Producing Prevention: The Complex Development of Vaccines
What does a hurricane have to do with vaccines? More than you might think.
In October 2016, Hurricane Matthew tore through the Caribbean and the southeastern seaboard of the United States. The Category 5 storm, one of the most powerful on record in recent years, proved particularly devastating for the island nation of Haiti, where more than 800 people died in the immediate aftermath. But the crisis is far from over. Cholera — a waterborne disease that causes severe, life-threatening diarrhea — has flourished in the wake of the storm. The disease is rare and treatable in developed countries like the United States, but for nations with weaker governments and health care systems, it can proliferate unchecked at an alarming rate.
To combat the spread of the disease, the Haitian government is undertaking the largest cholera immunization effort in history by vaccinating 800,000 people in regions most affected by Hurricane Matthew. Though the initiative promises to be “a huge logistical challenge,” it still testifies to one of the most powerful public health tools in existence: vaccines. The process used to create vaccines is steeped in regulation, testing and research — all intended to make sure that efforts to prevent disease don’t inadvertently threaten health in other ways.
The ABCs of Immunization and Vaccination
Though it’s common to hear the terms “immunization” and “vaccine” used interchangeably, they actually describe different things. A vaccine is “a product that produces immunity from a disease and can be administered through needle injections, by mouth or by aerosol.” Immunization, conversely, is any process by which an individual becomes protected from a disease — that could mean a vaccine, but it could also mean a virus that imbues its host with resistance to a particular illness in the future. Today, there are over 80 distinct vaccines licensed for use in the United States and more than 600 in development worldwide.
The key ingredient in an effective vaccine may seem counterintuitive: an inactive or weakened version of the very bacterial or viral infection it has been created to prevent. When we get sick, we produce antibodies, or proteins, that help our bodies fight illness. Vaccines weaponize our immune systems by imitating the virus or infection in question, which in turn prompts our bodies to create the same antibodies it would need to fight a full-blown version of that illness. When or if we encounter that bacteria or virus, our bodies are prepared to counter it.
Contrary to what anti-vaccination communities assert, vaccines are very safe and effective. According to the World Health Organization (WHO), severe health effects are “extremely rare,” and individuals are “far more likely to be seriously injured by a vaccine-preventable disease than by a vaccine.”
The Path to Prevention
The effectiveness and life-saving nature of vaccines leads people to pose the same question whenever a public health crisis, such as Zika or Ebola, hits the news cycle: “When will a vaccine be available?” The answer, which also considers which types of professionals are needed at each stage of development, is complicated. According to the Centers for Disease Control and Prevention (CDC), there are six stages of vaccine development: exploratory, pre-clinical, clinical development, regulatory review and approval, manufacturing and quality control.
Exploratory: This research-intensive phase of the vaccine development process is designed to identify “natural or synthetic antigens that might help prevent or treat a disease.” Antigens might include weakened strains of a particular virus.
Pre-clinical: During this phase, researchers — usually in private industry — use tissue-culture or cell-culture systems and animal testing to determine whether the candidate vaccine will produce immunity. Many candidate vaccines don’t move on to the next stage of development because they fail to produce that immunity or prove harmful to test subjects.
Clinical development: At this point, a sponsor, usually a private company, submits an application for an Investigational New Drug (IND) to the U.S. Food and Drug Administration (FDA). This summarizes findings to date and describes how the drug will be tested and created. An institution that will host the clinical trial holds a review board for approval of the application. The FDA has 30 days to approve the application. Once the proposal has been approved, the vaccine must pass three trial stages of human testing:
- Phase I administers the candidate vaccine to a small group (less than 100 people) with the goal of determining whether the candidate vaccine is safe and to learn more about the responses it provokes among test subjects.
- Phase II, which includes hundreds of human test subjects, aims to deliver more information about safety, immunogenicity, immunization schedule and dose size.
- Phase III, which can include thousands or tens of thousands of test subjects, continues to measure the safety (rare side effects sometimes don’t appear in smaller groups) and effectiveness of the candidate vaccine.
Regulatory review and approval: If a vaccine passes through all three phases of clinical development, the vaccine developer submits a Biologics License Application (BLA) to the FDA.
Manufacturing: Major drug manufacturers provide the infrastructure, personnel and equipment necessary to create mass quantities of vaccines. They also reap the profits of successful or widely distributed drugs.
Quality control: The approval and distribution is far from the end of the line. Stakeholders must adhere to procedures that allow them to track whether a vaccine is performing as anticipated. Multiple systems — including Phase IV trials (optional studies that can be conducted following the release of a vaccine), the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink — are designed to monitor the performance, safety and effectiveness of an approved vaccine.
These processes, however, can’t happen without the skills and input of numerous stakeholders, from lab researchers to policymakers to medical professionals.
Who Is Involved in Vaccine Production?
Vaccine development requires careful work from trained professionals in a variety of sectors throughout the process. Certain people can wear many hats. An academic researcher, for instance, may also hold a position at an NGO and influence the way in which that institution works with manufacturers. As another example, a pharmaceutical company might employ a health professional who previously worked for a federal agency. With that in mind, some of the major stakeholders — people and organizations who directly affect the production process — include health professionals, manufacturers, nongovernmental organizations (NGOs), academia, government agencies, media, and individuals and communities.
Health professionals: Those with advanced degrees in biology, chemistry, epidemiology, medicine and a variety of other health fields play a crucial role in identifying and vetting vaccines. They also serve as subject matter experts throughout the approval and regulation process. According to The History of Vaccines, those leading the research in vaccine development typically have “a doctorate degree in cellular and molecular biology, biochemistry, or microbiology”; however, these professionals also require help with an array of research functions that can be conducted by those with bachelor’s or master’s degrees in those subject areas.
Manufacturers and private industry: Developing and testing a vaccine is expensive and rife with the potential for liability, which means that funding must come from private institutions, such as pharmaceutical companies. FiercePharma identified the top five vaccine producers of 2014 — those that generated the most revenue — as GlaxoSmithKline (GSK), Merck, Novartis, Pfizer and Sanofi.
Nongovernmental Organizations (NGOs): These institutions can act as an important conduit between communities and manufacturers with the goal of easing communication in regions where a vaccine is needed. This might include working directly with populations to facilitate immunization in an equitable way that accounts for social determinants, collaborating with local health systems and health workers, and funding the provision of vaccines.
Academia: The academic community conducts valuable research that has the potential to help other stakeholders understand what can be learned about myriad aspects of the vaccination development process. They may be able to advocate for evidence-based immunization practices, reflect on the socioeconomic implications of a vaccine for an at-risk community, or synthesize past research.
Government agencies: In the United States, federal agencies such as the FDA must serve as the check-and-balance for any vaccine that will be made available to the general public.
Media: Though members of the media may not be “hands-on” stakeholders, they can elevate the profile of a certain disease or condition that requires a vaccine. Reporting the result of a vaccine’s progress, challenges or dangers provides an important public service. At the other end of the spectrum, however, media can exacerbate unfounded fears around certain diseases or catalyze unrealistic expectations for the timing of a vaccine’s availability.
Individuals and communities: The general public plays a crucial role in determining the safety and effectiveness of a vaccine. From participating in trials to serving as end users for an approved drug, understanding the real-world implications of a vaccine comes down to this group.
Given the meticulous testing and approval protocols involved in vaccine development — as well as the sheer number of stakeholders involved — it can take years to move a vaccine from a lab to the general public. That timeline, however, can change when a public health crisis, such as an outbreak or a natural disaster, emerges suddenly.
Vaccines in Times of Crisis
The conversation around how vaccines and immunization practices are used to combat widespread health emergencies, from sudden outbreaks like Ebola to long-standing threats such as malaria, is complicated for a few reasons.
For one, drugmakers are often incentivized to move faster in the face of epidemics like Zika or Ebola because the payoff for cracking the code to a “blockbuster” vaccine can be enormous. In a recent Fortune article, Joseph Kim of Inovio Pharmaceuticals estimated that “the Zika market opportunity” could easily top $1 billion.
The rush to develop a vaccine in response to an outbreak, however, can threaten that region’s ability to counteract existing health threats. The Ebola epidemic in West Africa, for instance, diverted existing immunization resources from communities that were at risk for other serious conditions for which vaccines already exist. In hard-hit nations like Liberia and Sierra Leone, where doctor-to-patient ratios are as low as “one or two for every 100,000 people,” Ebola presented “an acute crisis on top of a chronic problem.” Milken Institute School of Public Health professor Dr. Ron Waldman commented on the ripple effect in a 2015 GlobalPost report:
“I like to talk about the epidemic of non-Ebola mortality that occurred in the Ebola-affected countries during the outbreak. There were many more deaths from malaria, many more deaths from pneumonia and diarrhea and non-Ebola causes because of the absolute disruption of the health care system.”
These ripple effects aren’t limited to the outbreak region, either. In September 2016, Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), told The Washington Post that the congressional debate over Zika funding has forced the federal government to tap into funding sources for other diseases.
Initially, funding was taken from other infectious diseases, such as tuberculosis and Ebola, but the financial need warranted an even more worrisome next step: “When we ran out of that, [Health and Human Services] Secretary [Sylvia Mathews] Burwell had to do something she really did not want to do. She had to take money using her transfer authority from cancer, diabetes, heart disease and mental health and give it to us to be able to continue to prepare the sites for the [Zika] vaccine trials that we will be performing.”
Determining how vaccines can be used for existing and emerging health threats — both in the United States and internationally — and understanding the inherent challenges of that learning process is crucial for the next generation of public health professionals.
Though vaccines are a powerful weapon in the fight to protect public health, they aren’t always the most cost-effective or efficient means of countering illness. Much effort — and risk — characterizes the processes used to create them. What steps can be taken to improve the ways in which we develop, regulate and deploy vaccines? Tell us in the comments or on Facebook, Twitter and LinkedIn.