Next-Gen Smallpox, Anthrax Vaccines To Be First Use Of Animal Efficacy

A next-generation smallpox vaccine is expected to be the first product licensed under FDA's animal efficacy rule, HHS Office of the Assistant Secretary for Public Health Emergency Preparedness Senior Advisor Philip Russell, MD, said Aug. 28.

The National Institutes of Health will contract out the development and manufacturing of a modified vaccinia Ankara vaccine for smallpox; a request for proposals was published Aug. 15. NIH expects to have the contract signed by Jan. 31.

Phase I studies are already planned for the fall; the RFP is a three-year contract for expanded Phase II trials in healthy subjects and Phase I and Phase II studies in "at risk" populations. NIH plans to issue a second RFP in June 2003 for the licensure plan and manufacture of 30 mil. vaccine doses.

Russell presented the outlook for the smallpox vaccine during the inaugural meeting of HHS Secretary Thompson's Council on Public Health Preparedness, held in Washington, D.C. Aug. 26-27. The next public meeting is slated for late December/early January.

The safety and efficacy of the smallpox vaccine will be based only on animal studies. "This may be one of the first vaccines licensed under the animal rule," Russell noted. "FDA's advice was to attempt to license it under protection of that very rule."

FDA's final rule on animal efficacy studies, published May 31, allows approvals based solely on animal data when studies in humans would be unethical, such as those for bioterrorism agents (¹ (Also see "FDA Animal Efficacy Rule Drops Superiority Requirement For New Agents" - Pink Sheet, 3 Jun, 2002.), p. 3).

A next-generation anthrax vaccine - a recombinant protective antigen vaccine - also will be licensed under the animal rule. A request for R&D proposals was issued April 22 and an initial purchase contract for up to 25 mil. doses should be signed in September 2003, Russell said. Licensure is targeted for 2004.

The anthrax vaccine will require multi-agency support, Russell stressed. "The way we approach it, and the way the research is done and the way the regulatory agencies respond is going to be very, very important. The leadership of the NIH will be very, very important."

"We're going to be setting important precedents with these two vaccines," he maintained. "Both will require animal rule for licensure [and] both will have to be tested in primates....These will be an interesting test of how effectively we can utilize that rule to bring products through licensure."

The anthrax vaccine will employ an inhalation aerosol challenge in rhesus monkeys, while the smallpox vaccine will rely on the monkey pox model. One of the "crunch points" will be retaining an adequate supply of primates and locating research facilities that can conduct aerosol challenge tests, Russell said. "We're convening interagency committees to deal with the prioritization of the supply of both."

A common theme of the contracts signed to date is that large-scale production is beginning while the vaccine is still in early-stage trials. In addition to speeding up the production time in case of an attack, the strategy affords manufacturers a guaranteed return on investment (see ² (Also see "Financial Disclosure Violations Are Unlikely To Warrant Clinical Holds – FDA" - Pink Sheet, 2 Sep, 2002.)).

Until the vaccines are licensed, the government will rely on products manufactured under INDs. Russell acknowledged that "use of IND products on an emergency basis is a difficult problem, but I don't think we can promise not to use IND products if there is an emergency sufficient to require them."

"We hope we can get licenses as early as possible, and use them under the licensing. If, in the meantime, there's an emergency requirement then there is a way of using an IND product."

Two nearer-term smallpox vaccines under INDs are being developed by Acambis. The Acambis 1000 cell culture vaccinia is under a September 2000 contract with the Centers for Disease Control & Prevention. The contract, originally for 40 mil. doses, was increased to 54 mil. after the Sept. 11 terrorist attacks.

Large-scale manufacturing of Acambis 1000 will commence in early 2003, as the vaccine enters a large-scale safety trial. A Phase I trial in 100 vaccinia-naïve subjects is complete and a Phase II trial with previously vaccinated subjects is underway.

In addition, Acambis and Baxter are developing a seed virus derived from Acambis 1000 under a separate CDC contract for 155 mil. doses, signed in November 2001 (³ (Also see "Acambis Smallpox Vaccine Contract Could Carry 30% To 40% Profit Margins" - Pink Sheet, 3 Dec, 2001.), p. 3). Acambis expects to receive BLA approval in the third quarter of 2003 (⁴ (Also see "Acambis Smallpox Vaccine FDA Review Expected In Third Quarter 2003" - Pink Sheet, 3 Dec, 2001.), p. 4).

An IND for the seed virus vaccine - Acambis 2000 - was filed Aug. 21, and 10 mil. doses have been produced. A Phase I/II trial will run from September to December, with a 9,000-patient Phase III trial commencing immediately afterward.

Russell noted that the Phase III clinical trials will not be typical efficacy studies, but will rather be treated as an "extended safety trial" by "getting data in the spectrum of the U.S. population at a large enough sample to ensure we really understand the safety issues."

"Other products, both the large-scale efficacy and safety, are combined in a single Phase III trial. But in this case, we're going to have to do the safety separately from the efficacy. But we will have to do very large-scale trials to be sure of the safety. That will be many thousands of folks."

In addition, NIH is diluting batches of Wyeth's DryVax smallpox vaccine by a 1 to 5 ratio, which would expand the current 15.4 mil. doses to 77 mil. The government also has on hand 85 mil. doses that Aventis donated after the stockpile was discovered (⁵ (Also see "Smallpox Vaccine Immunization Policy Should Be Subject Of Hearings – Frist" - Pink Sheet, 1 Apr, 2002.), p. 18).

One complication with administering smallpox vaccine is the way it is packaged, Council Chair D.A. Henderson, MD, noted.

The current stockpile has 100 to 500 doses in each vial, which last two weeks after reconstitution. Manufacturers have attempted to package less vaccine in each vial, but has found that at less than 100 doses, or .25 mL per vial, the product begins to show irregularities.

Intravenous vaccinia immune globulin could be available within weeks for use with the smallpox vaccine. CDC contracted with the Canadian company Cangene in August for the production of VIG for 30,000 treatment units. Delivery should begin in September and conclude early next year.

The shipments will approximate $40 mil. during Cangene's fiscal year 2003 (began Aug. 1), the company said. In addition to the supply contract, CDC will fund roughly $7 mil. of Cangene R&D costs.