Who should get vaccinated?

The mass rollout of Covid vaccines, accompanied in many countries by passports and mandates, has prompted a fierce public debate over vaccination. Do the vaccines work? Are they safe? Should they be mandated? At one extreme are those who argue that the vaccines don’t work at all or are completely unsafe, or even that they’re part of a depopulation plan instigated by Bill Gates. At the other extreme are those who argue that absolutely everyone needs to get vaccinated, and those who refuse should be punished with fines or even prison. (Note: I’m not claiming these two extremes are equally unreasonable; the depopulation theorists are clearly in a league of their own.)

Here I will attempt to answer the question of who should get vaccinated. By this I mean, “for whom does vaccination make sense?”, or “for whom do the benefits almost certainly outweigh the costs?” (I do not mean “for whom should the vaccines be mandatory?”) I will also address the related question of what the government’s policy ought to be. Of course, “ought to have been” would be more accurate, since governments have already implemented passports, mandates, boosters and other measures to which many people – including some credentialed experts – object.

Before establishing who should get vaccinated, it is necessary to say whether or not the vaccines actually work. And in this regard, I believe the evidence clearly shows that they do work, albeit not as well as originally claimed. When the vaccines first arrived, many leading scientists – including both Anthony Fauci (head of the NIAID) and Rochelle Walensky (head of the CDC) – said in no uncertain terms that they would stop the virus spreading. (Vaccinated people would become “dead ends” for the virus, Fauci told us.) This has proven not to be the case. However, “work” can obviously mean something other than “permanently stop transmission”.

Although vaccine effectiveness against infection declines to zero, or even lower, six months after vaccination, vaccine effectiveness against serious illness seems to hold up reasonably well. (It’s not clear how much of the declining effectiveness against infection is due to the waning of individuals’ immune responses, as opposed to the emergence of novel variants that the vaccines do not protect against.) Evidence for persistent effectiveness against serious illness comes in two main forms: the aggregate level, and the individual level.

Regarding the former, Western countries and US states with higher vaccination rates have generally seen lower mortality from Covid since their vaccine rollouts got underway (see above). These relationships are of course somewhat confounded. For example, Eastern European countries with low vaccination rates had higher Covid death rates even before their vaccine rollouts; and the same is true of some US states – such as those in the South with high levels of obesity. Nonetheless, I don’t believe confounding can explain all of these relationships. Places that managed to contain the virus for the first year – such as Iceland, New Zealand and Vermont – have not seen the massive spikes in Covid deaths you’d expect if the vaccines did nothing (see below).

Regarding the latter, numerous studies have shown that unvaccinated individuals are more likely to die from Covid than their vaccinated counterparts. These studies are consistent with the age-adjusted hospitalisation rates from many different countries, with rates being considerably higher among the unvaccinated. There is some evidence that average differences between the vaccinated and unvaccinated are confounded, and hence that vaccine effectiveness against severe illness has been overestimated. Specifically, vaccinated individuals have lower rates of death from non-Covid causes, indicating there’s a “healthy vaccinee” effect. It’s not entirely clear where this effect comes from; those who’ve had the vaccine may just be inherently healthier or more risk-averse than those who haven’t. But what it means is that people who choose not get the vaccine would be more likely to die even if they were vaccinated.

Once again, however, I do not believe that confounding can account for all of the disparity in hospitalisation and death rates between vaccinated and unvaccinated individuals, which are in some cases very large. Indeed, they are typically much larger than the apparent size of the “healthy vaccinee” effect. For example, whereas unvaccinated individuals might be three times more likely to die of non-Covid causes, they’re often more than ten times more likely to die of Covid itself. Hence even if you were to properly adjust for confounding, you’d still find evidence of vaccine effectiveness against death.

There’s also evidence that the vaccines are less effective among the elderly, which is rather concerning as this is the group most susceptible to Covid. For example, one Oxford study found that, conditional on infection, the vaccine does not protect against death in over 60s. Of course, it’s only one study, so shouldn’t be given too much credence. Indeed, the study may have underestimated vaccine effectiveness insofar as elderly people who catch Covid after having been vaccinated are among the frailest and hence most likely to die of the disease. The researchers tried to account for this, but their efforts may not have been sufficient.

Yet even if the study is correct, and the vaccines only protect against death among the elderly by temporarily stopping infection, they still “work” in the sense that they buy time for natural immunity to build up in the rest of the population, and for better treatments to be developed. Incidentally, the vaccines not protecting against death among the elderly would be consistent with evidence for the flu vaccine, which is apparently much less effective in the old and the very young (thanks to Yeyo for pointing this out).

All this suggests that there are some people who should get vaccinated. Covid poses a serious risk to the elderly and clinically vulnerable, and this risk almost certainly outweighs the risk posed by the vaccines. Even if the vaccines are less effective among the elderly, it still makes sense for these individuals to acquire temporary protection against infection, while they wait for the build up of natural immunity or better treatments. And there may be a few high-risk individuals who’d benefit from getting a booster every few months in perpetuity. (Though the fact that boosters may not even protect against infection when it comes to Omicron somewhat undermines this suggestion.)

So, some people – namely the elderly and clinically vulnerable – should get vaccinated. But should everyone else? It’s well known that the risk of death from Covid has a steep age gradient (see below). As Professor Mark Woolhouse notes, “People over 75 are an astonishing 10,000 times more at risk than those who are under 15.” In other words, people over 75 aren’t just three or four times more likely to die than people under 15; they’re three or four orders of magnitude more likely to die. This means that, regardless of exactly how effective the vaccines turn out to be, the benefits of vaccination are substantially lower for healthy, young people. (Of course, the benefits may still be quite high for young people with certain pre-existing health conditions.)

The chart below shows the age-distribution of Covid deaths in England over time, with darker colours corresponding to higher death rates. As you can see, very few people under 40 have died from Covid. And among under 40s who have died, the vast majority – between 70 and 80% – had pre-existing health conditions. (Those who did not have pre-existing health conditions were concentrated at the upper end of the age-range.) Of course, healthy people under 40 may still have unpleasant symptoms when they catch Covid, but they’re very unlikely to die. And those under 20 are extremely unlikely to die; less likely in fact, than if they catch seasonal flu.

Given that the vaccines only temporarily stop infection, the simple fact is that vaccinating healthy people under 40 will make very little difference to the overall number of deaths. Okay, but “very little difference” is not “no difference”; most of us would prefer a very, very small risk of death to a very small risk of death. Should these people get vaccinated or not? There are several factors to consider.

The first is that the vaccines do have side effects. These are generally mild, but in rare instances can be quite serious, including thromboembolic events (blood clots) and myocarditis (heart inflammation). It was initially assumed that the frequency of serious side effects was so low that they could be more or less discounted. For example, there was much consternation on Twitter when several EU countries suspended use of the AstraZeneca vaccine, after the link with rare blood clots was discovered. However, the fact that Covid poses so little risk to healthy, young people means that even rare side effects could tip the balance against vaccination. This is particularly true given that we’re nearly all going get Covid eventually, vaccinated and unvaccinated alike.

Early data suggested that myocarditis was actually more common after Covid itself than after vaccination, even among young people. Yet as Doctor Vinay Prasad points out, newer data shows that it’s more common after vaccination for men under 40, particularly after the 2nd dose. There’s tentative evidence that spacing doses more widely reduces this risk. Nonetheless, the risk of serious side effects among young people is real, as demonstrated by the fact that many countries have suspended the use of certain vaccines for under 30s or under 40s.

Another factor to consider is natural immunity. Studies have shown that natural immunity from previous infection protects better against infection than the vaccines, and also provides excellent protection against serious illness/death after reinfection with a different variant. Since natural immunity probably wanes on a timescale of years, this means that the benefits of vaccination for healthy, young people who’ve already had Covid are vanishingly small. Although so-called hybrid immunity (from both vaccination and previous infection) is stronger than natural immunity alone, the difference between the two is comparatively small.

What’s more, studies show that vaccine side effects are more common among those who’ve recently had Covid. And there’s at least one study showing this is true for serious side effects, not just mild ones. (Of course, it is only one study; though there may be others.) So not only are the benefits of vaccination lower among people with natural immunity; the risks are slightly higher too. Note: I suspect that both the reduced benefits and elevated risks of vaccination following acquisition of natural immunity return to zero as time since the initial infection increases.

Aside from the known side effects (which are mostly mild, but in rare cases quite serious), there are the unknown, longer term side effects. Now, there may of course be unknown side effects from Covid itself. But for people with natural immunity, these are a sunk cost. So the unknown side effects from vaccination are what matter. And it could turn out, say, that vaccination raises your risk of heart disease, or some other serious ailment, by a non-trivial percentage in the long term. (I’m not saying that it does; but it’s something for people with natural immunity to consider.)

Yet another factor to consider is the mysterious phenomenon of original antigenic sin, which has been observed for various pathogens, including influenza. When the immune system encounters a novel pathogen, it mounts a response to the pathogen’s antigens. Original antigenic sin means that when it encounters a different but related version of the pathogen, it may mount a response to the antigens carried by the original version – yielding weaker immunity. (See the diagram below, taken from Wikipedia.) From what I can tell, original antigenic sin is not yet well-understood. But it’s something that vaccine developers have to take very seriously. As a recent review notes, “In the case of vaccines, if we only immunize to a single strain or epitope, and if that strain/epitope changes over time, then the immune system is unable to mount an accurate secondary response.”

If original antigenic sin exists for the Covid vaccines (and that’s a big if), it would mean that vaccinating healthy young people against the original Wuhan strain of Covid could be deleterious in the long run. The reason is that we’d be vaccinating them against a version of Covid that poses almost no risk to them, at the cost of weakening their immunity to subsequent variants. As the blogger eugyppius notes, “A worst case scenario would be a future spike mutation that entirely escapes the anti-spike antibodies elicited by our vaccines. In this case, it seems possible that many vaccinated people will be stuck with permanently suboptimal immune responses.”

Concerns about original antigenic sin are largely speculative at this stage. But there is some evidence that’s consistent with the phenomenon (aside from the theoretical points that the virus is clearly still evolving, yet the vaccines target the spike protein of the Wuhan strain). Several datasets show what appears to be negative vaccine effectiveness against infection – i.e., vaccinated people having higher infection rates for a particular variant than unvaccinated people. (Note that negative vaccine effectiveness was seen with the swine flu vaccine as well.) Now, there are explanations for this finding other than original antigenic sin, such as vaccinated people being less risk-averse. But it certainly warrants further investigation.

Wouldn’t original antigenic sin apply to natural immunity too? In principle, yes – once enough viral evolution has taken place. But there’s reason to believe it would be more pronounced for vaccine-induced immunity, which is targeted to the most rapidly evolving part of the virus, the spike protein. By contrast, evidence suggests that natural immunity is broader than what the vaccines provide, as shown by its greater effectiveness against infection for novel variants.

Given the lack of evidence that original antigenic sin presents a major problem for the Covid vaccines, and the fact that very few scientists cited it as a reason not to vaccinate young people, I’m inclined not to put too much weight on this factor. On the other hand, few scientists cited the questionable risk-benefit ratios for young people as a reason not to vaccinate them (the Great Barrington authors being notable exceptions), so there might be some pressure not to speak up on these kinds of issues. I really don’t know. In any case, the possibility of original antigenic sin gives an additional reason to think twice before vaccinating those to whom Covid poses almost no risk.

Returning to the main question then: who shouldn’t get vaccinated? The risks may well outweigh the benefits for young men without pre-existing conditions. (Note: this is not advice; it’s just my opinion.) For healthy young people who’ve recently had Covid, the risk-benefit ratio is even less favourable; and I’d say almost certainly negative. For older people who’ve already had Covid, the risk-benefit ratio is less clear. Those at the upper end of the age-range might still want to get vaccinated; those at the lower end of the age-range might not. For healthy children, I’d say that vaccination at this stage does not make sense.

What about government policy? Given that the vaccines clearly don’t stop the virus spreading, the case for passports and mandates is extremely weak. The latest argument is that such measures are needed to reduce pressure on the health service. But as I’ve pointed out, this implies we should impose restrictions on other groups that put pressure on the health service, such as the obese. And few people would accept these kinds of restrictions. Unvaccinated people who’re healthy and young aren’t “putting pressure” on the health service. (While some of them may wind up in hospital, the numbers aren’t very big.) It’s unvaccinated older people who are overrepresented in the hospitals – particularly those who’re obese or otherwise in poor health. And the best way to encourage these individuals to get vaccinated is through persuasion; after all, vaccination obviously would benefit them.

Another consideration is the opportunity cost of vaccinating a large number of individuals to whom Covid poses little risk – especially healthy young people who’ve already had the virus. I certainly wouldn’t want to prevent such individuals from getting vaccinated; adults should be free to make their own healthcare decisions. Yet as I and others argued, there was almost certainly a better use for the vaccines they received, namely donating those vaccines to the elderly and clinically vulnerable in poor countries.

Even if I’m wrong and healthy young people should get vaccinated, the net benefit of offering them the vaccine isn’t going to be large. However, the net benefit of donating vaccines to people who really need them is very large. The risk of death from Covid for 70 year olds is about two orders of magnitude greater than that for 30 year olds, and is about three orders of magnitude greater than that for 20 year olds. This means you need to vaccinate about a thousand 20 year olds to save the same number of lives as vaccinating one 70 year old. For 20 year olds who’ve already had Covid, it’s probably closer to a million.

I believe what governments should have done is the following: offer the vaccine to all over 60s and clinically vulnerable persons, as well as 30–60 year olds who haven’t had Covid, and then donate the leftover vaccines to poor countries. While governments have an obligation to put their own citizens first, the benefits of vaccinating 70 year olds in poor countries is so vast relative to that of vaccinating 20 year olds in rich countries (for whom the long-term effect could be negative), that humanitarian concerns arguably take precedence. Some people have said: now that everyone’s been offered the vaccine, we should consider donating our leftover vaccines. But that ship has already sailed. The time to donate was in the late spring/early summer of last year when there were still a substantial number of people in poor countries who hadn’t had Covid.

Ironically, the extreme emphasis on vaccinating everyone in rich countries (regardless of age, health or prior Covid status) may have led to more global deaths than an alternative policy where we exempted healthy young people and/or those with natural immunity. This would also have allowed for the faster build up of natural immunity in low-risk groups, potentially shortening the pandemic. And note: vaccines are unlikely to be siphoned off by corrupt politicians or bureaucrats, which neutralises one major objection to this form of foreign aid. Like mosquito nets, they can do tangible good in the here and now.

All in all, there’s a large segment of the population who should get vaccinated, as well as another segment for whom it probably doesn’t make sense. Rather than trying to strong-arm every last adult into getting vaccinated, governments should have focussed on persuading people in high-risk groups to get the vaccine, while donating left over vaccines to their counterparts in poor countries. An important caveat to my analysis is that almost all the data is based on European-origin populations. Given the possibility that races differ in their susceptibility to Covid, the arguments might look slightly different when applied to other groups.

Image: Vials containing the Moderna COVID-19 vaccine, 2021

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The Daily Sceptic

I’ve written four more posts since last time. The first reports on new emails revealing that scientists sought to stifle discussion around the lab leak theory. The second argues that the most important lesson from the Downing Street parties is: the rules were wrong. The third summarises a recent study finding that most Covid patients discharged from the ICU make a good overall recovery. The fourth explains how we know that official Covid deaths are overestimated.

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