Imperial College London

ProfessorNicholasGrassly

Faculty of MedicineSchool of Public Health

Prof of Infectious Disease & Vaccine Epidemiology
 
 
 
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Contact

 

n.grassly Website

 
 
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Location

 

1102Building E - Sir Michael UrenWhite City Campus

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Summary

 

Publications

Publication Type
Year
to

147 results found

Grassly NC, 2022, Polio's detection in London is a wake-up call., BMJ, Vol: 377

Journal article

Pons-Salort M, John J, Watson OJ, Brazeau NF, Verity R, Kang G, Grassly NCet al., 2022, Reassessing reported deaths and estimated infection attack rate during the first 6 months of the COVID-19 epidemic, Delhi, India., Emerging Infectious Diseases, Vol: 28, ISSN: 1080-6040

India reported >10 million coronavirus disease (COVID-19) cases and 149,000 deaths in 2020. To reassess reported deaths and estimate incidence rates during the first 6 months of the epidemic, we used a severe acute respiratory syndrome coronavirus 2 transmission model fit to data from 3 serosurveys in Delhi and time-series documentation of reported deaths. We estimated 48.7% (95% credible interval 22.1%-76.8%) cumulative infection in the population through the end of September 2020. Using an age-adjusted overall infection fatality ratio based on age-specific estimates from mostly high-income countries, we estimated that just 15.0% (95% credible interval 9.3%-34.0%) of COVID-19 deaths had been reported, indicating either substantial underreporting or lower age-specific infection-fatality ratios in India than in high-income countries. Despite the estimated high attack rate, additional epidemic waves occurred in late 2020 and April-May 2021. Future dynamics will depend on the duration of natural and vaccine-induced immunity and their effectiveness against new variants.

Journal article

Cooper LV, Bandyopadhyay AS, Gumede N, Mach O, Mkanda P, Ndoutabé M, Okiror SO, Ramirez-Gonzalez A, Touray K, Wanyoike S, Grassly NC, Blake IMet al., 2022, Risk factors for the spread of vaccine-derived type 2 polioviruses after global withdrawal of trivalent oral poliovirus vaccine and the effects of outbreak responses with monovalent vaccine: a retrospective analysis of surveillance data for 51 countries in Africa, Lancet Infectious Diseases, Vol: 22, Pages: 284-294, ISSN: 1473-3099

BACKGROUND: Expanding outbreaks of circulating vaccine-derived type 2 poliovirus (cVDPV2) across Africa after the global withdrawal of trivalent oral poliovirus vaccine (OPV) in 2016 are delaying global polio eradication. We aimed to assess the effect of outbreak response campaigns with monovalent type 2 OPV (mOPV2) and the addition of inactivated poliovirus vaccine (IPV) to routine immunisation. METHODS: We used vaccination history data from children under 5 years old with non-polio acute flaccid paralysis from a routine surveillance database (the Polio Information System) and setting-specific OPV immunogenicity data from the literature to estimate OPV-induced and IPV-induced population immunity against type 2 poliomyelitis between Jan 1, 2015, and June 30, 2020, for 51 countries in Africa. We investigated risk factors for reported cVDPV2 poliomyelitis including population immunity, outbreak response activities, and correlates of poliovirus transmission using logistic regression. We used the model to estimate cVDPV2 risk for each 6-month period between Jan 1, 2016, and June 30, 2020, with different numbers of mOPV2 campaigns and compared the timing and location of actual mOPV2 campaigns and the number of mOPV2 campaigns required to reduce cVDPV2 risk to low levels. FINDINGS: Type 2 OPV immunity among children under 5 years declined from a median of 87% (IQR 81-93) in January-June, 2016 to 14% (9-37) in January-June, 2020. Type 2 immunity from IPV among children under 5 years increased from 3% (<1-6%) in January-June, 2016 to 35% (24-47) in January-June, 2020. The probability of cVDPV2 poliomyelitis among children under 5 years was negatively correlated with OPV-induced and IPV-induced immunity and mOPV2 campaigns (adjusted odds ratio: OPV 0·68 [95% CrI 0·60-0·76], IPV 0·82 [0·68-0·99] per 10% absolute increase in estimated population immunity, mOPV2 0·30 [0·20-0·44] per campaign). Vaccination campaig

Journal article

Parker EPK, Bronowski C, Sindhu KNC, Babji S, Benny B, Carmona-Vicente N, Chasweka N, Chinyama E, Cunliffe NA, Dube Q, Giri S, Grassly NC, Gunasekaran A, Howarth D, Immanuel S, Jere KC, Kampmann B, Lowe J, Mandolo J, Praharaj I, Rani BS, Silas S, Srinivasan VK, Turner M, Venugopal S, Verghese VP, Darby AC, Kang G, Iturriza-Gomara Met al., 2021, Impact of maternal antibodies and microbiota development on the immunogenicity of oral rotavirus vaccine in African, Indian, and European infants, NATURE COMMUNICATIONS, Vol: 12

Journal article

Srinivasan M, Sindhu KN, Ramanujam K, Ramasamy RK, Subramaniam S, Ganesan SK, Vajja S, David AS, Lankala P, Rose W, Moses PD, Grassly NC, Kang G, John Jet al., 2021, Factors Predicting Blood Culture Positivity Children With Enteric Fever, JOURNAL OF INFECTIOUS DISEASES, Vol: 224, Pages: S484-S493, ISSN: 0022-1899

Journal article

Srinivasan M, Sindhu KN, Giri S, Kumar N, Mohan VR, Grassly NC, Kang Get al., 2021, Salmonella Typhi Shedding and Household Transmission by Children With Blood Culture-Confirmed Typhoid Fever in Vellore, South India, JOURNAL OF INFECTIOUS DISEASES, Vol: 224, Pages: S593-S600, ISSN: 0022-1899

Journal article

Pons-Salort M, Lambert B, Kamau E, Pebody R, Harvala H, Simmonds P, Grassly NCet al., 2021, Changes in transmission of Enterovirus D68 (EV-D68) in England inferred from seroprevalence data

<jats:title>Abstract</jats:title><jats:p>The factors leading to the global emergence of enterovirus D68 (EV-D68) in 2014 as a cause of acute flaccid myelitis (AFM) in children are unknown. To investigate potential changes in virus transmissibility or population susceptibility, we measured the seroprevalence of EV-D68-specific neutralising antibodies in serum samples collected in England in 2006, 2011 and 2017. Using catalytic mathematical models, we estimate an approximately two-fold increase in the basic reproduction number over the 10-year study period, coinciding with the emergence of clade B around 2009. Despite such increase in transmission, the virus was already widely circulating before the AFM outbreaks and the increase of infections by age cannot explain the observed number of AFM cases. Therefore, the acquisition of or an increase in neuropathogenicity would be additionally required to explain the emergence of outbreaks of AFM. Our results provide evidence that changes in enterovirus phenotypes cause major changes in disease epidemiology.</jats:p>

Journal article

Williams LR, Ferguson NM, Donnelly CA, Grassly NCet al., 2021, Measuring vaccine efficacy against infection and disease in clinical trials: sources and magnitude of bias in COVID-19 vaccine efficacy estimates, Clinical Infectious Diseases, ISSN: 1058-4838

BACKGROUND: Phase III trials have estimated COVID-19 vaccine efficacy (VE) against symptomatic and asymptomatic infection. We explore the direction and magnitude of potential biases in these estimates and their implications for vaccine protection against infection and against disease in breakthrough infections. METHODS: We developed a mathematical model that accounts for natural and vaccine-induced immunity, changes in serostatus and imperfect sensitivity and specificity of tests for infection and antibodies. We estimated expected biases in VE against symptomatic, asymptomatic and any SARS͏CoV2 infections and against disease following infection for a range of vaccine characteristics and measurement approaches, and the likely overall biases for published trial results that included asymptomatic infections. RESULTS: VE against asymptomatic infection measured by PCR or serology is expected to be low or negative for vaccines that prevent disease but not infection. VE against any infection is overestimated when asymptomatic infections are less likely to be detected than symptomatic infections and the vaccine protects against symptom development. A competing bias towards underestimation arises for estimates based on tests with imperfect specificity, especially when testing is performed frequently. Our model indicates considerable uncertainty in Oxford-AstraZeneca ChAdOx1 and Janssen Ad26.COV2.S VE against any infection, with slightly higher than published, bias-adjusted values of 59.0% (95% uncertainty interval [UI] 38.4 to 77.1) and 70.9% (95% UI 49.8 to 80.7) respectively. CONCLUSIONS: Multiple biases are likely to influence COVID-19 VE estimates, potentially explaining the observed difference between ChAdOx1 and Ad26.COV2.S vaccines. These biases should be considered when interpreting both efficacy and effectiveness study results.

Journal article

Shaw A, Cooper L, Gumede N, Bandyopadhyay AS, Grassly N, Blake Iet al., 2021, Time taken to detect and respond to polio outbreaks in Africa and the potential impact of direct molecular detection and nanopore sequencing, Journal of Infectious Diseases, ISSN: 0022-1899

BackgroundDetection of poliovirus outbreaks relies on a complex laboratory algorithm of cell-culture, PCR and sequencing to distinguish wild-type and vaccine-derived polioviruses (VDPV) from Sabin-like strains. We investigated the potential for direct molecular detection and nanopore sequencing (DDNS) to accelerate poliovirus detection.MethodsWe analysed laboratory data for time required to analyse and sequence serotype-2 VDPV (VDPV2) in stool collected from children with acute flaccid paralysis in Africa (May 2016-February 2020). Impact of delayed detection on VDPV2 outbreak size was assessed through negative binomial regression.ResultsVDPV2 confirmation in 525 stools required a median of 49 days from paralysis onset (10th-90th percentile: 29-74), comprising collection and transport (median: 16 days), cell-culture (7 days), intratypic differentiation RT-qPCR (3 days) and sequencing (including shipping if required) (15 days). New VDPV2 outbreaks were confirmed a median of 35 days (27-60) after paralysis onset, which we estimate could be reduced to 16 days by DDNS (9-37). Because longer delays in confirmation and response were positively associated with more cases (p<0.001), we estimate that DDNS could reduce the number of VDPV2 cases before a response by 28% (95% CrI 12-42%).ConclusionsDDNS could accelerate poliovirus outbreak response, reducing their size and the cost of eradication.

Journal article

Molodecky NA, Jafari H, Safdar RM, Ahmed JA, Mahamud A, Bandyopadhyay AS, Shukla H, Quddus A, Zaffran M, Sutter RW, Grassly NC, Blake IMet al., 2021, Modelling the spread of serotype-2 vaccine derived-poliovirus outbreak in Pakistan and Afghanistan to inform outbreak control strategies in the context of the COVID-19 pandemic, Vaccine, ISSN: 0264-410X

BackgroundSince July 2019, Pakistan and Afghanistan have been facing an outbreak of serotype-2 circulating vaccine derived poliovirus (cVDPV2) in addition to continued transmission of serotype-1 wild poliovirus (WPV1) and SARS-CoV-2 in 2020. Understanding the risks of cVDPV2 transmission due to pause of global vaccination efforts and the impact of potential vaccination response strategies in the current context of COVID-19 mitigation measures is critical.MethodsWe developed a stochastic, geographically structured mathematical model of cVDPV2 transmission which captures both mucosal and humoral immunity separately and allows for reversion of serotype-2 oral polio vaccine (OPV2) virus to cVDPV2 following vaccine administration. The model includes geographic heterogeneities in vaccination coverage, population immunity and population movement. The model was fitted to historic cVDPV2 cases in Pakistan and Afghanistan between January 2010-April 2016 and July 2019-March 2020 using iterated particle filtering. The model was used to simulate spread of cVDPV2 infection from July 2019 to explore impact of various proposed vaccination responses on stopping transmission and risk of spread of reverted Sabin-2 under varying assumptions of impacts from COVID-19 lockdown measures on movement patterns as well as declines in vaccination coverage.ResultsSimulated monthly incidence of cVDPV2 from the best-fit model demonstrated general spatio-temporal alignment with observed cVDPV2 cases. The model predicted substantial spread of cVDPV2 infection, with widespread transmission through 2020 in the absence of any vaccination activities. Vaccination responses were predicted to substantially reduce transmission and case burden, with a greater impact from earlier responses and those with larger geographic scope. While the greatest risk of seeding reverted Sabin-2 was predicted in areas targeted with OPV2, subsequent spread was greatest in areas with no or delayed response. The proposed vaccin

Journal article

Williams LR, Ferguson NM, Donnelly CA, Grassly NCet al., 2021, Measuring vaccine efficacy against infection and disease in clinical trials: sources and magnitude of bias in COVID-19 vaccine efficacy estimates, Publisher: Cold Spring Harbor Laboratory

Background Phase III trials have estimated COVID-19 vaccine efficacy (VE) against symptomatic and asymptomatic infection. We explore the direction and magnitude of potential biases in these estimates and their implications for vaccine protection against infection and against disease in breakthrough infections.Methods We developed a mathematical model that accounts for natural and vaccine-induced immunity, changes in serostatus and imperfect sensitivity and specificity of tests for infection and antibodies. We estimated expected biases in VE against symptomatic, asymptomatic and any SARS-CoV-2 infections and against disease following infection for a range of vaccine characteristics and measurement approaches, and the likely overall biases for published trial results that included asymptomatic infections.Results VE against asymptomatic infection measured by PCR or serology is expected to be low or negative for vaccines that prevent disease but not infection. VE against any infection is overestimated when asymptomatic infections are less likely to be detected than symptomatic infections and the vaccine protects against symptom development. A competing bias towards underestimation arises for estimates based on tests with imperfect specificity, especially when testing is performed frequently. Our model indicates considerable uncertainty in Oxford-AstraZeneca ChAdOx1 and Janssen Ad26.COV2.S VE against any infection, with slightly higher than published, bias-adjusted values of 59.0% (95% uncertainty interval [UI] 38.4 to 77.1) and 70.9% (95% UI 49.8 to 80.7) respectively.Conclusion Multiple biases are likely to influence COVID-19 VE estimates, potentially explaining the observed difference between ChAdOx1 and Ad26.COV2.S vaccines. These biases should be considered when interpreting both efficacy and effectiveness study results.

Working paper

Uzzell CB, Troman CM, Rigby J, Mohan VR, John J, Abraham D, Srinivasan R, Nair S, Meschke JS, Elviss N, Kang G, Feasey N, Grassly NCet al., 2021, Environmental surveillance for <i>Salmonella</i> Typhi as a tool to estimate the incidence of typhoid fever in low-income populations

<jats:p>Background: The World Health Organisation recommends prioritised use of recently prequalified typhoid conjugate vaccines in countries with the highest incidence of typhoid fever. However, representative typhoid surveillance data are lacking in many low-income countries because of the costs and challenges of diagnostic clinical microbiology. Environmental surveillance (ES) of <jats:italic>Salmonella</jats:italic> Typhi in sewage and wastewater using molecular methods may offer a low-cost alternative, but its performance in comparison with clinical surveillance has not been assessed. Methodology/Principal Findings: We developed a harmonised protocol for typhoid ES and its implementation in communities in India and Malawi where it will be compared with findings from hospital-based surveillance for typhoid fever. The protocol includes methods for ES site selection based on geospatial analysis, grab and trap sample collection at sewage and wastewater sites, and laboratory methods for sample processing, concentration and quantitative PCR to detect <jats:italic>Salmonella</jats:italic> Typhi. The optimal locations for ES sites based on digital elevation models and mapping of sewage and river networks are described for each community and their suitability confirmed through field investigation. We will compare the prevalence and abundance of <jats:italic>Salmonella</jats:italic> Typhi in ES samples collected each month over a 12-month period to the incidence of blood culture confirmed typhoid estimated from cases recorded at referral hospitals serving the study areas and community surveys of healthcare seeking for individuals with fever. Significance: If environmental detection of <jats:italic>Salmonella</jats:italic> Typhi correlates with the incidence of typhoid fever estimated through clinical surveillance, typhoid ES may be a powerful and low-cost tool to estimate the local burden of typhoid fever and support

Journal article

Pons-Salort M, John J, Watson OJ, Brazeau NF, Verity R, Kang G, Grassly NCet al., 2021, Reconstructing the COVID-19 epidemic in Delhi, India: infection attack rate and reporting of deaths

<jats:title>Abstract</jats:title><jats:p>India reported over 10 million COVID-19 cases and 149,000 deaths in 2020. To estimate exposure and the potential for further spread, we used a SARS-CoV-2 transmission model fit to seroprevalence data from three serosurveys in Delhi and the time-series of reported deaths to reconstruct the epidemic. The cumulative proportion of the population estimated infected was 48.7% (95% CrI 22.1% – 76.8%) by end-September 2020. Using an age-adjusted overall infection fatality ratio (IFR) based on age-specific estimates from mostly high-income countries (HICs), we estimate that 15.0% (95% CrI 9.3% – 34.0%) of COVID-19 deaths were reported. This indicates either under-reporting of COVID-19 deaths and/or a lower age-specific IFR in India compared with HICs. Despite the high attack rate of SARS-CoV-2, a third wave occurred in late 2020, suggesting that herd immunity was not yet reached. Future dynamics will strongly depend on the duration of immunity and protection against new variants.</jats:p>

Journal article

Li X, Mukandavire C, Cucunuba ZM, Londono SE, Abbas K, Clapham HE, Jit M, Johnson HL, Papadopoulos T, Vynnycky E, Brisson M, Carter ED, Clark A, de Villiers MJ, Eilertson K, Ferrari MJ, Gamkrelidze I, Gaythorpe KAM, Grassly NC, Hallett TB, Hinsley W, Jackson ML, Jean K, Karachaliou A, Klepac P, Lessler J, Li X, Moore SM, Nayagam S, Duy MN, Razavi H, Razavi-Shearer D, Resch S, Sanderson C, Sweet S, Sy S, Tam Y, Tanvir H, Quan MT, Trotter CL, Truelove S, van Zandvoort K, Verguet S, Walker N, Winter A, Woodruff K, Ferguson NM, Garske Tet al., 2021, Estimating the health impact of vaccination against ten pathogens in 98 low-income and middle-income countries from 2000 to 2030: a modelling study, The Lancet, Vol: 397, Pages: 398-408, ISSN: 0140-6736

BackgroundThe past two decades have seen expansion of childhood vaccination programmes in low-income and middle-income countries (LMICs). We quantify the health impact of these programmes by estimating the deaths and disability-adjusted life-years (DALYs) averted by vaccination against ten pathogens in 98 LMICs between 2000 and 2030.Methods16 independent research groups provided model-based disease burden estimates under a range of vaccination coverage scenarios for ten pathogens: hepatitis B virus, Haemophilus influenzae type B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, Streptococcus pneumoniae, rotavirus, rubella, and yellow fever. Using standardised demographic data and vaccine coverage, the impact of vaccination programmes was determined by comparing model estimates from a no-vaccination counterfactual scenario with those from a reported and projected vaccination scenario. We present deaths and DALYs averted between 2000 and 2030 by calendar year and by annual birth cohort.FindingsWe estimate that vaccination of the ten selected pathogens will have averted 69 million (95% credible interval 52–88) deaths between 2000 and 2030, of which 37 million (30–48) were averted between 2000 and 2019. From 2000 to 2019, this represents a 45% (36–58) reduction in deaths compared with the counterfactual scenario of no vaccination. Most of this impact is concentrated in a reduction in mortality among children younger than 5 years (57% reduction [52–66]), most notably from measles. Over the lifetime of birth cohorts born between 2000 and 2030, we predict that 120 million (93–150) deaths will be averted by vaccination, of which 58 million (39–76) are due to measles vaccination and 38 million (25–52) are due to hepatitis B vaccination. We estimate that increases in vaccine coverage and introductions of additional vaccines will result in a 72% (59–81) reduction in lifetime mortality in t

Journal article

Srinivasan M, Giri S, Natarajan SK, Kumar N, Mohan VR, Grassly NC, John J, Kang Get al., 2020, Stool shedding of Salmonella Typhi in children with blood culture-confirmed typhoid fever, Publisher: ELSEVIER SCI LTD, Pages: 123-123, ISSN: 1201-9712

Conference paper

Grassly NC, Pons-Salort M, Parker EPK, White PJ, Ferguson NM, Imperial College COVID-19 Response Teamet al., 2020, Comparison of molecular testing strategies for COVID-19 control: a mathematical modelling study, Lancet Infectious Diseases, Vol: 20, Pages: 1381-1389, ISSN: 1473-3099

BACKGROUND: WHO has called for increased testing in response to the COVID-19 pandemic, but countries have taken different approaches and the effectiveness of alternative strategies is unknown. We aimed to investigate the potential impact of different testing and isolation strategies on transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We developed a mathematical model of SARS-CoV-2 transmission based on infectiousness and PCR test sensitivity over time since infection. We estimated the reduction in the effective reproduction number (R) achieved by testing and isolating symptomatic individuals, regular screening of high-risk groups irrespective of symptoms, and quarantine of contacts of laboratory-confirmed cases identified through test-and-trace protocols. The expected effectiveness of different testing strategies was defined as the percentage reduction in R. We reviewed data on the performance of antibody tests reported by the Foundation for Innovative New Diagnostics and examined their implications for the use of so-called immunity passports. FINDINGS: If all individuals with symptoms compatible with COVID-19 self-isolated and self-isolation was 100% effective in reducing onwards transmission, self-isolation of symptomatic individuals would result in a reduction in R of 47% (95% uncertainty interval [UI] 32-55). PCR testing to identify SARS-CoV-2 infection soon after symptom onset could reduce the number of individuals needing to self-isolate, but would also reduce the effectiveness of self-isolation (around 10% would be false negatives). Weekly screening of health-care workers and other high-risk groups irrespective of symptoms by use of PCR testing is estimated to reduce their contribution to SARS-CoV-2 transmission by 23% (95% UI 16-40), on top of reductions achieved by self-isolation following symptoms, assuming results are available at 24 h. The effectiveness of test and trace depends strongly on coverage and the timelines

Journal article

Parker EPK, Bronowski C, Sindhu KNC, Babji S, Benny B, Carmona-Vicente N, Chasweka N, Chinyama E, Cunliffe NA, Dube Q, Giri S, Grassly NC, Gunasekaran A, Howarth D, Immanuel S, Jere KC, Kampmann B, Lowe J, Mandolo J, Praharaj I, Rani BS, Silas S, Srinivasan VK, Turner M, Venugopal S, Verghese VP, Darby AC, Kang G, Iturriza-Gómara Met al., 2020, Impact of maternal antibodies and microbiota development on the immunogenicity of oral rotavirus vaccine in African, Indian, and European infants: a prospective cohort study

<jats:title>Abstract</jats:title><jats:p>Identifying risk factors for impaired oral rotavirus vaccine (ORV) efficacy in low-income countries may lead to improvements in vaccine design and delivery. We measured maternal rotavirus antibodies, environmental enteric dysfunction (EED), and bacterial gut microbiota development among infants receiving two doses of Rotarix in India (n = 307), Malawi (n = 119), and the UK (n = 60), using standardised methods across cohorts. ORV shedding and seroconversion rates were significantly lower in Malawi and India than the UK. Maternal rotavirus-specific antibodies in serum and breastmilk were negatively correlated with ORV response in India and Malawi, and this was mediated partly by a reduction in ORV replication. In the UK, ORV replication was not inhibited despite comparable maternal antibody levels. In both India and Malawi, pre-vaccination microbiota diversity was negatively correlated with ORV immunogenicity, suggesting that high early-life microbial exposure may contribute to impaired vaccine efficacy.</jats:p>

Journal article

Chilengi R, Simuyandi M, Chibuye M, Chirwa M, Sukwa N, Laban N, Chisenga C, Silwamba S, Grassly N, Bosomprah Set al., 2020, A pilot study on use of live attenuated rotavirus vaccine (Rotarix (TM)) as an infection challenge model, VACCINE, Vol: 38, Pages: 7357-7362, ISSN: 0264-410X

Journal article

Shaw AG, Troman C, Grassly N, 2020, Rapid and sensitive direct detection and identification of poliovirus from stool and environmental surveillance samples using nanopore sequencing, Journal of Clinical Microbiology, Vol: 58, Pages: 1-13, ISSN: 0095-1137

Global poliovirus surveillance involves virus isolation from stool and environmental samples, intratypic differential (ITD) by PCR, and sequencing of the VP1 region to distinguish vaccine (Sabin), vaccine-derived, and wild-type polioviruses and to ensure an appropriate response. This cell culture algorithm takes 2 to 3 weeks on average between sample receipt and sequencing. Direct detection of viral RNA using PCR allows faster detection but has traditionally faced challenges related to poor sensitivity and difficulties in sequencing common samples containing poliovirus and enterovirus mixtures. We present a nested PCR and nanopore sequencing protocol that allows rapid (<3 days) and sensitive direct detection and sequencing of polioviruses in stool and environmental samples. We developed barcoded primers and a real-time analysis platform that generate accurate VP1 consensus sequences from multiplexed samples. The sensitivity and specificity of our protocol compared with those of cell culture were 90.9% (95% confidence interval, 75.7% to 98.1%) and 99.2% (95.5% to 100.0%) for wild-type 1 poliovirus, 92.5% (79.6% to 98.4%) and 98.7% (95.4% to 99.8%) for vaccine and vaccine-derived serotype 2 poliovirus, and 88.3% (81.2% to 93.5%) and 93.2% (88.6% to 96.3%) for Sabin 1 and 3 poliovirus alone or in mixtures when tested on 155 stool samples in Pakistan. Variant analysis of sequencing reads also allowed the identification of polioviruses and enteroviruses in artificial mixtures and was able to distinguish complex mixtures of polioviruses in environmental samples. The median identity of consensus nanopore sequences with Sanger or Illumina sequences from the same samples was >99.9%. This novel method shows promise as a faster and safer alternative to cell culture for the detection and real-time sequencing of polioviruses in stool and environmental samples.

Journal article

Flaxman S, Mishra S, Gandy A, Unwin HJT, Mellan TA, Coupland H, Whittaker C, Zhu H, Berah T, Eaton JW, Monod M, Perez Guzman PN, Schmit N, Cilloni L, Ainslie K, Baguelin M, Boonyasiri A, Boyd O, Cattarino L, Cucunuba Perez Z, Cuomo-Dannenburg G, Dighe A, Djaafara A, Dorigatti I, van Elsland S, Fitzjohn R, Gaythorpe K, Geidelberg L, Grassly N, Green W, Hallett T, Hamlet A, Hinsley W, Jeffrey B, Knock E, Laydon D, Nedjati Gilani G, Nouvellet P, Parag K, Siveroni I, Thompson H, Verity R, Volz E, Walters C, Wang H, Watson O, Winskill P, Xi X, Walker P, Ghani AC, Donnelly CA, Riley SM, Vollmer MAC, Ferguson NM, Okell LC, Bhatt Set al., 2020, Estimating the effects of non-pharmaceutical interventions on COVID-19 in Europe, Nature, Vol: 584, Pages: 257-261, ISSN: 0028-0836

Following the emergence of a novel coronavirus1 (SARS-CoV-2) and its spread outside of China, Europe has experienced large epidemics. In response, many European countries have implemented unprecedented non-pharmaceutical interventions such as closure of schools and national lockdowns. We study the impact of major interventions across 11 European countries for the period from the start of COVID-19 until the 4th of May 2020 when lockdowns started to be lifted. Our model calculates backwards from observed deaths to estimate transmission that occurred several weeks prior, allowing for the time lag between infection and death. We use partial pooling of information between countries with both individual and shared effects on the reproduction number. Pooling allows more information to be used, helps overcome data idiosyncrasies, and enables more timely estimates. Our model relies on fixed estimates of some epidemiological parameters such as the infection fatality rate, does not include importation or subnational variation and assumes that changes in the reproduction number are an immediate response to interventions rather than gradual changes in behavior. Amidst the ongoing pandemic, we rely on death data that is incomplete, with systematic biases in reporting, and subject to future consolidation. We estimate that, for all the countries we consider, current interventions have been sufficient to drive the reproduction number Rt below 1 (probability Rt< 1.0 is 99.9%) and achieve epidemic control. We estimate that, across all 11 countries, between 12 and 15 million individuals have been infected with SARS-CoV-2 up to 4th May, representing between 3.2% and 4.0% of the population. Our results show that major non-pharmaceutical interventions and lockdown in particular have had a large effect on reducing transmission. Continued intervention should be considered to keep transmission of SARS-CoV-2 under control.

Journal article

Jorgensen D, Pons Salort M, Shaw A, Grassly Net al., 2020, The role of genetic sequencing and analysis in the polio eradication program, Virus Evolution, Vol: 6, ISSN: 2057-1577

Genetic sequencing of polioviruses detected through clinical and environmental surveillance is used to confirm detection, identify their likely origin, track geographic patterns of spread and determine the appropriate vaccination response. The critical importance of genetic sequencing and analysis to the Global Polio Eradication Initiative has grown with the increasing incidence of vaccine-derived poliovirus infections in Africa specifically (470 reported cases in 2019), and globally, alongside persistent transmission of serotype 1 wild-type poliovirus in Pakistan and Afghanistan (197 reported cases in 2019). Adapting what has been learned about the virus genetics and evolution to address these threats has been a major focus of recent work. Here we review how phylogenetic and phylogeographic methods have been used to trace the spread of wild-type polioviruses and identify the likely origins of vaccine-derived polioviruses. We highlight the analysis methods and sequencing technology currently used and the potential for new technologies to speed up poliovirus detection and the interpretation of genetic data. At a pivotal point in the eradication campaign with the threat of anti-vaccine sentiment and donor and public fatigue, innovation is critical to maintain drive and overcome the last remaining circulating virus.

Journal article

Walker PGT, Whittaker C, Watson OJ, Baguelin M, Winskill P, Hamlet A, Djafaara BA, Cucunubá Z, Olivera Mesa D, Green W, Thompson H, Nayagam S, Ainslie KEC, Bhatia S, Bhatt S, Boonyasiri A, Boyd O, Brazeau NF, Cattarino L, Cuomo-Dannenburg G, Dighe A, Donnelly CA, Dorigatti I, van Elsland SL, FitzJohn R, Fu H, Gaythorpe KAM, Geidelberg L, Grassly N, Haw D, Hayes S, Hinsley W, Imai N, Jorgensen D, Knock E, Laydon D, Mishra S, Nedjati-Gilani G, Okell LC, Unwin HJ, Verity R, Vollmer M, Walters CE, Wang H, Wang Y, Xi X, Lalloo DG, Ferguson NM, Ghani ACet al., 2020, The impact of COVID-19 and strategies for mitigation and suppression in low- and middle-income countries, Science, Vol: 369, Pages: 413-422, ISSN: 0036-8075

The ongoing COVID-19 pandemic poses a severe threat to public health worldwide. We combine data on demography, contact patterns, disease severity, and health care capacity and quality to understand its impact and inform strategies for its control. Younger populations in lower income countries may reduce overall risk but limited health system capacity coupled with closer inter-generational contact largely negates this benefit. Mitigation strategies that slow but do not interrupt transmission will still lead to COVID-19 epidemics rapidly overwhelming health systems, with substantial excess deaths in lower income countries due to the poorer health care available. Of countries that have undertaken suppression to date, lower income countries have acted earlier. However, this will need to be maintained or triggered more frequently in these settings to keep below available health capacity, with associated detrimental consequences for the wider health, well-being and economies of these countries.

Journal article

Shaw AG, Majumdar M, Troman C, OToole Á, Benny B, Abraham D, Praharaj I, Kang G, Sharif S, Masroor Alam M, Shaukat S, Angez M, Khurshid A, Mahmood N, Arshad Y, Rehman L, Mujtaba G, Akthar R, Salman M, Klapsa D, Hajarha Y, Asghar H, Bandyopadhyay A, Rambaut A, Martin J, Grassly Net al., 2020, Rapid and sensitive direct detection and identification of poliovirus from stool and environmental surveillance samples using nanopore sequencing

<jats:title>Abstract</jats:title><jats:p>Global poliovirus surveillance involves virus isolation from stool and environmental samples, intratypic differential (ITD) by PCR and sequencing of the VP1 region to distinguish vaccine (Sabin), vaccine-derived and wild-type polioviruses and ensure an appropriate response. This cell-culture algorithm takes 2-3 weeks on average between sample receipt and sequencing. Direct detection of viral RNA using PCR allows faster detection but has traditionally faced challenges related to poor sensitivity and difficulties in sequencing common samples containing poliovirus and enterovirus mixtures. We present a nested PCR and nanopore sequencing protocol that allows rapid (&lt;3 days) and sensitive direct detection and sequencing of polioviruses in stool and environmental samples. We developed barcoded primers and a real-time analysis platform that generate accurate VP1 consensus sequences from multiplexed samples. The sensitivity and specificity compared with cell-culture were 90.9% (95% Confidence Interval: 75.7-98.1%) and 99.2% (95.5-100.0%) for wild-type 1 poliovirus, 92.5% (79.6-98.4%) and 98.7% (95.4-99.8%) for vaccine and vaccine-derived serotype 2 poliovirus, and 88.3% (81.2-93.5%) and 93.2% (88.6-96.3%) for Sabin 1 and 3 poliovirus alone or in mixtures when tested on 155 stool samples in Pakistan. Variant analysis of sequencing reads also allowed identification of polioviruses and enteroviruses in artificial mixtures and was able to distinguish complex mixtures of polioviruses in environmental samples. The median identity of consensus nanopore sequences with Sanger or Illumina sequences from the same samples was &gt;99.9%. This novel method shows promise as a faster and safer alternative to cell-culture for the detection and real-time sequencing of polioviruses in stool and environmental samples.</jats:p>

Journal article

Macklin GR, O'Reilly KM, Grassly NC, Edmunds WJ, Mach O, Krishnan RSG, Voorman A, Vertefeuille JF, Abdelwahab J, Gumede N, Goel A, Sosler S, Sever J, Bandyopadhyay AS, Pallansch MA, Nandy R, Mkanda P, Diop OM, Sutter RWet al., 2020, Evolving epidemiology of poliovirus serotype 2 following withdrawal of the serotype 2 oral poliovirus vaccine, Science, Vol: 368, Pages: 401-405, ISSN: 0036-8075

Although there have been no cases of serotype 2 wild poliovirus for more than 20 years, transmission of serotype 2 vaccine-derived poliovirus (VDPV2) and associated paralytic cases in several continents represent a threat to eradication. The withdrawal of the serotype 2 component of oral poliovirus vaccine (OPV2) was implemented in April 2016 to stop VDPV2 emergence and secure eradication of all serotype 2 poliovirus. Globally, children born after this date have limited immunity to prevent transmission. Using a statistical model, we estimated the emergence date and source of VDPV2s detected between May 2016 and November 2019. Outbreak response campaigns with monovalent OPV2 are the only available method to induce immunity to prevent transmission. Yet our analysis shows that using monovalent OPV2 is generating more paralytic VDPV2 outbreaks with the potential for establishing endemic transmission. A novel OPV2, for which two candidates are currently in clinical trials, is urgently required, together with a contingency strategy if this vaccine does not materialize or perform as anticipated.

Journal article

Grassly N, Pons Salort M, Parker E, White P, Ainslie K, Baguelin M, Bhatt S, Boonyasiri A, Boyd O, Brazeau N, Cattarino L, Ciavarella C, Cooper L, Coupland H, Cucunuba Perez Z, Cuomo-Dannenburg G, Dighe A, Djaafara A, Donnelly C, Dorigatti I, van Elsland S, Ferreira Do Nascimento F, Fitzjohn R, Fu H, Gaythorpe K, Geidelberg L, Green W, Hallett T, Hamlet A, Hayes S, Hinsley W, Imai N, Jorgensen D, Knock E, Laydon D, Lees J, Mangal T, Mellan T, Mishra S, Nedjati Gilani G, Nouvellet P, Okell L, Ower A, Parag K, Pickles M, Ragonnet-Cronin M, Stopard I, Thompson H, Unwin H, Verity R, Vollmer M, Volz E, Walker P, Walters C, Wang H, Wang Y, Watson O, Whittaker C, Whittles L, Winskill P, Xi X, Ferguson Net al., 2020, Report 16: Role of testing in COVID-19 control

The World Health Organization has called for increased molecular testing in response to the COVID-19 pandemic, but different countries have taken very different approaches. We used a simple mathematical model to investigate the potential effectiveness of alternative testing strategies for COVID-19 control. Weekly screening of healthcare workers (HCWs) and other at-risk groups using PCR or point-of-care tests for infection irrespective of symptoms is estimated to reduce their contribution to transmission by 25-33%, on top of reductions achieved by self-isolation following symptoms. Widespread PCR testing in the general population is unlikely to limit transmission more than contact-tracing and quarantine based on symptoms alone, but could allow earlier release of contacts from quarantine. Immunity passports based on tests for antibody or infection could support return to work but face significant technical, legal and ethical challenges. Testing is essential for pandemic surveillance but its direct contribution to the prevention of transmission is likely to be limited to patients, HCWs and other high-risk groups.

Report

Hamisu AW, Blake IM, Sume G, Braka F, Jimoh A, Dahiru H, Bonos M, Dankoli R, Ahmed BM, Yusuf KM, Lawal NM, Ahmed F, Aliyu Z, John D, Nwachukwu TE, Ayeni MF, Gumede-Moeletsi N, Veltsos P, Giri S, Praharaj I, Metilda A, Bandyopadhyay A, Diop OM, Grassly NCet al., 2020, Characterizing environmental surveillance sites in Nigeria and their sensitivity to detect poliovirus and other enteroviruses, The Journal of Infectious Diseases, Vol: 225, ISSN: 0022-1899

BackgroundEnvironmental surveillance (ES) for poliovirus is increasingly important for polio eradication, often detecting circulating virus before paralytic cases are reported. The sensitivity of ES depends on appropriate selection of sampling sites, which is difficult in low-income countries with informal sewage networks.MethodsWe measured ES site and sample characteristics in Nigeria during June 2018 - May 2019, including sewage physicochemical properties using a water-quality probe, flow volume, catchment population and local facilities such as hospitals, schools and transit hubs. We used mixed-effects logistic regression and machine-learning (random forests) to investigate their association with enterovirus isolation (poliovirus and non-polio enteroviruses) as an indicator of surveillance sensitivity.ResultsFour quarterly visits were made to 78 ES sites in 21 states of Nigeria, and ES site characteristic data matched to 1,345 samples with an average enterovirus prevalence among sites of 68% (range 9% to 100%). A larger estimated catchment population, high total dissolved solids and higher pH were associated with enterovirus detection. A random forests model predicted ‘good’ sites (enterovirus prevalence >70%) from measured site characteristics with out-of-sample sensitivity and specificity of 75%.ConclusionsSimple measurement of sewage properties and catchment population estimation could improve ES site selection and increase surveillance sensitivity.

Journal article

Babji S, Manickavasagam P, Chen Y-H, Jeyavelu N, Jose NV, Praharaj I, Syed C, Kaliappan SP, John J, Giri S, Venugopal S, Kampmann B, Parker EPK, Iturriza-Gómara M, Kang G, Grassly NC, Uhlig HHet al., 2020, Immune predictors of oral poliovirus vaccine immunogenicity among infants in South India., NPJ Vaccines, Vol: 5

Identification of the causes of poor oral vaccine immunogenicity in low-income countries might lead to more effective vaccines. We measured mucosal and systemic immune parameters at the time of vaccination with oral poliovirus vaccine (OPV) in 292 Indian infants aged 6-11 months, including plasma cytokines, leukocyte counts, fecal biomarkers of environmental enteropathy and peripheral blood T-cell phenotype, focused on gut-homing regulatory CD4+ populations. We did not find a distinct immune phenotype associated with OPV immunogenicity, although viral pathogens were more prevalent in stool at the time of immunization among infants who failed to seroconvert (63.9% vs. 45.6%, p = 0.002). Using a machine-learning approach, we could predict seroconversion a priori using immune parameters and infection status with a median 58% accuracy (cross-validation IQR: 50-69%) compared with 50% expected by chance. Better identification of immune predictors of OPV immunogenicity is likely to require sampling of mucosal tissue and improved oral poliovirus infection models.

Journal article

Grassly N, 2020, Immune predictors of oral poliovirus vaccine immunogenicity among infants in south India, npj Vaccines, Vol: 5, Pages: 1-8, ISSN: 2059-0105

Identification of the causes of poor oral vaccine immunogenicity in low-income countries might lead to more effective vaccines. We measured mucosal and systemic immune parameters at the time of vaccination with oral poliovirus vaccine (OPV) in 292 Indian infants aged 6–11 months, including plasma cytokines, leukocyte counts, fecal biomarkers of environmental enteropathy and peripheral blood T-cell phenotype, focused on gut-homing regulatory CD4+ populations. We did not find a distinct immune phenotype associated with OPV immunogenicity, although viral pathogens were more prevalent in stool at the time of immunization among infants who failed to seroconvert (63.9% vs. 45.6%, p = 0.002). Using a machine-learning approach, we could predict seroconversion a priori using immune parameters and infection status with a median 58% accuracy (cross-validation IQR: 50–69%) compared with 50% expected by chance. Better identification of immune predictors of OPV immunogenicity is likely to require sampling of mucosal tissue and improved oral poliovirus infection models.

Journal article

O'Reilly KM, Grassly NC, Allen DJ, Bannister-Tyrrell M, Cameron A, Martin AIC, Ramsay M, Pebody R, Zambon Met al., 2020, Surveillance optimisation to detect poliovirus in the pre-eradication era: a modelling study of England and Wales, EPIDEMIOLOGY AND INFECTION, Vol: 148, ISSN: 0950-2688

Journal article

Bronowski C, Parker EPK, Sindhu KNC, Praharaj I, Babji S, Chinyama E, Darby AC, Grassly N, Kang G, Iturriza-Gomara Met al., 2019, IMPACT OF THE GUT MICROBIOTA ON ROTAVIRUS VACCINE RESPONSE IN INDIAN, AFRICAN AND EUROPEAN INFANTS: A PROSPECTIVE COHORT STUDY, Publisher: OXFORD UNIV PRESS, Pages: S65-S66, ISSN: 0035-9203

Conference paper

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