Boosters (And Winter) Are Coming

President Biden’s administration has announced that booster vaccinations for COVID-19 are coming beginning as early as September 20^th. What science underlies that decision?

The immunity afforded by the vaccines is waning

The CDC is citing three studies showing a decline in vaccination efficacy against breakthrough infections.

• A 74.7% to 53% decline in efficacy against the Delta variant in nursing home patients
• A 91.7% to 79.8% decline in efficacy among the 10 million vaccinated New Yorkers
• There was a very slight decrease in efficacy against hospitalizations from 86% to 84% in the period 3-6 months after complete vaccination.

The combination of rising breakthrough cases and the evident decline in our immune response is sufficient to recommend “boosters.”

“To develop an effective vaccine, one should mimic natural infection, without causing disease.  However, when natural immunity does not adequately protect against a pathogen, vaccines must be designed to induce “unnatural immunity”—that is, an effective immune response that natural infection either does not elicit, or does so poorly.”

Anthony S. Fauci, MD March 2016

Natural immunity to COVID

With respect to antibodies that neutralize COVID-19, our immune response focuses on two areas of COVID’s spike – the receptor-binding domain (RBD) and the N-terminal (NTD). In studies of the convalescent serum of patients recovering from COVID, 90% of the “neutralizing activity” was against the RBD area – they were 10 to 100 fold more potent than antibodies directed against the NTD segment.

Some diseases confer life-long immunity, like chickenpox. Their vaccines are also able to prevent the disease and provide that life-long coverage. Other conditions, notably seasonal flu and HIV, are more able to evade our natural immunity by mutation, changing their composition, and subsequently their shape – the shape of a foreign body is what our immune system recognizes as foreign and attacks.   

Seasonal influenza changes pretty quickly, so there is a new target and vaccine created annually. COVID-19 morphs more slowly

A recent study looked at the difference in the convalescent sera of patients who experienced COVID-19 and those treated with vaccines. The vaccine was far more targeted against the RBD portion of the spike than natural immunity and was far more effective against the single amino acid mutations that could occur within that region. Our inadequate natural immune response was supplanted by a more robust and broader response from vaccination.

To supplant the weak natural immunity conferred by a COVID infection, the mRNA vaccines were designed to strongly attack the spike configuration of COVID-version 1.

Lock and key

The lock and key model describes how the shapes of two chemical or biological compounds fit together. When the fit is “perfect,” they might catalyze a reaction, or in the case of COVID-19, its spike can bind to an ACE receptor on our cells and infect them.

Immunity comes from recognizing a foreign key, in this case, the COVID spike, and developing antibodies to block it from entering the lock, in this case, our ACE receptors. The Delta variant can jimmy the lock, evading our immune response because its shape is sufficiently different from the antibodies we have developed for COVID-version 1.

The Bomber’s Mafia

Malcolm Gladwell’s latest book, The Bomber’s Mafia, explores the idea of strategic bombing – that by focusing on destroying critical sites of production, we could defeat the Germans and Japanese in World War II. It serves as a good analogy for understanding the differences between mRNA vaccines and natural immunity. mRNA vaccines are exceedingly strategic; they create an immune response to the COVID version 1 spike, not to the Delta variant. [1] Natural immunity is a bit less discriminating; it develops a targeted response that envelops some of the spike along with some of its surroundings.

In theory, there is no difference between theory and practice. In practice, there is.

Yogi Berra

The natural immunity to COVID-19 is too indiscriminate to attack COVID-19’s variants of concern adequately. Just as we discovered in our attempts to strategically bomb Japan and Germany into surrender, the mRNA vaccines are too strategic. The Delta spike differs sufficiently to be targeted less effectively, hence the breakthrough infections.

What do we mean by a booster shot?

The current recommendation for a third shot of one of the two mRNA vaccines (Pfizer and Moderna) is for immunocompromised patients. These individuals have an ongoing disease or treatment that depresses their immune response, and the studies have shown that the two-dose protocols do not create a robust immune response for them. A third dose is necessary – a booster, in this instance, increases the strength of their response.

The efficacy of our current vaccinations diminishes with time. With the largest percentage of their population vaccinated, Israel has experienced increasing numbers of “breakthrough” cases in those vaccinated early last winter. Those having received vaccinations eight months ago were two-fold more likely to have a breakthrough infection than those vaccinated in the spring. [2] In this instance, the booster is meant to refresh our response, re-exposing us to the antigens.

There is one more sense of booster to consider. Both Moderna and Pfizer are in the process of tweaking the mRNA payloads to more effectively cover the now predominant Delta variant. This would boost both the range of variants treated and the strength of our immune response – a twofer.

The Upcoming Booster

At this juncture, the booster will not be broadening our immunity, just boosting that already present. In the grand scheme of things, it will move individuals with less efficient targeting of Delta to be more efficient. Reducing Delta as we have done with COVID-version 1 will require a change in the targeting, which will require some phase III trials. I think September 20^th will come and go before those trials are completed.

"Those who cannot remember the past are condemned to repeat it."

George Santayana

Just as we found that strategic bombing in World War II was insufficient to end the war, the original highly selected targeting of the mRNA vaccines must be repurposed. Just as we require updating our seasonal flu vaccine, we need to update our COVID vaccine. There is a nagging sense of déjà vu as the lessons of departing from Viet Nam play out as we now leave from Afghanistan. Despite the attempts of the administration to get ahead of the problem, I anticipate that the chaos of scheduling and obtaining our initial vaccinations will be revisited, as Dr. Bloom has pointed out as we queue up for those booster shots.

[1 The J&J vaccine has a similar specific target but uses a more traditional virus vector for delivery

[2] I would hasten to add that those cases were far less severe and meant fewer hospitalizations and deaths.