H7N9 Influenza Vaccine Clinical Trials Begin

March 15, 2018

Two new clinical trials testing an experimental vaccine to prevent influenza caused by an H7N9 influenza virus are now enrolling volunteers at sites across the United States. The Phase 2 studies, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), will test different dosages of the inactivated influenza vaccine candidate (called 2017 H7N9 IIV) as well as different vaccination schedules. The studies also will evaluate whether an adjuvant boosts the immune responses of people receiving the vaccine. 

H7N9 is an avian (bird) influenza virus first reported in humans in 2013 in China. Since then, six waves of H7N9 infection have occurred in China, resulting in more than 1,500 cumulative human infections, according to the World Health Organization. No human cases of H7N9 influenza have been detected to date in the United States. Currently, the virus does not spread easily from person to person; rather, people typically become infected through direct exposure to infected poultry or contaminated environments. However, if the virus mutates and becomes easily transmissible between humans, it could result in an influenza pandemic because most people have little to no immunity to it. H7N9 has a high mortality rate, resulting in death in 39 percent of those who became infected.

“As we experience one of the worst seasonal influenza epidemics in recent years here in the United States, we also must maintain a scientific focus on novel influenza viruses, such as H7N9, that have the potential to cause a pandemic,” said NIAID Director Anthony S. Fauci, M.D. “These new clinical trials will build upon initial studies of earlier versions of an H7N9 vaccine candidate to provide a more detailed picture of its safety and ability to generate a protective immune response to current H7N9 strains.”  

The two clinical trials will test the experimental 2017 H7N9 inactivated influenza vaccine developed by Sanofi Pasteur, based in Lyon, France, supported by the Biomedical Advanced Research and Development Authority (BARDA), a component of the U.S. Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response. NIAID funded previous research on the earlier version of the vaccine. The new version of the vaccine candidate uses an inactivated form of H7N9 influenza virus collected in 2017, to increase the likelihood that the vaccine will provide immunity against a newly-evolved strain of H7N9, which is currently circulating in the wild. During these clinical trials, some participants will receive an adjuvant, called AS03, along with the test vaccine, to confirm that the adjuvant can boost the immune response to the vaccine, as previously shown for other influenza viruses of pandemic potential. The adjuvant is produced by GSK’s vaccines business, headquartered in Wavre, Belgium, with support from BARDA. Both clinical trials will be conducted by the NIAID-funded network of Vaccine and Treatment Evaluation Units (VTEUs).

One clinical trial, led by principal investigator Lisa A. Jackson, M.D., of the Kaiser Permanente Washington Health Research Institute in Seattle, will test the vaccine candidate at different dosages, both with and without the AS03 adjuvant. The study will enroll as many as 420 male and non-pregnant female volunteers ages 19 to 64 years and up to 300 volunteers older than 65 years of age. Each participant will be randomly assigned to one of five groups.  Three of the groups (at least 480 volunteers in total) will receive the adjuvanted vaccine candidate, at different dosages (3.75 micrograms (mcg), 7.5 mcg or 15 mcg).  The two remaining groups (at least 160 volunteers in all) will receive unadjuvanted vaccine (15 mcg or 45 mcg). All five groups will be vaccinated twice: once at the first visit, and then again 21 days later. Volunteers will be monitored for seven days following each vaccination and assessed for side effects, and blood samples will be tested for H7N9 antibodies. Clinical staff will follow the volunteers for one year. The trial is being conducted at VTEU sites in Georgia, Iowa, Maryland, North Carolina and Washington.

The second clinical trial will be led by Kathleen M. Neuzil, M.D. of the University of Maryland School of Medicine. This trial will test the H7N9 vaccine candidate with AS03 adjuvant in conjunction with a quadrivalent seasonal influenza vaccine. By administering the vaccine candidate to some volunteers who have received the seasonal influenza vaccine and some who have not, investigators will be able to learn whether the H7N9 vaccine candidate affects the immune response to the seasonal influenza vaccine, and vice versa.

In this trial, the H7N9 vaccine candidate will be given to 150 healthy volunteers ages 19 to 64 years. Each volunteer will be randomly assigned to one of three groups. The first group (60 volunteers) will receive the investigational H7N9 vaccine with AS03 adjuvant (0.5 milliliter [ml] dose of 3.75 mcg) and the quadrivalent seasonal influenza vaccine (0.5 ml dose) intramuscularly within 15 minutes of each other on day 1 and then another dose (3.75 mcg) of the adjuvanted H7N9 vaccine candidate 21 days later. The second group (60 volunteers) will receive the seasonal influenza vaccine (0.5 ml dose) on the first day and two doses (3.75 mcg) of the H7N9 vaccine candidate with adjuvant on days 22 and 43. The third group (30 volunteers) will serve as a comparator and will receive only the seasonal influenza vaccine on day 1. Study participants will be monitored for seven days following each vaccination to assess for side effects, and blood samples will be tested for antibodies to the 2017 H7N9 virus and seasonal influenza. Some volunteers will also be tested for antibodies against other variants of H7N9, to see if the vaccine candidate is likely to provide protection as the virus continues to evolve in the wild. Follow-up for the volunteers will last up to one year after their last vaccination. The study is being conducted at three VTEU sites and one affiliated site. The sites are located in Alabama, Maryland, Ohio and Tennessee. 

For more information about the two clinical studies referenced in this press release, please see the Questions and Answers or visit ClinicalTrials.gov using the identifiers NCT03312231 and NCT03318315, respectively.

Question & Answer: 

Phase 2 H7N9 Influenza Vaccine Clinical Trials 

What is the purpose of these two H7N9 vaccine clinical trials?

These two Phase 2 clinical trials are designed to evaluate an investigational vaccine intended to protect against influenza caused by the H7N9 influenza virus. The two studies will test different dosages of the vaccine candidate (called 2017 H7N9 IIV) as well as different vaccination schedules. The studies also will test how the vaccine candidate works when co-administered with a current seasonal influenza vaccine. Additionally, the studies will evaluate whether an adjuvant, a substance added to a vaccine to boost its immune response, effectively improves the immune response of people receiving the experimental H7N9 vaccine. The clinical studies will build upon earlier research of an H7N9 vaccine candidate to provide a more detailed picture of its safety and ability to generate an immune response to current H7N9 strains. 

What is H7N9 influenza, and why do we need a vaccine to protect against it?

H7N9 is an avian (bird) influenza virus first reported in humans in 2013 in China. Since then, more than 1,500 human cumulative H7N9 infections have occurred in China, resulting in death in 39 percent of those who became infected, according to the World Health Organization. No human cases of H7N9 influenza have been reported in the United States. Most human cases have been reported in China, or have been reported in people who recently traveled to China. Currently, the virus does not spread between people easily. Rather, people typically become infected through direct exposure to infected poultry or contaminated environments. 

There is concern that if the virus mutates and becomes easily transmitted between people, it could lead to an influenza pandemic because most people would have little or no protective immunity to it. A vaccine offers the best way to stimulate immunity that protects against infection and the severe complications associated with influenza. An effective H7N9 vaccine could protect vaccinated individuals from becoming infected and limit the spread of an outbreak and greatly reduce illness and death caused by infection with the virus.

In 2013, NIAID sponsored Phase 2 trials of an earlier H7N9 vaccine candidate. However, the virus is constantly mutating as it circulates in poultry, and during the fifth wave of human infection in China, researchers found that the virus had changed significantly. The new H7N9 vaccine candidate uses a form of H7N9 that was isolated in 2017 in the hopes that it may provide better protection against currently-circulating strains of the virus.

Who is sponsoring, funding and conducting the two studies?

The National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health, is sponsoring and funding the two trials. One study will be led by principal investigator Lisa A. Jackson, M.D., of the Kaiser Permanente Washington Health Research Institute in Seattle. The other study will be headed by Kathleen M. Neuzil, M.D., of the University of Maryland School of Medicine in Baltimore. Several NIAID-funded Vaccine and Treatment Evaluation Units (VTEUs) will recruit patients at their sites to conduct the studies.

Describe the experimental vaccine that will be tested.

The experimental vaccine, called 2017 H7N9 IIV, is a monovalent influenza vaccine. It uses only one strain of flu, an inactivated form of H7N9 influenza virus recently isolated (in 2017) to increase the chances that the vaccine will protect against H7N9 strains currently circulating. The vaccine was developed with help from the CDC and BARDA and manufactured by Sanofi Pasteur.

Because H7 vaccines have historically been poorly immunogenic on their own, this study will also evaluate if an adjuvant can boost the immune response to the vaccine. Therefore, some study participants will also receive an adjuvant, called AS03, to determine if it can boost the immune response to the vaccine candidate. The AS03 adjuvant, manufactured by GSK Biologicals, is mixed with the 2017 H7N9 IIV (inactivated influenza vaccine) just prior to its administration.

What are the designs of the two clinical trials?

In one clinical trial, led by Dr. Jackson, the vaccine candidate will be tested at different dosages, both with and without the AS03 adjuvant (dose-ranging trial). The study will enroll at least 420 healthy male and non-pregnant female volunteers, ages 19 to 64 years, and at least 300 additional volunteers older than 65 years of age—an important population to study, as their immune responses may be different than those in younger age groups.

The participants will be randomly assigned to one of five groups. Three of the groups (at least 480 volunteers) will receive the AS03-adjuvanted vaccine candidate at different dosages: 3.75 micrograms (mcg), 7.5 mcg or 15 mcg of hemagglutinin (HA; a protein normally expressed on the surface of the flu virus). The two remaining groups (at least 160 volunteers) will receive the experimental vaccine without adjuvant at 15 mcg, or 45 mcg. All five groups will be vaccinated twice: once during the first visit, and then again 21 days later. Volunteers will be monitored for seven days after each vaccination and followed for 12 months following the second vaccination to assess for potential side effects. Blood samples collected periodically during the study will be tested for the presence of H7N9 antibodies.

The second clinical trial, led by Dr. Neuzil, will test the AS03-adjuvanted H7N9 vaccine candidate in conjunction with quadrivalent seasonal influenza vaccine (co-administration with seasonal vaccine trial). In this study, the H7N9 vaccine candidate will be given to 150 healthy male and non-pregnant female volunteers ages 19 to 64 years. Each volunteer will be randomly assigned to one of three groups. The first group (60 volunteers) will receive an AS03-adjuvanted dose of H7N9 vaccine containing 3.75 mcg of HA in one arm and the quadrivalent seasonal influenza vaccine in the other arm. They will receive a second dose of the AS03-adjuvanted H7N9 vaccine (3.75 mcg of HA) 21 days later.

The second group (60 volunteers) will receive the seasonal influenza vaccine on the first day, followed by two sequential doses (3.75 mcg of HA) of the AS03-adjuvanted H7N9 vaccine given on days 22 and 43, respectively. The third group (30 volunteers) will serve as a comparator, and will receive only the seasonal influenza vaccine. Volunteers will be monitored for seven days after each vaccination and followed for 12 months following the second vaccination to assess for potential side effects.  Blood samples collected periodically during the study will be tested for the presence of for the presence of antibodies to H7N9 and the four influenza viruses that make up the quadrivalent seasonal influenza vaccine. 

In both studies, volunteers’ blood will also be tested for antibodies against other variants of H7N9 to see if the vaccine candidate is likely to provide protection as the virus continues to evolve in poultry populations. 
 

Where will the two trials take place?

The two trials are taking place at several NIAID-funded Vaccine and Treatment Evaluation Unit (VTEU) sites, and some of their subcontractors.

The dose-ranging trial will be taking place in VTEUs located at the following institutions:

  • The Emory Vaccine Center (Decatur, Georgia)
  • The University of Iowa (Iowa City)
  • The University of Maryland School of Medicine (Baltimore)
  • The Duke Human Vaccine Institute (Durham, North Carolina)
  • The Kaiser Permanente Washington Health Research Institute (Seattle)

The clinical trial testing co-administration of the H7N9 vaccine with seasonal influenza vaccine will be conducted at VTEU sites and subcontractors located at the following institutions: 

  • The University of Maryland School of Medicine (Baltimore)
  • The Cincinnati Children’s Hospital Medical Center (Cincinnati, Ohio)
  • The Vanderbilt University Medical Center (Nashville, Tennessee)
  • The University of Alabama at Birmingham School of Medicine, a subcontractor of Vanderbilt’s VTEU site (Birmingham, Alabama)

How is NIAID ensuring the safety of the study participants?

Clinical study staff will carefully monitor the health of all study participants, and quickly report and manage any adverse health consequences. Additionally, an independent Data and Safety Monitoring Board (DSMB) will conduct periodic reviews of the study data to ensure participants’ safety. A DSMB includes clinical research experts and statisticians who meet at pre-determined times during a study to review safety and efficacy data as they are gathered. 

Content last reviewed on March 15, 2018