Monday, March 18, 2024

The Lancet Correspondence: Global Emergence of Neuraminidase Inhibitor-Resistant Influenza A(H1N1)pdm09 Viruses with I223V and S247N Mutations

Credit NIAID










#17,953

Twenty years ago Amantadine was the preferred influenza antiviral. It was cheap, plentiful, and worked reasonably well as both a treatment, and a preventative.  

It was so popular it was allegedly used by Chinese farmers to protect their flocks from avian flu, which is believed led to growing resistance (see Nature News China's chicken farmers under fire for antiviral abuse). 
By late 2005 Amantadine was beginning to lose its effectiveness against the H3N2 seasonal flu virus and some strains of the H5N1 bird flu. In January of 2006 the CDC issued a warning to doctors not to rely on Amantadine or Rimantadine to treat influenza.
Tamiflu (Oseltamivir) - an NAI (neuraminidase inhibitor) - was approved for use in the U.S. in 1999. While far more expensive, it became the new treatment standard.  

While occasional instances of Oseltamivir resistance were recorded prior to 2007, in nearly every case, it developed after a person was placed on the drug (i.e. `spontaneous mutations’). 

Although of obvious concern to the patient receiving treatment, it occurred in only about 1% of treated cases, and studies suggested that these resistant strains were `less biologically fit’, and were therefore thought unlikely to spread from human-to-human.

Which of course, is exactly what they did do. Between 2007 and 2008, the incidence of resistant seasonal H1N1 viruses literally exploded around the globe. 

So much so, that by the end of 2008, nearly all of the H1N1 samples tested in the United States were resistant to oseltamivir and the CDC was forced to issue major new guidance for the use of antivirals (see CIDRAP article With H1N1 resistance, CDC changes advice on flu drugs).

This resistance was primarily due to an H275Y mutation - where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 275 (Note: some scientists use 'N2 numbering' (H274Y)). 

It seemed as if antiviral crisis was inevitable, when in a Deus Ex Machina moment a new swine-origin H1N1 virus - that happened retain its sensitivity to Tamiflu - swooped in as a pandemic strain in the spring of 2009, supplanting the older resistant H1N1 virus. 

Both incidents showed that antivirals - much like antibiotics - can lose effectiveness over time, as pathogens evolve and resistant strains emerge. 

Since 2009 flu surveillance centers around the world have been looking for any signs of growing resistance to NAI inhibitors.  For the most part, we've seen the same 1% incidence of spontaneous mutations in people receiving the antiviral, although we've seen a few `clusters' of cases. 

As added insurance, in 2018 the FDA Approved Xofluza : A New Class Of Influenza Antiviral (aka baloxavir marboxil), but it too has shown signs of resistance (see Eurosurveillance: A community Cluster of Influenza A(H3N2) Virus infection with Reduced Susceptibility to Baloxavir - Japan 2023), particularly in seasonal H3N2.

The CDC's most recent FluView report (see below) - based on roughly 2,600 viruses tested since October 1st - finds very low levels of NAI resistance in our armamentarium of influenza antiviral drugs. 

  • One A(H1N1)pdm09 virus had NA-H275Y amino acid substitution and showed highly reduced inhibition by oseltamivir and peramivir.
  • One (H1N1)pdm09 virus had NA-I223V and NA-S247N amino acid substitutions and showed reduced  inhibition by oseltamivir.
  • One A(H3N2) virus had PA-I38T amino acid substitution and showed reduced susceptibility to baloxavir.

While this is exactly what we would hope to find, we've a correspondence from researchers at the University of Hong Kong  - published last week in The Lancet - of a much higher incidence of oseltamivir resistance among samples tested in Hong Kong in 2023 (along with a concurrent rise in GISAID sequences deposited since last summer). 

While the numbers are still relatively small, this is not a trend we'd want to see continue. 

First the gist of the correspondence (follow the link for supplementary information), after which I'll have a brief postscript.  


Rhoda Cheuk-Ying Leung, Jonathan Daniel Ip, Lin-Lei Chen , Wan-Mui Chan, Kelvin Kai-Wang To
Open Access Published: March 14, 2024 
DOI:https://doi.org/10.1016/S2666-5247(24)00037-5

Neuraminidase inhibitors (NAIs), such as oseltamivir and zanamivir, serve as the primary treatment for influenza virus infection. NAI-resistant influenza A(H1N1) strains were widespread during the 2008–09 influenza season, especially in Japan, where 100% of the strains were resistant to oseltamivir.1
However, after the NAI-susceptible 2009 pandemic subtype (A[H1N1]pdm09) replaced the previous seasonal A(H1N1) subtype in 2009, the incidence of A(H1N1)pdm09 with reduced inhibition (10-fold to 100-fold) or highly reduced inhibition (>100-fold) was only approximately 1% in the 2019–20 influenza season.2
After a period of quiescence during the COVID-19 pandemic, the incidence of influenza has increased following the relaxation of physical distancing measures. In Hong Kong, the resurgence of the influenza virus occurred in 2023 following the relaxation of all COVID-19 restriction measures, with a peak in the spring, predominantly driven by A(H1N1)pdm09 in April, 2023.3 
We have successfully sequenced the influenza neuraminidase gene in 92 individuals with A(H1N1) infection in Hong Kong in 2023. Among them, four individuals (4·35%) carried at least one mutation known to confer reduced susceptibility to the NAIs oseltamivir or zanamivir (appendix p 3).4 Notably, three of ten (30%) A(H1N1)pdm09 strains collected in October, 2023, harboured both I223V and S247N mutations.
To ascertain the global incidence of A(H1N1)pdm09 strains with I223V or S247N mutations, or a combination of both, we conducted a comprehensive analysis of A(H1N1)pdm09 strains available in the Global Initiative on Sharing All Influenza Data (GISAID) repository collected between January, 2016, and November, 2023 (appendix p 4).
The incidence of strains with I223V or S247N mutations, or both, increased in the fall of 2023. The incidence of the I223V mutation increased from fewer than 1200 per 100 000 individuals before August, 2023, to 1250–4972 per 100 000 individuals between August and November, 2023, whereas that of the S247N mutation increased from fewer than 1200 per 100 000 individuals before September, 2023, to 1775–2500 per 100 000 individuals between September and October, 2023.
None of the strains collected before July, 2023, harboured dual I223V/S247N mutations; however, since July, 2023, nine of 1023 strains (880 per 100 000 individuals) harboured dual I223V/S247N mutations, with the highest incidence in October, 2023 (five of 169 strains [2959 per 100 000 individuals]).
Of the nine strains with dual I223V/S247N mutations, five were collected from Europe (two from the Netherlands and one each from Norway, Sweden, and France), and four were collected from Oman. Additionally, among these nine strains, three were clustered under clade 6B.1A.5a.2a, and the remaining six were clustered within clade 6B.1A.5a.2a.1 (appendix pp 1–2).
Previous studies have shown that mutations at neuraminidase amino acid residue 223 are associated with an 11–28-fold increase in the half-maximal inhibitory concentration (IC50) for oseltamivir, whereas mutations at residue 247 are linked to a six-fold increase in the oseltamivir IC50, compared with the reference median IC50 values.2,5
However, investigations into such associations for dual I223V/S247N mutations have not been reported. Therefore, in this study, we assessed the susceptibility of a strain with dual I223V/S247N mutation (HKU-231217-085) to neuraminidase inhibitors using a chemiluminescent neuraminidase inhibition assay (appendix p 7).
The IC50 value for HKU-231217-085 was 10·63-fold higher (from 0·429 nM to 4·563 nM) against oseltamivir and 3·38-fold higher (from 0·924 nM to 3·120 nM) against zanamivir than the average IC50 value for the three A(H1N1) strains (HKU-231217-099/2023, HKU-231217-100/2023, and 415742/2009) without the dual mutation (appendix p 5). Hence, strains harbouring dual I223V/S247N mutations can be considered as having reduced inhibition, as per the WHO definition.
In summary, the findings highlight the global emergence of NAI-resistant A(H1N1)pdm09 strains with dual I223V/S247N mutations. These results emphasise the importance of continual monitoring of antiviral resistance in influenza viruses.

While the recent appearance of dual I223V/S247N mutations in A(H1N1)pdm09 sequences are  concerning, it isn't clear whether these are spontaneous mutations occurring people receiving oseltamivir, or if they represent biologically `fit' viruses actually spreading in the wild. 

Of course, in 2008 we saw H1N1 resistance go from one extreme to the other in the space of a little more than a year, so we'll definitely want to keep an eye out for future reports. 

Antivirals, antibiotics, and most anti-fungal medicals all share the same weakness. Over time, and particularly if they are used often enough, the pathogens (viruses, bacteria, or fungi) they were designed to suppress can evolve or mutate enough to render them ineffective

Making both improved surveillance, and better stewardship, crucial going forward.


Sunday, March 17, 2024

Nature Preprint: Serological Analysis in Humans in Malaysian Borneo Suggests Prior Exposure to H5 Avian Influenza

 

#17,952

We've a fascinating, albeit lengthy and fairly technical preprint this week in Nature Portfolio, which describes a seroprevalence survey looking for influenza antibodies (H1N1, H3N2 & 2 HP H5N1) that was conducted in 2015 on 2,000 residents living in Northern (Malaysian) Borneo. 

We've seen similar studies in the past - usually conducted either in the wake of a known H5N1 outbreak or among high risk poultry farmers - which have shown varying rates of presumed previous H5 exposure, including: 

  • In 2012, in H5N1 Seroprevalence Among Jiangsu Province Poultry Workers, we saw a study that found across three locations tested (Gaochun, Jianhu and Gaoyou counties) the percentage of workers testing positive ranged from zero (Gaochun) to 5.38% (95%CI, 2.19%–10.78%) in Gaoyou.
  • In 2011, a study (see Subclinical H5 & H9 Infections In Humans) tested 605 residents in and around Beijing China for antibodies to H5 and H9 avian flu viruses. Of these, just 5 (less than 1%) had antibodies to H9 avian influenza, and only 1 was positive for antibodies to H5.
  • In May of 2009 (see Cambodian Study Finds Rare Asymptomatic H5N1 Infections) we saw a study published in the Journal of Infectious Diseases on more than 600 members of a Cambodian village where 2 human H5N1 cases were detected in 2006. Antibody titers showed that only 1% (7 of 674) of the villagers tested had contracted, and fought off, the H5N1 virus. A figure much lower than many had expected.
  • In 2004 (see The Thailand Serological Study) 322 poultry farmers (in provinces where H5N1 had been detected) were tested. Researchers found that "no poultry workers had microneutralization titers >80, whereas 7 (2%) had lower titers that did not meet the WHO definition for seropositivity".
Complicating matters, detectable levels of influenza antibodies can wane over time and tests are designed to detect specific strains of H5N1, and may not reliably pick up others. 

Conversely, we've seen evidence that exposure to one influenza subtype can sometimes produce cross-neutralizing antibodies to another (see EID Journal: A(H5N1) NA Inhibition Antibodies in Healthy Adults after Exposure to Influenza A(H1N1)pdm09).

In other words, there has always been some degree of ambiguity regarding these seroprevalence surveys. 

Today's preprint not only offers methods for improving the accuracy of seroprevalence testing, it reports likely HPAI H5 exposure in some individuals living in a region of northern Borneo which - at that time - had never reported H5N1 in poultry or people

Exposure to poultry - particularly in live bird markets - is often cited as the biggest risk factor for contracting avian flu (see excerpt from WHO assessment below).

For avian influenza viruses, the primary risk factor for human infection appears to be exposure to infected live or dead poultry or contaminated environments, such as live bird markets. Slaughtering, defeathering, handling carcasses of infected poultry, and preparing poultry for consumption, especially in household settings, are also likely to be risk factors.

Today's study suggests that living in close proximity to large numbers of migratory birds could entail some risks as well, and that those people be included in routine surveillance.  

A finding that is bolstered by last year's H5N1 infection in Chile, where researchers found:

An epidemiological investigation being conducted by the Ministry of Health ascertained that the patient’s residence is located one block from the seashore where seabirds infected with H5N1 viruses had previously been detected. For that reason, an infection of environmental origin is suspected.

I've only included some excerpts from a much longer report, so follow the link to read it in its entirety.  I'll have a brief postscript after the break. 

Serological analysis in humans in Malaysian Borneo suggests prior exposure to H5 avian influenza

Hannah Klim, Timothy William, Caolann Brady, Tock Chua, Helena Brazal Monzó, and 10 more

This is a preprint; it has not been peer reviewed by a journal.
https://doi.org/10.21203/rs.3.rs-4021361/v1

This work is licensed under a CC BY 4.0 License

Abstract

Cases of H5 highly pathogenic avian influenzas (HPAI) are on the rise. Although mammalian spillover events are rare, H5N1 viruses have an estimated mortality rate in humans of 60%. No human cases of H5 infection have been reported in Malaysian Borneo, but HPAI has circulated in poultry and migratory avian species transiting through the region. 

Recent deforestation in Malaysian Borneo may increase the proximity between humans and migratory birds. We hypothesise that higher rates of human-animal contact, caused by this habitat destruction, will increase the likelihood of potential zoonotic spillover events. 

In 2015, an environmentally stratified cross-sectional survey was conducted collecting geolocated questionnaire data in 10,100 individuals. A serological survey of these individuals reveals evidence of H5 neutralisation that persisted following depletion of seasonal H1/H3 binding antibodies from the plasma.

The presence of these antibodies suggests that some individuals living near migratory sites may have been exposed to H5. There is a spatial and environmental overlap between individuals displaying high H5 binding and the distribution of migratory birds. We have developed a novel surveillance approach including both spatial and serological data to detect potential spillover events, highlighting the urgent need to study cross-species pathogen transmission in migratory zones.

         (SNIP)

Here, we perform a serological survey of human influenza exposure in Sabah, Malaysian Borneo to examine the immunological footprint of H5N1 in the region.
  • We present a method for minimizing the impact of influenza subtype cross-reactivity on these serological results. 
  • We define species distributions of domesticated poultry and migratory wild birds and demonstrate that environmental covariates can be used as proxy to model wild bird contact.
  • We additionally identify shared spatial distributions and environmental risk factors between the presence of migratory shorebirds and clade-specific H5N1 seroprevalence using a Bayesian framework. 
This study highlights the need to increase surveillance for rare zoonotic diseases at migratory sites and presents an approach for modelling the distributions of serological results and reservoir species.

         (SNIP)

Discussion

Our results show evidence of heterogenous serological responses to avian influenza in Sabah. These results are spatially correlated and follow the distribution and habitats of migratory wild birds over domesticated poultry in the region. As contact with avian species is currently necessary for a spillover event, it is critical to consider these migratory sights as key interfaces in stopping the viral spread.   

There are shared environmental risk factors between the wild bird distributions and H5 binding (Fig. 4b). The identification of proximity to the sea, low elevation (i.e. sea level) areas, closeness to the forest, and remote areas indicate that we are not only reporting wild migratory shorebirds in their natural habitats16–18, but that these habitats are also areas where binding to the H5 2.3.4 antigen was highest. Shared environmental risk factors and the overlapping spatial distributions between wild birds and H5 binding, suggest that some kind of contact may be occurring between humans and wild birds in these locations. Future studies could collect contemporaneous data on wild bird movements and pathogen presence.

One mechanism of H5 spillover is the spread of the virus from wild birds to domesticated poultry and then into humans36. We can surmise that H5 2.3.4 binding is not related to poultry contact in this study, the inclusion of poultry ownership as a fixed effect did not approve model fit. Although poultry farmers can be at risk of encountering avian influenza36, our findings suggest a need to consider individuals living close to these migratory sites as a part of regular surveillance efforts (Supplemental Fig. 5).

Migratory shorebirds transiting between countries may carry influenza and expose individuals in the surrounding areas to avian viruses. Our results suggest that individuals living within 10km of known migratory locations may have had previously unknown exposure to avian influenza of the 2.3.4 or similar clade. As shorebird habits are being destroyed due to rising sea levels and land use changes, there is an urgent need to consider how this may force zoonotic reservoirs including migratory wild birds into closer contact with humans and increasing the risk of HPAI spillover.

         (Continue . . . ) 


Despite the common assertion (even mentioned in this report) that 60% of those who contract H5N1 have died, that number is based on cases that were sick enough to be hospitalized and lucky enough to be tested. 

It is therefore likely that some number of cases (including mild or asymptomatic) go undetected.  Perhaps many.

Since we don't have a good handle on the denominator, we can't have a lot of faith in CFR estimates.  More reliable seroprevalence techniques could help us better understand that number, as well as track points of entry of the virus into humans.  

Ten years ago, HPAI H5 viruses had difficulty persisting in migratory birds (see PNAS: The Enigma Of Disappearing HPAI H5 In North American Migratory Waterfowl). After causing a record breaking epizootic in North America over the winter of 2014-2015, the virus failed to return the following fall. 

Over the next few years, the virus underwent several reassortments, which have increased its ability to spread via migratory birds.  

  • By 2017, HPAI H5 had crossed the equator for the first time and set up shop in South Africa. 

The virus is constantly evolving, as is its threat to humans.  As a result, we should expect that many of our long-standing beliefs about the virus - and the ways we study it - will have to change in the years ahead.  

To paraphrase an old proverb; Time and viral evolution wait for no man.

Saturday, March 16, 2024

Mpox Update From The CDC, A New Preprint On Transmission & Reports of Spread In Republic of Congo

#17,951

Although the declared global health emergency over the international spread of a new clade (IIb) of Mpox (formerly Monkeypox) was ended after only 10 months in the spring of 2023, we continue to see sporadic infections around the globe, while the more dangerous clade I mpox virus continues to rage (>12,000 cases in 2023) in the DRC,. 

Four months ago, the WHO Reported the 1st Confirmed Cluster Of Sexually Transmitted MPXV Clade 1 in the DRCwarning that `The risk of mpox further spreading to neighbouring countries and worldwide appears to be significant.'

Last week we looked at a report in Eurosurveillance: Ongoing Mpox Outbreak in South Kivu Province, DRC Associated With a Novel Clade I Sub-lineage, which contained the first genomic analysis of samples from a previously unaffected region of the DRC. 

This study revealed a novel clade I sub-linage had emerged - most likely from a zoonotic introduction - with changes that may render current CDC tests unreliable.

Over the past 48 hours there have been media reports from the DRC's neighbor, the Republic of Congo, of an outbreak of Mpox recorded in several regions not previously affected (see Republic of Congo reports its first mpox virus cases in several regions). 

Since I can find no confirmation on their Health Ministry website, we may have to wait for a WHO update. But spread beyond the DRC was one of the risks mentioned last November. 

Meanwhile, we've a new preprint on the medRxiv server, which further confirms last year's finding of (primarily heterosexual) sexual transmission of Mpox clade I in the DRC. 

Epidemiology, clinical characteristics, and transmission patterns of a novel Mpox (Monkeypox) outbreak in eastern Democratic Republic of the Congo (DRC): an observational, cross-sectional cohort study
Leandre Murhula Masirika, Jean Claude Udahemuka, Pacifique Ndishimye, Gustavo Sganzerla Martinez, Patricia Kelvin, Maliyamungu Bubala Nadine, Bilembo Kitwanda Steeven, Franklin Kumbana Mweshi, Léandre Mutimbwa Mambo, Bas B. Oude Munnink, Justin Bengehya Mbiribindi, Freddy Belesi Siangoli, Trudie Lang, Jean M. Malekani, Frank M. Aarestrup, Marion Koopmans, Leonard Schuele, Jean Pierre Musabvimana, Brigitte Umutoni, Ali Toloue, Benjamin Hewins, Mansi Dutt, Anuj Kumar, Alyson A. Kelvin, Jean-Paul Kabemba Lukusa, Christian Gortazar, David J Kelvin, Luis Flores
doi: https://doi.org/10.1101/2024.03.05.24303395

Preview PDF

Summary (abstract)


Background 

In August 2023, an outbreak of mpox was reported in the eastern part, South Kivu Province, of Democratic Republic of the Congo. In this study, we aimed to investigate the origin of this outbreak and to assess how monkeypox virus spread among humans in the city of Kamituga.

Methods 

We performed an observational cohort study by recruiting hospitalized patients with mpox-like symptoms. Furthermore, we compared structured, de-identified case report forms and interviews were conducted to determine the possible origins and modes of transmission of the mpox outbreak. We describe the clinical characteristics and epidemiology observed in reported infections.

Findings 

During the study period (24 September 2023 to 29 January 2024), 164 patients were admitted to the Kamituga hospital, 51 individuals were enrolled in the study and interviewed, and 37 (73%) of 51 individuals received a molecularly confirmed mpox diagnosis. 

The median age for males was 24 years (IQR 18-30; range 14-36) and 19 years for females (IQR 17-21; range 1-59). The cohort was comprised of 47 (92%) of 51 individuals who identified as heterosexual, and two (4%) of 51 as bisexual, with 31 (61%) of 51 individuals sexually active with more than one partner within the last six months. 

The direct transmission routes are unknown; however, it is expected that the majority of infections were transmitted via occupational exposures. Out of the 51 individuals, 24 (47%) were professional sex workers (PSWs), while five (10%) were gold miners, 6 (12%) were students, and four (8%) were farmers; the remaining individual occupations were unknown. 

The most common symptoms associated with clinical mpox diagnosis were fever, which was described in 38 (75%) of 51 individuals, and rash, which was described in 45 (88%) of 51 individuals. Among those with a rash, 21 (41%) of 51 individuals experienced oral lesions, and 32 (63%) of 51 presented anogenital lesions. Mpox viral DNA was detected by qPCR from vaginal, penile, and oral swabs in 37 (73%) of 51 enrolled individuals. Two deaths were reported.

Interpretation 

In this observational cohort study, mpox virus infection caused symptoms in a wide age range of participants with most cases presenting in sexually active individuals. Symptoms included fever, cough, lymphadenopathy, sore throat, chills, headache, back pain, muscle pain, vomiting, nausea, conjunctivitis, and rash (oral and anogenital). Heterosexual partners dominated human-to-human contact transmission suggesting that heterosexual close contact is the main form of transmission in this outbreak. Furthermore, Professional Sex Workers (PSWs) were the dominant occupation among infected individuals, indicating that PSWs and clients may be at higher risk for developing mpox virus infections.

The changing epidemiology and genetic evolution of mpox clade I in central Africa has sparked a number of risks assessments over the past few months, including:

There have been no cases of the type of mpox spreading in DRC reported in the United States at this time. The risk to the general public in the U.S. from the type of mpox circulating in the DRC is low.

But that assessment could change. Which is why the CDC continues to update their Mpox web page , adding the following guidance yesterday (March 15th).


Signs and Symptoms March 15, 2024

Mpox in Animals and Pets March 15, 2024

About Mpox March 15, 2024

During the decade leading up to Mpox clade IIb's world tour (Spring 2022), we saw repeated warnings that the virus was evolving into a more transmissible disease threat (see 2016's EID Journal:Extended H-2-H Transmission during a Monkeypox Outbreak).

A 2020 report, published by the Bulletin of the World Health Organization, warned that our waning immunity to smallpox put society at greater risks of seeing Monkeypox epidemics (see WHO: Modelling Human-to-Human Transmission of Monkeypox).

And in early 2023, in EID Journal: Monkeypox Virus Evolution before 2022 Outbreak, researchers suggested that` . . . the most likely scenario is that there has been silent and undetected circulation of MPXV, possibly including multiple non–MPXV-endemic countries outside Africa, since the 2017–2018 outbreak.'

While there are no guarantees that Clade I Mpox will follow suit, similar warning signs are there. Just as they are for novel or avian flu, Lassa Fever, Nipah, MERS-CoV, and an increasing array of other emerging infectious diseases.

A reminder that nature is nothing, if not persistent.

Friday, March 15, 2024

ODNI 2024 Annual Threat Assessment: Health Security


#17,950

While this blog is normally narrowly focused on emerging infectious diseases - with a smattering of individual and community preparedness - from time to time we take a look at (mostly governmental) reports on wider threats. 

In the past we've looked at such diverse topics as:

FEMA: Preparing the Nation for Space Weather Events




Every year the Office of the Director of National Intelligence (ODNI) releases an unclassified report on threats to our national security, which covers a wide range of scenarios.  One of the threats mentioned every year has been that of a pandemic, although prior to 2020 it was given fairly short shrift.

The only mention of the word `pandemic' in the 2019 edition, was limited to:

Global Health 

We assess that the United States and the world will remain vulnerable to the next flu pandemic or large scale outbreak of a contagious disease that could lead to massive rates of death and disability, severely affect the world economy, strain international resources, and increase calls on the United States for support. 

Although the international community has made tenuous improvements to global health security, these gains may be inadequate to address the challenge of what we anticipate will be more frequent outbreaks of infectious diseases because of rapid unplanned urbanization, prolonged humanitarian crises, human incursion into previously unsettled land, expansion of international travel and trade, and regional climate change.

In light of the events of the past 4 years, it is no surprise that in the latest edition - published last week by the ODNI - the issue of global health threats is given more attention.  

Some of the issues discussed include increased risks for future pandemics, failures of nations to report outbreaks in a timely fashion (as required by international law), and the potential risk from lab leaks. 

In the report's forward, the agency warns:

The accelerating effects of climate change are placing more of the world’s population, particularly in low- and middle income countries, at greater risk from extreme weather, food and water insecurity, and humanitarian disasters, fueling migration flows and increasing the risks of future pandemics as pathogens exploit the changing environment

 

Health Security 

National health system shortfalls, public mistrust and medical misinformation, and eroding global health governance will impede the capacity of countries to respond to health threats. Countries remain vulnerable to the introduction of a new or reemerging pathogen that could cause another devastating pandemic. 

  • The predicted shortage of at least 10 million healthcare workers by 2030 will occur primarily in low- and middle-income countries. 

  • Global health governance and adherence to UN health protocols may be eroded during the coming year by continued disregard by governments of international health institutions and norms and adversary interference in global health initiatives. 

  • Drivers for infectious disease emergence are on the rise, including deforestation, wildlife harvesting and trade, mass food production, and lack of international consensus on biosafety norms. These drivers are compounded by factors that facilitate global spread, such as international travel and trade, inadequate global disease surveillance and control, weakened health systems, public distrust, and medical misinformation. 

  • Significant outbreaks of highly pathogenic avian influenza, cholera, dengue, Ebola, monkeypox, and polio have stretched global and national disease detection and response systems further straining the international community’s ability to address health emergencies.

The origins of the SARS-CoV-2 virus remains murky, as China continues to resist sharing information: 

 

While much of this 41-page report is focused on state actors (China, Russia, Iran, North Korea, etc.), it also covers growing technological concerns which include the proliferation of AI, Cyber threats, and synthetic biotechnologies (see National Academy Of Sciences: Biodefense in the Age of Synthetic Biology).

Disruptive Technology 

New technologies—particularly in the fields of AI and biotechnology—are being developed and are proliferating at a rate that makes it challenging for companies and governments to shape norms regarding civil liberties, privacy, and ethics. 

The convergence of these emerging technologies is likely to create breakthroughs, which could lead to the rapid development of asymmetric threats—such as advanced UAVs—to U.S. interests and probably will help shape U.S. economic prosperity. 

• For example, stealth technology has significantly impacted conventional defense systems and has driven the efforts of varying countries to start a new round of research on detection systems and guided weapons. A key trend is the development of advanced materials with enhanced stealth properties with reduced reflection and absorption properties. 

Advances in AI and new machine learning models are moving AI into its industrial age, with potentially huge economic impacts for both winners and followers and unintended consequences— from rampant deepfakes and misinformation to the development of AI-generated computer viruses or new chemical weapons. Generative AI is a means for discovering and designing novel technologies and advanced system-level processes that could strengthen a country’s technological, economic, and broader strategic competitiveness. 

• China is pursuing AI for smart cities, mass surveillance, healthcare, drug discovery, and intelligent weapons platforms. Chinese AI firms are already world leaders in voice and image recognition, video analytics, and mass surveillance technologies. 

• PRC researchers have described the application of generative AI to drug discovery as “revolutionary.” On average, it takes more than 10 years and billions of dollars to develop a new drug. AI can make drug discovery faster and cheaper by using machine-learning models to predict how potential drugs might behave in the body and cut down on the need for painstaking lab work on dead-end compounds.

• Russia is using AI to create deepfakes and is developing the capability to fool experts. Individuals in warzones and unstable political environments may serve as some of the highest value targets for such deepfake malign influence.

Innovators in synthetic biology probably will control new military and commercial applications and hold trillions of dollars in production capacity, including supply chains for products that vary from disease-resistant crop seeds to metals to pharmaceuticals. 

• Countries, such as China and the United States, that lead biotechnological breakthroughs in fields such as precision medicine, synthetic biology, big data, and biomimetic materials, will not only drive industry growth, but also international competition and will exert substantial influence over the global economy for generations 

Admittedly this report makes for sobering reading, and while there isn't much any of us can to mitigate most of these threats, we can be better prepared if, and when, the next crisis occurs. 

Each year FEMA conducts a nationwide poll on preparedness, and they released their 2023 survey last December. Even though these are self-reported assessments, and `being prepared' means different things to different people, they report some small progress over the past 12 months.

It is a mixed bag, however.  More people have assembled supplies, but fewer people report practicing emergency drills or habits More have learned their evacuation routes, but fewer have made a plan.  And while more have tested a family communication plan, fewer report having signed up for alerts or warnings. 

While you can't be prepared for every eventuality, there are some basic goals one should strive for.

So . . . if a disaster struck your region today, and the power went outstores closed their doors, and water stopped flowing from your kitchen tap for the next 7 to 14 days . . . are you ready with:

  • A battery operated NWS Emergency Radio to find out what was going on, and to get vital instructions from emergency officials
  • A decent first-aid kit, so that you can treat injuries
  • Enough non-perishable food and water on hand to feed and hydrate your family (including pets) for the duration
  • A way to provide light when the grid is down.
  • A way to cook safely without electricity
  • A way to purify or filter water
  • A way to handle basic sanitation and waste disposal. 
  • A way to stay cool (fans) or warm when the power is out.
  • A small supply of cash to use in case credit/debit machines are not working
  • An emergency plan, including meeting places, emergency out-of-state contact numbers, a disaster buddy, and in case you must evacuate, a bug-out bag
  • Spare supply of essential prescription medicines that you or your family may need
  • A way to entertain yourself, or your kids, during a prolonged blackout

If not, you've got some important work to do. A good place to get started is by visiting Ready.gov.

Thursday, March 14, 2024

Eurosurveillance: Ongoing Mpox Outbreak in South Kivu Province, DRC Associated With a Novel Clade I Sub-lineage

 

Countries with endemic Mpox- Credit WHO

#17,949


Clade I Mpox (formerly Monkeypox) - which is endemic to central Africa (see map at top of post) - is far more severe than the Clade IIb Mpox virus which began its world tour in 2022. It appears more transmissible, can produce more disfiguring lesions, and is associated with a much higher fatality rate.

While we've seen no indication of international spread of the Clade I Mpox virus, last year's discovery of two clusters of sexually transmitted Mpox (in MSM and sex workers) (see WHO Reports 1st Confirmed Cluster Of Sexually Transmitted MPXV Clade 1 in the DRC) - has raised concerns that - like Clade IIb - this more aggressive strain could eventually turn up outside of Africa.

Since then we've looked at several reports and risk assessments, including:   

CDC HAN Advisory #00501: Mpox Caused by H-2-H Transmission with Geographic Spread in the Democratic Republic of the Congo

ECDC Risk Assessment On Transmission & Spread of Clade I Mpox From The DRC

CDC EID Journal: Clade I–Associated Mpox Cases Associated with Sexual Contact, the Democratic Republic of the Congo
Like all viruses, Mpox continues to evolve and diversify, as was discussed in the 2014 EID Journal article Genomic Variability of Monkeypox Virus among Humans, Democratic Republic of the Congo, where the authors cautioned:

Small genetic changes could favor adaptation to a human host, and this potential is greatest for pathogens with moderate transmission rates (such as MPXV) (40). The ability to spread rapidly and efficiently from human to human could enhance spread by travelers to new regions.

Today we have a the first report on a genomic analysis of samples from a recent outbreak in a previously unaffected region of the DRC, which reveals a novel clade I sub-linage has emerged - most likely from a zoonotic spillover - that may render current CDC tests unreliable. 

First some excerpts from the Eurosurveillance report (follow the link to read it in its entirety), after which I'll return with a postscript.
Rapid communication Open Access
 
Ongoing Mpox Outbreak in Kamituga, South Kivu province, associated with Monkeypox virus of a novel Clade I sub-lineage, Democratic Republic of the Congo, 2024


https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2024.29.11.2400106

In the Democratic Republic of the Congo (DRC), the numbers of people with suspected infection with monkeypox virus (MPXV), the virus that causes mpox, have increased since the start of 2023. A total of 12,569 suspected mpox cases have been reported up to 12 November, the highest number of annual cases ever recorded [1]. The case fatality rate has been estimated at 4.6% [1]; moreover, new cases have occurred in geographical areas of the country where the disease was previously not observed, such as Kinshasa and South Kivu province [1,2].
Despite this concerning situation, there is only limited genomic information available on the circulating viruses, which suggests that they belong to Clade I [3]. To gain more insight into the characteristics of the strains causing the epidemic, as well as assurance that current and commonly used molecular assays to diagnose MPXV infections can detect these strains, we sequenced monkeypox viral genomes from recently diagnosed cases in South Kivu, DRC.

Case definitions and patient characteristics
 

A case was listed as ‘suspect’ if presenting with an acute illness with fever, intense headache, myalgia, and back pain, followed by 1 to 3 days of a progressively developing rash often starting on the face and spreading on the body. A confirmed mpox case had a monkeypox virus infection which was laboratory-confirmed by PCR. A case was listed as ‘probable’ when satisfying the clinical definition of a suspected case and having an epidemiological link to a confirmed or probable case; a probable case was not laboratory-confirmed [4].

The study involved patients from South Kivu province in the territory of Mwenga, who were hospitalised in the Kamituga hospital, which is in the Kamituga health zone. The first mpox cases in this area were reported from September 2023 onwards.

A total of 10 patients were included in the study. All were young adults in their late teenage up to the age of mid-20 years and five were male and five females. Regarding professions comprised, the majority of the concerned individuals were sex workers. For these patients, admission to the Kamituga Hospital had been based on clinical diagnosis of mpox by hospital staff. According to routines, skin lesion and oropharyngeal swabs collected from the patients had been sent to the national medical research institute of the DRC (Institut National de la Recherche Biomédicale; INRB) in Goma for MPXV infection confirmation by PCR, and all patients had tested positive for the virus.

(SNIP)

The monkeypox virus outbreak strain in South Kivu lacks the target sequence used for identifying Clade I viruses
 
To check if the strains obtained in the current study could be detected by commonly used molecular assays to diagnose MPXV infections, their sequences were aligned to the closely related Clade I sequence EPI_ISL_13056243. This sequence matches primer and probe sequences recommended by the United States (US) Centers for Disease Control and Prevention (CDC) to diagnose MPXV [15]. The alignment was assessed using an in-house Primer Check Tool (https://viroscience-emc.shinyapps.io/primer-check/ ).


While the generic primers and probe still seem to be functional with only one mutation in the reverse primer, the specific Clade I virus real-time PCR target, recommended by the US CDC, is absent in the genomes of the novel MPXV strains ( Figure 2 and Supplementary Figure 3). The observed deletion is 1,114 nt in size and results in the complete deletion of the OPG032 gene. The coverage of this region ranged between 76× and 941× sequence reads depending on the sample. Due to the deletion, the rapid US CDC method to identify Clade I in newly diagnosed mpox cases is most likely not reliable for detection of the novel sub-lineage identified in the current study.

          (SNIP)

Discussion 

From the mpox outbreak in Kamituga, South Kivu, six near-to-complete MPXV sequences derived from local patients hospitalised with mpox were obtained. Phylogenetic analyses of these sequences together with those available for other Clade I and II viruses, placed them in a new sub-lineage near the root of Clade I, which suggests that the outbreak in this region results from a new introduction, most likely from a zoonotic reservoir. Although sequences from a small 2023 Kinshasa outbreak are not publicly available, the placement of those sequences in a published phylogenetic tree [3] suggests that the Kamituga outbreak is not related to the outbreak in Kinshasa. Our findings therefore suggest that there are at least two independent outbreaks ongoing in DRC.
Remarkably, a large stretch of sequence in the genomes belonging to the novel MPXV sub-lineage was absent compared to other Clade I genomes, which would lead to failure of the Clade I-specific real-time PCR recommended by the US CDC [15]. A deletion in the same region is also observed in Clade II MPXV, and this was the basis for clade assignment using the CDC PCR.
Therefore, if the viruses from the new lineage were to spread internationally, this molecular surveillance tool can no longer be used to rapidly identify these Clade I virus infections while the global Clade IIb outbreak is ongoing.
Conclusion
Altogether, the findings of this study strongly suggest that whole genome sequencing of a larger subset of MPXV currently causing mpox cases in DRC, as well as public data sharing, are essential to understand the ongoing epidemic. Further studies, sequencing and analyses are ongoing, but in accordance with the above statement we believe that rapid public sharing of all available information is essential to help to better understand and contain the current mpox emergence.

Although many experts voiced surprise when Mpox clade IIb began spreading internationally in the spring of 2022, we'd seen plenty of warning signs over the years, including in PLoS NTD: The Changing Epidemiology of Human Monkeypox—A potential threat?, which had been published just months prior. 

Most were ignored.  

While there are no guarantees that Clade I Mpox will follow suit, familiar warning signs are flashing once again. And round two may prove more difficult to contain than round one. 

Australian Government: Seabird & Seal Monitoring for HPAI H5




#17,948

Despite lying beneath both the West Pacific and East Asian–Australasian Flyway - which funnel migratory birds from high latitudes of Alaska and Siberia south, deep into the Southern Hemisphere - Australia, New Zealand and the islands of Oceania have yet to see the arrival of HPAI H5. 

Nine years ago, when HPAI H5N8 was winging its way around the world, we looked at Australia's Wild Bird Avian Influenza Surveillance, where their government reported:

Surveillance continues to show H5N1 avian influenza virus is not present in Australia. Waterfowl, which are the normal hosts of avian influenza and are thought to have had a role in the spread of the H5N1 virus in Europe, Asia and Africa do not migrate to Australia. A number of species of wading birds do migrate to Australia but they are not the normal hosts or spreaders of avian influenza. Australia’s strict quarantine measures prevent the disease coming into Australia through imported birds or poultry products. 

Even though H5N1 emerged in Southeast Asia more than 25 years ago, and has been widely reported across much of the Indonesian archipelago and parts of New Guinea, the virus has never managed to get a foothold in Oceania. 

This lack of HPAI H5 has often been attributed to the Wallace and Weber lines; imaginary dividing lines used to mark the difference between animal species found in Australia and Papua New Guinea and the rest of Southeast Asia (see 2008 study Will Wallace’s Line Save Australia from Avian Influenza?).

Separated by a relatively narrow strait, on the western side you'll find Elephants, monkeys, leopards, tigers, and water buffalo while on the eastern side, you'll mostly find marsupials (kangaroos, Koalas, wombats, etc.).

These stark faunal differences also extend to birds, reptiles, and even insects.

Importantly for avian flu, very few migratory birds appear to cross the Wallace line (see The Australo-Papuan bird migration system: another consequence of Wallace's Line).

That said, there were brief reports in 2007 of H5N1 being detected in poultry in both West Papua and the Maluku Islands; both of which lie on the Eastern side of the Wallace line. Details (and sequences) are limited, since the Indonesian government was notoriously refusing to share bird flu information at the time.  

The arrival of HPAI H5 to Antarctica over the past few months (albeit, thousands of kilometers distant  from Oceania - see map below) has the potential to provide the HPAI H5 virus with a different approach - from the south - assuming the virus is able to spread widely in Antarctica's wild birds and mammals. 


Credit OFFLU 

Last December OFFLU warned:

Given movement data demonstrating connectivity between the polar front to both the Antarctic and Subantarctic islands of Oceania, and Oceania itself, it is plausible that if HPAI H5 were present in the Antarctic region directly south of Oceania, it could be introduced to Oceania.

Overnight the Australian Antarctic Program - a part of the Australian Government's Department of the Environment - published an update on their surveillance program for avian flu, which identified skuas as the biggest threat for bringing the virus into the country.

I've only posted some excerpts from a longer report. Follow the link to read it in its entirety. 
SEABIRD, SEAL MONITORING CRUCIAL AS AVIAN INFLUENZA REACHES ANTARCTICA

Home > News and media > 2024 >

14 MARCH 2024

Monitoring bird and seal colonies in Antarctica has taken on a new urgency with the detection of the highly pathogenic Avian Influenza on the continent for the first time. The Council of National Managers of Antarctic Programs (CONMAP) has confirmed that two dead skuas found near the Argentinian Primavera station on the Antarctic Peninsula tested positive to the virus in late February.

There were always fears Avian Influenza would reach Antarctica this season but seabird ecologist Dr Louise Emmerson said it was a shock nonetheless.

“It has had a devastating effect in nearby South America,” she said.

“Tens of millions of birds have died globally and there is evidence that it also had a dramatic impact on southern elephant seals and fur seals.

(SNIP)

Cruise ships adopt new biosecurity measures

Dr Emmerson spent some of the summer monitoring bird colonies for the virus from a cruise ship on the Antarctic Peninsula with a colleague from Oxford University in the UK.

Dr Emmerson and her colleague, Dr Tom Hart, would join the expedition team on a zodiac and head out on a scouting trip to a penguin colony.

They would visually scout for signs of the disease and go ashore first, to conduct drone surveys of the penguin colonies and check the site was clear for passengers.

At the time, there were no signs of the mass deaths or neurological symptoms characteristic of the disease, but biosecurity measures on cruise ships had been ramped up in response to the risk.

“Before passengers came down to get on a small boat to visit a penguin colony they’d take their hiking boots and poles and their backpacks and camera bags – anything they were going to take into the field, and they’d disinfect them.

“The cruise ship provided rubber boots for everyone to walk in, and an outer layer with a hood and walking poles for people to use so we could make sure everything was clean.

“Then when we got back, everyone would scrub their boots and poles and make sure everything that had touched the ground was disinfected.

“This year, we didn’t allow people to sit on the ground or put their packs on the ground. But the passengers were great about it, they took the risk to the wildlife and themselves very seriously.”
"The species we were always most worried about was skuas"

Some colonies along the Peninsula had been closed to visitors while suspect deaths were investigated but none were confirmed as Avian Influenza.

However by then, the virus was confirmed on South Georgia and the Falkland Islands.

“The species we were always most worried about was skuas because they’re scavengers and they undertake considerable winter migrations. For example, the skuas from East Antarctica fly all the way up to Japan, Korea and China so the chance of them being exposed to the disease was always greater. Penguins that breed in Antarctica don’t go very far north in winter so if they get it, it will be from other wildlife, including the northerly migrating seabirds, or humans.”

Camera network vital for monitoring

As part of the summer monitoring project, Dr Emmerson and Dr Hart also maintained and downloaded data from Dr Hart’s camera network, set up along the Antarctic Peninsula to monitor nesting sites.

The network is based on an idea pioneered in Hobart by Australian Antarctic Division engineers in the early 2000s.

The AAD’s network has about 44 cameras set up at key locations along the East Antarctic coastline, taking ten photos a day of about 30 to 40 nests per camera.

Species monitored include surface nesters like Adelie penguins, cape petrels, fulmars, southern giant petrels and emperor penguins.

“The cameras are on tripods and they’re very robust,” Dr Emmerson said.

“We can use the images to monitor when the birds arrive and leave, the timing of chick creche and their breeding success.

(SNIP)
The AAD will also revisit its bird flu management protocols.

“We need to make sure all our expeditioners know what their responsibilities are and where the disinfectant is and what to do if there are signs of the virus,” Dr Emmerson said.

“We can’t stop it spreading through the natural migratory process, but we can stop ourselves moving it around and that’s what we need to focus on.”

While the arrival of HPAI H5 to Oceania is far from assured, should it happen, the virus would gain access to a number of new avian and mammalian species (including marsupials), along with a fresh array of genetically distinct LPAI viruses which which to potentially reassort.

Whether that would ultimately help the virus is unknown, but it is an unsupervised field experiment that is best avoided if possible.