Paul Has Measles is a free children's book about viruses and vaccines available in 16 languages (link). Paul Stays Home is a free children's book about COVID-19 (link).

By David Tuller, DrPH

I have recently written critically about the CODES trial of cognitive behavior therapy as a treatment for the phenomena that have long been called “psychogenic non-epileptic seizures” but that some neurologists and psychologists are trying to rebrand as “dissociative seizures.” (Many people understandably find it offensive to be told they have a “psychogenic” disorder; perhaps the term “dissociative” comes across as less dismissive.) Now Cochrane has published a review that relates directly to this issue–“Psychosocial interventions for conversion and dissociative disorders in adults.”

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Dr. Anthony Fauci joins TWiV to discuss SARS-CoV-2 transmission, testing, immunity, pathogenesis, vaccines, and preparedness.

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Dr. Fauci was previously on TWiV 219

Intro music is by Ronald Jenkees

Michael Mina joins TWiV to reveal why frequent and rapid SARS-CoV-2 testing is more important than accuracy, how a daily $1 rapid test could control the pandemic, and why group testing works.

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Show notes at microbe.tv/twiv

Vincent and Erling resume their discussion of virology Nobel Prizes, focusing on awards for research on tumor viruses, bacteriophages, virus structure, reverse transcriptase, hepatitis B virus, HIV-1, human papillomaviruses and much more.

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by Gertrud Rey

In a highly publicized press release dated May 18, 2020, the biotech company Moderna announced preliminary results from a phase I clinical trial for a SARS-CoV-2 vaccine candidate. However, the company only provided brief, conclusory statements at that time. On July 14, the results from the trial were finally published in the New England Journal of Medicine.

The vaccine candidate is named “mRNA-1273” because it consists of an mRNA (messenger RNA) that encodes the full length, 1,273 amino acid SARS-CoV-2 spike protein. The mRNA is encapsulated in a lipid nanoparticle, which protects the mRNA from degradation and ensures proper delivery into cells. Upon injection into a vaccine recipient, the mRNA would enter cells and be translated by the host protein synthesis machinery into the SARS-CoV-2 spike protein, which would then serve as an antigen to promote an immune response. The spike protein has been the primary antigenic choice for a number of SARS-CoV-2 vaccine candidates because it mediates binding of the virus to the ACE2 host cell receptor via its receptor-binding domain (RBD) and fusion of the viral particle with the host cell membrane via its fusion domain. Both of these domains are highly immunogenic and are targeted by neutralizing antibodies, which bind viral antigens to inactivate virus and prevent infection of new cells.  

Phase I clinical trials typically involve a small group of patients and aim to identify which dose of a new drug produces optimal outcomes with the fewest side effects. The Moderna trial enrolled 45 healthy adults, ranging in age from 18-55. Vaccine recipients were divided into three groups, with individuals in each group receiving a dose of either 25, 100, or 250 micrograms of mRNA-1273 in two injections spaced 28 days apart. The key observations were as follows:

  • side effects were mild to moderate;
  • all subjects produced RBD- and fusion domain-binding IgG antibodies by day 15 post-vaccination; 
  • responses were dose-dependent, with higher vaccine doses eliciting higher levels of antibodies; 
  • subjects in all dose groups produced RBD- and fusion domain-specific neutralizing antibodies only in response to the second dose;
  • binding and neutralizing antibody levels in recipients of the 100 and 250 microgram doses were similar in magnitude to those observed in sera from SARS-CoV-2-recovering patients; and,
  • recipients of the 25 microgram dose also produced T helper cells, while recipients of the 100 microgram dose produced both T helper cells and cytotoxic T cells specific to the vaccine spike protein (for a review of the relevance of these cells click here).  

Overall these results seem promising; mRNA-1273 activated both arms of the adaptive immune response by inducing both neutralizing antibody and T cell responses specific to the SARS-CoV-2 spike protein RBD and fusion domains. Moreover, because the mRNA encodes the full-length spike protein, vaccine recipients may also produce non-neutralizing antibodies specific to additional potentially immunogenic domains. As noted by immunologist Jon Yewdell in a recent letter to TWiV, non-receptor-binding domains may not mediate classic neutralization of virus in an vitro scenario, but they may provide additional protection in infected individuals. For example, flu studies in mice have shown that non-neutralizing antibodies may also protect against disease by various mechanisms that have yet to be identified. Furthermore, RNA-based vaccines are considered safer than traditional vaccines because they don’t contain infectious virus. They are particularly suitable for emerging pathogens because they can be produced more quickly and cost-effectively than traditional vaccines. 

However, the trial also had several limitations. The study group was small and the vaccine was not tested in subjects over the age of 55, a group who often mount a weaker immune response and are more likely to develop severe COVID-19. At the present time it is also impossible to know how long the observed immune responses will last because it has been less than two months since the trial participants were immunized. Because SARS-CoV-2 is considered a dangerous pathogen, traditional challenge trials, in which an immunized individual is intentionally infected with the pathogen against which he was immunized, will likely not be done, so we have no way of knowing if the vaccine is effective until vaccine recipients have been naturally exposed to the virus. It may also be difficult to know whether a person was exposed. Moreover, because mRNA vaccines have never been licensed for use in humans, there are many unknown factors, such as the potential for unanticipated long-term side effects.   

There is no doubt that we are in dire need of a vaccine for SARS-CoV-2. However, a vaccine has to be both safe and effective, two criteria that have repeatedly crippled the development of vaccines for respiratory syncytial virus, herpes simplex virus, hepatitis C virus, and HIV, just to name a few. While the results from the Moderna vaccine trial warrant cautious optimism, it is too early to draw valid conclusions in regard to efficacy and long-term protection. An ongoing placebo-controlled phase II trial evaluating the efficacy of 50 and 100 microgram doses of mRNA-1273 in 600 healthy adults, and an upcoming phase III efficacy trial aiming to evaluate the 100 microgram dose in 30,000 participants, will hopefully provide more definitive answers. 

[The Moderna mRNA-1273 vaccine was previously discussed on episodes 592616626, and 637 of TWiV.]

By David Tuller, DrPH

As post-covid syndrome has emerged as a major public health concern, so has the likelihood that members of the biopsychosocial ideological brigades will roll out their typical interventions for the “long-haulers”–patients suffering from profound exhaustion and other symptoms for many weeks and months after getting infected with the coronavirus. The situation has created an unforeseen dilemma for UK’s National Institute of Health and Care Excellence, which is currently in the process of revising its misguided 2007 guidance for what it then called chronic fatigue syndrome/myalgic encephalomyelitis and now calls ME/CFS.

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Daniel Griffin provides a clinical update on COVID-19, then Viviana Simon joins to review serological assays developed at Mt. Sinai for SARS-CoV-2 infection, tracking the outbreak in NYC, and listener questions.

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Intro music is by Ronald Jenkees

Send your virology questions and comments to twiv@microbe.tv

Show notes at microbe.tv/twiv

coronavirus Spike

Don’t believe the headlines that SARS-CoV-2 is becoming more transmissible! Virologists are making conclusions that are not justified by the data.

SARS-CoV-2 virus isolates from many parts of the world have a single amino acid change in the spike protein, D614G. This observation in itself doesn’t mean very much. It could be that the change arose early in the outbreak and as this virus spread to other areas it was maintained because it has no fitness cost. We call this behavior ‘founder effect’. Whether the change has been selected for – what we would call ‘positive selection’, as claimed by many virologists, needs to be proven by experiments that have not been done.

The D614G change appears to make the virus more infectious in cells in culture. However, there are limitations to the conclusions that may be drawn from these data. First, cells that have been used are irrelevant to human transmission, such as a kidney cell line (VERO) from Vervet monkeys. I would like to see data from cultures of human respiratory epithelial cells, including airway-liquid cultures and lung organoids. Second, SARS-CoV-2 was not used for these experiments, but pseudotyped viruses – recombinant retroviruses or vesicular stomatitis virus with the SARS-CoV-2 spike glycoprotein gene inserted. The reason for this approach is that working with SARS-CoV-2 requires a BSL-3 laboratory which is not easy to come by. Nevertheless, even if all these issues were addressed, do we really think that results in cell culture tell us anything about human to human transmission? Seriously, virology colleagues? A monolayer of cells in culture in no way compares with the architecturally complex respiratory epithelium with mucus, antibodies, innate and adaptive responses.

I don’t mention using an animal model to assess SARS-CoV-2 transmission potential because there are no good models (yet) for animal to animal transmission of the virus.

I can think of experiments that could be done to determine if viruses with D614G behave differently in humans, but they have not been done. One approach would be to determine if the change leads to higher shedding of infectious virus from the upper tract. One study reported higher levels of viral RNA in the upper tract of patients infected with 614G compared with patients infected with 614D. This observation is meaningless, because everyone knows that nucleic acids detected by PCR does not always mean that infectious virus is present. Increased RNA might be a consequence of a change in the viral RNA polymerase caused by another mutation that accompanies the spike change. What needs to be done is to measure the levels of INFECTIOUS VIRUS shed from the upper respiratory tract of humans infected with either variant. Even then I would argue that the results cannot be interpreted, because we do not know how much of an increase in virus shedding would lead to an increase in transmission. Would twofold more virus be enough? Fivefold? Tenfold? A thousand fold? Anyone who says they know is wrong.

We know that the dispersion factor, k, of SARS-CoV-2 is 0.1, which means that about 10% of cases lead to 80% of spread. Which virus are these individuals transmitting, 614D or 614G? The results would contribute to an understanding of the role of this amino acid change in transmission.

It’s unfortunate that during a serious outbreak, rigorous science appears to be relegated to the back seat. You might remember during the 2015 Ebolavirus outbreak in West Africa, a viruses with a single amino acid change in the spike protein arose early and predominated. This change made the virus more infectious in cells in culture in the laboratory, but was never shown to have any effect on human transmission. In a nonhuman primate model, the change actually reduced virulence of the virus. Whether the predominance of virus isolates with the amino acid change was a founder effect or positive selection was never determined.

An important consideration is to identify the selection pressure for SARS-CoV-2 viruses with increased transmission. By the time the virus was detected in China late in 2019, it was already very good at transmitting among humans. I fail to see what selection pressure would lead to the emergence of such a variant.

The D614 change does not appear to change the virulence of SARS-CoV-2, nor its ability to be neutralized by antibodies. Let’s toss all the above arguments aside and assume that D614G increases human transmission. What should we do? Wear face masks, avoid large gatherings of people, embrace physical distancing. All of which are already being done – or are they?

In this episode, approval of an Ad5 vectored SARS-CoV-2 vaccine for the military in China, description and clinical trials of a Novavax vaccine joining Operation Warp Speed, prevalence of SARS-CoV-2 in Spain, shedding and transmissibility of the virus, and listener email.

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From Georgia State University, Vincent speaks with Chris, Andrew, Priya, and Richard about their careers and their work on Ebolaviruses, rotavirus, and antiviral drug development.

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