Publications by authors named "Yonatan H Grad"

100 Publications

SARS-CoV-2 Reinfection: A Case Series from a 12-Month Longitudinal Occupational Cohort.

Clin Infect Dis 2021 Aug 28. Epub 2021 Aug 28.

National Basketball Association, Hospital for Special Surgery, New York, New York, USA.

Seven cases of COVID-19 SARS-CoV-2 reinfection from the NBA 2020-2021 occupational testing cohort are described including clinical details, antibody test results, genomic sequencing, and longitudinal RT-PCR results. Reinfections were infrequent and varied in clinical presentation, viral dynamics, and immune response.
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http://dx.doi.org/10.1093/cid/ciab738DOI Listing
August 2021

Evidence Of Respiratory Infection Transmission Within Physician Offices Could Inform Outpatient Infection Control.

Health Aff (Millwood) 2021 08;40(8):1321-1327

Michael Lawrence Barnett is an assistant professor in the Department of Health Policy and Management, Harvard T. H. Chan School of Public Health, and an assistant professor of medicine at Harvard Medical School.

Early in the COVID-19 pandemic, outpatient clinics throughout the US shifted toward virtual care to limit viral transmission in the office. However, as health care facilities have reopened, evidence about the risk of acquiring respiratory viral infections in medical office settings remains limited. To inform policy for reopening outpatient care settings, we analyzed rates of potential airborne disease transmission in medical office settings, focusing on influenza-like illness. We quantified whether exposed patients (that is, those seen in a medical office after a patient with influenza-like illness) were more likely to return with a similar illness in the next two weeks compared with nonexposed patients seen earlier in the day. Patients exposed to influenza-like illness in the medical office setting were more likely than nonexposed patients to revisit with a similar illness within two weeks (adjusted absolute difference: 0.7 per 1,000 patients). Similar patterns were not observed for exposure to urinary tract infection and back pain as noncontagious control conditions. These results highlight the potential threat of reopening outpatient clinics during the pandemic and the value of virtual visits for patients with suspected respiratory infections.
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http://dx.doi.org/10.1377/hlthaff.2020.01594DOI Listing
August 2021

Viral dynamics of acute SARS-CoV-2 infection and applications to diagnostic and public health strategies.

PLoS Biol 2021 07 12;19(7):e3001333. Epub 2021 Jul 12.

Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.

SARS-CoV-2 infections are characterized by viral proliferation and clearance phases and can be followed by low-level persistent viral RNA shedding. The dynamics of viral RNA concentration, particularly in the early stages of infection, can inform clinical measures and interventions such as test-based screening. We used prospective longitudinal quantitative reverse transcription PCR testing to measure the viral RNA trajectories for 68 individuals during the resumption of the 2019-2020 National Basketball Association season. For 46 individuals with acute infections, we inferred the peak viral concentration and the duration of the viral proliferation and clearance phases. According to our mathematical model, we found that viral RNA concentrations peaked an average of 3.3 days (95% credible interval [CI] 2.5, 4.2) after first possible detectability at a cycle threshold value of 22.3 (95% CI 20.5, 23.9). The viral clearance phase lasted longer for symptomatic individuals (10.9 days [95% CI 7.9, 14.4]) than for asymptomatic individuals (7.8 days [95% CI 6.1, 9.7]). A second test within 2 days after an initial positive PCR test substantially improves certainty about a patient's infection stage. The effective sensitivity of a test intended to identify infectious individuals declines substantially with test turnaround time. These findings indicate that SARS-CoV-2 viral concentrations peak rapidly regardless of symptoms. Sequential tests can help reveal a patient's progress through infection stages. Frequent, rapid-turnaround testing is needed to effectively screen individuals before they become infectious.
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http://dx.doi.org/10.1371/journal.pbio.3001333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297933PMC
July 2021

Identification of bile acid and fatty acid species as candidate rapidly bactericidal agents for topical treatment of gonorrhoea.

J Antimicrob Chemother 2021 Sep;76(10):2569-2577

Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.

Background: Novel therapeutic strategies are urgently needed for Neisseria gonorrhoeae, given its increasing antimicrobial resistance. Treatment of oropharyngeal N. gonorrhoeae infections has proven particularly challenging, with most reported treatment failures of the first-line drug ceftriaxone occurring at this site and lower cure rates in recent trials of new antibiotics reported for oropharyngeal infections compared with other sites of infection. However, the accessibility of the oropharynx to topical therapeutics provides an opportunity for intervention. Local delivery of a therapeutic at a high concentration would enable the use of non-traditional antimicrobial candidates, including biological molecules that exploit underlying chemical sensitivities of N. gonorrhoeae but lack the potency or pharmacokinetic profiles required for effective systemic administration.

Methods: Two classes of molecules that are thought to limit gonococcal viability in vivo, bile acids and short- and medium-chain fatty acids, were examined for rapid bactericidal activity.

Results: The bile acids deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA), but not other bile acid species, exerted extremely rapid bactericidal properties against N. gonorrhoeae, reducing viability more than 100 000-fold after 1 min. The short-chain fatty acids formic acid and hexanoic acid shared this rapid bactericidal activity. All four molecules are effective against a phylogenetically diverse panel of N. gonorrhoeae strains, including clinical isolates with upregulated efflux pumps and resistance alleles to the most widely used classes of existing antimicrobials. DCA and CDCA are both approved therapeutics for non-infectious indications and are well-tolerated by cultured epithelial cells.

Conclusions: DCA and CDCA are attractive candidates for further development as anti-gonococcal agents.
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http://dx.doi.org/10.1093/jac/dkab217DOI Listing
September 2021

Modeling the impact of racial and ethnic disparities on COVID-19 epidemic dynamics.

Elife 2021 05 18;10. Epub 2021 May 18.

Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, United States.

Background: The impact of variable infection risk by race and ethnicity on the dynamics of SARS-CoV-2 spread is largely unknown.

Methods: Here, we fit structured compartmental models to seroprevalence data from New York State and analyze how herd immunity thresholds (HITs), final sizes, and epidemic risk change across groups.

Results: A simple model where interactions occur proportionally to contact rates reduced the HIT, but more realistic models of preferential mixing within groups increased the threshold toward the value observed in homogeneous populations. Across all models, the burden of infection fell disproportionately on minority populations: in a model fit to Long Island serosurvey and census data, 81% of Hispanics or Latinos were infected when the HIT was reached compared to 34% of non-Hispanic whites.

Conclusions: Our findings, which are meant to be illustrative and not best estimates, demonstrate how racial and ethnic disparities can impact epidemic trajectories and result in unequal distributions of SARS-CoV-2 infection.

Funding: K.C.M. was supported by National Science Foundation GRFP grant DGE1745303. Y.H.G. and M.L. were funded by the Morris-Singer Foundation. M.L. was supported by SeroNet cooperative agreement U01 CA261277.
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http://dx.doi.org/10.7554/eLife.66601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221808PMC
May 2021

Childhood Respiratory Outpatient Visits Correlate With Socioeconomic Status and Drive Geographic Patterns in Antibiotic Prescribing.

J Infect Dis 2021 Jun;223(12):2029-2037

Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Background: Reducing geographic disparities in antibiotic prescribing is a central public health priority to combat antibiotic resistance, but drivers of this variation have been unclear.

Methods: We measured how variation in outpatient visit rates (observed disease) and antibiotic prescribing rates per visit (prescribing practices) contributed to geographic variation in per capita antibiotic prescribing in Massachusetts residents younger than 65 years between 2011 and 2015.

Results: Of the difference in per capita antibiotic prescribing between high- and low-prescribing census tracts in Massachusetts, 45.2% was attributable to variation in outpatient visit rates, while 25.8% was explained by prescribing practices. Outpatient visits for sinusitis, pharyngitis, and suppurative otitis media accounted for 30.3% of the gap in prescribing, with most of the variation in visit rates concentrated in children younger than 10 years. Outpatient visits for these conditions were less frequent in census tracts with high social deprivation index.

Conclusions: Interventions aimed at reducing geographic disparities in antibiotic prescribing should target the drivers of outpatient visits for respiratory illness and should account for possible underutilization of health services in areas with the lowest antibiotic consumption. Our findings challenge the conventional wisdom that prescribing practices are the main driver of geographic disparities in antibiotic use.
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http://dx.doi.org/10.1093/infdis/jiab218DOI Listing
June 2021

SARS-CoV-2 Transmission Risk Among National Basketball Association Players, Staff, and Vendors Exposed to Individuals With Positive Test Results After COVID-19 Recovery During the 2020 Regular and Postseason.

JAMA Intern Med 2021 07;181(7):960-966

Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Importance: Clinical data are lacking regarding the risk of viral transmission from individuals who have positive reverse-transcription-polymerase chain reaction (RT-PCR) SARS-CoV-2 test results after recovery from COVID-19.

Objective: To describe case characteristics, including viral dynamics and transmission of infection, for individuals who have clinically recovered from SARS-CoV-2 infection but continued to have positive test results following discontinuation of isolation precautions.

Design, Setting, And Participants: This retrospective cohort study used data collected from June 11, 2020, to October 19, 2020, as part of the National Basketball Association (NBA) closed campus occupational health program in Orlando, Florida, which required daily RT-PCR testing and ad hoc serological testing for SARS-CoV-2 IgG antibodies. Nearly 4000 NBA players, staff, and vendors participated in the NBA's regular and postseason occupational health program in Orlando. Persistent positive cases were those who recovered from a documented SARS-CoV-2 infection, satisfied US Centers for Disease Control and Prevention criteria for discontinuation of isolation precautions, and had at least 1 postinfection positive RT-PCR test(s) result.

Exposures: Person-days of participation in indoor, unmasked activities that involved direct exposure between persistent positive cases and noninfected individuals.

Main Outcomes And Measures: Transmission of SARS-CoV-2 following interaction with persistent positive individuals, as measured by the number of new COVID-19 cases in the Orlando campus program.

Results: Among 3648 individuals who participated, 36 (1%) were persistent positive cases, most of whom were younger than 30 years (24 [67%]) and male (34 [94%]). Antibodies were detected in 33 individuals (91.7%); all remained asymptomatic following the index persistent positive RT-PCR result. Cycle threshold values for persistent positive RT-PCR test results were typically above the Roche cobas SARS-CoV-2 limit of detection. Cases were monitored for up to 100 days (mean [SD], 51 [23.9] days), during which there were at least 1480 person-days of direct exposure activities, with no transmission events or secondary infections of SARS-CoV-2 detected (0 new cases).

Conclusions And Relevance: In this retrospective cohort study of the 2020 NBA closed campus occupational health program, recovered individuals who continued to test positive for SARS-CoV-2 following discontinuation of isolation were not infectious to others. These findings support time-based US Centers of Disease Control and Prevention recommendations for ending isolation.
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http://dx.doi.org/10.1001/jamainternmed.2021.2114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063131PMC
July 2021

A community-driven resource for genomic epidemiology and antimicrobial resistance prediction of Neisseria gonorrhoeae at Pathogenwatch.

Genome Med 2021 04 19;13(1):61. Epub 2021 Apr 19.

Centre for Genomic Pathogen Surveillance, Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, Oxfordshire, UK.

Background: Antimicrobial-resistant (AMR) Neisseria gonorrhoeae is an urgent threat to public health, as strains resistant to at least one of the two last-line antibiotics used in empiric therapy of gonorrhoea, ceftriaxone and azithromycin, have spread internationally. Whole genome sequencing (WGS) data can be used to identify new AMR clones and transmission networks and inform the development of point-of-care tests for antimicrobial susceptibility, novel antimicrobials and vaccines. Community-driven tools that provide an easy access to and analysis of genomic and epidemiological data is the way forward for public health surveillance.

Methods: Here we present a public health-focussed scheme for genomic epidemiology of N. gonorrhoeae at Pathogenwatch ( https://pathogen.watch/ngonorrhoeae ). An international advisory group of experts in epidemiology, public health, genetics and genomics of N. gonorrhoeae was convened to inform on the utility of current and future analytics in the platform. We implement backwards compatibility with MLST, NG-MAST and NG-STAR typing schemes as well as an exhaustive library of genetic AMR determinants linked to a genotypic prediction of resistance to eight antibiotics. A collection of over 12,000 N. gonorrhoeae genome sequences from public archives has been quality-checked, assembled and made public together with available metadata for contextualization.

Results: AMR prediction from genome data revealed specificity values over 99% for azithromycin, ciprofloxacin and ceftriaxone and sensitivity values around 99% for benzylpenicillin and tetracycline. A case study using the Pathogenwatch collection of N. gonorrhoeae public genomes showed the global expansion of an azithromycin-resistant lineage carrying a mosaic mtr over at least the last 10 years, emphasising the power of Pathogenwatch to explore and evaluate genomic epidemiology questions of public health concern.

Conclusions: The N. gonorrhoeae scheme in Pathogenwatch provides customised bioinformatic pipelines guided by expert opinion that can be adapted to public health agencies and departments with little expertise in bioinformatics and lower-resourced settings with internet connection but limited computational infrastructure. The advisory group will assess and identify ongoing public health needs in the field of gonorrhoea, particularly regarding gonococcal AMR, in order to further enhance utility with modified or new analytic methods.
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http://dx.doi.org/10.1186/s13073-021-00858-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054416PMC
April 2021

Concerns about SARS-CoV-2 evolution should not hold back efforts to expand vaccination.

Nat Rev Immunol 2021 05 1;21(5):330-335. Epub 2021 Apr 1.

Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.

When vaccines are in limited supply, expanding the number of people who receive some vaccine, such as by halving doses or increasing the interval between doses, can reduce disease and mortality compared with concentrating available vaccine doses in a subset of the population. A corollary of such dose-sparing strategies is that the vaccinated individuals may have less protective immunity. Concerns have been raised that expanding the fraction of the population with partial immunity to SARS-CoV-2 could increase selection for vaccine-escape variants, ultimately undermining vaccine effectiveness. We argue that, although this is possible, preliminary evidence instead suggests such strategies should slow the rate of viral escape from vaccine or naturally induced immunity. As long as vaccination provides some protection against escape variants, the corresponding reduction in prevalence and incidence should reduce the rate at which new variants are generated and the speed of adaptation. Because there is little evidence of efficient immune selection of SARS-CoV-2 during typical infections, these population-level effects are likely to dominate vaccine-induced evolution.
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http://dx.doi.org/10.1038/s41577-021-00544-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014893PMC
May 2021

Reduction in Antibiotic Prescribing Attainable With a Gonococcal Vaccine.

Clin Infect Dis 2021 Sep;73(6):e1368-e1371

Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.

We estimated the fraction of antibiotic prescribing in the United States attributable to gonorrhea. Gonorrhea contributes to an outsized proportion of antibiotic prescriptions in young adults, males, and in the southern and western United States. A gonococcal vaccine could substantially reduce antibiotic prescribing in these populations.
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http://dx.doi.org/10.1093/cid/ciab276DOI Listing
September 2021

Emergence and evolution of antimicrobial resistance genes and mutations in Neisseria gonorrhoeae.

Genome Med 2021 03 30;13(1):51. Epub 2021 Mar 30.

Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan.

Background: Antimicrobial resistance in Neisseria gonorrhoeae is a global health concern. Strains from two internationally circulating sequence types, ST-7363 and ST-1901, have acquired resistance to third-generation cephalosporins, mainly due to mosaic penA alleles. These two STs were first detected in Japan; however, the timeline, mechanism, and process of emergence and spread of these mosaic penA alleles to other countries remain unknown.

Methods: We studied the evolution of penA alleles by obtaining the complete genomes from three Japanese ST-1901 clinical isolates harboring mosaic penA allele 34 (penA-34) dating from 2005 and generating a phylogenetic representation of 1075 strains sampled from 35 countries. We also sequenced the genomes of 103 Japanese ST-7363 N. gonorrhoeae isolates from 1996 to 2005 and reconstructed a phylogeny including 88 previously sequenced genomes.

Results: Based on an estimate of the time-of-emergence of ST-1901 (harboring mosaic penA-34) and ST-7363 (harboring mosaic penA-10), and > 300 additional genome sequences of Japanese strains representing multiple STs isolated in 1996-2015, we suggest that penA-34 in ST-1901 was generated from penA-10 via recombination with another Neisseria species, followed by recombination with a gonococcal strain harboring wildtype penA-1. Following the acquisition of penA-10 in ST-7363, a dominant sub-lineage rapidly acquired fluoroquinolone resistance mutations at GyrA 95 and ParC 87-88, by independent mutations rather than horizontal gene transfer. Data in the literature suggest that the emergence of these resistance determinants may reflect selection from the standard treatment regimens in Japan at that time.

Conclusions: Our findings highlight how antibiotic use and recombination across and within Neisseria species intersect in driving the emergence and spread of drug-resistant gonorrhea.
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http://dx.doi.org/10.1186/s13073-021-00860-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008663PMC
March 2021

Estimating SARS-CoV-2 seroprevalence and epidemiological parameters with uncertainty from serological surveys.

Elife 2021 03 5;10. Epub 2021 Mar 5.

Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.

Establishing how many people have been infected by SARS-CoV-2 remains an urgent priority for controlling the COVID-19 pandemic. Serological tests that identify past infection can be used to estimate cumulative incidence, but the relative accuracy and robustness of various sampling strategies have been unclear. We developed a flexible framework that integrates uncertainty from test characteristics, sample size, and heterogeneity in seroprevalence across subpopulations to compare estimates from sampling schemes. Using the same framework and making the assumption that seropositivity indicates immune protection, we propagated estimates and uncertainty through dynamical models to assess uncertainty in the epidemiological parameters needed to evaluate public health interventions and found that sampling schemes informed by demographics and contact networks outperform uniform sampling. The framework can be adapted to optimize serosurvey design given test characteristics and capacity, population demography, sampling strategy, and modeling approach, and can be tailored to support decision-making around introducing or removing interventions.
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http://dx.doi.org/10.7554/eLife.64206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979159PMC
March 2021

GPS-estimated foot traffic data and venue selection for COVID-19 serosurveillance studies.

medRxiv 2021 Feb 5. Epub 2021 Feb 5.

Tracking the dynamics and spread of COVID-19 is critical to mounting an effective response to the pandemic. In the absence of randomized representative serological surveys, many SARS-CoV-2 serosurveillance studies have relied on convenience sampling to estimate cumulative incidence. One common approach is to recruit at frequently visited community locations ("venue-based" sampling), but the sources of bias and uncertainty associated with this strategy are still poorly understood. Here, we used data from a venue-based community serosurveillance study, GPS-estimated foot traffic data, and data on confirmed COVID-19 cases to report an estimate of cumulative incidence in Somerville, Massachusetts, and a methodological strategy to quantify and reduce uncertainty in serology-based cumulative incidence estimates obtained via convenience sampling. The mismatch between the geographic distribution of participants' home locations (the "participant catchment distribution") and the geographic distribution of infections is an important determinant of uncertainty in venue-based and other convenience sampling strategies. We found that uncertainty in cumulative incidence estimates can vary by a factor of two depending how well the participant catchment distribution matches the known or expected geographic distribution of prior infections. GPS-estimated business foot traffic data provides an important proxy measure for the participant catchment area and can be used to select venue locations that minimize uncertainty in cumulative incidence.
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http://dx.doi.org/10.1101/2021.02.03.21251011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872379PMC
February 2021

Disseminated Gonococcal Infection Complicated by Prosthetic Joint Infection: Case Report and Genomic and Phylogenetic Analysis.

Open Forum Infect Dis 2021 Feb 18;8(2):ofaa632. Epub 2020 Dec 18.

Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

infections have been increasing globally, with prevalence rising across age groups. In this study, we report a case of disseminated gonococcal infection (DGI) involving a prosthetic joint, and we use whole-genome sequencing to characterize resistance genes, putative virulence factors, and the phylogenetic lineage of the infecting isolate. We review the literature on sequence-based prediction of antibiotic resistance and factors that contribute to risk for DGI. We argue for routine sequencing and reporting of invasive gonococcal infections to aid in determining whether an invasive gonococcal infection is sporadic or part of an outbreak and to accelerate understanding of the genetic features of that contribute to pathogenesis.
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http://dx.doi.org/10.1093/ofid/ofaa632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850131PMC
February 2021

Model-informed COVID-19 vaccine prioritization strategies by age and serostatus.

Science 2021 02 21;371(6532):916-921. Epub 2021 Jan 21.

Department of Computer Science, University of Colorado Boulder, Boulder, CO 80309, USA.

Limited initial supply of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine raises the question of how to prioritize available doses. We used a mathematical model to compare five age-stratified prioritization strategies. A highly effective transmission-blocking vaccine prioritized to adults ages 20 to 49 years minimized cumulative incidence, but mortality and years of life lost were minimized in most scenarios when the vaccine was prioritized to adults greater than 60 years old. Use of individual-level serological tests to redirect doses to seronegative individuals improved the marginal impact of each dose while potentially reducing existing inequities in COVID-19 impact. Although maximum impact prioritization strategies were broadly consistent across countries, transmission rates, vaccination rollout speeds, and estimates of naturally acquired immunity, this framework can be used to compare impacts of prioritization strategies across contexts.
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http://dx.doi.org/10.1126/science.abe6959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963218PMC
February 2021

Model-informed COVID-19 vaccine prioritization strategies by age and serostatus.

medRxiv 2021 Jan 8. Epub 2021 Jan 8.

Department of Computer Science, University of Colorado Boulder, Boulder, CO, 80309, USA.

Limited initial supply of SARS-CoV-2 vaccine raises the question of how to prioritize available doses. Here, we used a mathematical model to compare five age-stratified prioritization strategies. A highly effective transmission-blocking vaccine prioritized to adults ages 20-49 years minimized cumulative incidence, but mortality and years of life lost were minimized in most scenarios when the vaccine was prioritized to adults over 60 years old. Use of individual-level serological tests to redirect doses to seronegative individuals improved the marginal impact of each dose while potentially reducing existing inequities in COVID-19 impact. While maximum impact prioritization strategies were broadly consistent across countries, transmission rates, vaccination rollout speeds, and estimates of naturally acquired immunity, this framework can be used to compare impacts of prioritization strategies across contexts.
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http://dx.doi.org/10.1101/2020.09.08.20190629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743091PMC
January 2021

The role of "spillover" in antibiotic resistance.

Proc Natl Acad Sci U S A 2020 11 2;117(46):29063-29068. Epub 2020 Nov 2.

Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115;

Antibiotic use is a key driver of antibiotic resistance. Understanding the quantitative association between antibiotic use and resulting resistance is important for predicting future rates of antibiotic resistance and for designing antibiotic stewardship policy. However, the use-resistance association is complicated by "spillover," in which one population's level of antibiotic use affects another population's level of resistance via the transmission of bacteria between those populations. Spillover is known to have effects at the level of families and hospitals, but it is unclear if spillover is relevant at larger scales. We used mathematical modeling and analysis of observational data to address this question. First, we used dynamical models of antibiotic resistance to predict the effects of spillover. Whereas populations completely isolated from one another do not experience any spillover, we found that if even 1% of interactions are between populations, then spillover may have large consequences: The effect of a change in antibiotic use in one population on antibiotic resistance in that population could be reduced by as much as 50%. Then, we quantified spillover in observational antibiotic use and resistance data from US states and European countries for three pathogen-antibiotic combinations, finding that increased interactions between populations were associated with smaller differences in antibiotic resistance between those populations. Thus, spillover may have an important impact at the level of states and countries, which has ramifications for predicting the future of antibiotic resistance, designing antibiotic resistance stewardship policy, and interpreting stewardship interventions.
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http://dx.doi.org/10.1073/pnas.2013694117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682407PMC
November 2020

Using rapid point-of-care tests to inform antibiotic choice to mitigate drug resistance in gonorrhoea.

Euro Surveill 2020 10;25(43)

GlaxoSmithKline, Collegeville, Pennsylvania, United States.

BackgroundThe first cases of extensively drug resistant gonorrhoea were recorded in the United Kingdom in 2018. There is a public health need for strategies on how to deploy existing and novel antibiotics to minimise the risk of resistance development. As rapid point-of-care tests (POCTs) to predict susceptibility are coming to clinical use, coupling the introduction of an antibiotic with diagnostics that can slow resistance emergence may offer a novel paradigm for maximising antibiotic benefits. Gepotidacin is a novel antibiotic with known resistance and resistance-predisposing mutations. In particular, a mutation that confers resistance to ciprofloxacin acts as the 'stepping-stone' mutation to gepotidacin resistance.AimTo investigate how POCTs detecting resistance mutations for ciprofloxacin and gepotidacin can be used to minimise the risk of resistance development to gepotidacin.MethodsWe use individual-based stochastic simulations to formally investigate the aim.ResultsThe level of testing needed to reduce the risk of resistance development depends on the mutation rate under treatment and the prevalence of stepping-stone mutations. A POCT is most effective if the mutation rate under antibiotic treatment is no more than two orders of magnitude above the mutation rate without treatment and the prevalence of stepping-stone mutations is 1-13%.ConclusionMutation frequencies and rates should be considered when estimating the POCT usage required to reduce the risk of resistance development in a given population. Molecular POCTs for resistance mutations and stepping-stone mutations to resistance are likely to become important tools in antibiotic stewardship.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.43.1900210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596916PMC
October 2020

Increased power from conditional bacterial genome-wide association identifies macrolide resistance mutations in Neisseria gonorrhoeae.

Nat Commun 2020 10 23;11(1):5374. Epub 2020 Oct 23.

Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

The emergence of resistance to azithromycin complicates treatment of Neisseria gonorrhoeae, the etiologic agent of gonorrhea. Substantial azithromycin resistance remains unexplained after accounting for known resistance mutations. Bacterial genome-wide association studies (GWAS) can identify novel resistance genes but must control for genetic confounders while maintaining power. Here, we show that compared to single-locus GWAS, conducting GWAS conditioned on known resistance mutations reduces the number of false positives and identifies a G70D mutation in the RplD 50S ribosomal protein L4 as significantly associated with increased azithromycin resistance (p-value = 1.08 × 10). We experimentally confirm our GWAS results and demonstrate that RplD G70D and other macrolide binding site mutations are prevalent (present in 5.42% of 4850 isolates) and widespread (identified in 21/65 countries across two decades). Overall, our findings demonstrate the utility of conditional associations for improving the performance of microbial GWAS and advance our understanding of the genetic basis of macrolide resistance.
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http://dx.doi.org/10.1038/s41467-020-19250-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584619PMC
October 2020

Cross-reactive memory T cells and herd immunity to SARS-CoV-2.

Nat Rev Immunol 2020 11 6;20(11):709-713. Epub 2020 Oct 6.

Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA, USA.

Immunity is a multifaceted phenomenon. For T cell-mediated memory responses to SARS-CoV-2, it is relevant to consider their impact both on COVID-19 disease severity and on viral spread in a population. Here, we reflect on the immunological and epidemiological aspects and implications of pre-existing cross-reactive immune memory to SARS-CoV-2, which largely originates from previous exposure to circulating common cold coronaviruses. We propose four immunological scenarios for the impact of cross-reactive CD4 memory T cells on COVID-19 severity and viral transmission. For each scenario, we discuss its implications for the dynamics of herd immunity and on projections of the global impact of SARS-CoV-2 on the human population, and assess its plausibility. In sum, we argue that key potential impacts of cross-reactive T cell memory are already incorporated into epidemiological models based on data of transmission dynamics, particularly with regard to their implications for herd immunity. The implications of immunological processes on other aspects of SARS-CoV-2 epidemiology are worthy of future study.
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http://dx.doi.org/10.1038/s41577-020-00460-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537578PMC
November 2020

Reductions in commuting mobility correlate with geographic differences in SARS-CoV-2 prevalence in New York City.

Nat Commun 2020 09 16;11(1):4674. Epub 2020 Sep 16.

Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

SARS-CoV-2-related mortality and hospitalizations differ substantially between New York City neighborhoods. Mitigation efforts require knowing the extent to which these disparities reflect differences in prevalence and understanding the associated drivers. Here, we report the prevalence of SARS-CoV-2 in New York City boroughs inferred using tests administered to 1,746 pregnant women hospitalized for delivery between March 22nd and May 3rd, 2020. We also assess the relationship between prevalence and commuting-style movements into and out of each borough. Prevalence ranged from 11.3% (95% credible interval [8.9%, 13.9%]) in Manhattan to 26.0% (15.3%, 38.9%) in South Queens, with an estimated city-wide prevalence of 15.6% (13.9%, 17.4%). Prevalence was lowest in boroughs with the greatest reductions in morning movements out of and evening movements into the borough (Pearson R = -0.88 [-0.52, -0.99]). Widespread testing is needed to further specify disparities in prevalence and assess the risk of future outbreaks.
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http://dx.doi.org/10.1038/s41467-020-18271-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494926PMC
September 2020

Potential Biases Arising From Epidemic Dynamics in Observational Seroprotection Studies.

Am J Epidemiol 2021 02;190(2):328-335

The extent and duration of immunity following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are critical outstanding questions about the epidemiology of this novel virus, and studies are needed to evaluate the effects of serostatus on reinfection. Understanding the potential sources of bias and methods for alleviating biases in these studies is important for informing their design and analysis. Confounding by individual-level risk factors in observational studies like these is relatively well appreciated. Here, we show how geographic structure and the underlying, natural dynamics of epidemics can also induce noncausal associations. We take the approach of simulating serological studies in the context of an uncontrolled or controlled epidemic, under different assumptions about whether prior infection does or does not protect an individual against subsequent infection, and using various designs and analytical approaches to analyze the simulated data. We find that in studies assessing whether seropositivity confers protection against future infection, comparing seropositive persons with seronegative persons with similar time-dependent patterns of exposure to infection by stratifying or matching on geographic location and time of enrollment is essential in order to prevent bias.
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http://dx.doi.org/10.1093/aje/kwaa188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499481PMC
February 2021

Efflux Pump Antibiotic Binding Site Mutations Are Associated with Azithromycin Nonsusceptibility in Clinical Neisseria gonorrhoeae Isolates.

mBio 2020 08 25;11(4). Epub 2020 Aug 25.

Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA

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http://dx.doi.org/10.1128/mBio.01509-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448274PMC
August 2020

The distribution and spread of susceptible and resistant Neisseria gonorrhoeae across demographic groups in a major metropolitan center.

Clin Infect Dis 2020 Aug 23. Epub 2020 Aug 23.

Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, United States of America.

Background: Genomic epidemiology studies of gonorrhea in the United States have primarily focused on national surveillance for antibiotic resistance, and patterns of local transmission between demographic groups of resistant and susceptible strains are unknown.

Methods: We analyzed a convenience sample of genome sequences, antibiotic susceptibility, and patient data from 897 gonococcal isolates cultured at the NYC Public Health Laboratory from NYC Department of Health and Mental Hygiene (DOHMH) Sexual Health Clinic (SHC) patients, primarily in 2012-13. We reconstructed the gonococcal phylogeny, defined transmission clusters using a 10 non-recombinant single nucleotide polymorphism threshold, tested for clustering of demographic groups, and placed NYC isolates in a global phylogenetic context.

Results: The NYC gonococcal phylogeny reflected global diversity with isolates from 22/23 of the prevalent global lineages (96%). Isolates clustered on the phylogeny by patient sexual behavior (p&0.001) and race/ethnicity (p&0.001). Minimum inhibitory concentrations were higher across antibiotics in isolates from men who have sex with men compared to heterosexuals (p&0.001) and white heterosexuals compared to black heterosexuals (p&0.01). In our dataset, all large transmission clusters (≥10 samples) of N. gonorrhoeae were susceptible to ciprofloxacin, ceftriaxone, and azithromycin and comprised isolates from patients across demographic groups.

Conclusions: All large transmission clusters were susceptible to gonorrhea therapies, suggesting that resistance to empiric therapy was not a main driver of spread, even as risk for resistance varied across demographic groups. Further study of local transmission networks is needed to identify drivers of transmission.
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http://dx.doi.org/10.1093/cid/ciaa1229DOI Listing
August 2020

Adaptation to the cervical environment is associated with increased antibiotic susceptibility in Neisseria gonorrhoeae.

Nat Commun 2020 08 17;11(1):4126. Epub 2020 Aug 17.

Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Neisseria gonorrhoeae is an urgent public health threat due to rapidly increasing incidence and antibiotic resistance. In contrast with the trend of increasing resistance, clinical isolates that have reverted to susceptibility regularly appear, prompting questions about which pressures compete with antibiotics to shape gonococcal evolution. Here, we used genome-wide association to identify loss-of-function (LOF) mutations in the efflux pump mtrCDE operon as a mechanism of increased antibiotic susceptibility and demonstrate that these mutations are overrepresented in cervical relative to urethral isolates. This enrichment holds true for LOF mutations in another efflux pump, farAB, and in urogenitally-adapted versus typical N. meningitidis, providing evidence for a model in which expression of these pumps in the female urogenital tract incurs a fitness cost for pathogenic Neisseria. Overall, our findings highlight the impact of integrating microbial population genomics with host metadata and demonstrate how host environmental pressures can lead to increased antibiotic susceptibility.
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http://dx.doi.org/10.1038/s41467-020-17980-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431566PMC
August 2020

Implications of Test Characteristics and Population Seroprevalence on "Immune Passport" Strategies.

Clin Infect Dis 2021 05;72(9):e412-e414

Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Various forms of "immune passports" or "antibody certificates" are being considered in conversations around reopening economies after periods of social distancing. A critique of such programs focuses on the uncertainty around whether seropositivity means immunity from repeat infection. However, an additional important consideration is that the low positive predictive value of serological tests in the setting of low population seroprevalence and imperfect test specificity will lead to many false-positive passport holders. Here, we pose a simple question: how many false-positive passports could be issued while maintaining herd immunity in the workforce? Answering this question leads to a simple mathematical formula for the minimum requirements of serological tests for a passport program, which depend on the population prevalence and the value of the basic reproductive number, R0. Our work replaces speculation in the press with rigorous analysis, and will need to be considered in policy decisions that are based on individual and population serology results.
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http://dx.doi.org/10.1093/cid/ciaa1019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454323PMC
May 2021

Targeted surveillance strategies for efficient detection of novel antibiotic resistance variants.

Elife 2020 06 30;9. Epub 2020 Jun 30.

Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, United States.

Genotype-based diagnostics for antibiotic resistance represent a promising alternative to empiric therapy, reducing inappropriate antibiotic use. However, because such assays infer resistance based on known genetic markers, their utility will wane with the emergence of novel resistance. Maintenance of these diagnostics will therefore require surveillance to ensure early detection of novel resistance variants, but efficient strategies to do so remain undefined. We evaluate the efficiency of targeted sampling approaches informed by patient and pathogen characteristics in detecting antibiotic resistance and diagnostic escape variants in , a pathogen associated with a high burden of disease and antibiotic resistance and the development of genotype-based diagnostics. We show that patient characteristic-informed sampling is not a reliable strategy for efficient variant detection. In contrast, sampling informed by pathogen characteristics, such as genomic diversity and genomic background, is significantly more efficient than random sampling in identifying genetic variants associated with resistance and diagnostic escape.
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http://dx.doi.org/10.7554/eLife.56367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326491PMC
June 2020

Potential biases arising from epidemic dynamics in observational seroprotection studies.

medRxiv 2020 May 6. Epub 2020 May 6.

Center for Communicable Disease Dynamics, Harvard TH Chan School of Public Health, Boston, MA, USA.

The extent and duration of immunity following SARS-CoV-2 infection are critical outstanding questions about the epidemiology of this novel virus, and studies are needed to evaluate the effects of serostatus on reinfection. Understanding the potential sources of bias and methods to alleviate biases in these studies is important for informing their design and analysis. Confounding by individual-level risk factors in observational studies like these is relatively well appreciated. Here, we show how geographic structure and the underlying, natural dynamics of epidemics can also induce noncausal associations. We take the approach of simulating serologic studies in the context of an uncontrolled or a controlled epidemic, under different assumptions about whether prior infection does or does not protect an individual against subsequent infection, and using various designs and analytic approaches to analyze the simulated data. We find that in studies assessing the efficacy of serostatus on future infection, comparing seropositive individuals to seronegative individuals with similar time-dependent patterns of exposure to infection, by stratifying or matching on geographic location and time of enrollment, is essential to prevent bias.
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http://dx.doi.org/10.1101/2020.05.02.20088765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273253PMC
May 2020

Comparative Impact of Individual Quarantine vs. Active Monitoring of Contacts for the Mitigation of COVID-19: a modelling study.

medRxiv 2020 Mar 8. Epub 2020 Mar 8.

Background: Voluntary individual quarantine and voluntary active monitoring of contacts are core disease control strategies for emerging infectious diseases, such as COVID-19. Given the impact of quarantine on resources and individual liberty, it is vital to assess under what conditions individual quarantine can more effectively control COVID-19 than active monitoring. As an epidemic grows, it is also important to consider when these interventions are no longer feasible, and broader mitigation measures must be implemented.

Methods: To estimate the comparative efficacy of these case-based interventions to control COVID-19, we fit a stochastic branching model to reported parameters for the dynamics of the disease. Specifically, we fit to the incubation period distribution and each of two sets of the serial interval distribution: a shorter one with a mean serial interval of 4.8 days and a longer one with a mean of 7.5 days. To assess variable resource settings, we consider two feasibility settings: a high feasibility setting with 90% of contacts traced, a half-day average delay in tracing and symptom recognition, and 90% effective isolation; and low feasibility setting with 50% of contacts traced, a two-day average delay, and 50% effective isolation.

Findings: Our results suggest that individual quarantine in high feasibility settings where at least three-quarters of infected contacts are individually quarantined contains an outbreak of COVID-19 with a short serial interval (4.8 days) 84% of the time. However, in settings where this performance is unrealistically high and the outbreak continues to grow, so too will the burden of the number of contacts traced for active monitoring or quarantine. When resources are prioritized for scalable interventions such as social distancing, we show active monitoring or individual quarantine of high-risk contacts can contribute synergistically to mitigation efforts.

Interpretation: Our model highlights the urgent need for more data on the serial interval and the extent of presymptomatic transmission in order to make data-driven policy decisions regarding the cost-benefit comparisons of individual quarantine vs. active monitoring of contacts. To the extent these interventions can be implemented they can help mitigate the spread of COVID-19.
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http://dx.doi.org/10.1101/2020.03.05.20031088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239061PMC
March 2020
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