Cross-Reactive Immunity to Clade 2 Strains of Influenza Virus A Subtype H5N1 Induced in Adults and Elderly Patients by Fluval, a Prototype Pandemic Influenza Virus Vaccine Derived by Reverse Genetics, Formulated with a Phosphate Adjuvant, and Directed to Clade 1 Strains

Abstract

High fatality rates and multiple cases of transmission of avian H5N1 influenza viruses to humans illustrate the urgent need for an efficacious, cross-protective vaccine against H5N1 strains. Extensive genetic characterization of H5N1 strains has elucidated the natural evolutionary relationship of these strains, linking groups known as clades to a common ancestor. Although the clades and subclades probably differ sufficiently in their antigenic structure to warrant the preparation of different vaccines, there is some evidence that cross-reactive immunity can be afforded. We aimed to assess the immunogenicity of a clade 1 H5N1 (NIBRG-14) whole-virus vaccine with an aluminum phosphate adjuvant and to determine whether it can induce cross-reactive immunity against antigenically drifted clade 2 H5N1 strains, both those derived by reverse genetics and wild-type isolates. A total of 88 (44 adult and 44 elderly) subjects, who received one dose (6 g) of the vaccine, were studied. As judged by U.S. and European licensing criteria based on hemagglutination inhibition, the subjects developed cross-reactive immunity against all studied H5N1 strains belonging to a clade different from that of the strain utilized to produce the vaccine. Our findings highlight the importance of stockpiling, since cross-immune reactions induced by prepandemic vaccines will likely reduce morbidity and mortality in case of a pandemic.

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

“…We are now extending these studies to children, as a trial with a 6-g dose of the present vaccine in pediatric subjects was recently completed (26). Also, studies of cross-reactive immunity in a subset of the present study population were recently published (9).…”

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

“…We previously reported the results of several clinical trials showing convincing immunogenicity and even crossreactive immunity in adult and elderly patients after one injection of a 6-g dose of a licensed monovalent prepandemic influenza A virus H5N1 vaccine (Fluval H5N1; Omninvest, Hungary) or a licensed monovalent pandemic H1N1 vaccine (Fluval P; Omninvest, Hungary) produced by essentially the same methods as reported for this trial (8,(14)(15)(16)(17)(18). Thus, the findings of this trial accord with our previous work with whole-virion, inactivated, adjuvanted prototype prepandemic and pandemic influenza vaccines (8,(14)(15)(16)(17)(18). We now extend the findings of strong immunogenicity with only 6 g of hemagglutinin to trivalent seasonal vaccines as well, as we found that the administration of the reduced-dose seasonal trivalent influenza vaccine containing 6 g of hemagglutinin/strain was safe in adult and elderly patients and met international criteria for licensing (5).…”

“…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).…”

“…Typical trivalent seasonal influenza vaccines are unadjuvanted split-virion or subunit vaccines and contain 15 g of hemagglutinin (HA) per virus strain. 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).…”

Pre-pandemic and pandemic influenza vaccines

“…These variants have been classified into genetically distinct clades to facilitate comparison of H5N1 isolates. 61 An important component of clinical trials 45,46,[62][63][64][65] and animals model studies 54,58,66,67 has therefore been determination of the breadth of the vaccineinduced antibody response against these different clades. In all of these studies, cross-reactive antibody could be demonstrated against H5N1 viruses representing several clades and subclades and the addition of an adjuvant appeared to be instrumental in achieving this ( Table 3).…”