virology blog

About viruses and viral disease

Five year persistence of Ebolavirus in humans

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Ebolavirus

The current outbreak of Ebolavirus disease in Guinea, which began in February 2021, may have originated from a survivor of the 2013-16 outbreak in the same country.

Phylogenetic analysis of genome sequences revealed that viruses from the current outbreak group with the Makona variant, which caused the 2013-16 epidemic. The new isolates are most closely related to viruses sampled in the same region in August 2014, differing by only 12 and 13 bases. Consequently the recent outbreak in Guinea was not initiated by a spillover from an animal reservoir, as has been the case for all previously studied Ebolavirus outbreaks. Rather the sequence data indicate that the isolates are somehow linked to the 2013-16 outbreak. However, the number of substitutions – 110 – is far less than would be expected had the viruses been transmitted silently from human to human since that time.

The implication of these data is that Ebolavirus remained undetected in a survivor of the 2013-16 outbreak for 5 years. While Ebolavirus is an acute infection – one that is resolved in the host – the extent of the 2013-16 outbreak revealed rare instances of persistence of the virus in survivors. In once case, an individual who had recovered from the disease developed unilateral uveitis 14 weeks after the onset of Ebolavirus disease and 9 weeks after clearance of viremia. Infectious Ebolavirus was isolated from the aqueous humor. Shortly after the declaration of the end of the Ebolavirus outbreak in December 2015, a new cluster of cases was detected in Guinea in February and March 2016. Genome sequence analysis and epidemiological tracing revealed that these cases all originated from a single individual who harbored infectious Ebolavirus in his testes for over 500 days. He passed the infection on to others during sexual intercourse. In this outbreak the viral genomes differed by just 5 mutations from isolates obtained during the previous outbreak.

These observations indicate that Ebolavirus can persist, for at least 5 years, in an infectious form in immunoprivileged sites such as the vitreous humor of the eye and the testes. The slow evolutionary rate of the genome during such persistent infections – 6 times less than occurs during human to human transmission – implies a very low level of replication. It is remarkable that Ebolavirus retains infectivity for such long periods with so little reproduction.

Such persistent Ebolavirus infections are of concern as they may lead to new outbreaks after many years. The frequency of such persistence can reach 75% of men at 6 months after infection. Antiviral drugs should be developed to eliminate persistent infections in individuals who have recovered from Ebolavirus disease. Individuals harboring virus in semen are easy to identify, but detection of virus in the eye – done by sampling the vitreous humor by needle inserted into the eye – will be more difficult to accomplish.

Trial By Error: Biopsychosocial Brigades Seek Traction with Long Covid

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By David Tuller, DrPH

Last week, two major articles on long Covid appeared in well-known US publications—one in the Atlantic, the other in Vox. Like the New York Times Magazine article that ran in January, these stories addressed with nuance the complex and unclear relationship between the varieties of long Covid and the group of entities collectively known these days as ME/CFS. They did not presume patients in either category were suffering from psychogenic symptoms.

Today, The New York Times ran an opinion piece from two women who helped spark the patient-directed long Covid movement. In their piece, Fiona Lowenstein and Hannah Davis made these pertinent observations about some of the inadequacies of the societal response to long Covid:

“We’ve seen this before with myalgic encephalomyelitis, also known as chronic fatigue syndrome. Because ME/CFS, as it is also called, is difficult to diagnose, many patients have gone uncounted, and research into treatments and cures remains underfunded compared to other illnesses. As a result, clinicians tend to be undereducated and patients are less likely to receive adequate care and government support. There’s a risk of repeating this cycle with people with long Covid.”

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The UK is still arguing over graded exercise therapy…

In the UK, much of the discourse has been different, so reading stuff from both sides of the Atlantic can be disorienting. Of course “exercise”–in the sense of “movement”–is being discussed and debated. It is a standard component of rehabilitative strategies, and variations of “exercise” for the range of long Covid presentations are being explored—although no one has a real clue about what’s going on for many or most of these patients. .

What I haven’t noticed in the US is this specific obsession with and controversy over graded exercise therapy (GET). This intervention, at least as designed for ME/CFS, attributes the perpetuation of the symptoms to deconditioning rather than any ongoing organic illness.

Aren’t we all bored with this already? Hasn’t the PACE trial testing this approach to ME/CFS been debunked? Why am I discussing this again? Because the biopsychosocial ideological brigades appear to have mounted a spirited campaign against the forces undermining their former hegemony in this field of medicine. Even Professor Peter White, the Queen Mary University of London psychiatrist and one of the lead PACE investigators, has reemerged from retirement to engage the naysayers. Professor White is one of three co-authors of a letter this week in The Guardian touting the benefits of GET for ME/CFS. For real!

The letter contained this doozy of a statement with no hint of irony or shame: “We know that graded exercise therapy is an effective treatment for chronic fatigue syndrome (or ME), a clearly related condition.”

It is hard to know how to respond to such a statement from Professor White. In the PACE trial, he and his colleagues reported GET to be “effective” only after rampant outcome-swapping. Re-analyses of the PACE data based on the investigators’ original outcome measures yielded either null results or very marginal benefits that wore off by long-term follow-up. It apparently needs to be repeated without cease that a study in which participants could be counted as “recovered” even if they got worse and in which 13 % of participants met an outcome threshold at baseline does not meet the minimal requirements for publication in any journal.

The Guardian letter is part of what seems to be a backlash emerging from some disgruntled folks against the UK’s National Institute for Health and Care Excellence, the agency that issues clinical guidelines for medical conditions. In November, NICE issued a draft for a new guidance that was three years in development. The draft categorically rejected GET or any interventions focused on increased activity and premised on the notion of deconditioning as a causative factor. It also rejected cognitive behavior therapy as a curative treatment, although it allowed for that and other approaches framed as supportive care.

An evidence review conducted for NICE as part of the guidance development process rated the quality of all the findings in support of GET and CBT as either “low” or “very low.” They applied a widely used system for this process called GRADE (for Grading of Recommendations Assessment, Development, and Evaluation). Since then, various luminaries in the biopsychosocial and evidence-based-medicine fields have assailed this negative assessment of the research base in statements posted on BMJ.com.

One group argued in an editorial that NICE’s findings were off because standard randomized controlled trials and GRADE are not the best way to assess complex interventions like those tested in PACE. One problem with that argument was that one of the editorial’s two co-authors had previously praised PACE as an excellent test of the interventions. (That was before PACE was publicly discredited. Oops!)

In a response, a second group defended the integrity of GRADE and assailed the authors of the editorial for not appreciating it. They argued that GRADE itself was fine but that the NICE team engaged in a “disastrous application” of the methodology. That these experts can’t agree among themselves about the reasons for their disapproval suggests they are flailing about for counter-arguments to the NICE draft that might stick—so far, without apparent success.

Those waging this debate over ME/CFS actually seem to be arguing about long Covid. The biopsychosocial brigadiers have been losing the argument over ME/CFS, given the questionable body of research they have produced and continue to cite. The NICE draft demonstrated that the tide was shifting in the other direction. With long Covid, they seem to be making much the same arguments over again—and simultaneously trying to un-write the last few years of critical debunking of the PACE approach. As the letter to The Guardian suggests with its call for a trial of GET for long Covid, they hope their efforts to reframe that narrative will help them gain footing and funding in a world awash with patients experiencing persistent and disabling symptoms after a viral illness.

Studies of all sorts of treatments for long Covid are of course warranted. However, the investigators responsible for much of the body of biopsychosocial ME/CFS research do not appear competent enough or knowledgeable enough about legitimate methodology and appropriate ethics to be entrusted with such an important mission.

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Is CBT different than the Lightning Process?

As a final point, I’m having trouble at this point understanding the distinction between the the PACE approach and the Lightning Process (LP). There is certainly a lot of cross-over among the investigators and experts. Professor Esther Crawley, Bristol University’s methodologically and ethically challenged pediatrician and grant rainmaker, conducted the methodologically and ethically disastrous trial of the LP for kids with ME/CFS. Professor Trudie Chalder, a CBT expert at King’s College London and a lead PACE investigator, has also been involved in LP research.

In a statement supportive of Professor Crawley’s LP trial, Professor Michael Sharpe, a psychiatrist at Oxford and another lead PACE investigator, drew favorable parallels between cognitive behavior therapy (CBT) and the LP. In Norway, proponents of CBT for ME/CFS are among those pushing for a new study of the LP. And Professor Paul Garner, an infectious disease expert at the Liverpool School of Tropical Medicine, has advised those with long Covid not to listen to sick ME/CFS patients and has directed them instead to Recovery Norway, a site full of LP testimonials. (Professor Garner was a co-signer with Professor White of the Guardian letter.)

As far as I can tell, the operating concept behind the PACE treatment approach and the LP are the same: Positive thoughts are good, negative thoughts are bad. Positive thoughts will heal you, negative thoughts will keep you sick. Being more active will also help.

That’s it. That’s the theory.

How vaccines work

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Vaccines work by educating the host’s immune system to recall the identity of a virus years after the initial encounter, a phenomenon called immune memory. Viral vaccines establish immunity and memory without the pathogenic consequences typical of a natural infection. The success of immunization in stimulating long-lived immune memory is among humanity’s greatest scientific and medical achievements.

Immune memory is maintained by dedicated T and B lymphocytes that remain after an infection has been resolved, and most activated immune cells have died. These memory cells can respond rapidly to a subsequent infection (Figure). Ideally, an effective and durable vaccine is one that induces and maintains significant numbers of memory cells. If the host is infected again with this same pathogen, the memory B and T cells initiate a response that rapidly controls the pathogen before disease develops. This paradigm is true for most human viruses for which vaccines exist, including measles, mumps, and varicella-zoster viruses and poliovirus. In some cases, antigenic variation, such as occurs with influenza virus, precludes complete protection by a memory immune response, necessitating re-vaccination.

Protection from Infection or Protection from Disease?

The memory response elicited by most human viral vaccines does not protect against reinfection, but rather against the development of disease. An individual may be exposed repeatedly to viruses and never be aware of it, because the memory response eliminates the virus before signs and symptoms develop. After vaccination with inactivated poliovirus vaccine, virus replication may take place in the intestine, but effectively blocks the development of poliomyelitis. On the other hand, the human papillomavirus vaccine is over 90% effective at blocking infection. Consequently the HPV vaccine induces sterilizing immunity.

Whether or not COVID-19 vaccines will block infection is unknown because it has not been adequately measured. The results of a few small studies suggest that some of the vaccines may prevent infection. However these studies are not conclusive because they are being done shortly after vaccination, when serum antibody levels are much higher than they will be in, say, 6 months. Only then will we have an accurate measure of how well vaccination blocks infection with SARS-CoV-2. I suspect that none of the COVID-19 vaccines will block infection, but will reduce virus reproduction sufficiently to impede transmission in the population.

Population-wide immunity (aka herd immunity)

To be effective, a vaccine must induce protective immunity in a significant fraction of the population. Not every individual in the population need be immunized to stop viral spread, but the number must be sufficiently high to impede virus transmission. Person-to-person transmission stops when the probability of infection drops below a critical threshold. This effect is called herd immunity.

The herd immunity threshold is calculated as 1- 1/R0. R0 is the number of nonimmune individuals that on average will be infected upon encounter with an actively infected individual. As the reproduction number, R0, increases the value of 1/R0 decreases, and thus 1 − 1/R0 gets closer to 1, or 100%. For smallpox virus, the herd immunity threshold is 80 to 85%, while for measles virus (which has a high R0), it is 93 to 95%. Early in the COVID-19 outbreak the R0 of SARS-CoV-2 was calculated to be 2-3, which would produce a herd immunity threshold of 50-70%.

Herd immunity only works when a vaccine either blocks infection, or sufficiently reduces virus reproduction in the host to impede person to person transmission. As stated above, I see no reason why COVID-19 vaccines will not sufficiently reduce transmission to enable herd immunity.

No vaccine is 100% effective at inducing immunity in a population. Consequently, the level of immunity is not equal to the number of people immunized. For example, when 80% of a population is immunized with measles vaccine, about 76% of the population is actually immune, well below the 93 to 95% required for herd immunity.

What about T cells?

For many virus infections, antibodies are crucial for preventing infection. However, resolution of infection often requires the action of cytotoxic T cells, which kill virus infected cells. For vaccines that do not induce sterilizing immunity, it is likely that T cells play a role in eliminating virus-infected cells and preventing the development of disease.

This division of labor has been largely ignored in the discussion of COVID-19 vaccines. Most of the dialog has concerned the induction of antibodies and their ability to neutralize virus infection. COVID-19 vaccines do induce virus-specific T cells and it is likely that these will clear infections that begin in vaccinated indivduals. It has been reported that amino acid changes in SARS-CoV-2 variants of concern do not affect T cell epitopes, and that T cell responses in individuals who have either recovered from infection or have been vaccinated are not affected by these changes. Therefore it seems likely that even if variants of concern are able to overcome to some degree previous antibody immunity, they will be cleared by T cell responses, avoiding severe disease and death. The results of the phase III trial of the J&J COVID-19 vaccine support this presumption.

Trial By Error: Psychosomatics Journal Linked to PACE Authors Highlights Bias from Subjective Outcome

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By David Tuller, DrPH

The Journal of Pyschosomatic Research, a high-profile publication from Elsevier, has recently published an article relevant to long-standing arguments about trials that are both unblinded and reliant on subjective outcomes–like, say, the PACE study and related research into psycho-behavioral treatments for ME/CFS. This specific question–how to assess research quality when subjective outcomes are involved–is at the core of ongoing debates over both draft guidelines for ME/CFS from the UK’s National Institute for Health and Care Excellence and Cochrane’s contested review of exercise therapies for chronic fatigue syndrome.

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One and Done

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by Gertrud U. Rey

On February 27, 2021, the FDA issued an emergency use authorization for a third SARS-CoV-2 vaccine. The vaccine was developed by Janssen Pharmaceutica, a Belgium-based division of Johnson & Johnson, in collaboration with Beth Israel Deaconess Medical Center in Boston. Perhaps the most exciting feature of this new vaccine is that it only requires one dose to be effective in inducing an immune response.

The vaccine is named Ad26.COV2.S because it consists of a human adenovirus vector, with a DNA genome, into which has been inserted the gene that encodes the full-length SARS-CoV-2 spike protein (pictured). Ad26.COV2.S is similar to AstraZeneca’s vaccine, based on a different adenovirus, and with a slightly different version of spike, which is not yet authorized in the U.S. The notion of using a virus as a vector to deliver vaccines to humans is based on the ability of viruses to enter cells by attaching to host cell receptors and releasing their genome into the cell. Upon injection into a vaccine recipient, the vaccine vector should enter cells and serve as a code for host proteins to synthesize the SARS-CoV-2 spike protein from the inserted gene. Ideally, the spike protein will then act as an antigen to prime the immune system to recognize SARS-CoV-2 if it infects the body at a later time. 

Adenoviruses are particularly suitable as vectors for delivering foreign genes into cells because they have a double-stranded DNA genome that can accommodate relatively large segments of foreign DNA, and because they infect most cell types without integrating into the host genome. However, because of the prevalence of adenovirus infections in humans, most people have adenovirus-specific antibodies that could bind and neutralize these vectors, thus rendering them less effective at stimulating antibodies to the inserted gene product. AstraZeneca circumvented this issue by using an adenovirus of chimpanzee origin that does not normally infect humans. The adenovirus used to make Ad26.COV2.S (Adenovirus 26) is of human origin; however, when tested, most people have very few antibodies that inactivate this adenovirus, compared to antibodies against other adenoviruses. Thus, potential Ad26.COV2.S recipients are less likely to have pre-existing antibodies to the adenovirus vector itself. To optimize Adenovirus 26 for use as a vaccine vector, Janssen investigators deleted the gene that regulates viral replication, thus ensuring that the virus vector cannot cause an infection in human cells.

During infection, the SARS-CoV-2 viral particle fuses with the host cell membrane; a process that is mediated by two main events: 1) a structural rearrangement of the spike protein from its pre-fusion conformation; and, 2) cleavage of the spike protein by a cellular enzyme called furin. Based on the knowledge that the pre-fusion, uncleaved form of spike is more stable and immunogenic, Janssen investigators also inserted two mutations into the spike gene: one that locks the translated spike protein into its pre-fusion conformation, and one that prevents its cleavage by furin.  

The FDA’s decision to issue an emergency use authorization for Ad26.COV2.S was based on safety and efficacy data from an ongoing Phase III clinical trial done in 39,321 participants who received either a single dose of Ad26.COV2.S or a placebo control. The trial was randomized, meaning that participants were randomly assigned to the experimental group receiving the Ad26.COV2.S vaccine, or the control group, so that the only expected differences between the experimental and control groups were the outcome variables studied (safety and efficacy). Randomizing trial participants eliminates unwanted effects that have nothing to do with the variables being analyzed. The trial was also double-blinded, meaning that neither the investigators nor the subjects knew who was receiving a particular treatment. Double-blinding leads to more authentic conclusions because they reduce researcher bias.

The basic findings of the trial were as follows:

  • side effects related to vaccination were mild to moderate; and
  • the vaccine was
    • 66% effective at preventing moderate to severe COVID-19 across all geographic areas and age groups (U.S., South Africa, and six countries in Latin America);
    • 72% effective at preventing moderate to severe COVID-19 across all age groups in the U.S.; 
    • 85% effective at preventing severe disease; and
    • 100% effective at preventing COVID-19-related hospitalization and death as of day 28 after vaccination.

The apparently reduced efficacy of Ad26.COV2.S compared to the Moderna and Pfizer vaccines has led to considerable public skepticism. However, this is an unfair comparison for several reasons. Ad26.COV2.S was tested at a time when more variants were in circulation, including in places where the Moderna/Pfizer vaccines are thought to be less effective against locally circulating variants. Some limited data also suggest that Ad26.COV2.S might protect from asymptomatic infection and may thus prevent transmission from vaccinated individuals to non-vaccinated individuals. Although there is some evidence to suggest that the Pfizer vaccine has a similar effect, no such data exist yet for the Moderna vaccine.

The most critical measure of a vaccine’s efficacy is how well it prevents severe disease, hospitalizations, and deaths, and in this regard, all three vaccines are comparable. Moreover, Ad26.COV2.S has at least two advantages over the Pfizer/Moderna vaccines: 1) it does not require a freezer and can be stored in a refrigerator for up to three months; and, 2) it can be administered in a single dose. This will increase vaccine uptake, because people won’t have to get two shots and/or remember to get the second shot.  It also makes it easier to immunize people with limited access to healthcare, such as the homeless and people living in remote areas. When all these factors are considered together, it is clear that Ad26.COV2.S will be a crucial additional tool in the fight against this pandemic.

Trial By Error: A Q-and-A with Tracie White, author of The Puzzle Solver

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By David Tuller, DrPH

Tracie White, a science writer at Stanford University, first stumbled across the story of Whitney Dafoe as an assignment from one of her editors. That initial encounter ultimately turned into The Puzzle Solver: A Scientist’s Desperate Quest to Cure the Illness that Stole His Son, an account that Kirkus called “a complex, well-related story of medical detective work.”

The story of Stanford geneticist Ron Davis and his son Whitney’s severe case of ME/CFS was certainly not unknown, given previous coverage–starting with Miriam Tucker’s excellent 2015 feature in The Washington Post. White’s is the first full-length account. During the reporting of the book, she grew close to the family, which included psychologist Janet Dafoe, Whitney’s mom, and his sister Ashley. I asked White a few questions about the process of writing the book.

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Understanding virus isolates, variants, and strains

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Many virology terms are being used these days by people who do not understand their meaning. Included are journalists, medical doctors, scientists, lawyers, and people from all walks of life. In normal times this word mis-usage would be so rare that it would not matter. However, because we are in a viral pandemic that affects nearly everyone, I will attempt to explain the meaning of virus isolates, variants, and strains.

Many of the terms used in virology are ill-defined. They have no universally accepted definitions and there is no ‘bible’ with the correct meanings. As each of us are trained by other virologists, we hear them using terms in certain contexts and we copy their usage – whether or not it is correct. I learned many good things from my mentors but also many things that are wrong.

Nevertheless, certain terms should have specific meanings. Some of my colleagues will certainly disagree with some of my definitions, others will agree. Kudos to the latter. I also recognize that few will read this post and it will have little impact. Perhaps one day a high school student will search for some of the terms and come across it. It is mainly meant for me to put my thoughts down in an orderly manner.

The virology terms I have in mind all have to do with attempts to place order on the huge varieties of viruses in the virosphere. Most of them today derive their meaning from the viral genome: the DNA or RNA that encodes the production of new virus particles. This reliance on the genome is relatively recent: until the 1980s we had no genome sequences; hence most categories were based on other properties, such as the size of the virus particle, whether or not it has a membrane, its type of symmetry, and much more. Today it’s all about the genome. Whether or not you think this myopia is a good idea is not the topic of this post.

Let’s start with the term virus isolate, because it’s the easiest to define. An isolate is the name for a virus that we have isolated from an infected host and propagated in culture. The first isolates of SARS-CoV-2 were obtained from patients with pnemonia in Wuhan in late 2019. A small amount of fluid was inserted into their lungs, withdrawn, and placed on cells in culture. The virus in the fluid reproduced in the cells and voila, we had the first isolates of the virus.

Virus isolate is a very basic term that implies nothing except that the virus was isolated from an infected host. An isolate comes from a single host. We can have my virus isolate, or yours, or the neighbor’s down the street. Most patients do not get to have virus isolates taken from them. Even though SARS-CoV-2 has infected millions, we do not have millions of isolates, probably just thousands. We do have genome sequences from many people, and those can be inferred to represent the isolate from each person – however in most cases infectious virus is not isolated from individual patients.

Isolates are given names so that their origin is known. For example, one of the early isolates of SARS-CoV-2 is called BetaCoV/Wuhan/WIV04/2019. This isolate name consists of the genus, Betacoronavirus, followed by the city of origin, the isolate number, and the year. SARS-CoV-2 is the name of the virus; it is not an isolate name. Isolates of other viruses are also precisely named. I’m a big fan of the very detailed influenza virus nomenclature, which is as follows: Virus name/antigenic type/host of origin if other than human/geographical origin/serial number/last two digits (or all four digits) of year of isolation/hemagglutinin subtype neuraminidase subtype. Examples include influenza A virus A/duck/Germany/1868/68 (H6N1) or influenza A virus A/chicken/Vietnam/NCVD- 404/2010 (H5N1).

A virus variant is an isolate whose genome sequence differs from that of a reference virus. No inference is made about whether the change in genome sequence causes any change in the phenotype of the virus. The meaning of variant has become clouded in the era of whole viral genome sequencing, because nearly every isolate may have a slightly different genome sequence. Such is the case for SARS-CoV-2: nearly every sequence from a different person is slightly different. Up until the end of 2020, any SARS-CoV-2 sequences from any two individuals differed by about ten nucleotide changes out of 30,000. They are all variants, but the term is rarely used in this context. However since then viral genomes with many more changes have been identified. These have been called ‘variants of concern’ (VOC) because it is thought that the changes confer new phenotypic properties such as increased fitness. British scientists did a good deed by calling them VOCs, because now the press must call them variants.

Unfortunately mainstream media, following in the footsteps of scientists who really should know better, have been using the term ‘strain’ to describe what are actually variants. This practice emerges in every viral outbreak: there is a new, more (fill in the blank with your favorite phenotype) strain of Ebolavirus, of Zika virus, and now of SARS-CoV-2. It began early in 2020 with the finding of variants with a single amino acid change in the spike protein, from D to G at position 614. The press called this a new strain that was more transmissible. But the use of strain was incorrect: it is a variant and remains so to this day.

A virus strain is a variant that possesses unique and stable phenotypic characteristics. Such characteristics can only be ascertained by the results of experiments done in the laboratory, in cells in culture and in animals, coupled with observations made in infected humans. The name strain is not easily earned: certainly it cannot simply be given by journalists! As Jens Kuhn has written, “The designation of a virus variant as a strain would be the responsibility of international expert groups”. No such designation of strain has been given more than once to SARS-CoV-2: there is one, and only one strain of this virus. No incorrect usage of that term will change this fact. As you might imagine, it can take some time for an international group of experts to agree on anything.

Viral strains are few and far between: it is a designation highly desired but given sparingly. A retrovirologist recently assured me that there is only one strain of HIV-1. The Lansing strain of poliovirus is derived from a human isolate that was passaged 99 times in mice until it acquired the ability to infect that species. That strain has demonstrably different properties from the human strain.

There are other terms to describe viruses but they are more confusing than contentious, and they are not used universally. The term serotype is used to describe viruses of the same species that are antigenically different. There are three serotypes of poliovirus; if you are infected with type 1, then immunity you generate will not protect you against infection with types 2 or 3. Same for the four serotypes of dengue virus, and the hundreds of rhinovirus serotypes. These days, the genome sequence of the virus is used to infer whether isolates are serologically different. The term genotype is used to describe the genetic makeup of a virus. For example, hepatitis C viruses are placed in different genotypes depending on the overall identity of their genomes. For other viruses, the term clade is used. A clade is a group of organisms composed of an ancestor and its descendants, as illustrated by the phylogenetic tree below. SARS-CoV-2 isolates and HIV-1 isolates are placed in clades based on phylogenetic trees constructed from their genome sequences.

I believe that the terms of virology should be used accurately and consistently. The terms isolate, strain, and variant have been frequently and incorrectly misused during the pandemic, which generates confusion. I have little faith that either the general public or the scientists will agree on any nomenclature. Rest assured that if you misuse isolate, variant, or strain, I will correct you according to my lexicon.

Trial By Error: National Institutes of Health Director Francis Collins on Plans for Long COVID Research

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By David Tuller, DrPH

The US government seems to be taking Long COVID seriously. In December, Congress allocated $1.15 billion over four years for research into the issue. This week, Francis Collins, director of the National Institutes of Health, announced the agency’s plans for that funding. (I’ve posted his announcement in full below.) In a post last month he highlighted the plight of the long-haulers and praised the most extensive report yet on their situation. That well-received research report was spearheaded and produced by a patient-led team from the Body Politic COVID-19 Support Group, an online community.

The relationship between what is generally being called ME/CFS and what is generally being called Long COVID is unclear. A number of high-profile news articles–including ones published by The New York Times, The Guardian, and Kaiser Health News–have noted the apparent overlaps in symptoms and in possible or hypothesized causes. These articles have taken at face value the notion that ME/CFS patients are suffering from a serious disease and have not presumed that psychotherapy and exercise are the optimal approaches to treatment.

Both ME/CFS and long COVID are complex phenomena–as is evident from confusion and disagreement over the appropriate nomenclature. ME/CFS is an unsatisfactory hybrid term used to refer to a range of described clinical entities. Long COVID is a convenient and easy-to-understand term but it conveys nothing about the condition’s expansive range of presentations. That variety is better expressed through the scientific name it has been given: Post-Acute Sequelae of SARS-CoV-2 infection (PASC). In other words, there are lots of different sequelae–not just one entity called Long COVID.

Ramped up funding for research into Long COVID could be beneficial for ME/CFS patients. My sense is that many of the latter are hopeful that these investigations could reveal biological mechanisms and pharmaceutical treatments that could be relevent for them as well–especially given apparent similarities in symptoms like post-exertional malaise and cognitive impairment. (I never expected to see the phrase “brain fog” in news headlines all around the world.)

At the same time, there is cause to be wary. This pandemic is now early in its second year, so so-called Long COVID is still a relatively short phenomenon–especially when compared to the decades of illness experienced by many with ME/CFS. Reports of persistent symptoms are known to be common after many viral infections. It is also known that these cases self-resolve most of the time–even if it can take a year or more in some cases.

If it is asserted prematurely or simplistically that Long COVID and ME/CFS are somehow the same, what happens if most of these legions of Long COVID patients get better in the next few months or over the next year? It could easily be presumed that the “multi-disciplinary rehabilitation”–or any number of helpful or non-helpful interventions–led to improvements, even if the recoveries would have happened in any event. In such a scenario, that advice could be presumed to be applicable to ME/CFS patients. Before declarative statements can be made, we need to see a lot more data.

In the meantime, it’s great that NIH has found more than $1 billion to investigate Long COVID. It certainly suggests that more money could have been found ten or twenty years ago to study ME/CFS than the pittance that has historically been allocated. While the amount has increased significantly in recent years, two or three times a pittance is still a relative pittance. (Jennie Spotila provides regular analyses of NIH funding at Occupy M.E., her blog)

Below is the announcement from NIH Director Francis Collins:

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NIH launches new initiative to study “Long COVID”

I write to announce a major new NIH initiative to identify the causes and ultimately the means of prevention and treatment of individuals who have been sickened by COVID-19, but don’t recover fully over a period of a few weeks. Large numbers of patients who have been infected with SARS-CoV-2 continue to experience a constellation of symptoms long past the time that they’ve recovered from the initial stages of COVID-19 illness. Often referred to as “Long COVID”, these symptoms, which can include fatigue, shortness of breath, “brain fog”, sleep disorders, fevers, gastrointestinal symptoms, anxiety, and depression, can persist for months and can range from mild to incapacitating. In some cases, new symptoms arise well after the time of infection or evolve over time. In December, NIH held a workshop to summarize what is known about these patients who do not fully recover and identify key gaps in our knowledge about the effects of COVID-19 after the initial stages of infection. In January, I shared the results from the largest global study of these emerging symptoms. While still being defined, these effects can be collectively referred to as Post-Acute Sequelae of SARS-CoV-2 infection (PASC). We do not know yet the magnitude of the problem, but given the number of individuals of all ages who have been or will be infected with SARS-CoV-2, the coronavirus that causes COVID-19, the public health impact could be profound.

In December, Congress provided $1.15 billion in funding over four years for NIH to support research into the prolonged health consequences of SARS-CoV-2 infection. A diverse team of experts from across the agency has worked diligently over the past few weeks to identify the most pressing research questions and the areas of greatest opportunity to address this emerging public health priority. Today we issued the first in a series of Research Opportunity Announcements (ROAs) for the newly formed NIH PASC Initiative. Through this initiative, we aim to learn more about how SARS-CoV-2 may lead to such widespread and lasting symptoms, and to develop ways to treat or prevent these conditions. We believe that the insight we gain from this research will also enhance our knowledge of the basic biology of how humans recover from infection, and improve our understanding of other chronic post-viral syndromes and autoimmune diseases, as well as other diseases with similar symptoms.

Some of the initial underlying questions that this initiative hopes to answer are:

  • What does the spectrum of recovery from SARS-CoV-2 infection look like across the population?
  • How many people continue to have symptoms of COVID-19, or even develop new symptoms, after acute SARS-CoV-2 infection?
  • What is the underlying biological cause of these prolonged symptoms?
  • What makes some people vulnerable to this but not others?
  • Does SARS-CoV-2 infection trigger changes in the body that increase the risk of other conditions, such as chronic heart or brain disorders?

These initial research opportunities will support a combination of ongoing and new research studies and the creation of core resources. We anticipate subsequent calls for other kinds of research, in particular opportunities focused on clinical trials to test strategies for treating long-term symptoms and promoting recovery from infection.

Research Studies: A SARS-CoV-2 Recovery Cohort—the central program of this initiative—will leverage ongoing COVID-19 studies, long-term cohort studies established well before the pandemic began, and new studies of people with Long COVID. These studies aim to characterize the long-term effects of infection in a diverse set of people and the trajectory of symptoms over time. The initiative will support a multidisciplinary consortium of investigators who collaborate and coordinate across studies. The initiative also will support two complementary studies: 1) large data studies from resources such as electronic health records and health systems databases that will be critical to understand how many people are affected and what factors contribute to recovery; 2) studies of biological specimens to understand injury to the brain and other organs.

Core Resources: A clinical science core, data resource core, and biorepository core will provide overall consortium coordination, clinical expertise in post-acute COVID symptoms, and facilitate the use of standardized data and biological specimens collected from the consortium studies by consented volunteers.

Our hearts go out to individuals and families who have not only gone through the difficult experience of acute COVID-19, but now find themselves still struggling with lingering and debilitating symptoms. Throughout this pandemic, we have witnessed the resilience of our patient, medical, and scientific communities as they have come together in extraordinary ways. NIH deeply appreciates the contributions of patients who have not fully recovered from SARS-CoV-2 infection and who have offered their experiences and insights to lead us to this point, including those with other post-viral infections. Through the PASC Initiative, we now ask the patient, medical, and scientific communities to come together to help us understand the long-term effects of SARS-CoV-2 infection, and how we may be able to prevent and treat these effects moving forward.

Francis S. Collins, M.D., Ph.D.
Director, National Institutes of Health

SARS-like bat coronaviruses are not only in China

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It is well past the time to stop blaming a laboratory in China for the release of SARS-CoV-2. Such fallacies reflect an ignorance of scientific facts, including the recent finding of closely related coronaviruses in bats in Thailand.

The bat CoV RatG13, sampled in 2013 in Yunnan province, shares 96% whole genome identity with SARS-CoV-2, suggesting a likely bat origin of the pandemic virus. To identify other possible sources for highly related viruses, a colony of 300 bats in eastern Thailand, consisting only of one species, Rhinolophus acuminatus, was sampled in June 2020. Thirteen of 100 bat rectal swab samples were positive for a single PCR amplicon with 95.86% sequence identity to SARS-CoV-2 and 96.21% identity to bat CoV-RaTG13. This virus, named RacCS203, appears to be the dominant coronavirus circulating in this bat colony. Phylogenetic analyses indicate that RacCS203 is a new member of the SARS-CoV-2 related CoV lineage (SC2r-CoV).

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Trial By Error: Happy Tenth Anniversary, PACE Trial!

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By David Tuller, DrPH

It’s been ten years since The Lancet published the first results of the PACE trial. Wow!

Ten years ago, I was 54 and still a graduate student in public health at UC Berkeley. I was also busy writing stories for The New York Times about the mouse retrovirus study that had roiled the field of research into chronic fatigue syndrome—the then-standard name for the illness now referred to as ME/CFS by US government agencies. The mouse retrovirus, XMRV, turned out to be a lab contaminant. The story had struck such a nerve at least in part because of long-standing and lingering speculations that a retrovirus could be involved—a position that retains some strong adherents.

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