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A young smallpox sufferer.

In an age of information overload, where headlines debate vaccine effectiveness and safety, knowledge will shape decisions.

A look at the some of the important milestones in vaccines history provides a foundation for better understanding this complex medical subject. Vaccines, biological preparations that train your immune system to fight infections, literally changed the course of history in the United States.

Smallpox: George Washington mandated that troops must be vaccinated since so many infected soldiers were not fit for duty. Smallpox was a devasting disease, killing up to 30% of infected people. Survivors often became permanently disfigured, bearing severe scars that marked them for life.

A centuries long history of vaccination began in China and India where smallpox vaccinations started in the 1500s. The vaccination was done by scraping pustules containing the active virus and scratching this material into uninfected individuals.

Enslaved people brought from Africa in the 1700s showed vaccination scars indicating that this practice was active in Africa during this time. A smallpox outbreak in Boston in 1721 prompted city-wide vaccination reducing mortality from 30% to 2%. While successful, these vaccinations could be dangerous, so physicians looked for alternatives.

Cowpox causes disease in cattle that may spread to humans causing minimal symptoms. The British physician Edward Jenner observed that cowpox-infected milkmaids did not become infected or seriously ill when exposed to smallpox.

In 1796 Jenner took pustule material from a  cowpox-infected milkmaid and injected this into an 8-year-old boy, James Phipps, who became ill but had a full recovery.

The next year Jenner exposed Phipps to smallpox material and the boy was completely protected.

Obviously, this type of experiment would not be done today, but it did lay the rationale for future studies. Smallpox vaccines created in the 1950s launched successful world-wide campaigns so that the World Health Organization declared smallpox eradicated in 1980.

Rabies: The very word rabies conjures images of dogs or people frothing at the mouth and dying a terrible death with a lethality rate of 100%. The rabies virus infects both the brain and the spinal cord.
Louis Pasteur observed a rabies outbreak in France and created a vaccine by infecting rabbits and removing their spinal cords. The virus was made less lethal by treating the spinal cord with formaldehyde, and this weakened virus prevented rabies in experimental animals.

In 1885 a 9-year-old boy was bitten several times by a rabid dog. The mother heard about Pasteur’s vaccine and brought her son for treatment within two days of being bitten. The rabies vaccine was injected each day for 14 days and the child made a complete recovery. Rabies vaccination centers were quickly set up and within a year Pasteur reported that 350 people were given the vaccine. Only one person died, due to starting the vaccine too late.

The rabies vaccine reduced the lethality rate from 100% to less than 1%. Observant readers will note that this study treated people after they were exposed to the disease while modern vaccines are given to people who do not have the disease.

Cholera: The bacteria Vibrio cholerae causes cholera, an acute diarrheal disease that causes rapid dehydration due to fluid loss, with an untreated mortality rate of 50%. The bacteria secretes a toxin that causes the diarrhea.

A vaccine developed against the bacteria in 1892 treated 40,000 people in Calcutta, India, and successfully reduced cholera mortality. This trial was notable since there was a control group, i.e. a placebo group that did not receive the vaccine.

Toxin vaccines: The Iditarod dog sled race rushed material to a remote Alaska village to save children from diphtheria infections. Toxins from a severe diphtheria infection stimulate inflammatory responses that can block the throat and cause death. Toxins are molecules released by pathogens that cause disease, as described above for cholera.

A new vaccine strategy targeted the toxins instead of the pathogen. For these vaccines, scientists created toxoids, compounds structurally similar to the actual toxin that do not cause symptoms. The immune response to the toxoid cross reacts with the toxin and prevents disease. The diphtheria toxoid was created by treating the toxin with formaldehyde to inactivate the toxin, similar to how Pasteur treated the rabies-infected spinal cords.

Toxins released from the bacteria Clostridium tetani causes tetanus, severe muscle spasms that may include the jaw resulting in “lockjaw.” The tetanus toxin targets the nervous system to cause muscle contractions. Incubating the tetanus toxin with formaldehyde and heat created the toxoid. 

The bacterium Bordetella pertussis causes pertussis, e.g. whooping cough, characterized by intense coughing spells. Coughing spreads droplets that linger in the air, making the disease highly infectious.
Vaccines were created using killed whole bacterial cells that contained the toxins. While effective, these early vaccines had severe side effects so toxoids were created in the laboratory.

Since bacterial cells were not used, this vaccine is termed acellular (no cells) pertussis. Currently the most common vaccine combines Diphtheria, Tetanus and acellular Pertussis, the DTaP vaccine.

Polio: Polio was a highly infectious, dreaded disease where the virus infects the nerve cells in the spinal cord to cause paralysis. In 1955 Jonas Salk created a polio vaccine that was tested on 1.6 million children in the USA, Canada and Finland. The clinical trial gave the vaccine to 1 million children and the placebo to 600,000. More children received  the vaccine compared to the placebo based on data that the vaccine would be effective, so more participants would benefit from receiving the vaccine.

This trial was remarkably effective and widespread vaccination campaigns were launched. The number of polio cases decreased from 58,000 in 1957 to only 161 in 1961.

People no longer receive the polio vaccine in the USA since the disease has largely been eradicated.

Influenza: The influenza virus causes symptoms including chills, fever and fatigue, with severe infections resulting in death.

The 1918 flu pandemic killed 20 to 50 million people across the world. A flu vaccine, tested against a placebo in randomized clinical trials, reduced infections and hospitalizations, leading to approval in 1945.

However, even in modern times the flu kills more than 5,000 people each year in the USA. Since the major strains of the influenza virus frequently mutate new vaccines need to be created each year. 
COVID-19: Most of us either had a COVID infection or know someone who did. The disease CoronaVirus Infectious Disease 2019 (COVID-19) caused a worldwide pandemic beginning in 2020 and 2.5 million people died from COVID infections by 2021.

Operation Warp Speed launched a race to develop and test new vaccines. Scientists built on research started in the 1980s using a technology incorporating messenger RNA (mRNA) for immunization. These new mRNA vaccines showed remarkable ability to prevent infection, hospitalization and death.

Randomized double-blind placebo-controlled trials resulted in vaccine approval in less than one year.

With so many infections rapid approval could be received since it was possible to compare the number of infections in vaccinated versus unvaccinated (placebo) individuals.

This brief history does not describe all of the vaccines currently available. The article is meant to provide a glimpse into the long history of the development, testing and effectiveness of vaccines to improve understanding of how they were created.

Daniel Remick, M.D. is Professor Emeritus of Pathology & Laboratory Medicine at the Boston University Chobanian and Avedisian School of Medicine and former Chair of that Department. Prior to moving to Boston, he was a Professor of Pathology and Assistant Dean of Admissions at the University of Michigan. His research has been supported by grants from the NIH for more than three decades. Dr. Remick grew up in Duluth and graduated from Central High school in 1971.