How Human Challenge Trials Can Accelerate Vaccine Development

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In 1955, Jonas Salk developed and debuted the inactivated polio vaccine. Within five years, cases of polio in the United States dropped drastically, and childhood vaccinations for infectious diseases like polio became a new standard of care.

The Salk vaccine heralded a new dawn for treating infectious diseases during the 1960s, specifically severe respiratory syncytial virus (RSV) infections in children. However, when a formalin-inactivated version of an RSV virus vaccine similar to the polio vaccine was trialed in 1967, many immunized infants actually experienced an enhanced form of RSV disease—complete with high fever, bronchopneumonia and wheezing—when they later became infected with wild-type, or naturally occurring, RSV viruses circulating in the community.

This so-called enhanced respiratory disease or enhanced RSV disease (ERD) led to increased hospitalization rates in vaccinated children and two deaths. The vaccine was shelved, and formalin-inactivated vaccine preparations largely fell out of favor. Other, more advanced polio vaccines designed to supplement the original Salk vaccine have also failed, causing oral polio vaccine viruses to revert to wild-type and become virulent again.

Although polio is now largely eradicated, these examples remind us that campaigns for the greater good may often come at the expense of individual harm, and that clinical advancement cannot be viewed as an exact or even linear process. Negative outcomes are not necessarily predictable from prior experimentation, and clinical trials cannot be wholly relied upon to evidence low-incidence adverse events. New clinical models, such as human challenge trials, can pick up where clinical trials leave off and enable the rapid development of prognostic efficacy data for many infectious diseases.

HOW BOTTLENECKS TAKE DOWN VACCINE CANDIDATES—EVEN PROMISING ONES

It’s no secret that the health care industry suffers from innovation bottlenecks. Three examples from the recent history of medicine illustrate this point:

    Despite nearly 40 years of research, there is no vaccine for HIV. Patients can be treated with antiretroviral drugs, which have proven to be remarkably effective and have dramatically improved life expectancy for those with the disease, but an easy-to-administer vaccine has yet to replace these expensive “drug cocktails” that patients must take for the rest of their lives.  
    Global overprescribing of antibiotics has led to resistance in almost every species of bacteria, and new alternatives have yet to be developed. Up to 60 percent of disease-causing Escherichia coli is now resistant to the best broad-spectrum antibiotics; the figure rises to 93 percent for urinary tract infections. Meanwhile, stronger strains of the Streptococcus pyogenes bacterium that causes scarlet fever have been found in Hong Kong and the United Kingdom. No alternatives to these antibiotics have been developed to date.
    In the early and critical days of treating patients with COVID-19, hospitals in Italy, New York City and around the world were forced to operate the mechanical ventilator—a device invented nearly 100 years ago and virtually unchanged since the middle of the 20th century—on just one patient at a time. This forced hospitals to ration care, which contributed to increased mortality rates.

These bottlenecks do not result from an unwillingness to address the problem. After all, we now have a polio vaccine, a smallpox vaccine and multiple COVID-19 vaccines. Even in the absence of “final steps” such as HIV vaccines or more effective antibiotics, antiviral drugs have dramatically improved life expectancy and quality of life for patients with HIV and AIDS, while in most cases antibiotics can prevent the major complications of scarlet fever.

Clearly, the will to innovate exists. Rather, bottlenecks are the result of a paradigm shift in the development process, when a positive result quickly turns negative or progress comes to a sudden stop. An idea that looks great on paper proves too difficult to realize.

Many scenarios can cause an innovation bottleneck to occur during vaccine development. Drug toxicity, vaccine ineffectiveness or patient side effects may become readily apparent. Design complexity may stand in the way of drug dose delivery or contribute to a costly manufacturing process. Additional barriers may include limited access to raw materials, poor stability or cold-chain requirements—as we have seen with Pfizer’s COVID-19 vaccine.

Even if all the right criteria are met, the most promising of therapies or vaccines may still fall from grace. A competitor may manufacture an equally effective product that can be made at a lower cost, administered more easily or used in a broader population, such as the very young, elderly or in immunosuppressed populations. While it’s currently too soon to tell, this may be the case with the one-dose Johnson & Johnson COVID-19 vaccine as compared to the two-dose vaccines from AstraZeneca and Moderna, which also bring the added challenges of follow-up appointment scheduling and clinical record-keeping.

HOW HUMAN CHALLENGE TRIALS CAN ACCELERATE VACCINE DEVELOPMENT

The most common bottlenecks in vaccine development are cost, risk, safety and time. A vaccine may show promise in a preclinical or Phase I trial, but if any of those factors are working against a research team, a sudden paradigm shift will fail to move the candidate forward.

Fortunately, clinical models such as human challenge trials provide an opportunity to move past these bottlenecks. In these trials, healthy volunteer participants are intentionally challenged, or infected, with an infectious disease. This enables researchers to study the effect of a vaccination on the disease itself in a controlled environment; participants stay on-site for the duration of the trial, and a fully staffed analytical laboratory can provide priority access to any care participants may need. In such a model, almost all experimental parameters can be controlled (the challenge agents, what the subjects are screened for, the schedule of assessments, the dose of infectious agents administered and the timing of inoculation).

Human challenge studies provide more valuable information than animal challenge studies, which produce results that must be extrapolated in order to determine the impact on humans. They also allow for trials on a small participant pool that faces minimal risk of adverse outcomes, clinical complications or hospitalization. Finally, the small size of the trial reduces the financial risk of failure, as much less vaccine product is required for a human challenge trial than a Phase II clinical trial.

It’s important to note that human challenge studies do not occur in isolation. It might be said that the clinical trial system currently in place and backed by decades of successful drug and vaccine development is, in effect, a quality control system. The goal of the clinical study is as much to fail the poor candidates as it is to advance the most promising ones. Biotechnology and pharmaceutical companies must obtain statistically significant data from heavily regulated and audited trials before a product receives market authorization. All steps in this process have quality gateways in place.

Rather, the role of the human challenge study is to serve as a gateway for promising vaccines once basic, preclinical and Phase I studies have provided initial validation of the safety of the candidate. It is also a model with a proven track record of success, having led to safe, effective and inexpensive vaccine solutions for almost all childhood infectious diseases as well as malaria, typhoid, cholera and the flu. These advances in medicine have shifted life expectancy forward by 10 years since the 1960s—and have the potential to help the average person live into their 90s by the year 2050.

COVID SHOWS WHY ACCELERATED VACCINE DEVELOPMENT MATTERS

The effort to develop a vaccine to stem the tide of the COVID-19 pandemic provides a clear example of the importance of eliminating barriers to health care innovation.

At the peak of vaccine development, there were at least 120 vaccines in the pipeline. A small number of now-obsolete candidate vaccines caused enhanced respiratory disease, severe acute lung injury and other types of organ damage. Experience has shown that only approximately 6 percent of all COVID-19 vaccine candidates will ultimately make it to market.

Given these risks, the industry approached the COVID-19 vaccine development process with caution, much as it has for countless development projects in the past. At the same time, the need for a vaccine was acute; it has been projected that SARS-CoV-2 may reduce mean life span in the United Kingdom by as many as six years. A timeline similar to what we’ve seen for an HIV vaccine would simply not be acceptable.

Within this context, there was a sea change in FDA and WHO guidance for developing a COVID-19 vaccine. Regulatory authorities created environments amenable to moving vaccines into late-phase studies centered on solid safety signals over markers of efficacy. This new view allows for safe products to be rapidly advanced while recognizing that a high attrition rate is to be expected, while unexpected events should not be treated as exceptional. Emphasis was placed not on the setbacks that should halt vaccine development altogether but on the progress that provides cause to move forward.

In this environment, established commercial companies in the human challenges trial market, including hVIVO, can pioneer epidemic and pandemic disease modeling to accelerate the development of vaccines with proven efficacy. These firms can serve as valuable partners to the pharma and biotech industries by removing longstanding bottlenecks to innovation.

By studying the effects of the vaccine in human challenge trial subjects who are known to have the disease the vaccine intends to target, researchers are able to screen potential vaccine candidates in a timely manner and move the most promising candidates to larger trials faster than the traditional clinical trial model. This allows for more people to receive “jabs in arms” in less time, which can mitigate the spread of a deadly disease and improve health outcomes around the world.

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