Peter A. Patriarca

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.

Prevention and Control of Type A Influenza Infections in Nursing Homes: Benefits and Costs of Four Approaches Using Vaccination and Amantadine

We developed a model to project morbidity, mortality, and costs attributable to type A influenza virus infections in nursing homes and to evaluate the relative benefits and costs of programs for prevention and control. Influenza vaccination was the most cost-effective intervention under various simulations in the model but usually allowed for higher rates of morbidity and mortality compared with other alternatives. The combined use of previous vaccination and chemoprophylaxis during outbreaks in the nursing home was associated with significantly fewer cases than use of vaccination alone, with only modest increases in net program costs. The use of chemoprophylaxis throughout the influenza season (without vaccination) resulted in the fewest number of illnesses, hospitalizations, and deaths but would cost at least 650% more than alternatives involving vaccination. Regardless of which strategy is chosen, our model suggests that influenza control programs in nursing homes are both beneficial and cost-effective and should be considered a part of standard care.

Expert review on poliovirus immunity and transmission.

Successfully managing risks to achieve wild polioviruses (WPVs) eradication and address the complexities of oral poliovirus vaccine (OPV) cessation to stop all cases of paralytic poliomyelitis depends strongly on our collective understanding of poliovirus immunity and transmission. With increased shifting from OPV to inactivated poliovirus vaccine (IPV), numerous risk management choices motivate the need to understand the tradeoffs and uncertainties and to develop models to help inform decisions. The U.S. Centers for Disease Control and Prevention hosted a meeting of international experts in April 2010 to review the available literature relevant to poliovirus immunity and transmission. This expert review evaluates 66 OPV challenge studies and other evidence to support the development of quantitative models of poliovirus transmission and potential outbreaks. This review focuses on characterization of immunity as a function of exposure history in terms of susceptibility to excretion, duration of excretion, and concentration of excreted virus. We also discuss the evidence of waning of host immunity to poliovirus transmission, the relationship between the concentration of poliovirus excreted and infectiousness, the importance of different transmission routes, and the differences in transmissibility between OPV and WPV. We discuss the limitations of the available evidence for use in polio risk models, and conclude that despite the relatively large number of studies on immunity, very limited data exist to directly support quantification of model inputs related to transmission. Given the limitations in the evidence, we identify the need for expert input to derive quantitative model inputs from the existing data.

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.

Expert Review on Poliovirus Immunity and Transmission

Successfully managing risks to achieve wild polioviruses (WPVs) eradication and address the complexities of oral poliovirus vaccine (OPV) cessation to stop all cases of paralytic poliomyelitis depends strongly on our collective understanding of poliovirus immunity and transmission. With increased shifting from OPV to inactivated poliovirus vaccine (IPV), numerous risk management choices motivate the need to understand the tradeoffs and uncertainties and to develop models to help inform decisions. The U.S. Centers for Disease Control and Prevention hosted a meeting of international experts in April 2010 to review the available literature relevant to poliovirus immunity and transmission. This expert review evaluates 66 OPV challenge studies and other evidence to support the development of quantitative models of poliovirus transmission and potential outbreaks. This review focuses on characterization of immunity as a function of exposure history in terms of susceptibility to excretion, duration of excretion, and concentration of excreted virus. We also discuss the evidence of waning of host immunity to poliovirus transmission, the relationship between the concentration of poliovirus excreted and infectiousness, the importance of different transmission routes, and the differences in transmissibility between OPV and WPV. We discuss the limitations of the available evidence for use in polio risk models, and conclude that despite the relatively large number of studies on immunity, very limited data exist to directly support quantification of model inputs related to transmission. Given the limitations in the evidence, we identify the need for expert input to derive quantitative model inputs from the existing data.

FluBlok, a recombinant hemagglutinin influenza vaccine

Abstract  FluBlok, a recombinant trivalent hemagglutinin (HA) vaccine produced in insect cell culture using the baculovirus expression system, provides an attractive alternative to the current egg‐based trivalent inactivated influenza vaccine (TIV) manufacturing process. FluBlok contains three times more HA than TIV and does not contain egg‐protein or preservatives. This review discusses the four main clinical studies that were used to support licensure of FluBlok under the ‘Accelerated Approval’ mechanism in the United States.

Evaluation of the safety, reactogenicity and immunogenicity of FluBlok trivalent recombinant baculovirus-expressed hemagglutinin influenza vaccine administered intramuscularly to healthy children aged 6-59 months.

BACKGROUND Recombinant baculovirus-expressed hemagglutinin (rHA [FluBlok]) influenza vaccine is unique in avoiding production in eggs and its rapid production capability. OBJECTIVE Compare the safety and immunogenicity of trivalent FluBlok to egg-grown trivalent influenza vaccine (TIV) in children. METHODS Healthy children were randomized to receive two doses of study vaccines. TIV (7.5 microg HA/antigen), FluBlok-22.5 (22.5 microg rHA/antigen), or FluBlok-45 (45 microg rHA/antigen) were given to 115 children ages 6-35 months. TIV (15 microg HA/antigen) or FluBlok-45 was given to 41 children ages 36-59 months. Safety and reactogenicity data were collected post-vaccination. Serum hemagglutination-inhibition antibody (HI) titers were measured before and 28 days after vaccination. RESULTS No serious vaccine-related adverse events occurred and reactogenicity events to equal volumes of TIV or FluBlok were generally similar. However, in the younger children, selected local and systemic symptoms were recorded significantly more frequently to 0.5 mL FluBlok-45 than to 0.25 mL doses of either the FluBlok-22.5 or 7.5 microg TIV vaccines. In the younger children, the immunogenicity to TIV was generally significantly superior to FluBlok. Serologic responses to FluBlok were higher in the older children than the younger group, but were still somewhat lower compared to TIV. CONCLUSION These data suggests that FluBlok is as safe but less immunogenic than similar volumes of TIV, particularly in the youngest children. The immunogenicity data is the converse of what has been observed in adults. Further studies examining the immunogenicity of FluBlok in older children are warranted.

Influenza Pandemic Preparedness Plan for the United States

In preparation for the next influenza pandemic, a comprehensive and action-oriented plan is presently under development that focuses on six major areas: (1) improvements in ongoing virologic and disease-based surveillance systems; (2) vaccination of high-priority target groups, and, given sufficient vaccine supplies, the entire US population; (3) liability programs for vaccine manufacturers and health care providers; (4) research to improve detection of new variants and to accelerate the availability of existing and novel vaccines and antiviral agents; (5) integrated, multicomponent communication systems for rapid information dissemination and exchange; and (6) emergency preparedness plans to provide for adequate medical care and maintenance of essential community services. The sudden and unpredictable emergence of pandemic influenza and its potential for causing severe health and social consequences dictate the need for close collaboration among a wide variety of organizations in both the public and private sectors.

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.

Review and Assessment of Poliovirus Immunity and Transmission: Synthesis of Knowledge Gaps and Identification of Research Needs

With the intensifying global efforts to eradicate wild polioviruses, policymakers face complex decisions related to achieving eradication and managing posteradication risks. These decisions and the expanding use of inactivated poliovirus vaccine (IPV) trigger renewed interest in poliovirus immunity, particularly the role of mucosal immunity in the transmission of polioviruses. Sustained high population immunity to poliovirus transmission represents a key prerequisite to eradication, but poliovirus immunity and transmission remain poorly understood despite decades of studies. In April 2010, the U.S. Centers for Disease Control and Prevention convened an international group of experts on poliovirus immunology and virology to review the literature relevant for modeling poliovirus transmission, develop a consensus about related uncertainties, and identify research needs. This article synthesizes the quantitative assessments and research needs identified during the process. Limitations in the evidence from oral poliovirus vaccine (OPV) challenge studies and other relevant data led to differences in expert assessments, indicating the need for additional data, particularly in several priority areas for research: (1) the ability of IPV-induced immunity to prevent or reduce excretion and affect transmission, (2) the impact of waning immunity on the probability and extent of poliovirus excretion, (3) the relationship between the concentration of poliovirus excreted and infectiousness to others in different settings, and (4) the relative role of fecal-oral versus oropharyngeal transmission. This assessment of current knowledge supports the immediate conduct of additional studies to address the gaps.