May 29, 2020

Credit: Jub Rubjub / Getty Images

Opinion

Anxiety about the likelihood and timeliness of a COVID-19 vaccine seems to be spreading more rapidly than the virus itself, as evidenced by irrationally exuberant rises and falls in financial markets. But we can look to history and readily find a powerful reflection of our current dilemma from more than a century ago, as well as a potential path forward. 

Moving quickly is essential, as we must prepare for a dreaded “second wave” in the autumn, by which time a vaccine will not yet be available. Such a treatment not only exists but is growing in supply with each passing day. This treatment might prove especially invaluable were COVID-19 to prove non-responsive to vaccines.

To understand the context, it is necessary to look both forward and backwards. In 1890, a pair of young scientists, a German and a Japanese, partnered to overcome one of the most dreaded and lethal killers the world has ever known. In the days after Christmas, this murderer would sneak into cities and choke to death as many as one in ten children. The assassin ravaged Spain in 1613, a year forever memorialized as the Year of Strangulations (El Año de los Garrotillos), an outbreak so devastating it continued to inspire the art of Francisco de Goya nearly two centuries later. This killer was not anonymous, instead leaving behind an infamous calling card: a leathery, gray coating on the inside of the throat, nose and tonsils. A French scientist recording an outbreak in the mid-nineteenth century invoked the Greek term for leather, diphthera, to describe the disease, a name that has remained largely unchanged to this day.

In 1883, the killer was finally cornered, a microorganism known for a time as the Klebs-Loeffler bacterium (now Corynebacterium diphtheriae). Although an important fundamental scientific breakthrough, this finding provided scant help to physicians combating the disease. The pioneering work did however prove an inspiration to two men whose rivalry reflected the animus of their native lands. In 1888, a Paris team led by Louis Pasteur announced the discovery of a toxin produced by the deadly bacteria. Months later, two scientists working in the Berlin laboratory of Robert Koch responded with a discovery that would help contain the Spanish strangler.

Emil von Behring and Baron Kitasato Shibasaburō (both would earn their honorary titles for this work) found that heating diphtheria toxin would render it harmless. The inactivated toxin (known as a toxoid) could then be used to immunize horses and other animals to produce a substance (an antisera) to treat diphtheria. Today, we know the diphtheria antisera is composed of antibodies, the guided missiles of the immune system. Whereas a vaccine elicits the production of antibodies (active immunity), therapeutic administration of antibodies themselves can be used when there is no vaccine or is insufficient time to await a vaccine. This approach is known as passive immunity.

Within months of their discovery, Behring and Kitasato had shown that passive immunity with horse antibodies could save the lives of children infected with diptheria. By 1900, the health departments in a handful of the most progressive American cities were producing diphtheria antisera to protect their youngest citizens. The approach suffered a catastrophic setback in 1901, when a horse named “Jim” used to produce diphtheria antisera for the city of St Louis unknowingly was contaminated with tetanus, an unrelated bacterial infection. As a result, ten children died. A local newspaperman, Joseph Pulitzer, spread word of the calamity throughout his national publishing empire, raising public ire and forcing the regulation of antisera production by a small laboratory that would evolve into the organization today known as the National Institutes of Health (NIH).

Today the NIH is leading the fight against COVID-19, and one of the most promising approaches is a throwback to the late nineteenth century. Patients who have recovered from COVID-19 often have antibodies that can inactivate the SARS-CoV-2 virus. The number of recovered patients is growing by the day, and each patient could serve a role analogous to the thousands of horses injected with toxoid more than a century ago.

To date, more than 10,000 patients have been transfused with convalescent plasma according to Jeffrey Henderson, a physician, who leads such studies at Washington University in St Louis. Throughout their investigation, convalescent plasma has proven quite safe, which is consistent with an early report from the Mayo Clinic. Any evidence of efficacy is purely anecdotal but the results, according to Henderson, are quite encouraging and ‘case-controlled studies should come out any day now.’

Advances in biotechnology have provided opportunities to make the antibodies from this “convalescent serum” safer and more effective. For one thing, pathogens that might cause a repeat of the St Louis disaster can be eliminated with technologies now routinely used to clean the nation’s blood supply.  Currently, universities across the nation are testing convalescent plasma programs to combat COVID-19. The 2014-15 campaign against Ebola virus in West Africa likewise included the use of convalescent sera treated to inactivate potential pathogens. These treatments could increase the availability of convalescent plasma from perceived high-risk groups, who have volunteered but been turned away from helping in the fight against COVID-19.

Over a longer term, recombinant DNA technologies could allow us to isolate and mass produce the most beneficial antibodies from convalescent plasma. To this end, companies with expertise in deriving monoclonal antibodies from patient blood have already announced early successes.

These results are heartening, revealing opportunities to combat SARS-CoV-2 in both the short term and to provide a much-needed back-up, should vaccines prove a disappointment. Convalescent plasma is growing in supply, and pathogen inactivation should make this material safe and abundant. Importantly, this material is ready to use. Over the longer term (a year or two), monoclonal antibody products could similarly be deployed. By layering our defenses against this deadly virus, we can more assuredly prevail over COVID-19 and return to a greater sense of normalcy. By gaining greater familiarity with these ideas, old and new, we can be better prepared to prevent future pathogens from disrupting our world.

Michael Kinch, associate vice chancellor and director of the Center for Research Innovation in Biotechnology at Washington University in St. Louis, is the author of “Between Hope and Fear: A History of Vaccines and Human Immunity.”

science, opinion, commentary, vaccines, science and tech, Michael Kinch, editorial

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