Scientists at the British Department of Health’s Pandemic Influenza Scientific Advisory Group have suggested that inoculating at least 75 percent of the population with a pre-pandemic H5N1 vaccine could confer sufficient immunity to cut infection dramatically if done in combination with massive use of antivirals.

But vast use of antivirals is just as worrisome. Authorities say some influenza strains have developed immunity to antivirals, including the most effective one, Tamiflu, made by F. Hoffmann-La Roche Ltd., Basel, Switzerland. They are concerned that the widespread use of Tamiflu could accelerate the viruses’ resistance, rendering the medication ineffective to later waves of infection.

In its pandemic preparedness-funding package two years ago, the government earmarked less than $2 billion for exploring new vaccine manufacturing methods, assisting manufacturers in retrofitting their half-a-century-old vaccine production process with 21st-century technology and expanding existing production lines.

In June, HHS awarded two contracts totaling $132.5 million to Sanofi Pasteur, Lyon, France, and MedImmune Inc., Gaithersburg, Md., over five years to retrofit their existing egg-based domestic vaccine manufacturing facilities on a cost-sharing basis to expand influenza vaccine manufacturing capacity that could be used in the event of a pandemic.

Upon completion, these facilities will expand domestic pandemic vaccine manufacturing capacity by 16 percent.

Also in June, Novartis Vaccines & Diagnostics, Basel, Switzerland, began construction of the first cell culture-derived flu vaccine plant in the United States. HHS awarded a $220.51 million grant to the company a year earlier to aid in the construction. The facility is expected to produce up to 150 million doses of monovalent vaccine supplemented with the company’s adjuvant technology in the event of a pandemic outbreak.

In May 2006, DynPort Vaccine Company LLC, Frederick, Md., and Baxter International Inc., Deerfield, Ill., received a potential $242.5 million contract from HHS to develop Baxter’s cell-cultured seasonal and pandemic influenza vaccines.

GlaxoSmithKline, Brentford, UK, received a $274.75 million assistance grant; MedImmune, $169.6 million; DynPort Vaccine, $40.97 million; and Solvay Pharmaceuticals Inc., Marietta, Ga., $298.59 million.

Dr. Robin Robinson, acting associate director for HHS’ Pandemic Influenza Program, said HHS wants to be able to produce 475 million doses of pandemic vaccine by 2011 within six months of a pandemic outbreak.

But according to sources familiar with the progress, adequate production capacity isn’t expected until well after 2012.

“We must be prepared to face the first wave of the next pandemic without vaccine and potentially without sufficient quantities of influenza antiviral medications,” a CDC statement warned.

Stockpiling and administering antivirals

Lacking a vaccine, authorities will have to rely on antivirals.

HHS’ goal is to have 81 million doses (10 capsules per dose) of Tamiflu, Relenza and Rimantidine available for the US population. Of this 81 million, 50 million are to be stored in the Strategic National Stockpile (SNS). Of this, approximately 44 million courses are to be held for emergency pandemic usage by states and 6 million reserved for domestic containment efforts at the onset of localized outbreaks.

Of the 50 million doses the government plans to put into the SNS, though, only about 36 million have been procured.

The Department of Defense has stockpiled many millions less, and only 37 states have stockpiled 13 million of the 31 million doses HHS is supposed to help states buy, largely because the remaining 14 states have had difficulty coming up with their share of the money for purchases, Hamburg said. HHS is authorized to subsidize 25 percent of the procurement costs states incur, apportioned based on population.

Oklahoma is among the states that haven’t yet stockpiled Tamiflu because of the cost. Even with manufacturer F. Hoffmann-La Roche giving states an 80-percent discount on the medication, states still must fork up $14.43 per dose. Oklahoma would have to spend $10 million to stockpile enough of the drug to treat a massive outbreak. The state is having a hard enough time just keeping its only Level 1 trauma center open.

States without stockpiles shouldn’t count on having supplies earmarked for them in the SNS. According to the HHS pandemic plan, “Should the military stockpile be exhausted and additional antiviral medication required to ensure national defense or continued support to civil authorities, use of antiviral drugs from the national stockpile may also be required.”

There’s another problem with Tamiflu, in particular. It has a shelf life of approximately five years, which means stockpiles must be replenished. Existing mass stockpiles will have to be replaced in order to ensure there are adequate stores beyond 2010, but according to F. Hoffmann—La Roche, new orders for future batches have dwindled, and there’s a lag time in making the drug.

The Food and Drug Administration manages a Shelf Life Extension Program, but only products in the federal SNS are eligible to receive an extended expiration date if a drug meets specific conditions. When states’ stockpiles expire, they will have to buy new supplies—without additional federal assistance. This problem combined with those states that have yet to procure their own stockpiles means there will likely be a widespread national shortage of antivirals.

Brit Oiulfstad, the pandemic influenza coordinator for the County of Los Angeles, told HSToday she and other authorities “are concerned about … the current push for community-wide antiviral prophylaxis when the effectiveness for such long-term use (several times the duration of the recommended treatment period) has not been evaluated.”

Even CDC’s community mitigation guidance cautions that “it is not known if influenza antiviral medication will be effective against a future pandemic strain.”

HHS’ pandemic plan calls for “targeted antiviral prophylaxis … of disease clusters, administration of antiviral treatment to persons with confirmed or suspected cases of pandemic influenza and provision of drug prophylaxis to all persons in [an] affected community.”

Oiulfstad noted that heavy reliance on antivirals is “even more troubling when we are currently dealing with the effects of overuse/misuse of antibiotics.”

HHS’ pandemic plan makes note of this concern: “CDC will work with state and local partners to monitor the development of resistance to antivirals … resistance may develop rapidly if these drugs are used widely.”

“Planning for antivirals is very complex as we are not certain that the current antivirals will be effective in whatever viral strain will be circulating,” Oiulfstad said. “However, planning for any pharmaceutical dispersal is good for other future events. In Los Angeles County, planning for antiviral use and distribution is going well as our overall goal is to use antivirals in medical settings to reduce serious illness and death among cases, not general prophylaxis.”

Oiulfstad added: “We do not know the effects of long-term antiviral use in a prophylactic setting. Therefore, we always consider that we must do no harm, and until we have some more answers, we proceed on those recommendations for prophylaxis with great caution. Until the science is in that shows that these drugs prevent illness, this seems to be the only reasonable way to approach the problem.”