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If a pandemic does come--as most scientists believe it will, despite our best efforts--there will be an urgent need to support responses at the community level. Like politics, all infectious diseases start locally. As generous as the President's proposed plan may be for developing drugs and vaccines against pandemic infectious diseases, primarily influenza, it has only a small portion, $500 million, for strengthening public health responsiveness in the 50 states. Howard Koh, former commissioner of Public Health for the Commonwealth of Massachusetts and head of our Division of Public Health Practice, with support from the CDC, has created a Center for Public Health Preparedness. David Gergen of Harvard's Kennedy School of Government, working with the HSPH Center's Leonard Marcus, has launched a program for national leadership training known as the National Preparedness Leadership Initiative. These programs are providing the best information we have at Harvard University for equipping government officials with the leadership skills they need to deal with emergencies and pandemics.

VACCINES AS CENTERPIECES
According to official Department of Health and Human Services projections, were a pandemic to occur, 200 million Americans could be infected, and perhaps a half-million would require hospitalization. If isolation and quarantine are unlikely to be very effective, we will require a host of alternative protection strategies, ranging from emphasizing hand washing, providing N95 respirators, and reducing social proximity, to preparing workplaces to keep employees at home, protecting medical personnel and first responders, providing treatments, and expanding hospital and mortuary surge capacity in cities and states.

As we undertake measures to reduce the risk of a pandemic and bolster our ability to respond if one does occur, developing an effective vaccine and the capacity to manufacture it in sufficient quantities must form the centerpiece of our preparations. Other public health interventions can postpone transmission of the virus or mitigate its effects, but vaccines are unique in their ability to prevent and provide long-term protection against infection with a new strain of influenza. As Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases (NIAID) put it, "The biggest challenge unequivocally is vaccine production capacity." The U.S. can produce about 60 million doses of vaccine for seasonal flu each year; the world can produce perhaps 300 million. Yet the H5N1 vaccine recently tested by NIAID required at least four times as much killed virus to produce a satisfactory immune response as is normally used in vaccines. That means we could expect to make only 15 million doses in the U.S. and 75 million worldwide--far short of the need in a pandemic.

How can we stretch this capacity? The single largest item in the president's proposal is $2.8 billion to develop a vaccine-production system that is cell-culture-based. Today, we make flu vaccines in chicken eggs, using an approach that dates back half a century and depends on adequate egg supplies and specialized equipment. Developing a new technology to grow the vaccine seed strain in cell culture, as other viral vaccine strains are grown, would be a major advance--one that would speed vaccine production and expand capacity by allowing emergency conversions of vaccine-production facilities from other viruses to influenza in the event of a pandemic. However, this strategy will have a payoff only in the medium- to long-term, at least five years from now.

LINKING VACCINE STRATEGIES
In the short run, one promising approach that could expand our manufacturing capacity is the use of adjuvant-containing vaccines. Adjuvants are chemical additives that augment the immune response, allowing smaller doses of vaccine to be effective and the existing production capacity to yield more doses. An exciting pilot study of an adjuvanted vaccine against influenza H5N3, a relative of the current avian strain, showed that two doses together containing one-third as much antigen as a normal flu vaccine, plus a novel adjuvant manufactured by one vaccine company, could produce a strong immune response. Equally important, this immune response appeared to be broadly effective across a range of different H5 viruses, suggesting that the adjuvant could make a vaccine effective even if it were not perfectly matched against the precise emergent pandemic strain. Alum, an aluminum salt that has been used as an adjuvant since the early 20th century, also appears to be an effective adjuvant in flu vaccines, and has the advantage of having been licensed for many years for use in the U.S. Clinical trials of adjuvanted H5N1 vaccines are now under way, but additional trials and regulatory hurdles must be cleared before such vaccines can be made ready for general use. If accelerated, this process could provide capacity to manufacture flu vaccine for nearly the entire U.S., and could also stretch capacity to provide doses for a significant proportion of the world. Careful clinical studies of vaccines with adjuvants will be essential, however, since an adjuvant that produces too strong an immune response to the infecting virus or an inappropriate immune response could conceivably increase pathology and exacerbate disease.

If we had a vaccine, how could we get people to take it, given that less than a quarter of the U.S. population receives seasonal flu vaccine in a given year? Indeed, even with a shortage, more unused seasonal flu vaccine was discarded in 2005 than in 2004. One strategy for introducing a bird flu vaccine, once we had a sufficient supply, would be to add it as a component of our trivalent seasonal influenza vaccine. We do better against seasonal flu, immunologically speaking, in part because we have already developed some immunity and immunological memory to related strains from previous years, which can then be boosted by vaccines or even by infection. We need to begin to prime our immune systems to a newly emergent, related pandemic bird-flu strain, even if it is not precisely the same as that which emerges as a pandemic.

Our annual seasonal flu vaccines generally are composed of the three strains judged by WHO's expert surveillance network as most likely to spread each year. In order to begin to engender some level of immunity to bird-flu strains, we propose to add to our regular seasonal influenza immunization program a fourth strain, an H5N1 strain, after demonstrating its safety in volunteers. If this multivalent flu vaccine were efficiently deployed to all Americans, this strategy would not only prevent many of the 36,000 deaths annually in the U.S. from seasonal flu and prime our immune systems against bird strains, but also enable rapid scale-up of a specific vaccine strain when the pandemic strain emerges and create a credible market for industry.

Any new vaccine program against a pandemic raises enormous ethical and regulatory questions. If supplies were limited, who would be given vaccines? First responders? Politicians? Would enough vaccine be produced to protect people in developing countries? How would its distribution be funded? Could adjuvanted vaccines gain the same rapid FDA approval as standard seasonal vaccines to which an H5N1 vaccine could be added as simply an additional strain? Would companies have to cut back on seasonal vaccine production to create capacity for a pandemic strain? In the event of a major pandemic, would vaccination be made compulsory, as it is in almost all states for children to attend school? And how would these ethical questions be resolved in a time of crisis?

As the tragic outcomes of the 1918 flu and hurricanes Katrina and Rita compellingly tell us, our tradition of throwing money at the problem only after a disaster has occurred will not work with pandemic flu and other health emergencies. This country, as well as every city and town, needs to prepare for a pandemic in advance. We at Harvard are doing our best to contribute our knowledge and skills to this global effort--by modeling possible epidemiologic scenarios, by collaborating with colleagues in Asia, by anticipating how to respond to outbreaks of influenza, and by training public health professionals in this country and abroad to lead efforts to thwart the next pandemic.

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