Vaccine won't stop infection?

The Quarantine Zone
1

I was operating under the impression that the COVID-19 vaccine would work something like this:

  • A vaccine is rolled to at-risk groups and then to the general population
  • A sufficient portion of people that get the vaccine produce an immune response similar to that which occurs during a natural infection and gain immunity from the disease, at least for a time
  • In addition to no longer being susceptible to the disease, they also no longer serve as carriers of the disease and don’t pass it to others
  • The combination of natural herd immunity and vaccine-induced immunity removes enough vectors of transmission that the disease stop spreading outside of pockets where immunity is lacking for some reason

I’m under the impression that most of the public is using this mental model when they’re thinking about a vaccine for COVID-19. As in, once a person takes the vaccine, they’re more or less “safe,” and once through this process we’ll be able to return to normal life.

I recently came across a couple articles that caught me by surprise. First, this article from The Lancet (bolding mine):

What can we expect from first-generation COVID-19 vaccines?

A first generation of COVID-19 vaccines is expected to gain approval as soon as the end of 2020 or early 2021. A popular assumption is that these vaccines will provide population immunity that can reduce transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and lead to a resumption of pre-COVID-19 “normalcy”.

Multiple COVID-19 vaccines are currently in phase 3 trials with efficacy assessed as prevention of virologically confirmed disease. WHO recommends that successful vaccines should show disease risk reduction of at least 50%, with 95% CI that true vaccine efficacy exceeds 30%. However, the impact of these COVID-19 vaccines on infection and thus transmission is not being assessed. Even if vaccines were able to confer protection from disease, they might not reduce transmission similarly.

These observations suggest that we cannot assume COVID-19 vaccines, even if shown to be effective in reducing severity of disease, will reduce virus transmission to a comparable degree. The notion that COVID-19-vaccine-induced population immunity will allow a return to pre-COVID-19 “normalcy” might be based on illusory assumptions.

Also, this article by William A. Haseltine, former professor at Harvard Medical School and founder of Harvard’s Division of Human Retrovirology:

Covid-19 Vaccine Protocols Reveal That Trials Are Designed To Succeed

Moderna, Pfizer, AstraZeneca, and Johnson & Johnson are leading candidates for the completion of a Covid-19 vaccine likely to be released in the coming months. These companies have published their vaccine trial protocols. This unusually transparent action during a major drug trial deserves praise, close inspection of the protocols raises surprising concerns. These trials seem designed to prove their vaccines work, even if the measured effects are minimal.

Prevention of infection must be a critical endpoint. Any vaccine trial should include regular antigen testing every three days to test contagiousness to pick up early signs of infection and PCR testing once a week to confirm infection by SARS-CoV-2 test the ability of the vaccines to stave off infection. Prevention of infection is not a criterion for success for any of these vaccines. In fact, their endpoints all require confirmed infections and all those they will include in the analysis for success, the only difference being the severity of symptoms between the vaccinated and unvaccinated. Measuring differences amongst only those infected by SARS-CoV-2 underscores the implicit conclusion that the vaccines are not expected to prevent infection, only modify symptoms of those infected.

We all expect an effective vaccine to prevent serious illness if infected. Three of the vaccine protocols—Moderna, Pfizer, and AstraZeneca—do not require that their vaccine prevent serious disease only that they prevent moderate symptoms which may be as mild as cough, or headache.

One of the more immediate questions a trial needs to answer is whether a vaccine prevents infection. If someone takes this vaccine, are they far less likely to become infected with the virus? These trials all clearly focus on eliminating symptoms of Covid-19, and not infections themselves. Asymptomatic infection is listed as a secondary objective in these trials when they should be of critical importance.

He goes on to critique the very low bar of “success” for these vaccine trials and points out that the only thing they’re evaluating, essentially is the presence or absence of mild cold symptoms between the experimental and control groups.

The average person thinks a vaccine will protect them from infection, not cause a mild reduction in severity of “moderate” symptoms. I believe when most people say “we need to wait for a vaccine,” this is not what they have in mind. Am I wrong in thinking this?

Also, if a reduction in infections isn’t likely to occur even with a vaccine, doesn’t this imply focusing on number of cases when making policy decisions will lead to endless restrictions? Maybe I’m interpreting this too pessimistically, but it seems like the light at the end of the tunnel is farther away than I thought.

2

The criticisms of the stringency of the vaccine trial protocols may be valid, I don’t know enough about normal protocols. Presumably it’s much easier to set up well controlled protocols to test the effect of a vaccine on symptoms for an established infection, rather than to test the effect on probability of initial infection. It’s possible that a vaccine could have a beneficial effect for mild cases but not reduce transmission and not improve serious cases or reduce mortality. Ideally, it would be better to set up protocols to test for these things directly. But you shouldn’t take that too far, to suppose that all these things are not correlated. If a vaccine works at all in any respect, that means that your body has acquired immunological memory for the virus, and the secondary immune response can destroy virus or kill infected cells more rapidly. This is likely to improve all aspects of your body’s response - likelihood of infection in the first place, seriousness of symptoms for all types of cases - even if it isn’t necessarily so.

What’s certainly likely to be true is that with the time pressure, the earliest vaccines might not be the best ones. But that’s in accord with common sense, surely.

3

Be very careful in assuming that “there’s no proof that the vaccine will reduce infections” and “a reduction in infections isn’t likely” are equivalent statements. They’re not at all.

The former is a statement about what was actually tested, and is not an implication of the likely outcome. To a first approximation, based on the way immune systems work, a vaccine that primes the immune system to be ready for a virus is very likely to reduce transmission because there will be a much shorter window during which the virus can multiply before it’s attacked by the immune system so there will be fewer virus particles to shed, etc. And a reduction in symptoms like coughing will also reduce transmission because coughs expel virus particles farther into the air.

Of course, immune systems are complicated, so it’s certainly possible that a vaccine could reduce symptoms without reducing transmission. But it’s certainly not likely.

4

There’s some more discussion of the issue in this article - the title is about political interference, but it talks also about the protocols and mention’s Haseltine’s comments in Forbes linked above.

The question is whether you take more time with more stringent protocols to find vaccines that will definitely improve outcomes in severe cases and reduce transmission; or whether you proceed more quickly with protocols that only assess whether a vaccine is likely to do so. It’s not a question with an easy answer - if I were elderly or in a high risk group, provided safety were adequately assessed, I think I’d certainly favor an immediate vaccination that will probably reduce my risk of this thing killing me than wait 6 months for one that will definitely reduce my risk.

As for Haseltine’s contention that we should use protocols that directly measure whether a vaccine reduces the probability of initial infection - I’m not sure how you’d do that, does anyone in this field know? With human subjects it’s obviously unethical to deliberately expose people, and if you just look at how many people get infected in the wild in vaccinated and unvaccinated groups there are so many confounding behavioral factors that would be difficult to control for. If you use indirect measures such as antibody titer - well, it’s not clear to me that this is any better than the indirect correlated measures in the existing protocols that look at severity of symptoms in infected subjects.

5

I linked this article elsewhere, and I think it’s a well-written, easy to understand analysis of what a vaccine means and what a return to “normalcy” looks like.

6

Great article, thanks.

Not that it’s the most important thing in the world by any means, but it makes me question whether we’re going to be able to go on our Alaska cruise with my mom that was rescheduled to late August 2021. (We were originally supposed to go in August 2020, and I rescheduled it back in March when everything shut down.)

7

Here’s one way to square the OP’s circle. IANA expert and I’m just discussing logical possiblities here, not specific vaccines or their test protocols.

There are many infections that most humans carry most of their life which cause little or no harm to almost all of them. A COVID vaccine that did little to prevent infection, and in turn infectiousness, but which prevented any material progression beyond asymptomatic would in fact be a huge boon.
A vaccine that did little to prevent infection, but did prevent subsequent infectiousness, even if it did nothing for subsequent disease severity, would also be a boon, albeit of a different nature.

The former situation amounts to “Me being vaccinated will protect me from harm no matter what others do”. Whereas the latter vaccine is the inverse: “Me being vaccinated does nothing for me, but helps all others. I gain only from what they all do.”

I think we can predict which one will be more effective at combatting a pandemic in the USA.

The reality is probably that no vaccine is purely one or the other effect. Far more likely the real vaccines will exhibit both effects, possibly in differing mixes. And certainly won’t be 100% effective in either dimension.

8

I’d be very interested in understanding the delta – if any – between the current definition of ‘efficacy’ as defined by the industry and the definition of ‘efficacy’ that most consumers/lay people/patients would use.

From a strict business perspective, it’s abundantly clear why you’d want an endpoint that’s relatively simple and much easier to measure.

But you can manage to a particular metric and still tank a large business. You get too focused on a number and lose track of what’s important to your consumer.

I’ve often used this example: atrial fibrillation (AF).

One ‘treatment’ for AF is catheter ablation (CA). When you look at the outcome data for CA, the numbers look pretty impressive.

Dig much deeper, though, and you find that they’re looking at outcomes at the 12 month mark and they’re including any patients who are still on anti-arrhythmic medication to treat persistent AF.

This is the industry definition of success.

But it isn’t the patients’ definition. Patients view success as … I have the procedure … I no longer have atrial fibrillation, and I don’t take medication to treat it because … it’s gone.

In the most expert centers in the world, the industry definition of success … equates to a success rate of about 70%.

Using a ‘patient-centric’ definition … it struggles to reach 50%.

And the two- and three-year outcome data is significantly worse (you get another ablation)

So I’d want to understand the difference in this case, almost surely based on the history we have with other vaccinations: how closely does the industry definition of success correlate with the real-world outcome that most of us really care about – returning to a carefree, pre-COVID life ?

9

But I don’t think this frames the issue correctly. I don’t think the FDA & drug companies are using an imperfect metric because they are out of touch with what we ideally want from a vaccine. It’s a question of time. Any vaccine with good efficacy as defined under the current protocols is likely to help reduce transmission significantly. Perhaps Haseltine is right that the protocols could be adjusted somewhat, but more stringent protocols to try to find the ideal vaccine with greater certainty would simply take longer. As with masks - it’s not as though we’re all holding off on wearing any mask until we can figure out the perfect mask and produce 10 billion of them. Any quantitative reduction in transmission and quantitative reduction in severity of symptoms is desirable as soon as possible.

And it’s not as though (on a global level) we’re putting all our eggs in one basket here. There are many candidates in trials, if we end up with a dozen that are proven safe and at least somewhat efficacious under current criteria, we’ll accumulate much more data after vaccination programs are underway, and we’ll find out eventually which of them are the best.

The articles linked in the OP make some valid points in terms of what our expectations should be. But we should not be making the perfect the enemy of the good.

10

I don’t disagree with you, but … a couple of things:

We already have a substantial portion of this country who self-report no interest in getting the vaccine. That’s a big hit to herd immunity numbers.

We also have a rather substantial portion of the population who don’t seem really expert at evaluating the science. Witness the mask debate. To your point: the perfect HAS become the enemy of the good for way too many.

Or … from my very personal perspective …

Understanding the delta between an industry metric and the “real-world” outcome will help inform when I might jump (ie, get a vaccine).

I’m extremely unlikely to be an early adopter. It’s a bad thing if everybody is cynical, reluctant, or skeptical like I am, but I don’t think that’s reality. I think many will take the first available vaccine.

But more info tends to be a very good thing … when it’s available for review by those who are sincerely able to competently evaluate it, and when it usefully informs their decisions.

I don’t think this is universally an example of the perfect/good dichotomy. I just think the info may have a somewhat limited audience.

But I’d like to have that info.

11

Your question has already been answered upthread by myself and others, but you keep asking about what you call a “delta” as thought the reasonable default assumption absent definitive evidence is that the vaccines that are being developed under current protocols are likely not be helpful at all. To be crystal clear - that is complete nonsense.

As described in the various links posted upthread, the industry metric is that a candidate vaccine must ameliorate symptoms in established infections. That in itself is a desirable outcome, and given how the immune system works it is likely that a vaccine that reduces symptoms will also reduce transmission, and likely that it will reduce the number of severe and fatal cases in vulnerable people.

Yet you have given no reason for this that makes any more sense than refusing to wear a mask because there is not incontrovertible evidence that it works perfectly.

The only sensible reason for not getting a vaccine as soon as it’s recommended would be on safety grounds, if there were undue political interference in taking shortcuts on the length of time required to assess side effects. I think we have much greater comfort on that issue with both the FDA and the industry participants now having told Trump to fuck off, and with a responsible administration taking over.

I will be getting a vaccine as soon as one is available (subject of course to more vulnerable people getting one first), and I think this situation is no different from any other vaccine. Anyone who refuses to participate in a vaccination program is irresponsible and selfish.

12

Unless you are a front line medical worker, you won’t have the opportunity to be an early adopter. By the time the vaccine is available to most of us, it will have already been taken be millions of other people ahead of us on the priority list. That should give a very good idea of the dangers of the vaccine itself. If there is some problem that got past the accelerated trials, we’ll know long before it’s time for most people to make a decision.

If the vaccine itself is safe, then there is really no serious downside in getting it. A shot hurts, a trip to the clinic is inconvenient, and maybe some expense. Those are all things I would put up with for a 50% reduction in the chance of getting Covid.

Also, once the first vaccine is out, development of the others will continue. Some may work better, have fewer side effects, easier to ship and store, cheaper to produce, etc. I’m hoping the problem isn’t whether to get a vaccine or not, but which one to get.

13

As stated, that’s not a proposition that admits to an answer.

The immune system does not prevent initial infection. The immune system reacts to infection.

14

No, this is not correct. The definition of “being infected” is that a pathogen multiplies and reaches some quantitative threshold in your body. But we are constantly exposed to a wide array of pathogens, and in most cases of exposure the immune system reacts promptly to destroy the pathogen before it can multiply to any significant level - it prevents infection. And this is certainly what happens with immunological memory. When you have acquired immunity from a first infection or from vaccination, upon subsequent exposure to the pathogen the immune system acts quickly to destroy the pathogen immediately - it prevents any recurrence of infection.

15
  • Lag (latent) phase

“This is the time from initial antigen exposure to when antibodies are detected in the blood, and takes about a week. In this time, specialized B and T cells are activated by contact with the antigen.”

16

I suggest if you want to quote something, give the source. Googling what you quoted takes me to a Korean blog with reproductions from a textbook - and the description of lag phase that you reproduced in your post refers to the PRIMARY immune response, which occurs upon first exposure to a pathogen when you DO become infected.

As that textbook also says - when you have acquired immunological memory from prior exposure to a pathogen, the lag phase in the SECONDARY immune response is much shorter, and:

Due to the rapidness of the secondary immune response the antigen can be eliminated from the body fairly soon after it has entered and before it causes disease.

17

You measure and grade by what is more realistically measurable to grade.

A vaccine that significantly decreases the risks of severe infection, hospitalizations and deaths, the numbers of each across society, significantly, even if just as many catch the disease in mild forms, would be a huge win. Really that is THE goal, whether gotten by preventing the number of infections or the severity of them. Preventing deaths and significant illness. But a trial of 30,000, most ages 20 to 60, will result in maybe 7 or 8 people expected to be hospitalized in each arm over 12 weeks at this point in the pandemic in the United States (if I did the back of envelope math right), and of course fewer deaths yet. Hard to get statistically significant numbers measured for that unless it is extremely effective (unlikely). Moderate illness is however a reasonable proxy for that risk. Measuring transmissibility risk is harder yet.

There are important questions that simply cannot be answered until we have years of follow up, expecting all of them before approval is unrealistic. My bigger concern is having enough of an n and follow up period of those infected to know that there is not MORE risk of severe disease after immunization (the fear of antibody-dependent enhancement and MISC-like syndromes), especially in groups at baseline relatively lower risk.

It does get tricky though to define what that quantitative significant threshold is between preventing an asymptomatic infection and having one. Short of weekly nasal swabs what metric would be used?

18

There is no such thing as natural herd immunity. As more people become immune from having and recovering from the disease, there is less people BECOMING immune because less are able to get it. Thus with new people entering the world all the time (and added the affects of global travel), the number of people who can catch it increases and gives the virus another chance one it gets a hold, called a second (third, etc.) wave. Herd immunity is impossible this way. This is why we had chicken pox and measles parties, to help that wave hit those who can most easily fight it off in a controlled manor (children) but at no time did we reach heard immunity till a vaccine was deployed, or is some cases (cow pox/small pox) a like virus was deployed.

19

Here’s a blog I frequently tout:
https://blogs.sciencemag.org/pipeline/archives/category/covid-19
The author is a medicinal chemist who’s not directly in the COVID biz. But who has worked on such easy problems as preventing cancer and curing Alzheimer’s. Smart, articulate, and intellectually scrupulously honest.

Pre-COVID he talked about a wide range of medchem topics for decades now. Since Jan it hasn’t quite been “all COVID all the time”, but it’s been pretty close. That link is to his COVID-specific archive.

If you want an education on what COVID is, how infectious diseases work, how vaccines work, and how the current candidates are panning out, you could do a lot worse than to read every post in that ongoing series. His audience is a mix of smart laymen like me and other chemists, medics, and biochem gurus. The comments are usually a treasure trove of knowledge at well. But like any blogger on a popular topic, during COVID he’s picked up his share of trolls too. Mostly over hydroquinilone conspiracy theories.

His work to date probably won’t directly answer the question(s) you think you want answered. But it will calibrate your understanding as to which questions are answerable, both in principal and as a matter of practicality given the time and resource constraints.

20

Looks like a fascinating site. Many thanks !