A Single-Dose Influenza A (H5N1) Vaccine Safe and Immunogenic in Adult and Elderly Patients: an Approach to Pandemic Vaccine Development

Abstract

With the ongoing pandemic of influenza A (H1N1) virus infection and the threat of high fatality rates for recent human cases of infection with highly pathogenic H5N1 strains, there has been considerable interest in developing pandemic vaccines. Here we report a randomized multicenter dose-finding clinical trial of a whole-virion, inactivated, adjuvanted H5N1 vaccine in adult and elderly volunteers. Four hundred eighty patients were randomly assigned to receive one or two doses of 3.5 g of the vaccine or one dose of 6 or 12 g. The subjects were monitored for safety analysis, and serum samples were obtained to assess immunogenicity by hemagglutination inhibition and microneutralization tests. The subjects developed antibody responses against the influenza A (H5N1) virus. Single doses of >6 g fulfilled EU and U.S. licensing criteria for interpandemic and pandemic influenza vaccines. Except for occasional injection site pain, malaise, and fever, no adverse events were observed. We found that the present vaccine is safe and immunogenic in healthy adult and elderly subjects and requires low doses and, unlike any other H5N1 vaccines, only one injection to trigger immune responses which comply with licensing criteria. A vaccine using the same methods as those described in this report, but based on a wild-type swine-origin 2009 (H1N1) influenza A virus isolate from the United States (supplied by the CDC), has been developed and is currently being tested by our group.With the ongoing pandemic of influenza A (H1N1) virus infection and the threat of high fatality rates for recent human cases of infection with highly pathogenic H5N1 strains, there has been considerable interest in developing pandemic influenza vaccines.With new cases continuing to emerge, as of June 2009, the avian influenza A (H5N1) virus subtype has caused 433 human infections in 15 countries, as confirmed by the World Health Organization (WHO), resulting in severe illness with a high fatality rate (30). Human-to-human spread has been strongly suspected and even evidenced by statistical methods (22,33). With new human infections continuing to develop, this subtype continues to represent a potential source of an influenza pandemic (33).Mass vaccination is the most effective approach to reduce illness and death from pandemic influenza. Therefore, vaccine producers are currently developing and assessing vaccines against H5N1 viruses (2,14,31). The effects of split, subvirion, and whole-virion H5N1 vaccines have been tested, with various immunogenicity results (31). Three whole-virion vaccines have been tested so far, two of which required two-dose regimens (4, 14), while a one-dose regimen with the present vaccine was found to be immunogenic in 146 adult subjects (24).The objective of the present study was to determine the safety and immunogenicity of an inactivated whole-virion vaccine against influenza A/Vietnam/1194/2004, using multiple dosing and administration schedules, for adult and elderly subjects. To date, this is the only influenza pandemic prototy...

A Single Immunization with CoVaccine HT-Adjuvanted H5N1 Influenza Virus Vaccine Induces Protective Cellular and Humoral Immune Responses in Ferrets

“…The use of safe and effective adjuvants in pandemic influenza virus vaccines is considered a dose-sparing strategy. Clinical trials evaluating candidate inactivated influenza A/H5N1 virus vaccines showed that the use of adjuvants can increase their immunogenicity and broaden the specificity of the induced antibody responses (2,7,19,23,27,36,41). These research efforts have resulted in the licensing of adjuvanted vaccines against seasonal and pandemic influenza viruses (17).…”

A Reduced-Dose Seasonal Trivalent Influenza Vaccine Is Safe and Immunogenic in Adult and Elderly Patients in a Randomized Controlled Trial

“…The reduced-dose vaccine (Fluval K, an inactivated, wholevirion, trivalent vaccine with 6 g of HA/strain/0.5 ml content and aluminum phosphate gel adjuvant; lot no. FL-K-004) was produced by Omninvest Ltd. (Budapest, Hungary) as described previously (8,(14)(15)(16)(17)(18)(19). With the exception of the antigen amount, the vaccine was prepared by the same method as for the licensed seasonal influenza vaccine Fluval AB (19) and the licensed prepandemic vaccine Fluval H5N1 and the licensed pandemic H1N1 vaccine Fluval P (8,(14)(15)(16)(17)(18).…”

“…We recently tested aluminum phosphate-adjuvanted whole-virion, monovalent prepandemic H5N1 and pandemic H1N1 influenza vaccines with only 6 g of HA and found them to be safe and immunogenic in pediatric, adult, and elderly subjects (8,(14)(15)(16)(17)(18). We also found that doses of 3.5 g did not trigger sufficient immune responses, while doses of 12 g were not substantially more immunogenic than 6-g doses when using monovalent vaccines (15). Thus, based on our experience with monovalent vaccines, the objective of this study was to evaluate the safety and immunogenicity of a trivalent seasonal influenza vaccine with 6 g HA/ strain in adult and elderly subjects.…”

Az új, csökkentett dózisú, hazai gyártású influenzavakcina (FluArt) forgalomba hozatalát követő első szezonjának biztonságossági vizsgálata

“…A használt technológia mellett a hatóanyag-tartalom növelése az immunválaszban további növekedést nem okozott [7]. A fejlesztést alátámasztotta az általunk korábban, szintén 6 µg hatóanyag-tartalmú pandémiás (H1N1) influenzavakcinákkal folytatott klinikai vizsgálatok eredménye, valamint a 2009. évi pandémia idején alkalmazott oltó-anyag vírusfertőzéssel szembeni hatékonysága [5][6][7][12][13][14][15]. A klinikai vizsgálati készítmények eredményei alapján az új, 6 µg hatóanyag-tartalmú készítmény forgalomba hozatali engedély megszerzését követően (OGYI-T-8998/03) a 2015/2016-os szezonban került először a piacra, 3FluArt néven.…”