Greater Expectations

In a small U.S. town of 10,000 people, 250 residents will die each year and 100 of those will be children under 5 years old. Few people in the town will live beyond 50 years old. Of all the children born there, 10% will die before their first birthday and 24% before their 5th birthday.¹ 

This town is not the setting of a dystopian novel or film. Instead, it describes the average mortality rate and life expectancy in the United States in 1900. In that year, five infectious diseases—pneumonia, influenza, tuberculosis, gastrointestinal infections, and diphtheria—caused more than one-third of all deaths, and vaccines existed for only smallpox and rabies.

In its 12,000 years of circling the globe, smallpox alone is estimated to have killed hundreds of millions, including as many as half a billion people worldwide in the 20th century alone. However, the smallpox vaccine was so effective the World Health Organization (WHO) launched its Smallpox Eradication Program in 1959. By 1980, the WHO declared smallpox eradicated worldwide—the only infectious human disease successfully extinguished.

Despite the effectiveness of local and global smallpox inoculation campaigns, for decades, the vaccine provoked fear, ignorance, apathy, and resistance—opposition that continues today against vaccines of all kinds. 

Echoes of old fears

Throughout the smallpox epidemics of the 19^th and 20^th centuries and the vaccination campaigns that accompanied them, opponents of the smallpox vaccine objected to the threats to their personal autonomy and religious beliefs. They railed against perceived governmental and medical tyranny. They created vivid illustrations warning people about one of the imagined dangers of the vaccine: transforming people into part human and part cow.

“The misinformation has been here all along, and it’s never been confined to vaccines,” says Gerald Pier, PhD, a microbiology and molecular genetics researcher in the Division of Infectious Diseases. “The issue of vaccine denial is newsworthy and prominent, but general denial of the utility of modern medicine has been around a long time.”

Today, in addition to denial, fear, and misinformation, apathy is at play. 

“Getting a vaccine isn’t always compelling to people who are generally healthy, especially for the flu or COVID,” says Daniel Solomon, MD, an infectious diseases clinician and educator at the Brigham. “Often, they’d rather take their chances of getting infected. However, infection always comes with the risk of complications.”

Seeing is believing

Another factor contributing to vaccine apathy is that many vaccines work by erasing the evidence of their usefulness. People in previous centuries were stalked by pandemics and epidemics of visibly devastating diseases. Smallpox was horribly disfiguring. Diphtheria often strangled children to death while family members watched helplessly. Polio was more unpredictable in its destruction. 

“Polio terrified my grandparents’ and parents’ generations,” says Stephen Walsh, MD, an infectious diseases researcher at the Brigham. “They saw firsthand how healthy kids could suddenly be paralyzed or die—and how vaccines changed that profoundly.”

While polio causes mild or no symptoms in most people, one in 200 infections leads to irreversible paralysis. Of those, 5 to 10% die when paralysis makes it impossible to breathe. At its peak, polio killed thousands of people each year and caused more than 15,000 cases of paralysis annually. 

“It’s easier to be in an information bubble about many vaccine-preventable diseases today because we’re not seeing lots of kids with leg braces and crutches,” says Walsh. “It reminds me of the cartoon character Homer Simpson complaining about his daughter, ‘We’re always buying Maggie vaccinations for diseases she doesn’t even have!’”

Managing expectations

The overwhelming success of vaccines in preventing some diseases—such as smallpox, polio, diphtheria, and measles—can make it seem like other vaccines are flawed if they mostly mitigate rather than prevent disease. But mechanisms of vaccine protection vary depending on several factors, including: 

• the diseases or pathogen(s) they target, 
• the immune response(s) they stimulate, 
• how widespread the targeted disease or pathogen is in a vaccinated person’s community, and 
• additional health issues a vaccinated person might have.

“It’s important to be honest about what vaccines can and can’t do,” says Solomon. “Some will not prevent you from ever getting infected, so it’s essential to be honest and match the intervention with each patient’s context.”

For example, the vaccine for measles, mumps, and rubella (MMR) is highly effective against all three diseases. Even so, a small percentage of people may still get one of those diseases after a vaccination or previous infection, especially if they: 

• live in an area experiencing an outbreak of one of those diseases,
• have compromised immune systems due to conditions such as HIV, cancer treatment, an organ transplant, or 
• are no longer protected by either vaccination or infection and recovery. 

Different vaccines have different goals, Solomon explains. The goal for the annual flu vaccine is to prevent influenza in 40 to 60% of the people who receive the annual flu shot, set by the U.S. Centers for Disease Control and Prevention.

“This doesn’t mean the flu vaccine doesn’t work,” says Solomon. “The data show, overwhelmingly, when you get the flu shot, you are much less likely to die or end up in the hospital with the flu or any related complications. Preventing severe illness is an important goal for all vaccines.” 

The quest for immunity

Protecting against severe illness is an essential component in building herd, or community, immunity. 

Community immunity is when a significant portion of a population is immune to or protected against a disease through vaccination or infection and recovery. The threshold for community immunity varies by virus or bacteria, with highly contagious diseases requiring higher thresholds of immunity within the community. For example, community immunity from measles requires at least 95% of the community to be protected by vaccination or previous infection. For polio, the community immunity threshold is about 80%.

However, community immunity is not achievable for all infectious diseases. Factors working against this include:

• Viruses that change or mutate frequently (such as influenza, HIV, and coronaviruses, like the one that causes COVID-19). 
• Diseases that can be spread by people who are contagious but asymptomatic or pre-symptomatic (such as COVID-19, HIV, and tuberculosis).
• Short-lived protection from previous infection or a vaccine (such as influenza, coronaviruses, norovirus, RSV, and rotavirus). 

Even for diseases that elude community immunity, vaccines save hundreds of thousands of lives and millions of dollars in healthcare expenses and lost wages each year by reducing the severity of infection, particularly among the most vulnerable.

Convincing the hesitant

Like other clinicians focused on infectious diseases, Solomon also has a front-row seat for worst-case scenarios, which helps him provide a broader perspective to vaccine-hesitant patients. 

“Given the successes of cancer and HIV treatments, organ and tissue transplants, and increased longevity, we are surrounded by people whose immune systems are compromised. So, I try to encourage a broader focus beyond the personal, to imagine a friend or relative you can help protect by getting a vaccine.”

Solomon increasingly relies on one of the main tools used by opponents of vaccines: storytelling.

“So much hesitancy is driven by personal stories, ranging from direct experiences to celebrity testimonies,” he says. “As a doctor, data really speaks to me. But stories speak louder than data for many people. I try to share stories about my experiences with people who had severe outcomes because they contracted vaccine-preventable diseases. ‘Here’s what we know and what we don’t know, based on my experience caring for patients like you.’”

Addressing risks and safety

Some people express fear or skepticism about the ingredients in vaccines. However, Walsh notes that all medications undergo rigorous safety testing before being released for public use. 

For example, he points to the concept of patient years, commonly used in cardiovascular research to explain the massive amount of safety data gathered for the COVID vaccines.

“Patient years may not be intuitive because, for each of us, one year is one year,” says Walsh. “But if we study 100 people for one year, researchers consider that to be 100 patient years of experience and data. With COVID vaccines, we went from 30,000 patient years in December of 2020 to hundreds of millions of people worldwide who have had mRNA vaccines over the past few years. That enabled us to gather millions of patient years of experience and data really quickly.”

Clinical trial veterans know that when testing a vaccine or other drug candidates against placebos, side effects or adverse events can often be higher in the placebo group than in the vaccine or drug group. 

“The first COVID vaccine trial in the summer of 2020 was a 30,000-person study, where 15,000 people got the vaccine and 15,000 got the placebo,” says Lindsey Baden, MD, infectious diseases specialist and vice president of clinical research at the Brigham. “We had 30 serious illnesses and one death in the placebo group and none in the vaccine group. With so much COVID around in 2020, this information signaled how effective the vaccine could be.”

What about side effects?

A professor at Harvard Medical School and deputy editor of The New England Journal of Medicine, Baden is a highly respected expert in developing new therapeutics and vaccines. During the COVID-19 crisis, Baden was the co-principal investigator for the Phase 3 vaccine trial, conducted in part at the Brigham, which led to the unprecedentedly rapid global use of those highly effective vaccines. Baden’s decades of experience with vaccine clinical trials has given him an insider’s view of side effects.

“Every drug has side effects,” Baden says. “We still use antibiotics, even though there are side effects such as with penicillin. Some side effects with vaccines have a mechanism we can identify and that are common when an immune response is provoked: fever, headache, soreness at the site of an injection. These side effects are transient and have to be balanced with the severity of the illness associated with infection. Vaccine science allows us to continually learn to improve efficacy and safety for each vaccine thus rebalancing the risk-benefit ratio for a given vaccine over time.”

And because each person’s context is different, what makes sense to one person may not make sense to another.

“Some people feel entitled to their own facts,” says Pier. “So we have to emphasize that any vaccine recommendation is based on a preponderance of evidence, which is collected first in trials and continues to be gathered after vaccines are manufactured and distributed.” 

Pier adds, “Without even thinking about it, people routinely engage in behaviors more risky than getting a vaccine: driving in a car being a prime example.”

Staying curious

When meeting with patients who are hesitant about vaccines, Brigham infectious diseases physician Mary Montgomery, MD, leads with curiosity. Her years of working with HIV patients have shown how shame and stigma undermine trust and make people reluctant to seek the care they need. 

In her work as an instructor at Harvard Medical School, Montgomery teams with social workers to create simulations for medical students, allowing them to experience firsthand how judgment and shame erode communications between physicians and patients.

“In one exercise, the social worker tells the medical students, ‘Close your eyes and think of a time you did something you’re ashamed of. Maybe you cheated or lied or stole something,’” Montgomery recalls. “When everyone indicates they’ve thought of something, she says, ‘Okay, now Dr. Montgomery is going to walk around, and if she taps you, we want you to share your moment with everyone in the class.’ Everybody’s eyes always fly open at that point, and they often gasp.”

Montgomery continues, “Then the social worker will say, ‘It’s okay, Dr. Montgomery isn’t tapping anyone. But what just happened? How did it feel when you thought you might get tapped?’”

While empathy and curiosity are building blocks for trusting relationships, shame and stigma can be life-threatening when it comes to getting the right healthcare at the right time.

“I know our students will learn all the medical stuff,” says Montgomery. “We’re teaching them to ask questions out of curiosity rather than judgment. When we can teach them how to have difficult conversations with patients, that’s my highest achievement.”

New vaccines for this century’s scourges?

Remember our small U.S. town of 10,000 people where infectious diseases were among the top 10 causes of death in 1900? Let’s revisit it after more than a century of scientific advancement and vaccine development.

Vaccines are one of the best public health interventions ever created.

Lindsey Baden, MD

In 2023, only 92 residents in this town died, compared to 250 in 1900. Only two or three of the dead were children under 5 years old, compared to 100 in 1900. Most people in the town will live into their mid- to late-70s, nearly 30 years longer than in 1900. Fewer than 1% of the children born there will die before their 5th birthday, compared to 24% in 1900. Over the intervening 123 years, heart disease, cancer, and COVID-19 have replaced pneumonia, influenza, tuberculosis, gastrointestinal infections, and diphtheria in the top 10 causes of death. In fact, COVID-19 was the only infectious disease among the top 10 causes of death in 2023.

“We have entire buildings dedicated to treating cardiovascular diseases, cancer, and neurologic diseases,” says Baden. “But we can only treat those now because people aren’t dying much earlier in life from smallpox, measles, or diphtheria.”

Advances in medical technologies and the successes of vaccines continue to inspire new ideas in vaccine research and testing for some of this century’s most lethal diseases. As of July 2024, there were 400 clinical trials underway nationwide for cancer vaccines. At least seven clinical trials are testing vaccines against Alzheimer’s disease, including a Phase 3 trial at the Brigham, the last stage of clinical research before applying for approval from the U.S. Food and Drug Administration.

Additionally, evidence increasingly shows that keeping current with all recommended vaccines helps protect the cardiovascular system from inflammation and other stresses, reducing risks of heart attacks and stroke. 

“Vaccines are one of the best public health interventions ever created,” says Baden. “Vaccines and sanitation, including hand washing,  are probably the main contributors to doubling our life expectancy over the past 200 years.”