Intranasal Influenza Vaccine: Title and subTitle BreakAdding to the Armamentarium for Influenza Control

In the United States, national influenza vaccine recommendations have typically been based on the prevention of complications and death among high-risk persons. More recent is the increasing awareness that above and beyond the more severe individual medical consequences of influenza, enormous societal economic costs are associated with disruptions due to school and work absences and days of illness. In this issue of THE JOURNAL, Nichol et al¹ report that use of a live, attenuated influenza virus (LAIV) vaccine, administered by intranasal spray to healthy, working adults (a group without a routine recommendation to receive influenza vaccine), was followed in the subsequent influenza epidemic season by a significant reduction in severe febrile illness, days lost from work, health care visits, and the medication use that accompanies these illnesses. Are these findings important? From an individual, medical, and public health point of view, the answer is clearly yes. Reductions in febrile illnesses, defined in various ways, ranged from approximately 13% to 27%, reductions in work days lost from 18% to 28%, and reductions in health care visits from 25% to 41%.

An example of the significance of influenza are the quantitative studies of the impact of influenza in the Houston, Tex, community. From 1974 to 1985, the annual infection rate was estimated at 300 per 1000 persons with approximately two thirds of these infections inducing illness.² Further estimates were that about 50% of those who become ill seek medical care, 1% of those who seek medical care are hospitalized, and 8% of those who are hospitalized die as a consequence of influenza.² These data were developed from families with young children, in which infection rates might be somewhat higher; hence, the true rates may be somewhat lower. Although these data were collected more than 10 years ago, recent reports of health care visits for febrile respiratory tract illness in 2 managed care systems during an influenza epidemic suggest that the impact of influenza in the community has not changed (W. Paul Glezen, MD, oral communication, June 1999). Extrapolation of these figures to the US population leads to annual influenza estimates of 65 million who develop symptomatic illness, 30 million who seek medical care, 300,000 who are hospitalized, and 25,000 who die of influenza.

Clearly, there are societal, medical, and economic benefits to preventing influenza. However, it is important to stress that the health benefits reported by Nichol et al are not unique to LAIV vaccines. Studies of the effectiveness of licensed inactivated influenza virus vaccine among working adults also have been reported, with similar findings. Four recent studies using influenza virus vaccine reported reductions of approximately 25% in illnesses, accompanied by a 43% reduction in days of illness, a 44% reduction in health care visits, a 30% reduction in weekly case rates, a 54% reduction in influenzal illnesses, and a 53% reduction in work days lost due to febrile respiratory tract illness.^{3 - 6} In all of these studies, the vaccine strain antigenically matched the epidemic strain. Nichol et al make the point that the circulating epidemic virus during their study period represented a virus with significant drift from the vaccine virus.¹ During the study period, the Centers for Disease Control and Prevention reported that only 23% of the isolates nationally were the same as the vaccine strain.⁷

While Nichol et al concede that a direct comparison with inactivated vaccine would be required to determine whether LAIV vaccine induced greater protection than influenza virus vaccine, they imply that enhanced protection might be expected from the live attenuated vaccine because of a potential for selected immune responses thought to occur more commonly following live vaccine–type infection than following inactivated vaccine infection. However, other potentially beneficial immune responses are greater after inactivated vaccine administration than after LAIV vaccine administration.^{8 - 9} Cross-reacting antibodies to antigenic variants appear after both inactivated vaccine and natural infection and their appearance has been related to protection.^{10 - 11} Additionally, comparison studies of similar LAIV vaccines administered intranasally and inactivated vaccines administered intramuscularly to healthy adults indicated that a similar degree of protection ensued, whether the epidemic virus was identical to the vaccine virus or was an antigenic variant.^{12 - 13} Thus, it seems most reasonable to believe that the 2 vaccines (LAIV and inactivated vaccines) are probably equivalent for inducing protection among healthy, working adults until data from direct comparison studies show otherwise.

Because influenza is exceedingly common, is highly transmissible, causes yearly outbreaks worldwide, and is responsible for significant morbidity and mortality, it would seem a prime candidate for prevention by a safe and effective vaccine. Yet, influenza immunization rates remain below desired levels, particularly for high-risk individuals and those in minority groups.¹⁴ Progress is being made, however. For instance, in 1985, the baseline rate of influenza immunization among the elderly was 20%. In the last 15 years, the influenza immunization rate in the elderly has increased to 65%,¹⁵ exceeding the Healthy People 2000 goal of a 60% immunization rate but staying well below the 90% immunization rate proposed for Healthy People 2010.¹⁴ Moreover, influenza immunization rates for high-risk persons younger than 65 years remain significantly below 50%.¹⁵

Why haven't the public health and medical communities done more to increase immunization rates against a disease that kills more people in the United States each year than acquired immunodeficiency syndrome? Despite the value of annual influenza vaccine programs in preventing hospitalizations and deaths, a number of barriers—including logistics, direct and indirect costs associated with the trained personnel needed to administer an injection, and patient and physician compliance—make annual influenza vaccine programs difficult, inconvenient, and expensive. In this regard, it appears that the major advantage of an intranasal vaccine is the ease with which it can be administered. In the study by Nichol et al, 70% of study participants self-administered the vaccine. This suggests a potential improvement in the ability to prevent influenza transmission by the widespread means of painlessly self-administering a vaccine whenever it is convenient. A further advantage would be the ability to obtain the vaccine over the counter, eliminating the cost and inconvenience barriers currently associated with mass influenza immunization programs. Additionally, these factors would have tremendous benefits for the development of a vaccine-based program to prevent pandemic influenza, assuming such a vaccine could be manufactured and distributed in sufficient quantity and in a timely manner.¹⁶ Such a vaccine also would be appealing for preventing epidemic influenza transmission by mass immunization among the most efficient transmitters of disease—school-aged children.¹⁷

The study by Nichol et al reinforces the costs of not preventing influenza and the savings that can result from immunization. Physicians must be knowledgeable about the efficacy and cost-effectiveness of influenza virus vaccine,^{18 - 21} the effectiveness of influenza vaccine among healthy, working adults, and the efficacy of influenza vaccine in reducing the risks of pneumonia, hospitalization, and death among elderly persons.^{19 - 23} The inactivated vaccines are safe and effective¹⁵ and the LAIV vaccines used in the study by Nichol et al also appear to be safe and effective for use in segments of the population. Notable in this regard is the recently described high level of efficacy of LAIV vaccine among healthy children aged 1 to 5 years.²⁴ Other influenza vaccines are under development, such as multidose live attenuated vaccines,^{25 - 26} virosome vaccines,²⁷ recombinant hemagglutinin baculovirus influenza A vaccines,^{28 - 30} and DNA vaccines,³¹ indicating that vaccine options for different circumstances and populations should become increasingly available in the future.

In light of the combination of vaccine options now available and under development, along with the demonstrated public health problems caused by influenza, the Institute of Medicine has placed the administration of influenza vaccines to the general population on its list of most beneficial vaccines and strategies for the 21st century.³² The development of new options for the prevention and control of influenza (including new antiviral drugs) represents important advances against an old but major disease. The intranasal LAIV vaccine studied by Nichol et al represents a major potential addition to the armamentarium for control of influenza, at least in children and healthy, working adults. Perhaps truly effective control of this challenging problem is a realistic goal for the early years of the next millennium.