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The Poliovirus Puzzle

During the years leading up to the development of the polio vaccine, scientists actively debated whether a killed/inactivated virus could induce sufficient immunity to protect against polio infection. While inactivated virus vaccines for influenza were by 1945, multiple failed to demonstrate protective effects when tested in primates and humans. The disease's unusual presentation and unique pathogenesis bred confusion, and conflicting study results lead scientists in different directions.

The problem was in part that scientists did not have a firm understanding of where the poliovirus replicated within host tissue. Preliminary evidence pointed simultaneously to the gastrointestinal tract, respiratory tract, and the central nervous system, which made establishing a vaccine delivery system difficult.

The work of 2 scientists helped to resolve these debates and facilitated the development of both an oral vaccine formulation and a killed/inactivated microbe-based vaccine. Amongst many other celebrated scientists and physicians, the works of of Johns Hopkins University and from Yale University were paramount to the vaccines' success.

Polio was a significant and widespread concern throughout the early lives of Morgan and Horstmann. Both scientists were born in 1911, just a few years before the in the °®¶¹´«Ã½ States, which resulted in approximately 6,000 deaths and thousands of cases of paralysis. To this day, there is no cure for polio and prevention via vaccination is the only effective defense against disease transmission.

Polio is a highly infectious viral disease that can affect a variety of organ systems, including the central nervous system (CNS). Polioviruses are enteroviruses, which are single-stranded RNA viruses transmitted via the fecal-oral route. , poliovirus infects and replicates within the mucosal epithelial cells of the gastrointestinal tract, eventually spreading throughout the bloodstream. This viremia facilitates access to the CNS, allowing it to replicate within motor neurons, causing lesions that lead to paralysis in around 1% of cases. If the motor neurons that control breathing are destroyed, the patient will need to live inside an iron lung—a negative-pressure mechanical ventilator that resembles an and encases the entire body. The potential for developing disabling sequelae caused polio to become one of the most feared infectious diseases of the time, until the advent of preventative vaccines.

Understanding Host Immunity to Poliovirus

Among the many scientists engaged in the fight against polio was Isabel Morgan. Morgan's research focused on the development of immunity to polio viruses, using a primate infection model. Her work led to the discovery that poliovirus includes : type 1, type 2, and type 3, all of which are considered wild-type viruses and must be incorporated as vaccine components for infection prevention. Previously tested inactivated vaccines in the 1930s consisted of , which contributed to their ineffectiveness. Morgan's discovery was a crucial turning point in understanding host immunity to polio, as polio vaccines containing only 1 virus subtype would not offer complete immunity against the infection.

also focused on developing a killed-virus for use in vaccinations. Morgan tested this hypothesis when she transferred antibodies from monkeys injected with killed-virus into healthy monkeys and challenged them with live polio virus. In doing so, she determined a threshold amount of inactivated virus inoculum was needed develop protective immunity, requiring  . Since boosters are generally unnecessary when using live vaccines, which were better understood at the time, researchers had not yet tried multiple dosings. Morgan's findings explained why you need of the inactivated polio vaccine. Her work also validated an existing method for inactivating the virus using formalin, later used by Salk, and she experimented with a mixture to enhance antibody response. These were significant breakthroughs in polio vaccine development, as killed virus vaccines are easier to produce and are more stable, providing advantages for large-scale manufacturing and distribution.

Morgan in 1949, before her inactivated vaccine could be tested in human clinical trials. Even today, every clinical trial presents unpredictability and has potential for unforeseen side effects. Morgan felt uneasy about the risks associated with first-in-human trials, and left her research position to start a family. Despite her departure, her discoveries promoted significant advancement in the development of inactivated polio vaccines. Jonas Salk's inactivated virus vaccine was available just 2 years after Morgan's discovery and is still used today. She is recognized for her accomplishments on the , located in Warm Springs, Ga.

Poliovirus' Infectious Journey

The mechanism for person-to-person transmission of polio presented another mystery and hotly contested question in the early 20th century, as clinical signs and symptoms of the infection could be highly heterogeneous. Why were some carriers of the disease asymptomatic or had only mild flu symptoms, while others developed paralysis? Many patients lacked detectable poliovirus in their bloodstreams, creating a puzzling barrier to developing a vaccine. The leading research at the time suggested that polio was transmitted intranasally and infected CNS tissue exclusively. This misleading conclusion was the result of researchers accidentally evolving a neurovirulent strain of the virus by multiple times. The resulting strain was so well-adapted to primate CNS tissue that it was no longer able to infect other cell types, which was not true of the wild-type circulating polioviruses. Monkeys, the animal model at the time, inoculated with poliovirus intranasally would show exclusive CNS involvement by this neurovirulent laboratory strain of poliovirus. This animal model and lab-adapted viral strain had resulted in the widely-held belief that polio was acquired via the respiratory tract.

that an alternate source of transmission existed. To test this, they of polio patients, including the nasal passages, pharynx, blood, and gastrointestinal tract. Samples taken over the course of 2 weeks of infection revealed some surprising results: fecal samples contained poliovirus throughout the 2 weeks tested, whereas fluids from the pharyngeal tract were inconsistently or transiently positive. These findings were the first indication  that the GI tract was likely a significant site of viral transmission and/or pathogenesis.

Horstmann built upon these findings to support the use of oral vaccination routes by further elucidating the "journey" of the poliovirus throughout the body during infection. Horstmann's study of blood obtained from 111 patients with suspected polio infection showed that only 1 sample, from the only patient in the study without paralysis, contained virus, whereas all 110 paralyzed patients had negative blood cultures. Horstmann found this outlier intriguing and designed a series of experiments in primates orally infected with poliovirus. She was only able to detect poliovirus in the primate bloodstream before the paralytic symptoms began, within 4-6 days after initial oral inoculation. Collectively, Horstmann's discoveries helped to reveal the stepwise process of polio pathogenesis from infection to transmission. While Horstmann did not directly collaborate with Albert Sabin, her discoveries paved the way for the development of an oral vaccine, which allows for immunity to develop in both the blood and GI tract. While many oral vaccines were in development during the late 1940s and early 1950s, Sabin's live-virus oral vaccine rose to prominence, as it showed in a primate model in comparison to others.

Both the Sabin and Salk vaccines are still in use today, with the U.S. only . Many other countries use the easily-administered, inexpensive, which is convenient for use in community vaccination campaigns in medically-underserved regions. On a global scale, polio prevention programs, which focus on vaccine access and administration, have been largely successful in eliminating polio from most countries.

These stories highlight the discoveries of women in science history, but women in science today continue to play a crucial role in eradicating polio by serving as outreach coordinators and advocates for vaccination in developing countries. Nigeria is one of 3 nations with active polio outbreaks, and Nigerian women are currently to increase education and participation in vaccination programs, achieving a notable decrease in the incidence of polio outbreaks.

Morgan's and Horstmann's discoveries represent significant accomplishments from women in science, who were significantly underrepresented in the field at that time (and still are, though and are actively making strides to ensure that women in microbiology are represented as speakers and leaders). It will be up to the next generation of scientists, including many talented and accomplished women, to lead the development of innovative solutions and preventative measures to diminish emerging threats to public health.