WHO Meets With Chinese Officials - Requests More Information On Mainland COVID Outbreak

 


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The lack of openness on the part of China regarding their current COVID epidemic has led numerous countries to reinstate testing requirements - either before departure or upon arrival - for travelers coming from China (see Spain, Italy, Japan & India Reinstate Testing For Travelers From China).

While the IHR 2005 rules and regulations require all countries to report novel disease outbreaks, and to provide sequences of novel viruses to the WHO, China - along with a number of other countries - often only comply with this international agreement when it suits them. 

Frustratingly, from Indonesia’s refusal to share H5N1 virus samples to the Saudi’s chronic foot dragging on MERS, to China's chronic belated reporting on avian flu, we’ve seen many examples where the spirit – and often the actual letter – of the 2005 IHR has been ignored by member nations.

As a result, we often only belatedly learn about spillovers of avian flu, coronaviruses, and other public health threats . . .  assuming we hear about them at all. 

Although China's daily reporting of COVID cases and deaths for the past 3 years has been highly suspect at best, over the past couple of weeks it has been completely dismantled as their COVID pandemic has abruptly worsened. 

On Christmas day - as anecdotal reports of swamped hospitals, and crematoriums operating 24/7, filtered out of the country - China's NHC announced they would no longer be reporting any data at all. 

While the WHO rarely publicly calls out member nations for not abiding by the IHR 2005 regulations (see here and here for two examples), late yesterday they published the following statement regarding a meeting with Chinese officials over their lack of disclosure. 

WHO meets with Chinese officials on current COVID-19 situation

30 December 2022
Statement

A high-level meeting took place on 30 December between WHO and China about the current surge in COVID-19 cases, to seek further information on the situation, and to offer WHO's expertise and further support.

High-level officials from China's National Health Commission and the National Disease Control and Prevention Administration briefed WHO on China's evolving strategy and actions in the areas of epidemiology, monitoring of variants, vaccination, clinical care, communication and R&D.

WHO again asked for regular sharing of specific and real-time data on the epidemiological situation — including more genetic sequencing data, data on disease impact including hospitalisations, intensive care unit (ICU) admissions and deaths — and data on vaccinations delivered and vaccination status, especially in vulnerable people and those over 60 years old. WHO reiterated the importance of vaccination and boosters to protect against severe disease and death for people at higher risk.

WHO called on China to strengthen viral sequencing, clinical management and impact assessment, and expressed willingness to provide support on these areas, as well as on risk communications on vaccination to counter hesitancy. Chinese scientists are invited to engage more closely in WHO-led COVID-19 expert networks including the COVID-19 clinical management network. WHO has invited Chinese scientists to present detailed data on viral sequencing at a meeting of the Technical Advisory Group on SARS-CoV-2 Virus Evolution on 3 January.

WHO stressed the importance of monitoring and the timely publication of data to help China and the global community to formulate accurate risk assessments and to inform effective responses.

While the IHR 2005 is described as a `legally binding' agreement, there is little recourse for the WHO and the international community when a nation decides - for political, economic, or prestige reasons - to withhold crucial information. 

Seven years ago, in Adding Accountability To The IHR, we looked at the Ebola Interim Assessment Panel's recommendations for strengthening the IHR. It is fair to say that whatever changes have been made, have not been sufficient.  

Hopefully, whatever COVID is brewing behind closed doors in China won't blow up in our faces.  But the problem doesn't end there. All around the world there are ample opportunities for novel viruses to spillover into humans; avian flu, swine flu, bat coronaviruses, and more.  

Unless, and until, all nations take the reporting of these types of events seriously - and share them as required by the IHR 2005 agreement - the world remains at significant risk of being blindsided by another emerging pandemic threat. 

And as bad as COVID has been, the next one could be worse. 

CDC Nowcast: A New Dominant Variant (XBB.1.5) For A New Year

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Although XBB.1.5  didn't even appear on last week's CDC Nowcast, we've been following a related Omicron variant - XBB - for about a month.  Last week it had shot up to about 18% of the known cases (from 7.2% two weeks ago) - although mostly in the Northeastern United States - but this week we learn that most of those cases were actually XBB.1.5, and it is growing at an impressive rate. 

Revised estimates (see below) indicate that XBB.1.5 has grown over 30-fold in the past month, going from 1.3% to over 40% of cases in the United States.  The parental XBB variant is now estimated to account for about 3.6% of cases. 

XBB.1.5 is most prevalent in HHS Regions 1 & 2 (see map below), and least common in the Midwest, but given its rapid rise in the Northeast, it will certainly gain ground across the nation in the next week or two. 

Right now, the only variant showing consistent growth is XBB.1.5.  The briefly dominant tag-team of BQ.1/BQ.1.1 appear to have peaked in early December with about a 63% share of the nation's cases.  

While data on this XBB.1.5 is limited, we have seen risk analyses suggesting that it may be the most transmissible, and immune evasive, variant we've seen to date.  The rapid (some would say spectacular) rise of XBB.1.5 in such a short time would seem to validate those concerns. 

What we don't know is whether XBB.1.5 produces more severe illness than earlier Omicron variants.  Hospitalization rates do seem to be rising in regions hardest hit by XBB, but it will take time to sort out the data, and the relative impacts of COVID vs. Influenza vs. RSV. 

How long XBB.1.5 will reign, and how bad it will be, remain open questions.  For now we know that wearing a face mask can reduce your risks of contracting the virus, and the new bivalent COVID booster shot is believed to be more protective against severe illness (but not necessarily infection) than the older shot. 

While pundits, politicians, and the media keep saying that we are nearing the end of this pandemic, the virus apparently hasn't gotten the memo.

And so we begin our 4th year of COVID with a new dominant strain sweeping the nation. 

Three Years Into The Pandemic: Spain, Italy, Japan & India Reinstate Testing For Travelers From China

 AFD Blog Tuesday, December 31, 2019

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We are literally only hours away from the third anniversary of our first indication of a serious outbreak in Wuhan, China of what would eventually become known as COVID-19 (aka SARS-CoV-2). 

While it would take several days for mainstream media to take notice - within 48 hours I'd written 6 blogs on the topic - and the newshounds on FluTrackers had amassed scores of reports.

But despite our early concerns, none of us could have predicted how dramatically the world was about to change, or that we'd still dealing with it 3 years later.

COVID has rewritten the textbooks on what a pandemic could be (in this case, a coronavirus), how long it could last (> 3 years), and the lengths countries would go (lockdowns) to prevent transmission.  

Early assurances that the virus was `mild', that asymptomatic transmission or airborne spread were not factors, and that the virus was `remarkably stable' and `unlikely' to mutate substantially all proved overly optimistic. 

Equally bad advice was proffered on `face masks' being useless (see below), and that `herd immunity' would end the outbreak quickly (see GAO: A Herd Immunity For COVID-19 Primer). 

On the positive side, we saw a number of (initially) highly effective vaccines developed in record time, and emergency vaccine production far exceeded anything that had been done before.  New treatments (some of which are no longer effective) were developed, including monoclonal antibodies and antivirals. 

Despite all of this, billions of people have likely been infected (many more than once), and an unknown number of people have died (estimates range from 7 to > 20 million).  In truth, we'll never really know its full impact. 

While initial expectations (based largely on the 1918 pandemic) were that this pandemic could last up to 18 months, we find ourselves about to enter our 36th month and - after six months of increasingly relaxed restrictions - the recent explosion of cases in China has many countries reimposing COVID tests before entry. 

Yesterday the United States Department of State issued a travel advisory for all arrivals from China, reinstating the requirement for a negative COVID test within 2 days of departure, joining a growing number of other countries including Spain, Italy, Japan, and India. 

These measures are being implemented not due to something we know, but due to what we don't know.  As discussed ad nauseam in this blog, China has a long history of holding back `bad' or `unflattering' news from its people, and the world. 

Now, with numerous anecdotal reports coming out of China of increased deaths, swamped hospitals, and `new' symptoms (all unverified) - and China's NHC shutting down official reporting -  the rest of the world is left wondering whether that a new, potentially worse, variant has emerged in China. 

Even the Secretary-General of the World Health Organization has expressed concerns about this lack of openness. 

 

I would stress that we have no information that a new variant has emerged, and no way to know the likelihood of that happening.  But the absence of reliable data from China is forcing many countries to take expensive, and sometimes divisive, steps to protect their people. 

Sadly, this is the sort of crisis that the 2005 IHR (International Health Regulations) was designed to prevent. It requires that all member nations develop mandated surveillance and testing systems and to report certain disease outbreaks and public health events to WHO in a timely manner (see Adding Accountability To The IHR).

But - for a variety of reasons - that doesn't happen nearly as often, or as immediately, as it should. For some countries, it boils down to a lack of resources, for others, there are political or economic incentives to stay silent.  

As a result we only rarely, and often belatedly, hear about human infections with novel viruses (e.g. MERS-CoV, H5N6, H5N1, H3N8, etc.), and large epidemics can rage under an `information blackout'. 

In the summer of 2021, in PNAS Research: Intensity and Frequency of Extreme Novel Epidemics, researchers suggested that the probability of novel disease outbreaks will likely grow three-fold in the next few decades.  

A short list of recently emerging zoonotic threats can be viewed in NEJM: A Novel Henipavirus With Human Spillover In China).

Whether COVID is about to enter a new, more dangerous phase - or China's epidemic is COVID's last hurrah - the world will almost certainly be faced with many new emerging disease threats in the years ahead. 

We either figure out how to effectively and consistently share disease and outbreak information, or we are going to find ourselves going from one public health crisis to the next, with little time to relax in between. 

FDA: SARS-CoV-2 Viral Mutations - Impact on COVID-19 Tests

Credit FDA 

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For evidence of COVID's continued evolution we need look no further than the loss of effectiveness of all of the monoclonal antibody treatments developed during the first two years of the pandemic (see FDA Withdraws EUA For Last COVID Monoclonal Antibody: Bebtelovimab) and the reduced  effectiveness of our current vaccines against newer variants.

Several antiviral medications (e.g. Paxlovid, Veklury and Lagevrio) still remain viable treatment options, along with steroids and supportive therapy, but newer, updated therapeutics are badly needed. 

This continual evolution can also affect the reliability of both laboratory and home rapid testing kits. While most of the existing tests are still believed effective, today the FDA has released a lengthy review of the evolution of the virus, and has listed a small number of tests that may be adversely impacted. 

Due to its length, I've only posted some excerpts, so follow the link to read it in its entirety. This, unfortunately, is likely to become a bigger issue over time. 

SARS-CoV-2 Viral Mutations: Impact on COVID-19 Tests

The SARS-CoV-2 virus has mutated over time, resulting in genetic variation in the population of circulating viral strains, also called lineages. This genetic variation may impact the virus's properties such as transmission (for example, it may spread more easily) or the severity of symptoms on infected individuals (for example, it may cause more severe disease).

This page provides information about tests authorized by the U.S. Food and Drug Administration (FDA) for the identification and differentiation of specific SARS-CoV-2 mutations and lineages as well as the impact of viral mutations on COVID-19 tests.

Recommendations for clinical laboratory staff and health care providers and information about certain tests for which the FDA has identified potential impacts on performance due to SARS-CoV-2 genetic mutations are also included on this page. The FDA will update this page when significant new information becomes available, including when the FDA's analyses identify tests for which performance may be impacted for known SARS-CoV-2 variants.

For consumer information on COVID-19 testing, visit Coronavirus Disease 2019 Testing Basics.

On this page:

• Genetic Variations: Background and Considerations
• General Information for Clinical Laboratory Staff and Health Care Providers
• Genotyping Tests: Tests Authorized for Identification of Genetic Variation
• Omicron Variant and Sub-Variants: Background
• Omicron Variant and Sub-Variants: Impact on Antigen Diagnostic Tests
• Tests Expected to Have Reduced Performance for the SARS-CoV-2 Omicron Variant and Sub-Variants
• Omicron Variant and Sub-Variants: Impact on Molecular Tests
• Tests Expected to Have Reduced Performance for the SARS-CoV-2 Omicron Variant and Sub-Variants
• Tests Expected to Fail to Detect the SARS-CoV-2 Omicron Variant and Sub-Variants
• Issue Resolved: Tests Previously Expected to Fail to Detect the SARS-CoV-2 Omicron Variant and Sub-Variants
• Tests with Detection Patterns that May Be Associated with the SARS-CoV-2 Omicron Variant and Sub-Variants
• Other Variants: Molecular Tests that May Be Impacted

(SNIP)

Tests Expected to Have Reduced Performance for the SARS-CoV-2 Omicron Variant and Sub-Variants

Luminostics, Inc. Clip COVID Rapid Antigen Test (as of 12/13/2022)

Manufacturer: Luminostics, Inc.

Test Name (Link to EUA): Clip COVID Rapid Antigen Test

The FDA's Analysis: Performance may be impacted when a patient sample containing the SARS-CoV-2 virus with certain viral mutations is tested. The mutations impacting performance include a mutation of the nucleocapsid protein, E136D, associated with the BE.1 and BQ.1/BQ.1.1 omicron variants.

Potential Impact: While the impact does not appear to be significant, the FDA is providing this information out of an abundance of caution.

Notes: The FDA's analysis included information provided by the manufacturer and the NIH RADx program.

Recommendations for Clinical Laboratory Staff and Health Care Providers Using This Test

Be aware of the current instructions for use for the Clip COVID Rapid Antigen Test, especially the "Results and Interpretation" tables, which describe when a result is positive, negative, invalid, and aborted, and how to interpret each result. In addition, please refer to the "Antigen EUA Revisions for Serial (Repeat) Testing" for further information regarding updates to the authorized uses regarding the need for serial (repeat) testing. Clinical laboratory staff and health care providers should contact Luminostics, Inc. if they have any questions or concerns or suspect an issue with their Luminostics test.

          (SNIP) 

Omicron Variant and Sub-Variants: Impact on Molecular Tests

The FDA's analysis to date has identified certain EUA-authorized molecular tests whose performance may be impacted by mutations in the SARS-CoV-2 omicron variant and its sub-variants. These tests fall into three categories, as described below: those that are expected to have reduced performance for the SARS-CoV-2 omicron variant and its sub-variants, those that are expected to fail to detect the SARS-CoV-2 omicron variant and its sub-variants, and those that are expected to detect the SARS-CoV-2 omicron variant and its sub-variants with a specific gene drop out detection pattern.

Tests Expected to Have Reduced Performance for the SARS-CoV-2 Omicron Variant and Sub Variants

DxTerity SARS-CoV-2 RT PCR CE Test (as of 12/29/2022)
Test Name (Link to EUA): DxTerity SARS-CoV-2 RT PCR CE Test
Manufacturer: DxTerity Diagnostics, Inc.

The FDA's Analysis: Test performance may be impacted when a patient sample contains certain viral mutations of the SARS-CoV-2 virus. Two of the three targets of the test (N-gene target and E-gene Target) have significantly reduced sensitivity due to certain SARS-CoV-2 Omicron variant mutations, including the N: 28370-28362 deletion and E: A26275G, C26270T mutations associated with the XBB variant, the BA.2.75 variant, and the BN.1 variant.

Potential Impact: Two of the three test targets have been shown to have significantly reduced sensitivity in certain variants. The test has an increased likelihood to produce an indeterminant result when testing positive samples of the XBB variant, BA.2.75 variant and the BN.1 variant.

Notes: The FDA's analysis included information provided by the manufacturer.

Recommendations for Clinical Laboratory Staff and Health Care Providers Using This Test

Be aware of the current instructions for use for the DxTerity SARS-CoV-2 RT PCR CE Test, especially the "Result Interpretation for Patient Samples" tables, which describe when a result is positive, negative, indeterminate, or invalid, and how to interpret each result. Specifically, "SARS-CoV-2 Indeterminate" results may indicate the presence of SARS-CoV-2 nucleic acids and repeat testing may be indicated; refer to the authorized instructions for use. Health care providers should contact DxTerity Diagnostics if they have any questions or concerns or suspect an issue with their DxTerity Diagnostics test.

Tests Expected to Fail to Detect the SARS-CoV-2 Omicron Variant and Sub-Variants

Due to the inability of these tests to detect the SARS-CoV-2 omicron variant and sub-variants, the FDA recommends that tests listed in this section, if any, should not be used until this issue is resolved. Once such an issue is resolved, tests are moved to the "Issue Resolved" section below with information about the resolution.

No tests as of 9/14/22

          (Continue . . . )

While the impacts on testing remain limited, COVID continues to evolve, and our technical abilities must change with it. 

U.S. Embassy Alert In China: Requirement For Negative COVID-19 Test For Air Passengers Entering U.S. From China

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With a raging - but poorly reported - COVID epidemic surging in China, many countries are once again considering implementing limited travel restrictions. Since the details of the epidemic - and viral sequences - are being withheld by the Chinese government, we'd never know if a new, more dangerous, variant were to emerge until it showed up outside of China. 

Media reports yesterday from Italy indicating that nearly half of all of the passengers on two flights arriving from China tested positive, combined with the upcoming Chinese New Year's, have only escalated international concerns. 

Yesterday the United States Department of State issued a travel advisory for all arrivals from China, reinstating the requirement for a negative COVID test within 2 days of departure (see below).

The text of the health alert from the U.S. Embassy follows.

HEALTH ALERT: CDC REQUIREMENT FOR NEGATIVE COVID-19 TEST FROM AIR PASSENGERS ENTERING THE U.S. FROM CHINA

By U.S. MISSION CHINA

11 MINUTE READ

DECEMBER 29, 2022

Event:  On January 5, at 12:01 ET, the U.S. Centers for Disease Control and Prevention (CDC) will require a negative COVID-19 test result (taken within two days of departure) or proof of recovery from the virus (within the last 90 days) for all travelers aged two years and older to the United States on flights originating from the People’s Republic of China (PRC), including the Special Administrative Regions of Hong Kong and Macau.  This requirement also applies to individuals boarding a flight to the United States from Incheon International Airport, Vancouver International Airport, or Toronto Pearson International Airport who have been in the PRC, including the Special Administrative Regions of Hong Kong or Macau, within the past ten days.

This public health policy is due to the surge in COVID-19 cases in the PRC and the risk of the emergence of a new viral variant.  Monitor the websites for the U.S. Mission China, the U.S. Consulate General Hong Kong & Macau , and the CDC’s Travel Health Information  page for the latest COVID 19- travel guidance.

These requirements apply to all air passengers regardless of vaccination status or nationality.  This will also apply to persons traveling from the PRC via third country transit and to passengers connecting through the United States onward to further destinations. Passengers must show one of the following to the airline or risk being denied boarding:

• A paper or digital copy of negative COVID-19 viral test results taken within two days of boarding. Check the CDC website for a list of authorized  viral tests that meet the testing requirement, or
• Documentation of recovery for passengers who tested positive more than 10 days and fewer than 90 days before boarding a flight to the United States.  See CDC page for details .

Only in very limited cases will an exception to these testing requirements be granted when emergency travel must occur to protect someone’s life or health from a serious threat or danger.  Contact the CDC for criteria on exceptions.

If you are uncertain whether this requirement applies to you and you have recently traveled to the PRC, including Hong Kong SAR or Macau SAR, you are encouraged to take a COVID-19 viral test within two days of boarding a flight to the United States.

Actions to Take:

• Consult the CDC website  for the most up-to-date information on pre-departure COVID-19 testing requirements.
• Check with your airline or travel operators regarding testing requirements including language requirements for test results or doctor’s notes, and for any updated information about your travel plans and/or restrictions, including potential COVID-19 vaccine or testing requirements for countries you are transiting through.
• Be aware that foreign countries might have their own travel restrictions and COVID-19 testing, vaccine, or quarantine requirements. Please visit the Embassy/Consulate webpages for each country you are traveling to or transiting through for additional information.
• Visit the COVID-19 crisis page on travel.state.gov for country-specific information related to COVID-19.
• For information on what you can do to reduce your risk of contracting COVID-19, please see the CDC’s latest recommendations .(Continue . . . )
• Visit the U.S. Embassy Beijing webpage on COVID-19 for information on conditions in The People’s Republic of China. COVID-19 Information – U.S. Embassy & Consulates in China (usembassy-china.org.cn). Visit the U.S. Consulate General Hong Kong & Macau’s webpage on Covid-19 for information on Hong Kong and Macau.

`          (Continue . . . )

As a practical matter, if (and its still an `if') a new, more dangerous variant were to appear in China, these testing requirements would only increase the time - by days, or perhaps weeks - before it arrived via a more circuitous route.

While that may not seem like much of an advantage, it could be enough time for many more people to get the updated booster shots, and that could save lives.  It might also give us an opportunity to better gauge its threat, and take any other precautionary actions. 

While the most immediate concern is COVID, we have very little visibility on what is happening in China with other infectious disease threats, including avian flu.  Yesterday's announcement by the WHO of the first fatal case of H5N1 clade 2.3.4.4b infection was on a case in Guangxi Province, China that occurred over 90 days ago. 

China's reporting on H5N6, H9N2, H3N8, and other avian flu subtypes has declined in recent months as well.  Whether that represents a genuine drop in cases, or a lack of surveillance and/or reporting is unknown. 

China, which is dealing with a variety of internal problems (see China At The Pandemic Crossroads) is often slow to report avian flu cases - or any other `bad news' for that matter - which is why `no news' doesn't always mean `good news' when it comes to Mainland China.

Of course, China is far from alone in keeping outbreaks secret (see Flying Blind In The Viral Storm), while many other countries simply don't have the resources to adequately detect and report these types of events.  

The bottom line is, we'd better be prepared for surprises in 2023.  Because our ability to see the next threat coming is severely limited.  

Hong Kong Relaxes Many COVID Social Distancing/Testing Requirements, But Masks Remain

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Unlike the Mainland -  where much of China's 1.4 billion people remain immunologically naive to the SARS-CoV-2 virus and vaccine uptake and effectiveness have been low - Hong Kong has seen the circulation of the virus for more than a year, and has a better record of vaccination, including the more effective imported mRNA vaccines. 

For those reasons officials are fairly confident that lifting many of their long-standing social distancing requirements - starting tomorrow - will not produce the kind of surge in cases that the Mainland is currently seeing. 

That said, some increase is likely, and the current (roughly) 20K cases per day will probably go up, at least in the short term.  These latest changes follow initial relaxation of some restrictions on Dec 8th (see Hong Kong Eases Some COVID Restrictions In Wake Of Mainland's Policy Changes).

The announcement from the Hong Kong government website follows. 

Social distancing lifted, masks remain
December 28, 2022

Play Video
Download Video| Transcript

(To watch the full press conference with sign language interpretation, click here.)

The Government today announced that the current social distancing measures, the Vaccine Pass and isolation order for close contacts of COVID-19 patients will be lifted from tomorrow.

Also from tomorrow, compulsory nucleic acid testing for inbound travellers will be replaced by rapid antigen tests that should be done for five consecutive days after arrival.

Among the social distancing measures set to be cancelled are the restrictions on group gatherings and on the number of people allowed to be seated together at one table in restaurants.

However, the mask-wearing requirement will not be relaxed.

Chief Executive John Lee said at a Command & Coordination Group press conference this afternoon that Hong Kong is heading towards normalisation.

“We have over 2.5 million (people) who have been infected (with COVID-19), so generally we have built quite a strong community immunity against the virus.

“We have very good confidence that we can control the risks because the medical service has enhanced its response system and also we have sufficient and effective medicine, and the community has good experience of three years to protect themselves.

“We are proceeding to normalisation. It has come to a time where we do not have to rely on the Vaccine Pass.”

Mr Lee also touched upon the resumption of normal travel with the Mainland.

“We will resume normal travel with the Mainland step by step, (in an) orderly (manner) with a view to full opening, full normalisation. And that is what we are doing now, in close discussion with the authorities of the Mainland.

“It is my intention to reach an agreement with our counterparts no later than a (certain) time so that we can report to the Central People's Government for endorsement, for implementation before the middle of January.”

WHO Rapid Risk Assessment on A(H5N1) clade 2.3.4.4b viruses (Includes 2 Severe/Fatal Human Infections)

Waves of HPAI H5N1 clade 2.3.4.4b since 2016 - Credit ECDC 

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Unlike the more virulent older clades of avian H5N1, all 4 reported human infections with the H5N1 clade 2.3.4.4b virus that is currently spreading in Europe, North America, Asia, and most recently South America have been mild, or asymptomatic. 

While comforting, we've seen numerous reports of severe infections in mammalian wildlife and continued evidence of the virus's evolution, including signs of mammalian adaptations.

At the same time, over the past three months both China and Vietnam have reported isolated, severe human infections (1 fatal) with either H5N1 (China), or H5 (Vietnam), without specifying the clade.  Given the location (Asia), and the severity, an older clade of H5 seemed a reasonable assumption. 

But today we learn from a WHO Rapid Risk Assessment that both were H5N1 clade 2.3.4.4b. The assessment, dated Dec 21st, only appears to have been posted in the past 24 hours.

These recent severe cases likely explain the spate of risk assessments, and guidance documents, coming from various public health entities the past couple of months (see UK HSA Technical Briefing: Risk Assessment On HPAI H5N1 & Human Infection).

While there is no evidence of widespread infection or human-to-human transmission, this raises the stakes should the virus begin to spread more efficiently. 

 Excerpts from the WHO announcement follow:

Rapid Risk Assessment 

Assessment of risk associated with recent influenza A(H5N1)clade 2.3.4.4b viruses 

Background 

During 2020, highly pathogenic avian influenza (HPAI) A(H5N1) clade 2.3.4.4b viruses arose from previously circulating A(H5Nx) viruses and spread predominantly via migratory birds to many parts of Africa, Asia and Europe. The epizootic has led to unprecedented numbers of deaths in wild birds and caused outbreaks in domestic poultry. In late 2021, these viruses crossed to North America and subsequently South America in the autumn of 2022. Additionally, there has been an increased spill over to non-avian species including wild terrestrial and marine mammals and, more recently, the detection of an outbreak in a mink farm in Spain. From 2020 to date, six human cases of influenza A(H5N1) belonging to the 2.3.4.4b clade were reported to WHO. 

The majority of the influenza A(H5N1) HPAI characterized genetically since 2020 related to these outbreaks are belonging to the 2.3.4.4b clade. This risk assessment focuses on the most recent A(H5N1) viruses belonging to the 2.3.4.4b clade.

Understanding of the virus 

Human infections with influenza A(H5N1) 2.3.4.4b viruses 

Since the beginning of 2020, detections in humans of influenza A(H5N1) clade 2.3.4.4b viruses have been reported to WHO from the following countries1 : China (one case)[1], Spain (two cases)[2], the United Kingdom of Great Britain and Northern Ireland (one case)[3], the United States of America (USA) (one case)[4], and Viet Nam (one case)[1]. 

All four human cases reported in Europe and North America were asymptomatic or mild, with only fatigue reported for the case detected in the USA. The case detected in China resulted in a fatality while the case in Viet Nam had severe symptoms but recovered. All human cases had exposure to infected poultry either through participation in response activities to poultry outbreaks or direct exposure to infected poultry in backyard holdings or live bird markets. 

Virus sequences from these human cases, where available, did not show markers for mammalian adaptation nor for resistance to neuraminidase inhibitors (such as oseltamivir) or endonuclease inhibitors (such as baloxavir).

Based on the available information for A(H5), although based on limited seroprevalence information available on other A(H5) virus subtypes and clades, human population immunity against the A(H5) clade 2.3.4.4b virus haemagglutinin is expected to be minimal. 

Infections in animals 

Avian influenza A(H5N1) viruses, especially those in clade 2.3.4.4b, continue to diversify genetically and spread geographically. From 2021 to 2022, Europe and North America have observed their largest and most extended epidemic of avian influenza with unusual persistence of the virus in wild bird populations. A broader range of wild bird species continue to be infected globally which has significant ecological consequences and has caused mass die offs in some species. 

Additionally, continuous infection in wild and migratory birds has led to multiple separate incursions in domestic species. These circumstances have led to increased opportunities to generate multiple genotypes with varied clinical signs. Some of the recent viruses have caused severe infections with neurological signs in mammals.[5]

There have been limited reports of transmission between mammals despite the increase in mammalian infections. Affected mammals include badger, black bear, bobcat, coyote, dolphin, ferret, fisher cat, fox, lynx, mink (mink-tomink in Spanish farm), opossum, otter, pig, polecat, porpoise, raccoon, raccoon dogs, seal (seal-to-seal in USA) and skunk.

Regular monitoring and screening of viral sequences found few sequences with markers of mammalian adaptation. These mutations likely occurred after transmission to the mammalian host and do not seem to transmit onwards. Continuous monitoring is warranted to understand if these changes continue to occur or accumulate over time. Available A(H5N1) clade 2.3.4.4b virus sequences from avian and mammalian hosts indicate that markers associated with reduced susceptibility to neuraminidase or endonuclease inhibitors are rare.

From published animal transmission studies, transmission between ferrets did not occur, however some genotypes resulted in severe disease in infected ferrets.[6, 7]

Candidate vaccine viruses

 The WHO Global Influenza Surveillance and Response System (GISRS), in collaboration with animal health and veterinary sector colleagues, regularly evaluate candidate vaccine viruses. Clade 2.3.4.4b A(H5) candidate vaccine viruses (CVV) have been developed. This includes a A(H5N8) clade 2.3.4.4b CVV made from A/Astrakhan/3212/2020 as well as a newly recommended A(H5N1) A/chicken/Ghana/AVL-76321VIR7050- 39/2021-like virus which is under development. The HA of A/Astrakhan/3212/2020 is closely related to the circulating strains

Summary of the assessment of current risk to humans posed by influenza A(H5N1) clade 2.3.4.4b viruses

Despite the high number of poultry outbreaks and likely human exposures to the virus at the human-animal environment interface since 2020, only six A(H5N1) clade 2.3.4.4b virus detections in samples from people directly exposed to infected poultry have been reported. In the four human cases from Europe and North America, the individuals had no symptoms or only mild clinical signs, however the two cases from Asia had severe and fatal outcome. The use of antivirals as part of the treatment of the severe and fatal cases is unknown.

Recently, there was an increase in reports of spill over from wild birds to some mammalian species in different countries in Europe and North America. This is likely a result of high prevalence of the virus in avian populations in these regions. There is still limited evidence for mutations associated with adaptation to mammals and humans even when transmission in mammals has been reported. At this juncture, the risk of infection for humans remains low and no sustained human-to-human transmission has been reported. 

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A week ago, in the ECDC/EFSA Avian influenza overview September – December 2022 we learned that 8 new genotypes have appeared in Europe over the past 3 months, while in November we saw several new genotypes described in North America. 

These new genotypes can vary greatly in their ability to infect avian and non-avian hosts, and in their virulence.  

It is a pretty safe assumption that in Asia, South America - and in many other parts of the world - additional genotypes are emerging, mostly outside of our view.  Most will provide no special advantage to the virus, and some may actually be detrimental to its survival.  

But the potential exists for the emergence of a biologically fit, and more dangerous virus. 

While the future evolution of these avian viruses is unknowable - and there may even be a `species barrier' that prevents an H5 virus from sparking a human pandemic (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?) - our recent luck in these matters hasn't been particularly reassuring.

Which is why we need to be preparing now for the next global health crisis, because another pandemic is inevitable. 

We just don't know when. 

Nature: Strong Attenuation of Omicron BA.1 & Increased Replication of the BA.5 Subvariant in Human Cardiomyocytes

Emergence of Omicron - Credit Our World In Data
 

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Just over a year ago the trajectory of the SARS-CoV-2 epidemic shifted dramatically with the emergence of a highly mutated Omicron variant, which - while causing less severe pneumonia than Delta - spread far more efficiently. 

As a result, the number of infections soared, but a much smaller percentage of patients developed severe illness and/or died (see chart above).  

The hope was the virus was losing its punch, and COVID would eventually join the plethora of seasonal respiratory diseases we deal with every year. And while that may still happen, we continue to see evidence that COVID is more than just `a bad cold' (see below). 

The Lancet: Neurological and Psychiatric Risk Trajectories After SARS-CoV-2 Infection

MMWR: Post–COVID-19 Symptoms and Conditions Among Children and Adolescents

More Evidence On The Long-term Impact of SARS-CoV-2 Infection

Nature: Long COVID After Breakthrough SARS-CoV-2 Infection

BMJ: Elevated Risk Of Blood Clots Up To 6 Months After COVID Infection

The Omicron variant (BA.1) that replaced Delta is long gone, having been supplanted by series of newer Omicron variants (e.g. BA.2, BA.5, BQ.1, and soon XBB), and while we've not seen a return to the severe pneumonia that Delta often produced, we have seen studies suggesting that Omicron may be gaining virulence in other ways.

Yesterday, in Preprint: Omicron BA.5 Infects Human Brain Organoids and is Neuroinvasive and Lethal in K18- 2 hACE2 Mice, we looked at research out of Australia finding that Omicron BA.5 infects and replicates in (lab grown) human brain cells more readily than earlier (BA.1) Omicron variants, and was more pathogenic in laboratory mice. 

Today we've a letter,  published in the Journal Nature, which looks at and compares the infectivity, and functional impact, of BA.5 and older Omicron variants on lab grown iPSC-derived human cardiomyocytes; the type of cells responsible for the contraction of heart muscle. 

We've seen considerable evidence linking SARS-CoV-2 infection with cardiac complications, including myocarditis, arrhythmias, and even sudden cardiac death (see Nature: Long-term Cardiovascular Outcomes of COVID-19).  

While most pronounced during the pre-Omicron phase of the pandemic, today's report suggests that BA.5 may be regaining some of COVID's ability to infect, and disrupt, the cardiovascular system.  

As we've discussed often, laboratory results don't always translate into real-world impacts - and we don't know if this trend will continue with XBB and whatever comes next - but it (along with yesterday's report) remind us that the trajectory of COVID is unpredictable going forward. 

I've only reproduced some excerpts from the letter, so follow the link to read it in its entirety.  I'll have a brief postscript when you return. 

Letter
Open Access
Published: 25 December 2022
Strong attenuation of SARS-CoV-2 Omicron BA.1 and increased replication of the BA.5 subvariant in human cardiomyocytes

Rayhane Nchioua, Federica Diofano, Sabrina Noettger, Pascal von Maltitz, Steffen Stenger, Fabian Zech, Jan Münch, Konstantin M. J. Sparrer, Steffen Just &Frank Kirchhoff

Signal Transduction and Targeted Therapy volume 7, Article number: 395 (2022) Cite this article

Dear Editor,

Since its first description in South Africa in November 2021, the SARS-CoV-2 Omicron variant rapidly outcompeted the previously dominating Delta variant. Omicron is the fifth variant of concern (VOC). It contains an unusually high number of mutations compared to previous VOCs, especially in the viral Spike protein, and shows high transmissibility and efficient escape of neutralizing antibodies. Due to these characteristics, it received this designation much faster than the four previous VOCs Alpha, Beta, Gamma, and Delta.

 

However, the original BA.1 Omicron variant seems to be less pathogenic than early SARS-CoV-2 strains and other VOCs.1 While SARS-CoV-2 primarily infects the respiratory tract, Coronavirus disease 19 (COVID-19) is a multi-organ disease, and patients show infection and disorders in the gastrointestinal, cardiovascular, and neurological systems. Thus, the ability of the various SARS-CoV-2 variants to infect and propagate in different cell types and organs clearly plays a key role in viral pathogenicity. Especially, cardiomyocytes express high levels of the primary SARS-CoV-2 receptor ACE2 and are highly permissive for viral replication.2

Cardiac injury and cardiomyopathies are common complications of COVID-19. Clinical manifestations leading to severe or even fatal outcomes include myocarditis, heart failure, arrhythmia, and Takotsubo cardiomyopathy (TCM).3 The mechanism(s) underlying heart injury in COVID-19 are not entirely clear. Direct effects of SARS-CoV-2 on cardiomyocytes are supported by their high susceptibility to virus infection and detection of viral RNA and Spike protein in autopsy cardiac tissues of COVID-19 patients.3 In addition, it has been shown that SARS-CoV-2 infects and efficiently replicates in cardiomyocytes but not in cardiac macrophages, fibroblasts, or endothelial cells.4,5 The BA.1 Spike shows altered ACE2 affinity, reduced dependency on TMPRSS2 for proteolytic activation, changes in cell tropism and reduced fusogenicity compared to the original HU-1 strain and the Delta VOC.6 However, it is currently not known whether early SARS-CoV-2 strains, Delta and Omicron BA.1, differ in their replication fitness, cytopathicity and fusogenicity in human cardiomyocytes.

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At the beginning of this study, BA.1 dominated the COVID-19 pandemic. Since then, several subvariants of Omicron emerged and outcompeted the original BA.1 VOC. BA.2 differs by a total of ~40 mutations from BA.1 and is the precursor of BA.5, which contains a deletion of H69/V70 and additional changes of L452R, F486V and R493Q in Spike and currently (August 2022) dominates the pandemic. Recent evidence suggests that BA.5 is not only more resistant to neutralizing antibodies but may also be more virulent than BA.1. We found that BA.5 replicates with faster kinetics and higher efficiency (Fig. 1f, Supplementary Fig. 8), produces more infectious virus (Fig. 1g), causes stronger CPE (Supplementary Fig. S9), and more rapidly disrupts beating (Fig. 1h, Supplementary movie 2) in cardiomyocyte cultures compared to BA.1, while BA.2 displayed an intermediate phenotype.

In summary, replication and cytopathic effects of the initial BA.1 Omicron VOC in spontaneously beating cultures of human cardiomyocytes are strongly attenuated compared to the early NL-02-2020 strain and the Delta VOC. However, BA.2 and especially BA.5 showed higher replication and caused stronger CPE than BA.1, consequently displaying features more similar to the Delta VOC. 

This does not come as a surprise since BA.5 shares some mutations in Spike thought to increase fusogenicity, such as L452R, with Delta. Our results add to the evidence that efficient evasion of adaptive immune responses by BA.1 came at the cost of reduced fusogenicity. However, acquisition of additional changes by BA.5 restored the full replicative potential and may potentially increase both transmissibility and virulence.

Our finding that BA.1 is strongly attenuated in iPSC-derived human cardiomyocytes suggests that this variant is less likely to cause cardiac injury and cardiomyopathies compared to other SARS-CoV-2 VOCs. It will be interesting to see whether this is confirmed by patient data and if Omicron-adapted vaccines may drive the evolution of attenuated forms of BA.5 and future SARS-CoV-2 variants.

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While it is true that 98%-99% of people survive the acute phase of COVID - and most deaths have occurred among the elderly, or those with serious comorbidities - the extrapulmonary manifestations of SARS-CoV-2 infection are many, varied, and only partially appreciated.

https://twitter.com/KartikSehgal_MD/status/1281695760879202304

In the summer of 2020 (see JAMA: Two Studies Linking SARS-CoV-2 Infection To Cardiac Injury), we examined the results of 39 autopsies on COVID cases, that showed even when pneumonia is the presumed cause of death - and even without overt histopathic evidence of acute myocarditis - the heart often shows a high viral load of SARS-COV-2.

A second, and arguably even more worrisome study, found a remarkable incidence of cardiac injury and myocardial inflammation among a relatively young cohort (avg. age 49 & without pre-existing cardiac hx) of COVID patients who mainly recovered at home but continued to experience a variety of symptoms following their illness.

An accompanying editorial (see Coronavirus Disease 2019 (COVID-19) and the Heart—Is Heart Failure the Next Chapter? by Clyde W. Yancy, MD, MSc1,2; Gregg C. Fonarow, MD3,4) raised serious concerns over the long-term impact of COVID on public health.

While everyone desperately longs to get past the acute phase of this pandemic, its long-term impact on individual and public health may persist for years, or even decades.  Once again, making COVID an illness best avoided if at all possible. 

 

 

Preprint: Omicron BA.5 Infects Human Brain Organoids and is Neuroinvasive and Lethal in K18- 2 hACE2 Mice

Credit NIAID

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While the serious health impacts of COVID appear to be less today than they were during the Delta wave, it is less than clear how much of that attenuation is due to a weakening of the virus, or to the combined effects of previous infection and vaccinations. 

That question might be answered if we could get reliable information out of China as Omicron spreads through their immunologically naive population.  But that information is unlikely to be shared, assuming they are even able to effectively track it themselves. 

Omicron variants do appear to produce less severe pneumonia, but - as we've seen in numerous studies (see below) - the extrapulmonary impacts of COVID infection can cause significant morbidity and mortality during and after the acute phase of the infection. 

A few (of many) studies include:

Neurology: Incidence of Epilepsy and Seizures Over the First 6 Months After a COVID-19 Diagnosis: A Retrospective Cohort Study

The Lancet: Neurological and Psychiatric Risk Trajectories After SARS-CoV-2 Infection

MMWR: Post–COVID-19 Symptoms and Conditions Among Children and Adolescents

Nature: Long-term Cardiovascular Outcomes of COVID-19
 
Nature: Long-term Neurologic Outcomes of COVID-19

There is also evidence that these risks appear to increase with every infection (see Nature: Acute and Postacute Sequelae Associated with SARS-CoV-2 Reinfection), both during the acute phase of the illness and the months that follow. 

While the exact mechanism behind `Long-COVID' sequelae isn't known, the extrapulmonary spread of the virus - particularly to the brain and the heart - is strongly suspected to be a contributing factor.

This is a topic we've explored repeatedly, including earlier this month in  Nature: SARS-CoV-2 Infection and Persistence in the Human Body and Brain at Autopsy, and last month in Nature: Enhanced Replication of SARS-CoV-2 Omicron BA.2 in Human Forebrain and Midbrain Organoids. 

Concerns over the neurological impact of COVID began almost immediately in the spring of 2020, after an early report from Wuhan, China (see JAMA: Neurologic Manifestations Of Patients With Severe Coronavirus Disease) found 1/3rd of a study group exhibiting troubling neurological signs and symptoms. 

Neurological manifestations ranged from relatively mild (headaches, dizziness, anosmia, mild confusion, etc.) to more profound (seizures, stupor, loss of consciousness, etc.) to potentially fatal (ischemic stroke, cerebral hemorrhage, muscle injury (rhabdomyolysis), etc.).

Since then we've seen a steady stream of studies describing neurological manifestations during, and following, COVID infection.  A few (of many) include:

Nat. Comms: Neuropathology and Virus in Brain of SARS-CoV-2 Infected Non-human Primates

J. Neurology: COVID-19 As A Potential Risk Factor For Chronic Neurological Disorders

The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings

Frequent Neurologic Manifestations & Encephalopathy‐Associated Morbidity in Covid‐19 patients

Admittedly, most of these studies were done before the switch to the Omicron phase of the pandemic - and many were pre-vaccine - so the impact of those viruses may have been far different than with today's variants.  

But - as with last Novembers study on Omicron BA.2 in Human Forebrain and Midbrain Organoids, today's preprint deals with newer (in this case, BA.5) Omicron variants. 

Human brain organoids (aka `mini-brains') are created from lab-grown stem cells that are designed to simulate the architecture and functionality of the human brain (cite), and have been increasingly used for many types of brain research (see Science: Zika Impairs Growth In Human Neurospheres And Brain Organoids). 

Today's preprint from researchers at Australia's QIMR Berghofer Medical Research Institute and Queensland University finds that BA.5 was more neuroinvasive than BA.1, and more pathogenic in K18-hACE2 lab mice, suggesting that the trajectory of Omicron isn't always towards a weaker virus. 

I've only reproduced the abstract, follow the link to read the full 38-page PDF.  I'll have a brief postscript when you return. 

Omicron BA.5 infects human brain organoids and is neuroinvasive and lethal in K18-hACE2 mice

Romal Stewart, Sevannah A Ellis, Kexin Yan, Troy Dumenil, Bing Tang, Wilson Nguyen, View ORCID ProfileCameron R Bishop, Thibaut Larcher, Rhys Parry, Robert K P Sullivan, Mary Lor, Alexander A Khromykh, View ORCID ProfileFrederic A Meunier, Daniel J Rawle, Andreas Suhrbier

doi: https://doi.org/10.1101/2022.12.22.521696

Preview PDF

Abstract

A frequently repeated premise is that viruses evolve to become less pathogenic. This appears also to be true for SARS-CoV-2, although the increased level of immunity in human populations makes it difficult to distinguish between reduced intrinsic pathogenicity and increasing protective immunity. 

The reduced pathogenicity of the omicron BA.1 sub-lineage compared to earlier variants is well described and appears to be due to reduced utilization of TMPRRS2. That this reduced pathogenicity remains true for omicron BA.5 was recently reported.

In sharp contrast, we show that a BA.5 isolate was significantly more pathogenic in K18-hACE2 mice than a BA.1 isolate, with BA.5 infection showing increased neurovirulence, encephalitis and mortality, similar to that seen for an original strain isolate.

BA.5 also infected human cortical brain organoids to a greater extent than a BA.1 and original strain isolate. Neurons were the target of infection, with increasing evidence of neuron infection in COVID-19 patients. 

These results argue that while omicron virus may be associated with reduced respiratory symptoms, BA.5 shows increased neurovirulence compared to earlier omicron sub-variants. 

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Admittedly, we can't assume that BA.5's enhanced pathogenicity in lab-mice was mirrored in humans, nor can we assume that lab-grown brain organoids are the perfect substitute for the human brain.  

But this study does show that BA.5 - at least in some hosts - produced different (and more severe) infection than earlier Omicron variants.   

The notion that if we wait long enough, COVID will evolve into a `less pathogenic' virus is comforting, but it may not be rooted in reality.  And despite the reduced mortality observed with Omicron, it may be years before we can fully appreciate the long-term impact of COVID infection on human health. 

Following the 1918 pandemic, the world saw a decade or more of increased neurological disorders (see The Lancet: COVID-19: Can We Learn From Encephalitis Lethargica?) - killing or disabling millions of people -  and while its exact cause remains unknown, a viral infection is strongly suspected.

Which is why, until we know more, it probably in your best interests to avoid being infected with COVID if at all possible.