Are boosters a viable long-term strategy or just a Super Mario power-up?

An FDA panel voted on Friday to recommend 3rd shot boosters to adults over 65 in the USA. Are boosters a good idea?

If so, do they have long-term value, or are they just a short-term fix?

Are they a Super Mario “Golden Mushroom” that temporarily boosts the immune system without conferring improved long-term protection?

I’ll explore some of my thoughts on these questions here. Does vaccine immune protection start to wane 5-6 months after vaccination?

The data are clear that it is, but perhaps not as much as people think.

3 Israeli papers show 1.5-2.2x higher infection risk for those vaccinated >5-6m; one showing reduction of VE=75-80% to VE=50-65%. Hardly full loss of immune protection vs. infection.

This paper and other data suggest that protection vs. severe disease is also waning, although not as much. Goldberg et al. estimate it declines from >90% down to 75-85% after 5-6m, especially noticeable in older adults that are at much higher risk of severe disease if infected. The waning appears driven by a reduction of neutralizing antibodies circulating in the blood (cAbs). These spike incredibly high after vaccination (>10x higher than after infection), but have been shown to reduce by 10-20x in the subsequent 5-6m. This has been shown in several papers, including this one by John Wherry, a University of Pennsylvania immunologist.

However, immune protection is not just from cAbs, but also other vaccine-stimulated immune markers like memory B-cells that can regenerate antibodies in the future as needed, & targeted T-cells that can directly kill virus or help activate B-cells.

B-cells don’t wane in 6m, as shown in Wherry's paper.

Thus, it is possible that long-term immune protection is not waning, but only the extra “boost” from high levels of cAbs. B-cells are still there and can generate new cAbs when exposed to the virus, but this can take several more days and delays the time to neutralize the virus relative to what it takes when the blood is flowing with abundant neutralizing antibodies. And these few days are enough of a time window for a virulant and aggressive variant like Delta to replicate sufficiently to produce a positive PCR test, or sometimes to produce a symptomatic breakthrough infection, or even in some cases produce severe or critical disease.

Making a Nintendo analogy, maybe the high levels of cAbs after vaccination are like the Golden Mushroom making Mario bigger and more powerful, better able to neutralize the Goombas.

This boost helps for a time, but eventually wanes, after which time Mario shrinks to normal size.

He can still fight the Goombas, but it is harder than when he had the benefit of the Golden Mushroom.

Boosters restore the Golden Mushroom.

Does this help? Of course.

High cAbs enable much more rapid neutralization of the virus Data from two papers in Israel, one just published in NEJM and the other a preprint in medRXiv, show this reduces risk of breakthrough infection or severe disease by >5-10x in adults >60yr. There are caveats to these studies, including the fact that in the NEJM study there is only an average of 7-14 days follow up after boosters kicked in, the study does not adjust for potential co-morbidities or immunocompromised status in some individuals, and does not adjust for the potential bias if recently boosted people are less likely to be tested.

In spite of these limitations, the study and analyses are very well done, these results are strong, and subsequent daily data posted by the Israeli Ministry of Health suggest these benefits are continuing.

We know that the boosters produce another huge spike in neutralizing antibodies, but do they produce any long-term benefit in terms of strengthening the other more robust components of the immune response that have not yet declined at 5-6m? Or is the benefit limited to just a temporary boost of cAbs, that might only last a few months?

This may help dampen the present Delta surge, but is it a sustainable long term strategy? Is it realistic or beneficial to try to maintain high levels of cAbs indefinitely? Is there some downside, immunologically or otherwise, to continuing this strategy? Data suggest vaccines are generally safe, outside some rare but potentially serious adverse events, e.g Myocarditis in young men These risks increase with 2nd dose, will a 3rd dose increase them further? That seems important to know before considering universal boosters. Are boosters really necessary for everyone? Do declining cAbs produce the same waning immune protection in young adults as for seniors? And does this lead to a substantially higher risk of severe disease? Published data on booster benefits are limited to >60yr adults.

Maybe boosters are a good idea right now. Given most vaccinated individuals in the USA were vaccinated by March or April, they are approaching the 5-6m mark this Fall. With the colder weather coming, especially in the Northern parts of the country, people will be moving indoors where spread is more efficient, and the cold, dry air will enhance the ability of the virus to spread and increase the viral loads upon infection. As a result, it is possible that as we move through the fall towards the winter, the Delta surge might get much worse in the USA.

Boosters could take the edge off of that surge.

Delta has been a pandemic game changer, bringing 2.25x greater transmissibility & much higher viral loads upon infection, supercharging it to make it more adept at evading our immune defenses. If the Goombas have their own Golden Mushrooms, maybe we need them too.

But we need more data before considering that – we need safety data, data on the benefit of boosters to middle age and younger adults, and not just for reducing infection, but also severe disease and death. We should see such data coming out of Israel in the next month. But I guess there is also a price for waiting, given that the Fall may worsen the Delta surge, so the FDA felt the need to act now. Beyond the immediate decision, our leaders need to think through long term strategy. Is our strategy really to keep ourselves dependent on Golden Mushrooms (high cAbs levels)? Or at some point do we trust longer term immune elements, even if they work a little slower?

To introduce an alternative analogy, if a marathon runner gets hunger pangs in the middle of the race, a Snickers bar might give them the instant energy for the moment to help them finish the race.

But a healthy runner should not make a habit of relying on candy for their long term energy needs. They should have a better long-term plan to manage their energy for the race.

Maybe these analogies are off base, but they resonate with me right now based on the data I have seen and some key principles of how the immune system is working.

We still have a lot to learn -- maybe the boosters are doing more than just providing a new flurry of circulating antibodies. Maybe as some suggest the third dose "completes" the vaccine sequence and overcomes what, for Pfizer, may be too short a time frame of 3 weeks between first and second dose. But my questions and concerns here are shared by others, including immunologists. An article in Nature today repeated some of the points I made here in this blog post.

I hope our leaders are thinking this all the way through …