The state of the vaccines

OK, here is what is going on with the COVID-19 vaccines:

We have 202 vaccines being developed. Most are in pre-clinical phase (R&D, animal studies, toxic/pharmacological properties, etc.). As of today (this info will get old fast) we have 15 in phase 1 human clinical trials (typically just a few young and healthy subjects, 20 to 50 people); 2 in phase 2 (typically some 500-600 to a couple of thousand people) still relatively young and healthy subjects.

Animal trials, phases 1 and 2 are very interested in two things: is the vaccine safe? Does it have good immunogenicity (that is, does it stimulate the immune system to produce antibodies and to get T-cell memory?). Phase 1 is also good to gauge vaccine dose and helpfulness of possible boosters. Phase 2 moves more into safety.

Then we have the front-runners, 7 in phase 3 (30,000 to 50,000 subjects). Phase 3 must include older and less healthy ones to have an ultimate look at safety; it's best done in hot spots of contagion so that not only safety but also efficacy in preventing the infection is field-tested.

So, what kinds of vaccines are out there, and how do they work?

Nucleic Acid Vaccines:

These use DNA or mRNA (messenger RNA). DNA ones go into the human cell's nucleus, while RNA ones act in the cytosol, or intracellular fluid, with no need to go into the cells nucleous, so the RNA ones don't carry the risk of being incorporated into the host's DNA.

Both intend to teach the human cell to produce viral protein, which then is thrown out of the cell and captured/consumed by APCs (antigen-presenting cells). These cells take the viral proteins to T-Helper cells. These are the memory centers of the immune system. T-Helper cells then do two things: they inform cytotoxic T cells which are killer cells that destroy virus-infected cells, and they also inform B-cells, which are the antibody factories, so that they produce antibodies that intend to neutralize the virus.

So, what Phase 3 vaccines are Nucleic Acid ones?

Moderna/NIH (mRNA)
Pfizer/BioNTech (mRNA)

The Inovio one is DNA, still in phase 1

Virus Vector Vaccines:

Next you have vaccines that use a different virus to carry the genetic material into the human cells. They may be replicating (in which case they need to actually enter the human cell) or non-replicating vectors (in which case they may just be circulating in the blood).

We have two of these in phase 3:

Oxford/AstraZeneca
CanSino Biologics/Beijing Institute of Biotechnology.

They are both non-replicating. Replicating ones haven't left pre-clinical phase yet.

And then we have the very anomalous case of the Gamaleya vaccine, from Russia.

It is also a vector vaccine (non-replicant) but it just had a phase 1 with 38 volunteers... and then... it got approved by the Russian government, with no phase 2 or 3, and they are starting the mass vaccination campaign in September. Risky, bold.

The Janssen one is also a vector vaccine but is kind of behind in the race, still in phase 1.

Subunit vaccines:

They use particles of the virus, empty shells, or protein units. They don't need to get into cells to act; they are directly gobbled by APCs and passed on to T-helpers.

We have no vaccine like this in phase 3. We have one in phase 2, and it's by Anhui Zhifei Longcom/Chinese Academy of Sciences.

Live attenuated virus vaccines or inactivated virus vaccines:

They use the actual SARS-CoV-2 but weakened or dead, so that it doesn't cause disease. It needs to get into the cell, make copies, and the copies are gobbled by APCs, etc. Dead virus vaccines also don't need to go into cells as they get directly gobbled by APCs.

We have no fewer than 3 like these in phase 3, all attenuated:

Two from Sinopharm, and one from Sinovac.

The only inactivated one that has left pre-clinical phase is the phase 1 Medicago.

Other vaccines:

There are 17 vaccines being studied, all in pre-clinical phase, that do not fall into any of the above and are all novel methods. They are things like gene-encoded antibodies, nanoparticles (vaults), chimeric (mixing SARS-CoV-2 and influenza viruses), administration of antigen-specific cytotoxic T-cells, a fusion protein of immunogenic peptides, etc.

-----------

Pros and cons:

DNA or mRNA vaccines:
Pros: fast to make
Cons: Never approved before. DNA is riskier. mRNA not as much (doesn't alter human genes, gets eliminated fast). Will likely need booster as they are not as potent as others. Also might have risks of ADE (antibody-enhanced disease).

Viral-vector vaccines:
Pros: Also fast to make; replicating ones have been approved before (Ebola, Dengue)
Cons: If people develop immunity against the vector, they become less effective. Non-replicant ones have never been approved (well, if we don't count the Russian one).

Subunit vaccines:
Pros: relatively potent. That's how the lifelong-lasting Hep B vaccine is made.
Cons: harder to make. More allergic reactions

Attenuated or inactivated viruses:
Pros: It's the traditional method, robust immunogenicity.
Cons: long to make (although they have more infrastructure already geared towards making them (that's how the MMR, Polio, and flu vaccines are made). Inactivated example is the HPV vaccine.

----------------

What comes after Phase 3? Regulatory approval. Well, it's been done in Russia already, like I said, for a phase 1 vaccine... but other countries will want to see a phase 3 showing safety and at least 50% efficacy (which is what the FDA is saying).

VERY IMPORTANT: while R&D and manufacturing and red tape have been extremely accelerated, including due to the United States' "Warp Speed" initiative which has invested already 9.5 billion dollars to expedite vaccines, there's been NO corners cut in terms of safety, and in terms of the progression from pre-clinical, phase 1, 2, 3, and regulatory approval, except in the case of Russia.

While the speed has been mind-boggling (the previous record was 4 years for the mumps vaccine), the size of the 3 phases has been standard. Moderna for example had 46 people in phase 1, 600 in phase 2, and they are recruiting 30,000 for their ongoing phase 3 (some 5,000 people have already received it). If a vaccine passes phase 3 and is approved by the FDA and by its counterparts in other developed countries, the vaccine WILL be safe and efficacious, and I encourage people to accept it.

----------------

If you want to explore the above in much more detail, here's the source:

https://covid-19tracker.milkeninstitute.org/

FasterCures, a center of the Milken Institute

The link above also tracks medications being studied to treat COVID-19; as of now there are 316 medications being studied.

 

Oh, the most important piece of info, I left out.

When?

Well, Pfizer thinks they will be able to deliver theirs to the public in December. Moderna and Oxford/AstraZeneca are aiming for January. The Chinese have already started vaccinating their armed forces, and Russia is starting a mass-campaign for millions of their citizens in September and October.

Do realize that whether or not Pfizer/BioNTech, Moderna/NIH, and Oxford/AstraZeneca will be able to deliver their vaccines in December and January, is if they do get to recruit at least 30,000 people each for their phase 3s, and if their results in phase 3 are clean, with no safety issues, and no low efficacy issues.

And...

If the virus does not mutate (or not too much, since it has mutated a little, already).

I think Pfizer will win the race given their infrastructure and multiple recruitment sites all over the world. Oxford/AstraZeneca and the Sino ones (the Chinese ones) are using Africa and Brazil as testing sites and should advance fast. I am less optimistic about Moderna's ability to move fast through phase 3. They were once the front-runners but I think they'll lose the race to Pfizer, Oxford/AstraZeneca (also huge infrastructure) and the Chinese ones (but people may have trouble trusting the Chinese ones, of course).

The good side:

About 75% of vaccines who have reached phase 3 in the history of medicine have earned regulatory approval. Big problems tend to be visible by phase 2.

 

Calculations based on a reproduction number R naught of 2.0 would indicate that for Herd Immunity Threshold we need 50% of the population protected by a vaccine and/or natural infection. To achieve 50% only with a vaccine that is, say, 70% effective (that's optimistic), we will need 71% of the population taking it. That's a tall order.

On the other hand we may have some 20% people immune from the disease itself, or more... and others less susceptible, such as type O blood, people who have encountered too many common cold coronaviruses in the past, etc.

So, with the help of even a partially effective vaccine, we may actually get the contagion down.

Americans need to accept the vaccine (provided that it passes phase 3 with flying colors). If lots of people accept it, it will be great help for the economy. Think of it, folks.

 

Putin's vaccine was called Sputinik-V, an obvious reference to his desire to recover Russia's technological fame.

20 countries have placed orders for more than a billion doses.

People who are criticizing Putin for this don't understand how he operates. This is not such a risky bet for him. There are four possibilities:

1. His vaccine is safe and effective. He poses as the savior of humankind, Russia's technology looks great, and they sell billions of doses to other countries (including because ultimately it will be the most tested vaccine, given that his mass vaccination campaign starting in October will be a much bigger test than phase 3 trials the others are doing.
2. His vaccine is effective but not safe. Still, even bad vaccines have relatively rare complications so he can claim it's justified due to the aggressive nature of this virus.
3. His vaccine is safe but not effective. He can say, no harm no foul, we had to try, we'll get it right next time.
4. His vaccine is neither safe nor effective. In that case Putin will probably just cook the data and hide the bad outcomes.

So it's 3 out of 4 win-win situations for him, and if the result is the bad 1 out 4, he'll just obfuscate and hide it.

Putin is a political genius. And he won't hesitate in killing a few of his citizens if this rushed vaccine backfires with deadly side-effects. Putin is used to considering his people, not a much more than puppets and cannon fodder.

 

Nobody knows about vaccines until millions are vaccinated, like the swine flu fiasco in the 1970's. Life is high risk, there's never certainty.

I hope Putin has the good stuff, for the sake of the people, but nobody has an inkling yet.

Over there they can't call Morgan & Morgan "for the people" if things go wrong.

 

True, but even the fiasco of the swine flu vaccine comparatively killed much fewer people than the swine flu itself. I looked at the numbers recently and don't remember them all but I think there were some 800 Guillain-Barré syndromes and some 12 or 16 of them died, but the swine flu killed several thousand. Like I said, even for bad vaccines, truly dangerous side effects are relatively rare. So maybe this was factored in Putin's calculations.

But an important point is that except for the Russian case, the other vaccines are being rushed in terms of how fast the development, production, and testing is going, but these companies and regulators are NOT cutting corners in terms of standard phase 1, 2, and 3 trials, so alarmists who say this vaccine will be dangerous are either disingenuous (with a political agenda) or not really understanding what is going on.

I say this because there is a lot of misinformation going on. I saw a horrible YouTube video (I won't quote it because I don't want to contribute to the misinformation) by someone who is a physician (a D.O.) telling the most horrible lies about the vaccine including nutsy conspiracy theories, that the vaccines are DNA-type (no, the front-runners are mRNA) that will alter the human genome forever (they don't do that) so that humans can be patented and owned (that's nuts), and say the companies didn't do animal studies (entirely untrue, they used Rhesus macaques), and are not field-testing it before distribution (false, that's precisely what phase 3 is).

So, some people don't want the vaccines to succeed. I'd like to dispel the misinformation. If one or more (likely more) of these vaccines pass phase 3, they will be reasonably effective and reasonably safe, although you are right that only in post-marketing phase when they are given to millions, we'll know if rare reactions occur.

Think of it: even in bad vaccines, bad reactions are usually not more frequent than, say, 1 in 10,000; they turn fatal in 1 in 20 cases so that gives us a fatal reaction in 1 in 200,000, while the virus itself is estimated to kill close to 1 in 100 and there is growing evidence that maybe it leaves 1 in 20 with serious consequences. Therefore chances are that a phase 3-approved vaccine will still be several times safer (in this calculation 10,000 times safer) and a natural infection by the virus itself, therefore, the vaccine's risks will be outweighed by its benefits.

 

I'm somewhat skeptical about this headlong dash to develop a vaccine in record time. First, despite the hysterical "media" hype this isn't an extinction event, far from it. Second, history has shown drugs deemed "safe" and put on the market being pulled at a later date due to unforeseen side effects (think Thalidomide). So I believe I'll take a pass on it until we see just what side effects pop up, and I'm in the "high risk" category.

 

@557 my apologies, I once told you the Oxford vaccine was also mRNA, turns out it isn't. The correct info is above.

 

Comparing with Thalidomide is a bit much. Vaccines are typically much safer than drugs... you know, a bad, bad vaccine has 1 in 10,000 reactions (of which 1 in 20 are fatal, so, a risk of 1 in 200,000), while drugs have reactions ranging from 1% to 12%, 25%, etc. Also, while 9 out of 10 drugs in development don't survive phase 3, 3 out of 4 vaccines do survive phase 3.

Again, the dash is in production, red tape, etc., NOT in curtailing the appropriate-sized phases 1, 2, and 3, which is what matters for safety.

Finally, if you are in the high risk category, I *strongly* encourage you to accept a vaccine if it passes phase 3 with flying colors, as the likelihood of you being harmed by it is MUCH smaller than the likelihood of you being harmed by the disease. You are right, it's not an extinction event, but this is a nasty disease. Sure, only 0.65% to 1% die, but I'd say it's likely (given new data I spoke of in other posts) that 5% of survivors will have bad permanent consequences and this is MUCH more than the people eventually harmed by a vaccine.

Put it this way: if you have to pick two roads to reach civilization from a high desert mountain, or else you'd die there so you have to travel either by road A or road B, and you have a map and guidebook, and it showed that road A is pretty safe as the risk of death there is 1 in 200,000 travelers, while road B is quite dangerous with avalanches and what not, and 1 in 20 travelers get killed or maimed, what road would you pick?

Those are the approximate odds of serious damage from the vaccine and from the disease. Are you sure you'd rather go for the risks of the disease?

It's amazing how people would call a no-brainer if they were facing the two roads situation above, but would still be all over-concerned about vaccines, when the odds are essentially the same in the two situations.

So, vaccine decisions *seem* to be rational but they are not. They are emotional and influenced by unwarranted fears and propaganda. Decisions about vaccines are as straightforward as the two roads situation above.

 

I just wish there were a vaccine to prevent people from turning another in the long line of viruses which have co-existed with mammals for millions of years into a dangerous political hoax...

The obsession with - and destructive political use of - this virus is VASTLY more dangerous than the virus itself, and seemingly beyond the reach of Zoloft et al.

 

No worries. Just looked it up and see this one is built on the foundation of work they did on MERS vaccines. It’s an exciting time to be alive if we are at the point we can develop vaccines in months instead of years.

 

Darn, this will result in huge distribution hurdles and I can think of situations in which the temp will rise and the vaccine will spoil. See the second page of this article:

https://www.mdedge.com/internalmedi...ne supply will be limited at first, ACIP says

 

Darn! Normal vaccines are enough of a PITA to maintain “cold chain” this will be even worse

 

Democrats:

"Only a vaccine can save the world from a virus as deadly as the flu!"

"But not THAT vaccine!!!"

(At least not until November 4th.)

 

More difficult? Yeh, but not insurmountable. The big question is can it be colder than -70C?If so, half the people I know could store it in their barn or garage.

If it has to be -70C I don’t know why a “vaccinemobile” couldn’t be put together pretty easily. We can do -70C with common refrigerants like R134A I believe. Get someone like Elon Musk on it and the distribution methods could be ready when the vaccine is.

 

we might need bigger drones

https://www.abc.net.au/news/2018-12-19/vaccines-delivered-by-drone-to-remote-vanuatu-island/10636586




But CF knows what a pain maintaining “cold chain” can be when it comes to vaccines

we have had a few incidents when the local substations have been slagged by lightning - it is even worse for places like Vanuatu

 

That’s a cool use for drones.

Yes, vaccines are a pain. I have to choose reliable suppliers that handle vaccines appropriately myself. Then I have to maintain storage once they are in my possession with backup refrigeration and power sources in the case of problems like you mention. Then at point of vaccination I have to maintain the proper temperature of the vaccine in an outdoor environment without power for up to eight hours in temps ranging from 0F to 90F. Keeping needles from freezing and obstructing in the cold is the most challenging.

The point a -70C maintenance temp is required for this one vaccine is well taken. It will certainly complicate things and create potential for errors that could destroy the vaccine. One mistake in handling from manufacturer to injection (or other delivery) makes the whole process a waste of time. What would be excellent in this case would be some kind of sensor or indicator on the packaging that would change color or something if the temperature range was ever breached. Then those administering the vaccine would know they had a viable product at point of use.

 

With shipping and handling costs, the vaccine may be out of reach for the average citizen.

 

Correction: it seems like the Sinovac vaccine which they've christened CoronaVac, is inactivated virus rather than attenuated virus as I previously posted. Its results have been truly extraordinary in phase 3, after tests in 24,000 subjects so far: 97% of immunogenicity with seroconversion to neutralizing antibodies, and 0.18% of fever being the harshest reaction it has caused so fall. No life-threatening side effects.

Ladies and gentlemen, we may have a winner.

This vaccine is now being given to Chinese healthcare workers and soldiers. China's partner in testing this, Brazil (which volunteered to help in exchange for technology transfer so they'd be able to make the vaccine domestically), through their very excellent Instituto Butantã, has recommended approval by ANVISA (their FDA) and is planning to make and deliver 45 million doses to their population in December, 60 million in March, and 100 million in May.

The world is likely to be seeing the first highly efficacious and highly safe SARS-CoV-2 vaccine. 97% efficacy is sufficient to foster herd immunity if at least 60% of the population takes it. I expect the whole Brazilian population to accept this vaccine given that anti-vaxxers are not prevalent there and the people very much trust their CDC (Fiocruz), their FDA (Anvisa), and their main vaccine maker (Instituto Butantã), and vaccines there are not a politicized issue. Also, the pandemic is raging there so the population is very much eager for a vaccine.

Given the relative sizes of their populations (1.4 billion in China, 210 million in Brazil), I expect Brazil to become the first country to achieve herd immunity through a vaccination program. This vaccine needs two doses, 14 days apart, but the production numbers anticipated by the Instituto Butantã will mean that 205 million doses will be delivered to their population by May. So this would immunize 102.5 million people, a tiny bit less than half of their population (49%). With a vaccine that is 97% effective, that means that 47.5% of the Brazilian population would get immune from the CoronaVac by June.

In 4 months Brazil got about 4 million confirmed cases. Let's say the contagion plateaus and keeps about the current rates for the next 8 months. So, 12 million cases. I'd estimate that 1 out of 3 cases are missed, so 36 million cases by May. That's 17% of the population.

47.5% of immunity through a vaccine + 17% of immunity through the natural infection = 64.5%.

This works for herd immunity for an R naught number of 2.6 which seems very decent for this virus.

 

Thanks for the well informed posts. They are a much needed counter to the BS that is flying around this forum & the internet more generally.

 

Tired BS that ignores the impact of the virus on people.

 

Well, maybe someday the COVID hoaxters will wake up to how dangerous & destructive their partisan propaganda is.

 

I wish there was a vaccine for conspiracy theory thinking

 

Indeed - it might prevent the conspiracy mongers from spreading the COVID Hoax.

But alas.

 

Have you considered how damaging calling COVID-19 a hoax is to efforts to control transmission? Why is controlling transmission important? Because people don't like getting sick and won't go out shopping and spending if the virus is circulating in their community.

You can say people were frightened into their response, but all you have to do to know this would occur is watch tv and see all the ads for therapies.

This was actual spending...



The economy can't survive at these spending levels without a lot more support for individuals and business.