Tag: virus

SARS-CoV-2 Life Cycle

What has emerged from 19 months of work, backed by decades of coronavirus research, is a blow-by-blow account of how SARS-CoV-2 invades human cells. Scientists have discovered key adaptations that help the virus to grab on to human cells with surprising strength and then hide itself once inside. Later, as it leaves cells, SARS-CoV-2 executes a crucial processing step to prepare its particles for infecting even more human cells. These are some of the tools that have enabled the virus to spread so quickly and claim millions of lives.

Dengue Progress

Her team released Wolbachia-carrying mosquitoes in parts of Yogyakarta as part of a randomized controlled trial. Wolbachia rapidly spread among the local mosquitoes, and reduced the incidence of dengue by 77%. “That provides the gold standard of evidence that Wolbachia is a highly effective intervention against dengue. It has the potential to revolutionize mosquito control.”

Orphan Vaccine Carriers

humanity was a lot braver / ingenious 200 years ago. today, people sit on their fat asses debating useless things, like whether human challenge trials are “ethical”:

At the end of the 18th century, smallpox was probably the scariest disease on Earth. It spread alarmingly quickly, and every cm of people’s skin, including their face, would erupt with 1000s upon 1000s of painful, pus-filled sores. Edward Jenner observed something strange, however: People who caught a related disease called cowpox never came down with its deadlier cousin. So in 1796, he began giving people cowpox intentionally, rendering them immune to smallpox and creating the first vaccine.

But the breakthrough introduced another dilemma: How could doctors deliver vaccines to people who needed them? The real trouble started when doctors tried to vaccinate people who were far away. The lymph could lose its potency traveling even the 350km from London to Paris, let alone to the Americas, where it was desperately needed: Smallpox outbreaks there were verging on apocalyptic, killing up to 50% of people who got the virus. Every so often threads of dried lymph did survive an ocean journey—a batch reached Newfoundland in 1800—but the lymph was typically rendered impotent after months at sea. Spain especially struggled to reach its colonies in Central and South America, so in 1803, health officials in the country devised a radical new method for distributing the vaccine abroad: orphan boys.

The plan involved putting 24 Spanish orphans on a ship. Right before they left for the colonies, a doctor would give 2 of them cowpox. After 10 days at sea, the sores on their arms would be nice and ripe. A team of doctors onboard would lance the sores, and scratch the fluid into the arms of 2 more boys. 10 days later, once those boys developed sores, a third pair would receive fluid, and so on.

New variants

Many virologists thought this very unlikely, you could never know that a new variety had higher transmission from mere incidence data: you must understand the biological mechanism. Are they correct? Obviously not.

Why did they think that a new, more transmissible variant of COVID-19 was unlikely? There are several reasons. One, they typically deal with viruses that have been around for a long time, like measles ( > 1000 years). An old virus is going to be pretty well-adapted to to humans. Probably it’s at a local optimum, where small changes would reduce infectivity. But you don’t expect that high degree of optimization in a virus that’s brand new in humans: while spreading to very many people, more than 100M, greatly increases the chance of transmission-increasing mutations. Fisherian acceleration.

Like most biologists and MDs, most virologists don’t know any theory, and in fact don’t _believe_ in theory. For this they occasionally pay a price.

2020 -98% flu

In 2019, during the third week of December, the CDC reported that 16% of samples were positive for influenza A. During the same week in 2020, the rate was 0.3%.The question, of course, is why SARS-CoV-2 continues to spread like wildfire when so many other viruses have been crushed. Viruses that have circulated for years are endemic. Because many of us have previously been exposed and therefore have developed immunity to them, social distancing can more easily cut the chain of transmission. Social distancing is probably not the only factor suppressing endemic pathogens. Walgreens, for instance, has seen “unprecedented demand” for flu vaccine shots this season

2021-06-03: Flu clade extinction?

With Covid suppression measures like mask wearing, school closures, and travel restrictions driving flu transmission rates to historically low levels around the world, it appears that 1 of the H3N2 clades may have gone extinct. The same phenomenon may also have occurred with 1 of the 2 lineages of influenza B viruses, known as B/Yamagata. “Without doubt this is definitely going to change something in terms of the diversity of flu viruses out there. The extent to which it changes and how long it stays changed are the big question marks. But we have never seen this before. I do think we’re likely to lose a little bit of the H3N2 diversity. That’s a great thing. Currently when we make recommendations for vaccine strains, it’s always the headache virus.”

Immune System Arms Race

The challenge for the immune system is that mammals do not evolve as fast as viruses. How then, in the face of this disadvantage, can the immune system hope to keep pace with viral evolution? If a protein is fragile, even small changes can render it completely unable to do its job. TRIM5α is not fragile; most random mutations increased, rather than decreased, the protein’s ability to prevent viral infection. TRIM5α can readily gain antiviral activity and, once gained, does not lose it easily during subsequent mutation.

2022-12-02: And new infections can be filmed

The early stages of the virus–cell interaction have long evaded observation by existing microscopy methods due to the rapid diffusion of virions in the extracellular space and the large 3D cellular structures involved. We present an active-feedback single-particle tracking method with simultaneous volumetric imaging of the live cell environment called 3D-TrIm to address this knowledge gap. 3D-TrIm captures the extracellular phase of the infectious cycle in what we believe is unprecedented detail. We report previously unobserved phenomena in the early stages of the virus–cell interaction, including skimming contact events at the millisecond timescale, orders of magnitude change in diffusion coefficient upon binding and cylindrical and linear diffusion modes along cellular protrusions. We demonstrate how this method can move single-particle tracking from simple monolayer culture toward more tissue-like conditions by tracking single virions in tightly packed epithelial cells. This multiresolution method presents opportunities for capturing fast, 3D processes in biological systems.

Dose variation

The reason we do a second vaccination is that these later doses help to solidify immune memory, in part by giving extra training to the cells that produce antibodies, a process called affinity maturation. But this process begins with the single dose, and the evidence collected between the time of the 1st and 2nd doses in 10Ks of people in the Phase 3 trials suggests that the level of affinity maturation may provide enough protection to meet the standards we have set for vaccine approval during this pandemic even without the 2nd dose. we should begin immediate single-dose trials, recruiting volunteers from low-risk populations who are 1st in line for the vaccinations.

Magical extra doses and supply chain optimization:

some of the vaccine distribution sites had access to low dead-volume syringes, syringes that leave less vaccine trapped between the plunger and needle — the “dead volume” — after a shot is given. Thus, less vaccine was wasted in the syringe and more available for putting into arms using the low dead-volume syringes.

This is quite remarkable. Increasing vaccine supply by 20% by building more factories could cost billions. We should do that, it would be worth it. But in this case, we managed to increase supply by at least 20% use a relatively inexpensive redesign of the syringe. What this indicates is the importance of thinking along the entire supply chain for opportunities for optimization.

Single-Shot and first doses first

The FDA panel voted unanimously to authorize the J&J vaccine. Good. Note, however, that the single-shot J&J vaccine is quite comparable to the first dose of the Pfizer and Moderna vaccines. Yet, few people are demanding that J&J be required to offer a second shot at all, let alone in 3-4 weeks (What about vaccine escape! How long does immunity with a single-shot last! What about the children!). It really is scandalous how these objections to a single-shot have disappeared. This is evidence of what I call magical thinking–an undue focus on the clinical trial design as having incantatory power.

Why did J&J focus on a single-shot? Was this because of “the science”, i.e. something unique about their vaccine? No. J&J focused on a single-shot vaccine for the same pragmatic reasons that I favor First Doses First.

J&J chose to begin with the single shot because the World Health Organization and other experts agreed it would be a faster, more effective tool in an emergency. (emphasis added).

Since that time, Dr Dolittle has insisted we stick to the 2 shots regime. Criminal negligence.

Fractional doses work

in an article on new vaccine boosters there is this revealing statement:

Any revised Moderna vaccine would include a lower dose than the original. The company went with a high dose in its initial vaccine to guarantee effectiveness, but the company is confident the dose can come down, reducing side effects without compromising protection.

Arrgh! Why wait for a new vaccine??? Fractional dosing now! The article also notes:

One of Moderna’s co-founders is known for his research on microneedles, tiny Band-Aid-like patches that can deliver medications without the pain of a shot. Moderna has said nothing about delivery plans, but it’s conceivable the company might try to combine the 2 technologies to provide a booster that doesn’t require an injection.

The skin is highly immunologically active so you can give lower doses with a microneedle patch. The microneedles are sometimes made from sugar and don’t hurt.

Dose stretching works extremely well

A new paper on dose-stretching makes 3 big points. First, “Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.” Future vaccines may not have to go through lengthy clinical trials but can instead rely on these correlates of immunity.

A 50% or 25% dose of the Moderna or Pfizer vaccine looks to be more effective than the standard dose of some of the other vaccines like the AstraZeneca, J&J or Sinopharm vaccines. The point is not that these other vaccines aren’t good–they are great! The point is that by using fractional dosing we could rapidly and safely expand the number of effective doses of the Moderna and Pfizer vaccines.

Second, even if efficacy rates for fractional doses are considerably lower, dose-stretching policies are still likely to reduce infections and deaths. A 50% dose strategy reduces infections and deaths under a variety of different epidemic scenarios as long as the efficacy rate is 70% or greater.

Third, it is better to start vaccination with a less efficacious vaccine than to wait for a more efficacious vaccine. Thus, Great Britain and Canada’s policies of starting First Doses first with the AstraZeneca vaccine and then moving to second doses, perhaps with the Moderna or Pfizer vaccines is a good strategy.