Investigation into monkeypox outbreak in England: technical briefing 5 – GOV.UK

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Updated 23 September 2022

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The UK Health Security Agency (UKHSA) is working with the NHS and the public health agencies of the 4 nations to investigate the monkeypox outbreak. This briefing is produced to share data useful to other public health investigators and academic partners undertaking related work. It includes early evidence and preliminary analyses which may be subject to change.
Data reported in the technical briefing is as of 1 August 2022 (or as specified in the text) to allow time for analysis.
The outbreak can be considered to fall into one of 4 potential levels of transmission:
Incursions from rest of the world – small numbers of imported cases with limited onward transmission.
Transmission within a defined sub-population.
Transmission within multiple sub-populations or larger sub-population.
Wider significant community transmission – with potential for endemic and local epi-zoonotic disease.
These may be refined with better understanding of modes of transmission.
At present, England is judged to be in level 2.
Over the past couple of weeks there has been approximately no change in the daily number of confirmed cases. Case ascertainment continues to challenge our understanding of the outbreak.
Assessment (confidence): zero (or low) daily case growth (high).
The proportion of cases resident in London was more than 75% from the start of the incident up to 20 June 2022. This proportion stayed at around 66% in July 2022.
Assessment (confidence): remaining concentrated in London (moderate) but with evidence of increasing geographic spread (low).
Whilst testing is freely available and a mixed population group is being tested, it is likely that there is under ascertainment. Atypical symptoms, including single or scarce lesions, are reported and there are international reports of subclinical infection.
Assessment (confidence): insufficient information.
Level 2 is defined as transmission within a defined sub-population, currently gay, bisexual and men who have sex with men (GBMSM) connected by sexual networks. Enhanced surveillance data does not suggest a change in case mix, although it is available on only 26% (703 out of 2,638) of cases and may not be representative of the whole cohort. There are 22 women with confirmed or highly probable monkeypox in England (out of 2,615 with known gender). There is no robust evidence of sustained transmission outside some sexual networks of GBMSM, although the increase in female cases requires close surveillance.
Assessment (confidence): level 2 (moderate).
Whilst the primary reported route is through close or sexual contact, monkeypox virus has been detected in air and environmental samples in the hospital room of infected patients. There are no confirmed instances of airborne transmission. Limited household transmission has been described in the UK. Detailed investigations of some cases have found small numbers with no known route of acquisition, due to reporting no sex or other potential exposures during their incubation period.
Assessment (confidence): transmitting primarily through close or sexual contact (moderate).
There are no reported deaths in the UK. There is significant morbidity in the majority of people who are admitted to hospital for clinical care reasons, including severe pain and complications due to secondary bacterial infection. 
Assessment (confidence): in current population group, low mortality but significant morbidity (moderate). In wider population, insufficient data.
UK genomic data is now available. The majority of outbreak cases are currently in a distinct lineage (B.1) which has mutations of unknown significance when compared with the closest previously characterised monkeypox virus genomes. A small number of cases, including 2 UK cases and some international cases, are in lineage A.2. Phylogeny suggest there may be under sampled circulation of this lineage alongside B.1, and this virus and outbreak requires separate characterisation. There is evidence suggestive of sustained human transmission prior to the 2022 outbreak but not clear-cut evidence of adaptation for improved human transmission. There is no phenotypic data available for this clade to date.
Assessment (confidence): insufficient data.
There is now indication of varying trajectories in different countries, with several countries probably having a plateau in daily cases, and some continuing to have increasing number of daily cases. Given the varying reporting practices globally, further time is needed to confirm changes in trajectory.
Assessment (confidence): the outbreak continues to grow in some countries, with indications of plateauing or decline in others (moderate).
Cases in previously non-endemic countries are reported as primarily in GBMSM. Small number of cases are reported in women and children. In countries with a longer history of monkeypox, apparent wider population transmission is reported with unclear routes. Phylogenetic data suggests that human transmission has been occurring for a number of years in some areas prior to the appearance of the outbreak clade and there is at present no reason to assume that the epidemic as a whole will naturally reduce without interventions globally. 
Assessment (confidence): transmitting primarily by close or sexual contact in non-endemic countries (low), unknown transmission routes in endemic countries.
UKHSA has carried out a research and evidence gaps analysis relating to the monkeypox outbreak in the UK. We are working collaboratively with academic partners, including National Institute for Health and Care Research Health Protection Research Units (NIHR HPRU) and national research funders, to develop and implement rapid studies to address these. The priority evidence gaps are shown in Table 1 and a full list of research questions developed with partners and shared with funding bodies in Table 2.
UKHSA has developed proposals to address specific research and evidence questions related to monkeypox, both as leaders and in collaboration with partners, including NIHR HPRUs. Any queries about research in UKHSA should be directed to the Monkeypox Research and Science cell.
Studies led by UKHSA include:
Other studies underway and in planning with UKHSA involvement include those designed to answer the following questions:
In addition, UKHSA and the Medicine and Healthcare products Regulatory Authority (MHRA) have also received funding from the Coalition for Epidemic Preparedness Innovations) (CEPI) for the development of a monkeypox antibody standard and assays:
The tools CEPI is supporting the development of are: assays, with UKHSA, to test for the presence of specific antibodies – indicative of an immune response to monkeypox – following either natural infection or vaccination. A reference antibody standard, with the UK MHRA, to harmonise how different laboratories assess the strength and duration of immune responses generated by current vaccines and those in development against monkeypox.
UKHSA researchers have authored or contributed to peer-reviewed publications for the current incident response. These can be accessed via the UKHSA Research Portal.
Cases of monkeypox infection were confirmed in England from 6 May 2022. As of 1 August 2022, there were 2,759 laboratory-detected cases of monkeypox in the UK. This includes 2,672 confirmed and 87 highly probable cases, collectively referred to as ‘cases’ in this briefing for simplicity and defined respectively as those who tested positive with a monkeypox and orthopox polymerase chain reaction (PCR) test. Positive results for orthopox, the genus of viruses that includes monkeypox, are considered highly probable due to the rarity of other orthopox viruses in the UK.
Of all cases, 65 were in Scotland, 24 were in Northern Ireland, 32 were in Wales and 2,638 were in England. The median age of cases in the UK was 37 years old (interquartile range 31 to 44).
Figure 1 shows the specimen dates of monkeypox cases over time in England. While the first reported case in England was identified 6 May 2022 in a traveller from an endemic country for monkeypox, the earliest known case in England has a specimen date of 7 March 2022. This case was identified in late July through retrospective testing of a residual sample. An additional small number of cases have also been detected with specimen dates in May 2022 but with symptom onset dates in early April 2022. Some of these early cases had no travel history in their incubation period.
Where specimen date is missing, the date the laboratory received the specimen is used. The data used in this graph can be found in the accompanying spreadsheet]
In England, a high proportion of cases were known to be London residents (overall 73%, 1,906 out of 2,626 with reported home address), see Table 4. The number of cases in other regions has been steadily increasing, particularly in the South East and North West of England (Figure 2). The proportion of cases in London has stayed around 66% in July 2022 (Figure 3).
Where gender information was available, 2,593 out of 2,615 (99.1%) cases in England were men, and 22 were women (Figure 4).
The data used in this graph can be found in the accompanying spreadsheet.
*If residential postcode is known, then region of residence is used, otherwise the region of the healthcare facility where testing occurred at is used
The data used in this graph can be found in the accompanying spreadsheet.
The data used in this graph can be found in the accompanying spreadsheet.
Of the 2,638 cases identified in England up to 1 August 2022, a total of 703 (26%) had completed enhanced surveillance questionnaires. This includes data collected via rapid sexual health questionnaires administered during the initial weeks of the outbreak (used from 27 to 31 May 2022), questionnaires completed by health protection teams during telephone interviews (used from 1 to 24 June 2022), and self-completed questionnaires sent electronically to cases (used from 25 June 2022 onwards). Information from enhanced questionnaires should be interpreted with caution, due to the low uptake and because uptake has changed overtime. People completing questionnaires may not be representative of all those affected.
Most respondents were of white ethnicity (76%), followed by mixed (9%) and Asian (7%) ethnicities. Additionally, most cases were born in the UK or other European countries, although 10% reported being born in Latin American or Caribbean countries.
As shown in Table 6 and reported in previous technical briefings, monkeypox is predominantly being transmitted in interconnected sexual networks of GBMSM: the majority of cases report multiple sexual partners in the last 3 months, history of a sexually transmitted infection (STI) in the last year, and/or use of human immunodeficiency pre-exposure prophylaxis (HIV PrEP).
N=703, some metrics have smaller denominators due to missing values
Figure 5 shows trends of the selected epidemiological metrics over time, among cases with completed questionnaires and with symptom onset dates between epidemiological weeks 18 to 28 (from 1 May 2022 to 16 July 2022). Cases with onset dates before or after these dates were excluded from these analyses due to small numbers. These metrics were consistent over time, suggesting transmission of monkeypox virus in England has continued to occur in defined sexual networks of GBMSM.
More detailed analyses of questionnaire data, in combination with manual review of case management notes, was undertaken to describe the small number of cases that are known to not be GBMSM including possible routes of acquisition. Of 22 cases who were women, 9 (41%) were transgender women. From all 22 women, 8 had evidence of possible transmission during sexual contact, 5 appeared to have non-sexual routes of acquisition (either household or no identified exposure route), and 9 had no information on transmission. Additionally, there were 15 cisgender heterosexual men who had not reported having sex with another man in the past 21 days. Of these, a small number had evidence of possible transmission during sexual contact with cisgender women.
Supplementary data is not available for this figure. Due to delays between symptom onset and questionnaire completion, data for the most recent epidemiological weeks may change and should be interpreted with caution.
Testing for monkeypox in the UK is conducted by the UKHSA Rare and Imported Pathogen Laboratory (RIPL) as well as several other NHS and private laboratories that have begun using monkeypox or orthopox PCR tests since early July 2022.
Testing analyses are available for RIPL, although these are currently not representative of testing across the UK and likely to under-represent testing in London.
Up to 29 July 2022, 4,921 monkeypox tests were carried out in RIPL, of which 48% (2,204) were positive. Figure 6 shows positivity by sex. Positivity in females has increased slightly in recent weeks, whereas positivity in males was higher between weeks 25 and 28 but more recently has decreased to 50%.
There is additional evidence that transmission has slowed since technical briefing 3. Nowcasting by both specimen date and reporting date suggests the epidemic has plateaued.
As the epidemic has grown, the availability of data with recorded symptom onset date has declined. This biases the epidemic curve by symptom onset date, since the proportion of cases being recorded will decay over time, even when adjusting for reporting delays. Therefore, here we model the epidemic using specimen date, which is the date the sample is collected from a patient. This reflects an epidemic curve lagged by the delay between infection and seeking healthcare.
Visualising the epidemic curve by specimen date is affected by the delay from specimen date to the case being reported to UKHSA. To correct for this delay, nowcasting methods adjust the observed data by the distribution of reporting delays to create predictions of the actual frequency. We use a generalised additive model to nowcast current cases and apply this to non-travel associated cases in England.
The nowcasting suggests that the growth in confirmed daily cases is zero, albeit with some uncertainty (Figure 7), with growth rates estimated between a 39-day doubling time and a 35-day halving time. Negative doubling times represent halving times. The nowcast estimate of cases is around 35 per day. The swathe that spans zero shows growth has slowed and is now consistently close to zero.
The charts exclude cases associated with travel. The shaded area is the 90% Credible Interval (CrI). The dark shaded area is the 50% CrI and the lighter area is the 90% CrI. Note: y-axis denotes incidence of cases by specimen date. Supplementary data is not available for these figures.
Thus far, the majority of cases have occurred in defined networks of GBMSM. To assess whether the outbreak is moving away from this initial subpopulation, we investigate temporal trends in the proportion of cases that do not identify as women. Assuming Monkeypox is being transmitted in sexual networks of GBMSM, the proportion of cases that identify as women should remain constant (allowing for random fluctuations in the observed proportion).
A small number of sporadic transmission events from GBMSM networks to women is expected. However, if the proportion of cases in women is increasing, this could suggest that there is sustained transmission outside GBMSM networks. If the proportion of cases in women with no known links to GBMSM networks is increasing, that could be even stronger evidence of sustained onward transmission.
To assess the evidence, we construct a null hypothesis of no change in the transmission network based on the gender-distribution of cases over the last 6 weeks. We then adjust this observed proportion to the number of cases in the current week, to create a 95% confidence region where we would expect the currently observed gender-distribution to lie if it follows the null hypothesis. By overlaying the currently observed gender-distribution, we can identify statistically significant perturbations. Note that although statistically significant, these perturbations may not reflect underlying transmission changes, since it could also be affected by changes in the relative ascertainment of cases in women relative to men, or unknown cases. We plot the statistical test as a rolling function of time for each week of the outbreak.
The proportion of cases in women is currently consistent with the null hypothesis, so there is insufficient evidence to support a change in the transmission dynamics (Figure 8). This is true whether cases in women which have a known link to a GBMSM primary case are included or excluded. However, over the last few weeks the proportion of cases in women has been increasing, so this trend needs to be monitored closely.
The purple shaded area is the null hypothesis (which implies no change in the rate). The solid black line is the proportion observed in the latest week, plotted by the first day of the focal week.
Plot a) removes 5 cases (at time of analysis) which were known to have a link to a GBMSM primary case. Plot b) analysis including all women.
Supplementary data is not available for these figures.
A total of 87 monkeypox genomes have been produced using Illumina metagenomics. Samples that have a monkeypox PCR cycle threshold (Ct) less than or equal to 20, are pre-treated to remove free nucleic acid before extraction and library preparation. This analysis includes information on the most recent 81 genomes that have been generated. This includes 2 pairs of sequences from the same samples in different runs. Both duplicates produced the same results.
A phylogenetic tree is shown in Figure 9. A total of 79 of the sequences contain the 11 B.1 mutations described in technical briefing 3. This clade has been collapsed in the image due to the large number of sequences within the clade internationally. The remaining 2 sequences belong to clade A.2, which contains 16 mutations not found in other clades. The UK genomes that are within the B.1 clade contain 105 distinct point mutations when compared to ON563414.3. A total of 79 of the mutations (75.24%) are consistent with the action of host apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC3) as described in the linked virological post. A further 15 mutations (14.29%) are either C>T or G>A changes but are not the canonical dinucleotides seen in APOBEC3 related mutations.
The tree includes a sample of the international data available in Genbank and the 87 UK genomes from the 2022 outbreak, along with some historic samples for context. Clades B.1 and A.2 are labelled on the tree. B.1 (containing 85 UK genomes) has been collapsed due to the large number of sequences available internationally. Sequences are labelled by accession number for publicly available data, and by internal identifier for new UK genomes. Country and specimen collection date are included in the label and indicated by the colour and shape, respectively. Underlying data is not available for this figure.
Approximately 38% of samples contain at least one mixed base (Figure 10). Mixtures are called within the sequence data if 2 bases are present at a given position and the total read depth at that position is more than or equal to 20X. Reads must have a MapQ score more than or equal to 30 and individual bases must have a QUAL score more than or equal to 33 to be included in depth calculations. In one set of duplicate sequences, the same 5 mixed positions were observed in both sets of read data. The potential for mixed populations has implications for inferences made about the structure of the B.1 clade. The utility of genomic data in assessing transmission may be reduced as samples from different individuals may have acquired unique mutations in the time between transmission and sampling.
The data used in this graph can be found in the accompanying spreadsheet.
Fifty-one of the 61 unique mutations (83.61%) observed at mixed positions are consistent with the action of host APOBEC3. The high-quality thresholds for calling mixed bases, and native nature of the sequencing protocol (that is, no PCR enrichment) combined with the APOBEC3 style mutations supports the hypothesis that diversity is acquired within a lesion. Additionally, sequence data from 2 different swabs taken from the same patient show 2 different sets of mixed bases, suggesting this diversity is acquired within an individual lesion over time.
Sequencing a single lesion may not be representative of the initial viral population acquired by an individual, or similarly of the population subsequently transmitted to contacts.
Sequencing of a UK sample showed 5 mixed bases at a frequency between 45 and 50% of reads. Four of the 5 mixed positions observed in this sample were present in the consensus sequence of 2 different B.1 subclades. It is not possible at this time to determine the probable cause of this observation, however superinfection, transmission of variation and convergent evolution are all possible explanations. The presence of mixed bases shared with other genomes instead of wildtype or alternate calls in the consensus genomes resulted in uncertainty in the placement of these sequences within phylogenies of the B.1 lineage.
Further sequencing of samples from different lesions or sites (for example, lesion versus blood), and the same lesion over time is required to fully understand the relevance of mixed bases in the genomic data. The detection of mixed bases in 38% of the sequenced samples coupled with the low overall diversity in the B.1 clade resulted in significant uncertainty in any phylogenetic representation of the clade. Uncertainty in the phylogeny will limit the molecular epidemiological inferences that are possible from the genomic data, therefore it is critical, as an initial step, that the extent and mechanisms leading to the generation of intra-host diversity are described.
Monkeypox virus PCR results are submitted to UKHSA daily by the Rare and Imported Pathogens Laboratory, Porton, UKHSA regional laboratories and NHS laboratories undertaking testing. Data on people testing positive since 6 May 2022 is enhanced with demographic, symptom, epidemiological, and exposure information extracted from the UKHSA Health Protection Team case management system (HPZone), or collected in enhanced surveillance questionnaires.
Enhanced surveillance questionnaires include data collected via rapid sexual health questionnaires administered during the initial weeks of the outbreak (used from 27 to 31 May 2022), questionnaires completed by health protection teams during telephone interviews (used from 1 to 24 June 2022), and self-completed questionnaires sent electronically to cases (used from 25 June 2022 onwards).
Zahidul Abedin, Carolina Arevalo, Paula Blomquist, Jessica Bridgen, Chloe Byers, Meera Chand, Kristine Cooper, Fergus Cumming, Julie Day, Jake Dunning, Ashley Goddard, Irene Gonsalvez, Alice Graham, Natalie Groves, James Guilder, Susan Hopkins, Luke Hounsome, Christopher I Jarvis, Nicholas Loman, Nicola Love, Richard Myers, Isabel Oliver, Karthik Paranthaman, Mateo Prochazka, Thomas Ward, Nick Watkins, William Welfare, Katie Wrenn.
UKHSA Data, Epidemiology and Analytics Cell
UKHSA Research and Science Cell
UKHSA Modelling Cell
UKHSA Genomics Public Health Analysis
UKHSA Sexual Health Liaison Group
UKHSA Monkeypox Incident Management Team
The Monkeypox Technical Group includes members with expertise in clinical infectious diseases, clinical research, epidemiology, genomics, modelling and virology:
The authors are grateful to those teams and groups providing data for these analyses including:
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