Influenza A H1N1 vaccine trials underway

The first vaccine to protect the U.S. population from novel influenza A H1N1 may be ready as early as mid-October, representatives from candidate vaccine manufacturers said yesterday in a meeting with the FDA Vaccines and Related Biologicals Advisory Committee.

In an effort to increase flexibility in response to the pandemic, FDA officials will allow manufacturers to test H1N1 vaccine candidates under the same guidelines used each year when new strains are selected for the seasonal influenza vaccines — omitting the necessity for new safety and effectiveness data traditionally required.

“We recognized very early on that we will need a vaccine that can be deployed in early fall and we need to be prepared for implications in a population that is immunogenically naive,” Wellington Sun, MD, director of the Division of Bacterial, Parasitic and Allergenic Products at the Center for Biologics Evaluation and Research (CBER) Office of Vaccine Research and Review said. “Time is not really on our side.”

Many uncertainties must be overcome before the vaccine is ready for distribution and clinical trials initiated this week are expected to help provide the answers.

Antigen yields obtained from reassortant strains shipped to the manufacturers earlier this month are low at around 30% of what would be expected from the seasonal H1N1 virus strain, raising questions about optimal dosing concentrations, whether the vaccine should be administered as one dose or a two-dose series (21 days apart) and whether an adjuvant will be necessary.

Any one of these variables may also have repercussions for interactions between the pandemic and seasonal vaccines, resulting in the potential for the reduced immunogenicity of either.

Currently, each of the five influenza vaccine manufacturers licensed in the United States are starting trials to determine which of several vaccine formulations is best.

While vaccine candidates must contain A/California/07/2009-like H1N1 virus and WHO recommends a monovalent live-attenuated vaccine, the following dosing options will be under scrutiny during clinical trials: an unadjuvanted vaccine containing 7.5 ug of antigen per dose, 15 ug per dose or 30 ug per dose; and a vaccine incorporating one-of-two novel oil-in-water adjuvants containing either 3.75 ug of antigen per dose or 7.5 ug per dose.

The two adjuvants in question, MF-59 and ASO3, have yet to be used in any vaccine licensed in the United States and an influenza vaccine containing these components may only be administered under Emergency Use Authorization as provided in section 564 of the Federal Food, Drug and Cosmetic Act.

Representatives from Novartis and GlaxoSmithKline, the two manufacturers testing adjuvant vaccines, reassured the committee that safety data accrued in the 10 years that have passed since the adjuvants’ use in Europe indicate increases in mild, temporal injection site adverse events only, and that the adjuvants inclusion in a vaccine may have dose-sparing benefits.

Officials hope that data generated in the ongoing trials will also help inform decisions concerning selection of target high-risk populations, including pregnant women and infants aged younger than 6 months. – by Nicole Blazek

The use of squalene-based adjuvants is probably the issue that’s likely to get the most amount of attention. Parents are concerned about the safety of combing those adjuvants with other vaccines in the regular childhood schedule and about giving these adjuvants to populations with autoimmune problems. The extent to which we have data on adverse events has to be absolutely and completely transparent or the very first time something untoward happens to a child with eczema, food allergies or something, it will be a very serious problem.

– Vicky Debold, PhD, RN

Director of Patient Safety

National Vaccine Information Center, Vienna, V.A.

Vaccines and Related Biologicals Advisory Committee member

While we need to keep our minds open, there are no data that I am aware of that should keep us from carefully evaluating and adopting adjuventated influenza vaccines for all ages. They could save many lives, especially when the vaccine production yields are compromised, as appears to be the case for novel H1N1 this year.

– John F. Modlin, MD

Dartmouth-Hitchock Medical Center, Lebanon, NH

Vaccines and Related Biologicals Advisory Committee member

I don’t want CBER to walk away from this meeting thinking that we’re all scared of adjuvant vaccines. Speaking for myself, I’m delighted that the option is there.

– Theodore C. Eickhoff, MD

Infectious Disease News Chief Medical Editor

Vaccines and Related Biologicals Advisory Committee member