In the 1940s Cohn and colleagues developed a relatively straightforward chemical process for fractionating human blood into many of its significant component proteins, thus enabling the production of the first immunoglobulin concentrates (although suitable for intramuscular use only). In the following decade, Bruton and others recognized the genetic basis of various types of primary immunodeficiency syndromes and further characterized them. These two discoveries allowed for the regular treatment of patients using replacement infusions of human immunoglobulins and the concomitant improvement in quality of life and, ultimately, survival. Subsequently, specific immunoglobulin preparations were produced for treatment of or prophylaxis against specific pathogens such as hepatitis B, polio, tetanus, and pertussis. All of these so-called hyperimmune globulins were administered by the intramuscular route.
It became quite clear that this means of administration was not adequate for both the provider and the patient. Injections were quite painful; doses were limited in size and frequency; muscle proteases degraded much of the infused immune globulins; and the remaining protein reached the circulation only after significant delay. Attempts to inject material directly into the vasculature proved to be dangerous, and occasionally catastrophic, apparently as a result of the IgG aggregates that formed as part of the fractionation process. Subsequent developments employing first partial enzyme digestion (using proteases such as pepsin and papain) and then improvements in the fractionation process allowed for the ultimate production of true intravenous immunoglobulin (IVIG) concentrates.