Self & Other · mRNA, and What COVID Taught Us

What Comes Next

First, immunity against respiratory viruses is more layered than the simple “antibodies prevent infection” picture suggests. The strong protection against severe disease that COVID vaccines have maintained, even as protection against infection has waned, has shown that T cell responses — which are harder to measure than antibody responses but appear to be more durable — do a great deal of the work in keeping serious illness at bay. Vaccination produces both antibodies and T cell memory; the antibody side fades, particularly in the face of viral mutation, but the T cell side persists. This has been a useful lesson for vaccine development generally, and it is shaping how the next generation of vaccines (including for flu) is being designed.

Second, the importance of mucosal immunity — the kind of immunity that lives in the linings of the airways and gut, which we met in Chapter 5 — has become much more visible. Most current vaccines, including the COVID mRNA vaccines, are injected into muscle, which produces strong systemic immunity in the bloodstream and throughout the body, but relatively weak immunity at the airway surface where respiratory viruses first land. This is part of why vaccinated people can still get infected even when they are well-protected against severe disease: the virus can establish a foothold at the upper airway before systemic immunity kicks in. The next generation of respiratory virus vaccines may include nasal sprays or other delivery methods designed to produce stronger mucosal immunity. Several such vaccines are in development.

Third, the role of long-term antiviral memory has been better characterized. Studies of COVID survivors years after infection have shown that, even when antibody levels have fallen, memory B cells and T cells specific to the virus persist and can rapidly respond to new exposure. This is a confirmation, in unprecedented detail, of the basic picture we sketched in Chapter 4. It is also a useful corrective to early pandemic concerns that immunity might not last — in fact, immunity to the underlying virus seems to last reasonably well, even though immunity to specific variants of that virus can wane.

What Comes Next

The mRNA platform that Karikó and Weissman built over thirty years has now produced more than the COVID vaccines. The technology has been, in some sense, validated. The infrastructure for producing mRNA at scale exists. The regulatory pathways are established. Several other applications are well into development.

mRNA vaccines for influenza, designed to be more flexible than current flu vaccines, are in advanced trials. mRNA vaccines for RSV (respiratory syncytial virus), for cytomegalovirus, for various sexually transmitted infections, and for tuberculosis are at various stages of development. Some are likely to be approved within the next several years.

The most exciting non-infectious-disease application is in cancer. We mentioned this briefly in Chapter 12 — the idea of personalized cancer vaccines, designed against the specific mutations in an individual patient’s tumor, delivered as mRNA. Several trials in melanoma, pancreatic cancer, and other malignancies have produced encouraging early results. The technology that defended us against a virus may, within the next decade, be one of the tools we use to attack the cancers that have, until now, escaped immunological detection.

Karikó and Weissman shared the 2023 Nobel Prize in Physiology or Medicine. The citation noted that their work, decades in the making, had been essential to the development of one of the most important vaccines in human history. Karikó, who had been demoted at Penn in 1995 for failing to bring in grants, had spent forty years on the work that the world finally needed.

A Note on Disagreement

Before we leave this chapter, one careful word.

The COVID vaccines have been one of the most politicized medical products of recent decades, and many readers will have lived through the pandemic having strong feelings about them, in either direction. The book has tried, in this chapter, to present what the science actually shows, with appropriate acknowledgment of both the strong evidence and the legitimate uncertainties.

What the science says is that the vaccines were safe, were highly effective at preventing severe disease, and very probably saved millions of lives. What the science does not say is that anyone who declined to be vaccinated was a bad person, that the public health response was perfect, that all of the recommendations made during the pandemic were optimal, or that there is no room for honest disagreement about specific policy decisions. Some recommendations were better than others. Some communication was clearer than other. Reasonable people drew different conclusions about specific questions — mandates, school closures, certain age-group recommendations — and the disagreements were, sometimes, about real trade-offs, not just bad faith.

What this book hopes is that, by knowing how the immune system actually works, what mRNA actually is, what the trials actually showed, and what the honest accounting of risks and benefits looks like, the reader is better equipped to think for themselves about future versions of these conversations. We will have more pandemics. We will have more vaccines. We will have more debates that mix legitimate scientific uncertainty with political conflict, and the line between the two will sometimes be difficult to find. The reader who has finished this chapter has, at least, more tools for the work of finding it.

So this is what mRNA is, and what it did, and what it taught us.

A Hungarian biochemist, who had worked on a problem that almost nobody believed was worth working on, kept working on it. The technology she helped to build was, at the moment of greatest need, ready. The vaccines made possible by that technology saved millions of lives. The same technology is now being applied to other diseases, including some of the most difficult ones medicine has ever faced.

The lesson, beyond any specific pandemic or any specific debate, is one the book has been making in different forms throughout. Long, patient, often unfunded scientific work, done by people who are not always recognized while it matters most, is what makes it possible for medicine to do what medicine sometimes does, which is to save lives that would otherwise have been lost. The wins of the next half century will rest on work being done now, in laboratories whose names you do not know, by researchers who are mostly not famous. Some of them will be wrong. Some of them will be right. The system that produces medicine, with all its slowness and imperfections and occasional moments of speed, is one of the more remarkable things humans have built. It is worth understanding from the inside, which this book has tried to provide. It is also worth, on occasion, simply noticing.

The next chapter circles back to a topic we touched on early and have returned to several times: the microbiome. There is now an enormous popular literature about gut bacteria, much of it overheated, and a careful look at what we actually know is the right way to bring this part of the book to a close before the glossary and the epilogue.

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