This is giving me flashbacks to the euphoria that greeted the results of the Phase 3 vaccine trial results last year showing that Pfizer and Moderna were each ~95 percent effective against the virus. We’d licked the coronavirus! The days of worrying about COVID were over.
The U.S. recorded more than 2,000 deaths from the disease on Tuesday of this week alone. And although most of them were unvaccinated, the reality of waning immunity following vaccination means not all were.
Here we are again a year later with Pfizer and BioNTech reporting stunning results from the first randomized clinical trial of their booster data. We already have real-world data from Israel demonstrating that third doses reduce the risk of illness but Pfizer and its partner wanted hard numbers. So they took 10,000 people who’d had two doses of their vaccine and split them into two groups. Half would get a third dose, the other half would get a placebo. Would the first group be meaningfully less likely to get COVID than the second?
They would. The booster restores the high degree of protection one gets upon completing the initial two-dose regimen — or maybe even exceeds it. After all, the booster study was conducted with Delta circulating through the population while the original vaccine trials were conducted when the original, much less contagious version of SARS-CoV-2 was prevalent. If the booster makes you as immune to Delta as the two-dose regimen makes you immune to its predecessor, that’s considerable protection.
All trial participants previously completed the primary two-dose series of the Pfizer-BioNTech vaccine, and then were randomized 1:1 to receive either a 30-µg booster dose (the same dosage strength as those in the primary series) or placebo. The median time between second dose and administration of the booster dose or placebo was approximately 11 months. Symptomatic COVID-19 occurrence was measured from at least 7 days after booster or placebo, with a median follow-up of 2.5 months. During the study period, there were 5 cases of COVID-19 in the boosted group, and 109 cases in the non-boosted group. The observed relative vaccine efficacy of 95.6% (95% CI: 89.3, 98.6) reflects the reduction in disease occurrence in the boosted group versus the non-boosted group in those without evidence of prior SARS-CoV-2 infection. Median age of participants was 53 years, with 55.5% of participants between 16 and 55 years, and 23.3% of participants 65 years and older. Multiple subgroup analyses showed efficacy was consistent irrespective of age, sex, race, ethnicity, or comorbid conditions.
Note the last line. Strong protection even for people with comorbidities. “Based on these findings we believe that, in addition to broad global access to vaccines for everyone, booster vaccinations could play an important role in sustaining pandemic containment and a return to normalcy,” said the head of BioNTech of the results. I’m reading that as code for “everyone will benefit from a third dose, not just senior citizens or the very ill.” Granted, Pfizer and BioNTech have a financial interest in advancing that perspective.
But what if it’s true?
I’m thinking back to a point that Fauci and others have made during the booster debate. If giving people a third shot enhances their immunity only for a month or two, that’s not great. There’d still be some benefit in giving them a little extra protection before the winter wave, a la the annual flu shot. But it’ll be hard to regain a sense of true normalcy, especially among seniors, if people reliably begin feeling less safe being out in society four months after they’ve had their latest dose due to fear that their immunity is waning again. What Fauci has argued, though, is that the COVID vaccine may be a “natural” three-dose vaccine, in which case the booster may end up providing more durable immunity than the first two shots did. Because the first two doses of Pfizer and Moderna are given in quick succession, with just a few weeks between them, the recipient’s immune system may react to them the way it would a single “prime” shot. Give a third shot many months later, though, and a more sophisticated immune response to the spike protein on the virus begins to evolve. That’s where durable immunity begins.
And if that’s what’s happening with the COVID vaccine, it really does mean everyone should have a third dose. (Or, at least, should have their first two doses spaced much farther apart than three weeks.)
Is there any evidence in the new Pfizer/BioNTech data that the third dose is creating durable immunity? Maybe:
Nice to see some neutralisation data on 3rd Pfizer (booster) dose. Neutralisation to WT, Beta and Delta all similar, no huge drops against Delta. Hopefully, this is sustained! https://t.co/sp4zlQoDvm pic.twitter.com/E6JDdkqkw2
— Ash Otter (@asherichia) October 21, 2021
Look at the trends in the top graph. Antibody titers after the second dose peaked after seven days and then began to drop. After a month, they’d already fallen by 20-30 percent. By the time the third dose was administered they’d declined considerably more.
But look what happened after the third dose. Antibodies surged after a week — and then kept climbing for the next three weeks. There’s no way to know yet when titers peak following the booster, as that’ll require longer trials, but clearly it takes them longer to peak than it did after the second dose. Note the raw numbers in the graph too, as the scale of the bars makes it appear at first glance that titers after the third dose are only a bit higher than they were after the second. In reality, they were more than three times as high. In the bottom graph, which tracks the response against Delta, boosted people had at least five to 10 times as many antibodies after three doses as they did after two.
“Interesting data suggesting the Pfizer/BioNTech works best as a three-dose vaccine,” said one geneticist about those results. “Initial 3-dose antibody titres being so much higher than 2-dose ones makes a stronger case than I had anticipated for administrating boosters outside just the most at-risk demographies.” There’s been some chatter over the past few days that the FDA will eventually extend booster eligibility to every American 40 and older who wants one, regardless of health. This Pfizer/BioNTech makes that even more likely.
Remaining questions: Given that the median delay between second and third doses in this study was 11 months, what kind of boosts would we see if we spaced the doses out by six months instead? Or 18 months? And what effect would “mixing-and-matching” Pfizer with Moderna or J&J have on antibody titers? Stay tuned.
