COVID-19 Vaccine Makers Are Looking Beyond the Spike Protein

It’s time for more weapons in the shots-versus-virus arms race.

a scan of a coronavirus particle
Radoslav Zilinsky / Andriy Onufriyenko / Getty / Katie Martin / The Atlantic

In the race to build the world’s first round of coronavirus vaccines, the spike protein—the thorny knobs that adorn each of the pathogen’s particles—was our MVP. Spike is a key ingredient in virtually every one of our current pandemic-fighting shots; it has been repeatedly billed as essential for tickling out any immune response worth its salt. “People put all their eggs in the spike basket,” Juliet Morrison, a virologist at UC Riverside, told me. And it undoubtedly paid off.

In recent months, though, it’s become clear that the coronavirus is a slippery, shape-shifting foe—and spike appears to be one of its most malleable traits. Eventually, our first generation of spike-centric vaccines will likely become obsolete. To get ahead of that inevitability, several companies are already looking to develop new vaccine formulations packed with additional bits of the coronavirus, ushering in an end to our monogamous affair with spike. The potential perks of this tactic run the gamut: More vaccine ingredients could help the body identify more targets to attack, and loop in untapped reservoirs of immune cells that have no interest in spike. Multifaceted shots also up the ante for the virus, which can alter only so many aspects of its anatomy at once. “It’s like diversifying a portfolio,” William Matchett, a vaccinologist at the University of Minnesota who’s researching reformulated COVID-19 vaccines, told me.

To be clear, setting our sights on spike has served us well. The vaccines we’ve built against the coronavirus continue to be astoundingly effective shields against disease largely because the protein is such an excellent teaching tool for an immune system that’s readying itself to duel. Spike, which helps the virus unlock and enter human cells, is one of the pathogen’s most salient and dangerous features, certainly among the first that will be spotted by immune cells and molecules on patrol.

Vaccines that teach the immune system to recognize the spike will, in all likelihood, be vaccines that teach the immune system to act effectively, and fast—quickly enough, perhaps, to waylay an invading virus before it even has a chance to break into cells. This process, called neutralization, is carried out by specific types of antibodies, and it holds a venerated status in the field of vaccinology, David Martinez, a vaccine expert at the University of North Carolina at Chapel Hill, told me. Once a vaccinated person produces enough neutralizing antibodies, so the theory goes, they need little else to stave off sickness. And the spike protein appears to be top-notch antibody bait. “Spike is here to stay—it is absolutely necessary,” Smita Iyer, an immunologist at UC Davis, told me.

But although antibodies zero in on targets with laser-sharp precision, they are easily discombobulated by change: Even subtle shifts in the spike’s structure can make it harder for molecules to glom on to the surface of the virus and bring it to heel. Antibody-dodging variants of the virus, each carrying slightly rejiggered versions of spike, have now appeared in several countries, including South Africa, Brazil, India, and the United States; more will certainly follow.

None of our current vaccines has yet been completely nullified by a coronavirus variant, and vaccine makers such as Moderna and Pfizer are planning to cook up additional shots containing tweaked, variant-conscious versions of spike. The problem is, strategies like these could quickly lock us into a woefully mismatched fencing bout: Microbes mutate much faster than humans invent vaccines, and with every new thrust, we’ll have time only to parry in return. When spike operates alone, it creates an obvious immunological loophole through which a virus might slip.

There’s another solution. We could simply give the immune system more hunks of the virus to target. Several vaccines containing whole coronavirus particles—which have been chemically incapacitated so they can’t cause true infections—have already been authorized, including a couple made by the Chinese company Sinopharm. Whole-virus vaccines, however, can be a pain to produce, and have delivered mixed results in the past.

Several companies, including the California-based Gritstone Bio, have decided to take a more targeted tack, selecting a subset of coronavirus traits to package into some of their repertoire of inoculations. One of Gritstone’s vaccines, which is currently in human trials, contains not only spike but also chunks of two proteins that the coronavirus keeps in its interior: one called nucleocapsid, which helps the pathogen package its genetic material, and another called ORF3a, which helps newly formed coronavirus particles mosey out of cells.

Neither of those internal proteins will be of much interest to neutralizing antibodies, which are built to latch on to only the outsides of pathogens as they bop around the body. But virus innards can be good fodder for another group of immune defenders—T cells—which recognize and kill infected cells that chew up pathogens and display chunks of them on their surface. If antibodies are like cameras that focus on a virus’s superficial appearance, T cells are X-rays that go a few layers deeper.

T cells are already an essential part of the immune response our bodies mount to our current vaccines, because they react very strongly to spike. But Andrew Allen, Gritstone’s CEO, told me that the T cells in our bodies could be doing more, if given the chance. T cells in people who have been infected by the coronavirus can home in on many parts of the virus that aren’t packaged into most vaccines. Some of these immune targets, encouragingly, have mutated more slowly than spike, raising hopes of protection that’s both potent and long-lived. Early studies suggest that new coronavirus variants that bamboozle certain antibodies are still nowhere near stumping the body’s diverse cavalry of T cells.

Strong and versatile T-cell responses may, on occasion, be powerful enough to fend off the coronavirus largely on their own. That could make spike-plus vaccines a huge boon for people who are on drugs that blunt the ability of immune cells called B cells to produce antibodies, such as the ones taken for certain types of autoimmune disease. Matchett, of the University of Minnesota, recently led a study (not yet peer-reviewed) showing that an experimental vaccine containing only nucleocapsid—a design that would specifically bait T cells, but not neutralizing antibodies—curbed the severity of COVID-19 in laboratory hamsters and mice. The rodents still got sick, “but the T cells are coming in and doing cleanup and preventing more disease from occurring,” he said.

The experiment was just proof of concept: A spike-free vaccine probably isn’t in the cards. But a shot that includes nucleocapsid makes for a pretty good insurance policy. What vaccine makers are after is “more layers of protection,” on top of the successful foundation the current vaccines have laid, Padmini Pillai, an immunologist at MIT, told me.

Another company, California-based ImmunityBio, plans to push the pro-T-cell paradigm even further. It has several versions of a spike-nucleocapsid combo vaccine in clinical trials, some of which are being delivered as drops into the mouth, and will soon be testing out an intranasal spray. Patrick Soon-Shiong, the company’s CEO, told me that this route of administration is a much better pantomime of how the coronavirus actually enters the human body—through the airway, where it will encourage the production of unique populations of antibodies and T cells tailor-made to guard these tissues. Many of those T cells will even hunker down in and around the lungs, where they can head off the virus immediately, something that doesn’t happen as efficiently when we inject vaccines into our deltoids. “I think local immunity is going to be what we need, if we’re thinking ahead,” Donna Farber, an immunologist at Columbia University, told me. Some next-generation vaccines could operate as solo acts for the un-immunized; others could be boosters for people whose defenses against the coronavirus are no longer up to snuff.

The spike-plus approach isn’t foolproof. Stuffing too many triggers into a vaccine could backfire if, for instance, an extraneous protein ended up distracting cells from spike. A poorly designed vaccine could also rev up T cells, but sap resources away from the B cells that might otherwise pump out neutralizing antibodies to stop the virus before it infects our tissues. “We need to make sure we have balance,” Pillai told me.

Worse still would be a vaccine candidate that inadvertently drives an overzealous immune response, burning up healthy tissues alongside the sick. There’s even precedent for this with the coronavirus that caused the 2002 SARS epidemic: Lab mice fared worse with the pathogen after taking a vaccine that included nucleocapsid. “I wouldn’t necessarily rule [nucleocapsid] out as a target yet,” Martinez, of UNC, told me. “But we have to proceed with a lot of caution.”

On one point, every expert I spoke with agreed: We’ll need to keep pace with the changing coronavirus for a good while yet. Even after the pandemic is declared over, the coronavirus will linger. Human and virus will need to grow accustomed to each other, forging a détente that hopefully grows more peaceful over time.

To accelerate that truce, our approaches to vaccination might need to become less reactive—responding to the virus after it alters itself—and more proactive, anticipating its next moves. Surveillance centers around the world have, in recent months, begun to sequence samples of the virus at an accelerated pace, cataloging every tweak in its genome, while researchers work to model the ways viral genes and proteins might change. SARS-CoV-2 has learned the strength of its costume changes and won’t be easy to put down. But perhaps our next round of vaccines will move us closer to the possibility of one-shot-fits-all.