Safety and Immunogenicity of Live Influenza A Vaccine for Avian Influenza H7N7

Overview

Every year the human population suffers from seasonal outbreaks of influenza resulting in both illness and death. However, the rates of illness and death from seasonal outbreaks are significantly lower than those suffered during times of influenza pandemic, such as those experienced in 1918, 1957, and 1968. The reason for this difference lies in presence of immunity within a population. With seasonal outbreaks of influenza most people have some immunity to the circulating strain and usually only those with weakened immune systems experience serious complications. Influenza pandemics, in contrast, are the result of a completely new viral subtype to which nobody possesses an immunity, leaving everyone vulnerable to the most serious of complications. It has been estimated that the next flu pandemic could cause over 200,000 deaths and over 700,000 hospitalizations in the US alone. The need for an effective viral vaccine is high. The purpose of this study is to test the safety and immunogenicity of a live influenza A strain vaccine, which would be able to combat an influenza pandemic.

Influenza, also called the flu, is an RNA virus belonging to the family Orthomyxoviridae that consists of 4 genera: influenza A, influenza B, influenza C, and Thogoto viruses. This vaccine study focuses on influenza A. Influenza A viruses are widely distributed in nature and can infect a wide variety of birds and mammals, including humans. Influenza viral infections affect the respiratory system and are particularly dangerous for those with weakened immune systems. Within the influenza A genus, there are several viral subtypes classified by the ability to produce an immune response of their surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). In contrast to other species, influenza A has relatively few subtypes capable of triggering outbreaks within the human population. Only viruses bearing both H1, H2, or H3 HA genes, and N1 or N2 NA genes have circulated among the human population throughout the 20th century. The years 1918, 1957, and 1968 were all marked by extremely high rates of morbidity and mortality related to influenza. These were also the years in which novel subtypes of influenza had begun to circulate among the population. Because the human immune system had not yet created antibodies for these viruses, the population easily succumbed to a flu outbreak which consequently left thousands dead or impaired. It has been estimated that the next flu pandemic could cause upwards of 200,000 deaths and possibly over 700,000 hospitalizations. Transmission of influenza subtypes through waterfowl, known as avian influenzas (AI), is of particularly great concern to the human population because it has the potential to cause a human influenza pandemic. In the last decade, it has been the AI viruses which have claimed the lives of hundreds during outbreaks. At the start of a pandemic, all humans are immunologically naïve if the nascent virus contains antigenically novel HA and NA subtypes. In the event of a pandemic, the need for an effective vaccine is unequivocal. This study will test the safety, infectivity, and immunogenicity of a live-attenuated pandemic virus vaccine. The study will be an open-label, inpatient trial that will be initiated between April 1st and December 20th of each calendar year, when wild-type influenza virus is unlikely to be circulating in the community. Eligible participants will attend a study screening, which includes medical history, physical examination, hematology testing, liver and renal function testing, H7N7 antibody titer, HIV and Hepatitis B and C screening, urine dipstick testing (with possible urinalysis in the event of an abnormal urine dipstick result), and urine drug toxicology testing. Female participants of child-bearing age may also have a pregnancy test. Two days prior to each vaccination, participants will be admitted to the isolation unit in order to become familiar with unit procedures. There will be two vaccinations during the course of the study. On the day of the first vaccination, a physical examination will be performed and all female participants will have a urine pregnancy test. Only if the participant is deemed healthy will a dose of vaccine in the form of nasal spray will be administered. Following vaccination, all participants will remain on the isolation unit for at least 9 days. Physical examination and test of NW for influenza virus culture will be performed daily until discharge. They will be discharged once nasal wash (NW) specimens test negative for influenza for at least 2 consecutive days beginning on or after Day 7. Physical examination and NW for influenza virus culture will be performed daily until discharge. Participants will return for inpatient treatment 26 days after receiving their first dose of the vaccine. Two days later, or 28 days after the first vaccine, participants will receive a second dose of the influenza vaccine. Participants will then follow the same procedures as before, undergoing daily physical exams and testing of NW specimens. They will be eligible for discharge after another 9 days, provided their NW specimens test negative for influenza for 2 consecutive days. All participants will undergo follow-up testing 56, 82, and 208 days after receiving the first dose of the vaccine. This testing will include providing an interim history, assessment for severe adverse events (SAEs), collection of a blood sample, completing a nasal wash, and assessment for treatments that could potentially interfere with vaccine-induced immunity.