August is National Immunization Awareness Month, a time to reflect on the importance of vaccinations and ongoing vaccine research.
Vaccines are among the most important weapons in the public health arsenal. They have significantly reduced the occurrence of preventable infectious diseases like measles, diphtheria, whooping cough and more recently, coronavirus. Like the history of clinical research, their development follows a complicated trajectory that reminds us of just how far we’ve advanced in safety and informed consent.
10 Milestones in Vaccine Research
Early Attempts At A Smallpox Vaccine
In some ways we "owe" vaccination to one particular viral scourge: Smallpox. Caused by the variola virus, smallpox was highly contagious and had about a 30% mortality rate. Many who survived this infectious disease were left with permanent scars, or pockmarks, especially on their faces. Others were left blind. The heavy pale makeup you often see in Medieval and Renaissance paintings was designed to hide smallpox scars.
As horrible as smallpox was, people typically only suffered from it once in a lifetime.
The idea of giving somebody a mild case of smallpox so they would develop immunity appears to have first been put into practical use in China in the 1500s. Smallpox scabs were dried up and blown into the nostrils of children.
This was not vaccination as we know it today, but an older technique called variolation — a controlled exposure to the disease-causing agent. It's also called inoculation, a term we still use to describe vaccines.
Jenner and the Milkmaids
In the 18th century, the idea of variolation spread to Europe, although Europeans preferred to make a puncture in the skin. Sometimes it worked. Sometimes it killed the patient. Sometimes it even caused an outbreak. But the death rate was under 2%, and many considered this a reasonable risk to take with themselves and their children.
Enter Edward Jenner. Jenner was not the only person to notice that milkmaids seldom caught smallpox, but he was the one who took action. It turned out that milkmaids tended to catch a zoonotic disease called cowpox from their charges. Cowpox produced much milder symptoms. Cavalry officers also enjoyed protection from catching another related disease known as horsepox. It seemed that the two diseases were similar enough that catching one gave you immunity to the other.
The concept of informed consent wasn’t widely practiced in the 18th century, so Jenner intentionally exposed a child to cowpox and then tried to infect him with smallpox. It wasn’t until 1974 that proper protection for human subjects was enshrined into law in the United States.
By today’s standards, Jenner’s approach was clearly unethical, but it worked, and intentional cowpox infection became the standard for protecting people from smallpox. By 1801, 100,000 people had been vaccinated. Initially, vaccination was performed by getting a cowpox victim to donate pustule from their sores, but later the vaccine was grown in cows.
This is also the origin of the word vaccine, which comes from the Latin “vacca” for cow.
Further development and global distribution of a smallpox vaccine continued for another century and a half, led by the World Health Organization, until the disease was declared eradicated in 1980.
The Arrival of Live Attenuated Vaccines
With cowpox and smallpox, we got oddly lucky. The majority of diseases don't have a convenient animal analog we can infect ourselves with. For a long time, smallpox remained the only common disease against which people were vaccinated.
Then came Louis Pasteur, the scientist who discovered pasteurization.
Pasteur started with anthrax, and the idea was to weaken, but not kill the pathogen by exposing it to oxygen and heat. The weakened pathogen would trigger an immune response while giving mild or no symptoms.
Live attenuated vaccines are still used today, although they can cause illness in people with weaker immune systems. For this reason, the research community moved on to killing the pathogen entirely. However, for some diseases, the greater effectiveness of live attenuated vaccines is worth the risk. Clinical researchers need to take all of this into account.
The Live vs. Inactivated Polio Vaccine
One quiet triumph of 2020, buried under all the bad news about COVID-19, was the final elimination of wild polio from Africa. Polio is a debilitating disease that often leaves survivors disabled for life. It's caused by one of three different viruses, and while most sufferers only experienced mild symptoms, 1 to 2% developed paralysis. US President Franklin Delano Roosevelt is perhaps the most famous victim of paralytic polio. A vaccination against polio was considered a major goal in the 1940s, and the first to achieve it was Jonas Salk, who used a killed vaccine.
In 1954, however, something unprecedented happened. One million children were enrolled in a clinical trial. This was the first vaccine trial to implement what we now consider the gold standard: the double-blind, placebo-controlled trial. The vaccine was approved the following year; however, more than 250 new polio cases were traced back to faulty batches of the Salk vaccine. The Cutter incident, as it became known, resulted in tightened safety precautions, and harkened back to the days when the FDA's primary role was to prevent adulteration of drugs. Since then, the Salk vaccine has not caused any cases of polio.
In 1962, Albert Sabin produced another polio vaccine, which consisted of a live virus that could potentially cause the disease in rare cases. There was a key difference — it was an oral vaccine stored at room temperature, and it was cheap and easy to produce. He donated it to developing countries and, despite the small risk of paralysis, it was instrumental in the slow eradication of polio. In the US, however, the Sabin vaccine was discontinued in 2000 and now only the Salk vaccine is used.
Swine Flu and Guillain-Barré Syndrome
In 1976, we had a potential pandemic when a version of swine flu began to spread. Health care officials quickly came into action, and over 40 million people ultimately received a vaccine.
However, researchers later discovered an increased risk for Guillain-Barré Syndrome, an immunological condition that causes damage to nerve cells, muscle weakness and potential paralysis, among some people who had received this influenza vaccine. Although the risk was low (about 1 in 100,000 cases), it was enough to stop the program.
Since then, vaccines have been carefully monitored for side effects. Several studies have demonstrated that while the flu shot carries with it a small risk of GBS, it's about 1 to 2 additional cases per million vaccine doses. GBS is more likely to happen after getting the flu than getting the vaccine, but the Centers for Disease Control and Prevention continue to monitor flu vaccines for any potential side effects. This is a vital part of ensuring the safety of any new vaccines as well. Vaccines have to be held to particularly high standards because they are given to so many healthy people.
Development of a Vaccine Schedule
Physicians began recommending some childhood vaccines, including diphtheria, tetanus and pertussis (DTaP), as early as the 1940s. However, it wasn’t until 1995 that the medical community officially endorsed a vaccine schedule for children beginning at infancy. The Advisory Committee on Immunization Practices, American Academy of Pediatrics and the American Academy of Family Physicians approved these guidelines and continues to review them annually. The National Vaccine Program Office also plays a crucial role in overseeing adult immunization efforts and coordinating various vaccination recommendations and programs.
The current schedule, updated in 2014, recommends a dozen different vaccinations, including the diphtheria, tetanus and acellular pertussis vaccine (DTaP), along with a measles vaccine combined with vaccines for mumps and a rubella vaccine (MMR). The MMR vaccine has undergone significant historical development and updates to its vaccination schedules. The CDC’s vaccine schedule also recommends FDA-approved vaccines for many other infectious diseases, including:
- A rotavirus vaccine
- A Hepatitis B vaccine
- A pertussis vaccine (whooping cough)
- Tetanus vaccines
- A pneumococcal vaccine
- Human papillomavirus (HPV) vaccines
- Meningococcal and Meningococcal B vaccines
- Vaccines for respiratory syncytial virus (RSV)
- Influenza vaccines
- COVID-19 vaccines
The pneumococcal vaccine was introduced in 1977 and expanded for adults in 2016, according to the FDA. The HPV vaccine, specifically the Gardasil HPV vaccine, has received FDA approvals and CDC recommendations for cancer prevention.
COVID-19 and Operation Warp Speed
The coronavirus pandemic brought about a federal initiative to deliver a vaccine in record time. Emergency rooms had become inundated with COVID-19 patients suffering serious side effects from the virus.
Prior to 2020, the record timeline for vaccine development was four years for the mumps vaccine.
More than a dozen pharmaceutical companies raced to conduct clinical trials for a COVID-19 vaccine. During this time, Remington-Davis supported treatment trials with antibody infusions or anti-viral agents, helping sponsors quickly recruit infected patients or patients who had been exposed, administer investigational drugs, and monitor patients for any adverse conditions. In one particular study, we set up an independent COVID research clinic with six IV infusion rooms, staffed with nurses who had to follow strict protocol to protect themselves.
Our proximity to The Ohio State University campus proved to be beneficial for recruitment purposes, as we created yard signs asking for COVID-positive patients located near drive-through testing centers. Between July 2020 and February 2021, we saw 236 patients, contributing to clinical research that ultimately helped sponsors secure approval for emergency -use vaccines. Since then, the FDA has approved five COVID-19 vaccines.
mRNA Vaccine Technology Expansion
Messenger RNA (mRNA) vaccine technology, which gained prominence with COVID-19 vaccines, has rapidly expanded into other areas. Research has shown the potential of mRNA vaccines to address various infectious diseases and conditions beyond COVID-19. In 2023, several major mRNA vaccine trials were initiated, targeting influenza, genital herpes, and melanoma. The success and rapid development of COVID-19 mRNA vaccines have laid the groundwork for these new applications, showcasing the technology's flexibility and effectiveness.
Combination Vaccines for Respiratory Diseases
The development of combination vaccines, especially for patients with chronic obstructive pulmonary disease (COPD), represents another significant advancement. These vaccines aim to combine immunizations for influenza, respiratory syncytial virus (RSV), and COVID-19 into a single shot. This approach is expected to improve patient compliance by reducing the number of injections required, thereby increasing vaccination rates and decreasing preventable infections.
Decentralized and Hybrid Clinical Trials
The pandemic has accelerated the adoption of decentralized clinical trials (DCTs), which leverage telemedicine and remote monitoring technologies. This model has proven beneficial for maintaining patient engagement and flexibility, especially in hybrid trial designs that combine in-person and remote methodologies. The rise of DCTs reflects a broader trend towards patient-centric trial designs, which are more convenient and accessible for participants.
Remington-Davis' Contribution to Vaccine Research
As an independent clinical research site in Columbus, Ohio, Remington-Davis stands at the forefront of vaccine research. Our team includes specialists in pulmonology, critical care medicine, dermatology, endocrinology, and other key areas, providing a comprehensive approach to clinical trials that enhances the quality and scope of research outcomes while ensuring vaccine safety. This fall, we are conducting vaccine trials for a combination flu/COVID vaccine, RSV/hMPV combination, and Norovirus. We have an ongoing vaccine trial for e. coli infections and have 55 subjects randomized to date.
We are uniquely positioned to attract a diverse patient population and collaborate with physicians who have specialized expertise. Our facility is easily accessible to both participants and researchers, and we have experience in both on-site clinical trials and decentralized trials.
Contact us today to learn more about how we can support your next clinical trial.