Breaking (with correction): Moderna protection did not wane at nearly 7 months.

New data shows Moderna holding up well. But last week, Pfizer told the FDA that vaccine protection was waning. Which is it?

Note: An earlier version of this article mistakenly referred to Pfizer instead of Moderna in analyzing new data. This article has been corrected to reflect that the data discussed in the article are from Moderna's trial, not Pfizer's. However, the main points remain. I've made a few changes to reflect that below. While Pfizer claimed waning immunity last week in its FDA bid for booster authorization, and Moderna's new data seemingly contradict the "waning immunity" hypothesis, it's likely that both options are holding up strongly.

Read on! -Jeremy Faust

Two studies were just published in the New England Journal of Medicine (NEJM). One looks at Covid-19 in healthcare workers, assessing the benefits of vaccination. The other reports the follow-up data from the original landmark Moderna clinical trial, now taken through the completion of the “blinded phase” during which the participants did not know whether they had received vaccine or placebo.

Both show that coronavirus vaccines work. That’s not news.

What strikes me as far more interesting are the data on immunity against infection and severe disease over time that are tucked in here. Last month, I wrote that the cause of the rise in recent breakthrough infections was primarily the dominance of the Delta variant and not waning immunity. The data today support that conclusion mightily.

Severe Covid-19 disease continued to be warded off by vaccines, even as recipients got further and further from their initial doses. If you look at the graphs of the Moderna study, it’s clear to the naked eye that even 3 months out from a completed vaccination series, breakthrough Covid-19 illnesses were starting to mount. And if you looked into the recesses of the study’s appendix (okay, I already did that for you), you would find that the same was true of all infection, not just documented symptomatic illnesses. Meanwhile, severe Covid-19 remained virtually unheard of among vaccine recipients, even almost 7 months out. This strongly implies that breakthrough hospitalizations that occurred this summer had something to do with waning protection against infection but far more to do with the Delta variant’s ability to simply cause more infections in the first place.

Did I just cede territory by implying that waning protection against infection plays a role? No. These data clearly show that vaccine effectiveness against infection decreased after an early honeymoon period, but that a rise in breakthrough infections did not coincide with a rise in severe disease during the period that the researchers studied.

This is powerful new information. To understand why, we have to remember that the vaccine recipients in the Moderna trial were inoculated several months ahead of the rest of us. Their head start provides an exciting opportunity to study the effect of waning immunity over time during the pre-Delta era. If the Moderna trial participants had started dropping like flies and picking up severe disease due to waning immunity, that would have been noticed during the study period, which ended before the Delta era. We would have seen a rise in breakthrough severe disease in the trial recipients in January, February, and March. That never happened.

We don’t specifically know what happened to these trial participants during the Delta period, but we certainly do know that people who were vaccinated several months after the trial participants were vaccinated started experiencing breakthrough hospitalizations in higher numbers in this July and August. So, if there was virtually no breakthrough severe Covid-19 among the Moderna trial recipients up through nearly 7 months after vaccination, in the study ending in March, but there were such events among the general population this summer, a group with less time for the vaccine’s effectiveness to have waned, the explanation is obvious. It’s Delta, Delta, Delta.

If the Moderna trial participants had started dropping like flies and picking up severe disease due to waning immunity, that would have been noticed during the study period, which ended before the Delta era. We would have seen a rise in breakthrough severe disease in the trial recipients in January, February, and March. That never happened.

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You may have noticed that I used a phrase above that I’ve not written before: “Honeymoon phase.” I’m going to start using that phrase a lot. In study after study, we keep seeing the same pattern. The early outcomes in vaccine effectiveness against infection for the mRNA-based vaccines are extraordinarily high. But when we follow the study subjects up over longer periods, breakthrough infections start to rise. Accordingly, our calculated vaccine effectiveness creeps down simultaneously. Many people have interpreted this as “waning immunity.” But the reality is that vaccine effectiveness against infection that lands in the high 80%-90% range (or even 100% as we have seen in some short-term trials) is just not a sustainable goal with the current vaccines. Both the Moderna study and the healthcare worker study published in NEJM today show this plainly. And we’ve seen it in a variety of other studies as well. That’s why the phenomenon needs a name: the “honeymoon phase.”

In the case of the Moderna vaccine, the “honeymoon phase” appears to last around 6 weeks after the 2nd dose. After that, a few breakthrough infections started to occur. The great news is that there is no sudden increase in infections the further out you look in the data so far. If anything, things kind of settle. In today’s healthcare worker study, a similar (though slightly larger) drop occurred, with vaccine effectiveness settling in the low 80% range by the end of the study. This may be because the study lasted into May, by which time some other variants were circulating that, while nothing like Delta, have been noted to evade vaccine protection a bit more than the original strain. All of this argues strongly against the waning immunity theory as driving the summer surge in breakthrough cases or hospitalizations.

In the case of the Moderna vaccine, the “honeymoon phase” appears to last around 6 weeks after the 2nd dose.

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I don’t usually repeat myself in an article. But this is that important: Again, we know that millions of Americans got vaccinated in the late winter and spring of 2021, a few of whom have had breakthrough cases and among whom an even smaller subset had severe disease requiring hospitalization. But if some of those people experienced breakthrough infection around 4-6 months out from their injections (which we have seen in datasets from Israel and elsewhere) during the Delta period, while the initial cohort of Moderna trial participants did not experience this in the winter and spring, when they had reached the 6-month mark—which today’s trial results explicitly show—then I say again: it’s Delta, folks.

Where does this leave us with boosters? I would argue that these data undermine the case for universal boosters. Why? Because we now have pre-Delta data going out almost 7 months, and virtually no severe breakthrough cases of Covid-19 were found. Therefore, I repeat, mostly it’s not about waning immunity, it’s about Delta. Since boosting seems to temporarily keep older people from developing severe breakthrough Covid-19, one could argue that boosting makes sense for that demographic, from a purely scientific perspective (though clearly not through the lens of equity). But other data from Israel reveal that severe breakthrough cases among adults under age 40 who were vaccinated in January and February were so rare that researchers couldn’t even calculate whether any waning protection from severe illness had occurred.

Do these new findings from Moderna imply superiority over Pfizer? After all, Pfizer argued to the FDA that vaccine protection was waning, and boosters were needed. No. The likely scenario is that both Moderna and Pfizer are holding up well.

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What more do we need to know? That’s not a rhetorical question. We still need to know whether boosting older people provides a lasting benefit. That’s not yet clear. It’s now obvious that Israel, the US, and a few other places will test this in the real world and other nations will decide what to do based on our outcomes and based on available resources. We also need to know whether boosting some lower-risk people, such as healthcare workers, decreases spread to individuals who remain, either by choice or by eligibility, unvaccinated (or inadequately protected in some cases among the immunocompromised). Finally, we still need safety data on 3rd doses in younger people, males in particular, in whom rare but important adverse effects have been concentrated.

Today’s news, though, underscores two points. First, expecting the available coronavirus vaccines to maintain more than 90% effectiveness against infection is unrealistic after the honeymoon phase. Second, the fact that protection against severe disease persists as long as it does (up to 7 months and maybe far longer) for most people means that we can get the answers we need on boosting lower-risk populations without skipping vital steps that will help us assure that safety is maintained and that the presence or absence or any additional benefit is identified.

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Do these new findings from Moderna imply superiority over Pfizer? After all, Pfizer argued to the US Food and Drug Administration last week that its vaccine protection was waning, and thus boosters were needed. No. The likely scenario is that both Moderna and Pfizer are holding up well. We'll see that when Pfizer releases more data showing results from its trial participants during the winter and spring. So far, Pfizer has provided somewhat less information. In its 6 month follow up trial from last week, effectiveness against severe illness remained very high while protection against Covid-19 illness late in their trial dipped to 84%. Some of Moderna's numbers may look a bit better, but they also reported around 75% efficacy against all infection late in the trial if you look deep enough into their datasets. Overall, it's a wash.

While Moderna has yet to file a request to the FDA requesting emergency use authorization for boosting its recipients, it too has been studying boosters (at a lower dose), and data are expected soon.

What are your questions on Delta and boosters? Leave a comment below and join the conversation.

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