Christophe Fraser

Imperial College London | Imperial · Department of Infectious Disease Epidemiology

SARS-CoV-2 has spread across the world, causing high mortality and unprecedented restrictions on social and economic activity. Policymakers are assessing how best to navigate through the ongoing epidemic, with computational models being used to predict the spread of infection and assess the impact of public health measures. Here, we present OpenABM...

Background As the HIV epidemic in sub-Saharan Africa matures, evidence about the age distribution of new HIV infections and how this distribution has changed over the epidemic is needed to guide HIV prevention. We aimed to assess trends in age-specific HIV incidence in six population-based cohort studies in eastern and southern Africa, reporting ch...

Background Emerging evidence shows the substantial real-world impact of authorised vaccines against COVID-19 and provides insight into the potential role of vaccines in curbing the pandemic. However, there remains uncertainty about the efficacy of vaccines against different variants of the virus. Here we assessed efficacy of ChAdOx1 nCoV-19 (AZD122...

The COVID-19 pandemic has seen digital contact tracing emerge around the world to help prevent spread of the disease. A mobile phone app records proximity events between app users, and when a user tests positive for COVID-19, their recent contacts can be notified instantly. Theoretical evidence has supported this new public health intervention1–6,...

Background The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. Methods We did an ecological study to examine the associatio...

Extensive global sampling and sequencing of the pandemic virus SARS-CoV-2 have enabled researchers to monitor its spread, and to identify concerning new variants. Two important determinants of variant spread are how frequently they arise within individuals, and how likely they are to be transmitted. To characterize within-host diversity and transmi...

Contact tracing is increasingly used to combat COVID-19, and digital implementations are now being deployed, many based on Apple and Google’s Exposure Notification System. These systems utilize non-traditional smartphone-based technology, presenting challenges in understanding possible outcomes. In this work, we create individual-based models of th...

Background The HPTN 071 (PopART) trial showed that a combination HIV prevention package including universal HIV testing and treatment (UTT) reduced population-level incidence of HIV compared with standard care. However, evidence is scarce on the costs and cost-effectiveness of such an intervention. Methods Using an individual-based model, we simul...

Digital contact tracing is a public health intervention. It should be integrated with local health policy, provide rapid and accurate notifications to exposed individuals, and encourage high app uptake and adherence to quarantine. Real-time monitoring and evaluation of effectiveness of app-based contact tracing is key for improvement and public tru...

A new variant of SARS-CoV-2 has emerged which is increasing in frequency, primarily in the South East of England (lineage B.1.1.7 ( 1 ) ; VUI-202012/01). One potential hypothesis is that infection with the new variant results in higher viral loads, which in turn may make the virus more transmissible. We found higher (sequence derived) viral loads i...

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability o...

Bacteriocins, toxic peptides involved in bacterial fratricide, are extremely diverse. Understanding the mechanisms that maintain this diversity is an important aim in bacterial ecology. Previous work on bacteriocin diversity has focused on dynamics, particularly ‘rock-paper-scissors’ dynamics, at the within-host scale. Yet, in species such as Strep...

Predicting how pathogen populations will change over time is challenging. Such has been the case with Streptococcus pneumoniae, an important human pathogen, and the pneumococcal conjugate vaccines (PCVs), which target only a fraction of the strains in the population. Here, we use the frequencies of accessory genes to predict changes in the pneumoco...

Background In May 2020, the UK National Health Service (NHS) Test and Trace programme was launched in England in response to the COVID-19 pandemic. The programme was first rolled out on the Isle of Wight and included version 1 of the NHS contact tracing app. The aim of the study was to make a preliminary assessment of the epidemiological impact of...

SARS-CoV-2 has spread across the world, causing high mortality and unprecedented restrictions on social and economic activity. Policymakers are assessing how best to navigate through the ongoing epidemic, with models being used to predict the spread of infection and assess the impact of public health measures. Here, we present OpenABM-Covid19: an a...

The timing of SARS-CoV-2 transmission is a critical factor to understand the epidemic trajectory and the impact of isolation, contact tracing and other non- pharmaceutical interventions on the spread of COVID-19 epidemics. We examined the distribution of transmission events with respect to exposure and onset of symptoms. We show that for symptomati...

Contact tracing is increasingly being used to combat COVID-19, and digital implementations are now being deployed, many of them based on Apple and Google's Exposure Notification System. These systems are new and are based on smartphone technology that has not traditionally been used for this purpose, presenting challenges in understanding possible...

Mathematical models are powerful tools in HIV epidemiology, producing quantitative projections of key indicators such as HIV incidence and prevalence. In order to improve the accuracy of predictions, such models need to incorporate a number of behavioural and biological heterogeneities, especially those related to the sexual network within which HI...

Objectives: To evaluate the performance of a high-throughput research assay for HIV drug resistance testing based on whole genome next-generation sequencing (NGS) that also quantifies HIV viral load. Methods: Plasma samples (n = 145) were obtained from HIV-positive MSM (HPTN 078). Samples were analysed using clinical assays (the ViroSeq HIV-1 Ge...

Viral genetic sequencing can be used to monitor the spread of HIV drug resistance, identify appropriate antiretroviral regimes, and characterize transmission dynamics. Despite decreasing costs, next-generation sequencing (NGS) is still prohibitively costly for routine use in generalised HIV epidemics in low- and middle-income countries. Here, we pr...

In May 2020 the UK introduced a Test, Trace, Isolate programme in response to the COVID-19 pandemic. The programme was first rolled out on the Isle of Wight and included Version 1 of the NHS contact tracing app. We used COVID-19 daily case data to infer incidence of new infections and estimate the reproduction number R for each of 150 Upper Tier Lo...

Extensive global sampling and whole genome sequencing of the pandemic virus SARS-CoV-2 have enabled researchers to characterise its spread, and to identify mutations that may increase transmission or enable the virus to escape therapies or vaccines. Two important components of viral spread are how frequently variants arise within individuals, and h...

In this paper we discuss ethical implications of the use of mobile phone apps in the control of the COVID-19 pandemic. Contact tracing is a well-established feature of public health practice during infectious disease outbreaks and epidemics. However, the high proportion of pre-symptomatic transmission in COVID-19 means that standard contact tracing...

The extent to which evolution is constrained by the rate at which horizontal gene transfer (HGT) allows DNA to move between genetic lineages is an open question, which we address in the context of antibiotic resistance in Streptococcus pneumoniae . We analyze microbiological, genomic, and epidemiological data from the largest-to-date sequenced pneu...

The newly emergent human virus SARS-CoV-2 is resulting in high fatality rates and incapacitated health systems. Preventing further transmission is a priority. We analyzed key parameters of epidemic spread to estimate the contribution of different transmission routes and determine requirements for case isolation and contact-tracing needed to stop th...

Across sub-Saharan Africa, key populations with elevated HIV-1 incidence and/or prevalence have been identified, but their contribution to disease spread remains unclear. We performed viral deep-sequence phylogenetic analyses to quantify transmission dynamics between the general population (GP), fisherfolk communities (FF), and women at high risk o...

Mobile phone apps implementing algorithmic contact tracing can speed up the process of tracing newly diagnosed individuals, spreading information instantaneously back through a past contact network to inform them that they are at risk of being infected, and thus allow them to take appropriate social distancing and testing measures. The aim of non-p...

Objectives: HIV-1 integrase inhibitors are recommended as first-line therapy by WHO, though efficacy and resistance data for non-B subtypes are limited. Two recent trials have identified the integrase L74I mutation to be associated with integrase inhibitor treatment failure in HIV-1 non-B subtypes. We sought to define the prevalence of integrase r...

Recombination is an important feature of HIV evolution, occurring both within and between the major branches of diversity (subtypes). The Ugandan epidemic is primarily composed of two subtypes, A1 and D, that have been co-circulating for 50 years, frequently recombining in dually infected patients. Here, we investigate the frequency of recombinants...

Background: International and global organisations advocate targeting interventions to areas of high HIV prevalence (ie, hotspots). To better understand the potential benefits of geo-targeted control, we assessed the extent to which HIV hotspots along Lake Victoria sustain transmission in neighbouring populations in south-central Uganda. Methods:...

BACKGROUND: International and global organisations advocate targeting interventions to areas of high HIV prevalence (ie, hotspots). To better understand the potential benefits of geo-targeted control, we assessed the extent to which HIV hotspots along Lake Victoria sustain transmission in neighbouring populations in south-central Uganda. METHODS: W...

Background: Phylogenetic analysis can be used to assess HIV transmission in populations. We inferred the direction of HIV transmission using whole-genome HIV sequences from couples with known linked infection and known transmission direction. Methods: Complete next generation sequencing (NGS) data were obtained for 105 unique index-partner sampl...

Methicillin-resistant Staphylococcus aureus (MRSA) transmission in the hospital setting has been a frequent subject of investigation using bacterial genomes, but previous approaches have not yet fully utilised the extra deductive power provided when multiple pathogen samples are acquired from each host. Here, we use a large dataset of MRSA sequence...

Objectives The aim of this study was to investigate associations between baseline characteristics and CD4 cell count response on first-line antiretroviral therapy and risk of virological failure (VF) with or without drug resistance. Methods We conducted an analysis of UK Collaborative HIV Cohort data linked to the UK HIV Drug Resistance Database....

A diverse set of mobile genetic elements (MGEs) transmit between Streptococcus pneumoniae cells, but many isolates remain uninfected. The best-characterised defences against horizontal transmission of MGEs are restriction-modification systems (RMSs), of which there are two phase-variable examples in S. pneumoniae. Additionally, the transformation m...

Background: A universal testing and treatment strategy is a potential approach to reduce the incidence of human immunodeficiency virus (HIV) infection, yet previous trial results are inconsistent. Methods: In the HPTN 071 (PopART) community-randomized trial conducted from 2013 through 2018, we randomly assigned 21 communities in Zambia and South...

Near 60% of new HIV infections in the United Kingdom are estimated to occur in men who have sex with men (MSM). Age-disassortative partnerships in MSM have been suggested to spread the HIV epidemics in many Western developed countries and to contribute to ethnic disparities in infection rates. Understanding these mixing patterns in transmission can...

The extent to which evolution is constrained by the rate at which horizontal gene transfer (HGT) allows DNA to move between genetic lineages is an open question, which we address in the context of antibiotic resistance in Streptococcus pneumoniae . We analyze microbiological, genomic and epidemiological data from the largest-to-date sequenced pneum...

To prevent new infections with human immunodeficiency virus type 1 (HIV-1) in sub-Saharan Africa, UNAIDS recommends targeting interventions to populations that are at high risk of acquiring and passing on the virus. Yet it is often unclear who and where these ‘source’ populations are. Here we demonstrate how viral deep-sequencing can be used to rec...

Understanding which HIV-1 variants are most likely to be transmitted is important for vaccine design and predicting virus evolution. Since most infections are founded by single variants, it has been suggested that selection at transmission has a key role in governing which variants are transmitted. We show that the composition of the viral populati...

Resistance against different antibiotics appears on the same bacterial strains more often than expected by chance, leading to high frequencies of multidrug resistance. There are multiple explanations for this observation, but these tend to be specific to subsets of antibiotics and/or bacterial species, whereas the trend is pervasive. Here, we consi...

Background: We evaluated use of phylogenetic methods to predict the direction of HIV transmission. Methods: For 33 index-partner pairs with genetically-linked infection, samples were collected from partners and indexes close to time of partners' seroconversion (SC); 31 indexes also had an earlier sample. Phylogenies were inferred using env next-...

Predictions of how a population will respond to a selective pressure are valuable, especially in the case of infectious diseases, which often adapt to the interventions we use to control them. Yet attempts to predict how pathogen populations will change, for example in response to vaccines, are challenging. Such has been the case with Streptococcus...

Understanding which HIV-1 variants are most likely to be transmitted is important for vaccine design and predicting virus evolution. Since most infections are founded by single variants, it has been suggested that selection at transmission has a key role in governing which variants are transmitted. We show that the composition of the viral populati...

High-throughput viral genetic sequencing is needed to monitor the spread of drug resistance, direct optimal antiretroviral regimes, and to identify transmission dynamics in generalised HIV epidemics. Public health efforts to sequence HIV genomes at scale face three major technical challenges: (i) minimising assay cost and protocol complexity, (ii)...

Phylogenetic analysis of pathogens is an increasingly powerful way to reduce the spread of epidemics, including HIV. As a result, phylogenetic approaches are becoming embedded in public health and research programmes, as well as outbreak responses, presenting unique ethical, legal, and social issues that are not adequately addressed by existing bio...

HIV-1 undergoes multiple rounds of error-prone replication between transmission events, resulting in diverse viral populations within and among individuals. In addition, the virus experiences different selective pressures at multiple levels: during the course of infection, at transmission, and among individuals. Disentangling how these evolutionary...

Diversity and divergence over time, with individuals infected by multiple variants removed. This is identical to Fig 1, but with individuals i1, i2, i4, i9, i12, i14, i20, i25 and i34 removed since they show high diversity in the p24 gene region at the first sampling time point, indicative of infection by multiple variants from the same donor indiv...

Patterns of diversity and divergence over time for 34 individuals. A) Mean pairwise diversity over time at first, second, and third codon positions (top, middle, and bottom panels, respectively). B) Mean nonsynonymous and synonymous divergence over time (top and bottom panels, respectively). (PDF)

Time-scaled phylogenies for individual i17. Left: p24 gene tree. Right: gp41 gene tree. Numbers on the branches correspond to the posterior support (or posterior probability). (PDF)

Comparison of within-host evolutionary rates estimated from the original analysis (red), based on 34 individuals, and from a subset of 10 individuals (blue). (PDF)

Time-scaled phylogenies for individual i24. Left: p24 gene tree. Right: gp41 gene tree. Numbers on the branches correspond to the posterior support (or posterior probability). (PDF)

Within-host evolutionary rates per individual along the backbone, internal, and external branches. (CSV)

Comparison of within-host evolutionary rates estimated with three different gamma hyperpriors (defined by scale parameters 10, 100, and 1000, respectively) for the clock rate hierarchical model (see main text for details). (PDF)

Scatter plot of mean within-host evolutionary rates and set-point viral load. For both gene regions, we estimated the mean within-host evolutionary rates for external, internal, and backbone branches at both nonsynonymous (filled circles) and synonymous (open circles) sites. The points are coloured according to subtype as per Fig 2. The solid and d...

Contribution to the mismatch in evolutionary rates if founder-like virus has a transmission advantage, with individuals probably infected by multiple variants removed. This is identical to Fig 4, but with individuals i1, i2, i4, i9, i12, i14, i20, i25 and i34 removed since they show high diversity in the p24 gene region at the first sampling time p...

Viral load, CD4+ counts, and number of sequence reads per time point for all individuals. (CSV)

Mean nonsynonymous (red) and synonymous (blue) substitution rates for p24 and gp41 gene regions. The horizontal black lines correspond to overall mean for each gene region. (PDF)

Comparison of within-host evolutionary rates estimated using the full codon substitution model (red) and the renaissance counting method (blue). Solid lines and filled circles correspond to the nonsynonymous substitution rates, while dashed lines and open circles correspond to the synonymous substitution rates. (PDF)

Changes towards population consensus, with individuals probably infected by multiple variants removed. This is identical to S10 Fig, but with individuals i1, i2, i4, i9, i12, i14, i20, i25 and i34 removed since they show high diversity in the p24 gene region at the first sampling time point, indicative of infection by multiple variants from the sam...

Changes towards population consensus. For each gene region, the figures give: the proportion of polymorphic sites where a mutant allele represents a change towards the subtype-specific population consensus; the bias towards subtype-specific population consensus for polymorphic sites, with assumed mutational transition:transversion (ts:tv) ratios of...

Average within- and between-host rates per subtype. (DOCX)

Full description of the BEAST sensitivity analyses. (DOCX)

Background Near 60% of new HIV infections in the United Kingdom are estimated to occur in men who have sex with men (MSM). Patterns of mixing between different risk groups of MSM have been suggested to spread the HIV epidemics through age-disassortative partnerships and to contribute to ethnic disparities in infection rates. Understanding these mix...

Studying the evolution of viruses and their molecular epidemiology relies on accurate viral sequence data, so that small differences between similar viruses can be meaningfully interpreted. Despite its higher throughput and more detailed minority variant data, next-generation sequencing has yet to be widely adopted for HIV. The difficulty of accura...

We describe a detailed protocol for the manual workup of blood (plasma/serum) samples from individuals infected with the human immunodeficiency virus type 1 (HIV-1) for deep sequence analysis of the viral genome. The study optimizing the assay was performed in the context of the BEEHIVE (Bridging the Evolution and Epidemiology of HIV in Europe) pro...

Background Multidrug-resistant tuberculosis poses a major threat to the success of tuberculosis control programs worldwide. Understanding how drug-resistant tuberculosis evolves can inform the development of new therapeutic and preventive strategies. Methods Here, we use novel genome-wide analysis techniques to identify polymorphisms that are asso...

Hotspots of correlation between homoplastic sites. White and yellow indicate significant positive correlation (p<0.05) while red indicates significant negative correlation (p<0.05). (EPS)

Genome wide analysis with correction for population structure by principle components and Bonferroni correction for rifampicin, isoniazid, pyrazinamide and ethambutol drug resistance polymorphisms in M. tuberculosis. (EPS)

Homoplastic polymorphisms detected by phyC. (DOCX)

The cophenetic correlation coefficient of whole genome sequence, MIRU, MIRU and spoligotype combined (MIRU Spol) and spoligotype dendrograms. (EPS)

Genome wide analysis with correction for population structure by principle components and Bonferroni correction for streptomycin, kanamycin, capreomycin and ciprofloxacin drug resistance polymorphisms in M. tuberculosis. (EPS)

The most homoplastic polymorphisms. (DOCX)

The most topologically influential polymorphisms. (DOCX)