Safety and immunogenicity of a high-dose quadrivalent influenza vaccine administered concomitantly with a third dose of the mRNA-1273 SARS-CoV-2 vaccine in adults aged ≥65 years: a phase 2, randomised, open-label study.

BACKGROUND: Concomitant seasonal influenza vaccination with a COVID-19 vaccine booster could help to minimise potential disruption to the seasonal influenza vaccination campaign and maximise protection against both diseases among individuals at risk of severe disease and hospitalisation. This study aimed to assess the safety and immunogenicity of concomitant administration of high-dose quadrivalent influenza vaccine (QIV-HD) and a mRNA-1273 vaccine booster dose in older adults. METHODS: This study is an ongoing, phase 2, multicentre, open-label, descriptive trial at six clinical research sites in the USA. We describe the interim results up to 21 days after vaccination (July-August, 2021). Community-dwelling adults aged 65 years and older, who were previously vaccinated with a two-dose primary schedule of the mRNA-1273 SARS-CoV-2 vaccine, were eligible for inclusion. The second dose of the primary mRNA-1273 vaccination series was required to have been received at least 5 months before enrolment in the study. Participants were randomly assigned (1:1:1) using a permuted block method stratified by site and by age group (<75 years vs ≥75 years), to receive concomitant administration of QIV-HD and mRNA-1273 vaccine, QIV-HD alone, or mRNA-1273 vaccine alone. Randomisation lists, generated by Sanofi Pasteur biostatistics platform, were provided to study investigators for study group allocation. Unsolicited adverse events occurring immediately, solicited local and systemic reactions up to day 8, and unsolicited adverse events, serious adverse events, adverse events of special interest, and medically attended adverse events up to day 22 were reported. Haemagglutination inhibition antibody responses to influenza A/H1N1, A/H3N2, B/Yamagata, and B/Victoria strains and SARS CoV-2 binding antibody responses (SARS-CoV-2 pre-spike IgG ELISA) were assessed at day 1 and day 22. All analyses were descriptive. The study is registered with ClinicalTrials.gov, NCT04969276. FINDINGS: Between July 16 and Aug 31, 2021, 306 participants were enrolled and randomly assigned, of whom 296 received at least one vaccine dose (100 in the coadministration group, 92 in the QIV-HD, and 104 in the mRNA-1273 group). Reactogenicity profiles were similar between the coadministration and mRNA-1273 groups, with lower reactogenicity rates in the QIV-HD group (frequency of solicited injection site reactions 86·0% [95% CI 77·6-92·1], 91·3% [84·2-96·0], and 61·8% [50·9-71·9]; frequency of solicited systemic reactions 80·0%, [70·8-87·3], 83·7% [75·1-90·2], and 49·4% [38·7-60·2], respectively). Up to day 22, unsolicited adverse events were reported for 17·0% (95% CI 10·2-25·8) of participants in the coadministration group and 14·4% (8·3-22·7) of participants in the mRNA-1273 group, and tended to be reported at a slightly lower rate (10·9% [5·3-19·1]) in participants in the QIV-HD group. Seven participants each reported one medically attended adverse event (three in the coadministration group, one in the QIV-HD group, and three in the mRNA-1273 group). There were no serious adverse events, adverse events of special interest, or deaths. Haemagglutination inhibition antibody geometric mean titres increased from day 1 to day 22 to similar levels in the coadministration and QIV-HD groups, for each influenza strain (A/H1N1: 363 [95% CI 276-476] vs 366 [272-491]; A/H3N2: 286 [233-352] vs 315 [257-386]; B/Yamagata: 429 [350-525] vs 471 [378-588]; B/Victoria: 377 [325-438] vs 390 [327-465] for the coadministration and QIV-HD groups, respectively). SARS-CoV-2 binding antibody geometric mean concentrations also increased to similar levels in the coadministration and mRNA-1273 groups at day 22 (7634 [95% CI 6445-9042] and 7904 [6883-9077], respectively). INTERPRETATION: No safety concerns or immune interference were observed for concomitant administration of QIV-HD with mRNA-1273 booster in adults aged 65 years and older, supporting co-administration recommendations. FUNDING: Sanofi Pasteur.

Safety of recombinant quadrivalent influenza vaccine compared to inactivated influenza vaccine in Chinese adults: An observational study.

BACKGROUND: Recombinant influenza vaccine (RIV) has been in use in US adults since 2013. This study evaluated the safety of quadrivalent recombinant influenza vaccine (RIV4, Flublok® Quadrivalent, Sanofi Pasteur) compared with standard-dose quadrivalent inactivated influenza vaccine (SD-IIV4) in self-identified Chinese adults at Kaiser Permanente Northern California (KPNC). METHODS: This study evaluated adults aged 18-64 years within KPNC during the 2018-2019 influenza season who self-identified as Chinese (NCT03694392). We compared the rates of prespecified diagnoses of interest in the emergency department and inpatient settings as done in prior influenza studies, for three risk intervals: 0-2 days, 0-13 days, and 0-41 days following influenza vaccination, as well as number of deaths within 0-180 days after vaccination. We estimated the odds ratios (ORs) and 95% confidence intervals using logistic regression adjusted for sex, age group, presence of comorbidities, and same-day concomitant vaccination. RESULTS: Comparing 15,574 adults who received RIV4 with 27,110 who received SD-IIV4, there was no statistically significant difference in the prespecified diagnoses of interest and deaths between the 2 groups. There were 35 deaths total, none of which were considered to be related to influenza vaccination. CONCLUSIONS: This study did not identify any safety concerns regarding RIV4 use among 18-64-year-olds who self-identified as Chinese. This study supports the safety of RIV4 vaccine in this population.

Safety of Recombinant Influenza Vaccine Compared to Inactivated Influenza Vaccine in Adults: An Observational Study.

BACKGROUND: Recombinant trivalent influenza vaccine (RIV3) was initially licensed in 2013 and approved for all adults ≥18 in 2014. This study evaluated the safety of RIV3 compared with trivalent standard-dose, inactivated influenza vaccine (IIV3) in Kaiser Permanente Northern California (KPNC). METHODS: This Phase 4 observational, postmarketing safety study included persons ≥18 years vaccinated with RIV3 or IIV3 in KPNC during the 2015-2016 influenza season. We compared (1) the rates of prespecified diagnoses of interest (Guillain-Barré Syndrome, pericarditis, pleural effusion, narcolepsy/cataplexy, asthma, acute hypersensitivity reactions, and fever) during various postvaccination risk intervals as well as (2) all-cause hospitalization and mortality 0-180 days after vaccination. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression analyses adjusted for age, sex, race/ethnicity, month of vaccination, and concomitant receipt of other vaccinations. RESULTS: Comparing the 21 976 persons who received RIV3 with the 283 683 who received IIV3, there were statistically significant differences in the prespecified diagnoses of interest between the 2 groups. Specifically, RIV3 vaccination was associated with fewer fever diagnoses during the 0-41 days postvaccination (OR, 0.38; 95% CI, 0.14-0.86). Also, RIV3 was associated with fewer all-cause hospitalizations during the 0-180 days postvaccination (OR, 0.66; 95% CI, 0.61-0.73), which was mostly related to pregnancy-related hospitalizations in IIV3 recipients. There were no serious adverse events or deaths related to RIV3. CONCLUSIONS: This study did not identify any safety concerns regarding the use of RIV3 in adults.

Safety and Immunogenicity of a Recombinant Influenza Vaccine: A Randomized Trial.

OBJECTIVES: The recombinant influenza vaccine is well established in adults ≥18 years of age for preventing seasonal influenza disease. In this randomized controlled trial, we compared the safety and immunogenicity of the quadrivalent, recombinant influenza vaccine (RIV4) versus the inactivated influenza vaccine in children and adolescents 6 to 17 years of age. METHODS: Two age cohorts were enrolled sequentially: 159 subjects aged 9 to 17 years and, after reviewing for safety, 60 children aged 6 to 8 years. Enrollment of the younger children was halted prematurely at the onset of the influenza season. Subjects in each cohort were randomly assigned 1:1 to the RIV4 or inactivated vaccine. Hemagglutination inhibition antibody titers were obtained before and 28 days after vaccination. Tolerability and safety were monitored for 7 days and 6 months after vaccination, respectively. RESULTS: Both vaccines were well tolerated in both age groups, and long-term follow-up revealed no vaccine-related adverse events. Overall, immunogenicity (geometric mean titers and seroconversion rate differences) provided comparable antibody responses to most antigens in both vaccines in the older subjects. Low responses to the influenza B Victoria lineage in both vaccines made interpretation difficult. Immunogenicity in younger children was similar, but the truncated sample size was insufficient to support noninferiority comparisons. CONCLUSIONS: Despite low responses to influenza B lineages in both vaccines, the RIV4 provided safety and immunogenicity that were comparable to those of the licensed inactivated vaccine in pediatric subjects, which was most convincing in those aged 9 to 17 years. Future confirmatory clinical efficacy trials may be used to support the recombinant influenza vaccine as an alternative for the pediatric age group of ≥6 years.

Vaccination with a Recombinant H7 Hemagglutinin-Based Influenza Virus Vaccine Induces Broadly Reactive Antibodies in Humans.

Human influenza virus infections with avian subtype H7N9 viruses are a major public health concern and have encouraged the development of effective H7 prepandemic vaccines. In this study, baseline and postvaccination serum samples of individuals aged 18 years and older who received a recombinant H7 hemagglutinin vaccine with and without an oil-in-water emulsion (SE) adjuvant were analyzed using a panel of serological assays. While only a small proportion of individuals seroconverted to H7N9 as measured by the conventional hemagglutination inhibition assay, our data show strong induction of anti-H7 hemagglutinin antibodies as measured by an enzyme-linked immunosorbent assay (ELISA). In addition, cross-reactive antibodies against phylogenetically distant group 2 hemagglutinins were induced, presumably targeting the conserved stalk domain of the hemagglutinin. Further analysis confirmed an induction of stalk-specific antibodies, suggesting that epitopes outside the classical antigenic sites are targeted by this vaccine in the context of preexisting immunity to related H3 hemagglutinin. Antibodies induced by H7 vaccination also showed functional activity in antibody-dependent cell-mediated cytotoxicity reporter assays and microneutralization assays. Additionally, our data show that sera from hemagglutination inhibition seroconverters conferred protection in a passive serum transfer experiment against lethal H7N9 virus challenge in mice. Interestingly, sera from hemagglutination inhibition nonseroconverters also conferred partial protection in the lethal animal challenge model. In conclusion, while recombinant H7 vaccination fails to induce measurable levels of hemagglutination-inhibiting antibodies in most subjects, this vaccination regime induces homosubtypic and heterosubtypic cross-reactive binding antibodies that are functional and partly protective in a murine passive transfer challenge model. IMPORTANCE Zoonotic infections with high case fatality rates caused by avian H7N9 influenza viruses have been reported since early 2013 in China. Since then, the fifth wave of the H7N9 epidemic emerged in China, resulting in higher numbers of laboratory-confirmed cases than in previous years. Recently, H7N9 has started to antigenically drift and split into two new lineages, the Pearl River Delta and Yangtze River Delta clades, which do not match stockpiled H7 vaccines well. Humans are immunologically naive to these subtypes, and an H7N9 strain that acquires the capability of efficient human-to-human transmission poses a credible pandemic threat. Other characteristics of H7N9 are raising concerns as well, like its ability to bind to receptors in the human upper respiratory tract, the recent emergence of highly pathogenic variants, and the ability to quickly gain resistance to neuraminidase inhibitors. Therefore, developing and testing H7N9 vaccines constitutes a priority for pandemic preparedness.

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.

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 .).

Analysis of Anti-Influenza Virus Neuraminidase Antibodies in Children, Adults, and the Elderly by ELISA and Enzyme Inhibition: Evidence for Original Antigenic Sin.

Antibody responses to influenza virus hemagglutinin provide protection against infection and are well studied. Less is known about the human antibody responses to the second surface glycoprotein, neuraminidase. Here, we assessed human antibody reactivity to a panel of N1, N2, and influenza B virus neuraminidases in different age groups, including children, adults, and the elderly. Using enzyme-linked immunosorbent assays (ELISA), we determined the breadth, magnitude, and isotype distribution of neuraminidase antibody responses to historic, current, and avian strains, as well as to recent isolates to which these individuals have not been exposed. It appears that antibody levels against N1 neuraminidases were lower than those against N2 or B neuraminidases. The anti-neuraminidase antibody levels increased with age and were, in general, highest against strains that circulated during the childhood of the tested individuals, providing evidence for "original antigenic sin." Titers measured by ELISA correlated well with titers measured by the neuraminidase inhibition assays. However, in the case of the 2009 pandemic H1N1 virus, we found evidence of interference from antibodies binding to the conserved stalk domain of the hemagglutinin. In conclusion, we found that antibodies against the neuraminidase differ in magnitude and breadth between subtypes and age groups in the human population. (This study has been registered at ClinicalTrials.gov under registration no. NCT00336453, NCT00539981, and NCT00395174.)IMPORTANCE Anti-neuraminidase antibodies can afford broad protection from influenza virus infection in animal models and humans. However, little is known about the breadth and magnitude of the anti-neuraminidase response in the human population. Here we assessed antibody levels of children, adults, and the elderly against a panel of N1, N2, and type B influenza virus neuraminidases. We demonstrated that antibody levels measured by ELISA correlate well with functional neuraminidase inhibition titers. This is an important finding since ELISA is a simpler method than functional assays and can be implemented in high-throughput settings to analyze large numbers of samples. Furthermore, we showed that low titers of broadly cross-reactive antibodies against neuraminidase are prevalent in humans. By the use of an appropriate vaccination strategy, these titers could potentially be boosted to levels that might provide broad protection from influenza virus infection.

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.

Recombinant hemagglutinin influenza vaccine provides broader spectrum protection.

INTRODUCTION: Influenza causes annual epidemics worldwide that pose a significant public health burden and current predominant vaccines, while the most effective means of combatting the disease, provide sub-optimal protection. New more broadly effective vaccines are an important public health need. AREAS COVERED: Influenza hemagglutinin (HA) is the principal viral surface protein that induces protective immunity to influenza infection. A recombinant seasonal influenza hemagglutinin (rHA) vaccine, recently introduced in the U.S., has demonstrated promising efficacy and safety in a number of clinical trials in adults. The immunodominant globular head of the HA protein induces antibodies that are narrowly specific to individual antigenically varied strains of influenza virus, resulting in poor affinity for antigenically drifted strains and the need for repeated annual vaccination. Broader spectrum protection may be achieved with immunity directed at more conserved viral antigens. We reviewed the data from clinical trials of the rHA vaccine conducted during seasonal epidemics characterized by antigenic mismatch between vaccine and circulating strains of influenza. Expert commentary: These data suggest that the rHA proteins produced in Lepidopteran cells offer broader-spectrum protection and result in clinical benefit.

Age Dependence and Isotype Specificity of Influenza Virus Hemagglutinin Stalk-Reactive Antibodies in Humans.

UNLABELLED: Influenza remains a major global health burden. Seasonal vaccines offer protection but can be rendered less effective when the virus undergoes extensive antigenic drift. Antibodies that target the highly conserved hemagglutinin stalk can protect against drifted viruses, and vaccine constructs designed to induce such antibodies form the basis for a universal influenza virus vaccine approach. In this study, we analyzed baseline and postvaccination serum samples of children (6 to 59 months), adults (18 to 49 years), and elderly individuals (≥65 years) who participated in clinical trials with a recombinant hemagglutinin-based vaccine. We found that baseline IgG and IgA antibodies against the H1 stalk domain correlated with the ages of patients. Children generally had very low baseline titers and did not respond well to the vaccine in terms of making stalk-specific antibodies. Adults showed the highest induction of stalk-specific antibodies, but the elderly had the highest absolute antibody titers against the stalk. Importantly, the stalk antibodies measured by enzyme-linked immunosorbent assay (ELISA) showed neutralizing activity in neutralization assays and protected mice in a passive-transfer model in a stalk titer-dependent manner. Finally, we found similar patterns of stalk-specific antibodies directed against the H3 and influenza B virus hemagglutinins, albeit at lower levels than those measured against the H1 stalk. The relatively high levels of stalk-specific antibodies in the elderly patients may explain the previously reported low influenza virus infection rates in this age group. (This study has been registered at ClinicalTrials.gov under registration no. NCT00336453, NCT00539981, and NCT00395174.) IMPORTANCE: The present study provides evidence that titers of broadly neutralizing hemagglutinin stalk-reactive antibodies increase with age, possibly due to repeated exposure to divergent influenza viruses. These relatively high levels of antistalk titers may be responsible for lower circulation rates of influenza viruses in older individuals. Our findings suggest that the level of antistalk antibodies is a good surrogate marker for protection against influenza virus infection. In addition, the levels of antistalk antibodies might determine the breadth of protection against different drifted strains.

Randomized comparison of the safety of Flublok(®) versus licensed inactivated influenza vaccine in healthy, medically stable adults ≥ 50 years of age.

BACKGROUND: The safety and tolerability of Flublok(®), a purified recombinant hemagglutinin seasonal influenza vaccine, was compared to AFLURIA(®) in a randomized, blinded clinical trial in adults ≥ 50 years of age with attention to hypersensitivity reactions. METHODS: This blinded, randomized trial of healthy adults ≥ 50 years of age compared safety of Flublok vs. AFLURIA with respect to pre-specified possible hypersensitivity: "rash," "urticaria," "swelling" and "non-dependent edema;" solicited reactogenicity and unsolicited adverse events. Subject-reported outcomes were collected for 30 days after vaccination. All adverse event terms were reviewed by physicians blinded to vaccine group, who added other terms possibly reflecting hypersensitivity. Case records of subjects with possible hypersensitivity were adjudicated by independent experts blinded to treatment assignment to identify likely hypersensitivity reactions. Non-inferiority of the incidence of hypersensitivity in the two vaccine groups was pre-defined as an absolute difference with an upper bound of 2-sided 95% confidence limits ≤ 0.015. RESULTS: A total of 2640 subjects were enrolled, evenly split in age cohorts of 50-64 and ≥ 65 years. Fifty-two subjects reported at least one term possibly representing hypersensitivity, with a slight imbalance of 31 on Flublok and 21 on AFLURIA. The adjudicators determined that six and four subjects on Flublok and AFLURIA, respectively, likely met clinical criteria for hypersensitivity, yielding a difference in incidence between the two vaccine groups of 0.15% (upper bound of 2-sided 95% CI=0.9%). Reactogenicity and overall adverse event profiles were similar across both vaccines. CONCLUSIONS: Flublok was non-inferior to AFLURIA in adults ≥ 50 years of age with respect to expert-adjudicated events of likely hypersensitivity during 30 days following vaccination (Sponsored by Protein Sciences Corporation; ClinicalTrials.gov number NCT01825200).

Safety, efficacy, and immunogenicity of Flublok in the prevention of seasonal influenza in adults.

Flublok is the first recombinant hemagglutinin (HA) vaccine licensed by the US Food and Drugs Administration for the prevention of influenza in adults aged 18 and older. The HA proteins produced in insect cell culture using the baculovirus expression system technology are exact analogues of wild type circulating influenza virus HAs. The universal HA manufacturing process that has been successfully scaled to the 21,000L contributes to rapid delivery of a substantial number of doses. This review discusses the immunogenicity, efficacy and safety data from five pivotal clinical studies used to support licensure of trivalent Flublok for adults 18 years of age and older in the United States. The trial data demonstrate that the higher antigen content in Flublok results in improved immunogenicity. Data further suggest improved efficacy and a slightly lower local reactogenicity compared with standard inactivated influenza vaccine, despite the presence of more antigen (statistically significant). Flublok influenza vaccine can include HAs designed to mimic 'drift' in influenza viruses as the process of predicting antigenic drift advances and, at a minimum, could address late appearing influenza viruses. The implementation of the latter will require support from regulatory authorities.

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.

Protective efficacy of a trivalent recombinant hemagglutinin protein vaccine (FluBlok®) against influenza in healthy adults: a randomized, placebo-controlled trial.

BACKGROUND: Development of influenza vaccines that do not use embryonated eggs as the substrate for vaccine production is a high priority. We conducted this study to determine the protective efficacy a recombinant, baculovirus-expressed seasonal trivalent influenza virus hemagglutinin (rHA0) vaccine (FluBlok(®)). METHODS: Healthy adult subjects at 24 centers across the US were randomly assigned to receive a single injection of saline placebo (2304 subjects), or trivalent FluBlok containing 45 mcg of each rHA0 component (2344 subjects). Serum samples for assessment of immune responses by hemagglutination-inhibition (HAI) were taken from a subset of subjects before and 28 days after immunization. Subjects were followed during the 2007-2008 influenza season and combined nasal and throat swabs for virus isolation were obtained from subjects reporting influenza-like illness. RESULTS: Rates of local and systemic side effects were low, and the rates of systemic side effects were similar in the vaccine and placebo groups. HAI antibody responses were seen in 78%, 81%, and 52% of FluBlok recipients to the H1, H3, and B components, respectively. FluBlok was 44.6% (95% CI, 18.8%, 62.6%) effective in preventing culture-confirmed influenza meeting the CDC influenza-like illness case definition despite significant antigenic mismatch between the vaccine antigens and circulating viruses. CONCLUSIONS: Trivalent rHA0 vaccine was safe, immunogenic and effective in the prevention of culture confirmed influenza illness, including protection against drift variants.