Why a COVID-19 vaccine will be no easy feat

Viruses are wily and many have eluded our best efforts

VACCINES HAVE HAD a greater impact on human health than any medical intervention in history. We are all hoping an effective vaccine against COVID-19 will soon join the ranks of these extraordinary disease prevention measures. But it’s worth understanding first how viruses – and effective vaccines against them – work. Doing so makes clear what we are now up against, and why we should approach the vaccine quest with some humility and recognition that the task is much easier said than done.  

Smallpox, caused by Variola major virus, was the deadliest disease in human history, with a fatality rate of roughly 30 percent and as high as 90 percent in indigenous peoples of North America and Australia where it was introduced by European explorers. In the 20th century alone, more than 300 million people died of smallpox. In one of the greatest public health achievements in human history, a WHO-sponsored program eradicated this disease in 1976 through worldwide vaccination with a related but relatively harmless virus call vaccinia (from whence “vaccination” derives).

This strategy of inducing a powerful protective immune response by infection with a related but non-pathogenic virus underlies many of the most successful vaccines today: measles, mumps, rubella, yellow fever are all attenuated viral vaccines. A protective vaccine against COVID-19 would be an extraordinary breakthrough, and dozens of biotech and pharmaceutical companies are aggressively spending many hours and dollars in pursuit of this goal. Current headlines anticipate this as reality in 8-12 months; however, a review of recent history suggests that there are no guarantees.

Through many decades of immunology research, we know a great deal about what happens when we are infected by a virus and our immune system mobilizes to respond. Two essential cellular elements of immunity are activated: B cells and T cells, the stalwarts the “adaptive” immune system. B cells make customized and highly specific molecules directed against protein structures on the virus, called antibodies. These elegant immunological weapons bind tightly to a virus and catalyze its destruction.

But viruses survive and reproduce by pirating the biologic machinery of our cells. Once they enter a cell they are protected from even the most effective antibodies, which work outside the cell. While T cells help B cells make antibodies, they have another important role. Every cell in the body, whether in the lung, the skin, or the GI tract, takes the proteins made within it and methodically chops them up into peptides to display on the cell surface. Certain T cells—cytotoxic or “killer” T cells—are trained to continuously scan these peptides on the cell surface like auditors looking for errors. If these immune auditors find a peptide that looks foreign—for example, a peptide from a protein made by a virus—they destroy the cell. Thus, the virus has no place to hide from the combined surveillance of T cells and B cells; neither inside nor outside the cell is safe.

Most vaccines today are focused principally on antibody production, which is necessary but perhaps not sufficient for protective immunity. Indeed, laboratory surrogates of vaccine efficacy involve measuring the antibody response in the bloodstream after a subject is vaccinated. Circulating antibodies are tested for “neutralizing” properties, the ability to block the virus from infecting cells in culture. Vaccines that generate high levels of “neutralizing antibodies” are considered promising. In contrast, the capacity of a vaccine to induce a cytotoxic T cell response against a virus is largely ignored. It may be time to reassess this fashion of testing vaccine function in laboratory studies.

Viruses and the mammalian immune system have evolved together antagonistically and heuristically over millions of years, each seeking the upper hand through novel strategies. Vaccines against viruses that exploit the hard-won wisdom of the immune system by mimicking or approximating authentic viral infection have an enviable track record. The recently approved vaccine against Ebola virus involves an Ebola protein genetically inserted into a harmless live virus. This tricks the immune system into making antibodies and killer T cells against the Ebola virus protein, leading to protective immunity.

A 21st century smallpox vaccine was recently FDA approved—a weakened and safe version of vaccinia virus called MVA, which infects cells (provoking the complex antiviral immune response) but cannot hijack the cells machinery to make copies of itself. Certain viral diseases, however, have defied enormous attempts to generate protective vaccines.

Through no lack of effort, vaccines against HIV have thus far been ineffective. Seasonal influenza vaccine, delivered into muscle, is an inactivated virus—it cannot infect cells—and must be fashioned anew every year to keep pace with this rapidly mutating virus. While the current vaccine saves countless lives every year, human deaths from influenza still number in the tens of thousands per year in this country alone. It is difficult to argue that we do not need a better influenza vaccine.

Nearly all vaccines today are delivered into muscle via hypodermic needle. But muscle has never had to evolve the immune machinery to optimize a protective immune response. Our bodies are in contact with the outside world through large protective interfaces called barrier tissues: skin, respiratory tract, GI tract. This is where we encounter viral infections, and these tissues—skin in particular – have highly evolved machinery for initiating powerful immune responses and harboring protective immune memory. Smallpox was eliminated from the world by scratching and infecting the top layer of skin with vaccinia virus — the same vaccine delivered into muscle was much less effective.

What might we be losing by delivering vaccines into muscle instead of skin? Microneedle patches applied to the skin have been developed with this in mind, although the bifurcated needle used to eradicate smallpox is tried and true. It may well be that delivery makes a critical difference, particularly for the generation of protective T cells.

Successful vaccines against infectious viruses have proven surprisingly hard to make, and success hinges on not only skill and wisdom but also serendipity and luck. I believe that COVID-19 will be no different.

Clinical trials are already ongoing for vaccines based on mRNA, DNA, and proteins from from the novel coronavirus, which undoubtedly will generate a robust antibody response against the virus. These vaccines can all be made rapidly, which is a major advantage to a world desperately waiting for them.

Will antibodies, in the absence of T cells generated in response to authentic viral infection, be enough to protect against COVID-19? Perhaps, but strategies that generate antibodies alone may not be effective.

Viruses are wily and tough adversaries, and a successful vaccine against COVID-19 will likely require many different approaches before one emerges that is effective and safe. My belief is that it is likely to involve a design that mimics true viral infection, generating not only antibodies but also antiviral killer T cells.

Meet the Author

Thomas S. Kupper

Professor and Chairman of Dermatology Dept, Brigham and Women's Hosp/Harvard Medical School
Many approaches need to be taken, and ultimately the best vaccine will prevail. We all hope that process plays out rapidly, but history tells us there are few certainties in the race to outsmart our viral adversaries.

Thomas S. Kupper, MD, is Fitzpatrick Professor and chairman of the Department of Dermatology at Brigham and Women’s Hospital and Harvard Medical School. His laboratory is funded by the National Institute of Allergy and Infectious Diseases to produce a “universal” influenza vaccine based on T cell immunity, and recently received additional NIAID support to create a “universal” coronavirus vaccine that would protect broadly against COVID-19.