H1N1 Vaccine With Adjuvant Would Need Twice The Follow-up, FDA Recommends

FDA's Vaccines and Related Biological Products Advisory Committee meets July 23 to discuss clinical trials for vaccines against the 2009 H1N1 flu virus.

Trials for adjuvanted H1N1 flu vaccines do not need more subjects than those for unadjuvanted vaccines, but would need twice the safety follow-up, according to FDA documents released prior to a July 23 meeting of the Vaccines and Related Biological Products Advisory Committee.

FDA says in the briefing documents that the sample sizes necessary for the H1N1 vaccine trials would be 100 subjects per arm, including those arms containing an adjuvant. For safety follow-up, trials of adjuvanted vaccines would require 12 months follow-up, compared to six months for antigen-only vaccine trials.

The FDA briefing documents reflect the agency's thinking as of the end of June. H1N1 vaccine production is well underway by the five seasonal flu manufactures, who will collaborate with the federal government and the World Health Organization to conduct trials on the products. Those trials could begin as early as this month or in August.

During the meeting, the committee will hear and discuss a variety of presentations, including the status of surveillance for and epidemiology of the H1N1 virus, the status of vaccine manufacture, and FDA's plans to evaluate these products and facilitate the availability of a vaccine.

Potential pandemic forces FDA decisions on adjuvants

The panel's advice to FDA on how adjuvanted H1N1 vaccines should be handled will likely be of great interest to vaccine manufacturers, as the agency to date has been reluctant to approve adjuvanted vaccines. Both Novartis and GlaxoSmithKline are developing adjuvanted H1N1 flu vaccines, MF-59 and AS03, respectively.

But if immunizing the public against the H1N1 virus requires an additional immune boost or a higher yield than would be possible with antigen alone, an adjuvant would be necessary - and quickly - thus opening the door to both the first adjuvanted vaccine approvals and the ability to gain safety data in large swaths of the population ( (Also see "Chick Eggs Cannot Yield Enough Vaccine For Pandemic: NYAS Swine Flu Mtg." - Pink Sheet, 8 Jun, 2009.), p. 24).

How the vaccines are licensed will depend on whether adjuvants are used. If they are manufactured using the same process as for the seasonal flu vaccine, the vaccines will be licensed for use as a strain change. If an adjuvant is used, the product would be released under an Emergency Use Authorization ( (Also see "Flu Vaccine Licensure Depends On Adjuvant; Fall Vaccination Campaign Likely" - Pink Sheet, 13 Jul, 2009.), p. 21).

HHS is coordinating postmarketing evaluation efforts

FDA explains to the panel in the briefing material the overarching trial-design principles to develop immunogenicity data shortly after the vaccine is available, stating that the goal of the trials would be to define the dose for each population and to obtain limited safety data.

Since the data prior to utilization will be limited, FDA states that postmarketing surveillance studies are critical.

Adverse events will be monitored through reports to the vaccine adverse event reporting system (VAERS), the Vaccine Safety Data link system, the Department of Defense, the Centers for Medicare and Medicaid Services, the Veterans Health Administration and other population based health care organizations.

HHS is coordinating that effort, and working to develop data mining tools, daily reports designed for H1N1 vaccines, and vaccine cards with vaccine adjuvant details, including the manufacturer, lot numbers and date of administration, as well as "how to make a VAERS report" information to enhance AE reporting.

FDA and CDC are planning safety surveillance systems which adapt to the various scenarios of public/private payment and administration of vaccines. They are working to prepare surveillance systems which could be adapted to study sub-populations and to respond to epidemiologic data identifying the populations that should be targeted for early vaccination.

FDA outlines trial design principles

In general, separate but concurrently-conducted adult and pediatric studies are recommended. Pediatric studies may include use of an active control arm, and adult studies may include a placebo or active control arm.

The trials should enroll healthy subjects six months to 64 years of age who would be administered two doses of vaccine: 7.5 ug and 15 ug HA of H1N1 in both pediatric and adult populations. Evaluation of higher dose (30ug HA) is recommended in subjects 18 years of age and older. FDA suggests 100 subjects for each antigen dose level and for every dose given with an adjuvant.

After each vaccination, FDA says subjects should be monitored for age appropriate local and systemic reactogenicity for seven days, and for adverse events, serious adverse events and deaths for 21 days.

After the second vaccination, subjects should be followed for six months. If the study includes use of an adjuvant, subjects should be followed for 12 months, and FDA recommends safety lab evaluation at baseline and at early and late time points post-vaccination.

Immunogenicity endpoints, evaluated at 21 days post-vaccination, would include: the proportion of subjects in each group with hemagglutination inhibition and antibody titers ?1:40; seroconversion rate: the proportion of subjects with a 4-fold rise in HI titer; and GMT.

H1N1 vaccine status update

The World Health Organization has recommended that the vaccines should contain A/California/7/2009 (H1N1)v-like virus, and CDC has now antigenically characterized 144 novel A viruses, all related to that virus.

As of June 15, 2009, two classical and three reverse genetics reassortants that have undergone virus characterization and are suitable for vaccine production, were sent to all the WHO collaborating centers and vaccine manufacturers to prepare seed virus for vaccine production.

Studies assessing virus yield are underway, but initial growth studies suggest the yield from the A/California/7/2009 (H1N1)v-like virus is lower relative to the yields of many reassortants used for seasonal flu vaccines.

All U.S. seasonal flu vaccine manufacturers are prepared to make monovalent H1N1 vaccine. Manufacturers include: Novartis, Sanofi-Pasteur, CSL and GSK. MedImmune will supply live attenuated novel influenza A (H1N1) virus vaccine.

-Jamie Hammon ([email protected])