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History of Typhoid Vaccine: The Journey to Overcoming a Deadly Disease

This photomicrograph illustrates histopathological alterations induced 

by Salmonella enterica serovar Typhi infection in liver tissue.


The development of a typhoid vaccine has been a long and arduous journey, spanning over a century of scientific exploration, setbacks, and breakthroughs. The story of this vaccine's evolution is a testament to the perseverance and dedication of countless researchers who sought to conquer this deadly disease.


Key Takeaways

  • Typhoid fever was a major scourge in the 19th century, with key discoveries made regarding its clinical symptoms, mode of transmission, and causative agent (Salmonella typhi).

  • The first typhoid vaccine was developed in 1896 by Almroth Wright and Richard Pfeiffer, using heat-killed, phenol-preserved bacteria.

  • Typhoid vaccination remains crucial, especially for travelers, as the disease still causes over 21 million cases and 200,000 deaths annually in endemic regions.


The Scourge of Typhoid Fever Before Vaccines

Before the advent of vaccines, typhoid fever was a dreaded disease, causing symptoms like fever, stomach pains, weakness, and headaches in most of its victims. 


About 10 to 30% of the patients died of complications such as intestinal bleeding and perforation. Those who survived often returned to communities teeming with more typhoid carriers.


Typhoid has been a bane to humanity throughout recorded history, known by different names like "putrid fever" and "morbus lenticularis." 


In the absence of knowledge about microorganisms, the disease was attributed to miasma, filth, and foul air emanating from decay. Typhoid thrived wherever clean water and effective sewage treatment were absent, persisting even in the urban slums of the early 20th century.


  • Early History of Typhoid Fever


Typhoid has likely plagued humanity across the ages, with some historians proposing it was behind the 430 BC plague that killed a third of Athens, including its leader Pericles. Records also suggest over 6,000 Jamestown settlers perished from 1607 to 1624 epidemics, eliminating the fledgling Virginia colony.


  • Typhoid Fever During the 1800s


Military forces were especially hard hit by waves of typhoid fever. Over 80,000 Union and Confederate soldiers died of typhoid or dysentery during America’s Civil War. The 1898 Spanish-American War also saw major typhoid infections in training camps and abroad.


  • The Notorious Typhoid Mary of the 19th Century


One notorious asymptomatic carrier, cook Mary Mallon (known as “Typhoid Mary”), is thought to have infected 51 people while working in New York, killing three. Forcibly quarantined off and on from 1907 to 1938 to prevent spread, Mallon’s tragic story demonstrated challenges managing highly contagious illnesses long before modern disease control measures.


Early Discoveries on Typhoid Fever

In the late 19th century, typhoid fever was a scourge that plagued many parts of the world. It was during this time that significant strides were made in understanding the disease:


  • In 1829, P.C.A. Louis in Paris described the clinical symptoms of typhoid fever and associated them with lesions found in the intestines, mesenteric lymph nodes, and spleen.

  • In 1873, Budd's research demonstrated that water contamination, primarily through bowel discharge, is a major mode of transmission for typhoid fever, highlighting the importance of sanitation in preventing its spread.

  • In 1880, Karl Joseph Eberth identified the causative agent, Salmonella typhi, from a patient's tissue sample, marking a pivotal moment in the fight against typhoid fever.

  • In 1884, Gaffky further confirmed the discovery by cultivating and isolating Salmonella typhi (S. typhi) in pure culture from the spleen of typhoid patients, providing concrete evidence of its role in the disease.


The Birth of Typhoid Vaccination

These discoveries paved the way for the development of the first typhoid vaccine, which was a joint effort by two pioneering scientists:


  • In 1896, Almroth Wright, a British researcher, reported the use of a heat-killed, phenol-preserved typhoid vaccine in human trials, demonstrating its potential for protection against the disease.

  • Around the same time, German scientists Richard Pfeiffer and Wilhelm Kolle published their work on prophylactic vaccination against typhoid fever, showcasing the protective antibodies present in the sera of recovered patients and experimentally infected animals.


While a debate ensued over who deserved the credit for this groundbreaking discovery, it is now widely accepted that both Wright and Pfeiffer played crucial roles in the development of the first typhoid vaccine.


Evaluating Efficacy and Improving Formulations

As the 20th century dawned, the use of typhoid vaccines became more widespread, particularly among military personnel involved in various conflicts. However, their efficacy remained a subject of debate, with some outbreaks occurring even among vaccinated troops, raising doubts about the vaccine's effectiveness.


To address these concerns, the World Health Organization (WHO) sponsored a series of controlled field trials between 1960 and 1970. These trials compared various formulations of killed whole-cell vaccines, including heat-inactivated, phenol-preserved, alcohol-inactivated, and acetone-inactivated preparations.


The results of these trials were pivotal, demonstrating the superior efficacy of the acetone-inactivated vaccine (known as the "K" vaccine) over the heat-phenol inactivated vaccine (the "L" vaccine). The K vaccine showed protection rates ranging from 79% to 88%, while the L vaccine offered protection rates between 51% and 66%.


The Emergence of Vi Polysaccharide Vaccines

Despite the efficacy of whole-cell killed vaccines, their poor tolerance prompted researchers to explore alternative formulations. One promising candidate was the Vi polysaccharide, a capsular antigen of S. typhi recognized as a potential immunogen.


In the 1970s, researchers were able to purify the Vi antigen in a non-denaturing manner, paving the way for the development of the first chemically defined parenteral vaccine candidate against typhoid fever.


This vaccine, known as Typhim Vi, underwent successful clinical trials and was found to confer about 65% protection against typhoid fever for at least two years after a single 25mg intramuscular dose.


Live Attenuated Mutants: An Oral Alternative

In recent decades, researchers have explored the potential of live attenuated mutants of S. typhi as an alternative approach to typhoid vaccination. The rationale behind this approach is that administering live, attenuated strains orally could elicit strong mucosal immunity, as the portal of entry for typhoid fever is the intestinal mucosa.


One of the pioneering efforts in this area was the development of the galE mutant strain Ty21a by Germanier and Furer in 1975. This strain, obtained through chemical mutagenesis, showed promising results in field trials, with an outstanding 96% protective efficacy observed in a study involving children in Egypt.


However, subsequent studies with Ty21a highlighted the importance of formulation and dosing, with varying levels of protection observed in different trials. This led to the search for new attenuated vaccine candidates, including genetically engineered strains with precise attenuating mutations targeting regulatory pathways or auxotrophic mutations.


Among the most promising candidates is the CVD908 strain, an auxotrophic mutant of S. typhi Ty2 strain with aroC and aroD mutations. 


While showing promising results in terms of safety and immunogenicity in volunteers, further fine-tuning and optimization are still required for this and other live attenuated candidates.


Typhoid Vaccines Currently Available

In 2023, the CDC recommended typhoid vaccinations for travelers visiting regions where the illness is endemic or epidemic. Prevention through vaccination still plays a vital role curtailing transmission.


Two types of typhoid vaccines approved for use in the U.S. include:


  • Injected Vi-capsular polysaccharide (ViCPS) vaccine: Given as a single dose by injection, efficacy is around 55-75%. Protection may last for 2 years initially but can decrease to 50% thereafter without a booster. This can be administered to those 2 years and older.


  • Oral live attenuated Ty21a vaccine: Taken in enteric-coated capsule formulation in four spaced doses for optimal effect. Efficacy reaches nearly 90% with protection lasting 5 to 7 years. Due to the live bacteria, it shouldn’t be given to immunocompromised individuals. Approved for those 6 years or older. 


Get Vaccinated Against Typhoid Fever Before You Travel

Widespread vaccination, sanitation infrastructure, and access to healthcare have greatly reduced typhoid’s impact in industrialized nations. But the disease persists globally with over 21 million cases and 200,000 deaths occurring annually.


To keep yourself protected against Typhoid fever and other travel vaccinations, Away Clinic offers convenient services. With locations in Scottsdale, Phoenix, and Chandler, they provide yellow fever vaccines, Japanese encephalitis, and other rare-to-find vaccines, as well as offer competent advice on recommended vaccinations for your destination and ensure you’re safe before your upcoming voyage.


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