antibody assay (Roche Elecsys anti-SARS-CoV-2 S) were evaluated in a cohort of vaccine recipients. Levels were correlated with pseudotype neutralizing antibodies (NAb) across SARS-CoV-2 variants. We recruited adults receiving a two-dose series of mRNA-1273 or BNT162b2 and collected serum at scheduled intervals up to 8 months post-first vaccination. Anti-S and NAb levels were measured, and correlation was evaluated by (i) vaccine type and (ii) SARS-CoV-2 variant (wild-type, Alpha, Beta, Gamma, and three constructs Day 146*, Day 152*, and RBM-2). Forty-six mRNA vaccine recipients were enrolled. mRNA-1273 vaccine recipients had higher peak anti-S and NAb levels compared with BNT162b2 ( < 0.001 for anti-S levels;  < 0.05 for NAb levels). When anti-S and NAb levels were compared, there was good correlation (all values ≥ 0.85) in both BNT162b2 and mRNA-1273 vaccine recipients across all evaluated variants; however, these correlations were nonlinear in nature. Lower correlation was identified between anti-S and NAb for the Beta variant (= 0.88) compared with the wild-type (WT) strain (= 0.94). Finally, the degree of neutralizing activity at any given anti-S level was lower for each variant compared with that of the WT strain, ( < 0.001). Although the Roche anti-S assay correlates well with NAb levels, this association is affected by vaccine type and SARS-CoV-2 variant. These variables must be considered when interpreting anti-S levels. We evaluated anti-spike antibody concentrations in healthy mRNA vaccinated individuals and compared these concentrations to values obtained from pseudotype neutralization assays targeting SARS-CoV-2 variants of concern to determine how well anti-spike antibodies correlate with neutralizing titers, which have been used as a marker of immunity from COVID-19 infection. We found high peak anti-spike concentrations in these individuals, with significantly higher levels seen in mRNA-1273 vaccine recipients. When we compared anti-spike and pseudotype neuralization titers, we identified good correlation; however, this correlation was affected by both vaccine type and variant, illustrating the difficulty of applying a "one size fits all" approach to anti-spike result interpretation. Our results support CDC recommendations to discourage anti-spike antibody testing to assess for immunity after vaccination and cautions providers in their interpretations of these results as a surrogate of protection in COVID-vaccinated individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/spectrum.00211-22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9045317PMC
April 2022

Virus-like Particle Display of -Specific Polysaccharide as a Potential Vaccine against Cholera.

ACS Infect Dis 2022 03 16;8(3):574-583. Epub 2022 Feb 16.

Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States.

, a noninvasive mucosal pathogen, is endemic in more than 50 countries. Oral cholera vaccines, based on killed whole-cell strains of , can provide significant protection in adults and children for 2-5 years. However, they have relatively limited direct protection in young children. To overcome current challenges, in this study, a potential conjugate vaccine was developed by linking -specific polysaccharide (OSP) antigen purified from O1 El Tor Inaba strain PIC018 with Qβ virus-like particles efficiently via squarate chemistry. The Qβ-OSP conjugate was characterized with mass photometry (MP) on the whole particle level. Pertinent immunologic display of OSP was confirmed by immunoreactivity of the conjugate with convalescent phase samples from humans with cholera. Mouse immunization with the Qβ-OSP conjugate showed that the construct generated prominent and long-lasting IgG antibody responses against OSP, and the resulting antibodies could recognize the native lipopolysaccharide from O1 Inaba. This was the first time that Qβ was conjugated with a bacterial polysaccharide for vaccine development, broadening the scope of this powerful carrier.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsinfecdis.1c00585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9119010PMC
March 2022

Disease characteristics and serological responses in patients with differing severity of COVID-19 infection: A longitudinal cohort study in Dhaka, Bangladesh.

PLoS Negl Trop Dis 2022 01 4;16(1):e0010102. Epub 2022 Jan 4.

International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh).

Background: COVID-19 caused by SARS-CoV-2 ranges from asymptomatic to severe disease and can cause fatal and devastating outcome in many cases. In this study, we have compared the clinical, biochemical and immunological parameters across the different disease spectrum of COVID-19 in Bangladeshi patients.

Methodology/principal Findings: This longitudinal study was conducted in two COVID-19 hospitals and also around the community in Dhaka city in Bangladesh between November 2020 to March 2021. A total of 100 patients with COVID-19 infection were enrolled and classified into asymptomatic, mild, moderate and severe cases (n = 25/group). In addition, thirty age and sex matched healthy participants were enrolled and 21 were analyzed as controls based on exclusion criteria. After enrollment (study day1), follow-up visits were conducted on day 7, 14 and 28 for the cases. Older age, male gender and co-morbid conditions were the risk factors for severe COVID-19 disease. Those with moderate and severe cases of infection had low lymphocyte counts, high neutrophil counts along with a higher neutrophil-lymphocyte ratio (NLR) at enrollment; this decreased to normal range within 42 days after the onset of symptom. At enrollment, D-dimer, CRP and ferritin levels were elevated among moderate and severe cases. The mild, moderate, and severe cases were seropositive for IgG antibody by day 14 after enrollment. Moderate and severe cases showed significantly higher IgM and IgG levels of antibodies to SARS-CoV-2 compared to mild and asymptomatic cases.

Conclusion/significance: We report on the clinical, biochemical, and hematological parameters associated with the different severity of COVID-19 infection. We also show different profile of antibody response against SARS-CoV-2 in relation to disease severity, especially in those with moderate and severe disease manifestations compared to the mild and asymptomatic infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pntd.0010102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759637PMC
January 2022

Structural basis for continued antibody evasion by the SARS-CoV-2 receptor binding domain.

Science 2022 01 21;375(6578):eabl6251. Epub 2022 Jan 21.

Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.

Many studies have examined the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants on neutralizing antibody activity after they have become dominant strains. Here, we evaluate the consequences of further viral evolution. We demonstrate mechanisms through which the SARS-CoV-2 receptor binding domain (RBD) can tolerate large numbers of simultaneous antibody escape mutations and show that pseudotypes containing up to seven mutations, as opposed to the one to three found in previously studied variants of concern, are more resistant to neutralization by therapeutic antibodies and serum from vaccine recipients. We identify an antibody that binds the RBD core to neutralize pseudotypes for all tested variants but show that the RBD can acquire an N-linked glycan to escape neutralization. Our findings portend continued emergence of escape variants as SARS-CoV-2 adapts to humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.abl6251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9127715PMC
January 2022

Systemic, Mucosal, and Memory Immune Responses following Cholera.

Trop Med Infect Dis 2021 Oct 27;6(4). Epub 2021 Oct 27.

Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.

O1, the major causative agent of cholera, remains a significant public health threat. Although there are available vaccines for cholera, the protection provided by killed whole-cell cholera vaccines in young children is poor. An obstacle to the development of improved cholera vaccines is the need for a better understanding of the primary mechanisms of cholera immunity and identification of improved correlates of protection. Considerable progress has been made over the last decade in understanding the adaptive and innate immune responses to cholera disease as well as infection. This review will assess what is currently known about the systemic, mucosal, memory, and innate immune responses to clinical cholera, as well as recent advances in our understanding of the mechanisms and correlates of protection against O1 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/tropicalmed6040192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8628923PMC
October 2021

Case 34-2021: A 38-Year-Old Man with Altered Mental Status and New Onset of Seizures.

N Engl J Med 2021 Nov;385(20):1894-1902

From the Departments of Neurology (A.J.C.), Emergency Medicine (J.E.S.), Medicine (E.T.R.), Radiology (M.H.L.), and Pathology (G.E.), Massachusetts General Hospital, and the Departments of Neurology (A.J.C.), Emergency Medicine (J.E.S.), Medicine (E.T.R.), Radiology (M.H.L.), and Pathology (G.E.), Harvard Medical School - both in Boston.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMcpc2027080DOI Listing
November 2021

Scalable production and immunogenicity of a cholera conjugate vaccine.

Vaccine 2021 11 27;39(47):6936-6946. Epub 2021 Oct 27.

Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address:

There is a need to develop cholera vaccines that are protective in young children under 5 years of age, which induce long-term immunity, and which can be incorporated into the Expanded Programme of Immunization (EPI) in cholera-endemic countries. The degree of protection afforded by currently available oral cholera vaccines (OCV) to young children is significantly lower than that induced by vaccination of older vaccine recipients. Immune responses that protect against cholera target the O-specific polysaccharide (OSP) of Vibrio cholerae, and young children have poor immunological responses to bacterial polysaccharides, which are T cell independent antigens. To overcome this, we have developed a cholera conjugate vaccine (CCV) containing the OSP of V. cholerae O1, the main cause of endemic and epidemic cholera. Here, we describe production of CCV through a scalable manufacturing process and preclinical evaluation of immunogenicity in the presence and absence of aluminum phosphate (alum) as an adjuvant. The vaccine displays V. cholerae O1 Inaba OSP in sun-burst display via single point attachment of core oligosaccharide to a recombinant tetanus toxoid heavy chain fragment (rTTHc). Two different pilot-scale production batches of non-GMP CCV were manufactured and characterized in terms of physico-chemical properties and immunogenicity. In preclinical testing, the vaccine induced OSP- and lipopolysaccharide (LPS)-specific IgG and IgM responses, vibriocidal responses, memory B cell responses, and protection in a V. cholerae O1 challenge model. The addition of alum to the administered vaccine increased OSP-specific immune responses. These results support evaluation of CCV in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vaccine.2021.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8609181PMC
November 2021

An AAV-based, room-temperature-stable, single-dose COVID-19 vaccine provides durable immunogenicity and protection in non-human primates.

Cell Host Microbe 2021 09 7;29(9):1437-1453.e8. Epub 2021 Aug 7.

Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02118, USA.

The SARS-CoV-2 pandemic has affected more than 185 million people worldwide resulting in over 4 million deaths. To contain the pandemic, there is a continued need for safe vaccines that provide durable protection at low and scalable doses and can be deployed easily. Here, AAVCOVID-1, an adeno-associated viral (AAV), spike-gene-based vaccine candidate demonstrates potent immunogenicity in mouse and non-human primates following a single injection and confers complete protection from SARS-CoV-2 challenge in macaques. Peak neutralizing antibody titers are sustained at 1 year and complemented by functional memory T cell responses. The AAVCOVID vector has no relevant pre-existing immunity in humans and does not elicit cross-reactivity to common AAVs used in gene therapy. Vector genome persistence and expression wanes following injection. The single low-dose requirement, high-yield manufacturability, and 1-month stability for storage at room temperature may make this technology well suited to support effective immunization campaigns for emerging pathogens on a global scale.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chom.2021.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346325PMC
September 2021

A Combination of Metagenomic and Cultivation Approaches Reveals Hypermutator Phenotypes within Vibrio cholerae-Infected Patients.

mSystems 2021 Aug 24;6(4):e0088921. Epub 2021 Aug 24.

Department of Biological Sciences, University of Montreal, Montreal, Quebec, Canada.

Vibrio cholerae can cause a range of symptoms, from severe diarrhea to asymptomatic infection. Previous studies using whole-genome sequencing (WGS) of multiple bacterial isolates per patient showed that V. cholerae can evolve modest genetic diversity during symptomatic infection. To further explore the extent of V. cholerae within-host diversity, we applied culture-based WGS and metagenomics to a cohort of both symptomatic and asymptomatic cholera patients from Bangladesh. While metagenomics allowed us to detect more mutations in symptomatic patients, WGS of cultured isolates was necessary to detect V. cholerae diversity in asymptomatic carriers, likely due to their low V. cholerae load. Using both metagenomics and isolate WGS, we report three lines of evidence that V. cholerae hypermutators evolve within patients. First, we identified nonsynonymous mutations in V. cholerae DNA repair genes in 5 out of 11 patient metagenomes sequenced with sufficient coverage of the V. cholerae genome and in 1 of 3 patients with isolate genomes sequenced. Second, these mutations in DNA repair genes tended to be accompanied by an excess of intrahost single nucleotide variants (iSNVs). Third, these iSNVs were enriched in transversion mutations, a known hallmark of hypermutator phenotypes. While hypermutators appeared to generate mostly selectively neutral mutations, nonmutators showed signs of convergent mutation across multiple patients, suggesting V. cholerae adaptation within hosts. Our results highlight the power and limitations of metagenomics combined with isolate sequencing to characterize within-patient diversity in acute V. cholerae infections, while providing evidence for hypermutator phenotypes within cholera patients. Pathogen evolution within patients can impact phenotypes such as drug resistance and virulence, potentially affecting clinical outcomes. V. cholerae infection can result in life-threatening diarrheal disease or asymptomatic infection. Here, we describe whole-genome sequencing of V. cholerae isolates and culture-free metagenomic sequencing from stool of symptomatic cholera patients and asymptomatic carriers. Despite the typically short duration of cholera, we found evidence for adaptive mutations in the V. cholerae genome that occur independently and repeatedly within multiple symptomatic patients. We also identified V. cholerae hypermutator phenotypes within several patients, which appear to generate mainly neutral or deleterious mutations. Our work sets the stage for future studies of the role of hypermutators and within-patient evolution in explaining the variation from asymptomatic carriage to symptomatic cholera.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mSystems.00889-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407408PMC
August 2021

Defining Polysaccharide-Specific Antibody Targets against Vibrio cholerae O139 in Humans following O139 Cholera and following Vaccination with a Commercial Bivalent Oral Cholera Vaccine, and Evaluation of Conjugate Vaccines Targeting O139.

mSphere 2021 08 7;6(4):e0011421. Epub 2021 Jul 7.

Division of Infectious Diseases, Massachusetts General Hospitalgrid.32224.35, Boston, Massachusetts, USA.

Cholera caused by Vibrio cholerae O139 could reemerge, and proactive development of an effective O139 vaccine would be prudent. To define immunoreactive and potentially immunogenic carbohydrate targets of Vibrio cholerae O139, we assessed immunoreactivities of various O-specific polysaccharide (OSP)-related saccharides with plasma from humans hospitalized with cholera caused by O139, comparing responses to those induced in recipients of a commercial oral whole-cell killed bivalent (O1 and O139) cholera vaccine (WC-O1/O139). We also assessed conjugate vaccines containing selected subsets of these saccharides for their ability to induce protective immunity using a mouse model of cholera. We found that patients with wild-type O139 cholera develop IgM, IgA, and IgG immune responses against O139 OSP and many of its fragments, but we were able to detect only a moderate IgM response to purified O139 OSP-core, and none to its fragments, in immunologically naive recipients of WC-O1/O139. We found that immunoreactivity of O139-specific polysaccharides with antibodies elicited by wild-type infection markedly increase when saccharides contain colitose and phosphate residues, that a synthetic terminal tetrasaccharide fragment of OSP is more immunoreactive and protectively immunogenic than complete OSP, that native OSP-core is a better protective immunogen than the synthetic OSP lacking core, and that functional vibriocidal activity of antibodies predicts protection in our model but depends on capsule thickness. Our results suggest that O139 OSP-specific responses are not prominent following vaccination with a currently available oral cholera vaccine in immunologically naive humans and that vaccines targeting V. cholerae O139 should be based on native OSP-core or terminal tetrasaccharide. Cholera is a severe dehydrating illness of humans caused by Vibrio cholerae serogroup O1 or O139. Protection against cholera is serogroup specific, and serogroup specificity is defined by O-specific polysaccharide (OSP). Little is known about immunity to O139 OSP. In this study, we used synthetic fragments of the O139 OSP to define immune responses to OSP in humans recovering from cholera caused by V. cholerae O139, compared these responses to those induced by the available O139 vaccine, and evaluated O139 fragments in next-generation conjugate vaccines. We found that the terminal tetrasaccharide of O139 is a primary immune target but that the currently available bivalent cholera vaccine poorly induces an anti-O139 OSP response in immunologically naive individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mSphere.00114-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386440PMC
August 2021

Gut Microbiota and Development of Vibrio cholerae-Specific Long-Term Memory B Cells in Adults after Whole-Cell Killed Oral Cholera Vaccine.

Infect Immun 2021 08 16;89(9):e0021721. Epub 2021 Aug 16.

Department of Medicine, University of Washington, Seattle, Washington, USA.

Cholera is a diarrheal disease caused by Vibrio cholerae that continues to be a major public health concern in populations without access to safe water. IgG- and IgA-secreting memory B cells (MBC) targeting the V. cholerae O-specific polysaccharide (OSP) correlate with protection from infection in persons exposed to V. cholerae and may be a major determinant of long-term protection against cholera. Shanchol, a widely used oral cholera vaccine (OCV), stimulates OSP MBC responses in only some people after vaccination, and the gut microbiota is a possible determinant of variable immune responses observed after OCV. Using 16S rRNA sequencing of feces from the time of vaccination, we compared the gut microbiota among adults with and without MBC responses to OCV. Gut microbial diversity measures were not associated with MBC isotype or OSP-specific responses, but individuals with a higher abundance of and lower abundance of were more likely to develop an MBC response. We applied protein-normalized fecal supernatants of high and low MBC responders to THP-1-derived human macrophages to investigate the effect of microbial factors at the time of vaccination. Feces from individuals with higher MBC responses induced significantly different IL-1β and IL-6 levels than individuals with lower responses, indicating that the gut microbiota at the time of vaccination may "prime" the mucosal immune response to vaccine antigens. Our results suggest the gut microbiota could impact immune responses to OCVs, and further study of microbial metabolites as potential vaccine adjuvants is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/IAI.00217-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370679PMC
August 2021

Development of a qualitative real-time RT-PCR assay for the detection of SARS-CoV-2: a guide and case study in setting up an emergency-use, laboratory-developed molecular microbiological assay.

J Clin Pathol 2021 Aug 28;74(8):496-503. Epub 2021 May 28.

Infectious Disease and Microbiome Program, Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA

Developing and deploying new diagnostic tests are difficult, but the need to do so in response to a rapidly emerging pandemic such as COVID-19 is crucially important. During a pandemic, laboratories play a key role in helping healthcare providers and public health authorities detect active infection, a task most commonly achieved using nucleic acid-based assays. While the landscape of diagnostics is rapidly evolving, PCR remains the gold-standard of nucleic acid-based diagnostic assays, in part due to its reliability, flexibility and wide deployment. To address a critical local shortage of testing capacity persisting during the COVID-19 outbreak, our hospital set up a molecular-based laboratory developed test (LDT) to accurately and safely diagnose SARS-CoV-2. We describe here the process of developing an emergency-use LDT, in the hope that our experience will be useful to other laboratories in future outbreaks and will help to lower barriers to establishing fast and accurate diagnostic testing in crisis conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jclinpath-2020-207128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311084PMC
August 2021

Vibrio cholerae Sialidase-Specific Immune Responses Are Associated with Protection against Cholera.

mSphere 2021 04 28;6(2). Epub 2021 Apr 28.

Infectious Diseases Division, icddr,b (International Centre for Diarrhoeal Disease Research, Bangladesh), Dhaka, Bangladesh

Cholera remains a major public health problem in resource-limited countries. Vaccination is an important strategy to prevent cholera, but currently available vaccines provide only 3 to 5 years of protection. Understanding immune responses to cholera antigens in naturally infected individuals may elucidate which of these are key to longer-term protection seen following infection. We recently identified O1 sialidase, a neuraminidase that facilitates binding of cholera toxin to intestinal epithelial cells, as immunogenic following infection in two recent high-throughput screens. Here, we present systemic, mucosal, and memory immune responses to sialidase in cholera index cases and evaluated whether systemic responses to sialidase correlated with protection using a cohort of household contacts. Overall, we found age-related differences in antisialidase immune response following cholera. Adults developed significant plasma anti-sialidase IgA, IgG, and IgM responses following infection, whereas older children (≥5 years) developed both IgG and IgM responses, and younger children only developed IgM responses. Neither older children nor younger children had a rise in IgA responses over the convalescent phase of infection (day 7/day 30). On evaluation of mucosal responses and memory B-cell responses to sialidase, we found adults developed IgA antibody-secreting cell (ASC) and memory B-cell responses. Finally, in household contacts, the presence of serum anti-sialidase IgA, IgG, and IgM antibodies at enrollment was associated with a decrease in the risk of subsequent infection. These data show cholera patients develop age-related immune responses against sialidase and suggest that immune responses that target sialidase may contribute to protective immunity against cholera. Cholera infection can result in severe dehydration that may lead to death within a short period of time if not treated immediately. Vaccination is an important strategy to prevent the disease. Oral cholera vaccines provide 3 to 5 years of protection, with 60% protective efficacy, while natural infection provides longer-term protection than vaccination. Understanding the immune responses after natural infection is important to better understand immune responses to antigens that mediate longer-term protection. Sialidase is a neuraminidase that facilitates binding of cholera toxin to intestinal epithelial cells. We show here that patients with cholera develop systemic, mucosal, and memory B-cell immune responses to the sialidase antigen of O1 and that plasma responses targeting this antigen correlate with protection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mSphere.01232-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092141PMC
April 2021

An assessment of potential biomarkers of environment enteropathy and its association with age and microbial infections among children in Bangladesh.

PLoS One 2021 22;16(4):e0250446. Epub 2021 Apr 22.

Infectious Diseases Division, icddr,b, Dhaka, Bangladesh.

Interventional studies targeting environment enteropathy (EE) are impeded by the lack of appropriate, validated, non-invasive biomarkers of EE. Thus, we aimed to validate the association of potential biomarkers for EE with enteric infections and nutritional status in a longitudinal birth cohort study. We measured endotoxin core antibody (EndoCab) and soluble CD14 (sCD14) in serum, and myeloperoxidase (MPO) in feces using commercially available enzyme-linked immunosorbent assay (ELISA) kits. We found that levels of serum EndoCab and sCD14 increase with the cumulative incidence of enteric infections. We observed a significant correlation between the fecal MPO level in the children at 24 months of age with the total number of bacterial and viral infections, the total number of parasitic infections, and the total number of diarrheal episodes and diarrheal duration. We observed that the levels of serum EndoCab, sCD14, and fecal MPO at 3 months of age were significantly associated with whether children were malnourished at 18 months of age or not. Biomarkers such as fecal MPO, serum EndoCab and sCD14 in children at an early age may be useful as a measure of cumulative burden of preceding enteric infections, which are predictive of subsequent malnutrition status and may be useful non-invasive biomarkers for EE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250446PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061931PMC
September 2021

Impact of Immunoglobulin Isotype and Epitope on the Functional Properties of O-Specific Polysaccharide-Specific Monoclonal Antibodies.

mBio 2021 04 20;12(2). Epub 2021 Apr 20.

Division of Infectious Disease, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA

causes the severe diarrheal disease cholera. Clinical disease and current oral cholera vaccines generate antibody responses associated with protection. Immunity is thought to be largely mediated by lipopolysaccharide (LPS)-specific antibodies, primarily targeting the O-antigen. However, the properties and protective mechanism of functionally relevant antibodies have not been well defined. We previously reported on the early B cell response to cholera in a cohort of Bangladeshi patients, from which we characterized a panel of human monoclonal antibodies (MAbs) isolated from acutely induced plasmablasts. All antibodies in that previous study were expressed in an IgG1 backbone irrespective of their original isotype. To clearly determine the impact of affinity, immunoglobulin isotype and subclass on the functional properties of these MAbs, we re-engineered a subset of low- and high-affinity antibodies in different isotype and subclass immunoglobulin backbones and characterized the impact of these changes on binding, vibriocidal, agglutination, and motility inhibition activity. While the high-affinity antibodies bound similarly to O-antigen, irrespective of isotype, the low-affinity antibodies displayed significant avidity differences. Interestingly, despite exhibiting lower binding properties, variants derived from the low-affinity MAbs had comparable agglutination and motility inhibition properties to the potently binding antibodies, suggesting that how the MAb binds to the O-antigen may be critical to function. In addition, not only pentameric IgM and dimeric IgA, but also monomeric IgA, was remarkably more potent than their IgG counterparts at inhibiting motility. Finally, analyzing highly purified F(ab) versions of these antibodies, we show that LPS cross-linking is essential for motility inhibition. Immunity to the severe diarrheal disease cholera is largely mediated by lipopolysaccharide (LPS)-specific antibodies. However, the properties and protective mechanisms of functionally relevant antibodies have not been well defined. Here, we have engineered low and high-affinity LPS-specific antibodies in different immunoglobulin backbones in order to assess the impact of affinity, immunoglobulin isotype, and subclass on binding, vibriocidal, agglutination, and motility inhibition functional properties. Importantly, we found that affinity did not directly dictate functional potency since variants derived from the low-affinity MAbs had comparable agglutination and motility inhibition properties to the potently binding antibodies. This suggests that how the antibody binds sterically may be critical to function. In addition, not only pentameric IgM and dimeric IgA, but also monomeric IgA, was remarkably more potent than their IgG counterparts at inhibiting motility. Finally, analyzing highly purified F(ab) versions of these antibodies, we show that LPS cross-linking is essential for motility inhibition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.03679-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092325PMC
April 2021

Parenteral Vaccination with a Cholera Conjugate Vaccine Boosts Vibriocidal and Anti-OSP Responses in Mice Previously Immunized with an Oral Cholera Vaccine.

Am J Trop Med Hyg 2021 04 19;104(6):2024-2030. Epub 2021 Apr 19.

1Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts.

Oral cholera vaccination protects against cholera; however, responses in young children are low and of short duration. The best current correlates of protection against cholera target Vibrio cholerae O-specific polysaccharide (anti-OSP), including vibriocidal responses. A cholera conjugate vaccine has been developed that induces anti-OSP immune responses, including memory B-cell responses. To address whether cholera conjugate vaccine would boost immune responses following oral cholera vaccination, we immunized mice with oral cholera vaccine Inaba CVD 103-HgR or buffer only (placebo) on day 0, followed by parenteral boosting immunizations on days 14, 42, and 70 with cholera conjugate vaccine Inaba OSP: recombinant tetanus toxoid heavy chain fragment or phosphate buffered saline (PBS)/placebo. Compared with responses in mice immunized with oral vaccine alone or intramuscular cholera conjugate vaccine alone, mice receiving combination vaccination developed significantly higher vibriocidal, IgM OSP-specific serum responses and OSP-specific IgM memory B-cell responses. A combined vaccination approach, which includes oral cholera vaccination followed by parenteral cholera conjugate vaccine boosting, results in increased immune responses that have been associated with protection against cholera. These results suggest that such an approach should be evaluated in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4269/ajtmh.20-1511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176512PMC
April 2021

Humoral signatures of protective and pathological SARS-CoV-2 infection in children.

Nat Med 2021 03 12;27(3):454-462. Epub 2021 Feb 12.

Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to spread relentlessly, associated with a high frequency of respiratory failure and mortality. Children experience largely asymptomatic disease, with rare reports of multisystem inflammatory syndrome in children (MIS-C). Identifying immune mechanisms that result in these disparate clinical phenotypes in children could provide critical insights into coronavirus disease 2019 (COVID-19) pathogenesis. Using systems serology, in this study we observed in 25 children with acute mild COVID-19 a functional phagocyte and complement-activating IgG response to SARS-CoV-2, similar to the acute responses generated in adults with mild disease. Conversely, IgA and neutrophil responses were significantly expanded in adults with severe disease. Moreover, weeks after the resolution of SARS-CoV-2 infection, children who develop MIS-C maintained highly inflammatory monocyte-activating SARS-CoV-2 IgG antibodies, distinguishable from acute disease in children but with antibody levels similar to those in convalescent adults. Collectively, these data provide unique insights into the potential mechanisms of IgG and IgA that might underlie differential disease severity as well as unexpected complications in children infected with SARS-CoV-2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-021-01263-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315827PMC
March 2021

Coronavirus Disease 2019 (COVID-19) Diagnostic Clinical Decision Support: A Pre-Post Implementation Study of CORAL (COvid Risk cALculator).

Clin Infect Dis 2021 12;73(12):2248-2256

Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.

Background: Isolation of hospitalized persons under investigation (PUIs) for coronavirus disease 2019 (COVID-19) reduces nosocomial transmission risk. Efficient evaluation of PUIs is needed to preserve scarce healthcare resources. We describe the development, implementation, and outcomes of an inpatient diagnostic algorithm and clinical decision support system (CDSS) to evaluate PUIs.

Methods: We conducted a pre-post study of CORAL (COvid Risk cALculator), a CDSS that guides frontline clinicians through a risk-stratified COVID-19 diagnostic workup, removes transmission-based precautions when workup is complete and negative, and triages complex cases to infectious diseases (ID) physician review. Before CORAL, ID physicians reviewed all PUI records to guide workup and precautions. After CORAL, frontline clinicians evaluated PUIs directly using CORAL. We compared pre- and post-CORAL frequency of repeated severe acute respiratory syndrome coronavirus 2 nucleic acid amplification tests (NAATs), time from NAAT result to PUI status discontinuation, total duration of PUI status, and ID physician work hours, using linear and logistic regression, adjusted for COVID-19 incidence.

Results: Fewer PUIs underwent repeated testing after an initial negative NAAT after CORAL than before CORAL (54% vs 67%, respectively; adjusted odd ratio, 0.53 [95% confidence interval, .44-.63]; P < .01). CORAL significantly reduced average time to PUI status discontinuation (adjusted difference [standard error], -7.4 [0.8] hours per patient), total duration of PUI status (-19.5 [1.9] hours per patient), and average ID physician work-hours (-57.4 [2.0] hours per day) (all P < .01). No patients had a positive NAAT result within 7 days after discontinuation of precautions via CORAL.

Conclusions: CORAL is an efficient and effective CDSS to guide frontline clinicians through the diagnostic evaluation of PUIs and safe discontinuation of precautions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciab111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929052PMC
December 2021

Yellow Fever Vaccine Administration at Global TravEpiNet (GTEN) Clinics during a Period of Limited Vaccine Availability in the United States, 2017-2018.

Am J Trop Med Hyg 2021 01 18;104(3):1079-1084. Epub 2021 Jan 18.

4Travelers' Advice and Immunization Center, Massachusetts General Hospital, Boston, Massachusetts.

In 2016, Sanofi Pasteur (S-P) experienced a manufacturing disruption of YF-Vax, the only U.S.-licensed yellow fever vaccine depleting the U.S. supply by mid-2017. Sanofi Pasteur received approval to import Stamaril, S-P's French-manufactured yellow fever vaccine, for use in 260 U.S. civilian clinics under an Expanded Access Program (EAP). The CDC also broadened its yellow fever vaccination indication in early 2018. Our objective was to assess usage at participating Global TravEpiNet (GTEN) clinics, a U.S. CDC-supported national consortium of clinical sites that administer vaccines, during this period of limited availability and changing recommendations. We analyzed 2012-2018 GTEN data for yellow fever vaccine usage, unavailability, and reasons for refusal. We also performed a brief voluntary survey of GTEN sites to better understand their experience during the shortage. YF-Vax unavailability at certain GTEN clinics was intermittent and recurrent, starting months before total depletion. Unavailability at GTEN clinics peaked weeks before the total depletion. Compared with historic norms, yellow fever vaccine usage following initial vaccine availability limitations did not change until vaccine recommendations were broadened. Refusal of recommended yellow fever vaccine also decreased during this period. Queried sites participating in the EAP felt their supply of vaccine was adequate. Our analysis suggests that in response to depletion of a travel vaccine, an EAP can make an unlicensed product available, patients will participate in such a program, and the program can respond to expanding recommendations for vaccine usage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4269/ajtmh.19-0859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941836PMC
January 2021

Immunogenicity of an AAV-based, room-temperature stable, single dose COVID-19 vaccine in mice and non-human primates.

bioRxiv 2021 Jan 19. Epub 2021 Jan 19.

The SARS-CoV-2 pandemic has affected more than 70 million people worldwide and resulted in over 1.5 million deaths. A broad deployment of effective immunization campaigns to achieve population immunity at global scale will depend on the biological and logistical attributes of the vaccine. Here, two adeno-associated viral (AAV)-based vaccine candidates demonstrate potent immunogenicity in mouse and nonhuman primates following a single injection. Peak neutralizing antibody titers remain sustained at 5 months and are complemented by functional memory T-cells responses. The AAVrh32.33 capsid of the AAVCOVID vaccine is an engineered AAV to which no relevant pre-existing immunity exists in humans. Moreover, the vaccine is stable at room temperature for at least one month and is produced at high yields using established commercial manufacturing processes in the gene therapy industry. Thus, this methodology holds as a very promising single dose, thermostable vaccine platform well-suited to address emerging pathogens on a global scale.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.01.05.422952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805441PMC
January 2021

Acquisition and Long-term Carriage of Multidrug-Resistant Organisms in US International Travelers.

Open Forum Infect Dis 2020 Dec 21;7(12):ofaa543. Epub 2020 Dec 21.

Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.

We performed prospective screening of stool for multidrug-resistant organisms from 608 US international travelers and identified an acquisition rate of 38% following travel. Carriage rates remained significantly elevated for at least 6 months post-travel. Travel-related diarrhea was a risk factor for acquisition, as well as for long-term carriage upon return.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ofid/ofaa543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759211PMC
December 2020

Phylogenetic analysis of SARS-CoV-2 in Boston highlights the impact of superspreading events.

Science 2021 02 10;371(6529). Epub 2020 Dec 10.

Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA.

Analysis of 772 complete severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from early in the Boston-area epidemic revealed numerous introductions of the virus, a small number of which led to most cases. The data revealed two superspreading events. One, in a skilled nursing facility, led to rapid transmission and significant mortality in this vulnerable population but little broader spread, whereas other introductions into the facility had little effect. The second, at an international business conference, produced sustained community transmission and was exported, resulting in extensive regional, national, and international spread. The two events also differed substantially in the genetic variation they generated, suggesting varying transmission dynamics in superspreading events. Our results show how genomic epidemiology can help to understand the link between individual clusters and wider community spread.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.abe3261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857412PMC
February 2021
-->