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
to

134 results found

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

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

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

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

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

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

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

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

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

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

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