Vaccines for Durable Immune Response

(DARPASB Trial)

Recruiting at 2 trial locations

Overseen By Nadine Rouphael, MD, MSc

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: Emory University

Must not be taking: Immunosuppressants, Antineoplastics

Disqualifiers: Impaired immunity, Hepatitis B/C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

60 Participants Needed

Trial Summary

What is the purpose of this trial?

The ability of the vaccines today to generate a long-lasting protection against infections varies greatly from one vaccine to another. The yellow fever vaccine (YF-17D) is one of the most successful vaccines ever developed, having been administered to over 600 million people globally. A single vaccination is known to induce durable protection over several decades. In contrast, the quadrivalent influenza vaccine (QIV) generates an immunity that wanes quickly with no long-lasting protection. Currently, the duration of immune protection for new vaccines is difficult to predict during vaccine product development and can only be ascertained by a "wait and see" approach. This is due, in part, to the fact that some of the signals that activate a durable immune system protection remain unknown. This study aims to provide a better understanding of this problem by vaccinating willing participants with either the FDA-approved yellow fever vaccine or the quadrivalent influenza vaccine and collecting baseline and follow-up biologic samples to compare how the immune system reacts.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on medications that affect the immune system, you might not be eligible to participate.

Is the yellow fever vaccine safe for humans?

The yellow fever vaccines, including Stamaril and YF-VAX, have been shown to be generally safe for humans, with rare serious side effects. Most people experience no serious reactions, and the vaccines have been used safely in millions of doses worldwide. ^{1 2 3 4 5}

How is the 'Vaccines for Durable Immune Response' treatment different from other treatments for yellow fever and influenza?

This treatment combines the live attenuated yellow fever vaccine, known for its long-lasting immune response, with a quadrivalent seasonal influenza vaccine, which targets four different flu virus strains. This combination aims to provide a broad and durable immune response against both yellow fever and multiple strains of influenza, which is unique compared to standard single-disease vaccines. ^{1 2 6 7 8}

Research Team

Nadine Rouphael, MD

Principal Investigator

Emory University

Eligibility Criteria

This trial is for healthy adults aged 18-50 who can consent and agree to use birth control if applicable. Excluded are those with severe liver or kidney disease, insulin-dependent diabetes, compromised immunity, high blood pressure risks, pregnancy, breastfeeding intentions within 3 months of the study start, recent receipt of blood products or immune globulin product. Military personnel are also excluded.

Inclusion Criteria

I agree not to take any live vaccines around the time of my trial vaccination.

Women of reproductive age must commit to utilizing effective contraception methods for the initial quarter of the study.

Urine pregnancy must be tested and confirmed prior to vaccination or tissue sampling.

Exclusion Criteria

You are currently taking or have taken Immunosuppressive Agents

I have a condition that weakens my immune system, but not skin cancer or cured non-lymphatic tumors.

I have chronic health issues that could interfere with my immune response.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Vaccination

Participants receive either the yellow fever vaccine (YF-17D) or the quadrivalent influenza vaccine (QIV) and are observed for immediate hypersensitivity reactions

1 day

1 visit (in-person)

Tissue Sampling

Lymph node and bone marrow samples are collected to evaluate immune response

Up to 3 months

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after vaccination, including adverse events and antibody response

Up to 270 days

Multiple visits (in-person and virtual)

Treatment Details

Interventions

• Live Attenuated Yellow Fever 17D Vaccine
• Quadrivalent seasonal influenza vaccine

Trial Overview The study compares the long-term immune response between two vaccines: the yellow fever vaccine (YF-17D) known for its lasting protection and the seasonal quadrivalent influenza vaccine (QIV), which has short-lived immunity effects. Participants will receive one of these FDA-approved vaccines and provide biological samples over time for analysis.

Participant Groups

Group I: YF-17D Vaccination Experimental Treatment 1 Intervention

Yellow Fever Vaccine (YF-17D) vaccination: Eligible participants will be asked to read the Vaccine Information Sheet for YF-17D per the Centers for Disease Control and Prevention (CDC) guidelines. Participants will then receive the YF-17D vaccine. They will be observed for a minimum of 20 minutes for any immediate hypersensitivity reactions. They will also be given the International Certificate of Vaccination documenting receipt of YF-17D.

Group II: QIV Vaccination Experimental Treatment 1 Intervention

Quadrivalent seasonal influenza vaccine (QIV) vaccination: Eligible participants will be asked to read the Vaccine Information Sheet for QIV per the CDC guidelines. Participants will then receive QIV. They will be observed for a minimum of 20 minutes for any immediate hypersensitivity reactions.

Live Attenuated Yellow Fever 17D Vaccine is already approved in United States, European Union for the following indications:

Approved in United States as YF-VAX for:

• Prevention of yellow fever in persons 9 months of age and older traveling to or living in endemic areas

Approved in European Union as Stamaril for:

• Prevention of yellow fever in persons 9 months of age and older traveling to or living in endemic areas

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

Open Philanthropy

Collaborator

Trials

8

Recruited

6,800+

Defense Advanced Research Projects Agency

Collaborator

Trials

19

Recruited

78,900+

Findings from Research

A total of 627,079 individuals received the STAMARIL vaccine from May 2017 to June 2021, with only 0.2% reporting adverse events, indicating a strong safety profile for this alternative yellow fever vaccine during a supply shortage.

Serious adverse events were rare, with only seven cases of neurotropic disease and three cases of viscerotropic disease reported, supporting the conclusion that STAMARIL is a safe and effective option for yellow fever vaccination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced safety surveillance of STAMARIL® yellow fever vaccine provided under the expanded access investigational new drug program in the USA. Rojas, A., Hachey, W., Kaur, G., et al.[2023]

The newly developed live-attenuated yellow fever vaccine candidate vYF-247 shows a significantly lower neurovirulence compared to existing vaccines (Stamaril and YF-VAX), suggesting it may have a safer profile with reduced risk of severe reactions like YEL-AVD and YEL-AND.

In preclinical studies, vYF-247 demonstrated strong immunogenicity and effective protection against yellow fever in animal models, indicating it could provide robust protection in humans similar to current vaccines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Next generation live-attenuated yellow fever vaccine candidate: Safety and immuno-efficacy in small animal models. Piras-Douce, F., Raynal, F., Raquin, A., et al.[2021]

The review of 276 million doses of Stamaril® vaccine shows a favorable safety profile, particularly regarding serious adverse events, which are reported at lower rates than previously estimated for yellow fever vaccines.

The findings provide valuable insights for healthcare providers, confirming that Stamaril's safety is consistent with its product characteristics, especially for at-risk groups like the elderly, pregnant women, and immunosuppressed individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of the yellow fever vaccine Stamaril®: a 17-year review. Cottin, P., Niedrig, M., Domingo, C.[2013]

Two fatal cases of hemorrhagic fever were reported in Brazil following the yellow fever 17DD vaccine, highlighting a rare but serious complication associated with this vaccine.

The cases involved a 5-year-old girl and a 22-year-old woman, both of whom exhibited severe symptoms and died shortly after vaccination, suggesting that individual host factors may play a role in these adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serious adverse events associated with yellow fever 17DD vaccine in Brazil: a report of two cases. Vasconcelos, PF., Luna, EJ., Galler, R., et al.[2019]

In a study involving 211 healthy adults, the new yellow fever vaccine (PM-YF) demonstrated higher immune response levels shortly after vaccination compared to the commercially available vaccine (Arilvax), but both provided equivalent protection one month later (100% vs 99% seroprotection).

Both vaccines were found to be safe, with no serious adverse reactions or significant liver function abnormalities reported, indicating that they are both effective and well-tolerated options for yellow fever vaccination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the immunogenicity and safety of two 17D yellow fever vaccines. Lang, J., Zuckerman, J., Clarke, P., et al.[2019]

The study found that immune-compromised patients had similar neutralizing antibody levels and T-cell responses to the yellow fever vaccine as healthy individuals, suggesting that the vaccine remains effective even in those on immunosuppressive drugs.

Despite a negative correlation between time since vaccination and the number of YFV-specific CD8(+) T-cells, the presence of early-differentiated memory T-cells indicates a robust memory response that can effectively expand upon re-exposure to the virus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

17D yellow fever vaccine elicits comparable long-term immune responses in healthy individuals and immune-compromised patients. Wieten, RW., Goorhuis, A., Jonker, EFF., et al.[2018]

Both the 17D-204 and 17DD substrains of the yellow fever vaccine induce strong cellular and humoral immune responses, demonstrating similar immunogenicity, which is crucial for effective protection against yellow fever.

The adverse effects of both vaccines are mostly mild, indicating that they are safe options for vaccination, especially important given the recent re-emergence of yellow fever in certain regions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The 17D-204 and 17DD yellow fever vaccines: an overview of major similarities and subtle differences. Ferreira, CC., Campi-Azevedo, AC., Peruhype-Magalhāes, V., et al.[2019]

In a study of 75 individuals (35 healthy and 40 immunosuppressed), it was found that long-term immunity against yellow fever virus remains intact in most immunosuppressed patients who received the vaccine before starting their treatment, with 88% of them still showing protective antibodies after an average of 21.1 years.

However, a second dose of the yellow fever vaccine may be necessary for some individuals to ensure long-term immunity, as 12% of subjects had insufficient antibody levels, particularly those with longer durations of rheumatic diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term immunogenicity after yellow fever vaccination in immunosuppressed and healthy individuals. Burkhard, J., Ciurea, A., Gabay, C., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Enhanced safety surveillance of STAMARIL® yellow fever vaccine provided under the expanded access investigational new drug program in the USA. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Next generation live-attenuated yellow fever vaccine candidate: Safety and immuno-efficacy in small animal models. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Safety profile of the yellow fever vaccine Stamaril®: a 17-year review. [2013]

4. England pubmed.ncbi.nlm.nih.gov

Serious adverse events associated with yellow fever 17DD vaccine in Brazil: a report of two cases. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Comparison of the immunogenicity and safety of two 17D yellow fever vaccines. [2019]

6. England pubmed.ncbi.nlm.nih.gov

17D yellow fever vaccine elicits comparable long-term immune responses in healthy individuals and immune-compromised patients. [2018]

7. England pubmed.ncbi.nlm.nih.gov

The 17D-204 and 17DD yellow fever vaccines: an overview of major similarities and subtle differences. [2019]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Long-term immunogenicity after yellow fever vaccination in immunosuppressed and healthy individuals. [2022]