Horses for courses – an introduction to passive immunity

Setting it Straight - Issue #5

Written by Nobel Laureate Professor Peter Doherty

While there’s great biomedical science in every Australian capital, the Parkville Precinct – or the Melbourne Biomedical Precinct as it’s formally known – may be our most concentrated “research engine”.  The tiny residential suburb of South Parkville is separated from the University of Melbourne by Royal Parade, the elegant avenue that’s the final kilometres of the old Sydney Road. Transitioning again at the Royal Parade/Grattan Street intersection, the four corners that see the beginning of Elizabeth Street anchor the University of Melbourne Medical School, The Royal Melbourne Hospital, the Victorian Comprehensive Cancer Centre housing Peter Mac and the Doherty Institute.

Two blocks west of Royal Parade, the Parkville street where Phyrne Fisher (of the ABC’s Miss Fisher’s Murder Mysteries) has her mansion ends near an imposing brick wall that, commemorating Melbourne’s 1850’s-1930’s Horse, Hay and Corn Market, features a prominently protruding, sculpted horse’s head. Carthorses and carriage horses, which burned around 15 kilograms of hay a day, were central to the life of any city in the pre-automobile era. That north market wall, with its high-mounted horse-head, now borders a campus including part of the Veterinary School, the great Walter and Eliza Hall Institute and the Bio21 Institute.

Bio21, which co-locates university biochemists with high-tech industry, hosts a research hub for the global CSL Behring Biotech company. Formed in 2007 as part of the Australian CSL group of companies, a merger brought together elements of the Commonwealth Serum Laboratories (CSL), which was founded in 1916 and listed on the ASX as CSL Ltd in 1994, and Behringwerke (founded 1904). Horses are central to both stories. That narrative starts in the late 19th century at two great, and enduring Berlin institutions, the Charite’ Hospital and the Robert Koch Institute. As is the case for physician/scientists of today, German medical doctor and researcher, Emil von Behring, split his early working life between patient care and medical science.

On Netflix, forget Ozark or Peaky Blinders and be informed by Season 1 of Charite‘. This tells how Behring and his colleagues, who included Shibasaburo Kitasato and Paul Ehrlich (I’ll write about them later), injected (immunised) horses with an attenuated (weakened) strain of the bacterium Corynebacterium diphtheriae then used horse immune serum (antitoxin) obtained after a month or more to save patients choking to death with diphtheria, where a toxin made by C. diphtheriae causes the upper airways to clog. This was the very first example of immunotherapy.

Prior to that, von Behring and colleagues did the necessary “pre-clinical” testing to show that serum (the straw-coloured fluid phase separated as freshly drawn blood clots in a flask or tube) from immunised guinea pigs, rats or rabbits, could, when injected into other “naïve” animals protect them from a later challenge with the diphtheria toxin. Treating humans requires a lot more serum. Horses are big; the equine jugular vein is like a water pipe, and it’s easy to draw repeated “buckets of blood”.

In 1901, von Behring was awarded the very first Nobel Prize for Medicine. He soon moved to Marburg and founded Behringwerke to produce immune serums and vaccines. Medical Doctor and CSL Chief Scientist (since 2000) Andrew Cuthbertson told me that non Behring’s Marburg site, which came to them via shape-shifting commercial mergers involving the Swiss blood plasma company ZLB and Aventis-Behring, is still part of the CSL Behring operation. Along with the original CSL facility in West Parkville, across the Australian bushland of Royal Park, CSL Behring retains long established operations at Broadmeadows and Woodend. Andrew recalls visiting his uncle, who managed the farm at Woodend that accommodated the big Percheron draft horses used to produce a spectrum of antisera for neutralising, for example, diphtheria and tetanus toxoids, and snake venoms.

Immune sera are therapeutics, not vaccines, though they come from vaccinated animals or immune people. When injected into us they induce a state we call “passive immunity”, which declines over the days and weeks as these “transferred” proteins slowly disappear from our circulation. A major product for CSL Behring is human immunoglobulin (Intragam or IVIg) that, separated and purified from the cellular fractions used for blood transfusion, is the plasma (or serum) provided by Red Cross donors. People, including children, who have defective immune systems are given regular doses of IVIg to protect them from common infections. When we read about the use of “convalescent serum” from recovered COVID-19 patients as a treatment for those who have been recently infected, this is essentially a more “specialised” IVIg that will, in Australia, be produced by CSL Behring.

As I draft this on 29 April, Day of Immunology for 2020, we no longer focus on horses as “serum providers”. Horses served us well in medicine, as they have in other contexts through thousands of years of human history. Now, we mainly use monoclonal antibodies (the “marvellous mAbs”) for immunotherapy. That’s a big story for COVID-19, and it’s where I’ll go next as I continue the story of passive immunity.