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Human challenge studies are experimental trials where researchers intentionally expose volunteers to pathogens to better understand how the body responds to infections. The goal is to observe the progression of the disease, evaluate the effectiveness of treatments or vaccines, and gather critical data on immunity.

The first vaccination is attributed to Edward Jenner, who on May 14, 1796, inoculated a person with smallpox. This first patient survived the experiment and was thus protected against smallpox. This variolization was the first vaccination and took place in the shape of a Human Challenge Study. This method has enabled the eradication of the disease in 1980.

During the COVID-19 pandemic, human challenge studies were used to quickly assess how the virus spreads, as well as the immune response triggered by vaccines, accelerating vaccine development and bringing data about the virus operating mode.

The main advantage of human challenge studies lies in their ability to speed up the research process. Traditional clinical trials often take years to complete because they rely on natural exposures in large, diverse populations.

On the other hand, human challenge studies will lead to faster results by intentionally exposing volunteers to a pathogen providing data more quickly which is crucial during public health emergencies such as pandemics.

Human challenge studies are performed under controlled conditions making it easier to identify cause-and-effect relationships between the infection and the immune response, or the efficacy of a treatment.

Historically, human challenge studies have been used to improve our knowledge on diseases and develop vaccines. With Malaria for example, volunteers have been infected with the malaria parasite to test the effectiveness of new drugs and vaccines. These studies have contributed to the development of several promising malaria vaccines.

Human challenge studies have also been used to test vaccines against influenza and to study the immune response to different strains of the virus. They have been used in 2020 during the COVID-19 Pandemic to accelerate the development of vaccines. Volunteers were then deliberately infected with SARS-CoV-2 to test vaccine efficacy in a controlled environment, providing critical data that contributed to the vaccine’s development.

A challenge agent is a specific microorganism (virus, bacterium, parasite, or other pathogens) that is intentionally introduced into the body of a healthy volunteer during a human challenge study under controlled conditions to study various aspects of the disease, including infection dynamics, immune response, or the efficacy of vaccines and treatments.

The challenge agent is carefully selected, cultured, and tested to ensure it has the right properties for the study, including the ability to cause a controlled, mild infection that can be safely monitored. This is a crucial part of medical research, especially when investigating diseases with no effective treatments or vaccines, as it allows researchers to obtain data quickly and efficiently.

There are different types of challenge agents based on the pathogen being studied such as viruses with Influenza, SARS-CoV-2, Rhinovirus or Norovirus, Bacteria with Salmonella, Vibrio cholerae or Mycobacterium tuberculosis and even Parasites with Plasmodium or Hookworm.

The manufacturing process of a challenge agent is highly controlled and follows strict regulatory guidelines, as the pathogens are designed to be used in human trials. The challenge agent must be consistent across batches as this consistency is crucial for ensuring that all volunteers in a trial are exposed to the same level of pathogen, making the results of the study more reliable and reproducible.

The general steps for manufacturing challenge agents start with the culture of the pathogen (virus, bacteria, or parasite) often in animal cells, cell lines, or culture media, to grow enough material for the study. For viruses, cells like Vero cells (used for growing SARS-CoV-2) or Madin-Darby Canine Kidney (MDCK) cells (used for influenza) are commonly used while bacteria and parasites are typically grown in specialized media, sometimes under controlled temperature and environmental conditions to mimic natural growth patterns.

After the culture step, the pathogen is purified to remove unnecessary contaminants to ensure that only the pathogen is present in the challenge agent.

The challenge agent is then titrated to determine the correct dose that will be administered to volunteers. The goal is to infect participants with a dose high enough to trigger an immune response but low enough to avoid serious health risks. The standardization of the challenge agent ensures that the same dose is given to all volunteers, making the trial results comparable.

Once the pathogen has been prepared and standardized, it is usually formulated into a stable liquid, often in a sterile saline solution, for easy administration such as nasal spray, injection, or ingestion. Some challenge agents, particularly those used in large-scale trials, can be freeze-dried or cryopreserved for longer-term storage and shipping.

Before any use in humans, the challenge agent will go through rigorous quality control testing to verify that it meets safety standards. This can include tests for sterility, endotoxin levels, potency, and stability.

Naobios is proud to offer Human Viral Challenge Agent (HVCA) manufacturing to the biotech and pharmaceutical industry as well as to academic institutions and agencies like Bill and Melinda Gates Foundation, EVI and others. As a GMP-certified establishment and with our BSL2 and BSL3 GMP suites we are uniquely suited for the manufacturing of HVCA. We have a broad experience in bioprocess development and clinical manufacturing of a wide range of viral vectors on many cell lines and we provide full range of analytical testing in-house.

Relying on a strong CDMO expertise based on 20 years of experience as a GMP pharmaceutical establishment, Naobios have produce more than 55 GMP batches of Drug Substances for Clinical phase studies including challenge agents. Naobios regulatory approach is to manufacture HVCA following as close as possible the GMP requirements performing risk-analysis for any technical gap identified.

Human challenge studies are an essential tool in advancing medical research, particularly in vaccine development as there are used to test the efficacy of vaccines before large-scale clinical trials. Vaccines are given to healthy volunteers, and then they are exposed to the challenge agent to see if the vaccine prevents infection or reduces the severity of symptoms. This method will speed up the vaccine development, gathering more data in a shorter period compared to traditional observational studies.

Challenge agents are also used to test the effectiveness of new antiviral, antibacterial, or antifungal treatments. For example, a new flu medication can be tested in a challenge study by infecting volunteers with the influenza virus and administering the drug to see if it reduces the severity or duration of symptoms.

By infecting healthy volunteers with a known challenge agent, researchers can better understand how the immune system responds to different pathogens, identify new biomarkers, and test novel immunotherapies. It is also possible to understand how the body react with disease such as malaria or cholera, only possible through challenge studies as animal models do not always replicate human immune responses perfectly.

Ethics is one of the most significant challenges facing human challenge studies. Deliberately exposing healthy individuals to infectious agents, particularly those that could cause serious illness or even death, raises difficult questions. The risks must be clearly understood by the volunteers as they could be exposed to potentially harmful pathogens. Another question regarding participants arises with the vulnerability for those in financial needs that might feel pressured to participate. Rules must therefore be established. Taking into example the well-known FluCamp organized in London by Hvivo, you can participate every 3 months depending on trial availability and participant eligibility.

It is important to demonstrate that the benefits of the study outweigh the risks to the volunteers. This is especially important when studying pathogens that can cause severe illness, such as SARS-CoV-2, malaria, or cholera. For this reason, participants are closely monitored throughout the study under strict medical supervision with treatment to minimize bad effects from the challenge agent.

While short-term health risks are carefully monitored, the long-term effects of exposure to some pathogens (especially chronic ones like malaria or certain viruses) may not be fully understood at the time of the study. Participants are often followed long after the study to monitor any delayed health consequences.

Manufacturing challenge agents and running human challenge studies requires highly specialized infrastructure, resources, and coordination. Challenge studies must indeed be conducted in clinical research units or specialized facilities where volunteers can be closely monitored with a tightly controlled environment and quarantine capacity to prevent the pathogen from spreading beyond the study.

As mentioned earlier, manufacturing the pathogen and ensuring its purity, safety, and consistency is a complex task. The challenge agent must be grown, tested, and prepared under strict laboratory conditions to avoid contamination and ensure it is effective for the study. For some viruses, a BSL3 facility is required and at Naobios we have the capabilities and experience to manufacture viral challenge agents BSL2 and BSL3 for CHIM studies. We have already manufactured a clinical batch of a RSV (respiratory syncytial virus) challenge agent for EVI and we are working with the Bill and Melinda Gates foundation for a Covid-19 challenge agent. We have also manufactured several BSL2 & BSL3 viral challenge agents for respiratory diseases.

Despite the challenges, human challenge studies have enormous potential, and their role in medical research will continue to evolve. The COVID-19 pandemic highlighted the importance of accelerating vaccine development as human challenge studies were used to test vaccine efficacy quickly, shortening the timeline for vaccine approval. As new infectious diseases are emerging, challenge studies will be critical to test rapidly vaccines and treatments, even in the absence of widespread natural infections. In the future, challenge studies may even be used to test vaccines or treatments in more targeted ways, such as identifying which populations are most likely to benefit from specific interventions based on genetic or immunological markers.

Human challenge studies have yet been primarily focused on diseases with well-known and established pathogens, such as influenza, malaria, cholera, and COVID-19. However, researchers are now increasingly looking to extend human challenge trials to more complex or less studied pathogens. This includes emerging infectious diseases such Norovirus, Rotavirus, EBV intestinal viruses, antimicrobial-resistant bacteria, and coronaviruses as well as rare diseases caused by neglected pathogens such as certain parasitic diseases or rare bacterial infections. The expansion of human challenge studies will help accelerate the development of vaccines and therapies for diseases that have not yet received significant attention from the pharmaceutical industry.

Moreover, human challenge studies are essential to understand how the immune system responds to infections. As vaccine development accelerates for emerging diseases, researchers will place greater focus on studying the longevity and breadth of immunity in response to vaccines and infections. A new role for challenge studies could be the evaluation of vaccines booster for diseases like COVID-19, to assess how immunity wanes over time and whether additional doses are needed for long-term protection.

At Naobios we are facing the challenges related to Human Challenge Studies and we want to support challenge agents projects on new viral strain. To better understand why you need Human viral challenge agents for your clinical studies, we have created a short video presenting how CHIM studies work to accelerate your vaccine development.