Tag: medicine

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.

Path to Herd Immunity

We believe COVID-19 herd immunity (>60% of population immune) will be reached in the US during summer 2021 (Jul-Sep 2021). At the time herd immunity is reached, 50% of the immunity will be achieved through natural infection, and the other half will be achieved through vaccination. New infections may become minimal before herd immunity is reached (Jun-Aug 2021). But due to imported cases and localized clusters, it is unlikely that new infections will drop to zero until 2022. Deaths may drop to low levels even earlier (May-Jul 2021), in part due to a vaccine distribution strategy that initially prioritizes high-risk individuals. Once deaths fall to minimal levels, we may begin seeing a relaxation of restrictions. Summarizing the above findings, our best estimate of a complete “return to normal” in the US is mid-summer 2021 (Jun-Aug 2021).

False Side Effects

if you reach a large enough population, you are literally going to have cases where someone gets the vaccine and drops dead the next day (just as they would have if they didn’t get the vaccine). It could prove difficult to convince that person’s friends and relatives of that lack of connection, though. Post hoc ergo propter hoc is one of the most powerful fallacies of human logic, and we’re not going to get rid of it any time soon.

Warp Speed is Normal

one big reason we got vaccines so quickly was that work had already gone into coronaviruses:

That was a really good—well, not “guess,” I suppose, but a good hypothesis, right? That a coronavirus was going to be a problem?

We were hedging our bets. No one knew what the next outbreak would be. It could have been a variant of influenza; it could have been one of a number of pathogens. But yeah, the short answer is, if you look at a list of outbreaks over the last 20 years, if 2 of the viruses on the list are in the coronavirus family, then you shouldn’t be shocked that it comes up again. SARS was 2002. MERS was 2012. In pandemic history, that’s a pretty short timeframe.

So we did some work with Moderna on designing MERS vaccines—all early, preclinical—so we were able to test how our mRNA worked, and we could test some designs on what the RNA should teach the body to make an immune response against. We had a lot of groundwork already laid when we found out the new virus was a coronavirus.

to prepare for the next pandemic:

It took nearly 20 years to understand coronaviruses well enough to work on. But what if the next one’s not a coronavirus?

There’s a reasonable possibility that a virus could emerge from a different virus family, and we would not be as prepared. We know that there are ~20 major virus families in the world that infect humans, and almost every outbreak we’ve seen in the past 50 years or more has come from one of those 20 virus families. What if we made a concerted effort to study every family in detail, to make vaccines to every family, and do what we did for coronavirus? Make some prototypes. So that if a cousin in that family emerges, a virus we’ve never seen before, we at least have laid some groundwork for vaccine design. One could, for $20m per virus family, make a prototype vaccine and test in the clinic. You’re talking a few billion $ over 5 years for that kind of project. That used to seem like it wouldn’t be tenable. But now it’s like, well, if I could be prepared for the next pandemic, that’s probably a really good investment.

Generic Solutions

Fighting a disease through targeting its pathophysiologies is, in a sense, an attempt to outflank it rather than attack it head-on. Instead of looking for the magic bullet that will kill the virus, or the tumor, it’s about making the body an unfriendly place for the disease to be in.

The main advantage to this approach is that there already exists a formidable arsenal to assist in this fight: 9500 drugs approved worldwide.

“We believe that in the bank of drugs we have now, the 9500 drugs there are in the world, we have the answers for virtually all diseases. Around 500 of them are still patented. So there’s opportunity to work through the other 9000 off-patent drugs — the generic drugs — and look at the impact that 1 can have for $1 a day.”
Cureosity is a repository of manually curated knowledge about novel treatments for serious, chronic, and intractable diseases.

Metagenomic testing

Scientists have developed a single clinical laboratory test capable of zeroing in on the microbial miscreant afflicting a patient in as little as 6 hours – irrespective of what body fluid is sampled, the type or species of infectious agent, or whether physicians start out with any clue as to what the culprit may be.

The test will be a lifesaver, speeding appropriate drug treatment for the seriously ill, and should transform the way infectious diseases are diagnosed. Conventional diagnostic tests are designed to detect only 1 or sometimes a small panel of potential pathogens. In contrast, the new protocol employs powerful “next-generation” DNA-sequencing technology to account for all DNA in a sample, which may be from any species – human, bacterial, viral, parasitic, or fungal. Clinicians do not need to have a suspect in mind. To identify a match, the new test relies on specially developed analytical software to compare DNA sequences in the sample to massive genomic databases covering all known pathogens.

T-Cell testing

T cell assays are very labor intensive indeed, and the sample sizes in the papers on them tend to be in the 10s. The Oxford Immunotec people are trying to improve that. “There has. . .never been great demand for wading into the intricacies of T cell tests.” The test is definitely better at determining whether a person has had a previous coronavirus infection (as opposed to antibody measurements), and if we put that together with the other papers mentioned, it could be that this extends to saying how much protection these people retain. So the story is coming together. And just as vaccine work is never going to be the same after the huge amounts of work during this pandemic, it looks like T-cell research is never going to be the same, either. They’re both going to be better, faster, and more detailed, and that’s good. Because we’re going to need all this again some day.

Medicinal chemists uplevel

Are medicinal chemists taking it too easy?

In medicinal chemistry, we have now reached a state where millions of building blocks have previously been engineered and can now be used in molecular design and synthesis. In addition to the increase in the number of new amines, boronic acids have been another fast-expanding reagent class since the introduction of the Suzuki coupling method. And if we can get our work done via such easy reactions – plenty of experience in doing the reactions, relatively easy purifications, existing scaleup expertise, and so on – then why shouldn’t we?