Why COVID Vaccines Proliferate as Monoclonal Antibody Drugs Fade

Monoclonal antibody drugs to fight COVID are being taken off the market while new COVID vaccines are arriving, even as the old ones are standing up quite well against new viral variants. How can two interventions that tweak an immune response have such different outlooks? It stems from the biology.

Understanding what antibodies are, how our bodies make them, and how vaccine and monoclonal antibody technologies work and differ, explains the distinction.

The Antibody Response is Naturally Polyclonal

The immune system is a vast army of cells and their secretions that recognize and respond to the presence of “non-self” cells and molecules, like the spike proteins that fringe SARS-CoV-2, the virus behind COVID. One of the first things I learned in college is that “biology is really chemistry,” and that’s certainly true for the immune response. It’s all about recognizing molecules.

Shortly after infection, white blood cells called B lymphocytes or B cells recognize “foreign” (“non-self”) molecules on or from a pathogen. Then the B cells divide, over and over, eventually spawning the more highly specialized plasma cells. These cells maintain the ability to secrete antibody proteins that target a specific molecule on the pathogen, like a key fits a lock, at the astonishing rate of about a thousand per second. Also in college, my “unknown” in cell biology lab was such a plasma cell. I got lucky – it’s instantly recognizable by its gigantic clear center, a Golgi apparatus engorged with antibodies. (Phish cringingly mispronounces this cell part in their song Golgi Apparatus. Clearly Trey and company didn’t take Bio 101.)

Of the five classes of antibodies, defined by structure and sites in the body, the simplest is shaped like the letter Y, the others aggregates of Ys. The important parts are the tips of the Y arms, which fit into molecules that are part of the pathogen, called antigens. A viral spike is such an antigen. (An antigen is anything that evokes an immune response.)

The flood of antibodies that follows infection is amazingly diverse, because they assemble rapidly, in parts. As B cells form in bone marrow, genes encoding antibody sections actually move about the chromosomes, mixing and matching in ways that create an almost limitless variety. It’s a little like assembling outfits.

The choreography of antibodies binding diverse antigens that are part of a pathogen reminds me of the Indian parable of the blind men and the elephant, in which men who’ve never encountered the animal before feel different parts of one and reach different conclusions about what it looks like. Similarly, antibodies glom onto different antigens that festoon a pathogen’s surface.

The antibody response is termed polyclonal – it recognizes different parts of a pathogen’s surface. It’s more diverse and broader than protection from a vaccine, which targets just the spikes. (See COVID-19 Vaccine Will Close in on the Spikes, one of my first COVID articles, published here exactly three years ago.)

In addition to being diverse, the antibody response remembers. Some plasma cells hang around, quiescent, until the threat – SARS-CoV-2 – looms again. Then the reaction is so fast that sniffles or fatigue may not even arise.

Monoclonal Antibodies

As their name implies, monoclonal antibodies – MAbs – differ from the natural polyclonal antibody response in that they zero in on and bind to one highly specific antigen. The MAb may destroy the antigen, or alert a specific immune response.

MAbs debuted in 1975, when British researchers George Köhler and Cesar Milstein harnessed the immune system’s specificity by mass-producing a single B cell type to manufacture large amounts of a single antibody type. They received the Nobel prize for inventing the technology.

The specificity of MAb-based drugs is why they work so well as targeted cancer therapies, like Herceptin and Avastin. (Such a drug’s generic name ends in “mab.”) But cancer cells do not mutate nearly as fast as the revved up, changeling SARS-CoV-2 and other viruses. A MAb-based cancer drug might hold the disease at bay for months or even years, but a MAb-based COVID drug can’t keep up with a shifting viral landscape.

Still, MAb-based drugs, so far, have kept people with compromised immune systems from severe COVID. Over the pandemic years, the FDA authorized for emergency use six MAb-based COVID drugs, plus an existing one. But the drugs are losing their potency as the virus presents a different face to the immune system, although the flurry of mutations is now settling into a persistence of Omicrons.

“So one by one, they have gone off of the market, their emergency use authorization revoked in time as they became thought to have no more use,” said Jeremy Faust, MD, editor-in-chief of Medpage Today.

The last to go is Evusheld, for which FDA revoked the Emergency Use Authorization on January 26, 2023. The drug, actually a duo of MAbs, is slated for return to use only when susceptible viral variants comprise more than 10 percent of circulating viruses. Right now, the virus seems to be settling on small variations of Omicron. (See the recent DNA Science post On COVID Origin and Omicron Persistence: This Geneticist’s View.)

Vaccines and Monoclonal Antibodies Are, in a Way Opposite

A MAb-based drug is a single weapon that attacks an already-present enemy. A vaccine, in contrast, prompts the body to unleash different weapons should the pathogen present itself.

Vaccines are parts of pathogens, sometimes natural, sometimes synthetic, sometimes tweaked or embellished, that induce a powerful polyclonal antibody response. For COVID, the evoked diverse antibodies target multiple nooks and crannies of the viral spikes. And fortunately, when newer vaccines came along to counter the slightly shifted nooks and crannies of the Omicron variants, the older vaccines still worked just fine. Plus, the next generation of COVID vaccines will likely also target a different viral protein, the nucleocapsid that protects its genetic material.

In short, a monoclonal antibody focused on one tiny part of viral anatomy can lose its efficacy when that part changes. But a vaccine’s diversity enables it to stand up against the evolution of the virus … to a point.

CODA

What frightens me the most is the bigger picture, envisioning where evolution may take us in the face of unleashing monoclonal antibodies, in the long run. Consider natural selection.

Have MAb-based drugs weeded out the older variants against which they were developed, leaving more recent and resistant ones to vacate the suddenly expanded niche, keeping the vaccine makers in business as the enemy shifts its face once again?

So in the long run, the MAb-based drugs may have actually ignited and then accelerated the further evolution of the virus. But the vaccines wouldn’t have done that, because by presenting the immune system with spikes, even tweaked ones, the vaccines encourage a more natural, polyclonal, immune response.

Put another way, a vaccine mimics the body’s diverse immune response, whereas a monoclonal antibody restricts the response. Bioethically speaking, the issue becomes weighing protecting a few in the near term – the immunocompromised – with protecting many in the long term.

The different trajectories of vaccines and MAb-based drugs illustrate starkly how the repercussions of the pandemic will reverberate for years, perhaps for decades. But underlying it all, as it does all of biology, is evolution.