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Safety and Immunogenicity of a Baculovirus- Expressed Hemagglutinin Influenza Vaccine a Randomized Controlled Trial

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Safety and Immunogenicity of a Baculovirus- Expressed Hemagglutinin Influenza Vaccine a Randomized Controlled Trial PRELIMINARY COMMUNICATION Safety and Immunogenicity of a Baculovirus- Expressed Hemagglutinin Influenza Vaccine A Randomized Controlled Trial John J. Treanor, MD Context A high priority in vaccine research is the development of influenza vaccines Gilbert M. Schiff, MD that do not use embryonated eggs as the substrate for vaccine production. Frederick G. Hayden, MD Objective To determine the dose-related safety, immunogenicity, and protective ef- ficacy of an experimental trivalent influenza virus hemagglutinin (rHA0) vaccine pro- Rebecca C. Brady, MD duced in insect cells using recombinant baculoviruses. C. Mhorag Hay, MD Design, Setting, and Participants Randomized, double-blind, placebo-controlled Anthony L. Meyer, BS clinical trial at 3 US academic medical centers during the 2004-2005 influenza season Jeanne Holden-Wiltse, MPH among 460 healthy adults without high-risk indications for influenza vaccine. Hua Liang, PhD Interventions Participants were randomly assigned to receive a single injection of saline placebo (n=154); 75 µg of an rHA0 vaccine containing 15 µg of hemagglutinin Adam Gilbert, PhD from influenza A/New Caledonia/20/99(H1N1) and influenza B/Jiangsu/10/03 virus Manon Cox, PhD and 45 µg of hemagglutinin from influenza A/Wyoming/3/03(H3N2) virus (n=153); or 135 µg of rHA0 containing 45 µg of hemagglutinin each from all 3 components LL CURRENTLY LICENSED IN- (n=153). Serum samples were taken before and 30 days following immunization. fluenza vaccines in the United Main Outcome Measures Primary safety end points were the rates and severity of States are produced in em- solicited and unsolicited adverse events. Primary immunogenicity end points were the bryonated hen’s eggs. There rates of 4-fold or greater increases in serum hemagglutinin inhibition antibody to each Aare several well-recognized disadvan- of the 3 vaccine strains before and 28 days after inoculation. The prespecified primary tages to the use of eggs as the sub- efficacy end point was culture-documented influenza illness, defined as development strate for influenza vaccine. Eggs re- of influenza-like illness associated with influenza virus on a nasopharyngeal swab. quire specialized manufacturing Results Rates of local and systemic adverse effects were low, and the rates of systemic facilities and could be difficult to scale adverse effects were not different in either vaccine group than in the placebo group. He- up rapidly in response to an emerging magglutinin inhibition antibody responses to the H1 component were seen in 3% of pla- need such as a pandemic. It is usually cebo, 51% of 75-µg vaccine, and 67% of 135-µg vaccine recipients, while responses to necessary to adapt candidate vaccine vi- B were seen in 4% of placebo, 65% of 75-µg vaccine, and 92% of 135-µg vaccine recipi- ents. Responses to the H3 component occurred in 11% of placebo, 81% of 75-µg vac- ruses for high-yield growth in eggs, a cine, and 77% of 135-µg vaccine recipients. Influenza infections in the study population process that can be time consuming, is were due to influenza B and A(H3N2), and influenza A infections were A/California/7/2004– not always successful, and can select re- like viruses, an antigenically drifted strain. Seven cases of culture-confirmed CDC-defined ceptor variants that may have subop- influenza-like illness occurred in 153 placebo recipients (4.6%) compared with 2 cases (1.3%) timal immunogenicity.1 In addition, ag- in 150 recipients of 75 µg of vaccine, and 0 cases in recipients of 135 µg of vaccine. ricultural diseases that affect chicken Conclusions In this study, a trivalent rHA0 vaccine was safe and immunogenic in a flocks, and that might be an impor- healthy adult population. Preliminary evidence of protection against a drifted influenza tant issue in a pandemic due to an avian A(H3N2) virus was obtained, but the sample size was small. Inclusion of a neuraminidase influenza virus strain, could easily dis- component did not appear to be required for protection. rupt the supply of eggs for vaccine Trial Registration clinicaltrials.gov Identifier: NCT00328107 manufacturing. Therefore, develop- JAMA. 2007;297:1577-1582 www.jama.com ment of alternative substrates for in- fluenza vaccine production2 has been identified as a high-priority objective. (HA)usingrecombinantDNAtechniques. Author Affiliations are listed at the end of this article. One potential alternative method for In this study, we evaluated an experimen- Corresponding Author: John J. Treanor, MD, Univer- sity ofRochester Medical Center, Room 3-630, 601 productionofinfluenzavaccineisexpres- tal influenza vaccine consisting of recom- Elmwood Ave, Rochester, NY 14642 (John_Treanor sion of the influenza virus hemagglutinin binant HA expressed in insect cells by a @urmc.rochester.edu). ©2007 American Medical Association. All rights reserved. (Reprinted) JAMA, April 11, 2007—Vol 297, No. 14 1577 Downloaded From: https://jamanetwork.com/ on 09/26/2021 BACULOVIRUS-EXPRESSED HEMAGGLUTININ INFLUENZA VACCINE recombinantbaculovirus(rHA0).Thisal- ration containing the purified rHA0 of word of mouth. Race/ethnicity data for all ternative avoids dependence on eggs and the A/New Caledonia/20/99(H1N1), particiapnts were collected from self- is very efficient because of the high lev- A/Wyoming/3/03(H3N2), and B/Jiangsu/ reports. Participants were compensated els of protein expression under the 10/03 influenza viruses expressed from for each visit (Ϸ$25). control of the baculovirus polyhedrin genes cloned by reverse transcriptase After screening medical history and promoter. Monovalent and bivalent polymerase chain reaction from the same physical examination to determine eligi- baculovirus-derived influenza vaccines Centers for Disease Control and Preven- bility, 10 mL of blood was collected from have been evaluated in young adults and tion (CDC)–derived vaccine seed vi- an arm vein for serologic studies, and par- in community-dwelling adults older than ruses used for the licensed TIV and for- ticipants were randomly assigned to re- 65 years.3-6 These studies found that the mulated in phosphate-buffer saline ceive a single dose of either rHA0 at 135 vaccines are well tolerated and immuno- containing 0.005% detergent without µg, rHA0 at 75 µg, or saline placebo using genic. Recently, doses of a trivalent vac- preservative. Sodium dodecyl sulfate– apermuted-blockrandomizationscheme cine ranging from 15 µg to 135 µg per polyacrylamide gel electrophoresis of the stratified by study site. Vaccine was ad- component were shown to be well toler- purified monovalent materials indi- ministered as a single intramuscular in- ated in elderly persons and to induce an- cated that hemagglutinin constitutes ap- jection in the upper deltoid. tibodyresponsesatratescomparablewith proximately 95% of the total protein. Participants measured their oral tem- or superior to the licensed trivalent vac- The experimental vaccine was formu- perature daily and maintained a diary cine.7 While a clear dose-response rela- lated at 2 different concentrations, as card for 7 days after vaccination on which tionship has been shown for the H3 com- determined by SRID. The high-dose for- they recorded local and systemic reac- ponent in both healthy adults and in mulation contained 45 µg of each com- tions graded as mild (noticeable but not elderly persons, relatively little difference ponent, for a total dose of 135 µg of rHA0 interfering with normal activities), mod- hasbeenobservedintheimmuneresponse per 0.5-mL dose based on the SRID val- erate (some interference with normal ac- to doses ranging from 15 µg to 135 µg of ues on the preblend bulk. After formu- tivities), and severe (symptom pre- the H1 and B components. However, this lation, it was determined that this dose vented normal daily activities). analysis has been confounded by a poor contained 35 µg rather than 45 µg of the Participants also returned on day 2 and correlation between the antigen content H1 component. The low-dose formula- day 7 after vaccination for review of the of the H1 and B components of rHA0 vac- tion contained 45 µg of the H3 rHA0 and diary card, concomitant medications and cines, as determined by measurement of 15 µg each of the H1 and B rHA0, for a medical history, and examination of the total protein content, compared with the total dose of 75 µg of rHA0. Placebo con- vaccination site. Participants returned ap- values determined by single radial immu- sisted of normal saline for injection. Vac- proximately 28 days after vaccination for nodiffusion(SRID),thestandardmeasure- cine and placebo were supplied in coded, review of interim medical history. In ad- ment used for trivalent inactivated vac- identical-appearing single-dose vials. dition, 10 mL of venous blood was ob- cine (TIV). tained from an arm vein for assessment Therefore, the primary objective of Clinical Study Design of antibody to influenza virus. A final the current study was to evaluate the The study was conducted as a random- study visit occurred at day 180, during relative immunogenicity of the H1 and ized, double-blind, placebo-controlled which participants underwent a physi- B components of the vaccine when for- study at 3 medical centers (University of cal examination and interval medical mulated at either 15 µg or 45 µg per Rochester, Rochester, NY; Cincinnati history. component, as determined by SRID. In Children’sHospital,Cincinnati,Ohio;and The study protocol was reviewed and addition, we used the opportunity to University of Virginia, Charlottesville) approved by the investigational
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