By David Tuller, DrPH

The BMJ has published an online “editorial” slamming the new draft of clinical guidelines for ME/CFS from the National Institute for Health and Care Excellence. The position expressed is an interesting one: Non-pharmacological treatments for “complex conditions” cannot be adequately measured by randomized trials, according to the two authors. It is, of course, noteworthy that The BMJ is mounting this argument only after an authoritative review commissioned by NICE found the evidence for CBT and GET was mostly of “very low” quality– although some was just of “low” quality.

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by Helen Stillwell

The results from a phase I clinical trial to test the safety and immunogenicity of a universal flu vaccine candidate reported encouraging results – strong titers of broad and functional antibodies persisted for over a year in healthy adults following vaccination. 

Influenza viruses contain segmented RNA genomes. The viral envelope contains two types glycoproteins or ‘spikes’ that facilitate viral entry into host cells – hemagglutinin (HA) and neuraminidase (NA). Typically, HA and NA proteins stud the viral envelope at a ratio of four to one. Additionally, there are three types of influenza virus – A, B, and C. Influenza A viruses are further characterized by subtype based on their HA and NA proteins. Three HA subtypes (H1, H2, H3) and two NA subtypes (N1, N2) have be shown to cause widespread influenza transmission in humans.

The HA molecule contains two structural regions: the head and stalk. Spatially, the head is more prominent than the stalk, and antibodies to the head of the HA molecule have been shown to neutralize viral infectivity. The structural and functional characteristics of influenza viruses allow for antigenic drift and antigenic shift. Antigenic drift results when influenza virus strains develop frequent amino acid changes in the head domain, and the strain eventually evolves into one that can no longer be neutralized by antibodies to the parent virus. Antigenic shift occurs when an influenza A virus acquires the HA domain (and potentially the NA domain) from a different viral subtype. 

The combination of these phenomena requires that flu vaccines be reassessed each year based on the viral strains currently circulating in the human population. These vaccines are efficacious when they are well matched to the circulating strains; however, mismatches are not uncommon. As such, vaccinologists have been seeking to develop a ‘universal’ flu vaccine that would confer protection against all seasonal, zoonotic, and emerging pandemic influenza viruses. 

Current seasonal influenza vaccines primarily target the HA head domain of the circulating strains. However, as mentioned previously, the head domain can escape neutralization by accumulating sufficient mutations through antigenic drift. The HA stalk domain, however, is more conserved; therefore, researchers hypothesized that a vaccine targeting the HA stalk domain might offer protection independent of antigenic drift or shift. 

To provoke an immune response to the HA stalk domain, researchers at Mount Sinai developed a sequential vaccine strategy by generating chimeric HA (cHA) proteins consisting of conserved stalk and head domains from various avian influenza subtypes. Most adults already possess immune memory to the H1 HA domain as well as antibodies and memory B cells specific to the stalk domain; therefore, it was proposed that vaccinating individuals with cHA constructs that consist of head domains from different avian influenza virus subtypes and a conserved stalk domain might redirect the immune response to the stalk.

The clinical trial consisted of 5 different treatment groups:

Group 1: LAIV8-IIV5/AS03

Day 1: Intranasal (i.n.) live-attenuated influenza virus (LAIV) vaccine expressing ch8/1 HA and an N1 NA.
Day 85: Intramuscular (i.m.) inactivated influenza virus (IIV) vaccine expressing ch5/1 HA and an N1 NA with an adjuvant (AS03). 

Group 2: LAIV8-IIV5

Day 1: (i.n.) LAIV vaccine expressing ch8/1 HA and an N1 NA.
Day 85: (i.m.) IIV vaccine expressing ch5/1 HA and an N1 NA with no adjuvant. 

Group 3: Placebo Control 1

Day 1: (i.n.) Saline solution.
Day 85: (i.m.) PBS 

Group 4: IIV8/AS03-IIV5/AS03

Day 1: (i.m.) IIV vaccine expressing cH8/1N1 with AS03.
Day 85: (i.m.) IIV vaccine expressing cH5/1N1 with AS03. 

Group 5: Placebo Control 2

Day 1: (i.m.) PBS
Day 85: (i.m.) PBS

The regimen for Groups 1 and 3 comprised live-attenuated influenza virus (LAIV) followed by an inactivated influenza virus (IIV). This combination was tested based on previous studies showing that it had provoked optimal antibody responses with influenza virus vaccines in humans and non-human primates and with chimeric HA-based vaccines in ferrets. This combination had also been found to convey better protection against infection than the chimeric HA-based IIV-IIV regimen in ferrets; therefore, it was hypothesized that the intranasal LAIV followed by the intramuscular IIV boost might confer better protection than the two intramuscular doses of IIV (Group 4).

Ultimately, the study reported that Group 1 participants did not produce significant anti-stalk antibody titers after the day 1 LAIV dose; however, when these participants were boosted with IIV5/AS03 they induced a strong anti-stalk antibody response. When the boost was given without an adjuvant in Group 2, lower anti-stalk antibody titers were observed. In Group 4, however, the initial administration of IIV8/AS03 induced a very strong anti-stalk antibody response. Although these titers dropped slightly between days 25 and 85, they increased again after the administration of IIV5-AS03 on day 85. Further, these antibody titers persisted above baseline levels at 420 days after vaccine administration. While Groups 1 and 2 antibodies also persisted, they did so at lower levels. Anti-stalk antibodies did not increase in the placebo groups over the course of the study, and no significant adverse reactions to the vaccine were reported. Additionally, mice treated with post vaccination serum were protected from viral challenge as compared to mice treated with pre-vaccination serum. Although one might have predicted Groups 1 and 2 to show better protection than Group 4 based on the data established in ferrets, animal models do not always approximate vaccine responses in humans.Though encouraging, these results are still preliminary, and future trials will shed light on whether antibodies to the stalk protein will prove to be as protective as those elicited by natural infection. It may take several years to develop the diversity of chimeric hemagglutinins needed to make a universal flu vaccine, and later phase clinical trials to test the vaccine’s efficacy and superiority to existing vaccines would need to be conducted. This study does demonstrate, however, that “you can develop a vaccine strategy that produces stalk-reactive antibodies in humans,” said virologist Florian Krammer in an interview for Science, one of the lead investigators on the project. It represents an important step towards developing a universal vaccine strategy that could replace the seasonal model.

Image credit: Principles of Virology, ASM Press

On this episode, FDA EUA for Pfizer mRNA vaccine, efficacy of AstraZeneca ChAdOx1 COVID-19 vaccine, and an orally administered drug that blocks SARS-CoV-2 transmission in ferrets.

Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, Rich Condit, and Brianne Barker

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Download TWiV 693 (69 MB .mp3, 115 min)
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Show notes at microbe.tv/twiv

By David Tuller, DrPH

On November 10^th, the National Institute of Health and Care Excellence published a draft of new clinical guidelines for ME/CFS. The draft represented a blunt rejection of the argument that the combination of “unhelpful cognitions” and deconditioning drives the illness. Under this once-hegemonic framework, indicated therapies include cognitive behavior therapy to overcome the unhelpful cognitions and graded exercise therapy to reverse the deconditioning. A review of the literature published along with the NICE draft assessed the quality of evidence from dozens of CBT and GET studies as “low” or “very low.”  

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COVID-19 vaccine candidates are garnering all the news these days, which is appropriate as they are our key to ending this pandemic. Earlier in this outbreak antiviral drugs received a good deal of attention, but they have proven less useful in curtailing infection. Less discussed are the many antiviral drug candidates that are in testing, including one that appears to be effective in a ferret model of infection.

MK-4482 is an orally available pro-drug of the nucleoside analog N4-hydroxycytidine (NHC) (pictured above). The latter is a nucleoside analogue which is incorporated into RNA by the viral RNA-dependent RNA polymerase. Once incorporated into RNA, NHC is recognized as either C or U by the RNA polymerase. As a consequence, many mutations are introduced into the viral genome, causing lethal mutagenesis and inhibition of infectivity. NHC has been previously shown to have broad-spectrum anti-RNA virus activity and blocks transmission of influenza virus in a guinea pig model of infection.

When ferrets are inoculated intransally with SARS-CoV-2, the virus reproduces efficiently in the upper and lower respiratory tract. Infectious virus is detectable in nasal wash up to 7 days post-infection. The animals lose weight but do not succumb to disease. Oral administration of MK-4482 at 12 or 36 hours after infection, followed by treatment twice daily for 3.5 days, leads to complete clearance of infectious virus 24 – 36 hours later, demonstrating oral efficacy of therapeutic administration of the drug in ferrets.

To assess whether MK-4482 can impact transmission of SARS-CoV-2, animals were inoculated intranasally with virus and then co-housed with naive animals 30 hours later for 3 days. In experiments with untreated animals, all co-housed ferrets became infected. In contrast, when ferrets were treated with MK-4482 12 hours after infection, they did not transmit infection to co-housed animals, demonstrating that NHC can block transmission when given 12 hours after infection.

These results are promising and justify studies of the efficacy of MK-4482 in humans. The drug has already passed phase I safety trials which revealed that the drug reaches concentrations in the blood that exceed the antiviral level needed for inhibition of SARS-CoV-2 in cell culture. Consequently efficacy trials in humans appear to be warranted.

My one main concern with this study is that the drug was only administered to ferrets 12 and 36 hours after infection. It would be important to know how long after infection the drug can be administered and still limit infection and transmission. If, like the influenza antivirals Tamiflu and Relenza, the drug must be administered 24-48 hours after infection to have an effect on disease outcome, the usefulness might be limited.

With COVID-19 vaccines advancing in many countries, does it still make sense to pursue clinical development of antiviral compounds? The answer is yes. Antiviral drugs might be used to stop outbreaks and prevent transmission. For example, if an outbreak is detected in a nursing home, all occupants could be treated to prevent spread of infection. Indeed, if compounds such as MK-4482 had been available in December 2019, it might have been possible to impede the spread of SARS-CoV-2 before it left China.

By David Tuller, DrPH

Earlier today, I posted a blog about the decision by the Royal College of General Practice to remove from its site a training program called METRIC, which promoted the GET/CBT approach. I then sent the following letter to Carolyn Chew-Graham, a professor of general practice research at Keele University in Staffordshire and the main author of the training program.

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By David Tuller, DrPH

In early 2019, I wrote about an awful online training course for general practitioners on recognizing and caring for patients diagnosed with what was referred to as CFS/ME. The module, called METRIC, promised to provide “GPs and other primary care practitioners with an overview of the presentation, diagnosis, assessment and ongoing management” of the illness. It was based on the discredited PACE trial and a related effort called the FINE trial.

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By David Tuller, DrPH

On Monday, I gave a Zoom-talk hosted by the Sheffield ME & Fibromyalgia Group on the new draft of ME/CFS clinical guidelines from UK’s National Institute of Health and Care Excellence. The draft rejected the GET/CBT treatment paradigm. I haven’t watched the video, but most likely one of my eyebrows is hopping up and down as I talk. Not sure why that happens!

Watch the video here.

Recently I had a false positive PCR result for SARS-CoV-2. To confirm that I was not infected, I did an assay for viral antibodies in my blood using a rapid, at home, lateral flow assay. In this video I explain how the assay works and what my results mean.