Pfizer pledges equitable access to COVID-19 pill through new license pact

 On Tuesday, U.S. pharmaceutical giant Pfizer announced that it signed a new licensing agreement with the Medicines Patent Pool, a United Nations-backed organization, that will help supply Pfizer's antiviral COVID-19 pill to lower- and middle-income countries.

Earlier this month, Pfizer announced that its COVID-19 pill reduced the risk of hospitalization and death among COVID-19 patients by 89%, fueling hope that the drug will give the world another defense against the worst effects of the coronavirus.

Pfizer's new partnership with the MPP opens the door for Pfizer to supply its COVID drug to the world’s poorest and most vaccine-starved countries. The licensing agreement authorizes the MPP to facilitate production of the pill by granting "sub-licenses" to qualified generic drug manufacturers and distribute doses based on need, according to a statement.

“We must work to ensure that all people—regardless of where they live or their circumstances—have access to these breakthroughs, and we are pleased to be able to work with MPP to further our commitment to equity,” Albert Bourla, Pfizer CEO, said in the statement.

Pfizer’s COVID-19 pill, called Paxlovid, is given to patients at high risk of developing severe infections after an initial COVID diagnosis. An interim trial found that 0.8% of patients who received Paxlovid after getting diagnosed with COVID-19 were hospitalized after 28 days. For patients who received a placebo, 7% required hospitalization after 28 days.

Pfizer’s pill has not been approved by the U.S. Food and Drug Administration or any other health authority, and the company has not yet released detailed data from its interim study. Still, Bourla says Pfizer plans to submit its FDA application before Thanksgiving and expects to have 21 million doses ready to deploy by the first half of 2022. Pfizer says it has ceased enrolling new patients in its clinical trial due to the “overwhelming efficacy” demonstrated in the trial and plans to submit documentation to the FDA for approval as soon as possible.

Pfizer’s commitment to equitable access to its new COVID-19 treatment comes as the firm reported strong revenue this month on the back of its highly-effective mRNA COVID-19 vaccine that it developed with Germany’s BioNTech. Pfizer reported in early November that through the third quarter of 2021 it had earned $24.3 billion in revenue from its COVID-19 vaccine. It expects its 2021 COVID-19 vaccine revenue to rise to $36 billion by the end of the year.

Pfizer has faced criticism for earning such profits during the pandemic while much of the world’s poorest countries continue go without vaccines.

“It is obscene that just a few companies are making millions of dollars in profit every single hour, while just 2% of people in low-income countries have been fully vaccinated against coronavirus,” Maaza Seyoum, African coordinator of the People's Vaccine Alliance, said in a press release on Tuesday. “Pfizer, BioNTech and Moderna have used their monopolies to prioritize the most profitable contracts with the richest governments, leaving low income countries out in the cold."

The World Health Organization, the U.S., and dozens of countries have backed a call for the World Trade Organization to drop manufacturers' exclusive intellectual property rights to COVID-19 vaccines. Supporters of a waiver say it could help ramp up vaccine production and allow lower-income countries to access the jabs.

Bourla opposes waiving intellectual property rights for COVID-19 vaccines. He argues that doing so would “create more problems” by potentially disrupting the supplies of raw materials.

But with its oral antiviral pill, Pfizer appears to be taking a different path in providing its formula to generic manufacturers.

In October, Merck made a similar decision to allow generic manufacturers to produce its antiviral pill, which trials show reduces the risk of hospitalization and death among COVID-19 patients by 50%. The U.S. drugmaker is also partnering with the MPP to send Merck's recipe to a network of global manufacturers.

Twenty-four leading pharmaceutical manufacturers around the world have committed to an MPP pledge to collaborate on producing COVID-19 treatments like Pfizer's pill for low income countries. One of the signatories of the MPP's pledge, Indian generic drugmaker Dr. Reddy's, said this week that it's willing to produce Pfizer's antiviral pill once it gets approved in the U.S. Dr. Reddy's did not specify what it might charge for the drug, but said it does not expect to make profits from selling antiviral treatments.

“[Pfizer's licensing agreement with the MPP] is so important because, if authorized or approved, this oral drug is particularly well-suited for low- and middle-income countries,” Charles Gore, executive director of MPP, said in a statement.

https://fortune.com/2021/11/16/pfizer-covid-pill-equitable-access-generic-manufacturing-low-income-countries/

72% plan to celebrate holidays with just their household: poll

 Most American adults intend to take COVID-19-related precautions as they prepare to celebrate the holiday season with their loved ones.

Seventy-two percent of people who took part in a national survey from The Ohio State University Wexner Medical Center said they planned to celebrate the holidays with only members of their household compared to 79 percent last year.

The poll also showed that just over half of the people surveyed would ask their guests to wear masks at holiday parties this year compared to 67 percent in 2020. 

“If everyone in attendance is vaccinated and are without major health risks, you can have a safe gathering without a lot of additional precautions. With all guests vaccinated, you don’t need to use masks or force the celebration outdoors. You can have a normal holiday as you would any other year,” Dr. Iahn Gonsenhauser, who serves as chief quality and patient safety officer at Ohio State, said in a statement.

"Unvaccinated individuals really pose the greatest threat, and that’s when it becomes necessary to put some rules and precautions in place, even though those conversations can be a little bit awkward," Gonsenhauser added.

Half of people surveyed said they would ask their guests about their vaccination status, and 46 percent said they intended to ask unvaccinated guests to test negative for COVID-19 before attending the gathering, according to the poll. 

The survey was conducted online by The Harris Poll on behalf of The Ohio State University Wexner Medical Center. It took place between Oct. 29 and Nov. 1 and included 2,042 U.S. adults.

Nearly 60 percent of Americans are fully vaccinated against COVID-19 as the country battles a daily case average of over 80,000, according to The New York Times.

https://thehill.com/policy/healthcare/581677-72-percent-plan-to-celebrate-holidays-with-just-their-household-poll

Using T cells to target malignant brain tumors

 Doctors and scientists from the German Cancer Research Center (DKFZ) and from Heidelberg University's Medical Faculty Mannheim have successfully tested a neoantigen-specific transgenic immune cell therapy for malignant brain tumors for the first time using an experimental model in mice.

Cellular immunotherapies that specifically target malignant tumors are thought to be a promising approach in cancer medicine. However, a basic requirement for this kind of targeted immunotherapy is to identify target molecules that are found exclusively on the tumor cells and are recognized by the immune system.

Malignant gliomas are incurable brain tumors that spread in the brain and cannot be completely removed by surgery. "Gliomas are very difficult to treat, and the lack of suitable target structures is a considerable challenge for developing immunotherapies," explained Lukas Bunse, an immunologist at the DKFZ and a doctor at University Hospital Mannheim (UMM).

Using an experimental mouse model, Bunse and his team have now demonstrated for the first time that transgenic T cells targeting tumor neoepitopes can be used to treat gliomas.

Tumor neoepitopes arise as a result of genetic mutations in cancer cells that lead to structural changes in the proteins produced. They therefore occur exclusively in the cancer cells. Using a prediction model, Bunse and his team identified a segment of the CIC protein (capicua transcriptional repressor) as a promising target structure for T cell attacks; around two percent of all gliomas show a recurrent mutation in this protein.

Mice vaccinated with the CIC neoepitope developed a population of T helper cells that showed a high level of activation in response to the vaccine peptide. The researchers used particularly active T cells to isolate the gene for the T cell receptor (TCR) responsible for epitope recognition.

They subsequently transferred the isolated TCR gene to cells and were thus able to grow large amounts of "transgenic" T cells in a petri dish that all had an identical, highly active TCR targeting the CIC neoepitope.

In order to study their efficacy, the researchers injected the transgenic cells directly into the brain ventricles of glioma-bearing mice. In combination with radiotherapy, the T cell therapy led to glioma rejection in some of the animals.

"Here we have shown for the first time in an experimental model that a neoantigen-specific TCR-transgenic cell therapy can be effective against gliomas," explained Michael Kilian, first author of the study. "These kinds of neoepitope-specific TCR-transgenic T cells could be used in future in cancer patients who cannot be treated using CAR T cells," he added.

Chimeric antigen receptor (CAR) T cells, which have already been approved for treating patients with B cell leukemia, can only attack tumor antigens present on the surface of the cancer cells. However, these proteins are not usually found exclusively on tumor cells, so CAR T cells could damage healthy tissue too.

In contrast, the TCR-transgenic T cells can also attack mutated proteins from the cell interior, which must be exposed on the cell surface by special presentation molecules known as major histocompatibility complex (MHC) proteins. Most T cells respond solely to antigens presented by MHC molecules. To achieve results that can be transferred to humans, Lukas Bunse and his team therefore needed to work with mice transgenic for human MHC molecules.

"Our work suggests that TCR-transgenic T cells can also be used to treat patients with brain tumors," remarked Michael Platten, head of the Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology at the DKFZ and Medical Director of Mannheim University Hospital's Department of Neurology. In collaboration with Wolfgang Wick, Medical Director of the Medical Faculty of Heidelberg's Department of Neurology, Platten and the team of neurooncologists hope to use comparable approaches to refine the TCR-transgenic T cell therapy and to study it in early clinical trials.

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Story Source:

Materials provided by German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). Note: Content may be edited for style and length.

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Journal Reference:

1. Michael Kilian, Mirco Friedrich, Khwab Sanghvi, Edward Green, Stefan Pusch, Daisuke Kawauchi, Martin Löwer, Jana K. Sonner, Christopher Krämer, Julia Zaman, Stefanie Jung, Michael O. Breckwoldt, Gerald Willimksy, Stefan B. Eichmüller, Andreas von Deimling, Wolfgang Wick, Felix Sahm, Michael Platten, Lukas Bunse. T cell receptor therapy targeting mutant capicua transcriptional repressor in experimental gliomas. Clinical Cancer Research, 2021; clincanres.1881.2021 DOI: 10.1158/1078-0432.CCR-21-1881

https://www.sciencedaily.com/releases/2021/11/211115123437.htm

Altered fat metabolism, enzyme, likely plays key role in Lou Gehrig’s disease

 A new study using genetically engineered mice and human cell and tissue samples has added to evidence that higher levels of inflammatory chemicals involved in fat metabolism occur in people with amyotrophic lateral sclerosis (ALS), the neuromuscular disorder, also known as Lou Gehrig's disease.

The study, which focused on genetic pathways involved in how spinal motor cells process fats, found that compared with people without ALS, those with the disorder have about 2.5-fold higher levels of arachidonic acid, a lipid commonly found in the fatty parts of meat and fish and that is known to spur on inflammatory processes needed to repair wounds or tissue damage.

Notably, by tampering with the arachidonic acid pathway in mice bred to develop the biological hallmarks of ALS, the researchers say they were able to reduce the condition's muscle-weakening symptoms in the mice -- which experienced a 20%-25% increase in grip strength -- and extend their survival by two to three weeks.

A report on the work, led by Johns Hopkins Medicine researchers, appears in the Nov. 15 issue of Nature Neuroscience.

The scientists used caffeic acid, an anti-inflammatory compound found naturally in coffee, tea, tomatoes and wine, to tamp down the arachidonic acid pathway, but they caution that people with ALS should not rush to treat themselves with the substance, which is sold as an unregulated dietary supplement. More studies are needed to determine safe levels of a caffeic acid supplement -- some reports have indicated potentially harmful side effects, including cancers and gut problems.

Also sold in alleged muscle enhancement powders, arachidonic acid in inappropriate and untested amounts can be toxic, triggering brain cells to die off, experts say.

Some 30,000 people in the U.S. have ALS, according to the researchers, and about 10% of cases can be attributed to heritable genetic alterations. The rest occur sporadically. There is no known curative treatment.

The new study built on the established observation that though patients with ALS lose most of their muscle control because of damaged spinal motor neurons, generally they can still control their eye movements, which are guided by ocular neurons, says Gabsang Lee, D.V.M., Ph.D., associate professor of neurology at the Johns Hopkins University School of Medicine and member of the Institute for Cell Engineering at Johns Hopkins Medicine.

To explore the potentially important genetic differences between disease-free ocular neurons and spinal motor neurons that bear the brunt of ALS, Lee's team studied stem cell lines they cultivated from a person with ALS. Looking at the genetic pathways actively making proteins, the scientists found more activity in genes that control lipid metabolism -- the process in which cells process fat.

Lee then sent to colleagues at the University of Southern California samples of ocular neurons and spinal motor neurons from 17 people with ALS who were treated at The Johns Hopkins Hospital, and six sample sets of people without the condition. The researchers confirmed that spinal motor neurons of the people with ALS contained completely different amounts and types of lipids than did ocular neurons, compared to people without the condition.

Further analysis to identify which lipid pathways were most altered between cells of people with ALS and cells of people without the disease showed that one pathway stood out -- arachidonic acid.

An omega-6 fatty acid that controls the body's inflammatory response, arachidonic acid has been linked to Alzheimer's and Parkinson's diseases and, two decades ago, researchers found higher than expected amounts of the enzyme in neuromuscular tissue of people with ALS.

Lee says lipid pathways have been highly studied because they are critical parts of the cell membrane, that enable the flow of molecules in and out of cells. Cell membranes often break when there is inflammation, and Lee says the body must tightly regulate arachidonic acid, or inflammation can run amok and send signals to the immune system to destroy neural tissue.

To further test the role of arachidonic acid, the investigators performed experiments to reverse its effects by feeding caffeic acid first to fruit flies genetically engineered to develop ALS-type symptoms. Flies fed caffeic acid were able to move around more, climb up the test tube more often and live longer than flies that did not receive the compound.

The scientists then conducted similar experiments with caffeic acid in mice bred to develop ALS, and those that received the compound lived two to three weeks longer than mice not fed the compound.

Although the new evidence may one day offer potential new strategies for therapy, Lee says that questions linger. "We don't know yet why ocular and spinal neurons differ in lipid metabolism or what percentage of ALS patients have alterations in the arachidonic acid pathway," he says.

Lee has filed provisional patents for technology related to the potential use of the arachidonic acid pathway to treat ALS.

Funding for the research was provided by the Robert Packard Center for ALS Research, the National Institutes of Health (R01NS093213), the National Research Foundation of Korea, the Donald E. and Delia V. Baxter Foundation, and the Department of Molecular Microbiology and Immunology at the University of Southern California.

In addition to Lee, scientists who conducted the research are Hojae Lee, Sandeep Kumar Dubey, Kai Ruan, Seong-Hyun Park, Shinwon Ha, Irina Kovlyagina, Seongjun Kim, Yohan Oh, Hyesoo Kim, Sung-Ung Kang, Thomas Lloyd and Nicholas Maragakis from Johns Hopkins; Jae Jin Lee and Hyungjin Eoh from the University of Southern California; Na Young Park and Young Bin Hong from Dong-A University in South Korea; Taeyong Kim from San Diego State University; Su Bin Lim from the Ajou University School of Medicine in South Korea, and Kyung-tai Kim and Mi-Ryoung Song from the Gwangju Institute of Science and Technology in South Korea.

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Story Source:

Materials provided by Johns Hopkins Medicine. Note: Content may be edited for style and length.

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Journal Reference:

1. Hojae Lee, Jae Jin Lee, Na Young Park, Sandeep Kumar Dubey, Taeyong Kim, Kai Ruan, Su Bin Lim, Seong-Hyun Park, Shinwon Ha, Irina Kovlyagina, Kyung-tai Kim, Seongjun Kim, Yohan Oh, Hyesoo Kim, Sung-Ung Kang, Mi-Ryoung Song, Thomas E. Lloyd, Nicholas J. Maragakis, Young Bin Hong, Hyungjin Eoh, Gabsang Lee. Multi-omic analysis of selectively vulnerable motor neuron subtypes implicates altered lipid metabolism in ALS. Nature Neuroscience, 2021; DOI: 10.1038/s41593-021-00944-z

https://www.sciencedaily.com/releases/2021/11/211115123501.htm

COVID patients on SSRI antidepressants are less likely to die, study finds

 A large analysis of health records from 87 health care centers across the United States found that people taking a class of antidepressants called selective serotonin reuptake inhibitors (SSRIs), particularly fluoxetine, were significantly less likely to die of COVID-19 than a matched control group.

The results add to a body of evidence indicating that SSRIs may have beneficial effects against the worst symptoms of COVID-19, although large randomized clinical trials are needed to prove this.

"We can't tell if the drugs are causing these effects, but the statistical analysis is showing significant association," said Marina Sirota, PhD, associate professor of pediatrics and a member of the Bakar Computational Health Sciences Institute (BCHSI) at UC San Francisco. "There's power in the numbers."

The UCSF-Stanford research team analyzed electronic health records from the Cerner Real World COVID-19 de-identified database, which had information from almost 500,000 patients across the U.S. This included 83,584 adult patients diagnosed with COVID-19 between January and September, 2020. Of those, 3,401 patients were prescribed SSRIs.

The large size of the dataset enabled researchers to compare the outcomes of patients with COVID-19 on SSRIs to a matched set of patients with COVID-19 who were not taking them, thus teasing out the effects of age, sex, race, ethnicity, and comorbidities associated with severe COVID-19, such as diabetes and heart disease, as well as the other medications the patients were taking.

The results showed that patients taking fluoxetine were 28 percent less likely to die; those taking either fluoxetine or another SSRI called fluvoxamine were 26 percent less likely to die; and the entire group of patients taking any kind of SSRI was 8 percent less likely to die than the matched patient controls.

Though the effects are smaller than those found in recent clinical trials of new antivirals developed by Pfizer and Merck, the researchers said more treatment options are still needed to help bring the pandemic to an end.

"The results are encouraging," said Tomiko Oskotsky, MD, a research scientist in Sirota's lab at BCHSI. "It's important to find as many options as possible for treating any condition. A particular drug or treatment may not work or be well tolerated by everyone. Data from electronic medical records allow us to quickly look into existing drugs that could be repurposed for treating COVID-19 or other conditions."

Other authors include David K. Stevenson, MD, Ivana Marić, PhD, Ronald J. Wong, PhD, and Nima Aghaeepour, PhD, of Stanford University; and Alice Tang and Boris Oskotsky, PhD, of UCSF.

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Story Source:

Materials provided by University of California - San Francisco. Original written by Laura Kurtzman. Note: Content may be edited for style and length.

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Journal Reference:

1. Tomiko Oskotsky, Ivana Marić, Alice Tang, Boris Oskotsky, Ronald J. Wong, Nima Aghaeepour, Marina Sirota, David K. Stevenson. Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants. JAMA Network Open, 2021; 4 (11): e2133090 DOI: 10.1001/jamanetworkopen.2021.33090

https://www.sciencedaily.com/releases/2021/11/211115123538.htm

Tau proteins in people living with ALS

 A team led by investigators at Massachusetts General Hospital (MGH) has shown that people living with amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, who carry a mutation in the C9orf72 gene exhibit elevated levels of tau and phosphorylated tau protein in the motor cortex region of the brain. The research, which is published in Brain Pathology, also identified new genetic mutations in the tau gene and revealed that the ratio of different forms of tau protein may be an indicator of disease progression in ALS.

"This study focused on tau, a protein that is critical for stabilizing the structure of nerve cells and has been implicated in Alzheimer's disease, and whether it plays a role in ALS pathogenesis as it can form aggregates and lead to cellular dysfunction in a number of neurodegenerative disorders," says senior author Ghazaleh Sadri-Vakili, PhD, director of the NeuroEpigenetics Laboratory at the MassGeneral Institute for Neurodegenerative Disease and the Sean M. Healey and AMG Center for ALS at Mass General.

Using post-mortem brain samples from people with ALS, the researchers discovered that tau and one of its phosphorylated forms are increased in the brains of patients whose cells carry a mutation in the C9orf72 gene that was linked to ALS and dementia 10 years ago. "We also identified new genetic mutations in the tau gene that are specific to ALS and may have functional consequences that may exacerbate disease onset or progression," says Sadri-Vakili.

To determine if tau protein is a viable biomarker for ALS, the team measured tau and its phosphorylated form in cerebrospinal fluid from people living with ALS. The investigators demonstrated that increases in these particular forms of tau protein in patients' cerebrospinal fluid correlated with disease progression. Therefore, tau levels -- and specifically the ratio between tau and the phosphorylated form of the tau protein -- might help clinicians predict patients' rate of disease progression. "These findings are exciting as there is an unmet and urgent need for disease biomarkers in ALS," notes Sadri-Vakili.

Co-authors include Tiziana Petrozziello, Ana C. Amaral, Simon Dujardin, Sali M.K. Farhan, James Chan, Bianca A. Trombetta, Pia Kivisäkk, Alexandra N. Mills, Evan A. Bordt, Spencer E. Kim, Patrick M. Dooley, Caitlin Commins, Theresa R. Connors, Derek H. Oakley, Anubrata Ghosal, Teresa Gomez-Isla, Bradley T. Hyman, Steven E. Arnold, Tara Spires-Jones, Merit E. Cudkowicz, and James D. Berry.

Funding was provided by the Judith and Jean Pape Adams Charitable Foundation, the Byrne Family Endowed Fellowship in ALS Research, the Alzheimer's Association, the Jack Satter Foundation, and the National Institute on Aging.

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Story Source:

Materials provided by Massachusetts General Hospital. Note: Content may be edited for style and length.

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Journal Reference:

1. Tiziana Petrozziello, Ana C. Amaral, Simon Dujardin, Sali M. K. Farhan, James Chan, Bianca A. Trombetta, Pia Kivisäkk, Alexandra N. Mills, Evan A. Bordt, Spencer E. Kim, Patrick M. Dooley, Caitlin Commins, Theresa R. Connors, Derek H. Oakley, Anubrata Ghosal, Teresa Gomez‐Isla, Bradley T. Hyman, Steven E. Arnold, Tara Spires‐Jones, Merit E. Cudkowicz, James D. Berry, Ghazaleh Sadri‐Vakili. Novel genetic variants in MAPT and alterations in tau phosphorylation in amyotrophic lateral sclerosis post‐mortem motor cortex and cerebrospinal fluid. Brain Pathology, 2021; DOI: 10.1111/bpa.13035

https://www.sciencedaily.com/releases/2021/11/211115123558.htm

Why China is still trying to achieve zero Covid

 Around the world people are getting used to post-lockdown life with vaccines doing the heavy lifting against Covid-19 as restrictions are eased. In China however, a hard elimination policy remains where the pandemic first began.

A person walks into a five-star hotel to ask briefly for directions and ends up in two weeks quarantine because a guest had some coronavirus contact. One crew member on a high-speed train has close contact with an infected person, and a trainload of passengers is sent to quarantine for mass testing. In Shanghai Disneyland, 33,863 visitors suddenly have to undergo mass testing because a visitor the day before got infected.

Welcome to life in the country which now feels like a perpetual, back-to-zero-Covid world.

China was the first country to impose restrictions to combat this pandemic and it will be one of the last to ease them.

When you speak to ordinary Chinese people in the street, you will find that many do not seem to mind the continued strict anti-virus measures as long as they are kept safe.

I asked one woman whether China should open faster and she said it would be best to wait until the pandemic is sorted out properly because safety is number one.

Another woman heading home from work told me the virus is not completely understood, that vaccines would improve and so, for the sake of social stability, it would be best to hold off opening up.

Not so long ago, other countries like Australia, New Zealand and Singapore were also approaching each outbreak of the coronavirus as something that had to be completely stamped out in the community, sending cities into lockdown until the virus stopped spreading.

The goal was to reach zero local transmissions.

The two things that changed this approach were the emergence of the much tougher to control Delta variant of the disease and, more crucially, reaching high vaccination levels.

High vaccination rates meant people might still contract Covid-19, but not have to go to hospital.

As a result, borders elsewhere are opening to international travel. In China however, visas for foreigners remain hard to come by and Chinese people are still not having their passports renewed after they expire.

Elsewhere, people are "living with the virus". Not in China, where yet another Delta outbreak is being attacked with the same zeal as before the vaccine.

If the official figures are accurate, over 1,000 local transmissions have been recorded since October. The figure is not that high, but the spread is significant, hitting 21 provinces. This matters because even a couple of cases in China will trigger the same strict measures as hundreds or thousands of new infections.

'Not a single infection is acceptable'

The authorities have shown no inclination to alter this approach, even as some Chinese scientists urge a re-think.

Professor Guan Yi, a virologist from Hong Kong University and adviser to the government, has called for a switch from mass nucleic acid tests (which find infections) to mass antibody tests (which might help scientists understand the effectiveness of vaccines).

In an interview with Phoenix TV he said that in the long run, there is no chance that a zero-Covid strategy could work in terms of achieving complete elimination.

"The virus is permanent now," he said. "It's the same as influenza, which will circulate in humans for a long time".

IMAGE SOURCE,GETTY IMAGES

Image caption,

33,863 visitors to Shanghai Disneyland underwent mass testing as a visitor the previous day had become infected

This concept will not come as a surprise to people in other countries. In China however, the government has drilled the population to mobilise to get back to zero cases with each new surge of the virus. Changing this message will be hard.

Asked how much protection China's vaccines might offer against mutant strains of the coronavirus, Prof Guan said that this is something the vaccine producers would have to answer.

He is not alone amongst academics who are now questioning Beijing's direction.

Dr Huang Yanzhong, from the New-York based Council on Foreign Relations, says a key problem is that vaccines cannot achieve what the Chinese government would like them to, making Beijing wary.

"They're not confident about the effectiveness of the vaccines - the ability to prevent infections," he told the BBC, "because actually even the best vaccines can't prevent infections - but the zero-tolerance strategy says we can't accept even one single infection."

Dr Huang added the Chinese government has found itself in a political and ideological bind when trumpeting its successes to its people.

"The zero-tolerance strategy is also part of the official narrative, to claim the success of the Chinese pandemic response model, the superiority of the Chinese political system. So if you give up that strategy, and then you saw the cases increasing significantly, you know that would lead people to question the model."

'A million reasons'

Add to the mix that Beijing has some big events coming up and there is great desire amongst officials to hold them in an environment free of any Covid outbreak.

Most immediately there is the Winter Olympics in February. Tickets have not gone on sale but the goal is to have spectators in the stands.

Next October is the Communist Party's five-yearly Congress, when Xi Jinping is expected to begin a historic third term in office.

Of course, there will always be something on the horizon.

IMAGE SOURCE,GETTY IMAGES

Image caption,

Sporadic outbreaks of Covid-19 in China is casting doubt on the country's ability fo maintain zero-Covid cases ahead of the 2022 Beijing Winter Olympics

Another rather bleak interpretation is that General Secretary Xi Jinping and his administration like the idea of reducing foreign influence in China, and the pandemic has provided an excellent excuse to move in this direction.

On social media, some posts by nationalists have decried international influence on "China's" way of doing things.

The emphasis of governance here has certainly shifted from a "reform and opening up" philosophy to one that places the Communist Party at the centre of everything and its leader Xi Jinping at its very core.

Given that other countries have been opening their borders, the BBC asked Foreign Ministry spokesman Wang Wenbin when his country might do the same.

He replied that China has been watching the experience of other countries and would follow science to make its decisions in light of new variants that were emerging.

Either way, experts close to those in power here are not signalling an imminent end to zero-Covid. In fact, it is quite the opposite.

'Too high' a cost

Dr Zhong Nanshan is seen as something of a medical hero in China. The specialist in respiratory medicine shot to global fame in 2003 for challenging the then-government's line that the Sars outbreak was not so severe.

These days, people - including officials - listen to what he has to say.

In a recent interview, he said China's strict Covid amelioration measures would remain for "a rather long time".

He added that a global Covid-19 mortality rate of 2% was too high for China to accept even with vaccines in place. The cost of opening too quickly was not worth it, he said, adding that China would be watching the experience of other countries under their "living-with-Covid" plans.

It is also important to consider that China's officials can be quite conservative in their approach. It is possible that they plan to "re-open" the country again and are simply in no great rush to do so.

For many of those wanting to enter China or to leave it, they have no choice but to wait and see.

While middle and upper class people may be lamenting the lack of freedom to move about internationally, many ordinary Chinese citizens seem content to allow the government to manage the situation if it keeps them healthy.

In the meantime, mass testing, centralised quarantine, transport controls, high-level surveillance, delivering track and trace as well as strict, localised lockdowns will remain a big part of life in China.

https://www.bbc.com/news/world-asia-china-59257496