Wednesday, September 18, 2013

NIH Begins Phase II Clinical Trials On H7N9 Vaccine Candidates




# 7785


As we’ve discussed before, the production of an H7N9 vaccine is not going to be as simple, or straightforward, as was the H1N1 pandemic vaccine in 2009.   With that flu - it was essentially a strain change - substituting the swine-origin H1N1 virus for the seasonal H1N1 component that has been part of the flu shot for decades.


Avian viruses – like H5 and H7 – are an entirely different kettle of fish, and prior experiences with H5N1 and H7N1 vaccines has shown that they are not so easily made.


Last May we saw an analysis of some of the problems inherent in creating and deploying an  H7N9 vaccine published in JAMA, penned by CIDRAP’s  Michael T. Osterholm, PhD, MPH; Katie S. Ballering, PhD; and Nicholas S. Kelley, PhD.

Major Challenges in Providing an Effective and Timely Pandemic Vaccine for Influenza A(H7N9)

Michael T. Osterholm, PhD, MPH; Katie S. Ballering, PhD; Nicholas S. Kelley, PhD

JAMA. 2013;():1-2. doi:10.1001/jama.2013.6589.

Published online May 9, 2013


Previous  H5 and H7 experimental vaccines have required unusually large amounts of antigen (up to 12x normal) to induce a good immune response, a specification that would greatly reduce the number of shots that could be produced each year.   One possible solution is the use of adjuvants   - additives often used in European flu vaccines to increase their immune response.


But adjuvants have never been used in the U.S. flu vaccines, would likely require an EUA (Emergency Use Authorization), and might make some people reluctant to take the vaccine.


Right now, no one knows what the optimal antigen/adjuvant formulation would be for an effective, and practical H7N9 vaccine.


Today, the NIH released a detailed summary of their plans to test a variety of H7N9 vaccine formulations across two clinical trials - involving as many as 1700 volunteers - who will received various strength H7N9 vaccines (adjuvanted and non-adjuvanted). When complete, we should have a much better idea of what will be involved in creating a pandemic H7N9 vaccine.  Full results, however,  are not expected until December of 2014.


National Institute of Allergy and Infectious Diseases (NIAID)


Jennifer Routh 

For Immediate Release: Wednesday, September 18, 2013

NIH begins testing H7N9 avian influenza vaccine candidate

Possible role for adjuvants to be examined

Researchers at nine sites nationwide have begun testing in humans an investigational H7N9 avian influenza vaccine. The two concurrent Phase II clinical trials, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, are designed to gather critical information about the safety of the candidate vaccine and the immune system responses it induces when administered at different dosages and with or without adjuvants, substances designed to boost the body’s immune response to vaccination.


Human cases of H7N9 influenza first emerged in China in February 2013, with the majority of reported infections occurring in the spring. As of Aug. 12, 135 confirmed human cases, including 44 deaths, have been reported by the World Health Organization. Most of these cases involved people who came into contact with infected poultry. Although no H7N9 influenza cases have been reported outside of China and the virus has not demonstrated sustained person-to-person transmission, there is concern that it could mutate to pose a much greater public health threat.


“H7N9 avian influenza virus — like all novel influenza virus strains to which people have not been exposed — has the potential to cause widespread sickness and mortality,” said NIAID Director Anthony S. Fauci, M.D. “We are now testing a vaccine candidate with and without adjuvant in an effort to prepare for and, hopefully, protect against this possibility.”


The two clinical trials, which will enroll healthy adults ages 19 to 64, will evaluate an investigational H7N9 vaccine developed by Sanofi Pasteur. The candidate vaccine was made from inactivated H7N9 virus isolated in Shanghai, China in 2013. Adjuvants are being tested with the investigational vaccine because previous vaccine research involving other H7 influenza viruses has suggested that two doses of vaccine without adjuvant may not produce an immune response adequate to provide effective protection. In pandemic situations, adjuvants also can be used as part of a dose-sparing strategy, which would allow production of more doses of vaccine from the available supply of the viral antigen, thereby allowing a greater number of people to be vaccinated more quickly.


The first clinical trial, led by Mark J. Mulligan, M.D., of Emory University in Atlanta, will enroll as many as 700 study participants who will be randomly assigned to one of seven groups (up to 100 participants in each group). Each group will receive two equivalent dosages (3.75 micrograms [mcg], 7.5 mcg, 15 mcg or 45 mcg) of the candidate vaccine, approximately 21 days apart. Five of the groups will receive the vaccinations along with MF59 adjuvant, developed by Novartis Vaccines and Diagnostics.


Of these five groups, three will receive adjuvant with both vaccinations; one group of participants will receive adjuvant only with the first vaccination; and another group of participants will receive adjuvant only with the second vaccination. Two groups of participants will not receive adjuvant. The MF59 adjuvant that is being tested is also contained in the Fluad seasonal influenza vaccine currently licensed in Europe and Canada for use in people age 65 years or older.


The second trial, led by Lisa A. Jackson, M.D., M.P.H., of Group Health Research Institute in Seattle, will enroll as many as 1,000 participants. Each participant will be randomly assigned to one of 10 groups (up to 100 participants per group) and will receive two equivalent doses (same dosages as the other trial) of the investigational H7N9 vaccine given 21 days apart.


Seven of these groups will receive the vaccinations either with or without AS03 adjuvant, developed by GlaxoSmithKline Biologics. Two groups will receive their first vaccination with AS03 or MF59 adjuvant and then receive the alternate adjuvant at time of second vaccination. One group will receive the MF59 adjuvant at both vaccinations. The AS03 adjuvant that is being tested was used in a 2009 H1N1 influenza vaccine, Pandemrix, used in several European countries during the 2009-2010 H1N1 influenza pandemic.


In both studies, which are expected to conclude in December 2014, a panel of independent experts will closely monitor safety data at regular intervals throughout the trial.


The vaccine studies are being conducted at the eight NIAID-funded Vaccine and Treatment Evaluation Units: Baylor College of Medicine, Houston; Children’s Hospital Medical Center, Cincinnati; Emory University, Atlanta; Group Health Cooperative, Seattle; Saint Louis University, St. Louis; University of Iowa, Iowa City; University of Maryland School of Medicine, Baltimore; and Vanderbilt University, Nashville. The University of Texas Medical Branch at Galveston will conduct the trial as a subcontractor to Baylor College of Medicine.


Further information about both clinical trials can be found at using the identifiers: NCT01938742 and NCT01942265.

For more information, visit NIAID’s Influenza Web portal. For U.S. government information on avian and pandemic influenza, see External Web Site Policy


NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at


Regardless of what influenza virus causes the next pandemic, the reality is that it will take 5 or 6 months to begin to produce any useful quantity of vaccine, and many people would be waiting a year or more to receive one.


Instead – at least in the opening months -   we will be looking to measures like social distancing, school closures, hand hygiene & masks (aka Nonpharmaceutical Interventions NPIs) along with neuraminidase (NA) inhibiting antiviral drugs (NAIs) like oseltamivir (Tamiflu ®) and Zanamivir (Relenza ®) to help mitigate its impact.





Should H5N1, H7N9, MERS-CoV or any other novel virus threaten, we’ll be talking a good deal more about NPIs.