DEPARTMENT OF HEALTH & HUMAN SERVICES

US Food and Drug Administration

 CBER/OVRR/DVRPA

1401 Rockville Pike

                                                                Rockville, MD 20852-1448

 

MEMORANDUM

 

 

Background:

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 20^th 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.[1]^, [2]

 

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 Southeast Asia.  The first documented human infections with influenza A H5N1 occurred in Hong Kong in 1997.  Since then, additional human infections have been documented with influenza A/HIN1 virus that mutated from the original isolates, and while rare, possible human-to-human transmission appears to have been documented.  These viruses are highly virulent and mortality associated with confirmed infection is approximately 60%.  Of additional concern is the observation that recent H5N1 strains appear to be more lethal in animal models and that the host range for H5N1 strains has expanded into mammalian species previously thought to be resistant to avian strains.^{2, [3], [4]}  Further information on the number of confirmed clinical cases due to H5N1 strains can be located at the World Health Organization’s website.[5]  These disturbing events highlight the need for influenza vaccines against potential pandemic strains.

 

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 including Canada and countries in the European Union, and the U.S. Government (the Centers for Disease Control, the National Institutes of Health (NIH), and the FDA) are developing guidances and evaluating influenza vaccines for use during an influenza pandemic.  For example, the NIH evaluated an inactivated monovalent influenza A/H5N1 vaccine.  The results from this study are the topic of the first session of this VRPBAC meeting.  Data from this study demonstrated that higher antigen doses and repeat dosing produced a higher antibody response.  The need for larger amounts of antigen and for the administration of two doses approximately one month apart create supply and logistical concerns when preparing for administration of a vaccine to a large population at risk.  Additional challenges to be overcome in planning for a mass vaccination campaign include creation of infrastructure, early identification and generation of the correct reference strain or strains to be included in the vaccine, identification of dosing and schedule of administration, and delays introduced by current manufacturing processes.  Given the multiple potential barriers to assuring maximum deployment of a pandemic influenza vaccine once human-to-human spread has been identified, alternate approaches are under consideration.  One such strategy that we intend to discuss today is pre-pandemic vaccination.

 

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[6], or when vaccine antigens differ in the “booster” dose administered in following season.[7] 

 

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. [8]

 

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.[9]

 

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.[10]  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%.[11]  

 

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[12] 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 Institute of Medicine committee found that evidence favored the acceptance of a causal relationship, yet safety data following administration of influenza vaccine obtained in the years after 1976 did not demonstrate an association with Guillain-Barre syndrome.  Currently, the ACIP estimates that if influenza vaccine posed a risk of Guillain-Barre syndrome, the risk would be approximately one additional case per 1 million persons vaccinated.[13]  Thus, the risk/benefit of the administration of a seasonal influenza vaccine is well-balanced, where risk of influenza in circulation and its complications are clearly known and the benefits of vaccination are established.  In a situation where a pandemic influenza can not be reliably predicted, the risk/benefit of the pre-pandemic administration of a pandemic influenza vaccine containing one or more antigens can not be determined.  A very large safety database might be necessary for consideration of licensure in this setting where there is a very high level of certainty about vaccine safety, for example, a safety database that ruled out a serious adverse event rate of greater than 1 per 100,000.

 

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.