Opinion by Kent Sepkowitz
I have no idea. And I promise, neither does anyone else. This is a heated moment with too much hope, too much fear, and too much on the line for anyone to have clear-eyed perspective. That said, for me, fall 2020 seems overly ambitious; even January 2021 is quite early for a safe and effective vaccine to be available for millions of people.
Vaccines usually take years to develop; CanSinoBIO, a leading company in Beijing, recently received praise for moving an Ebola vaccine from concept to approval in just a little more than three years.Why it is so difficult? After all, the basic approach to vaccine development has remained more or less the same for the past 200 years: trick the immune system into developing protection against a specific infection, be it smallpox or rotavirus. Sure, the scientific sleight of hand has changed dramatically. We have moved from injecting live pathogens, to killed pathogens, to weakened but still alive pathogens to injecting genetic scraps from the pathogen using the latest techniques. But chicanery has remained the basic MO.
Given all this know-how and our powerful computers, brilliant vaccine experts, lab space and plenty of money, many still wonder why we can’t just muscle our way forward.
Alas, it turns out that the modern age, though surely higher tech than the eras that came before, is still not up to the task of medical miracles on demand. Human biology remains far too complex for our minds (and our computers) to comprehend.
That said, this is an exciting moment. On April 30, the World Health Organization posted an up-to-date inventory of Covid-19 vaccine initiatives. The list included eight trials — half of which are in China — currently enrolling human volunteers, and 94 trials still in pre-clinical development.In addition, health agencies, pharmaceutical and biotech companies, and researchers have pledged to collaborate closely across countries and scientific communities.Before digging into the vaccine list, a quick terminology review: The starting place for a clinical trial is “Phase 1,” which is designed only to assess product safety. If there is no evidence of danger, the product progresses to “Phase 2” to determine whether the disease responds to the new product. If things look good, the last is “Phase 3,” usually a large randomized trial involving thousands of people to determine safety and efficacy at long last.Of the eight trials currently enrolling volunteers, only three are in Phase 2. Of these, only the “Oxford Trial” (a Phase 1/Phase 2 hybrid) from the United Kingdom has prevention of Covid-19 infection, rather than a laboratory result, as the primary desired outcome.Why? The Oxford team has the odd advantage of conducting the trial in Britain, where rates of infection are still high. Germany and China, however, lack sufficient cases to accurately test vaccine efficacy. And since ethical constraints prevent scientists from infecting participants with a serious disease, a consortium of German, Chinese and American companies are developing a product currently being tested only in Germany, that instead uses surrogate markers — antibody measurements — against the virus. Teams will examine both the amount and duration of antibodies against the disease created in response to the vaccine.
These groups have benefited from extensive experience in the field of vaccine development. They already have worked out certain techniques and theories, giving them a substantial head start — a screaming endorsement for the long-term value of research that may not seem immediately pressing. As we now see, what may seem like an interesting but obscure pathogen today may be the cause of a pandemic tomorrow.
Though many teams are working toward a vaccine, many roadblocks have been developed to intentionally slow the process in the name of safety. The history of vaccination has cast a long, dark shadow of side effects, both real and imagined. Injecting foreign material into people hoping that it will trigger a specific reaction without stirring up anything else is a medical high-wire act that has come to seem routine. It is anything but, as the history of vaccines — and vaccine discontinuation — attests.There is another potential pitfall as well: a worry that the vaccine might make the infection more severe.This is more than just theory. For decades, dengue fever, a viral infection common in tropical climates, has been known to cause a much more severe infection the second time certain people develop the disease.Many clinicians believe this phenomenon may occur after other respiratory infections — including coronavirus — though thorough investigation similar to the dengue work has not been done. Indeed, the increased severity of the “second wave” of the 1918 Spanish Flu, with the predominance of fatalities in younger people, may have been due to hyper-inflammation, perhaps due to previous influenza exposure.
Thus some experts fear that if a Covid-19 vaccine does its job provoking the immune system, the body could go into a destructive overdrive when exposed to the actual virus.
This is a doomsday scenario to be sure, but one that is giving the scientific community substantial pause as the world rushes headlong toward a vaccine. Veteran vaccinologists remain haunted by past missteps and are speaking up; indeed, placing the focus on caution, not speed, is the plea of many who have been through this before.
The appropriate balance of urgent need against patient safety, they all agree, can be accomplished with thorough screening of volunteers and monitoring not only symptoms but markers of immune activity and over-activity. Regulatory involvement to aggregate any adverse events across a large study population also will be necessary to detect any early clusters of unexpected symptoms.
In many ways the new “hurry versus slow down” tension over vaccine development exactly recapitulates the “anti-lockdown versus shelter-in-place” conflict: one side desperate to return to life before the pandemic at any cost and the other arguing that safety must always come first.
And curiously, President Donald Trump’s bromide that the cure must not be worse than the disease, while completely misguided for the issue of shelter-at-home, is on target for vaccine development. Because the only thing worse than no vaccine during a pandemic is a vaccine that makes matters worse.