Diluting H5N1 vaccine may protect more people, study says

Jun 26, 2007 (CIDRAP News) – Limited supplies of prepandemic influenza vaccine may prevent more illness cases overall if they are administered to more people in lower-than-recommended doses, University of Hong Kong researchers contend in a study published this month in Public Library of Science (PLoS) Medicine.

Steven Riley and colleagues, who used a mathematical model to predict illness attack rates under different dosing scenarios, report that "substantial reductions in the attack rate are likely if vaccines are given to more people at lower doses."

The authors note that it is unlikely that enough doses of prepandemic vaccines will ever be available to allow universal coverage at maximally protective doses in many countries. The concern over supplies has led scientists and policy-makers to debate who should have priority access to the vaccine, with some arguing for groups at highest risk for severe illness and others for those who are most likely to spread the disease.

In their model, the authors included all three prepandemic H5N1 flu vaccine candidates with available data from phase 2 clinical trials. The data showed that two of the vaccines produced immune responses after doses in the 1.25- to-10 microgram (mcg) and 7.5- to 30-mcg range. The third vaccine yielded immune responses with doses of 7.5 to 90 mcg. In trials of all three vaccines, blood serum samples from at least half of the subjects who received two inoculations at the recommended dose were able to neutralize target flu antigens.

The authors combined data on the immunogencity of the three prepandemic vaccines with data on person-to-person transmission in the past three flu pandemics to create their models. Their aim was to predict how giving the vaccine to different numbers of people at varying doses would affect the number of people infected in a pandemic.

The models predicted that for all three vaccines, giving more people a lower dose of vaccine would limit the spread of disease better than giving fewer people the dose recommended for maximal individual protection, according to the report.

For example, in one scenario, the model showed that if 20 million of the United States' 300 million residents were given two 10-mcg doses of one vaccine, the attack rate would drop from 73.2% to 69.5%, and if the same amount of vaccine antigen were spread out over 80 million with two 2.5-mcg doses, the attack rate would drop to 67.7%.

Another scenario envisioned dividing the planned US vaccine stockpile among 160 million people instead of the targeted 20 million. That approach would lower the overall attack rate from 67.6% to 58.7%, according to the model.

"Our results suggest that a lower vaccine dose may be justified in order to increase population coverage, thereby reducing the infection attack rate overall," the researchers concluded.

Other experts contacted by CIDRAP News had a number of reservations about the authors' findings and their applicability to pandemic preparedness.

Using low doses to spread the vaccine supply to more people would be able to prevent many deaths at the public health level, but it's far from ideal, said Gregory Poland, MD, director of the Vaccine Research Group at the Mayo Clinic in Rochester, Minn. He called the approach "the least attractive option mandated by being unprepared and having an insufficient manufacturing capacity for a pandemic or prepandemic influenza vaccine."

It is impractical to expect individuals to undergo vaccination when they may not derive much benefit from it, Poland said. "From an individual perspective, if you're going to go through the pain, risk, and cost, you want to know you're protected from it," he said. "You want it to be potent enough so you have a 90% -plus chance of responding with protective levels of antibody."

William Schaffner, MD, chairman of the Department of Preventive Medicine and professor of medicine in the Division of Infectious Diseases at Vanderbilt University in Nashville, said that although mathematical modeling studies are rarely practical, "they can be very provocative in stimulating thinking, and I think in that regard, this is very provocative."

However, several issues keep the study results from offering immediate applications, two of which the authors acknowledge in their report, he said. First, data on the efficacy of such low doses of flu vaccine are lacking. Second, the virus that causes the next pandemic may differ significantly from the H5N1 strains that are currently circulating. "The closer the match between the influenza virus represented in the vaccine and the actual virus that's circulating, the more likely it might be that their approach may have some measure of success," he said. "But they acknowledge that influenza viruses change, so if it's not a good match, a low dose will be even less effective" than the recommended dose.

What the authors did not discuss, Schaffner added, is that pandemics occur in waves, and the protection conferred by a low-dose immunization will not last long enough to protect someone against multiple waves that might occur months apart. "You might have some measure of protection for the first wave, but you would be completely vulnerable for the second wave," he said.

Michael T. Osterholm, PhD, MPH, said it would be scientifically, politically, and socially irresponsible to initiate a plan on the basis of this study with so many unknowns. "While conceptually it's important to consider how to protect the most people that we can with what will be inadequate supplies of vaccine, to extrapolate any level of protection using a prepandemic vaccine and the unknowns of immunogenecity is like trying to predict the next lightning strike during an upcoming thunderstorm," said Osterholm, director of the University of Minnesota Center for Infectious Disease Research and Policy, publisher of CIDRAP News.

Schaffner said the use of adjuvants (chemicals included in some vaccines to stimulate the immune system) is a much more positive approach to dealing with the vaccine shortage than simply lowering the vaccine dose. The use of an adjuvant—which he refers to as "Hamburger Helper"— has more relevance to the people who are vaccinated, he said.

"I actually think that concept to stretch the amount of vaccine is a better one because it has the potential for satisfying both goals: you can reduce the amount of actual vaccine dose, but by also providing the adjuvant, you're actually protecting people," he said.

Riley S, Wu JT, Leung GM. Optimizing the dose of pre-pandemic influenza vaccines to reduce the infection attack rate. PLoS Medicine 2007 June;4(6):1032-40 [Full text]

See also:

Fraser C. Influenza pandemic vaccines: Spread them thin? PLoS Medicine 2007 June;4(6):0977-9

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