Biology subjects

Nokes, D. J.

Publications and source records attributed to Nokes, D. J..

5 recordsLinked to original sources

bioRxiv2021

Phylogenomic analysis of Uganda influenza type-A viruses to assess their relatedness to the vaccine strains and other Africa viruses: a molecular epidemiology study.

BackgroundGenetic characterisation of circulating influenza viruses is essential for vaccine selection and mitigation of viral transmission. The current scantiness of viral genomic data and underutilisation of advanced molecular analysis methods on influenza viruses circulating in Africa has limited their extensive study and representation in the global influenza ecology. We aimed to sequence influenza type-A viruses (IAVs) that previously circulated in Uganda and characterised their genetic relatedness to the vaccine viruses and publicly available Africa IAVs. MethodsThis was an observational study nested to the Uganda national influenza surveillance programme. We used Next-generation sequencing to locally generate genomes from 116 A(H1N1)pdm09 and 118 A(H3N2) viruses collected between 2010 and 2018 from 7 districts across Uganda. A total of 206 hemagglutinin (HA), 207 neuraminidase (NA), and 213 matrix protein (MP) sequences were genetically compared to the WHO-recommended vaccines and other viruses isolated from Africa since 1994. Viral temporal and spatial divergence and circulating genetic clades were characterised using phylogenetic methods. FindingsWe successfully generated gene sequences for 91{middle dot}9% (215/234) viruses. Uganda A(H1N1)pdm09 and A(H3N2) virus HA, NA, and MP proteins had 96{middle dot}36-99{middle dot}09%, 96{middle dot}49-99{middle dot}39%, and 97{middle dot}48-99{middle dot}95% amino acid similarity, respectively, to vaccines recommended from 2010 through 2020. The local viruses incorporated amino acid substitutions (AAS) in their antigenic, receptor binding, and glycosylation sites each year causing them to antigenically drift away from vaccines. For seasons when vaccine formulations differed, Uganda IAV antigenic sites had 1-2 extra AAS relative to the Southern than Northern hemisphere vaccine viruses. All Uganda IAVs carried the adamantine-resistance marker S31N but not the neuraminidase inhibitor (NAI) resistance markers H274Y and H275Y. However, some A(H1N1)pdm09 viruses had permissive substitutions V234I, N369K, and V241I typical of NAI-resistant viruses. The 2017-2018 A(H1N1)pdm09 viruses belonged to global genetic clade 6B.1, while the A(H3N2) viruses isolated in 2017 belonged to clades 3C.2a and 3C.3a. Uganda IAVs obtained before 2016 clustered distinctly from other Africa viruses while later viruses mixed with other Africa, especially Kenya and Congo, and global viruses. Several unique viral lineages (bootstrap >90) persisted in Uganda and other countries for 1-3 years. InterpretationThe study reveals Uganda as part of the global influenza ecology with continuous importation, antigenic drift, and extensive local transmission of IAVs, presenting a potential risk of future outbreaks. For a country with limited health resources and where social distancing is not sustainable, viral prevention by vaccination should be prioritized. The notable viral diversity in Africa is a warning to countries to broaden and incorporate genome analysis in routine surveillance to monitor circulating and detect new viruses. This knowledge can inform virus selection for vaccine production and assist in developing cost-effective virus control strategies. FundingThis work was supported by the Makerere University-Uganda Virus Research Institute Centre of Excellence for Infection and Immunity Research and Training (MUII). MUII is supported through the Developing Excellence in Leadership, Training and Science (DELTAS) Africa Initiative (Grant no. 107743). The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS), Alliance for Accelerating Excellence in Science in Africa (AESA), and supported by the New Partnership for Africas Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (Grant no. 107743) and the UK Government. The work was also funded in part by a Wellcome Trust grant (102975).

evolutionary biology↗

bioRxiv2019

Reducing RSV hospitalisation in a lower-income country by vaccinating mothers-to-be and their households

Respiratory syncytial virus is the leading cause of lower respiratory tract infection among infants. RSV is a priority for vaccine development. In this study, we investigate the potential effectiveness of a two-vaccine strategy aimed at mothers-to-be, thereby boosting maternally acquired antibodies of infants, and their household cohabitants, further cocooning infants against infection. We use a dynamic RSV transmission model which captures transmission both within households and communities, adapted to the changing demographics and RSV seasonality of a low-income country. Model parameters were inferred from past RSV hospitalisations, and forecasts made over a 10-year horizon. We find that a 50% reduction in RSV hospitalisations is possible if the maternal vaccine effectiveness can achieve 75 days of additional protection for newborns combined with a 75% coverage of their birth household co-inhabitants ([~]7.5% population coverage).

epidemiology↗

bioRxiv2018

Comprehensive profiling of antibodies against multiple infectious diseases in serum and the airway mucosa using synthetic peptide-based linear epitope microarrays

BackgroundDespite the considerable progress that has been achieved in the development of vaccines, infectious diseases continue to be the major cause of morbidity and mortality in developing countries. The first year of life remains the time of greatest risk with more than half of all deaths caused by infectious diseases in children under the age of five years occurring during this period. For most infections, antibodies are the strongest immune correlate of protective immunity and characterizing the breadth of the antibody repertoire against infectious diseases in early life is key to profiling individual disease risk.\n\nMethodsIn order to comprehensively profile the antibody repertoire against infectious diseases in early life, we developed a synthetic peptide-based microarray to simultaneously measure antibodies against forty one common infectious diseases. 82 empirically-validated linear B-cell epitopes were selected from the Immune Epitope Database (IEBD), expressed as synthetic peptides and printed onto microarray glass slides (microarray chip). The chip was used to simultaneously measure antigen-specific IgG and IgA in serum and mucosal samples from thirty eight infants and young children presenting to hospital with different illnesses. We also used the data from the microarray to estimate antibody decay kinetics for the five most frequently detected antigens during the first year of life.\n\nResultsA synthetic peptide microarray to measure antibodies against forty one infectious diseases was successfully developed. Although the combination of antigens that were recognized were different for each child, antigens derived from Epstein-Barr virus, poliovirus, Streptococcus pneumoniae, plasmodium falciparum and varicella zoster were recognized by most study participants. While the combination of antigens recognized in serum was generally similar as those recognized in mucosal samples, antibodies to antigens such as herpesvirus, rubella and echinococcus were more predominant in either serum or mucosal samples. With the exception of the pneumococcus, we observed a progressive decline in serum IgG specific to all the infections above in the first six months of life. Pneumococcal IgG in serum exhibited a continuous rise in the first six months of life.\n\nConclusionsWe successfully developed a synthetic peptide microarray and used it to profile the diversity of systemic and mucosal antibody against multiple infectious diseases in children. The data from the slide provide a snapshot overview of the breadth and kinetics of infectious disease antibodies early in life and opens the opportunity for conducting in-depth multi, multi-target serological studies of infectious diseases in future.

immunology↗

bioRxiv2018

Whole genome analysis of local Kenyan and global sequences unravels the epidemiological and molecular evolutionary dynamics of RSV genotype ON1 strains

The respiratory syncytial virus (RSV) group A variant with the 72-nucleotide duplication in the G gene, genotype ON1, was first detected in Kilifi in 2012 and has almost completely replaced previously circulating genotype GA2 strains. This replacement suggests some fitness advantage of ON1 over the GA2 viruses, and might be accompanied by important genomic substitutions in ON1 viruses. Close observation of such a new virus introduction over time provides an opportunity to better understand the transmission and evolutionary dynamics of the pathogen. We have generated and analyzed 184 RSV-A whole genome sequences (WGS) from Kilifi (Kenya) collected between 2011 and 2016, the first ON1 genomes from Africa and the largest collection globally from a single location. Phylogenetic analysis indicates that RSV-A transmission into this coastal Kenya location is characterized by multiple introductions of viral lineages from diverse origins but with varied success in local transmission. We identify signature amino acid substitutions between ON1 and GA2 viruses within genes encoding the surface proteins (G, F), polymerase (L) and matrix M2-1 proteins, some of which were identified as positively selected, and thereby provide an enhanced picture of RSV-A diversity. Furthermore, five of the eleven RSV open reading frames (ORF) (i.e. G, F, L, N and P), analyzed separately, formed distinct phylogenetic clusters for the two genotypes. This might suggest that coding regions outside of the most frequently studied G ORF play a role in the adaptation of RSV to host populations with the alternative possibility that some of the substitutions are nothing more than genetic hitchhikers. Our analysis provides insight into the epidemiological processes that define RSV spread, highlights the genetic substitutions that characterize emerging strains, and demonstrates the utility of large-scale WGS in molecular epidemiological studies.\n\nAuthor summaryRespiratory syncytial virus (RSV) is the leading viral cause of severe pneumonia and bronchiolitis among infants and children globally. No vaccine exists to date. The high genetic variability of this RNA virus, characterized by group (A or B), genotype (within group) and variant (within genotype) replacement in populations, may pose a challenge to effective vaccine design by enabling immune response escape. To date most sequence data exists for the highly variable G gene encoding the RSV attachment protein, and there is little globally-sampled RSV genomic data to provide a fine resolution of the epidemiology and evolutionary dynamics of the pathogen. Here we use long-term RSV surveillance in coastal Kenya to track the introduction, spread and evolution of a new RSV genotype known as ON1 (having a 72-nucleotide duplication in the G gene). We present a set of 184 RSV-A whole genomes, including 176 of RSV ON1 (the first from Africa), describe patterns of local ON1 spread and show genome-wide changes between the two major RSV-A genotypes that may define the pathogens adaptation to the host. These findings have implications for vaccine design and improved understanding of RSV epidemiology and evolution.

epidemiology↗

bioRxiv2017

Assessing The Efficiency Of Catch-Up Campaigns For Introduction Of Pneumococcal Conjugate Vaccine; A Modelling Study Based On Data From Kilifi, Kenya

BackgroundThe World Health Organisation recommends the use of catch-up campaigns as part of the introduction of pneumococcal conjugate vaccines (PCVs) to accelerate herd protection and hence PCV impact. The value of a catch-up campaign is a trade-off between the costs of vaccinating additional age groups and the benefit of additional direct and indirect protection. There is a paucity of observational data, particularly from low-middle income countries to quantify the optimal breadth of such catch-up campaigns.\n\nMethodsIn Kilifi, Kenya PCV10 was introduced in 2011 using the 3-dose EPI infant schedule and a catch-up campaign in children <5 years old. We fitted a transmission dynamic model to detailed local data including nasopharyngeal carriage and invasive pneumococcal disease (IPD) to infer the marginal impact of the PCV catch-up campaign over hypothetical routine cohort vaccination in that setting, and to estimate the likely impact of alternative campaigns and their dose-efficiency.\n\nResultsWe estimated that, within 10 years of introduction, the catch-up campaign among <5y olds prevents an additional 65 (48 to 84) IPD cases, compared to PCV cohort introduction alone. Vaccination without any catch-up campaign prevented 155 (121 to 193) IPD cases and used 1321 (1058 to 1698) PCV doses per IPD case prevented. In the years after implementation, the PCV programme gradually accrues herd protection and hence its dose-efficiency increases: 10 years after the start of cohort vaccination alone the programme used 910 (732 to 1184) doses per IPD case averted. We estimated that a two-dose catch-up among <1y olds uses an additional 910 (732 to 1184) doses per additional IPD case averted. Furthermore, by extending a single dose catch-up campaign to children 1 to <2y old and subsequently to 2 to <5y olds the campaign uses an additional 412 (296 to 606) and 543 (403 to 763) doses per additional IPD case averted. These results were not sensitive to vaccine coverage, serotype competition, the duration of vaccine protection or the relative protection of infants.\n\nConclusionsWe find that catch-up campaigns are a highly dose-efficient way to accelerate population protection against pneumococcal disease.

epidemiology↗