Karen L. Goldenthal

Evaluation of the safety, reactogenicity and immunogenicity of FluBlok ® trivalent recombinant baculovirus-expressed hemagglutinin influenza vaccine administered intramuscularly to healthy adults 50-64 years of age

BACKGROUND Alternative methods for influenza vaccine production are needed to ensure adequate supplies. METHODS Healthy adults 50-64 years were assigned randomly to receive one intramuscular injection of trivalent recombinant hemagglutinin (rHA) or U.S. licensed trivalent inactivated vaccine (TIV) containing H1, H3 and B antigens (Ag) derived from 2007 to 2008 influenza virus strains A/Solomon Islands/03/2006 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004. Each rHA dose contained 45 μg HA/strain of the 2007-2008 FDA-recommended Ag vs. 15 μg/strain for TIV. Antibody (Ab) responses were measured using a hemagglutination-inhibition (HAI) assay at baseline and 28 days post-vaccination. Respiratory samples for viral culture were collected from subjects with influenza-like illness (ILI) during the 2007-2008 season in the U.S. RESULTS 601 subjects were enrolled. Vaccines were well tolerated. Seroconversion (the percentage of subjects with either (a) a pre-vaccination HAI titer ≤ 10 and a post-vaccination HAI titer ≥ 40 or (b) a pre-vaccination titer ≥ 10 and a minimum four-fold rise in post-vaccination HAI antibody titer) in the TIV and rHA groups, respectively, was obtained in 66% vs. 72% for H1; 44% vs. 61% for H3; and 41% vs. 41% for B. Proportions achieving titers ≥ 40 were 96% vs. 96% for H1, 75% vs. 85% for H3, and 94% vs. 93% vs. B. Geometric mean titer ratios at day 28 (TIV/rHA) were 0.77 for H1; 0.58 for H3; and 1.05 for B, respectively. ILI frequencies were low and similar in both groups. CONCLUSIONS Both vaccines were safe and immunogenic. Ab responses vs. H1 and H3 Ags were significantly higher in the rHA group, with similar responses to B. Furthermore, the FluBlok group had a statistically significantly higher seroconversion rate against influenza A/H3N2 compared to the TIV group.

Evaluation of safety and immunogenicity of recombinant influenza hemagglutinin (H5/Indonesia/05/2005) formulated with and without a stable oil-in-water emulsion containing glucopyranosyl-lipid A (SE + GLA) adjuvant

BACKGROUND Expression of recombinant hemagglutinin (rHA) in insect cells represents a technology with proven efficacy in seasonal influenza and with the potential for a rapid response to the emergence of new, pandemic strains. We evaluated the safety and immunogenicity of rHA vaccine (H5/Indonesia/5/05) produced in SF+ insect cells using a baculovirus expression vector system (BEVS). The rHA vaccine was tested with and without the adjuvant glucopyranosyl lipid A/stable emulsion (GLA/SE). METHODS Healthy adults 18-49 were randomized to two IM doses on Days 0 and 21 of placebo; unadjuvanted rHA 135 μg or 45 μg, or rHA 45 μg, 15 μg, 7.5 μg or 3.8 μg with GLA/SE. A pioneer group was monitored through Day 42 before randomizing remaining subjects. H5-specific antibody was determined by hemagglutination inhibition (HAI) and microneutralization (MN) on Days 0, 21 and 42. RESULTS 392 subjects were randomized, of whom 380 (97%) received two doses and 386 (98%) completed 12 months of follow-up. Injection site pain and tenderness were seen in 50-70% of rHA+GLA/SE recipients and 4-9% of rHA alone and placebo recipients, but most complaints were mild to moderate in intensity. After two doses, the proportions of subjects with HAI titers ≥1:40 were 32% and 15% in the unadjuvanted 135 μg and 45 μg groups, and 82%, 75%, 66%, and 72% in those receiving 45 μg, 15 μg, 7.5 μg, or 3.8 μg with GLA/SE. The geometric mean titers (GMTs) of HAI antibody on Day 42 were 128, 95, 69, and 72 in the 45 μg, 15 μg, 7.5 μg, or 3.8 μg with GLA/SE groups, respectively. CONCLUSIONS rHA GLA/SE was well tolerated and immunogenic in healthy adults, and GLA/SE substantially improved the serum antibody response. rHA expressed using BEVS recombinant DNA platform technology represents a promising strategy for pandemic control.

Efficacy of Recombinant Influenza Vaccine in Adults 50 Years of Age or Older

BACKGROUND Improved influenza vaccines are needed to control seasonal epidemics. This trial compared the protective efficacy in older adults of a quadrivalent, recombinant influenza vaccine (RIV4) with a standard‐dose, egg‐grown, quadrivalent, inactivated influenza vaccine (IIV4) during the A/H3N2‐predominant 2014–2015 influenza season, when antigenic mismatch between circulating and vaccine influenza strains resulted in the reduced effectiveness of many licensed vaccines. METHODS We conducted a randomized, double‐blind, multicenter trial of RIV4 (45 μg of recombinant hemagglutinin [HA] per strain, 180 μg of protein per dose) versus standard‐dose IIV4 (15 μg of HA per strain, 60 μg of protein per dose) to compare the relative vaccine efficacy against reverse‐transcriptase polymerase‐chain‐reaction (RT‐PCR)–confirmed, protocol‐defined, influenza‐like illness caused by any influenza strain starting 14 days or more after vaccination in adults who were 50 years of age or older. The diagnosis of influenza infection was confirmed by means of RT‐PCR assay and culture of nasopharyngeal swabs obtained from participants with symptoms of an influenza‐like illness. The primary end point was RT‐PCR–confirmed, protocol defined, influenza‐like illness between 14 days or more after vaccination and the end of the influenza season. RESULTS A total of 9003 participants were enrolled and underwent randomization; 8855 (98.4%) received a trial vaccine and underwent an efficacy follow‐up (the modified intention‐to‐treat population), and 8604 (95.6%) completed the per‐protocol follow‐up (the modified per‐protocol population). Among RIV4 recipients, the RT‐PCR–confirmed influenza attack rate was 2.2% (96 cases among 4303 participants) in the modified per‐protocol population and 2.2% (96 cases among 4427 participants) in the modified intention‐to‐treat population. Among IIV4 recipients, the attack rate was 3.2% (138 cases among 4301 participants) in the modified per‐protocol population and 3.1% (138 cases among 4428 participants) in the modified intention‐to‐treat population. A total of 181 cases of influenza A/H3N2, 47 cases of influenza B, and 6 cases of nonsubtypeable influenza A were detected. The probability of influenza‐like illness was 30% lower with RIV4 than with IIV4 (95% confidence interval, 10 to 47; P=0.006) and satisfied prespecified criteria for the primary noninferiority analysis and an exploratory superiority analysis of RIV4 over IIV4. The safety profiles of the vaccines were similar. CONCLUSIONS RIV4 provided better protection than standard‐dose IIV4 against confirmed influenza‐like illness among older adults. (Funded by Protein Sciences; ClinicalTrials.gov number, NCT02285998.)

Prelicensure Evaluation of Combination Vaccines

There is considerable public health interest in licensing safe and effective combination vaccines. Because combination vaccines may progress rapidly from phase 1 to a pivotal phase 2 immunogenicity trial, a rigorous approach to address product issues early in development is warranted. Clinical studies to evaluate the safety, immunogenicity, and (when necessary) clinical end point efficacy of combination vaccines should be randomized and well controlled in most cases. A large phase 3 safety study (i.e., a study that enrolls thousands of vaccinees) should be included in the development plan if a phase 3 (clinical end point) efficacy trial will not be conducted. Often, the new combination vaccine under development contains immunogens that have all been previously licensed, have demonstrated efficacy in earlier clinical trials, or both. For such products, comparative immunogenicity data may be sufficient to support efficacy. When applicable, clinical data to support simultaneous administration with other relevant vaccines should be obtained. Given the complexity of combination vaccine development, early consultation with United States Food and Drug Administration can be invaluable.

Template protocol for clinical trials investigating vaccines—Focus on safety elements

This document is intended as a guide to the protocol development for trials of prophylactic vaccines. The template may serve phases I-IV clinical trials protocol development to include safety relevant information as required by the regulatory authorities and as deemed useful by the investigators. This document may also be helpful for future site strengthening efforts.

Testing and Licensure of Combination Vaccines for the Prevention of Infectious Diseases

Vaccines are exceptionally cost-effective agents for infectious disease prevention, control, and (potentially) eradication. Combination vaccines can reduce the number of immunizations required to achieve protection against multiple diseases and consequently can lead to increased vaccine coverage (1,2). These advantages will become even more apparent as vaccines for new indications are approved (3,4). The current Advisory Committee on Immunization Practices (ACIP) recommendations already necessitate that a large number of vaccines be given to infants within a short time interval (5). The ACIP now recommends a sequential vaccination schedule of two doses of inactivated poliovirus vaccine (IPV) followed by two doses of oral poliovirus vaccine (OPV) for routine childhood vaccination (6), anticipated to be an interim step before the implementation of an “all IPV” policy in the United States. Thus, the advantages of combination vaccines are especially evident for pediatric populations.

Stable emulsion (SE) alone is an effective adjuvant for a recombinant, baculovirus-expressed H5 influenza vaccine in healthy adults: A Phase 2 trial

BACKGROUND Influenza A viruses of the H5 subtype have been identified as important targets for development of vaccines. Achievement of potentially protective antibody responses against pandemic strains has usually required the use of adjuvants. OBJECTIVES We evaluated a candidate A/Indonesia/05/2005 (H5) vaccine generated by baculovirus expression of recombinant hemagglutinin (HA) protein with or without stable emulsion (SE) as an adjuvant. METHODS Healthy subjects 18-49years old were randomized (1:1:1:1) to receive two doses of rHA at 7.5ug per dose (no adjuvant), or 3.8ug, 7.5ug, or 15ug per dose formulated with 2% SE separated by 21days, and serum from day 0, 21, 42, and 201 assessed by hemagglutination-inhibition. RESULTS 341 subjects were enrolled in the study and 321 received two doses of vaccine. Vaccination was well tolerated in all groups. After two doses, seroconversion was noted in only 9% (95% confidence interval 4%, 17%) of recipients of unadjuvanted vaccine at 7.5ug, but in 70% (59%, 80%), 76% (65%, 85%), and 83% (73%, 91%) of those receiving adjuvanted vaccine at 3.8ug, 7.5ug, or 15ug respectively. CONCLUSIONS Stable emulsion alone is an effective adjuvant for rH5 vaccine in healthy adults. All three adjuvanted dose groups met the current criterion for seroconversion rate for pandemic vaccines. This dose-ranging study also identified a group (15ug per dose formulated with 2% SE) that met the criteria for both seroconversion and percentage of subjects achieving an HI antibody titer⩾40. These Phase 2 data support the further clinical development of SE adjuvanted Panblok H5. CLINICAL TRIAL REGISTRATION NCT01612000. The protocol was approved by the relevant Institutional Review Board for each study site, and the study was conducted in accordance with the Declaration of Helsinki, International Conference of Harmonisation - Good Clinical Practice, and all applicable laws and regulations. All participants provided written informed consent before study procedures.

Kawasaki disease and immunisation: Standardised case definition & guidelines for data collection, analysis

http://dx.doi.org/10.1016/j.vaccine.2016.09.025 0264-410X/ 2016 Published by Elsevier Ltd. Abbreviations: ADR, adverse drug reaction; AHA, American Heart Association; ALT, alanine transaminase; AST, aspartate transaminase; BCG, Bacillus Calmette (vaccine); CAAs, coronary artery aneurysms; CMRA, cardiac magnetic resonance angiography; CRP, C-reactive protein; DTP, diphtheria, tetanus, pertussis diphtheriatetanus, acellular pertussis; EBV, Epstein Barr Virus; ESR, erythrocyte sedimentation rate; GGT, gamma glutamyl transferase; HHV, human herpes vi Haemophilus influenza type b; HPF, high powered field; HSP, heat shock protein; IVIG, intravenous gamma globulin; JMoH, Japanese Ministry of Health; KD, Kawasaki LAD, left anterior descending; LV, left ventricular; MRI, magnetic resonance imaging; MSCT, multi, slice computed tomography; PAN, polyarteritis nodosa; PCV, pneum conjugate vaccine; PCR, polymerase chain reaction; RCA, right coronary artery; RMSF, Rocky Mountain Spotted Fever; RTPE,, recurrent toxin, mediated perineal er sJIA, systemic juvenile idiopathic arthritis; SPECT, single photon emission computed tomography; TSS, toxic shock syndrome; TST, tuberculin skin test; WBC, wh cells. ⇑ Corresponding author at: The Brighton Collaboration Foundation, c/o Universitäts-Kinderspital beider Basel, Spitalstrasse 33, 4056 Basel, Switzerland. E-mail address: contact@brightoncollaboration.org (J. Bonhoeffer). 1 Brighton Collaboration homepage: http://www.brightoncollaboration.org.

Randomized Comparison of Immunogenicity and Safety of Quadrivalent Recombinant Versus Inactivated Influenza Vaccine in Healthy Adults 18–49 Years of Age

Background Seasonal influenza vaccines are transitioning to quadrivalent formulations including the hemagglutinins of influenza A subtypes H1N1 and H3N2 and B lineages Yamagata and Victoria. Methods A new quadrivalent recombinant influenza vaccine (RIV4) was compared directly with a standard-dose, egg-grown, quadrivalent-inactivated influenza vaccine (IIV4) for immunogenicity and safety in adults 18-49 years of age. The coprimary endpoints for noninferiority were hemagglutination inhibition seroconversion rates and postvaccination geometric mean titer ratios for each antigen using US regulatory criteria. Reactogenicity solicited for 7 days, other safety events collected for 28 days, and serious or medically attended adverse events collected for 6 months after vaccination comprised the safety evaluation. Results The immunogenicity of RIV4 was comparable to that of IIV4; the coprimary noninferiority criteria were met for 3 antigens, and the antibody responses to the fourth antigen, influenza B/Brisbane/60/2008, were low in each group, making comparisons uninterpretable. Systemic and injection site reactions were mild, transient, and similar in each group, whereas none of the spontaneously reported adverse events, serious or nonserious, were considered related to study vaccine. Conclusions This first head-to-head comparison of recombinant versus inactivated quadrivalent influenza vaccines in 18-49 year old adults showed comparable immunogenicity, safety, and tolerability for both vaccines.

Kawasaki disease and immunisation: A systematic review.

BACKGROUND Kawasaki disease is a complex and potentially serious condition. It has been observed in temporal relation to immunisation. METHODS We conducted a systematic literature review using various reference sources to review the available evidence published in the literature. RESULTS We identified twenty seven publications reporting a temporal association between immunisation and Kawasaki disease. We present a systematic review of data drawn from randomised controlled trials, observational studies, case series and reports, and reviews. Overall there was a lack of standardised case definitions, making data interpretation and comparability challenging. CONCLUSIONS Although a temporal relationship between immunisation and Kawasaki disease is suggested, evidence for an increased risk or a causal association is lacking. Implementation of a standardised Kawasaki disease case definition would increase confidence in the findings and add value to future studies of pre- or post-licensure vaccine safety studies.