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
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114 results found

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

Parker EPK, Praharaj I, Giri S, Allen D, Silas S, Revathi R, Kalliappan S, John J, Prasad J, Kampmann B, Iturriza-Gómara M, Grassly N, Kang Get al., 2018, Influence of nonpolio enteroviruses and the bacterial gut microbiota on oral poliovirus vaccine response: A study from south India, Journal of Infectious Diseases, 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., 2018, FUT2 secretor status is not associated with oral poliovirus vaccine immunogenicity in south Indian infants, Journal of Infectious Diseases, 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

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

Parker EPK, Praharaj I, John J, Kaliappan SP, Kampmann B, Kang G, Grassly NCet al., 2017, Changes in the intestinal microbiota following the administration of azithromycin in a randomised placebo-controlled trial among infants in south India, Scientific Reports, Vol: 7, ISSN: 2045-2322

Macrolides are among the most widely prescribed antibiotics worldwide. However, their impact on the gut’s bacterial microbiota remains uncertain. We characterised the intestinal microbiota in 6–11 month-old infants in India who received a 3-day course of azithromycin or placebo during a randomised trial of oral poliovirus vaccine immunogenicity (CTRI/2014/05/004588). In 60 infants per study arm, we sequenced the V4 region of the bacterial 16S rRNA gene in stool samples collected before and 12 days after finishing treatment. We also tested for the presence of common bacterial, viral, and eukaryotic enteropathogens in the same samples using real-time PCR in a Taqman array card (TAC) format. Azithromycin induced a modest decline in microbiota richness and a shift in taxonomic composition driven by a reduction in the relative abundance of Proteobacteria and Verrucomicrobia (specifically Akkermansia muciniphila). The former phylum includes pathogenic strains of Escherichia coli and Campylobacter spp. that declined in prevalence based on the TAC assay. These findings differ from previous observations among older children and adults in Europe and North America, suggesting that the effects of azithromycin on the bacterial flora may be specific to the age and geographic setting of its recipients.

Journal article

Li LM, Grassly NC, Fraser C, 2017, Quantifying Transmission Heterogeneity Using Both Pathogen Phylogenies and Incidence Time Series., Molecular Biology and Evolution, Vol: 34, Pages: 2982-2995, ISSN: 1537-1719

Heterogeneity in individual-level transmissibility can be quantified by the dispersion parameter k of the offspring distribution. Quantifying heterogeneity is important as it affects other parameter estimates, it modulates the degree of unpredictability of an epidemic, and it needs to be accounted for in models of infection control. Aggregated data such as incidence time series are often not sufficiently informative to estimate k. Incorporating phylogenetic analysis can help to estimate k concurrently with other epidemiological parameters. We have developed an inference framework that uses particle Markov Chain Monte Carlo to estimate k and other epidemiological parameters using both incidence time series and the pathogen phylogeny. Using the framework to fit a modified compartmental transmission model that includes the parameter k to simulated data, we found that more accurate and less biased estimates of the reproductive number were obtained by combining epidemiological and phylogenetic analyses. However, k was most accurately estimated using pathogen phylogeny alone. Accurately estimating k was necessary for unbiased estimates of the reproductive number, but it did not affect the accuracy of reporting probability and epidemic start date estimates. We further demonstrated that inference was possible in the presence of phylogenetic uncertainty by sampling from the posterior distribution of phylogenies. Finally, we used the inference framework to estimate transmission parameters from epidemiological and genetic data collected during a poliovirus outbreak. Despite the large degree of phylogenetic uncertainty, we demonstrated that incorporating phylogenetic data in parameter inference improved the accuracy and precision of estimates.

Journal article

Molodecky NAL, Blake IM, O'reilly KM, Wadood MZ, Safdar RM, Wesolowski A, Buckee CO, Bandyopadhyay AS, Okayasu H, Grassly NCet al., 2017, Risk-factors and short-term projections for serotype-1 poliomyelitis incidence in Pakistan: a spatio-temporal analysis, Plos Medicine, Vol: 14, ISSN: 1549-1676

BackgroundPakistan currently provides a substantial challenge to global polio eradication, having contributed to 73% of reported poliomyelitis in 2015 and 54% in 2016. A better understanding of the risk factors and movement patterns that contribute to poliovirus transmission across Pakistan would support evidence-based planning for mass vaccination campaigns.Methods and findingsWe fit mixed-effects logistic regression models to routine surveillance data recording the presence of poliomyelitis associated with wild-type 1 poliovirus in districts of Pakistan over 6-month intervals between 2010 to 2016. To accurately capture the force of infection (FOI) between districts, we compared 6 models of population movement (adjacency, gravity, radiation, radiation based on population density, radiation based on travel times, and mobile-phone based). We used the best-fitting model (based on the Akaike Information Criterion [AIC]) to produce 6-month forecasts of poliomyelitis incidence. The odds of observing poliomyelitis decreased with improved routine or supplementary (campaign) immunisation coverage (multivariable odds ratio [OR] = 0.75, 95% confidence interval [CI] 0.67–0.84; and OR = 0.75, 95% CI 0.66–0.85, respectively, for each 10% increase in coverage) and increased with a higher rate of reporting non-polio acute flaccid paralysis (AFP) (OR = 1.13, 95% CI 1.02–1.26 for a 1-unit increase in non-polio AFP per 100,000 persons aged <15 years). Estimated movement of poliovirus-infected individuals was associated with the incidence of poliomyelitis, with the radiation model of movement providing the best fit to the data. Six-month forecasts of poliomyelitis incidence by district for 2013–2016 showed good predictive ability (area under the curve range: 0.76–0.98). However, although the best-fitting movement model (radiation) was a significant determinant of poliomyelitis incidence, it did not improve the predictive ability of the multivariable mo

Journal article

O'Reilly KM, Lamoureux C, Molodecky NA, Lyons H, Grassly NC, Tallis Get al., 2017, An assessment of the geographical risks of wild and vaccine-derived poliomyelitis outbreaks in Africa and Asia, BMC Infectious Diseases, Vol: 17, ISSN: 1471-2334

BackgroundThe international spread of wild poliomyelitis outbreaks continues to threaten eradication of poliomyelitis and in 2014 a public health emergency of international concern was declared. Here we describe a risk scoring system that has been used to assess country-level risks of wild poliomyelitis outbreaks, to inform prioritisation of mass vaccination planning, and describe the change in risk from 2014 to 2016. The methods were also used to assess the risk of emergence of vaccine-derived poliomyelitis outbreaks.MethodsPotential explanatory variables were tested against the reported outbreaks of wild poliomyelitis since 2003 using multivariable regression analysis. The regression analysis was translated to a risk score and used to classify countries as Low, Medium, Medium High and High risk, based on the predictive ability of the score.ResultsIndicators of population immunity, population displacement and diarrhoeal disease were associated with an increased risk of both wild and vaccine-derived outbreaks. High migration from countries with wild cases was associated with wild outbreaks. High birth numbers were associated with an increased risk of vaccine-derived outbreaks.ConclusionsUse of the scoring system is a transparent and rapid approach to assess country risk of wild and vaccine-derived poliomyelitis outbreaks. Since 2008 there has been a steep reduction in the number of wild poliomyelitis outbreaks and the reduction in countries classified as High and Medium High risk has reflected this. The risk of vaccine-derived poliomyelitis outbreaks has varied geographically. These findings highlight that many countries remain susceptible to poliomyelitis outbreaks and maintenance or improvement in routine immunisation is vital.

Journal article

Sindhu KNC, Cunliffe N, Peak M, Turner M, Darby A, Grassly N, Gordon M, Dube Q, Babji S, Praharaj I, Verghese V, Iturriza-Gomara M, Kang Get al., 2017, Impact of maternal antibodies and infant gut microbiota on the immunogenicity of rotavirus vaccines in African, Indian and European infants: protocol for a prospective cohort study, BMJ Open, Vol: 7, ISSN: 2044-6055

Introduction Gastroenteritis is the leading cause of morbidity and mortality among young children living in resource-poor settings, majority of which is attributed to rotavirus. Rotavirus vaccination can therefore have a significant impact on infant mortality. However, rotavirus vaccine efficacy in Sub-Saharan Africa and Southeast Asia is significantly lower than in high-income countries. Maternally derived antibodies, infant gut microbiota and concomitant oral polio vaccination have been proposed as potential reasons for poor vaccine performance in low-income settings. The overall aim of this study is to compare the role of maternally derived antibodies and infant gut microbiota in determining immune response to rotavirus vaccine in high-income and low-income settings, using the same vaccine and a similar study protocol.Methods and analysis The study is an observational cohort in three countries—Malawi, India and UK. Mothers will be enrolled in third trimester of pregnancy and followed up, along with infants after delivery, until the infant completes two doses of oral rotavirus vaccine (along with routine immunisation). The levels of prevaccination maternally derived rotavirus-specific antibodies (IgG) will be correlated with infant seroconversion and antibody titres, 4 weeks after the second dose of rotavirus vaccine. Both within-country and between-country comparisons of gut microbiome will be carried out between children who seroconvert and those who do not. The impact of oral polio vaccine coadministration on rotavirus vaccine response will be studied in Indian infants.Ethics and dissemination Ethical approvals have been obtained from Integrated Research Application System (IRAS, NHS ethics) in UK, College of Medicine Research and Ethics Committee (COMREC) in Malawi and Institutional Review Board (IRB), Christian Medical College, Vellore in India. Participant recruitment and follow-up is ongoing at all three sites. Analysis of data, followed by publicatio

Journal article

John J, Giri S, Karthikeyan AS, Lata D, Jeyapaul S, Rajan AK, Kumar N, Dhanapal P, Venkatesan J, Mani M, Hanusha J, Raman U, Moses PD, Abraham A, Bahl S, Bandyopadhyay AS, Ahmad M, Grassly NC, Kang Get al., 2016, The duration of intestinal immunity after an inactivated poliovirus vaccine booster dose in children immunized with oral vaccine: a randomized controlled trial, Journal of Infectious Diseases, Vol: 215, Pages: 529-536, ISSN: 0022-1899

Background.In 2014, 2 studies showed that inactivated poliovirus vaccine (IPV) boosts intestinal immunity in children previously immunized with oral poliovirus vaccine (OPV). As a result, IPV was introduced in mass campaigns to help achieve polio eradication.Methods.We conducted an open-label, randomized, controlled trial to assess the duration of the boost in intestinal immunity following a dose of IPV given to OPV-immunized children. Nine hundred healthy children in Vellore, India, aged 1–4 years were randomized (1:1:1) to receive IPV at 5 months (arm A), at enrollment (arm B), or no vaccine (arm C). The primary outcome was poliovirus shedding in stool 7 days after bivalent OPV challenge at 11 months.Results.For children in arms A, B, and C, 284 (94.7%), 297 (99.0%), and 296 (98.7%), respectively, were eligible for primary per-protocol analysis. Poliovirus shedding 7 days after challenge was less prevalent in arms A and B compared with C (24.6%, 25.6%, and 36.4%, respectively; risk ratio 0.68 [95% confidence interval: 0.53–0.87] for A versus C, and 0.70 [0.55–0.90] for B versus C).Conclusions.Protection against poliovirus remained elevated 6 and 11 months after an IPV boost, although at a lower level than reported at 1 month.

Journal article

Sarkar R, Rose A, Mohan VR, Ajjampur SSR, Veluswamy V, Srinivasan R, Muliyil J, Rajshekhar V, George K, Balraj V, Grassly NC, Anderson RM, Brooker SJ, Kang Get al., 2016, Study design and baseline results of an open-label cluster randomized community-intervention trial to assess the effectiveness of a modified mass deworming program in reducing hookworm infection in a tribal population in southern India, Contemporary Clinical Trials Communications, Vol: 5, Pages: 49-55, ISSN: 2451-8654

Introduction: Hookworm infection is a leading cause of iron deficiency anemia and malnutrition inresource-poor settings. Periodic mass deworming with anthelminthic drugs remains the cornerstone ofhookworm control efforts worldwide. Reinfection following treatment occurs, reflecting the humanhost's inability to acquire immunity following exposure to an untreated reservoir of infection. Thiscluster randomized trial will evaluate the effectiveness of a modified, population-based, massdeworming strategy in reducing hookworm infection in an endemic southern Indian population.Methods: Forty five tribal villages were randomized into three groups: one received annual treatment;the second received two rounds of treatment at 1-month intervals; and the third received four rounds oftreatment e two rounds 1 month apart at the beginning, followed by another two after 6 months. Stoolsamples collected through cross-sectional parasitological surveys pre- and post-intervention, and at 3-monthly intervals for a period of 1 year were tested for presence of hookworm ova. Long-term effectivenessof treatment will be assessed through another survey conducted 2 years after the last treatmentcycle.Results: From a population of 11,857 individuals, 8681 (73.2%) were found to be eligible and consented toparticipate, out-migration being the primary reason for non-participation. Baseline stool samples wereobtained from 2082 participants, with 18.5% having hookworm infection, although majority were lowintensity infections (<2000 eggs per gram of feces).Discussion: This study will help identify the optimal mass deworming strategy that can achieve thegreatest impact in the shortest period of time, particularly in settings where long-term program sustainabilityis a challenge

Journal article

Shirreff G, Wadood MZ, Vaz RG, Sutter RW, Grassly NCet al., 2016, Estimated Effect of Inactivated Poliovirus Vaccine Campaigns, Nigeria and Pakistan, January 2014-April 2016, Emerging Infectious Diseases, Vol: 23, Pages: 258-263, ISSN: 1080-6040

In 2014, inactivated poliovirus vaccine (IPV) campaigns were implemented in Nigeria and Pakistan after clinical trials showed that IPV boosts intestinal immunity in children previously given oral poliovirus vaccine (OPV). We estimated the effect of these campaigns by using surveillance data collected during January 2014–April 2016. In Nigeria, campaigns with IPV and trivalent OPV (tOPV) substantially reduced the incidence of poliomyelitis caused by circulating serotype-2 vaccine–derived poliovirus (incidence rate ratio [IRR] 0.17 for 90 days after vs. 90 days before campaigns, 95% CI 0.04–0.78) and the prevalence of virus in environmental samples (prevalence ratio [PR] 0.16, 95% CI 0.02–1.33). Campaigns with tOPV alone resulted in similar reductions (IRR 0.59, 95% CI 0.18–1.97; PR 0.45, 95% CI 0.21–0.95). In Pakistan, the effect of IPV+tOPV campaigns on wild-type poliovirus was not significant. Results suggest that administration of IPV alongside OPV can decrease poliovirus transmission if high vaccine coverage is achieved.

Journal article

Pons-Salort M, Molodecky NA, O'Reilly KM, Wadood MZ, Safdar RM, Etsano A, Vaz RG, Jafari H, Grassly NC, Blake IMet al., 2016, Population immunity against serotype-2 poliomyelitis Leading up to the global withdrawal of the oral poliovirus vaccine: spatio-temporal modelling of surveillance data, Plos Medicine, Vol: 13, ISSN: 1549-1676

BackgroundGlobal withdrawal of serotype-2 oral poliovirus vaccine (OPV2) took place in April 2016. This marked a milestone in global polio eradication and was a public health intervention of unprecedented scale, affecting 155 countries. Achieving high levels of serotype-2 population immunity before OPV2 withdrawal was critical to avoid subsequent outbreaks of serotype-2 vaccine-derived polioviruses (VDPV2s).Methods and FindingsIn August 2015, we estimated vaccine-induced population immunity against serotype-2 poliomyelitis for 1 January 2004–30 June 2015 and produced forecasts for April 2016 by district in Nigeria and Pakistan. Population immunity was estimated from the vaccination histories of children <36 mo old identified with non-polio acute flaccid paralysis (AFP) reported through polio surveillance, information on immunisation activities with different oral poliovirus vaccine (OPV) formulations, and serotype-specific estimates of the efficacy of these OPVs against poliomyelitis. District immunity estimates were spatio-temporally smoothed using a Bayesian hierarchical framework. Coverage estimates for immunisation activities were also obtained, allowing for heterogeneity within and among districts. Forward projections of immunity, based on these estimates and planned immunisation activities, were produced through to April 2016 using a cohort model.Estimated population immunity was negatively correlated with the probability of VDPV2 poliomyelitis being reported in a district. In Nigeria and Pakistan, declines in immunity during 2008–2009 and 2012–2013, respectively, were associated with outbreaks of VDPV2. Immunity has since improved in both countries as a result of increased use of trivalent OPV, and projections generally indicated sustained or improved immunity in April 2016, such that the majority of districts (99% [95% uncertainty interval 97%–100%] in Nigeria and 84% [95% uncertainty interval 77%–91%] in Pakistan) had >70

Journal article

Mangal TD, Aylward RB, Shuaib F, Mwanza M, Pate MA, Abanida E, Grasslyl NCet al., 2016, Spatial dynamics and high risk transmission pathways of poliovirus in Nigeria 2001-2013, PLOS ONE, Vol: 11, Pages: 1-14, ISSN: 1932-6203

The polio eradication programme in Nigeria has been successful in reducing incidence to just six confirmed cases in 2014 and zero to date in 2015, but prediction and management of future outbreaks remains a concern. A Poisson mixed effects model was used to describe poliovirus spread between January 2001 and November 2013, incorporating the strength of connectivity between districts (local government areas, LGAs) as estimated by three models of human mobility: simple distance, gravity and radiation models. Potential explanatory variables associated with the case numbers in each LGA were investigated and the model fit was tested by simulation. Spatial connectivity, the number of non-immune children under five years old, and season were associated with the incidence of poliomyelitis in an LGA (all P < 0.001). The best-fitting spatial model was the radiation model, outperforming the simple distance and gravity models (likelihood ratio test P < 0.05), under which the number of people estimated to move from an infected LGA to an uninfected LGA was strongly associated with the incidence of poliomyelitis in that LGA. We inferred transmission networks between LGAs based on this model and found these to be highly local, largely restricted to neighbouring LGAs (e.g. 67.7% of secondary spread from Kano was expected to occur within 10 km). The remaining secondary spread occurred along routes of high population movement. Poliovirus transmission in Nigeria is predominantly localised, occurring between spatially contiguous areas. Outbreak response should be guided by knowledge of high-probability pathways to ensure vulnerable children are protected.

Journal article

Parker EPK, Grassly NC, 2016, Unravelling mucosal immunity to poliovirus, The Lancet Infectious Diseases, Vol: 16, Pages: 1310-1311, ISSN: 1474-4457

Journal article

Kaliappan SP, Venugopal S, Giri S, Praharaj I, Karthikeyan AS, Babji S, John J, Muliyil J, Grassly N, Kang Get al., 2016, Factors determining anti-poliovirus type 3 antibodies among orally immunised Indian infants, Vaccine, Vol: 34, Pages: 4979-4984, ISSN: 1873-2518

BackgroundAmong the three poliovirus serotypes, the lowest responses after vaccination with trivalent oral polio vaccine (tOPV) are to serotype 3. Although improvements in routine immunisation and supplementary immunisation activities have greatly increased vaccine coverage, there are limited data on antibody prevalence in Indian infants.MethodsChildren aged 5–11 months with a history of not having received inactivated polio vaccine were screened for serum antibodies to poliovirus serotype 3 (PV3) by a micro-neutralisation assay according to a modified World Health Organization (WHO) protocol. Limited demographic information was collected to assess risk-factors for a lack of protective antibodies. Student’s t-test, logistic regression and multilevel logistic regression (MLR) model were used to estimate model parameters.ResultsOf 8454 children screened at a mean age of 8.3 (standard deviation [SD]-1.8) months, 88.1% (95% confidence interval (CI): 87.4–88.8) had protective antibodies to PV3. The number of tOPV doses received was the main determinant of seroprevalence; the maximum likelihood estimate yields a 37.7% (95% CI: 36.2–38.3) increase in seroprevalence per dose of tOPV. In multivariable logistic regression analysis increasing age, male sex, and urban residence were also independently associated with seropositivity (Odds Ratios (OR): 1.17 (95% CI: 1.12–1.23) per month of age, 1.27 (1.11–1.46) and 1.24 (1.05–1.45) respectively).ConclusionSeroprevalence of antibodies to PV3 is associated with age, gender and place of residence, in addition to the number of tOPV doses received. Ensuring high coverage and monitoring of response are essential as long as oral vaccines are used in polio eradication.

Journal article

Parker EPK, Grassly NC, 2016, Polio vaccination: preparing for a change of routine (vol 388, pg 107, 2016), LANCET, Vol: 388, Pages: E2-E2, ISSN: 0140-6736

Journal article

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