DEPARTMENT OF HEALTH & HUMAN SERVICES
US Food and Drug Administration
1401 Rockville Pike
Influenza pandemic outbreaks occur when a new Type A hemaglutinin subtype gains the ability for efficient human-to-human transmission in a population that has little if any immunity. The hemaglutinin is one of two major proteins on the outer surface of influenza viruses and while variant hemaglutinins emerge frequently resulting in seasonal outbreaks of disease, entire new subtypes occur less regularly. Three influenza pandemic outbreaks associated with new influenza A subtypes occurred during the 20th century. Pandemic strains may evolve as a result of reassortment between co-circulating viruses or as a result of a multiple of genetic mutations, such as what appeared to have occurred in an avian influenza virus and resulted in the 1918-1919 pandemic strain allowing it to adapt and spread among humans., 
In recent years, the documentation of human infections with
avian influenza strains have led to increasing concern that one or more of
these strains may evolve to a pandemic strain able to spread among humans. Of particular concern is the influenza A/H5NI
subtype with well-documented avian-to-avian transmission among poultry or wild
birds. This subtype has sporadically
infected humans primarily in
International planning is underway to begin to
address the production and licensure of influenza vaccines for prevention of disease
caused by pandemic influenza strains. The
World Health Organization, regulatory authorities in many other countries
Challenges with Influenza Vaccines Indicated for use During a Pandemic:
The WHO and the VRBPAC meet in the winter of each year to discuss the selection of the strains to be used for production of seasonal influenza vaccine for the subsequent influenza season. For a trivalent manufacturing process, the time involved for an egg-based production is at least four to five months, or longer depending on the growth characteristics of the selected strains. Although a monovalent vaccine might be produced in a somewhat shorter amount of time, the selection and preparation of a suitable pandemic vaccine strain to be used and the egg-based production process would still require months before monovalent vaccine availability. Long-term stability data are usually not considered for seasonal trivalent influenza vaccines because of the need to change the antigen components year-to-year. If a decision is made to stockpile inactivated monovalent influenza vaccine for use during a future pandemic, another challenge would be the stability data requirements of the inactivated influenza vaccines over the time course of years.
Pre-pandemic or Inter-pandemic Vaccination:
The concept of “priming” vaccination has been proposed in order to circumvent some of the challenges associated with a mass vaccination campaign during an influenza pandemic. The “priming” concept is the basis for the recommendation that children younger than nine years of age who are receiving their initial influenza vaccination be given two doses separated in time. It is likely that, in addition to immaturity of the immune system in this population, the lack of natural influenza infection is considered an important factor in the need for two doses. In children, priming appears to have a favorable effect on the immune responses to subsequent vaccination even when “booster” doses are separated widely in time, or when vaccine antigens differ in the “booster” dose administered in following season.
In a small study, a “priming” dose and a “booster” dose widely separated in time appeared to demonstrate an effect of “priming”. Study subjects who received an experimental influenza A/H5 vaccine approximately 6 years previously appeared to have immune responses following administration of a single dose of a monovalent inactivated influenza A/H5N1 vaccine. The preliminary results of this study were presented at the 2006 meeting of the Infectious Disease Society of America. 
Observational studies designed to evaluate heterologous or homologous immunity suggest that prior antigenic experience may protect or ameliorate serious influenza illness. For example, persons with previously documented influenza A/H3N2 or who had serological evidence of past infection with influenza A/H3N2 appeared to be protected from severe illness due to antigenically drifted influenza A/H3N2 in subsequent circulation.
Some studies of culture-confirmed influenza A infection evaluated the effects of influenza vaccine that represented antigenically drifted variants in comparison to the influenza in circulation. A recent publication evaluated trivalent vaccine efficacy during the 2004-2005 influenza season. The influenza A/H3N2 virus in circulation represented an antigenically drifted strain in comparison to the influenza A/H3N2 strain used vaccine manufacturing. A high level of vaccine efficacy (greater than 70%) was observed. Culture-confirmed cases of influenza were examined during a 1977 outbreak of influenza A/Texas/1/77-like strain among a population who could clearly identify whether seasonal influenza vaccine had been administered. Persons who received influenza vaccine representing a drifted variant influenza A/Victoria/3/75 were observed to have a high level of vaccine efficacy of approximately 80%.
The addition of adjuvant in order to reduce the amount of antigen administration might have significant public health importance in the setting of limited pandemic influenza vaccine supply. The addition of adjuvant in order to prolong the duration of the immune response or result in a broad heterologous immunity, as suggested in some small studies and might be advantageous in a pre-pandemic setting, would require confirmatory studies.
Therefore, there are data to suggest that administration of a booster dose of influenza vaccine, containing the same or drifted antigens, may achieve acceptable immune responses even when the timing of the second dose is widely separated in time. In addition, previous infection or evidence of exposure to influenza A antigens appear to provide protection against drifted influenza A strains in circulation. Finally, culture-confirmation studies suggest that administration of an influenza vaccine representing influenza A strain that is antigenically drifted from influenza A strain in circulation can result in high levels of vaccine efficacy.
Risk versus potential benefit:
Risk and benefit should be carefully considered if a mass
pre-pandemic vaccination campaign is employed in order to prevent disease from influenza
that is not yet in circulation. The “Swine
Flu Vaccine” experiences in 1976 highlight the risk concerns, when additional
cases of Guillain-Barre syndrome appeared to be associated with administration
of influenza vaccines containing a H1N1 antigen. An
Issues for Committee Consideration:
The purpose of this VRBPAC session is to assist the Office of Vaccine Research and Review in the guidance of clinical development and ultimate licensure of vaccines for use in the pre-pandemic setting, for the prevention of influenza A/H5N1, or other influenza A antigens that might represent a pandemic influenza A subtype. Specific discussion items are being finalized at this time, and may include some of the following issues:
· Clinical trial design of adequate and well-controlled studies to be used for purposes of licensure of a pandemic influenza vaccine for use in a pre-pandemic setting.
· Duration of immune responses and length of time necessary to demonstrate a desired “boost” response to a homologous antigen or to a heterologous antigen. For example, continue to follow all subjects enrolled in studies of all phases of clinical development in order to administer a vaccine “boost” at 12 months or 24 months.
· The size of the safety database that would be required for licensure of a vaccine to be used in the pre-pandemic setting, which may depend on different scenarios:
o Sponsor has a licensed manufacturing process for seasonal influenza vaccine
o Sponsor has a novel manufacturing process
o Sponsor intends to administer the vaccine with a novel adjuvant.
· Collaboration among different sponsors for studies to determine the heterologous immune response “boost” with an antigenically drifted strains or different clades.
· The use of immune response assays, including HAI antibody assay and other assays such as neutralizing antibody or cell-mediated immune response, in the determination of appropriate heterologous or homologous immune responses.
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 Department of Health and Human Services, NIH News. “Preliminary Results Suggest Priming Boosts Immune Responses to Variant H5N1 Vaccine”, which can be found on the World Wide Web at: http://www.nih.gov/news/pr/oct2006/niaid-12b.htm
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