Imperial College London

ProfessorNicholasGrassly

Faculty of MedicineSchool of Public Health

Prof of Infectious Disease & Vaccine Epidemiology
 
 
 
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Contact

 

+44 (0)20 7594 3264n.grassly Website

 
 
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Location

 

G36Medical SchoolSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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128 results found

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

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, 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

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, 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, 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

O'Reilly KM, Grassly NC, Allen DJ, Bannister-Tyrrell M, Cameron A, Carrion Martin AI, Ramsay M, Pebody R, Zambon Met al., 2020, Surveillance Optimization to Detect Poliovirus in the Pre-Eradication Era: a Modelling Study of England and Wales., Epidemiol Infect, Pages: 1-28

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, 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

Flaxman S, Mishra S, Gandy A, Unwin H, Coupland H, Mellan T, Zhu H, Berah T, Eaton J, Perez Guzman P, Schmit N, Cilloni L, Ainslie K, Baguelin M, Blake I, Boonyasiri A, Boyd O, Cattarino L, Ciavarella C, Cooper L, Cucunuba Perez Z, Cuomo-Dannenburg G, Dighe A, Djaafara A, Dorigatti I, van Elsland S, Fitzjohn R, Fu H, Gaythorpe K, Geidelberg L, Grassly N, Green W, Hallett T, Hamlet A, Hinsley W, Jeffrey B, Jorgensen D, Knock E, Laydon D, Nedjati Gilani G, Nouvellet P, Parag K, Siveroni I, Thompson H, Verity R, Volz E, Walters C, Wang H, Wang Y, Watson O, Winskill P, Xi X, Whittaker C, Walker P, Ghani A, Donnelly C, Riley S, Okell L, Vollmer M, Ferguson N, Bhatt Set al., 2020, Report 13: Estimating the number of infections and the impact of non-pharmaceutical interventions on COVID-19 in 11 European countries

Following the emergence of a novel coronavirus (SARS-CoV-2) and its spread outside of China, Europe is now experiencing large epidemics. In response, many European countries have implemented unprecedented non-pharmaceutical interventions including case isolation, the closure of schools and universities, banning of mass gatherings and/or public events, and most recently, widescale social distancing including local and national lockdowns. In this report, we use a semi-mechanistic Bayesian hierarchical model to attempt to infer the impact of these interventions across 11 European countries. Our methods assume that changes in the reproductive number – a measure of transmission - are an immediate response to these interventions being implemented rather than broader gradual changes in behaviour. Our model estimates these changes by calculating backwards from the deaths observed over time to estimate transmission that occurred several weeks prior, allowing for the time lag between infection and death. One of the key assumptions of the model is that each intervention has the same effect on the reproduction number across countries and over time. This allows us to leverage a greater amount of data across Europe to estimate these effects. It also means that our results are driven strongly by the data from countries with more advanced epidemics, and earlier interventions, such as Italy and Spain. We find that the slowing growth in daily reported deaths in Italy is consistent with a significant impact of interventions implemented several weeks earlier. In Italy, we estimate that the effective reproduction number, Rt, dropped to close to 1 around the time of lockdown (11th March), although with a high level of uncertainty. Overall, we estimate that countries have managed to reduce their reproduction number. Our estimates have wide credible intervals and contain 1 for countries that have implemented all interventions considered in our analysis. This means that the reproducti

Report

Walker P, Whittaker C, Watson O, Baguelin M, Ainslie K, Bhatia S, Bhatt S, Boonyasiri A, Boyd O, Cattarino L, Cucunuba Perez Z, Cuomo-Dannenburg G, Dighe A, Donnelly C, Dorigatti I, van Elsland S, Fitzjohn R, Flaxman S, Fu H, Gaythorpe K, Geidelberg L, Grassly N, Green W, Hamlet A, Hauck K, Haw D, Hayes S, Hinsley W, Imai N, Jorgensen D, Knock E, Laydon D, Mishra S, Nedjati Gilani G, Okell L, Riley S, Thompson H, Unwin H, Verity R, Vollmer M, Walters C, Wang H, Wang Y, Winskill P, Xi X, Ferguson N, Ghani Aet al., 2020, Report 12: The global impact of COVID-19 and strategies for mitigation and suppression

The world faces a severe and acute public health emergency due to the ongoing COVID-19 global pandemic. How individual countries respond in the coming weeks will be critical in influencing the trajectory of national epidemics. Here we combine data on age-specific contact patterns and COVID-19 severity to project the health impact of the pandemic in 202 countries. We compare predicted mortality impacts in the absence of interventions or spontaneous social distancing with what might be achieved with policies aimed at mitigating or suppressing transmission. Our estimates of mortality and healthcare demand are based on data from China and high-income countries; differences in underlying health conditions and healthcare system capacity will likely result in different patterns in low income settings. We estimate that in the absence of interventions, COVID-19 would have resulted in 7.0 billion infections and 40 million deaths globally this year. Mitigation strategies focussing on shielding the elderly (60% reduction in social contacts) and slowing but not interrupting transmission (40% reduction in social contacts for wider population) could reduce this burden by half, saving 20 million lives, but we predict that even in this scenario, health systems in all countries will be quickly overwhelmed. This effect is likely to be most severe in lower income settings where capacity is lowest: our mitigated scenarios lead to peak demand for critical care beds in a typical low-income setting outstripping supply by a factor of 25, in contrast to a typical high-income setting where this factor is 7. As a result, we anticipate that the true burden in low income settings pursuing mitigation strategies could be substantially higher than reflected in these estimates. Our analysis therefore suggests that healthcare demand can only be kept within manageable levels through the rapid adoption of public health measures (including testing and isolation of cases and wider social distancing meas

Report

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

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

Macklin GR, Grassly NC, Sutter RW, Mach O, Bandyopadhyay AS, Edmunds WJ, O'Reilly KMet al., 2019, Vaccine schedules and the effect on humoral and intestinal immunity against poliovirus: a systematic review and network meta-analysis., Lancet Infectious Diseases, ISSN: 1473-3099

BACKGROUND: The eradication of wild and vaccine-derived poliovirus requires the global withdrawal of oral poliovirus vaccines (OPVs) and replacement with inactivated poliovirus vaccines (IPVs). The first phase of this effort was the withdrawal of the serotype 2 vaccine in April 2016, with a switch from trivalent OPVs to bivalent OPVs. The aim of our study was to produce comparative estimates of humoral and intestinal mucosal immunity associated with different routine immunisation schedules. METHODS: We did a random-effect meta-analysis with single proportions and a network meta-analysis in a Bayesian framework to synthesise direct and indirect data. We searched MEDLINE and the Cochrane Library Central Register of Controlled Trials for randomised controlled trials published from Jan 1, 1980, to Nov 1, 2018, comparing poliovirus immunisation schedules in a primary series. Only trials done outside western Europe or North America and without variation in age schedules (ie, age at administration of the vaccine) between study groups were included in the analyses, because trials in high-income settings differ in vaccine immunogenicity and schedules from other settings and to ensure consistency within the network of trials. Data were extracted directly from the published reports. We assessed seroconversion against poliovirus serotypes 1, 2, and 3, and intestinal immunity against serotype 2, measured by absence of shedding poliovirus after a challenge OPV dose. FINDINGS: We identified 437 unique studies; of them, 17 studies with a maximum of 8279 evaluable infants were eligible for assessment of humoral immunity, and eight studies with 4254 infants were eligible for intestinal immunity. For serotype 2, there was low between-trial heterogeneity in the data (τ=0·05, 95% credible interval [CrI] 0·009-0·15) and the risk ratio (RR) of seroconversion after three doses of bivalent OPVs was 0·14 (95% CrI 0·11-0·17) compared with three do

Journal article

Praharaj I, Parker EPK, Giri S, Allen D, Silas S, Revathi R, Kalliappan S, John J, Prasad J, Kampmann B, Iturriza-Gómara M, Grassly N, Kang Get al., 2019, Influence of nonpolio enteroviruses and the bacterial gut microbiota on oral poliovirus vaccine response: A study from south India, Journal of Infectious Diseases, Vol: 219, Pages: 1178-1186, ISSN: 0022-1899

BackgroundOral poliovirus vaccine (OPV) is less immunogenic in low- or middle-income than in high-income countries. We tested whether bacterial and viral components of the intestinal microbiota are associated with this phenomenon.MethodsWe assessed the prevalence of enteropathogens using TaqMan array cards 14 days before and at vaccination in 704 Indian infants (aged 6–11 months) receiving monovalent type 3 OPV (CTRI/2014/05/004588). Nonpolio enterovirus (NPEV) serotypes were identified by means of VP1 sequencing. In 120 infants, the prevaccination bacterial microbiota was characterized using 16S ribosomal RNA sequencing.ResultsWe detected 56 NPEV serotypes on the day of vaccination. Concurrent NPEVs were associated with a reduction in OPV seroconversion, consistent across species (odds ratio [95% confidence interval], 0.57 [.36–.90], 0.61 [.43–.86], and 0.69 [.41–1.16] for species A, B, and C, respectively). Recently acquired enterovirus infections, detected at vaccination but not 14 days earlier, had a greater interfering effect on monovalent type 3 OPV seroresponse than did persistent infections, with enterovirus detected at both time points (seroconversion in 44 of 127 infants [35%] vs 63 of 129 [49%]; P = .02). The abundance of specific bacterial taxa did not differ significantly according to OPV response, although the microbiota was more diverse in nonresponders at the time of vaccination.ConclusionEnteric viruses have a greater impact on OPV response than the bacterial microbiota, with recent enterovirus infections having a greater inhibitory effect than persistent infections.

Journal article

Church JA, Parker EP, Kirkpatrick BD, Grassly NC, Prendergast AJet al., 2019, Interventions to improve oral vaccine performance: a systematic review and meta-analysis, Lancet Infectious Diseases, Vol: 19, Pages: 203-214, ISSN: 1473-3099

BackgroundOral vaccines underperform in low-income and middle-income countries compared with in high-income countries. Whether interventions can improve oral vaccine performance is uncertain.MethodsWe did a systematic review and meta-analysis of interventions designed to increase oral vaccine efficacy or immunogenicity. We searched Ovid-MEDLINE and Embase for trials published until Oct 23, 2017. Inclusion criteria for meta-analysis were two or more studies per intervention category and available seroconversion data. We did random-effects meta-analyses to produce summary relative risk (RR) estimates. This study is registered with PROSPERO (CRD42017060608).FindingsOf 2843 studies identified, 87 were eligible for qualitative synthesis and 66 for meta-analysis. 22 different interventions were assessed for oral poliovirus vaccine (OPV), oral rotavirus vaccine (RVV), oral cholera vaccine (OCV), and oral typhoid vaccines. There was generally high heterogeneity. Seroconversion to RVV was significantly increased by delaying the first RVV dose by 4 weeks (RR 1·37, 95% CI 1·16–1·62) and OPV seroconversion was increased with monovalent or bivalent OPV compared with trivalent OPV (RR 1·51, 95% CI 1·20–1·91). There was some evidence that separating RVV and OPV increased RVV seroconversion (RR 1·21, 95% CI 1·00–1·47) and that higher vaccine inoculum improved OCV seroconversion (RR 1·12, 95% CI 1·00–1·26). There was no evidence of effect for anthelmintics, antibiotics, probiotics, zinc, vitamin A, withholding breastfeeding, extra doses, or vaccine buffering.InterpretationMost strategies did not improve oral vaccine performance. Delaying RVV and reducing OPV valence should be considered within immunisation programmes to reduce global enteric disease. New strategies to address the gap in oral vaccine efficacy are urgently required.

Journal article

Parker EPK, Whitfield H, Baskar C, Giri S, John J, Grassly N, Kang G, Praharaj Iet al., 2019, FUT2 secretor status is not associated with oral poliovirus vaccine immunogenicity in south Indian infants, Journal of Infectious Diseases, Vol: 219, Pages: 578-581, ISSN: 0022-1899

FUT2 determines whether histo-blood group antigens are secreted at mucosal surfaces. Secretor status influences susceptibility to enteric viruses, potentially including oral poliovirus vaccine (OPV). We performed a nested case–control study to determine the association between FUT2 genotype (single-nucleotide polymorphisms G428A, C302T, and A385T) and seroconversion among Indian infants who received a single dose of monovalent type 3 OPV. Secretor prevalence was 75% (89 of 118) in infants who seroconverted and 80% (97 of 122) in infants who did not seroconvert (odds ratio, 0.79; 95% confidence interval, .43–1.45). Our findings suggest that FUT2 genotype is not a key determinant of variation in OPV immunogenicity.

Journal article

Grassly NC, Wadood MZ, Safdar RM, Mahamud AS, Sutter RWet al., 2018, Effect of Inactivated Poliovirus Vaccine Campaigns, Pakistan, 2014-2017, EMERGING INFECTIOUS DISEASES, Vol: 24, Pages: 2113-2115, ISSN: 1080-6040

Journal article

Grassly NC, Orenstein WA, 2018, Securing the Eradication of All Polioviruses, CLINICAL INFECTIOUS DISEASES, Vol: 67, Pages: S1-S3, ISSN: 1058-4838

Journal article

Blake IM, Pons Salort M, Molodecky N, Diop O, Chenoweth P, Bandyopadhyay A, Zaffran M, Sutter R, Grassly Net al., 2018, Type 2 Poliovirus Detection After Global Withdrawal of Trivalent Oral Vaccine, New England Journal of Medicine, Vol: 379, Pages: 834-845, ISSN: 0028-4793

BackgroundMass campaigns with oral poliovirus vaccine (OPV) have brought the world close to the eradication of wild poliovirus. However, to complete eradication, OPV must itself be withdrawn to prevent outbreaks of vaccine-derived poliovirus (VDPV). Synchronized global withdrawal of OPV began with serotype 2 OPV (OPV2) in April 2016, which presented the first test of the feasibility of eradicating all polioviruses.MethodsWe analyzed global surveillance data on the detection of serotype 2 Sabin vaccine (Sabin-2) poliovirus and serotype 2 vaccine–derived poliovirus (VDPV2, defined as vaccine strains that are at least 0.6% divergent from Sabin-2 poliovirus in the viral protein 1 genomic region) in stool samples from 495,035 children with acute flaccid paralysis in 118 countries and in 8528 sewage samples from four countries at high risk for transmission; the samples were collected from January 1, 2013, through July 11, 2018. We used Bayesian spatiotemporal smoothing and logistic regression to identify and map risk factors for persistent detection of Sabin-2 poliovirus and VDPV2.ResultsThe prevalence of Sabin-2 poliovirus in stool samples declined from 3.9% (95% confidence interval [CI], 3.5 to 4.3) at the time of OPV2 withdrawal to 0.2% (95% CI, 0.1 to 2.7) at 2 months after withdrawal, and the detection rate in sewage samples declined from 71.0% (95% CI, 61.0 to 80.0) to 13.0% (95% CI, 8.0 to 20.0) during the same period. However, 12 months after OPV2 withdrawal, Sabin-2 poliovirus continued to be detected in stool samples (<0.1%; 95% CI, <0.1 to 0.1) and sewage samples (8.0%; 95% CI, 5.0 to 13.0) because of the use of OPV2 in response to VDPV2 outbreaks. Nine outbreaks were reported after OPV2 withdrawal and were associated with low coverage of routine immunization (odds ratio, 1.64 [95% CI, 1.14 to 2.54] per 10% absolute decrease) and low levels of population immunity (odds ratio, 2.60 [95% CI, 1.35 to 5.59] per 10% absolute decrease) within affected cou

Journal article

Pons Salort M, Grassly NC, 2018, Serotype-specific immunity explains the incidence of diseases caused by human enteroviruses, Science, Vol: 361, Pages: 800-803, ISSN: 0036-8075

Human enteroviruses are a major cause of neurological and other diseases. More than 100 serotypes are known that exhibit unexplained complex patterns of incidence, from regular cycles to more irregular patterns, and new emergences. Using 15 years of surveillance data from Japan (2000–2014) and a stochastic transmission model with accurate demography, we show that acquired serotype-specific immunity can explain the diverse patterns of 18 of the 20 most common serotypes (including Coxsackieviruses, Echoviruses, and Enterovirus-A71). The remaining two serotypes required a change in viral characteristics, including an increase in pathogenicity for Coxsackievirus-A6, which is consistent with its recent global rise in incidence. On the basis of our findings, we are able to predict outbreaks 2 years ahead of time (2015–2016). These results have implications for the impact of vaccines under development.

Journal article

Parker EPK, Grassly NC, 2018, Enhancing rotavirus vaccination: a microbial fix?, Cell Host and Microbe, Vol: 24, Pages: 195-196, ISSN: 1931-3128

Oral rotavirus vaccines have consistently underperformed in low-income countries. In this issue of Cell Host & Microbe,Harris et al. (2018b) explore whether vaccine response can be enhanced via antibiotic-mediated modification of the bacterial microbiota.

Journal article

Church JA, Parker EP, Kosek MN, Kang G, Grassly NC, Kelly P, Prendergast AJet al., 2018, Exploring the relationship between environmental enteric dysfunction and oral vaccine responses., Future Microbiology, Vol: 13, Pages: 1055-1070, ISSN: 1746-0913

Oral vaccines significantly underperform in low-income countries. One possible contributory factor is environmental enteric dysfunction (EED), a subclinical disorder of small intestinal structure and function among children living in poverty. Here, we review studies describing oral vaccine responses and EED. We identified eight studies evaluating EED and oral vaccine responses. There was substantial heterogeneity in study design and few consistent trends emerged. Four studies reported a negative association between EED and oral vaccine responses; two showed no significant association; and two described a positive correlation. Current evidence is therefore insufficient to determine whether EED contributes to oral vaccine underperformance. We identify roadblocks in the field and future research needs, including carefully designed studies those can investigate this hypothesis further.

Journal article

Grassly NC, 2018, Eradicating polio with a vaccine we must stop using, LANCET INFECTIOUS DISEASES, Vol: 18, Pages: 590-591, ISSN: 1473-3099

Journal article

Giri S, Kumar N, Dhanapal P, Venkatesan J, Kasirajan A, Iturriza-Gomara M, John J, Abraham AM, Grassly NC, Kang Get al., 2018, Quantity of Vaccine Poliovirus Shed Determines the Titer of the Serum Neutralizing Antibody Response in Indian Children Who Received Oral Vaccine, JOURNAL OF INFECTIOUS DISEASES, Vol: 217, Pages: 1395-1398, ISSN: 0022-1899

Replication of oral poliovirus vaccine (OPV) in the intestine (ie, vaccine take) is associated with seroconversion and protection against poliomyelitis. We used quantitative polymerase chain reaction analysis to measure vaccine shedding in 300 seronegative infants aged 6–11 months and in 218 children aged 1–4 years 7 days after administration of monovalent or bivalent OPV. We found that the quantity of shedding correlated with the magnitude of the serum neutralizing antibody response measured 21 or 28 days after vaccination. This suggests that the immune response to OPV is on a continuum, rather than an all-or-nothing phenomenon, that depends on efficient vaccine virus replication.

Journal article

O'Reilly KM, Grassly N, Verity R, 2018, Population sensitivity of acute flaccid paralysis and environmental surveillance for serotype 1 poliovirus in Pakistan: an observational study, BMC Infectious Diseases, Vol: 18, ISSN: 1471-2334

BackgroundTo support poliomyelitis eradication in Pakistan, environmental surveillance (ES) of wastewater has been expanded alongside surveillance for acute flaccid paralysis (AFP). ES is a relatively new method of surveillance, and the population sensitivity of detecting poliovirus within endemic settings requires estimation.MethodsData for wild serotype 1 poliovirus from AFP and ES from January 2011 to September 2015 from 14 districts in Pakistan were analysed using a multi-state model framework. This framework was used to estimate the sensitivity of poliovirus detection from each surveillance source and parameters such as the duration of infection within a community.ResultsThe location and timing of poliomyelitis cases showed spatial and temporal variability. The sensitivity of AFP surveillance to detect serotype 1 poliovirus infection in a district and its neighbours per month was on average 30.0% (95% CI 24.8–35.8) and increased with the incidence of poliomyelitis cases. The average population sensitivity of a single environmental sample was 59.4% (95% CI 55.4–63.0), with significant variation in site-specific estimates (median varied from 33.3–79.2%). The combined population sensitivity of environmental and AFP surveillance in a given month was on average 98.1% (95% CI 97.2–98.7), assuming four samples per month for each site.ConclusionsES can be a highly sensitive supplement to AFP surveillance in areas with converging sewage systems. As ES for poliovirus is expanded, it will be important to identify factors associated with variation in site sensitivity, leading to improved site selection and surveillance system performance.

Journal article

Pons-Salort M, Oberste MS, Pallansch MA, Abedi GR, Takahashi S, Grenfell BT, Grassly NCet al., 2018, The seasonality of nonpolio enteroviruses in the United States: Patterns and drivers, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 115, Pages: 3078-3083, ISSN: 0027-8424

Nonpolio enteroviruses are diverse and common viruses that can circulate year-round but tend to peak in summer. Although most infections are asymptomatic, they can result in a wide range of neurological and other diseases. Many serotypes circulate every year, and different serotypes predominate in different years, but the drivers of their geographical and temporal dynamics are not understood. We use national enterovirus surveillance data collected by the US Centers for Disease Control and Prevention during 1983−2013, as well as demographic and climatic data for the same period, to study the patterns and drivers of the seasonality of these infections. We find that the seasonal pattern of enterovirus cases is spatially structured in the United States and similar to that observed for historical prevaccination poliomyelitis (1931−1954). We identify latitudinal gradients for the amplitude and the timing of the peak of cases, meaning that those are more regularly distributed all year-round in the south and have a more pronounced peak that arrives later toward the north. The peak is estimated to occur between July and September across the United States, and 1 month earlier than that for historical poliomyelitis. Using mixed-effects models, we find that climate, but not demography, is likely to drive the seasonal pattern of enterovirus cases and that the dew point temperature alone explains ∼30% of the variation in the intensity of transmission. Our study contributes to a better understanding of the epidemiology of enteroviruses, demonstrates important similarities in their circulation dynamics with polioviruses, and identifies potential drivers of their seasonality.

Journal article

Imran H, Raja D, Grassly N, Wadood MZ, Safdarq RM, O'Reilly KMet al., 2018, Routine immunization in Pakistan: comparison of multiple data sources and identification of factors associated with vaccination, International Health, Vol: 10, Pages: 84-91, ISSN: 1876-3405

BackgroundWithin Pakistan, estimates of vaccination coverage with the pentavalent vaccine, oral polio vaccine (OPV) and measles vaccine (MV) in 2011 were reported to be 74%, 75% and 53%, respectively. These national estimates may mask regional variation. The reasons for this variation have not been explored.MethodsData from the Multiple Indicator Cluster Surveys (MICS) for Balochistan and Punjab (2010–2011) are analysed to examine factors associated with receiving three or more doses of the pentavalent vaccine and one or more MVs using regression modelling. Pentavalent and OPV estimates from the MICS were compared to vaccine dose histories from surveillance for acute flaccid paralysis (AFP; poliomyelitis) to ascertain agreement.ResultsAdjusted coverage of children 12–23 months of age were estimated to be 16.0%, 75.5% and 34.2% in Balochistan and 58.0%, 87.7% and 72.6% in Punjab for the pentavalent vaccine, OPV and MV, respectively. Maternal education, healthcare utilization and wealth were associated with receiving the pentavalent vaccine and the MV. There was a strong correlation of district estimates of vaccination coverage between AFP and MICS data, but AFP estimates of pentavalent coverage in Punjab were biased toward higher values.ConclusionsNational estimates mask variation and estimates from individual surveys should be considered alongside other estimates. The development of strategies targeted towards poorly educated parents within low-wealth quintiles that may not typically access healthcare could improve vaccination rates.

Journal article

Parker EPK, Ramani S, Lopman BA, Church JA, Iturriza-Gómara M, Prendergast A, Grassly NCet al., 2017, Causes of impaired oral vaccine efficacy in developing countries, Future Microbiology, Vol: 13, Pages: 97-118, ISSN: 1746-0913

Oral vaccines are less immunogenic when given to infants in low-income compared with high-income countries, limiting their potential public health impact. Here, we review factors that might contribute to this phenomenon, including transplacental antibodies, breastfeeding, histo blood group antigens, enteric pathogens, malnutrition, microbiota dysbiosis, and environmental enteropathy. We highlight several clear risk factors for vaccine failure, such as the inhibitory effect of enteroviruses on oral poliovirus vaccine. We also highlight the ambiguous and at times contradictory nature of the available evidence, which undoubtedly reflects the complex and interconnected nature of the factors involved. Mechanisms responsible for diminished immunogenicity may be specific to each oral vaccine. Interventions aiming to improve vaccine performance may need to reflect the diversity of these mechanisms.

Journal article

Parker EPK, Praharaj I, Zekavati A, Lazarus RP, Giri S, Operario DJ, Liu J, Iturriza-Gómara M, Kampmann B, John J, Kang G, Grassly NCet al., 2017, Influence of the intestinal microbiota on the immunogenicity of oral rotavirus vaccine given to infants in south India, Vaccine, Vol: 36, Pages: 264-272, ISSN: 0264-410X

Oral rotavirus vaccines have consistently proven to be less immunogenic among infants in developing countries. Discrepancies in the intestinal microbiota, including a greater burden of enteropathogens and an altered commensal community composition, may contribute to this trend by inhibiting the replication of vaccine viruses. To test this possibility, we performed a nested case–control study in Vellore, India, in which we compared the intestinal microbiota of infants who responded serologically or not after two doses of Rotarix delivered at 6 and 10 weeks of age as part of a clinical trial (CTRI/2012/05/002677). The prevalence of 40 bacterial, viral, and eukaryotic pathogen targets was assessed in pre-vaccination stool samples from 325 infants using singleplex real-time PCR on a Taqman array card (TAC). In a subset of 170 infants, we assessed bacterial microbiota composition by sequencing the 16S rRNA gene V4 region. Contrary to expectations, responders were more likely than non-responders to harbor ≥1 bacterial enteropathogen at dose 1 (26% [40/156] vs 13% [21/157] of infants with TAC results who completed the study per protocol; χ2, P = .006), although this was not apparent at dose 2 (24% [38/158] vs 23% [36/158]; P = .790). Rotavirus shedding after dose 1 was negatively correlated with the replication of co-administered oral poliovirus vaccine (OPV). We observed no consistent differences in composition or diversity of the 16S bacterial microbiota according to serological response, although rotavirus shedding was associated with slightly more bacterial taxa pre-vaccination. Overall, our findings demonstrate an inhibitory effect of co-administered OPV on the first dose of Rotarix, consistent with previous studies, but in the context of OPV co-administration we did not find a strong association between other components of the intestinal microbiota at the time of vaccination and Rotarix immunogenicity.

Journal article

Lazarus RP, John J, Shanmugasundaram E, Rajan AK, Thiagarajan S, Giri S, Babji S, Sarkar R, Kaliappan PS, Venugopal S, Praharaj I, Raman U, Paranjpe M, Grassly NC, Parker EPK, Parashar UD, Tate JE, Fleming JA, Steele AD, Muliyil J, Abraham AM, Kang Get al., 2017, The effect of probiotics and zinc supplementation on the immune response to oral rotavirus vaccine: A randomized, factorial design, placebo-controlled study among Indian infants, Vaccine, Vol: 36, Pages: 273-279, ISSN: 0264-410X

BackgroundStrategies are needed to improve oral rotavirus vaccine (RV), which provides suboptimal protection in developing countries. Probiotics and zinc supplementation could improve RV immunogenicity by altering the intestinal microbiota and immune function.MethodsInfants 5 weeks old living in urban Vellore, India were enrolled in a randomized, double-blind, placebo-controlled trial with a 4-arm factorial design to assess the effects of daily zinc (5 mg), probiotic (1010 Lactobacillus rhamnosus GG) or placebo on the immunogenicity of two doses of RV (Rotarix®, GlaxoSmithKline Biologicals) given at 6 and 10 weeks of age. Infants were eligible for participation if healthy, available for the study duration and without prior receipt of RV or oral poliovirus vaccine other than the birth dose. The primary outcome was seroconversion to rotavirus at 14 weeks of age based on detection of VP6-specific IgA at ≥20 U/ml in previously seronegative infants or a fourfold rise in concentration.ResultsThe study took place during July 2012 to February 2013. 620 infants were randomized equally between study arms and 551 (88.9%) completed per protocol. Seroconversion was recorded in 54/137 (39.4%), 42/136 (30.9%), 40/143 (28.0%), and 37/135 (27.4%) infants receiving (1) probiotic and zinc, (2) probiotic and placebo, (3) placebo and zinc, (4) two placebos. Seroconversion showed a modest improvement among infants receiving probiotic (difference between groups 1, 2 and 3, 4 was 7.5% (97.5% Confidence Interval (CI): −1.4%, 16.2%), p = 0.066) but not zinc (difference between groups 1, 3 and 2, 4 was 4.4% (97.5% CI: −4.4%, 13.2%), p = 0.272). 16 serious adverse events were recorded, none related to study interventions.ConclusionsZinc or probiotic supplementation did not significantly improve the low immunogenicity of rotavirus vaccine given to infants in a poor urban community in India. A modest effect of combined supplementation deserves further investigation.

Journal article

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